Adult Congenital Heart Disease

Effect of Losartan or Atenolol on Children and Young Adults With Bicuspid Aortic Valve and Dilated Aorta. Flyer JN, Sleeper LA, Colan SD, Singh MN, Lacro RV. Am J Cardiol. 2020 Dec 29:S0002-9149(20)31400-4. doi: 10.1016/j.amjcard.2020.12.050. Online ahead of print. PMID: 33383013   Take Home Points: In children and young adults with bicuspid aortic valve and dilated ascending aorta, in this retrospective, single centre, non-placebo controlled, non-blinded and non-randomised study of 41 patients: Treatment with losartan or atenolol over an average three year period reduced aortic root and ascending aorta Z-scores. Both resulted in an apparent reduction in absolute aortic diameter growth rates. Losartan or atenolol may reduce proximal aortic growth rates in young patients with bicuspid valve aortic aortopathy.   Commentary from Dr Simon MacDonald (London, UK), section editor of ACHD Journal Watch: It is established that beta-blockade and angiotensin II blockade protects against aortic dilatation in Marfan’s syndrome but their role and possible effectiveness in other types of aortopathy is unclear. The authors studied whether atenolol or losartan prophylaxis reduces aortic dilatation in children and young adults with bicuspid aortic valve and dilated ascending aorta. In this group, severe dilatation is associated with risk of dissection and death.   They reviewed patients with bicuspid aortic valve and aortic dilatation (aged 1 day to 29 years) at Boston Children’s Hospital over the time period 1990-2018. Their hospital protocol recommended medical prophylaxis with losartan or atenolol for patients with bicuspid aortic valve and severe aortic root or ascending aorta dilatation. Patients were identified via their hospital database with BAV and aortic root or ascending aorta diameter with z-score ≥ 4SD and/or absolute diameter ≥ 4cm, and history of prophylaxis with losartan or atenolol. Patients with other congenital heart disease, apart from coarctation, or known connective tissue disorders were excluded.   The primary outcome analysed was the annual rate of change in maximal aortic root and ascending aorta z-scores (SD/yr) compared with those before treatment. Mean changes over time in aortic diameter and BSA adjusted z-scores for the treatments were analysed using a mixed effects linear regression model.   They included gender as a subgroup, in addition to age at initiation (<15 yrs. and ≥ 15years), aortic z-score, coarctation surgery, presence or absence of moderate aortic insufficiency or stenosis. Forty-one patients were included in the analysis, 27 in the losartan group and 18 in the atenolol (4 patients included in both groups as received each drug at different times) with similar baseline characteristics (Table 1A). Median treatment duration was 3.1 years for losartan (IQR 2.4, 6.0) and 3.7 for atenolol (IQR 1.4,6.6) with mean age of initiation of therapy 14.2±5.1 and 15±4.9 years respectively.     Treatment was associated with decreases in aortic root and ascending aorta z-scores (SD/yr) for losartan and atenolol (pre- vs post-treatment) with: Losartan, n=27: Aortic root: +0.06± 0.02 pre vs -0.14±0.03 post, p<0.001 Ascending aorta: +0.2±0.03 pre vs -0.09±0.05 post, p<0.001   Atenolol, n=18: Aortic root: +0.07±0.03 pre vs -0.02±0.04 post, p<0.01 Ascending aorta: +0.21±0.04 pre vs -0.06±0.006, p<0.001   There was a decrease in absolute growth rate (cm/year) for all comparisons (p≤0.02) too.     There were no deaths, with four patients in the losartan group and five in the atenolol having surgery. This was for Sinus of Valsalva fistula (1), aortic size (2), and progressive aortic regurgitation (6). Seven had aortic valve repair/replacement and 8 had replacement/reduction of the aortic root and or ascending aorta.   Patients were not randomised, it was a single centre retrospective study, variable drug dosing, and unblinded echo assessment were potential limitations. In terms of subgroup analysis, there were a small number of patients assessed, and coarctation surgery, aortic valve dysfunction and timing of growth spurts in male/female patients were potential confounders. The authors conclude that additional large clinical studies are warranted with these medications to confirm possible effect and help decrease the rate of serious aortic events during adulthood.   

Pulmonary Arterial Hypertension Associated with Congenital Heart Disease in Adults over the Age of 40 Years Maurer SJ, Stöckemann K, Pujol C, Hörer J, Ewert P, Tutarel O. J Clin Med. 2020 Dec 17;9(12):4071. doi: 10.3390/jcm9124071. PMID: 33348628 Free PMC article.   Take Home Points: In patients over age 40, with congenital heart disease and pulmonary hypertension, a quarter died during the follow up period of 4 years. Creatinine and NT pro-BNP were the only factors significantly associated with the primary end-point. Commentary by Dr. Helen Parry (Leeds, UK), section editor of ACHD Journal Watch: There is currently relatively little research looking at the natural history and prognostic factors in pulmonary arterial hypertension in older adults with congenital heart disease. This study focuses on this cohort of patients over 40 years of age.   All patients at the German Heart Centre in Munich with a diagnosis of congenital heart disease and pulmonary arterial hypertension (PAH) above the age of 40 were included. Pulmonary arterial hypertension was diagnosed based on echo, MRI and/ or catheter studies. The patients were sub-categorised as: Shunt lesions Complex congenital heart disease Segmental PAH, i.e. patients with major aorto-pulmonary collaterals (MAPCAs) The primary end-point was all-cause mortality. Variables examined included: NYHA score Echo assessment of left and right ventricular function Presence of arrhythmia NTpro-BNP Creatinine Arrhythmia Presence of Down’s syndrome Use of advanced PAH therapies. Univariate analysis was used to assess whether these variable were associated with death (Students’ t test for continuous variables and Chi squared test for categorical variables). Multivariate analysis by Cox proportional hazard regression modelling was used to assess their relative significance. P-value <0.05 was classed as significant.   Results: Sixty-five patients were included; 70.8% had a shunt lesion, 18.5% complex CHD and 10.8% segmental PAH. Median follow-up was 4.2 years. Atrial arrhythmia occurred in 23.1% and ventricular arrhythmia in 9.2%. Sixteen patients (24.6%) died during the follow up period. Univariate analysis showed an association between both creatinine and NT-pro-BNP and all-cause mortality:   VariableUnivariate HR (95%CI)Univariate p-valueMultivariate HR (95% CI)Multivariate p-value Creatinine12.76 (2.05–79.32)0.006316.28 (2.23–118.690.0059 NT pro-BNP3.54 (1.08–11.64)0.0374.08 (1.16–14.41)0.0289   Conclusions: A quarter of the patients above 40 years of age with combined congenital heart disease and PAH died during the follow up period. Creatinine and NT pro-BNP were the only factors significantly associated with the primary end-point.   Positive aspects of the study: There is very little in the literature about this group of patients so this study was a useful contribution. The identified predictors of poor prognosis, namely, raised creatinine and raised NT pro BNP can be relatively easily measured routinely in most centres. May contribute towards counselling regarding in certain patients. Negative aspects of the study: Small sample size. The majority of patients had shunt lesions so it is difficult to extrapolate the results to the other groups as they were relatively under-represented, could survival be worse or better in these groups? The sample sizes were too small to draw confident conclusions. The study does not really help to guide treatment in these patients. The questions are posed: should we try to improve creatinine and NT pro-BNP in these patients and will this improve their prognosis? NT pro-BNP is generally improved by increasing heart failure therapies, many of which are nephrotoxic so likely to increase creatinine. Follow up period varied significantly from 1.2 years to 7 years.  

Patients with Single-Ventricle Physiology over the Age of 40 Years Pujol C, Schiele S, Maurer SJ, Hock J, Fritz C, Hager A, Ewert P, Tutarel O. J Clin Med. 2020 Dec 18;9(12):4085. doi: 10.3390/jcm9124085. PMID: 33352831 Free PMC article   Take Home Points: Patients over 40 years with single ventricular physiology are burdened with morbidity and mortality. This group of patients frequently has arrhythmia and required cardioversion, pacemakers, or antiarrhythmic medications. The presence of renal disease is associated with mortality.   Commentary from Dr. M.C. Leong (Kuala Lumpur, Malaysia), section editor of ACHD Journal Watch: The survival of single ventricular hearts has improved over the years owing to improved surgical techniques, understanding of the underlying physiology and follow-up care. However, the long-term morbidities and mortality remain unresolved and is largely due to the limitations of the Fontan circulation. These morbidities become more evident as the patients age.   In this article, Pujol and colleagues reported on the outcome data from their cohort of patients with single ventricle physiology above the age of 40 years. In this cohort, 49 patients (19 female, mean age 49.2 ± 6.4 years, median follow up duration: 4.9 years, IQR: 1.8–8.5) were identified. Baseline characteristics were as tabulated in Table 1.   Strikingly, although over 80% of these patients were in NYHA functional class I-II, 35 (71.4%) of patients had a prior hospital admission for heart failure. Many of them were plagued with comorbidities. Arrhythmias were a frequent challenge. 23 (53%) of these patients had lost sinus rhythm; amongst them, 13 patients required pacemakers. Another 8 patients required pacemakers during the follow-up period. On follow-up, 9 (18.4%) of patients underwent electrophysiological procedures. Cardioversion was required in 20 (40.8%) patients, amongst them, 14 patients required multiple episodes of cardioversion. In relation to the frequency of atrial arrythmias, the type of Fontan circulation was not specified (Atriopulmonary, lateral tunnel or extra-cardiac conduit). Arrhythmias in patients with severely dilated atria are notoriously difficult to control and often they affect the quality of lives of these patients despite medications.   During the follow-up, there were 10 (20.4%) mortalities. The authors subsequently analysed the factors associated with death in this cohort (Table 2). On univariate analysis, renal disease and liver cirrhosis were predictors of all-cause mortality. However, on multivariate analysis, only renal disease (HR: 12.5, 95% CI: 1.5–106.3, p = 0.021) remained as an independent predictor (Figure 1). End organ damage has commonly been found to be a good surrogate marker for disease progression. The cause for end organ damage may be attributed to the chronic elevation of systemic venous pressure, low perfusion to the end organs due to chronic heart failure and possibly, repeated episodes of end organ injuries during acute heart failure which may be triggered by acute arrhythmias, surgeries or infections. Renal disease is a useful predictor of mortality and thus aids in the planning of follow-up and risk stratification of these patients.       In summary, this is a study looking at the outcome of a special cohort of older patients with Fontan palliation. Although this data highlights the burden of morbidities and mortality, it is difficult to draw the same conclusion to the younger cohort who has mostly undergone the extracardiac type of Fontan palliation which, hopefully, has a low burden of arrhythmia. On the other hand, this younger cohort of Fontan population may have a poorer substrate i.e., heterotaxies and hypoplastic left heart syndromes, which may give rise to a different set of morbidities and mortality risk.    

Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients. Freisinger E, Gerß J, Makowski L, Marschall U, Reinecke H, Baumgartner H, Koeppe J, Diller GP.Eur Heart J. 2020 Nov 14;41(43):4168-4177. doi: 10.1093/eurheartj/ehaa844.PMID: 33184662   Take Home Points Observational dataset of 44,000 ACHD patients between 2005-2018. 5,465 ACHD patients on oral anticoagulant treatment were within the dataset. ACHD patients identified from a German health insurance dataset which covered 9 million insured persons (Total population Germany 83 million). It is unclear the proportion of patients in this dataset under specialist ACHD care – it is possible, many were not. Evaluation of the use of DOAC agents compared to vitamin K antagonists. Use of oral anticoagulants (NOAD/DOAC and vitamin K antagonists) doubled from 6% to 12%. In this German dataset, DOACs accounted for 45% of prescribed anticoagulants by 2018 - most frequently prescribed agents were rivaroxaban and apixaban (80% of dataset). ACHD patients on DOACs had higher thromboembolic (3.8% vs 2.8%); MACE (7.8% vs 6%); bleeding rates (11.7% vs 9%) and all-cause mortality (4% vs 2.8%) after 1 year of therapy compared to vitamin K antagonists. After adjustment for patient characteristics, DOACs remained associated with a greater risk of MACE (HR 1.22; 95% CI 1.09-1.36), all-cause mortality (HR 1.43; 95% CI 1.24-1.65; both P<0.001) and bleeding (HR 1.16; 95% CI 1.04-1.29; p=0.007).     Commentary from Dr. Damien Cullington (Liverpool, United Kingdom), section editor of ACHD Journal Watch: Novel oral anticoagulant agents (NOACs) have been approved for use for approximately a decade which means they are not so novel and more commonly referred to direct oral anticoagulant agents (DOACs). DOACs are a revolution in anticoagulant management. Take once or twice a day plus no irritating visits to the INR clinic, plus avoidance of the rollercoaster of INRs and shifting warfarin dose means there is all round delight with the therapeutic simplicity. Not all patients welcome DOACs with open arms. Some patients who have been treated with warfarin for long periods of time are skeptical and the lack of ‘knowing’ how anticoagulated they are with a DOAC causes concern and so often prefer to stay on warfarin (or other vitamin K antagonists), feeling more confident in its reliability (and predictability). Naturally, DOACs are not to be used in patients with mechanical valves.   Following the introduction of most medicines, comes potential indication creep. DOACs were and are often prescribed outside the limits of their original licensing indication. This is only natural. This is a part of a more generic therapeutics issue in the world of ACHD where vanishingly few large randomised controlled trials of drug therapy exist and essentially most medical therapy indication is logically extrapolated from ‘acquired’ cardiology datasets. Rightly pointed out by the authors of this paper, “medical adherence, reach of effective doses or INRs, as well as potential pharmacological interactions in a real-world scenario may relevantly differ from controlled study settings.”   This large observational ACHD dataset (n=44, 097) by Freisinger et al. makes one reflect about our prescribing habits with respect to choosing DOACs instead of vitamin K antagonists in ACHD patients. More specifically, using DOACs in an ‘off license’ fashion and in ACHD patient groups who have not been fully evaluated in randomised clinical trials. Figure 1 shows growth of DOAC use in this dataset between 2005-2018.   Figure 1. Temporal growth of DOAC use in ACHD patients within a large German insurance dataset.     The characteristics of the dataset are shown in Table 1. The total dataset comprised 44,097 ACHD patients. Of the total cohort, 12% (n=5465) were on anticoagulant treatment in 2018. As one would expect, the vast majority of patients (93%) had ‘simple’ or ‘moderate’ ACHD lesions. Increasing complexity of ACHD lesion was associated with a higher likelihood of being treated with an anticoagulant – 9% in simple lesions; 11% in moderate lesions and 14% in complex lesions (p <0.001). By 2018, the number of patients prescribed a DOAC in each of the complexity groups was similar. Patients with mechanical heart valves were excluded from longitudinal analysis. Median follow up time from first prescription of VKA was 90 months and 39 months for DOAC. The commonest reason for anticoagulation was atrial arrhythmias – two thirds of the group.     Results (Table 2) The primary outcome data relating to bleeding, thromboembolic events and MACE are shown in Table 2. After adjustment for patients’ characteristics, there was increased bleeding risk for DOACs vs VKAs in follow up – HR 1.16; 95% CI 1.04-1.29; p=0.007. Of note, however, it is unclear the efficacy of anticoagulation in patients prescribed a VKA i.e. how much time is in range. One would expect lower rates of bleeding if anticoagulation were sub-therapeutic compared to DOACs where anticoagulation is ‘complete’. The adjusted risk of major bleeding or thromboembolism did not differ between treatment groups.     MACE (HR 1.23; 95% CI 1.10-1.37; p<0.001) and all-cause mortality (HR 1.43; 95% CI 1.24-1.65; p<0.001) were significantly higher in ACHD patients prescribed a DOAC vs VKA. Univariable Cox regression analysis is shown in Figure 2. The authors comment that patients with chronic kidney or liver disease were particularly prone to complications. No interaction was seen between complexity of ACHD and risk posed by anticoagulation – complications were independent to anatomical lesion.   Figure 2 Limitations This is a sizable dataset but it is observational, so caution is needed to draw absolute conclusions compared to RCTs. However, in the absence of any large RCTs comparing DOACs to VKA in patients with ACHD, the ‘signal’ from the results should be reflected upon. There is a significant amount of extra data in supplementary material which the reader is advised to scrutinise alongside the paper. Patients within this analysis are not specifically followed up in an ACHD specialist centre – the authors comment that up to a third of ACHD patients in Germany are not followed up in centres specialising in ACHD. This may well have a significant bearing on outcomes since it has been shown that care of ACHD patients in non-specialist centres is associated with worse outcomes. Other co-variates are missing from the analysis, such as ventricular dysfunction.   Conclusions This large observational dataset has shown that after adjustment for patients’ characteristics, the HR for MACE (acute MI; ischaemic stroke; VF; resuscitation or death) was 1.2 and the HR=1.4 for all-cause death. Given this, as I am sure we all do, the results should be reflected upon and considered when prescribing DOACs to ACHD patients, particularly in the absence of clear RCT evidence.   As I write my last sentence I feel the need to pull out an all too frequent trope which I state in all things ACHD, particularly with relation to medical treatment - randomised controlled data is needed to ensure results are not by chance and reflective of usual guideline based care of ACHD patients in specialist centres.    

Assessment of hemodynamic responses to exercise in aortic coarctation using MRI-ergometry in combination with computational fluid dynamics. Schubert C, Brüning J, Goubergrits L, Hennemuth A, Berger F, Kühne T, Kelm M.Sci Rep. 2020 Nov 3;10(1):18894. doi: 10.1038/s41598-020-75689-z.PMID: 33144605 Free PMC article.   Take Home Points: MRI ergometry in combination with Computational Flow Dynamics (CFD) can be used to noninvasively assess trans-stenotic pressure gradients, aortic flow patterns and stroke volume in patients with aortic coarctation at rest and during physical exercise. Therefore, no simulation of exercise using adrenergic drugs is necessary. This information has promising implications for clinical application and further research on the pathophysiology of aortic coarctation.   Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch:   Introduction For aortic coarctation, in the current clinical decision-making process, pressure gradients across the aortic narrowing is one of the decisive factors for potential re-intervention. As pressure gradients increase during exercise due to increased cardiac output, patients with gradients below the threshold for intervention at rest may develop pathologically high gradients during exercise. In the case of a borderline indication for surgical or catheter-based treatment, stress tests can help to unmask the hemodynamic relevance of the stenosis.   Commonly used non-invasive methods for determining pressure gradients at rest or during physical exercise (e.g. echocardiography, cuff measurements) are often inaccurate. Alternatively, adrenergic drug infusions can be used during cardiac catheterization, simulating physical exercise, while measuring peak-to-peak gradients. However, the hemodynamic response during pharmacological stress is far from representing responses to actual physical exercise.   The combination of MRI-ergometry and computational fluid dynamics (CFD) could be an approach to quantitatively assess the hemodynamic response to physical exercise. Combining these two methods, would allow an accurate and non-invasive assessment of pressure gradients, aortic and left ventricular hemodynamics at rest and during physical exercise, without the need for adrenergic drugs to simulate exercise.   Patients and Methods: This is a prospective study in patients with aortic coarctation, who underwent cardiac MRI due to elevated Doppler gradients or follow-up after an intervention, between November 2018 and September 2019.   Study design:   Figure 1. (Upper panel) Visual illustration of the study design. Cardiac MRI of 20 participants with aortic coarctation was acquired during rest and moderate exercise. An absolute increase in heart rate of 50 bpm was targeted during exercise. Using the MRI images, the participant-specific aortic geometry was reconstructed Using computational fluid dynamics, the transstenotic pressure gradient was calculated during rest and exercise.(Lower panel) Visualization of the image data used for segmentation. The participant-specific anatomy of the aorta was segmented from 3D SSFP (steady-state free precession) images (A,C). If the respective participant was treated using a stent, additional image information from black blood MR sequences (D) was used to improve the segmentation of the stented region of the aorta. An example from only 3D SSFP images is shown in panel (B), whereas a combined segmentation of a previously stented patient is shown in panel (E).   Computational fluid dynamics (CFD) simulation: Numerical simulations for calculation of patient specific hemodynamics at rest and during exercise were performed using an approach that was previously validated against in-vivo catheter-based measurements as well as 4D-flow-MRI measurements. At the descending aorta, the maximal volume flow rate was measured using the 4D QF sequence during rest and exercise was applied as an outlet boundary condition. At the ascending aorta, the patient-specific peak systolic velocity vector profiles, which were measured using planar 4D VEC MRI at rest and during exercise, were applied.     End Points The primary outcome measure was the pressure gradient across the stenosis at rest and during exercise. Secondary outcomes were wall shear stress (WSS), secondary flow degree (SFD), normalized flow displacement (NFD), cardiac index, stroke volume index and heart rate, at rest and during exercise.   Results The analysis was carried out in 20 patients. The baseline characteristics of the included patients are shown in Table 1.     Of the 20 patients (13 men, 7 women) included, 3 patients were untreated, 5 had undergone surgical repair by end-to-end-anastomosis, 11 were treated by stent-implantation and one stented patient was also treated surgically. The mean age of included patients was 21.5 ± 13.7 years.   No symptoms occurred during exercise. The average workload present during exercise was 83.5 ± 37.8 W.   On average, 85.79 ± 10.28% of the calculated target heart rate was reached during exercise. Patients’ systolic blood pressure, measured using cuff-measurements at the arm, significantly increased from rest to exercise (128.45 ± 21.45 to 158.65 ± 33.97 mmHg, p = 0.002).   The relative static pressure distributions at rest and during exercise that were calculated using CFD are shown in Fig. 3.   The mean trans-stenotic pressure gradient was 17.99 ± 16.61 mmHg at rest and 28.45 ± 22.56 mmHg during stress (Fig. 4).   Those patients had lower resting heart rates than the patients who featured a stroke volume increase during exercise (61.2 vs. 89.9 bpm, p < 0.001). Also, with exception of one patient, they all were in the lower part of the cardiac index distribution (3.2 vs. 4.0, p < 0.05 at rest and 4.3 vs. 5.6, p < 0.05 during exercise).   No relevant difference in the increase of the trans-stenotic pressure gradient was observed between those two groups (8.9 vs 11.1 mmHg, p = 0.55). The measured maximum volume flow rate in the ascending (rest 407.0 ± 87.3, stress 494.4 ± 225.5 ml/min, p < 0.001) and descending (rest 225.5 ± 76.7, stress 274.8 ± 83.8 ml/min, p = 0.002) aorta significantly increased during exercise.   However, the ratio of the peak-systolic volume flow rate measured in the ascending and descending aorta did not change significantly (p = 0.287). An overview of changes in hemodynamic parameters is provided in Table 2.     Conclusion In this feasibility study, MRI-ergometry and image-based computational fluid dynamics were combined. This approach allows assessing the individual hemodynamic response to exercise under nearly physiological conditions.   As pressure gradients at rest and during physical exercise can be determined noninvasively, it has the potential to serve as an alternative to pharmacological stress testing during cardiac catheterization. While the numerical method used has been validated previously, a thorough validation of the translation towards assessment of pressure gradients during dynamic exercise is required before clinical application.   However, as currently no clinical standard for measurement of the trans-stenotic pressure gradient during dynamic exercise exists, this combined approach seems promising. In general, the method has the potential for measuring individual changes in trans-stenotic pressure gradients, aortic flow patterns, the left ventricular response to dynamic exercise, providing valuable information for studying the pathophysiology of aortic coarctation.   Currently, those parameters can only be assessed in a very limited matter or cannot be assessed at all during dynamic exercise.    

Peripheral venous pressure accurately predicts central venous pressure in the adult Fontan circulation. Tan W, Small A, Gallotti R, Moore J, Aboulhosn J.Int J Cardiol. 2020 Nov 13:S0167-5273(20)34081-X. doi: 10.1016/j.ijcard.2020.11.007. Online ahead of print.PMID: 33189798   Take Home Points: A higher central venous pressure (CVP) is required to drive pulmonary blood flow in the Fontan circulation, although chronically elevated CVP is associated with long-term Fontan complications. Peripheral venous pressure (PVP) has previously been shown to be a relatively robust non-invasive surrogate for CVP in pediatric Fontan patients. This study of adult Fontan patients showed a PVP measurement cutoff 14 mmHg was associated with 100 % sensitivity and 55 % specificity for detecting elevated Fontan pressure. PVP measurement may be a useful screening tool to identify high-risk Fontan patients with elevated CVP, with reassurance for those with a PVP less than 14 mmHg, and consideration of further evaluation indicated for those with elevated PVP.   Commentary from Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: Patients with a Fontan circulation lack a subpulmonary ventricle and require a higher central venous pressure (CVP) to drive pulmonary blood flow. The long-term consequences of higher CVP can include liver cirrhosis and protein losing enteropathy, and mortality has been reported to be higher amongst those with a high CVP compared to those with lower CVP. Pulmonary artery pressure cannot be estimated non-invasively by traditional means in the Fontan circulation. Peripheral venous pressure (PVP) has been demonstrated to be a good surrogate for CVP in patients with acquired heart disease, while studies in pediatric Fontan patients have reported correlation between PVP and CVP. The current study aimed to compare PVP and CVP in adult Fontan patients undergoing cardiac catheterization, with the hypothesis that correlation between these measurements would be reproducible and robust, providing a non-invasive technique to estimate CVP in the outpatient setting.   This was a single-centre, prospective, cross-sectional study of adult Fontan patients undergoing clinically indicated cardiac catheterization. All adult patients (age 18 years) were included, and those with a known stenosis or obstruction of either the Fontan pathway or an upper extremity vein were excluded. A total of 43 cases were included. Catheterisation was performed under general anaesthetic. A peripheral intravenous line was placed in an upper extremity vein. Central venous pressure was measured at the superior vena cava level using a 5F – 7F wedge pressure catheter. Equipment was meticulously zeroed prior to measurements, and catheter location confirmed with fluoroscopy. Peripheral venous pressure was measured immediately after CVP measurement by transferring the same pressure transducer, or by using pressure tubing attached to a 3-way stopcock that was attached to the pressure transducer. The peripheral IV catheter was positioned at the level of the mid-axillary line. Both CVP and PVP measurements were recorded with an Edwards TruWave pressure transducer. Linear regression and a Bland-Altman plot analysis for differences were performed. Receiver operator characteristic (ROC) curve for PVP was created, using CVP of 14 mmHg or higher as a cutoff.   Table 1 demonstrates baseline demographics and patient characteristics in those undergoing cardiac catheterization. Mean age was 30.7 years, and 24 years post original Fontan surgery.     Mean CVP was 17.3 mmHg (SD 4.7 mmHg, range 9 – 30 mmHg), and mean PVP was 18.4 mmHg (SD 5 mmHg, range 9 – 35 mmHg). PVP was strongly correlated to CVP (figure 1):   Bland-Altman plot of PVP and CVP showed that PVP overestimated CVP by a mean of 1.2 mmHg (95% CI 0.47 – 1.9 mmHg) with limits of agreement between CVP and PVR from -5.2 to +2.8 mmHg:   PVP measurement cutoff 14 mmHg was associated with 100 % sensitivity and 55 % specificity for detecting elevated Fontan pressures. This corresponded to a 100 % negative predictive value and 84 % positive predictive value for the identification of elevated invasive Fontan pressures.   This study has found a very strong correlation between PVP and CVP in an older cohort of Fontan patients with more comorbidities and higher Fontan pressures than several other previous studies. PVP measurement may be a useful screening tool to identify high-risk Fontan patients with elevated CVP, with reassurance for those with a PVP less than 14 mmHg, and consideration of further evaluation suggested for those with elevated PVP. An important caveat to the extrapolation of these findings to the outpatient setting is the data arising from intubated and sedated patients; study in awake patients is clearly required before PVP measurement can be routinely recommended in Fontan patients.   

Time Course of Ventricular Remodeling after Atrial Septal Defect Closure in Adult Patients. Bae YH, Jang WS, Kim JY, Kim YS.Korean J Thorac Cardiovasc Surg. 2020 Nov 18. doi: 10.5090/kjtcs.20.098. Online ahead of print.PMID: 33203805   Take Home Points: In patients post-surgical ASD repair, the RV volumes were markedly decreased by one month post-op, and continued to decrease (though at a slower rate) by one year. The RV remodeling however did not result in complete normalization by one year. The Late Gadolinium Enhancement (LGE) on CMR in most patients did not improve / resolve at one year post-op.   Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch: Atrial septal defects represent the most common form of congenital heart disease (10-15%). A Qp:Qs ratio of over 1.5 is an indication for percutaneous or surgical closure. Even post closure, there remains an increased risk of arrythmias with potential neurological complications. In light of this, cardiac chamber remodeling may be an important determinant of long-term outcomes. This is a single center study conducted at a tertiary cardiology unit in Korea aimed at assessing ventricular remodeling post-ASD repair by utilizing cardiac magnetic resonance imaging (CMR).   Patients who underwent surgical ASD closure between November 2017 and January 2019 and had consented for CMR were included – a total of 13 patients. Clinical, demographic and echocardiography data was obtained from folder review. All patients had CMR imaging pre-operatively, at one month post-op and at 1 year post op.   The median age at the time of surgery was 51.4 years. Pre-operative symptoms included chest pain (38.5%, n=5), dyspnoea (30.8%, n=4) and palpitations (15.4%, n=2). None of the patients had atrial fibrillation documented prior to surgery.   Of the 13 patients, 12 had an ASD patch closure and one a primary closure. No early or late surgical mortality nor any surgery-related morbidity was noted. At one year follow-up, all but one patient showed resolution of symptoms. The pre-operative NT proBNP showed a trend (non-significant) to increase at one month post-op (83pg/ml to 167pg/ml, p=0.059) and then a reduction by one year post-op to 105.5pg/ml (p=0.118).   The median pre-operative Qp:Qs ratio was 2.3 and this correlated positively with RV size parameters (RVEDVi: r=0.862, p=0.001; RVESVi: r=0.784, p=0.004), but did not correlate with LV size parameters.     RVEF and LVEF negatively correlated with RVESVi (r=-0.626, p=0.022) and LVESVi (r=-0.743, p=0.004) respectively.   RVEF and RVEDVi did not show a meaningful correlation (r=-0.328l p=0.274).   No significant differences were seen between NT-pro-BNP levels and any of the CMR parameters (p >0.05 for all). The pre-operative mean RVEDVi and RVESVi showed a significant reduction at 1 month. The RVEDVi and RVESVi further decreased by 1 year, but the rate of decrease was slower (table 2 below).   Tricuspid valve regurgitation (TVR) also showed a decrease over time. The pre-operative LVEDVi and LVESVi increased at one month and then remained unchanged at one year.   There was no significant change in LVEF at one month or one year follow-up.   Late gadolinium enhancement was detected in 12 out of the 13 patients on the pre-operative CMR. At the RV basal septum insertion point. In 7 patients (53.8%) this was still present at the same intensity at one year follow-up.    

Left Valvar Morphology is Associated with Late Regurgitation in Atrioventricular Canal Defect Ho DY, Katcoff H, Griffis HM, Mercer-Rosa L, Fuller SM, Cohen MS. Ann Thorac Surg. 2020 Feb 20. pii: S0003-4975(20)30219-8. doi: 10.1016/j.athoracsur.2020.01.012. [Epub ahead of print] PMID: 32088289 Similar articles Select item 32079620   Take Home Points: Residual left atrioventricular valve regurgitation (LAVVR) is commonly seen after surgery. Complex leaflet morphology, which results in complex valve repair is associated with early LAVVR. However, after controlling the weight at surgery, presence of genetic syndrome and bypass time, multivariate analysis showed presence of widely spaced papillary muscles and larger mural leaflet area were associated with late LAVVR. There may be other pathology, other than the progression of LAVVR which is responsible for late onset LAVVR.   Commentary from Dr. M.C. Leong (Kuala Lumpur, Indonesia), section editor of ACHD Journal Watch: Left atrioventricular valve regurgitation (LAVVR) following repair of atrioventricular canal repair is not uncommon and it causes significant morbidity. The authors sought to characterise the left mural leaflet and papillary muscle morphology in patients with atrioventricular canal defects to determine if variation in leaflet anatomy were risk factors for postoperative LAVVR.   This is single-centre, retrospective review of all patients with complete or transitional atrioventricular canal who underwent repair from January 2011 until December 2016. During this period, 156 patients, of whom 84% had complete atrioventricular septal defect were included (Table 1). Majority of these patients underwent repair using a two-patch technique and cleft closure. Of these patients, 58 (37%) patients had significant early postoperative LAVVR. 16 (10%) patients underwent left atrioventricular valve reoperation or replacement. In 11 of these patients, reoperation occurred within the first 3 months. Four patients required two or more reoperation and of these, 3 eventually underwent mechanical valve replacement. In the long term, 30 of 93 (32%) had significant LAVVR (Figure 3).     Longer bypass time, deep hypothermia circulatory arrest, and repeat bypass runs were associated with early postoperative LAVVR but not late LAVVR (Table 5). This underscored the surgical complexity as the cause for early postoperative LAVVR. However, late LAVVR was associated with papillary morphology. The authors characterised the morphology into (a) widely spaced papillary muscle, (b) closely spaced papillary muscles, (c) Dominant papillary muscle, (d) mural leaflet area : overall left atrioventricular valve area and cleft length: overall left atrioventricular valve diameter (Figure 2). They noted that after controlling the weight at surgery, presence of genetic syndrome and bypass time, multivariate analysis showed presence of widely spaced papillary muscles and larger mural leaflet area were associated with late LAVVR (Table 6).         The results of the study came as a surprise for a few reasons. Firstly, patients with complex valve morphology was associated with early but not late LAVVR suggesting that late AVVR may not be a progression of the early LAVVR. Secondly, patients with widely spaced papillary muscles usually has a larger mural leaflet area which generally confer less atrioventricular valve regurgitation post-operatively but has been shown to be associated to late LAVVR, which suggest other pathology being the cause the late LAVVR. Unfortunately, the study was not powered to assess these causes of the late LAVVR.    

Pulmonary artery size is associated with functional clinical status in the Fontan circulation Ridderbos FS, Bonenkamp BE, Meyer SL, Eshuis G, Ebels T, van Melle JP, Willems TP, Berger RMF. Heart. 2020 Feb;106(3):233-239. doi: 10.1136/heartjnl-2019-314972. Epub 2019 Sep 6. PMID: 31492699 Similar articles Select item 30826267   Take Home Points: The Nakata index = (left pulmonary artery cross sectional area + right pulmonary artery cross sectional area) by body surface area (mm2/m2). Single centre study of 39 (child and adult) patients with a Fontan circulation – mean age at time of CMR study 18 ±7 yrs. Cross sectional, single centre study of patients with a Fontan circulation exploring whether the Nakata index is associated with longer term functional clinical status – subjective and objective. The Nakata index in patients with a Fontan was significantly smaller compared to normal control subjects (n=40) – 239±79 mm2/m2 vs 330±30mm2/m2 (p<0.001). Nakata index was positively correlated to higher peak VO2. Nakata index was negatively correlated to NYHA functional class. Nakata index was an independent predictor of peak VO2. Patients with a Fontan circulation and higher Nakata index have a higher peak VO2 and are subjectively less breathless compared to similar patients with a smaller Nakata index.   Commentary from Dr. Damien Cullington (Liverpool, UK), section editor of ACHD Journal Watch: The Fontan circulation is a palliative procedure with no shortage of long-term problems. We are continually striving to understand in more detail what constitutes the ‘good Fontan’ – good ventricular function, a predominantly systemic LV, no significant valvular dysfunction and an unobstructed Fontan pathway are four key elements.   It seems relatively intuitive that patients with a Fontan circulation and larger pulmonary arteries (PAs) would be a ‘better Fontan’ compared to patients with relatively smaller PAs. This analysis from Ridderbos et al sought to investigate whether relative PA size post Fontan completion correlates to longer term subjectively reported symptoms (NYHA) and objective measurement of functional capacity (peak VO2). The authors state that no CMR based study has assessed this relationship previously. The primary end points to assess subjective and objective clinical status were NYHA class and the standard cardiopulmonary measure of peak VO2 respectively. The authors nicely illustrate the comparative difference in PA size (measured by Nakata index) in patients with a Fontan compared to the Nakata indices of normal subjects (Figure 1).   The baseline characteristics of the cohort are shown in Table 1. The mean age of patients was 18±7 yrs., 98% of the cohort had a lateral tunnel or extra-cardiac conduit type Fontan and 82% had a systemic left ventricle. This was a mixed cohort of paediatric and adult patients – the majority of patients were <20 years old with a mean duration between Fontan completion and CMR of 12 ±7 years.     Correlation between Nakata Index, baseline characteristics and functional status   Nakata index correlated negatively with age at CMR (r= -0.39, p=0.013) and time since Fontan completion (r = -0.34, p=0.034). Patients with an extracardiac conduit had a significantly higher Nakata index (p=0.03) compared to those with a lateral tunnel (269 ± 90 mm2/m2 vs 214 ± 57 mm2/m2).   The Nakata index was negatively correlated with NYHA class (Figure 2) and positively correlated with peak VO2 (indexed for weight and % of predicted peak VO2) (Figure 3). The Nakata index was a significant univariable predictor of peak VO2 and remained so in a multivariable model incorporating maximum heart rate and O2 pulse at peak exercise.   Patients with previous central PA banding (n=13) or a systemic-to-PA shunt (n=15) had smaller Nakata indices than patients who had not had such interventions (p=0.045).   Based on these results, what can we do better?   This study found that patients with a Fontan circulation who have a higher Nakata index, therefore, larger PAs, have higher functional capacity (measured by peak VO2) and lower self-reported NYHA class.   So, what can the congenital cardiology team do to help achieve better long-term functional outcomes for our Fontan patients? It is clear that some factors are easily modifiable, others not so. There may be some signal to suggest an extracardiac conduit is associated with a higher Nakata index and PAs are larger in patients who avoid PA banding or BT shunts, but naturally, some surgical interventions are a necessity. Pulmonary distensibility is an important component of functional capacity so meticulous surgical technique throughout the palliative pathway is required to avoid PA injury/scar and achieve high quality Fontan conduit anastomoses.   Patients with a Fontan circulation, compared to normal subjects have a significantly smaller pulmonary artery cross sectional area. This is probably to be due to an attenuation of growth of the pulmonary vasculature due to, atypical, non-pulsatile flow through the pulmonary arteries. Further, sequential analyses need to be performed to understand how PA size (and therefore the Nakata index) changes as patients age. This is now easily achievable since most patients with a Fontan have cross sectional imaging repeated as part of a standard protocol every 3-5 years. Repeated cross sectional imaging will help to serially reappraise whether proactive catheter interventions are required to help optimise Fontan flow. Application of 4D flow analysis may also be ancillary to decision making.    

Septal Flash-like Motion of the Earlier Activated Ventricular Wall Represents the Pathophysiology of Mechanical Dyssynchrony in Single-Ventricle Anatomy Hayama Y, Miyazaki A, Ohuchi H, Miike H, Negishi J, Sakaguchi H, Kurosaki K, Shimizu S, Kawada T, Sugimachi M. J Am Soc Echocardiogr. 2020 Feb 20. pii: S0894-7317(19)31183-6. doi: 10.1016/j.echo.2019.11.016. [Epub ahead of print] PMID: 32089381 Similar articles Select item 30422578   Take Home Point: In patients with single ventricle physiology and a prolonged QRS, early shortening and paradoxical post systolic stretch are associated with poorer clinical state according to greater BNP and reduced peak VO2. Commentary from Dr. Helen Parry (Leeds UK), section editor of ACHD Journal Watch:   Aim: To assess whether dyssynchrony of contraction has clinical consequences in univentricular hearts   Methods: Inclusion criteria: Post op Glenn or Fontan Prolonged QRS defined as z score >=2 in patients under 18 or >120ms in patients 18 or over Regular R-R interval Good echo windows Patients fulfilling these criteria had echocardiography with strain, focusing on the apical view that included the aorta, the free wall of the dominant/ apex forming ventricle and its opposite wall/ septal remnant.   AV valve and aortic valve opening and closure times were assessed using pulsed wave Doppler. Strain studies (GLS) were then performed on the 2 walls as divided above.   Strain ratio (Rs) was used to quantify early shortening followed by post systolic paradoxical stretch - Rs= (100+ GLS at aortic valve closure)/(100+ GLS at aortic valve opening)   BNP was measured in all patients and exercise testing was undertaken where possible to allow comparison between degree of dyssynchrony and clinical status.   6 patients underwent CRT for heart failure symptoms refractory to medical management   Results: 70 patients were enrolled. 25 were female.   Time to peak strain of the earlier activated wall was associated with BNP levels (p<0.001). Strain ratio was associated with both BNP and peak VO2 (p<0.001 for both). There were no statistically significant associations between BNP and peak VO2 and either time to peak strain or strain ratio of the later activated wall.   Patients who underwent CRT had improvement in dyssynchrony quantified by improved strain ratio as above.   Discussion: The authors conclude that early shortening and paradoxical post systolic stretch are associated with poorer clinical state according to greater BNP and reduced peak VO2.   Strengths of the study: Novel Clear strategy for assessment of dyssynchrony in single ventricle physiology outlined Pathophysiology seems logical Weaknesses: The number of patients undergoing CRT was too small to draw any conclusion Single centre study GLS on Phillips machine- specific to this machine and cannot be compared with other manufacturers Many patients with single ventricle physiology do not have good enough transthoracic windows for strain    

Identifying Risk Factors for Massive Right Ventricular Dilation in Patients With Repaired Tetralogy of Fallot Cochran CD, Yu S, Gakenheimer-Smith L, Lowery R, Lu JC, Mahani MG, Agarwal PP, Dorfman AL. Am J Cardiol. 2020 Mar 15;125(6):970-976. doi: 10.1016/j.amjcard.2019.12.016. Epub 2019 Dec 28. PMID: 31964501 Similar articles Select item 31918854   Take Home Points: In patients with rTOF, age at complete repair >6 months, longer QRS duration > 160 milliseconds, and non-Caucasian race were significantly associated with massive RV dilation by CMR. An age cutoff of 6 months is clinically relevant, proposed explanations include prolonged cyanosis or elevated RV pressure load leading to myocardial damage and subsequent dilation Non-Caucasian race was an unexpected and strong predictor of massive dilation. This finding could potentially contribute to an evolving understanding of inequality in outcomes and merits further investigation Earlier referral for CMR in the presence of these risk factors may be indicated.   Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch:   Introduction: Surgical relief of RVOTO in TOF surgical repair results in pulmonary valve insufficiency and related long-term sequelae; therefore, pulmonary valve replacement (PVR) has been widely utilized to reduce RV volume overload, but optimal timing is unknown. Indexed right ventricular end-diastolic volume (RVEDVi) by CMR is a widely used predictor of poor outcomes and a subset of patients seem to have a propensity for rapid progression to severe RV dilation before initial CMR evaluation. This study aims to identify risk factors for massive RV dilation among rTOF patients presenting for their first CMR at a tertiary US institution.   Patients and Methods: A retrospective study, identified patients with a diagnosis of TOF who underwent their first CMR imaging study between October 2007 and March 2015. Inclusion criteria for the study were a diagnosis of TOF following complete surgical repair and first CMR performed post repair at their center. Exclusion criteria included PVR before first CMR, unknown date or type of initial repair, or lack of ventricular size measurements on CMR. Cases of massive RV dilation were defined as patients with an RVEDVi ≥200 ml/m2 measured by CMR. Controls consisted of patients within the same cohort with RVEDVi <200 ml/m2 on first CMR.   Results: A total of 387 patients with TOF were identified. A total of 39 cases were identified and matched to 73 controls. A flowchart depicting patient identification is shown in figure 1   Figure 1. Patient identification using CMR database. CMR = cardiac magnetic resonance; PVR = pulmonary valve replacement; RV = right ventricle; RVEDVi = indexed right ventricular end-diastolic volume; TOF = tetralogy of Fallot; rTOF = repaired tetralogy of Fallot   Median age at complete repair was 0.6 years (IQR 0.3 to 3.0 years). Transannular patch repair, a known risk for RV dilation was the most common type of repair followed by RV to pulmonary artery conduit placements, and finally, other repairs which included transatrial muscle bundle resection and ventricular septal defect closure without pulmonary artery patch. No non-transannular or “limited” transannular patches were identified as having a massive RV by our criteria. Less than half of our study cohort (46 patients, 41.1%) had total bypass time and/or cross-clamp times (45 patients, 40.2%) recorded in their surgical reports.   Three clinical factors were significant from univariate analysis: Non-Caucasian race, age at complete repair >6 months, and QRS duration. In multivariable analysis, all 3 factors, non-Caucasian race (AOR 7.84, p = 0.01), age at repair >6 months (AOR 2.90, p = 0.03), and QRS duration (AOR 1.03, p = 0.005) remained significant (Table 1).   Table 1:   Discussion: In patients with rTOF, age at complete repair >6 months, longer QRS duration, and non-Caucasian race were significantly associated with massive RV dilation at first CMR. In this population, 10% is unlikely to have their RV return to normal size after PVR. To our knowledge, this is the first study reporting these risk factors.   An age cutoff of 6 months is clinically relevant, as it is at the latter end of the typical range for primary repair of TOF. An exact mechanism for this risk factor is unclear. Proposed explanations include prolonged cyanosis or elevated RV pressure load leading to myocardial damage and subsequent dilation. RV dysfunction in the setting of chronic hypoxia has not been widely investigated. Furthermore, reoxygenation of chronically hypoxic hearts during and after cardiopulmonary bypass leads to myocardial reperfusion injury.   The QRS interval is a clinical measurement used in some guidelines as an indication for PVR. Preoperative QRS duration has previously been shown to be an indicator of postoperative RV size and functional recovery following valve replacement. Severe QRS prolongation (≥180 milliseconds) has been linked with ventricular tachycardia and sudden death. RV ejection fraction by CMR has been shown to negatively correlate with QRS duration. The mean QRS duration in this study (160 milliseconds) matches the cutoff used as a criterion for PVR in one highly-referenced publication.   Non-Caucasian race was an unexpected and strong predictor of massive dilation. Additional exploration into the causes of this finding was beyond the scope of this study. However, there is a small body of literature looking at racial and ethnic disparity in mortality following congenital heart surgery. This finding could potentially contribute to an evolving understanding of inequality in outcomes and merits further investigation.   Conclusion: Age > 6 months at complete repair, prolonged QRS duration, and non-Caucasian race are independently associated with a massively dilated RV (RVEDVi ≥200 ml/m2) at first CMR in our rTOF patients. Earlier referral for CMR in the presence of these risk factors may be indicated. The potential role of healthcare disparities in these findings requires further investigation.    

Tricuspid regurgitation severity after atrial septal defect closure or pulmonic valve replacement Martin-Garcia AC, Dimopoulos K, Boutsikou M, Martin-Garcia A, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Babu-Narayan SV, Sanchez PL, Li W, Shore D, Gatzoulis MA. Heart. 2020 Mar;106(6):455-461. doi: 10.1136/heartjnl-2019-315287. Epub 2019 Aug 23. PMID: 31444268 Similar articles Select item 31589989   Take Home Points: RV volume-offloading procedures (ASD closure, PVR for pulmonic regurgitation) were associated with significant reductions in the severity of functional tricuspid regurgitation, in addition to a reduction in RV and RA size, irrespective of intervention on the tricuspid valve itself Most positive remodeling of the right heart was seen within 6 months of intervention Baseline right atrial size was predictive of persistent TR at 12 months on multivariate analysis.     Commentary from Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: Surgical and catheter interventions to reduce right ventricular (RV) volume overload are common in the ACHD population, including closure of atrial septal defects (ASD) and pulmonic valve replacement (PVR). However, the effect of RV volume reduction on pre-existing tricuspid regurgitation (TR) following ASD closure and PVR is largely unknown and thus indications for concomitant tricuspid valve (TV) surgery at the time of such procedures is largely at the discretion of the surgeon and ACHD team. The aim of this study was to examine the effect of interventions aimed at reducing RV volume overload on pre-existing TR, and the additional contribution of concomitant TV surgery.   Methods This was a single-centre retrospective study of patients treated between 2005 and 2014 at The Royal Brompton Hospital, London.   Inclusion criteria were: Secundum ASD, sinus venosus ASD, PAPVD or pulmonic regurgitation (moderate or severe). At least mild TR pre-operatively. Full echocardiographic study available at baseline and six- and twelve- months post index intervention. Exclusion criteria were: Primary TR due to malformed TV (e.g. Ebstein anomaly). Significant LV systolic or diastolic dysfunction due to myocardial or left-sided valvular disease. Cardiac lesions were categorized as secundum ASD, sinus venosus ASD, PAPVD, and pulmonic valve insufficiency after repair of TOF or PS. Two-dimensional echocardiographic measurements for RV function were performed offline, and included: RV basal, mid, and longitudinal dimensions from the apical 4-chamber view at end-diastole; RVFAC; end-systolic RV eccentricity index; RVOT dimensions at end-diastole; and RA/LA area ratio. TV regurgitant severity was measured using annulus diameter; systolic tenting area; coaptation distance; CW Doppler of the TR jet; and vena contracta width.   Results 162 patients met inclusion criteria and formed the study cohort. Mean age was 41 +/- 16 years, and 62 (38%) were male. 101 underwent repair of ASD/PAPVD (82 secundum ASD [50.6%)], 18 sinus venosus ASD (11.1%), and 1 PAPVD [0.6%]), while for PVR 56 (34.6%) had PR after TOF repair and 5 (1.9%) were following PS surgery.   Ninety-eight (60.5%) patients underwent surgery, and 64 (39.5%) catheter interventions. Overall, tricuspid repair was performed in 18 (11.1%) patients, by ring annuloplasty (10, 55.6%), suture annuloplasty (7, 38.9%) and leaflet suture without annuloplasty (1, 5.6%).   Changes in echocardiographic parameters at six and twelve months are shown below in Table 2 and figure 2:   Key changes six months after intervention included a significant reduction in TR severity in the overall cohort, tricuspid annulus diameter, systolic tenting area, coaptation distance, RV area, 2-D sizes, and right atrial area. Less change was seen at 12-month follow up. Those with moderate or severe TR 6 months after intervention had worse pre-operative functional class compared to those with less TR. No differences in RV size and function parameters was seen between those with and without residual TR after repair.   Reduction in TR severity was seen in both the ASD/PAVR and TOF/PS groups (figure 3) with no difference in residual TR between groups (5.9% vs. 8.2% respectively, P=0.75):     Reduction in TR was also seen after excluding those who underwent TV repair at the time of surgery (figure 4):     Risk factors for residual TR at 12 months on univariate analysis included age, pre-operative TR severity, tenting area, TAPSE, RA area, LA area, and septal E/e’. Only RA area remained in the model on multivariable logistic regression included all univariable correlates.   Conclusions   Severity of TR was reduced following RV volume-offloading procedures (ASD closure, PVR for pulmonic regurgitation), in addition to reduction in RV and RA size, irrespective of intervention on the tricuspid valve. Most positive remodeling of the right heart was seen within 6 months of intervention. Baseline right atrial size was predictive of persistent TR at 12 months on multivariate analysis.   The key limitation of this paper is the retrospective data. Nonetheless the sample size is strong for a congenital heart disease cohort, and reflective of the general ACHD population. The authors correctly warn against direct comparisons between those who underwent TV repair and those who did not given differences in baseline TR severity.   Further studies are required to better identify patients who should be offered TV surgery. In the meanwhile, decisions to intervene will likely continue to be made on a case-by-case basis by the cardiac surgeon and/or ACHD team.    

Reduced biventricular contractility during exercise in adults with small, unrepaired ventricular septal defects: an echocardiographic study. Maagaard M, Heiberg J, Redington AN, Hjortdal VE. Eur J Cardiothorac Surg. 2020 Mar 1;57(3):574-580. doi: 10.1093/ejcts/ezz278. PMID: 31625565 Similar articles Select item 31972544   Take Home Points: Patients with small, unrepaired ventricular septal defect (VSD) who are apparently well, do have physiological impairment. A reduction in systolic and isovolumetric acceleration and isovolumetric velocity at the left and right ventricular free wall and septum at rest and during exercise were noted in patients with small VSD compared to controls. The left ventricular isovolumetric acceleration is inversely correlated to the size of the shunt.     Commentary from Dr. M.C. Leong (Kuala Lumpur, Indonesia), section editor of ACHD Journal Watch: Patients with a small ventricular septal defect (VSD) and non-significant shunt were often perceived to be healthy. These small VSD were seen to be haemodynamically insignificant and hence do not bring any damage to health apart from the slight but negligible increase in the risk for infective endocarditis. However, recent studies have demonstrated their effect in limiting patient’s functional capacity. This study aimed to assess the effect of small, haemodynamic insignificant VSD’s on the cardiac contractility especially during exercise. Cardiac contractility was assessed via isovolumetric acceleration, a sensitive echocardiographic marker of cardiac contractility which is independent of the loading condition of the ventricles.   This is a case control study, involving 34 patients with insignificant VSD shunts (median shunt ratio on cardiac magnetic resonance flow assessment: 1.2) and 28 healthy individuals. At baseline, the two groups were found to be comparable in terms of age, body weight, heart rate and blood pressures. At rest, patients with small VSD’s were noted to have a lower isovolumetric acceleration (IVA) and isovolumetric velocity (IVV) at the left and right ventricular free wall as well as the septal wall (Table 2).   During exercise, patients with small VSD’s demonstrated a lower IVA, IVV and peak systolic velocity at the left and right ventricular free wall and septum compared to controls (Figure 1). On further analysis, left ventricular IVA was noted to be inversely correlated to the shunt size. Peak exercise capacity was positively correlated with right ventricular IVV and septal IVV but not the left ventricular IVV (Figure 2).       This study, albeit being a small one, provides insights to the non-benign nature of small, haemodynamically insignificant VSDs. The effect of small VSDs on cardiac contractility is present not only at rest but also during exercise. However, these findings have yet to translate into a recommendation for closure as a different study by the same group of authors showed lower peak systolic velocity and IVA in patients post VSD closure compared to controls during exercise (ref). This study showed that even after closure of the VSD, there was impairment of the ventricular contractility during exercise which suggests that the ventricular contractility does not improve with VSD closure. Long term outcome of these group of patients with small VSDs compared to normal controls would be interesting to note.    

Determinants of Sudden Cardiac Death in Adult Patients With Eisenmenger Syndrome Chiriac A, Riley DC, Russell M, Moore JP, Padmanabhan D, Hodge DO, Spiegel MR, Vargas ER, Phillips SD, Ammash NM, Madhavan M, Asirvatham SJ, McLeod CJ. J Am Heart Assoc. 2020 Mar 17;9(6):e014554. doi: 10.1161/JAHA.119.014554. Epub 2020 Mar 15. PMID: 32174228 Free Article Similar articles Select item 32172648   Take Home Points: This is a large contemporary longitudinal study of Eisenmenger patients at 2 large US Academic centers Predictors of sudden cardiac death in this cohort were (on univariate analysis): Older age HR 1.03 LVEF <40% HR 3.38 Right Atrial Pressure > 10mmHg HR 2.49 Atrial fibrillation HR 6.36 Complete Heart block HR 27.49 QRS duration >120ms HR 2.34 Presence of a pacemaker HR 2.75 Advanced pulmonary hypertensive drugs – protective HR 0.21 On multivariate analysis, only AF and QRS duration >120ms remained as adverse predictors, the use of advanced pulmonary hypertensive drugs remained protective.     Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch: In patients with Eisenmenger syndrome, little is known about the risk factors for sudden cardiac death (SCD). Previously recognized predictors for all-cause mortality in this population included oxygen saturations, arrythmias and type of defect (pre-vs post-tricuspid). In this retrospective review, 2 tertiary centers in the USA followed up patients with Eisenmenger syndrome to help elucidate the predictive factors for SCD.   The review was conducted at The Mayo Adult Congenital Heart Disease Clinic and the Ahmanson/UCLA Adult Congenital Heart Disease Center for the period 1987 to 2015. A total of 246 patients were reviewed. Sixty-five percent were women and the mean age was 37.3 years. The median follow-up period was 7.1 years.   The defect distribution was as follows: ventricular septal defect (42%, n=104), atrial septal defect (24.4%, n=48 secundum, 11 sinus venosus, 1 coronary sinus ASD), PDA (12%, n=30). Atrioventricular canal defects were present in 17% (n=42), and 13% (n=32) had characteristics of single ventricle physiology. Of these patients, 15.4% (n=38) have in fact had a palliative procedure in the past. A total of 42 patients (17%) had Downs syndrome, with atrioventricular canal defects being the most common defect in this group.   Heart failure was seen in 42.3% of patients. Only 3.7% had documented coronary artery disease. Syncope was documented in 20 patients (8.1%). Nineteen patients were listed for transplant – 7 (3%) had received a combined heart/double lung transplant.   Two-hundred and eighteen patients had a systemic LV – with a mean LVEF of 52%. More than 60% of patients had RV enlargement and moderate to severe RV dysfunction was present in 55.3%. The RA pressure was elevated in 92 patients (49.7%). The estimated RVSP was >80mmHg in 83.4% of cases   Most patients were in sinus rhythm at first consultation, but many exhibited intermittent atrial arrythmias. After complete follow up, atrial fibrillation was noted in up to 16.7% (n=41) of patients. Both atrial and other supraventricular tachycardias were seen in an additional 20% of patients on follow-up. Only 3.7% had sustained ventricular arrythmias. Thirty percent of patients were on anti-arrhythmic drugs..   Thirteen patients had pacemakers (5.3%) – 7 epicardial and 6 transvenous systems. Four had intra-cardiac defibrillators (ICD’s). The indications for pacing were complete heart block, sinus node dysfunction, sinoatrial exit block. Anticoagulation was prescribed in 22.4% (n=55), mainly for atrial fibrillation or atrial flutter. Forty-three percent (n=105) were treated with advanced pulmonary hypertension therapies.     A total of 136 patients died during follow-up. In 40 patients (16.3%), the cause was sudden cardiac death (see figure 1 above). The patients with non-sudden cardiac death was mainly due to heart failure.     On univariate analysis – table 3 above, age (p<0.001), male sex (p=0.02), clinical heart failure (p<0.001) and atrial fibrillation at presentation (p=0.022) were significant independent predictors of total mortality. Advanced pulmonary hypertensive therapies were protective (p<0.001). Combined ASD and VSD was associated with a higher mortality (HR 4.34, 95% CI 1.72-10.95, p=0.002).     For sudden cardiac death, age (p=0.011) and atrial fibrillation (p<0.011) remain independent predictors. The presence of a pacemaker increases risk of SCD – HR 2.75 (95% CI 1.07 – 7.06). There was no association between type of anatomical defect and risk of SCD. Downs syndrome also did not confer increased risk (HR 1.24, p=0.582)   Once again, advanced therapies for pulmonary hypertension was strongly protective, reducing the risk 5-fold (HR 0.21, 95% CI 0.1-0.44, p<0.001).     Independent echo predictors of mortality for sudden cardiac death were: Reduced LVEF (<40% - for these the overall mortality was 83% - HR 3.38, 95%CI 1.71-6.66, p<0.001), increased RA pressure >10mmHg (HR 2.49, 95%CI 1.13-5.48, p=0.024), RV index for myocardial performance (RIMP)(HR 6.16, 95%CI 1.92-19.61, p=0.002).     Please refer to the table 6 above for the ECG predictors of sudden cardiac death: Atrial fibrillation (HR 6.35), Complete Heart block (HR 27.49), QRS duration >120ms (HR 2.34), Right atrial enlargement (HR 2.11), RBBB (HR 2.4). Arrythmia surveillance was not part of a protocol, and screening was done at the discretion of the attending clinician. There was no significant association between anti-arrhythmic medication use or ablation in the prevention of SCD – these numbers were small though so it’s unlikely that meaningful conclusions could be drawn.   The presence of a pacemaker was significantly associated with an increased risk of SCD (HR 2.75, 95%CI 1.07-7.06, p=0.036). Of the 13 with pacemakers, 5 had SCD. Those with a high ventricular pacing burden were more likely to suffer SCD compared to those with atrial only pacing.     On multivariate analysis, atrial fibrillation, QRS duration>120ms, and advanced therapies for pulmonary hypertension remained significant – Figure 3 above shows the survival curves for these 3 groups:   A: Atrial fibrillation (HR 11.45, p<0.0001) B: QRS duration >120ms (HR 2.51, p=0.0072) C: Advanced ongoing therapies for pulmonary hypertension conferred benefit (HR 0.14, p<0.0001)   This is obviously a retrospective review and subject to the same limitations and biases.    

Tetralogy of Fallot or Pulmonary Atresia with Ventricular Septal Defect after the Age of 40 Years: A Single Center Study   Hock J, Schwall L, Pujol C, Hager A, Oberhoffer R, Ewert P, Tutarel O.J Clin Med. 2020 May 19;9(5):E1533. doi: 10.3390/jcm9051533.PMID: 32438748 Free article.   Take Home Points   Managing the older adult with ACHD is increasingly common in clinical practice but there is limited data available for this particular group This was a retrospective analysis of patients aged >40 years old between 2005 and 2018 Combined primary endpoint was death, prevention of sudden cardiac death, aborted sudden cardiac death, pacemaker implant, arrhythmia or new-onset heart failure 184 patients were identified who were aged > 40 years – 86% with tetralogy of Fallot and 14% with pulmonary atresia/VSD Median follow up was 3.1 years (IQR 0.6-6.5 years) The combined primary endpoint was defined as any cause death, prevented sudden death, implanted pacemaker, new onset heart failure or new arrhythmia – this was occurred in 19% (n=35). The combined secondary end point was defined as all cause death or prevented sudden cardiac death – this occurred in 8% (n=13) An acquired co-morbidity was present in over two thirds of patients (n=126) and nearly half of the cohort (n=72) had 2 or more co-morbidities NYHA class (HR 2.1, 95% CI 1.2-3.6, p=0.009) and age were independent risk predictors of the primary outcome in multivariable analysis     Commentary from Dr. Damien Cullington (Liverpool, UK), section editor of ACHD Journal Watch: Collective efforts to improve the care of patients with ACHD presents new challenges of the care of adults who are increasingly aged. Over the last few decades, these changes in demographics have resulted in the ‘new norm’ in most of our practices. It now means that acquired heart disease needs to be considered increasingly frequently when assessing symptoms. Often overlooked in a busy outpatient clinic, but closer consideration of risk factor modifications to avoid the development of acquired heart disease needs more of our attention i.e. weight management advice, blood pressure control, lipid modification, exercise advice – a non-exhaustive to-do list and this is just for starters!   There is limited data/analysis which has focused primarily on outcomes of the older adult with ACHD. The authors nicely present a table of other comparative analyses to their own (Table 1). Hock et al. identified 184 patients > 40 years old and followed up at the German Heart Centre over a 15-year period (mean age 45.3 7.2 years). Surgical repairs were performed between 1958 and 2000 with a mean age of repair at 10 7.8 yrs. The primary combined endpoint was classified as the occurrence of a major cardiovascular event and the secondary endpoint as either all cause death or aborted SCD. All patients had previously undergone total corrective repair – patients with a ‘palliative repair’ or who had not undergone surgery (n=15) were excluded from the final analysis (n-169) although it would have been of interest to the reader understand the outcomes of this minority cohort too. The baseline demographics of the cohort are shown in Table 2.   Table 1. Hock et al. study data vs comparable datasets   Table 2. Patient demographics at baseline In 2005, 31 patients were aged >40 years old, increasing to 93 patients in 2017. Approximately 80% of patients included (n=149) were aged in the range 40-50 years. LV and RV function were qualitatively assessed – 78% had normal RV function and 92% normal LV function.   Patient co-morbidities are listed in Table 3. This cohort had high rates of co-incident co-morbidity – only about a third of patients had none (n=58). Of interest, 78 patients (n=42%) had at least one interventional procedure after their 40th birthday. Similarly, 48 patients (26%), had an EP procedure. Almost a third of patients (n=55) had experienced arrythmias – mostly atrial.   Table 3 – Co-morbidity prevalence                                 Primary and Secondary outcomes   During a median follow up of 3.1 years (IQR 0.6-6.5 years), 3 patients died. The primary endpoint occurred in 35 patients – death (n=3), prevented sudden cardiac death (n=10); pacemaker implant (n=9); new onset heart failure (n=8) and clinically significant arrhythmias (n=5).   Univariable and multivariable predictors of primary endpoint are shown in Table 4.   Table 4 - Univariable and multivariable analyses Conclusions   This analysis of older patients with TOF or PA/VSD showed that acquired co-morbidities are common and likely to be increasingly so as the individual ages. Although co-morbidity of any kind was not an independent risk predictor of outcome, this is perhaps a reflection of the duration of follow up – some co-morbidities require decades to manifest pathologically. Assessment of primary prevention risk factors as part of a holistic strategy to modify risk needs to be made more systematically than is likely to be done at present – one hopes that modification will translate into better longer term outcomes. This is something which needs closer attention by all of us involved in the care of ACHD patients – too often this takes a backseat to our concentrated focus on the gross anatomy.    

Skeletal muscle index determined by bioelectrical impedance analysis is a determinant of exercise capacity and a prognostic predictor in patients with congenital heart disease.   Sato M, Inai K, Asagai S, Harada G, Shimada E, Sugiyama H.J Cardiol. 2020 May 18:S0914-5087(20)30159-3. doi: 10.1016/j.jjcc.2020.04.011. Online ahead of print.PMID: 32439338   Take Home Messages   Bioelectrical impedance analysis (BIA) has been introduced in several clinical fields, such as cardiology, nephrology, hepatology, nutrition, and rehabilitation. BIA is a non-invasive, rapid, and safe assessment method that involves the application of alternating currents to the body to acquire eight-polar tactile-electrode impedance. Skeletal muscle Index (SMI) determined by BIA is a determinant of exercise capacity and can be used as a prognostic predictor in patients with CHD.     Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch:   Patients with congenital heart disease (CHD) reportedly have reduced exercise capacity. Underlying cardiac anatomy, a sedentary lifestyle, and chronotropic incompetence are thought to be associated with exercise impairment (Figure 1). Bioelectrical impedance analysis (BIA) has been introduced in several clinical fields, such as cardiology, nephrology, hepatology, nutrition, and rehabilitation. BIA is a non-invasive, rapid, and safe assessment method that involves the application of alternating currents to the body to acquire eight-polar tactile-electrode impedance. The first signs of heart failure (HF) are thought to appear during exercise. If BIA parameters can predict impaired exercise capacity and detect unbalanced body composition, it could be used to evaluate the early stages of HF in patients with CHD.                 The present study aimed to clarify the correlation between BIA parameters and exercise capacity as well as the prognostic importance of the skeletal muscle index (SMI) in patients with CHD.   This retrospective single-center study included 305 consecutive patients aged > 12 years with CHD. Patients with a cardiac pacemaker were excluded because the electric current generated by BIA could interfere with device function. Additionally, pregnant patients were excluded because BIA in pregnancy is unreliable.   Blood samples were obtained to analyze the hemoglobin, albumin, creatinine, sodium, and brain natriuretic peptide (BNP) levels. Using the M-mode of the parasternal short-axis view, the left ventricular fraction shortening (LVFS) was determined. Similarly, they measured the tricuspid annual plane systolic excursion using the M-mode of the apical 4-chamber view. The early mitral inflow velocity (E) was measured using pulsed Doppler imaging with the sample volume at the mitral tip. The early diastolic mitral annular velocity (e’) was measured at the septal annulus using TDI, and the E/e’ ratio was calculated.   The 6-minute walking test (6MWT) was performed. A cardio-pulmonary exercise test (CPX) on a treadmill using the ramp protocol performed to assess peak oxygen uptake (peakVO2) and oxygen uptake at the aerobic threshold (ATVO2).   Bioelectrical impedance analysis (BIA)   The BIA was performed in patients 2–4 h after lunch and the oral administration of medicines. In the present study, to compare skeletal muscle and mineral levels in a wide range of body sizes, skeletal muscle mass was indexed to height squared (that is, the Skeletal muscle index - SMI), and mineral content was indexed to height squared (that is, the mineral index, MI). Additionally, the Extracellular Index (EI), which is the ratio of Extra-cellular water (ECW) divided by the total body water, was assessed. The BIA parameters were blinded to physicians who determined the HF related admissions and those who performed the 6MWT and CPX.   Assessments   Correlation between exercise capacity and bioelectrical impedance parameters   To clarify the factors associated with exercise capacity, the correlation between peak VO2 and BIA parameters in patients with biventricular as well as single ventricular morphology was determined. Reduced exercise capacity was defined as peak VO2 under 20 ml/kg/min.   Comparison of bioelectrical impedance parameters and exercise capacity with regard to ventricular morphology   To elucidate any influence that ventricular morphology might have, the BIA and exercise capacity (6MWT, peak VO2, and AT VO2) parameters of patients with biventricular morphology as well as those with single ventricular morphology were compared.   Skeletal muscle index as a predictor of HF-related admission   To clarify the prognostic role of SMI, the ratio of HF-related admission in patients with SMI above the median value in the present study was compared with that of patients with SMI equal to or less than the median value using a Kaplan–Meier analysis. HF-related admissions were identified as new-onset decompensated HF or decompensation of chronic HF with symptoms that warranted admission   Results   The multivariate analysis revealed a significant correlation between peak VO2 and EI (r = -0.55) and peak VO2 and SMI (r = 0.49) Figure 2. The receiver operating characteristic curve analysis showed that the EI cut-off for peak VO2 <20 ml/kg/min was 0.386 [area under the curve (AUC), 0.77; sensitivity, 0.67; specificity 0.76], and the SMI cut-off was 7.6 kg/m2 (AUC, 0.78; sensitivity, 0.76; specificity 0.75).   Compared with patients who had biventricular morphology, patients with single ventricular morphology had a higher EI (mean, 0.381 vs. 0.387, respectively) and lower SMI (8.5 vs. 7.7, respectively), resulting in a lower peakVO2 (27.1 vs. 20.8, respectively).   Fig. 2. Receiver operating characteristic curve analysis of bioelectrical impedance parameters for predicting reduced exercise capacity (defined as peak VO2 under 20 ml/kg/ min) (A, edema index; B, skeletal muscle index). AUC, area under the receiver operating characteristic curve.   The Kaplan–Meier analysis showed that a low SMI was associated with an increased risk of future heart failure-related admissions. (Figure 3 below)   Fig. 3. The Kaplan–Meier analysis of the incidence of heart failure-related admissions of patients with biventricular (left) or single ventricular (right) morphology by SMI. The red line shows the patients with a high SMI. The blue line shows those with a low SMI. HF, heart failure; SMI, skeletal muscle index.   Conclusions:   SMI determined by BIA is a determinant of exercise capacity and can be used as a prognostic predictor in patients with CHD.          

Assessment and Implications of Right Ventricular Afterload in Tetralogy of Fallot. Egbe AC, Taggart NW, Reddy YNV, Sufian M, Banala K, Vojjini R, Najam M, Osman K, Obokata M, Borlaug BA. Am J Cardiol. 2019 Dec 1;124(11):1780-1784. doi: 10.1016/j.amjcard.2019.08.035. Epub 2019 Sep 9. PMID: 31586531 Similar articles Select item 30772131   Take Home Points: In adult patients with repaired tetralogy of Fallot (TOF), higher right ventricle systolic pressure (RVSP) is associated with worse prognosis including a higher risk of death or transplant. However, there was no such association with right ventricle outflow tract (RVOT) obstruction severity. In this study, there was good correlation between invasively measured and Doppler derived RVSP. Commentary from Dr. Maan Jokhadar (Atlanta GA), section editor of ACHD Journal Watch: Repaired TOF patients commonly have residual RVOT obstruction and increased right ventricle (RV) pressure overload. This is in addition to the increased risk of pulmonary valve regurgitation after repair and right ventricle volume overload. Dr. Egbe and colleagues from Mayo Clinic in Rochester, Minnesota performed a retrospective cohort analysis of 266 adult TOF patients who had contemporaneous echocardiography and cardiac catheterization (within 48 hours) between 1990 and 2015. Patients with aortopulmonary collaterals were excluded. The mean age was about 35 and the mean follow-up with just under 13 years. In this study, invasively measured RVSP was used as an index of RV afterload, which can increase as a result of any number of factors that include RVOT obstruction, pulmonary artery vascular obstruction, pulmonary vascular resistance, and increased left heart filling pressure. Study participants were divided into 2 groups based on RVOT gradient of less or more than 36 mmHg. About 66% (175 patients) had significant RVOT obstruction and the rest did not. During a follow-up period of almost 13 years, there was no significant mortality difference between patients with and without RVOT obstruction: 27/175 patients died in the RVOT obstruction group and 8/91 patients died in the no RVOT obstruction group. Of the 35 patients who died, right heart failure was the cause in 14, sudden-death in 11, sepsis with multi organ system failure in 3, postoperative death in 4, major bleeding in 2, and 1 died of unknown causes. There were 4 patients who had heart transplant. In this study, there was good correlation between invasively measured and Doppler derived RVSP. In adult repaired TOF patients, higher RVSP, as a marker of RV afterload, was independently associated with death and heart transplant, whether assessed invasively or non-invasively. However, there was no such association with RVOT obstruction. Thus, increased RV pressure overload from any cause is a marker of worse prognosis in repaired TOF patients. Further study is needed to determine if reducing RV pressure overload improved outcomes. The results of the study bolster the notion that elevated RVSP is helpful in the risk stratification and decision-making regarding pulmonary valve intervention for patients with repaired TOF and pulmonary regurgitation. However, further study is needed.  

Fontan protein-losing enteropathy is associated with advanced liver disease and a proinflammatory intestinal and systemic state. Rodríguez de Santiago E, Téllez L, Garrido-Lestache Rodríguez-Monte E, Garrido-Gómez E, Aguilera-Castro L, Álvarez-Fuente M, Del Cerro MJ, Albillos A. Liver Int. 2020 Jan 8. doi: 10.1111/liv.14375. [Epub ahead of print] PMID: 31912956 Similar articles Take Home Points: Fontan patients with PLE demonstrated more severe liver damage and cardiac impairment, and greater systemic inflammation, intestinal inflammation and intestinal permeability than those without PLE. Timely reminder that liver assessment and close surveillance is essential in all Fontan patients, and especially those with PLE. Faecal calprotectin is complementary to faecal alpha-1-antitrypsin and may be useful as a biomarker for the diagnosis and follow-up of Fontan PLE. Data originates from an observational single-centre case-control study (n=29). Commentary from Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: Background Protein-losing enteropathy (PLE) affects 3 – 18 % of patients after a Fontan operation, and is thought to be contributed by factors including elevated central venous pressure and inflammation. Aims of this study: to investigate in patients with Fontan circulation and PLE: a. the presence of intestinal and systemic inflammation; b. the relationship between PLE and severity of liver and cardiac damage. Methods All Fontan subjects diagnosed prospectively with PLE were included. PLE was defined as a 24 hours alpha-1-antitrypsin faecal clearance value above 27 mL/day. Exclusion criteria were coexisting inflammatory bowel disease, coeliac disease or gastrointestinal infection. Controls were matched at a 1:1 ratio by age (±2 years) and Fontan surgery procedure (atriopulmonary vs total cavopulmonary). Initial assessment included a structured medical interview, physical examination, blood and faeces tests, abdominal Doppler-ultrasonography, liver elastography, abdominal angio-magnetic resonance imaging (MRI) or computed tomography (CT) scan when MRI was contraindicated, and echocardiography. A cardiac MRI and cardiac haemodynamic study were also performed when clinically indicated. Results Of 61 subjects, 15 had PLE (24.6 %) with one excluded following diagnosis of coeliac disease. Fifteen control Fontan patients were included (see Figure 1, below). Faecal calprotectin was significantly increased in the PLE group (80 vs 30 ug/g, P < 0.001; Figure 2). Serum I-FABP, used as a marker of intestinal barrier disruption, was elevated in PLE (9 vs 5 ng/ml, P = 0.019), while pro-inflammatory cytokines TNF-alpha and IL-6 were also elevated in the PLE cohort (Figure 3). Cardiac index was lower in PLE subjects in the hemodynamic study (2.54 vs 4.25 L/min/m2, P = .016), lower ventricular ejection fraction on cardiac MRI (58.5% vs 63.5%, P = .04) and lower systemic oxygen saturation (93% vs 96%, P = .025). No difference in BNP was observed. No difference in routine liver function testing was observed (bilirubin, ALT, AST, GGT, ALP). Platelet count was lower, while liver stiffness was greater (25.4 vs 14.3 kPA; P < 0.001) in the PLE group. No cases of hepatocarcinoma were diagnosed. Conclusions Fontan patients with PLE demonstrated more severe liver damage and cardiac impairment, and greater systemic inflammation, intestinal inflammation and intestinal permeability than those without PLE. Faecal calprotectin is complementary to faecal alpha-1-antitrypsin and may be useful as a biomarker for the diagnosis and follow-up of Fontan patients diagnosed with PLE.  

Inspiratory muscle training did not improve exercise capacity and lung function in adult patients with Fontan circulation: A randomized controlled trial. Fritz C, Müller J, Oberhoffer R, Ewert P, Hager A. Int J Cardiol. 2020 Jan 9. pii: S0167-5273(19)33852-5. doi: 10.1016/j.ijcard.2020.01.015. [Epub ahead of print] PMID: 31992463   Take Home Points: Daily IMT for a 6 month period did not improve exercise and lung capacity and lung volumes in Fontan patients. Daily IMT for 6 months in adult patients with Fontan was associated with an increase in O2 saturation at rest. Larger studies are warranted in order to gain more insight into the mechanisms of exercise training and the Fontan physiology. Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch: Background: In Fontan patients, due to the hemodynamic limitations of an absent sub-pulmonic chamber, pulmonary arterial and systemic venous blood flow are strongly affected by modest intrathoracic pressure shifts, since ± 30% of flow in the systemic venous pathway is driven by respiration. In patients with Fontan circulation, blood flow in the IVC is increased during inspiration, enhancing the systemic venous blood return into the lungs considerably. Young adults with Fontan circulation show respiratory and skeletal muscle weakness, and higher prevalence of respiratory muscle dysfunction, comparable to adults with advanced heart failure. In a recent study in children with Fontan circulation, daily inspiratory muscle training (IMT) of six weeks improved inspiratory muscle strength and ventilatory efficiency in a cardiopulmonary exercise test (CPET). It is therefore reasonable that an individually adjusted IMT in adult patients with Fontan circulation improves parameters of ventilation and exercise capacity. The aims of the current study were to investigate the effect of a telephone-supervised, daily inspiratory muscle training for 6 months on exercise capacity and on lung volumes in adult patients with Fontan circulation. Methods Study subjects 42 patients (50% female; 30.5 ± 8.1 years; age 18 to 51 years old) out of 209 eligible patients participated from January 2017 until October 2018. After baseline assessments (visit 1), consisting of a lung function test (LFT) and a CPET, 42 patients were randomized into either an intervention group (IG, n = 20) or control group (CG, n = 22). The IG started performing a telephone-supervised, daily IMT until six months follow-up (visit 2). The daily intervention was performed with an inspiratory resistive training device (POWER breathe International Ltd., Southam, UK). Within the first six months after baseline evaluation the CG continued their usual activities and did not get any treatment. At the six months follow-up (visit 2) this group started IMT under the same conditions, including weekly telephone supervision till 12 months re-evaluation (visit 3). To assess the sustainability of the training program, the IG was asked to continue performing IMT without weekly telephonic-supervision until 12 months reevaluation (visit 3). This independent six-months IMT period of the CG was performed from 12 months follow-up until 18 months re-evaluation (visit 4). (Figure 1) The study consisted of three visits for the IG and four visits for the CG, where a CPET and a LFT were performed, respectively. All tests were implemented by the same experienced sports scientist. Inspiratory muscle training (IMT) After baseline evaluation patients were instructed by an experienced sports scientist in term of the IMT. Patients were instructed to begin the inhalation phase with diaphragmatic breathing and to continue inhaling by expanding the rib cage. Incorrect breathing and malposition were corrected immediately. Patients used an inspiratory resistive training device for three sets with 10–30 repetitions once daily. During the second 6 months training period, patients were instructed to continue the IMT independently, since no telephone supervision was implemented. Both groups performed IMT under the same conditions. Measurement of exercise capacity Incremental symptom-limited CPET until exhaustion. Gas exchange and ventilation were measured via a breath-by-breath gas exchange analysis. Peak oxygen uptake (VO2 peak) was calculated as the highest mean O2 consumption obtained during any 30-second time interval. Compliance criteria for a valid CPET were achieved when either respiratory exchange ratio (RER) was ≥1.05, or peak heart rate was ≥85%. Cyanotic patients (oxygen saturation b 90% at rest or at peak exercise) were rarely able to reach the above-mentioned thresholds, however they were included in the study, independent of those criteria. Measurement of lung function Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and the FEV1/FVC ratio were performed. Results: Exercise capacity At 6 months re-evaluation both groups had not improved their VO2 peak and VO2 peak predicted, without any significant difference between IG and CG. Additionally, no significant difference was found between the IG and the CG concerning ventilatory efficiency. The only significant result was an increase of O2 saturation at rest in the IG in comparison to the CG after six months IMT. These results indicate an enhancement of hypoxic pulmonary vasoconstriction resulting in an improvement in ventilation/perfusion matching, which favors systemic oxygen delivery by the constriction of intrapulmonary arteries reacting to alveolar hypoxia. Another plausible mechanism could be a reduction in chronic atelectasis following IMT. Hence IMT may improve blood flow of the lungs. Lung function After 6 months of IMT, no significant changes could be observed between the IG and the CG concerning FVC and FVC predicted. Further, FEV1 and FEV1 predicted did not change significantly after IMT between the IG and CG. Conclusions Six months of weekly telephone-supervised, daily IMT could not improve exercise and lung capacity in adult patients with Fontan circulation. According to current evidence, beneficial effects of IMT in adult patients with Fontan circulation cannot be verified. Therefore, larger studies are warranted in order to gain more insight into the mechanisms of exercise training and the Fontan physiology.  

Fontan-associated nephropathy: Predictors and outcomes. Khuong JN, Wilson TG, Grigg LE, Bullock A, Celermajer D, Disney P, Wijesekera VA, Hornung T, Zannino D, Iyengar AJ, d'Udekem Y. Int J Cardiol. 2020 Jan 10. pii: S0167-5273(19)34728-X. doi: 10.1016/j.ijcard.2020.01.014. [Epub ahead of print] PMID: 31955974   Take Home Points: 20% of patients with Fontan circuits have mild to moderate renal dysfunction as per eGFR. Atrio-pulmonary Fontan and the absence of a prior bidirectional were the only predictors of renal dysfunction In this cohort, renal dysfunction did not impact the outcomes of death, cardiac transplantation or Fontan failure. Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch: Although nephropathy is a known complication of a Fontan circuit, not much data is available in contemporary literature on this topic. This study from the Australia and New Zealand Fontan Registry aimed to ascertain the prevalence of nephropathy, identify its predictors and characterize their long term outcomes in young adults with Fontan circuits. Patients >age 16 with Fontan circuits were included if they had a serum creatinine measurement when between the ages of 16 and 25. Those with primary renal diagnoses, those who underwent Fontan take-downs, received heart transplantation or died before age 16, were excluded. Baseline renal function was assessed by glomerular filtration rate (GFR) as per the Modification of Diet in Renal Disease (MDRD) equation. Renal dysfunction was defined as a GFR < 90ml/kg/min/1.73m2. The primary end-point for Fontan failure was death, heart transplantation, plastic bronchitis, protein losing enteropathy, Fontan take-down and NYHA III-IV. The secondary outcome was chronic kidney disease – GFR < 90ml/kg/min/1.73m2. A total of 328 patients were included. Fifty-two percent were male and the mean age was 26 years. The prevalence of renal dysfunction was 20% (n=67). Most had mild renal dysfunction, though 1% (3 patients) had moderate renal dysfunction with a GFR < 60ml/kg/min/1.73m2. The following factors were associated with increased renal dysfunction on univariate analysis: Atrio-pulmonary Fontan (AP Fontan) – OR 2.22 (95% CI 1.11-4.30, p=0.024) Absence of prior bidirectional cavo-pulmonary shunt – OR 2.23 (95% CI 1.28-3.98, p=0.005) This did not hold for multi-variate analysis though. Two patients in the renal dysfunction group (2%) and 19 (7%) of the non-renal dysfunction group died during follow-up. From Figure 1 below, it is evident that fewer deaths occurred in the renal dysfunction group (2/67 deaths vs 9/261 deaths) Ten year survival for the renal dysfunction group was 96% compared to 89% in the non-renal dysfunction group. (p=0.1) No independent risk factors for mortality were identified. Figure 2 below shows that the 10-year freedom from death and transplant for the renal dysfunction and no renal dysfunction groups were 96% and 87% respectively (p=0.05) Fontan failure occurred in 12% of patients (n=38) over a 7 year follow-up period. There was no difference in the prevalence of Fontan failure between those with and without renal dysfunction. Ten year freedom from Fontan failure was 82.5% in the renal dysfunction group and 81% in the no renal dysfunction group (p=0.84) – see figure 3 below. Independent risk factors for Fontan failure were right atrial isomerism and developing >moderate ventricular systolic dysfunction. Over an 8 year follow-up period, no significant differences in mean eGFR were found in the group who had renal dysfunction at the outset (eGFR 78 vs 80ml/kg/min/1.73m2, p=0.4). The group with normal renal function initially, did show a decline in eGFR (120 to 108ml/kg/min/1.73m2, p<0.001).  

Prevalence of pulmonary hypertension in adults after atrial switch and role of ventricular filling pressures. Miranda WR, Jain CC, Connolly HM, DuBrock HM, Cetta F, Egbe AC, Hagler DJ. Heart. 2020 Oct 7:heartjnl-2020-317111. doi: 10.1136/heartjnl-2020-317111. Online ahead of print. PMID: 33028672   Take Home Points: In patients palliated with an atrial switch repair for transposition of the great arteries (TGA): Prevalence of an elevated systolic RV end-diastolic pressure was low (1/3 of patients) Almost 60% had an increased pulmonary arterial wedge pressure (PAWP), with prominent V waves Elevation in pulmonary pressures was present in nearly all patients who had a concomitant elevation in PAWP Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch: Both systemic RV systolic and diastolic dysfunction are well known complications after atrial switch procedures for Transposition of the Great Arteries (TGA). The contribution and effect of atrial baffles on cardiac output and ventricular filling is poorly understood. This is a retrospective review aimed at assessing the prevalence of elevated systemic filling pressures and pulmonary arterial hypertension late after atrial switch repairs. All adult patients with TGA and an atrial patients who underwent cardiac catheterization at the Mayo Clinic between January 2004 and December 2018. Patients with single ventricle physiology and those with atrial switch take-downs were excluded. Forty-two patients were included in the analysis. Their mean age at time of cardiac catheterization was 37.6 years, the median age at atrial switch surgery was 15 months. 90.5% of patients had a Mustard palliation. In 36 patients (85.7%), moderate or greater RV systolic dysfunction was noted. The mean sRVEF was 33%. In 35.7%, moderate or greater TR was noted. In terms of cardiac Catheterisation data: Pulmonary venous baffle obstruction in 16.7% Systemic venous baffle obstruction in 54.7% (in 10 cases percutaneous interventions were performed) Mean sRVEDP 13.2mmHg ±5.1mmHg. Mean Right PAWP 18.9, mean Left PAWP 18.5mmHg. sRVEDP was significantly lower than both right and left PAWP, even once baffle obstruction was excluded (right difference -2.4mmHg, left difference -2.5mmHg, p=0.02 and 0.004 respectively). Pulmonary venous baffle stiffness therefore likely plays a significant role in ventricular filling pressures. An elevated sRVEDP >15mmHg was seen in 35.1% of patients (older at the time of atrial switch with no other clinical differences). An elevated PAWP >15mmHg seen in 58.1% of patients (more likely to have a higher prevalence of NYHA class 3, to be on diuretic therapy, to have moderate or greater RV systolic dysfunction, and a lower EF. Pulmonary hypertension was seen in 47.5% of patients (n=17). Median PVR 1.3 Woods units. Among those with pulmonary hypertension, PAWP > 15mmHg in all but one patient. In addition to the systolic and diastolic dysfunction in the systemic RV, the pulmonary venous baffle has an important role in augmenting preload and on ventricular filling pressures as shown in this study by the relatively normal/low RVEDP and the elevated PAWP- with no end-diastolic gradient and a large v wave (as shown above). This is attributed to a combination the pulmonary venous atrium being of a small size compared to the left atrium, the baffle is non-distensible/partially calcified and increased atrial fibrosis/scarring.

Aorta size mismatch predicts decreased exercise capacity in patients with successfully repaired coarctation of the aorta. Mandell JG, Loke YH, Mass PN, Opfermann J, Cleveland V, Aslan S, Hibino N, Krieger A, Olivieri LJ. J Thorac Cardiovasc Surg. 2020 Oct 7:S0022-5223(20)32707-0. doi: 10.1016/j.jtcvs.2020.09.103. Online ahead of print. PMID: 33131888   Take Home Points: In patients with repaired coarctation of the aorta: Ascending to descending aorta size mismatch is associated with a decrease in exercise tolerance. Patients with ascending : descending aortic diameter of close to 1 had the best exercise capacity. The geometry of the aortic arch and the normalized aortic dimension were not associated with exercise capacity. Commentary from Dr. M.C. Leong (Kuala Lumpur, Indonesia), section editor of ACHD Journal Watch: Despite a successful initial repair, patients with coarctation of the aorta (CoA) remain to be at risk of long term morbidities. One of such is the decreased in exercise capacity. A decreased in exercise capacity does not only affects the quality of lives of patients, but it also increases the risk of hospitalization and death. In this paper, the authors sought to evaluate the relationship between aortic arch geometry, size and flow characteristics, and exercise capacity in patients with repaired CoA. The authors studied the above mentioned in an interesting way. Firstly, they looked at the patients with repaired CoA, who had a cardiac magnetic resonance (CMR) and cardiopulmonary stress test and achieved anaerobic threshold, within their database. Correlations were sought between the aortic arch geometry (Romanesque which is normal and Crenel and Gothic which are abnormal – Figure 1), the dimensions of the aorta measured at the usual locations, and the ascending and descending aortic flow measured on phase contrast imaging. Subsequently, the authors, innovatively, created a mock circulatory system to mimic circulatory flow within the arch by printing the 3D model of repaired CoA of all the subjects and measured the flow and pressures within the 3D arch models at rest and exercise, to simulate the effect of the flow of blood within the repaired arches during these conditions – Figure 2.   15 patients (mean age 26.8 8.6 years), of which 6 had bicuspid aortic valve, were recruited. Baseline characteristics were as tabulated in Table 1 and 2. The authors found that exercise capacity had a significantly positive correlation with normalized descending aortic diameter (DAo) diameter. Patients with a smaller ascending aorta: descending aorta diameter ratio (DAAo/DDAo) had better exercise capacity – Table 3 & Figure 3. Patients with DAAo/DDAo close to 1 had the best exercise capacity while worse peak oxygen consumption (VO2) was associated with a smaller DAo and a larger AAo. Normalised aortic root, sinotubular junction, AAo and isthmus diameters did not correlate with exercise capacity. Similarly, the geometry of the arch did not correlate to the VO2. In the mock circulatory simulation study, the percentage of DAo flow at rest and during exercise correlated negatively to DAAo/DDAo (rho = -0.68, p<0.01; and rho = -0.59, p=-0.02) and the ratio of percent of DAo flow in exercise to rest was positively correlated with DAAo/DDAo (rho=0.64, p<0.01) and negatively correlated with VO2 (rho =-0.60, p=0.02) – Figure 6. This study demonstrated that the ascending : descending aortic size mismatch is an important cause of exercise intolerance. Our initial perception that a smaller size aortic arch or an abnormal geometry of the aortic arch might cause an increased in flow resistance and a long term implication to the left ventricular muscles was not translated into a decrease in exercise capacity, nor is a dilated aortic root which may potentiate energy loss as blood flows through a large AAo. Rather, a smaller DAo is more closely related to exercise capacity rather than the dilated AAo which may be due to limited perfusion to the lower limbs.

Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease. Morton SU, Shimamura A, Newburger PE, Opotowsky AR, Quiat D, Pereira AC, Jin SC, Gurvitz M, Brueckner M, Chung WK, Shen Y, Bernstein D, Gelb BD, Giardini A, Goldmuntz E, Kim RW, Lifton RP, Porter GA Jr, Srivastava D, Tristani-Firouzi M, Newburger JW, Seidman JG, Seidman CE. JAMA Cardiol. 2020 Oct 21:e204947. doi: 10.1001/jamacardio.2020.4947. Online ahead of print. PMID: 33084842   Take Home Points: There is a significant genetic component to the known increased rates of cancer in patients with congenital heart disease compared to the background population. There is no association between a particular cancer risk gene and specific congenital heart disease sub-type. Commentary from Dr. Helen Parry (Leeds UK), section editor of ACHD Journal Watch: Objective of the study: To analyse the frequency of rare loss of function (LoF) cancer risk genes in a large cohort of patients with congenital heart disease Method: Genetic analysis was performed on participants in the Paediatric Cardiovascular Genetics consortium (n=4443) and controls (n=9808). Their genetic data were analysed for 723 genes associated with cancer risk, 38 of these were previously associated with congenital heart disease and 227 were LoF variants. These genes were previously identified and held on the Catalogue of Mutations in Cancer- Cancer-Gene consensus database. Frequency of the above genetic variants were analysed in the cohort with congenital heart disease and compared with the control cohort. Binomial testing was performed and significance was taken as p value < 0.05. A separate sub-analysis was performed for 7 genes with multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease. Results: The table shows analysis of the frequency of the above genetic variants in the congenital heart disease cohort versus controls. Genes analysed Number of gene variants Odds ratio 95% CI P value Cancer risk genes 723 1.34 (1.21-1.49) 2.31 × 10−11b Cancer risk genes also associated with CHD 38 7.19 (4.23-12.22) <2.2 × 10−16b LoF mechanisms 227 1.43 (1.21-1.69) 1.58 × 10−7 There was no association between a particular cancer risk gene and specific congenital heart disease sub-type. The prevalence of seven cancer risk genes with multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease was also tabulated (not replicated here as sub-analysis with very small numbers). Conclusions: There is a significant genetic component to the known increased rates of cancer in patients with congenital heart disease compared to the background population. Critique Positive aspects: Large cohort available for genetic analysis. Genes identified and validated by a well-recognised and independent database were used to form the basis of the study. Comprehensive cover of the genes of interest. Provides some insight into an topic with relatively little research. Negative aspects: There was almost no reference to potential confounding factors: were any of the gene variants also more common in individuals with particular behaviours also associated with cancer, e.g. smoking or substance misuse? The study was limited to patients of European extraction. There were no real details regarding the potential clinical relevance. There was a comment at the end of the paper that this may help guide screening programmes in the future but without any expansion on whether this will be limited to specific cancers or how this might work in a practical sense. The analysis looking at multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease had such small numbers it would be very difficult to draw any conclusions, this has been largely omitted from this review as a result.  

Left ventricular strain and fibrosis in adults with repaired tetralogy of Fallot: A case-control study View Article de Alba CG, Khan A, Woods P, Broberg CS. Int J Cardiol. 2020 Sep 1:S0167-5273(20)33719-0. doi: 10.1016/j.ijcard.2020.08.092. Online ahead of print. PMID: 32882293 Take Home Points: Left ventricular dysfunction is an expected complication after rTOF and has significant prognostic implications. CMR can provide quantification of both myocardial strain analysis and diffuse fibrosis, both of which have associations with other clinical variables and outcomes: LVECV (left ventricular myocardial extracellular volume) was the only univariate predictor of arrhythmia. All 2D strains were significantly associated with hospitalization and death. However, no association was seen between global systolic strain and LV-ECV. The study suggests these metrics are reflective of different pathologic processes and related to different types of outcome. Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch:  The long-term follow-up of repaired tetralogy of Fallot (rTOF) is typically focused on RV systolic and diastolic function. However, the LV is also a factor contributing to decreased exercise capacity, ventricular arrhythmias, and mortality. A plausible explanation is that moderate to severe pulmonary insufficiency creates chronic RV volume load which drives RV dilation and increased RV wall stress, which in turn lead to LV dysfunction via ventricular-ventricular interactions. Myocardial extracellular volume (ECV), a surrogate of diffuse interstitial myocardial fibrosis, can be evaluated by T1 mapping. Increased myocardial fibrosis has been found in patients with TOF, even at a young age and has been associated with abnormal LV mechanics. In addition, CMR-based feature tracking (CMR-FT) assessment of myocardial strain can be used as a measure of both global and regional myocardial function. Its use in rTOF remains limited. Because both LV-ECV and strain measures reflect LV myocardial change, and because both have limited association with clinical endpoints, the study postulated that the two measures would be associated with one another. The primary aim of the study was to determine whether LV myocardial fibrosis measured by T1 mapping is associated with LV systolic strain measured by CMR-FT.  The secondary aim was to determine the association between LV systolic strain and LV-ECV with three major clinical outcomes: death, arrhythmia and hospitalization for heart failure. Patients and Methods: CMR studies from adults with rTOF and healthy subjects without known cardiovascular disease were retrospectively reanalyzed.  Strain analysis was done using the tissue tracking algorithm in Circle Cardiovascular Imaging Software (Version 5.6.8 Calgary, Canada). LV-ECV was quantified using a single short axis Look-Locker sequence at the midmyocardium, for which signal intensity vs. time curves were plotted for myocardium and blood pool before and several time points up to 25 min after contrast administration. New atrial arrhythmia was defined as a sustained atrial arrhythmia, either symptomatic or requiring treatment. Ventricular arrhythmia was defined as non-sustained ventricular tachycardia lasting 30 beats, or any symptomatic ventricular arrhythmia requiring treatment. Non-elective hospitalizations for heart failure symptoms or elevated BNP requiring diuresis were considered. Results: The initial study cohort consisted of 52 rTOF subjects. Upon review, four rTOF subjects did not have adequate quality cine imaging in all views, either because of respiratory artifact or gating issues, to make accurate strain quantifications and were not included.  The remaining 48 rTOF subjects constituted our patient cohort (age 40.5, SD = 14.3 years, 42% female) with 20 controls (age 39.4, SD = 11.9, 45% female). Group comparisons are presented in Table 1. As expected, the groups also differed by LV systolic volume, LV ejection fraction, left atrial volume, and RV size and function. Global circumferential strain (GCS), both 2 dimensional (2D) and 3 dimensional (3D) were lower in rTOF subjects (p ≤0.0001 for both, Table 1). Global longitudinal strain (GLS) both by 2D and 3D were also significantly lower in rTOF subjects (p ≤0.0001 for both). Global 2D radial strain (GRS) was lower in rTOF subjects compared to controls (Table 1). LVEF and LVESV were both significantly associated with all global (2D and 3D) peak systolic strain values. No significant association was seen between strain and right ventricular volumetric parameters. There was a weak association between all 2D strain parameters and RVEF, however this was not significant after adjusting for multiple comparisons. There was no association between global systolic strain and LV-ECV. Kaplan-Meier plots for arrhythmia free survival and death (Figure. 1), for both LV-ECV and GLS are shown. By Cox-regression analysis, LVECV was the only univariate predictor of arrhythmia. All 2D strains were significantly associated with hospitalization and death (univariate). LV-ECV was also a significant univariate predictor of both hospitalization and death. Based on limited multivariate models, the only consistent independent predictor of arrhythmia was LV-ECV (HR=1.198, 95% CI 1.04–1.38, p=0.013). GLS was the only consistent multivariate predictor of hospitalization (HR = 1.48, 95% CI 1.11–1.96, p = 0.007) and of death (HR = 1.63, 95% CI 1.16–2.30, p = 0.005). Discussion: ECV and myocardial strain have gained wide interest in the last decade as tools for myocardial assessment. Our study confirms that both LV-ECV and global systolic strain are abnormal compared to controls and are associated with cardiac chamber size and function and clinical outcome. Previous studies have shown associations between these measures and clinical events such as arrhythmias, LV systolic and diastolic dysfunction and death, though with some mixed results. Therefore, strain and fibrosis both appear to demonstrate different myocardial characteristics that may both play a role in the natural history of rTOF. This study explored the relationship between fibrosis and strain quantified from the same imaging examination. It included a wide range of strain parameters and found no association between these two types of metrics. Our results differ from previous investigators who found that T1-derived markers for myocardial fibrosis in rTOF patients were moderately related to peak LV radial strain and weakly associated to circumferential strain. Interestingly, that study was performed in a younger population than ours (mean age 26 ± 11 years) who had a mean lower LV-ECV overall (24.5 ± 5.1). The varying findings may also reflect different strain analysis algorithms inherent in different commercially available analysis modules. Conclusion: While both LV strain abnormalities and fibrosis are present in rTOF, they are associated with different types of clinical outcome, and not to each other. The findings suggest that these measures reflect different long-term adverse adaptations to abnormal hemodynamics. Limitations: Strain quantification methods and algorithms differ between software vendors, and strain values between echo and CMR are not comparable. The study is small with low number of outcomes. A larger cohort would allow stronger confirmation of the findings. Multivariate regression was limited given the low number of clinical outcomes.

Comparison of risk stratification models for pregnancy in congenital heart disease View Article Denayer N, Troost E, Santens B, De Meester P, Roggen L, Moons P, Van Calsteren K, Budts W, Van De Bruaene A. Int J Cardiol. 2020 Sep 12:S0167-5273(20)33814-6. doi: 10.1016/j.ijcard.2020.09.033. Online ahead of print. PMID: 32931856 Take Home Points: There are several risk stratification tools which are utilised to ‘predict’ adverse outcomes in women with congenital heart disease who become pregnant. There are 4 commonly employed maternal risk predictive tools – CARPREG, CARPREG II, ZAHARA and the modified WHO score. This study randomly selected 100 women and for each woman, the 4 risk prediction tools were calculated and summarised in a weighted average risk for each stratification model. To evaluate accuracy of each model, the weighted average risk was plotted against the actual observed number of “cardiac events” as defined in the respective risk models. Maternal adverse events occurred in 8% of the study population – all in patients with at least moderately complex CHD. All the risk models over-estimated maternal cardiac risk but in this selected cohort, the ZAHARA risk model appeared to be a closer reflection of maternal risk. Commentary from Dr. Damien Cullington (Liverpool, UK), section editor of ACHD Journal Watch:  Neil’s Bohr rightly pointed out: “Prediction is very difficult, especially if it’s about the future” and predicting risks to women with CHD during pregnancy is no different. The CARPREG, CARPREG II, ZAHARA and modified WHO (mWHO) score are the main risk predictive scores employed to estimate risk in pregnant women with CHD – the most recently updated ESC guidelines for the management of cardiovascular disorders during pregnancy advocate the use of the mWHO score. Head-to-head comparison is challenging “since the different models have been constructed in different patient populations with different outcome measures”. This study sought to compare the 4 scores against each other to assess which predicts outcome best. The characteristics of the patient cohort (n=100) are shown in Table 1. Over half of patients were primigravida (n=52) and the mean maternal age was 30.4 ± 3.7 yrs. 98% had a biventricular circulation. The four commonest CHD conditions were VSD (n=34), coarctation (n=16), TOF (n=15) and ASD (n=14). Pre-pregnancy, 97% had no symptoms of heart failure. Only 15% of the cohort were taking medication pre-pregnancy. Outcomes The actual rate of maternal cardiac complications was 8% - (Tables 2a and 2b). For each of the 4 models, a composite risk was calculated. The predictive accuracy for each risk model is shown in Table 3. There was one sudden cardiac death in a patient with Marfan syndrome 4 days post-partum but aside from this case, all CV complications occurred in patients with at least moderate complexity CHD – (4 TOF, 2 atrial switch and 1 Fontan). No complications were seen in patients with simple CHD lesions. Conclusions All models tended to over-estimate risk but ZAHARA was the closest in making an accurate prediction of CV event for this selected dataset. Work continues to refine how we predict risk. The authors suggest that work should also be focused on developing a risk score for patients referred and managed in cardio-obstetric centres.  

Outcomes of heart transplantation in adult congenital heart disease with prior intracardiac repair View Article Kainuma A, Sanchez J, Ning Y, Kurlansky PA, Axsom K, Farr M, Sayer G, Uriel N, Takayama H, Naka Y, Takeda K. Ann Thorac Surg. 2020 Sep 16:S0003-4975(20)31478-8. doi: 10.1016/j.athoracsur.2020.06.116. Online ahead of print. PMID: 32949612 Take Home Points: Operative risk in orthotopic heart transplantation is higher in ACHD patients with prior intracardiac repair as compared to propensity matched non-ACHD patients for both: 30-day mortality (8.2% vs. 3.9%, p=0.004) perioperative need of dialysis (22.7% vs. 13.3%, p<0.001) 10-year survival, however, is equivalent (ACHD 66.0% vs. control 64.1%, log-rank p=0.353) This data supports ACHD patients being listing for heart transplantation. Earlier listing of ACHD patients prior to the onset of end-organ dysfunction, and detailed preoperative planning with modern techniques including 3D modelling, may help reduce early surgical mortality. Commentary by Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch:  The proportion of cardiac transplants performed in ACHD patients remains low, despite a greater number requiring such intervention as survival improves and more patients face end stage heart failure. Data from earlier this century has demonstrated increased operative mortality, however more contemporary outcomes are lacking. This current paper is a retrospective analysis of ACHD patients with prior intracardiac repair undergoing orthotopic heart transplantation (OHT) between 2008 – 2019 using the United Network for Organ Sharing database. Adult (age > 17) cardiac transplant recipients who had a history of prior sternotomy were divided into ACHD and non-ACHD (control) groups. 792 ACHD and 8385 non-ACHD patients were included for propensity score matching. Clinical (body mass index, diabetes, smoking, history of malignancy, history of cerebrovascular disease, creatinine, dialysis, total bilirubin, need for transfusion, extracorporeal membrane oxygenation, intra-aortic balloon pump, ventricular assist device, total times on waiting list, ventilator dependent, inotrope dependent, pulmonary capillary wedge pressure, ischemic time, functional status, intensive care unit stay) and demographic (age, gender) characteristics were used for propensity scoring. ACHD and control groups were matched 1:1; 486 (5.8%) cases in control and 486 (61.4%) in ACHD were matched successfully. Table 1 shows ACHD and non-ACHD recipient group characteristics, before propensity score matching. At the time of transplant ACHD patients were younger, had a higher proportion of females, a higher total bilirubin at transplant, had spent more time on the waiting list, and were more inotrope dependent. Table 2 illustrates 30-day post-transplant outcomes for ACHD and non-ACHD recipients after propensity score matching. ACHD patients had an increased need of dialysis, longer length of stay, and greater 30-day mortality. Risk factors for 30-day mortality in the ACHD group were BMI ( 25 kg/m2), history of cerebrovascular disease, dialysis after listing, total bilirubin ( 1.2 mg/dl), ischaemic time ( 4 hours), and donor age ( 50 years). The need for post-transplant dialysis had a profound impact on 10-year mortality in both ACHD (70.1% vs 45.1%, p<0.001) and non-ACHD (60.0% vs 28.4%, p<0.001) groups. Findings from the current study again identify higher operative mortality. Likely explanations for this include the complex anatomical variation in ACHD patients, multiple prior palliative or corrective surgeries, and extensive reconstruction requirements with resultant longer ischemic time and increased bleeding risk. The authors found pretransplant end-organ dysfunction and longer ischemic times were independent predictors of mortality. Earlier listing of ACHD patients prior to the onset of end-organ dysfunction, and detailed preoperative planning with modern techniques including 3D modelling may be beneficial.

Neurological complications in aortic coarctation: Results of a Nationwide analysis based on 11,907 patients View Article Trenk L, Lammers AE, Radke R, Baumgartner H, Wort SJ, Gatzoulis MA, Diller GP, Kempny A. Int J Cardiol. 2020 Aug 14:S0167-5273(20)33568-3. doi: 10.1016/j.ijcard.2020.08.041. Online ahead of print. PMID: 32798628 Take Home Points: In patients presenting for coarctation repair, the rate of spinal injury at the time of primary repair is low – 0.05-0.2% Patients with coarctation have a reduced survival rate compared to the general population Ongoing neurological complications, mainly in the form of subarachnoid bleeding and ischemic strokes occur in patients with repaired coarctation of the aorta Many patients had, at last follow-up, traditional risk factors for atherosclerosis Almost 25% had hypertension at last visit Subarachnoid bleeds occurred at a median age of 28.6 years Ischemic strokes displayed a bimodal peak with the median adult age 56.1 years The one-year mortality after a subarachnoid bleed was 16.2 % and post an ischemic infarct was 20%. Arterial hypertension (OR 3.75) was an independent risk factor for subarachnoid bleeding and both arterial hypertension (OR 4.10) and smoking (OR 13.46) emerged as independent risk factors for ischemic infarcts. This study findings emphasize the need for diligent ongoing care and control of risk factors for patients with repaired coarctation of the aorta Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch:  Coarctation of the aorta represent 6-8% of congenital heart disease malformations. The timing and mode of clinical presentation depends largely on the severity of the lesion. Neurological complications following surgical or percutaneous have been reported. In this United Kingdom, nationwide retrospective study, the socio-demographic, clinical and surgical data of all patients being hospitalized with a diagnosis of coarctation of the aorta between 1997 and 2015 were reviewed. Data was obtained from the National Health Service Hospital Episode Statistics Database (HES, NHS Digital) using the appropriate search ICD-10 coding for the various diagnoses of interest. A total of 11 907 patients with coarctation of the aorta were identified. Almost 60% were male. During the period of 1997-2015, 8456 surgical or interventional procedures were performed. For the surgical procedure group, mortality on the same admission amounted to 2.5% (150 of 5905 surgeries) and the intervention mortality 0.3% (8 of 2550 interventions). The first operation was an end-to-end anastomosis in 56.9% of cases (n=2737), a subclavian flap in 12.5% (n=603) and a patch graft in 9.7%(n=469). Four hundred and seventy-two (9.8%) had percutaneous intervention as a first procedure. Neurological complications related to surgical or percutaneous intervention occurred in 10 patients (0.1% of all procedures): eight hemiplegia, one paralytic syndrome and one upper limb monoplegia. In those patients born after 1997, the neurological complication rate was 0.05% for surgeries and 0.21% for percutaneous interventions. For those with a revision, the complication rate was slightly higher – for a first revision, the surgical neurological complication rate was 0.24%. Cardiovascular risk factors in this cohort included: arteriosclerotic disease (3.3%), current smoking (5.3%), diabetes (1.7%), hyperlipidemia (3.5%), obesity (1.9%), renal dysfunction 4.3%), SVT’s (4.6%), and arterial hypertension in 24.5%.  Subarachnoid bleeds (n=37) and cerebral infarction (lnn= late neurological complications) were seen in 225 patients over a follow-up period of 146 295 patient-years at a rate of 0.15% per year. Subarachnoid bleeds occurred in 37 patients; the median age was 28.7 years (20.2-44.5 years). All but one had no history of a previously diagnosed cerebral aneurysm. 10.8% died on the same admission and the one year mortality in this complication was 16.2%. When matched for age and gender with those coarctation patients who did not experience a bleed, only arterial hypertension was an independent risk factor for bleeding (OR 3.75, 95% CI 1.25-11.3, p=0.019). Ischemic stroke occurred in 188 patients with a bimodal age distribution (peak in 1st year of life and then again over age 60). The median age of the adult population was 56.1 years. Index admission mortality was 6.9% and the one year mortality 20%. On multivariate analysis, arterial hypertension (OR 4.10, 95% CI 1.55-10.79, p=0.004) and smoking (OR 13.46 ,95% CI 1.57-115.35), p=0.018) remained adverse risk factors for ischemic stroke. The Kaplan -Meier curves show the greatest mortality rates are in the first year post-event but it continues to drop off in both cohorts.

Risk Factors for Failed Fontan Procedure Following Stage 2 Palliation View Article Ono M, Burri M, Mayr B, Anderl L, Strbad M, Cleuziou J, Hager A, Hörer J, Lange R. Ann Thorac Surg. 2020 Aug 20:S0003-4975(20)31323-0. doi: 10.1016/j.athoracsur.2020.06.030. Online ahead of print. PMID: 32828751 Take Home Points: The outcome of Glenn shunt is generally good with the majority of the patients proceeding to Fontan completion. Hypoplastic left heart syndrome, unbalanced atrioventricular septal defect, high pulmonary artery pressure and a reduced ventricular function at the time of superior cavopulmonary shunt were identified as risk factors for failure to successfully complete the Fontan procedure. Atrio-ventricular valve regurgitation, despite associated with unbalanced atrioventricular septal defect and a reduced ventricular function, is not associated with failure to successful Fontan completion. Commentary from Dr. MC Leong (Kuala Lumpur, Malaysia), section editor of ACHD Journal Watch:  While the outcomes of total cavopulmonary connections are widely reported, there is a paucity of outcome data on the second stage single ventricular palliation. Such palliation includes fashioning of a superior cavopulmonary connection (bidirectional Glenn shunt) or in some centers, a hemi-Fontan procedure. This study aimed at analyzing the outcomes of all single ventricles which have undergone the second stage palliation and identifying the factors that are associated with death or failure to progress to a Fontan completion. This is a single center, retrospective review of a database of 525 patients with single ventricles who underwent bidirectional Glenn shunt at the German Heart Center in Munich between January 1998 and December 2018. Baseline characteristics of the patient population were as tabulated in Table 1.  The median time of Glenn shunt was 4.7 month (IQR, 3.0-7.4) while the median weight was 5.6 kg (IQR, 4.7-7.0). The perioperative data was summarized in Table 2. Of note is the patients with unbalanced atrioventricular septal defect were at greatest risk of early death (10.0%), whereas early death occurred in hypoplastic left heart syndrome patients was only 3.6% of all patients. Interestingly, in the early postoperative period, 55 patients required cardiac catheterization because of severe cyanosis and subsequent surgical/catheter interventions. The etiology for cyanosis were Glenn pathway stenosis (n=31), veno-venous collaterals (n=11), cavopulmonary pathway thrombus (n=4), and undetermined (n=9). In all 9 patients whose etiology was undetermined, placement of a systemic to the branch pulmonary shunt and performing a pulmonary septation to create unilateral Glenn shunt to the contralateral pulmonary artery was performed, out of which, five patients died postoperatively. Of the 514 early survivors, 15 patients were lost to follow-up after hospital discharge (Figure 1). The median follow-up period was 3.4 years (IQR, 1.5-8.7) for the remaining 499 patients. A competitive risk analysis was performed onto patients who had Fontan completion, death, and 'being alive without Fontan'. Patients who failed to achieve successful Fontan completion was defined as those who died before Fontan completion; patients who were considered unsuitable for Fontan completion; and patients who died early after Fontan completion (death within 30 days), because they failed to establish successful Fontan circulation. The cumulative incidence of Fontan completion (83.9% at 3 years and 87.1% at 5 years), the cumulative incidence of death (10.4% at 3 years and 10.7% at 5 years), and survival without Fontan completion (5.7% at 3 years and 2.2% at 5 years) are shown in Figure 2. Freedom from mortality before the Fontan procedure, unsuitability for the Fontan procedure, and early mortality after the Fontan procedure at 1, 2, and 3 years were 91.9%, 87.3%, and 86.1%, respectively. ] Figure 2. Multivariate analysis showed that hypoplastic left heart syndrome, unbalanced atrio-ventricular septal defect (AVSD), high pulmonary artery pressure and a reduced ventricular function at Glenn shunt were associated with failure to achieve an eventual successful Fontan completion. Although significant atrioventricular valve regurgitation requiring intervention was not identified as an independent risk in multivariate model, the incidence of atrioventricular valve intervention was significantly higher in patients with unbalanced AVSD (26.7% vs. 10.3%, p=0.006) and in patients with reduced ventricular function (26.1% vs. 9.8%, p=0.001). Apart from the conclusions that the study came to, this study also raised two important issues. (1) The timing of Glenn shunt needs to be balanced between overloading the ventricle with a systemic to pulmonary artery shunt and the need to grow the pulmonary artery to a caliber suitable for the eventual Fontan completion. In this study, the Glenn shunts were performed relatively early at the median age of 4.7 month (IQR, 3.0-7.4). Meanwhile, pulmonary artery reconstruction was required in 189 (36%) patients during Glenn shunt. As many as 129 (25%) patients required bilateral branch pulmonary arteries repair. It is possible that many of them required pulmonary artery intervention to enlarge the pulmonary arteries, which may alter the dimension of the pulmonary artery outside of the lungs but not the pulmonary arterial tree within the lungs. The calibers of the pulmonary arteries are not only anatomical but also physiologically linked to the long-term outcome of the eventual Fontan procedure; (2) If a patient presents with unexplained cyanosis post Glenn shunt, the prognosis is poor. In this study, 9 patients had no recognizable anatomic defect, and hypoxemia was perceived to be secondary to inadequate pulmonary blood flow. Implanting an additional systemic to pulmonary shunt and pulmonary artery septation which supposedly meant to improve oxygenation, unfortunately, yielded in 5 deaths. These patients may perhaps benefit from other treatment options.    

Echocardiographic predictors of recoarctation following surgical repair - a Swedish national study View Article Weismann CG, Grell BS, Odermarsky M, Mellander M, Liuba P. Ann Thorac Surg. 2020 Jun 30:S0003-4975(20)31030-4. doi: 10.1016/j.athoracsur.2020.05.062. Online ahead of print. PMID: 32619613 Take Home Points: Post-operative pre-discharge echocardiography dimensions predicted risk for re-coarctation. Both the dimension-based and Z-score based algorithms predicted re-coarctation risk accurately. Patients with an aortic isthmus Z-score of < -2.8 and a weight of < 4.4kg at time of surgery or a proximal aortic arch Z score < -2.8 were deemed high risk and at greatest risk for re-coarctation. Prudent regular follow-up in these patients were advised. In 75% of cases, re-coarctation occurred within the first 6 months post-surgery. Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch:   Coarctation of the aorta is frequently repaired surgically in the neonatal period. The surgical procedure performed depends on the presence and degree of arch hypoplasia as well as the associated anomalies. A widely variable rate of  re-coarctation is reported. Previous factors associated with an increased risk included:  infants <2kg, pre-operative aortic arch hypoplasia, lower ascending aortic root dimensions, BP gradient at discharge of >13mmHg and age of initial repair < 1-3 months. There is conflicting evidence regarding the type of repair on re-coarctation rates. This retrospective Swedish study aimed to identify post-operative pre-discharge echocardiography features predictive of re-coarctation.  The cohort consisted of all patients in Sweden with a biventricular circulation who underwent surgical coarctation repair between 2011 and 2017. Demographic, clinical and surgical data was collected in addition to the echocardiographic data. All echocardiograms were analysed and reported by one senior operator who was blinded to the outcomes. A total of 289 patients were identified – 8 international patients, 5 deaths and 23 with missing echo information were excluded. The final analysis included 253 patients with a median age of repair of 10 days and median weight 3.6 kg. An end-to-end anastomosis was done in 149 patients (59%), an end-to-side anastomosis in 52 (21%), a subclavian flap repair in 2 patients (1%), and a patch augmentation in 50 (20%). Associated simultaneous other cardiac surgery was performed in 64 (25%) of patients, with VSD being the most common associated defect. Complex associated surgery was done in an additional 30% (n=19), including arterial switch operations, Rastelli, AVSD repairs and a truncus arteriosus repair. Re-coarctation occurred in 34 patients (13%) at a median follow-up of 3.9 years. All but 2 patients had balloon angioplasty for re-coarctation. Twenty-five (74%) occurred within 6 months and 31 (91%) within one year following  surgical repair. Patients with re-coarctation were younger and had a lower birth weights and BSA at time of repair and were more likely to have patch augmentation and associated simultaneous congenital surgery for other lesions. When adjusting for associated surgery, patch augmentation did not remain as a risk factor for re-coarctation. Aortic valve dimensions but not Z scores was significantly smaller in the re-coarctation group. The re-coarctation group also had significantly smaller proximal and distal aortic arch and isthmus dimensions on pre-discharge echo. The mean gradient across the isthmus was higher in those who developed subsequent re-coarctation. Based on the aortic isthmus dimension, 3 risk categories were identified – high (<3.3mm), moderate-high (>3.3-3.7mm) and low risk (>3.7mm). In the high risk group, 67% developed re-coarctation, 32% in the moderate group and 5% in the low risk group. Using Z scores instead of dimensions resulted in a more sensitive screening algorithm. Those at greatest risk of  re-coarctation had an aortic isthmus Z score of <-2.8 and a weight of < 4.4kg. This algorithm had a sensitivity of 71% and a specificity of 92% with a positive predictive value of 59% and a negative predictive value of 95%.

Changes in REVEAL risk score in patients with pulmonary arterial hypertension treated with macitentan in clinical practice: results from the PRACMA study View Article Escribano-Subias P, López R, Almenar L, Lázaro M, Forn I, Torrent A, Blanco I, Barberà JA; PRACMA investigators. BMC Pulm Med. 2020 Jun 2;20(1):154. doi: 10.1186/s12890-020-01197-5. PMID: 32487059 Take Home Points: REVEAL = Registry to Evaluate Early and Long-Term PAH Disease Management. The PRACMA study is a Spanish retrospective, observational analysis of patients with pulmonary hypertension or pulmonary arterial hypertension associated with connective tissue disease or CHD. All patients were treated with macitentan for > 6 months as monotherapy or as part of combined therapy. The REVEAL risk score and risk strata were calculated at the start of macitentan treatment and > 6 months in patients with > 7 out of 12 valid REVEAL components In the final analysis, 57 patients had enough data to calculate a REVEAL score Median time of macitentan treatment was 10.5 months. The mean REVEAL score was 8.7 points at baseline and 7.2 points after > 6 month follow up. REVEAL components which significantly improved with macitentan treatment were WHO class (64% class III at initiation and 24% after > 6 months, p=0.00001); 6 minute walk test (mean change 42m, p<0.01); BNP or NTproBNP (mean change of -157pg/ml and -530 pg./ml, respectively, p<005) and pulmonary vascular resistance (mean change -3.4 WU, p<0.01). Only 12% of patients (n=10) had ACHD. Commentary from Dr. Damien Cullington (Liverpool, UK), section editor of ACHD Journal Watch:  The PRACMA study is a Spanish observational dataset of patients with inherited and acquired pulmonary hypertension (PH) – only 12% of patients in this study had congenital heart disease. 28 PH centres in Spain contributed data between Sept 2016-Sept 2017. This primary aim was to measure change in REVEAL risk score in patients with PH who were started on macitentan treatment. The REVEAL score (originally published in 2012) is calculated from 12 variables (Figure 1). It is generically used  as a composite measure of disease stability/improvement/deterioration in patients with PH. In the analysis, ‘incident’ patients were defined as those diagnosed < 6 months prior to starting macitentan. ‘Prevalent’ patients were those diagnosed with PH > 6 months before starting macitentan. The REVEAL risk score was calculated at baseline and at > 6 month time points. Patients were selected with at least 7/12 valid components. Although 88 patients were originally assessed for eligibility for this analysis, only 57 patients of the original group had enough data points to calculate a REVEAL score. The demographics of the baseline dataset are shown in Table 1. Results At baseline, the mean REVEAL score was 8.7 points, and at > 6 month time point, had decreased to 7.2 points – the mean change in score was -1.4 (-2.0, -0.9 ) points (p<00001). In the ‘incident’ patient group, the REVEAL score improved in 61% versus, in the ‘prevalent’ group, 56% of patients’ REVEAL scores improved. A more detailed analysis of the change in REVEAL risk score within incident/prevalent groups and according to their mono or combination therapy with macitentan is shown in Table 2. The REVEAL score improved in 57% of patients - 26% had no change and it increased in 16% (Figure 2). The mean effect of Macitentan in a aetiologically heterogenous cohort of patients with PH is an improvement functional capacity and objective measures such as 6MWT, natriuretic peptide levels and PVR in patients with PH who are new to treatment (‘incident’) or who are known to have PH and macitentan is introduced either as an add on agent or new treatment (Table 3). Table 3. Changes in individual REVEAL components at > 6-month time point Limitations This observational study had very low numbers of ACHD patients and we should not be tempted to draw generic conclusions to then generically treat ACHD-PH patients with macitentan. The MAESTRO study in 2019, which enrolled patients with Eisenmenger syndrome, showed that macitentan had no statistically significant benefit compared to placebo in terms of improving exercise capacity over a 4 month follow up. Further research and longer term follow up will be helpful to guide longer term treatment decisions. Conclusions Macitentan is no doubt useful agent in the therapeutic armamentarium to selectively treat patients with PH. The PRACMA study shows that therapeutic improvements are possible in patients either as a mono-agent treatment or as part of a combined regimen – improvements are seen in REVEAL score across all severities of PH. This was a relatively small study group with mixed aetiology of PH and a very small number of patients with ACHD. Extrapolating these results to specifically guide treatment choice in our patient group requires caution and comparative review of other larger studies.    

Modified Ventricular Global Function Index Correlates With Exercise Capacity in Repaired Tetralogy of Fallot View Article Ta HT, Critser PJ, Alsaied T, Germann J, Powell AW, Redington AN, Tretter JT. J Am Heart Assoc. 2020 Jul 21;9(14):e016308. doi: 10.1161/JAHA.120.016308. Epub 2020 Jul 7. PMID: 32633206 Take Home Points: Establishing RV effective Global function index (eGFI) as a novel and more robust predictor of hard clinical end points in patients with rTOF. RV eGFI may be a more comprehensive marker of poor myocardial health and exercise intolerance than currently used indices. The association between reduced RV eGFI with impaired exercise performance establishes biologic plausibility which may form the basis of larger scale studies assessing the value of preoperative eGFI in timing of PVR , Commentary by Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch: Despite improvements in early survival in rTOF, there continues to be a high incidence of impaired functional status, heart failure, arrhythmias, and death, which often occur in the setting of RV dysfunction with either volume- and/or pressure-loading of the RV. To improve these outcomes, PVR is often performed in symptomatic patients or asymptomatic patients who have significant RV dilation or RV systolic dysfunction. However, using current guidelines, PVR does not lead to survival benefit or reduce other major adverse postoperative events. Recent investigations have shown that preoperative RV hypertrophy and dysfunction, not ventricular volumes, particularly in patients approaching their 3rd decade of life, are associated with worse outcomes—highlighting the importance of maintaining myocardial health. CMR derived ventricular global function index (GFI), has been proposed as a better marker of ventricular function because it incorporates structural, mechanical, and preload indices. Establishing eGFI, or the lesion-specific modification described in the current study, as a novel and more robust predictor of hard clinical end points in patients with rTOF will require prospective testing in a large, likely multi-center, study after biologic plausibility has been established. To do the latter, this "proof-of-principle" study leverages the known association between impaired exercise capacity as assessed by cardiopulmonary exercise testing (CPET) and poorer outcomes in patients with rTOF. Methods 75 patients with rTOF who underwent CMR were identified. Clinical variables were recorded and biventricular GFI calculated. RV effective GFI (eGFI) was derived by incorporating effective stroke volume. 35 pediatric patients were matched with 29 age-matched healthy controls. 25 patients completed cardiopulmonary exercise tests within 6 months of CMR. RV effective Global function index Results: Median age at CMR was 20 years (interquartile range, 13–28). Pediatric rTOF patients had lower RV eGFI (P < 0.001), RV-EF (P=0.002), but higher indexed RV EDV and ESV (P < 0.001, P < 0.001) compared with controls. Univariate analysis demonstrated a correlation between indexed peak VO2 with RV eGFI (R2=0.32, P=0.004), but with neither RVGFI, RV ejection fraction, indexed RV volumes nor RV mass.  RV eGFI remained significantly associated with indexed peak VO2 during multivariable modeling Discussion This study demonstrates that the novel modification of the GFI, incorporating effective stroke volume rather than total stroke volume (eGFI), may be a useful non-invasive method to assess myocardial health in patients with rTOF. Reduced RV eGFI was associated with impaired exercise capacity in patients with rTOF, while RV EF, RV GFI using the total RV stroke volume, indexed RV volumes and mass were not. While preoperative RV volumes and EF are the most commonly used indices to determine the need for PVR in asymptomatic patients, their optimal thresholds continue to be debated, and they do not appear to be related to hard clinical end points such as death, heart failure or ventricular tachycardia after PVR. Patients had significantly lower RV function as measured by both RV EF and RV eGFI values compared with controls. Importantly, in multivariate analysis, RV eGFI but neither RV GFI, RV EF, nor RV volume indices was correlated with exercise performance. Those finding of an association between reduced RV eGFI with impaired exercise performance is important for 2 reasons—first, impaired exercise performance correlates with poor outcomes; and second, this establishes biologic plausibility may form the basis of larger scale studies of the value of preoperative GFI in defining potential thresholds for PVR and predicting outcomes thereafter. This data disagrees somewhat with the findings of Rashid and colleagues who evaluated a larger cohort of similarly aged patients with rTOF who underwent CPET and CMR. Similar to current findings, RV size did not correlate with peak VO2 in their study, but indices of RV systolic function including RV EF and stroke volume index did correlate significantly. Of note, patients in current had lower indexed RV volumes and higher RV EF when compared with the study by Rashid and are consistent with a study in younger patients with rTOF that demonstrated only a weak association between RV EF and exercise performance. Limitations There were several limitations to this study including its retrospective nature from a single center. Conclusions Patients with rTOF had lower RV eGFI compared with age-matched controls. Reduced RV eGFI was associated with reduced exercise capacity, while RV EF, indexed RV volumes, and mass were not. This supports RV eGFI as a potentially valuable non-invasive marker of cardiac function in the rTOF population.

Predicting the Risk of Adverse Events in Pregnant Women With Congenital Heart Disease View Article Chu R, Chen W, Song G, Yao S, Xie L, Song L, Zhang Y, Chen L, Zhang X, Ma Y, Luo X, Liu Y, Sun P, Zhang S, Fang Y, Dong T, Zhang Q, Peng J, Zhang L, Wei Y, Zhang W, Su X, Qiao X, Song K, Yang X, Kong B. J Am Heart Assoc. 2020 Jul 21;9(14):e016371. doi: 10.1161/JAHA.120.016371. Epub 2020 Jul 14. PMID: 32662348 Commentary from Dr. Helen Parry (Leeds UK), section editor of ACHD Journal Watch: The aim of this paper was to produce a model to improve the accuracy of risk assessment in pregnant women with congenital heart disease. Method A total of 318 pregnancies in women with congenital heart disease were included in the study.  These were divided into a development cohort, used to create the risk model (n=213) and validation cohort, used to test whether the models were accurate (n=105).  Models were created to assess both maternal risk and neonatal risk to the baby.  Patients were excluded if maternal death occurred prior to delivery or if spontaneous abortion occurred prior to 28 weeks gestation. A regression analysis model was used to identify independent risk factors for poor outcome.  Variables were regarded as significant if the p-value was <0.10.  Once the model was established, this was tested on the validation cohort and assess for positive predictive value, negative predictive value, sensitivity and specificity. Results Ten per cent of patients gave birth vaginally.  Forty-one (12.9%) of the women experienced adverse maternal events whilst 93 (29.3%) of neonates experienced adverse events.  A number of risk factors for worse outcomes for the mother or neonate were identified including pulmonary hypertension, Eisenmenger’s syndrome, higher NYHA functional class, left heart obstruction, significant impairment in left ventricular function, oxygen saturations and sinus tachycardia. There were 13 maternal deaths, 2 of which were due to heart failure developing after Caesarean section to remove the fetus following intrauterine death. Conclusion The risk models will help guide clinicians when looking after patients with congenital heart disease. Critique Positive aspects: N=318 is a reasonable sample size, especially in a study examining patients with congenital heart disease, which are notorious for small samples. There was an indication of sinus tachycardia being a risk factor for adverse outcome, which I don’t believe is quite so widely recognised as the other risk factors identified. Negative aspects: Although the overall sample size is reasonable, there are actually very small numbers of patients in some of the subgroups. For example, there were only 8 patients with Eisenmenger’s syndrome in the validation cohort and it is difficult to conclude that the model is valid for this group with a sample of this size.  It is recognised that studying large numbers of patients with Eisenmenger’s syndrome who become pregnant is incredibly challenging given that these patients would generally be advised not to conceive as they are too high risk.  It raises the possibility that this is actually a self-selecting group of patients with relatively good physiology within the Eisenmenger’s group; otherwise, they would be unlikely to carry the pregnancy beyond the 28 week gestation period required for the inclusion criteria. The lack of inclusion of pregnancies that did not continue to the 28 week stage means the data cannot be used when counselling patients regarding risk of early miscarriage and is likely to exclude some of the highest risk mothers. The same is true of exclusion if maternal death occurred before delivery. The cut off value for statistical significance was p<0.10. This is unusually high; most papers do not regard a p-value of >0.05 as statistically significant. It is unclear whether the conclusions actually add anything to the assessment and management of patients with congenital heart disease who become pregnant. The risk factors identified are in keeping with those categorised under the modified WHO categorization and there are other obstetric scoring systems that already take these factors into account. It is difficult to see how management improves as a result of the risk scores generated as we already knew about the risk factors and the paper provides no information on whether intervention reduces risk. Does beta-blockade in patients with sinus tachycardia reduce their risk or is it detrimental as it impedes an appropriate response to reduced cardiac output? Of note, it is interesting there is such a low proportion of vaginal deliveries. In our centre, vaginal delivery is preferred if at all possible.

Echocardiographic Identification of Pulmonary Artery Flow Reversal: An Indicator of Adverse Outcomes in Single Ventricle Physiology. View Article Spearman AD, Ginde S, Goot BH, Schaal AM, Feng M, Pan AY, Frommelt MA, Frommelt PC. Pediatr Cardiol. 2020 Jul 24. doi: 10.1007/s00246-020-02421-z. Online ahead of print. PMID: 32710282 Take Home Points: Pulmonary artery flow reversal in patients with palliated single ventricular physiology is the continuous reversal of blood flow from the pulmonary artery into the contralateral pulmonary artery. Compared to patient without pulmonary artery flow reversal, patients with such physiology were associated with: Longer length of stay post superior cavopulmonary connection surgery; Less probability of eventual Fontan completion; and Lower 10-year transplant-free survival Commentary from Dr. MC Leong (Kuala Lumpur), section editor of ACHD Journal Watch:  In the absence of a forward pulmonary arterial flow, palliated single ventricle, either in the form of a superior cavopulmonary connection (Glenn shunt) or a total cavopulmonary connection (Fontan), is non-pulsatile and unidirectional, i.e. from the cavopulmonary shunt into the pulmonary arteries. Pulmonary artery flow reversal is the continuous reversal of blood flow from the pulmonary artery into the contralateral pulmonary artery as detected by Color Doppler (Figure 1). The authors retrospectively reviewed all patients seen at their centre from 1999-2019 with single ventricle congenital heart disease and superior cavopulmonary connection and compared the clinical outcomes between those with reversal of blood flow and those without (Table 1). A total of 560 patients (21, 3.8% with pulmonary artery flow reversal) were recruited. Over the median follow up period of 8.2 years (median 5.3[range 0.2-20.2] years for the pulmonary artery reversal group and median 8.2 years [range <0.1-20.5] years for the non-reversal group, patients with flow pulmonary artery reversal was associated with a poorer outcome. They are associated with a poorer 10-year transplant-free survival, a longer post-operative length of stay (Figure 2-3). However, the 10-year overall survival and the post-operative length of Fontan stay were comparable to those of the non-reversal group. Of patients older than 2 years old who had pulmonary artery flow reversal, only 4 out of 11 (36.4%) proceeded to Fontan completion. They either died (n=4), underwent orthotopic heart transplant (n=1) or remain with superior cavopulmonary connection physiology (n=2). Heterotaxy was not found to be associated with pulmonary artery flow reversal. In the article, the authors mentioned that they detected pulsatile retrograde flow into the pulmonary artery suggesting the presence of aorto-pulmonary collateral arteries. The authors demonstrated that patients who had pulmonary artery flow reversal had a poorer clinical outcome. The study could pave the way for a new noninvasive indicator to predict patients with poorer long-term prognosis and aid in decision making and clinical management. Pulmonary artery flow reversal is easy to diagnose and is cost-efficient. The logic behind its occurrence is plausible. Ipsilateral pulmonary artery which is high in pressure or obstructed tended to receive less pulmonary blood flow and hence blood tends flow to the contralateral pulmonary artery. Unfortunately, the incidence of pulmonary artery flow reversal is not high, the study may not have the power to associate it with poorer long term outcomes convincingly. We may have to await more studies before this concept translates into a solid evidence.

Asschenfeldt B, Evald L, Heiberg J, Salvig C, Østergaard L, Dalby RB, Eskildsen SF, Hjortdal VE.J Am Heart Assoc. 2020 Jun 2;9(11):e015843. doi: 10.1161/JAHA.120.015843. Epub 2020 May 19.PMID: 32427039 Free article.   Abstract Background Neurodevelopmental impairments are common in survivors of complex congenital heart defects (CHD). We report neuropsychological and brain imaging assessments in adults operated for isolated septal defects. Methods and Results Patients (mean age 25.6 yrs) who underwent childhood surgery for isolated atrial septal defect (n=34) or ventricular septal defect (n=32), and healthy matched peers (n=40), underwent a standard battery of neuropsychological tests and a 3.0T brain magnetic resonance imaging scan. Patient intelligence was affected with lower scores on Full-Scale intelligence quotient (P<0.001), Verbal Comprehension (P<0.001), Perceptual Reasoning (P=0.007), and Working Memory (P<0.001) compared with controls. Also, the CHD group had poorer visuospatial abilities (Immediate Recall, P=0.033; Delayed Recall, P=0.018), verbal memory (Trial 1, P=0.015; Total Learning, P<0.001; Delayed Recall, P=0.007), executive function (Executive Composite Score, P<0.001), and social recognition (Reading the Mind in the Eyes Test, P=0.002) compared with controls. Self-reported levels of executive dysfunction, attention deficits and hyperactivity behavior, and social cognition dysfunction were higher in the CHD group compared with population means and controls. We found similar global and regional morphometric brain volumes and a similar frequency of brain magnetic resonance imaging abnormalities in the 2 groups. The CHD group had a high occurrence of psychiatric disease and a larger need for special teaching during school age. Conclusions Children operated for simple CHD demonstrate poorer neurodevelopmental outcomes in adulthood when compared with healthy controls and expected population means. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03871881.   Source:https://pubmed.ncbi.nlm.nih.gov/32427039/   

Hoashi T, Shimada M, Imai K, Komori M, Kurosaki K, Ohuchi H, Ichikawa H.Eur J Cardiothorac Surg. 2020 May 1;57(5):951-957. doi: 10.1093/ejcts/ezz355.PMID: 31883324   Abstract Objectives: The aim of this study was to identify the long-term therapeutic effect of total cavopulmonary connection (TCPC) conversion with an extracardiac conduit. Methods: Between 1991 and 2014, 36 patients underwent TCPC conversion with an extracardiac conduit. Half of these patients were diagnosed with tricuspid atresia or its variant. The left ventricle was dominant in 26 patients (72.2%). Median age at conversion and interval from initial Fontan operation to conversion were 24.1 years (interquartile range 18.9-29.2) and 17.8 years (15.4-20.9), respectively. Surgical cryoablation was concomitantly performed in 32 patients (88.9%). Cardiac catheter examination was performed preoperatively (36 patients, 100%) and at 1 year (31 patients, 86%), 5 years (25 patients, 69%) and 10 years (13 patients, 36%) after TCPC conversion. Symptom-limited treadmill exercise with expired gas analysis was performed preoperatively (32 patients, 88.9%) and at 1 year (27 patients, 75.0%), 5 years (20 patients, 55.6%) and 10 years (12 patients, 33.3%) after conversion. Results: All patients received follow-up; the mean follow-up period was 8.2 ± 4.8 years. Actuarial survival rate, protein-losing enteropathy-free survival rate and rate of survival with sinus rhythm maintenance at 10 years were 79.2%, 67.8% and 48.5%, respectively. The survival curve declined steeply when the duration of Fontan circulation exceeded 25 years. New cases of protein-losing enteropathy developed postoperatively in 2 patients. Permanent pacemakers were implanted in 12 patients (33%), but atrial tachyarrhythmia was not sustained in any of the remaining patients. Pulmonary arterial pressure (11.0 ± 3.1 to 9.5 ± 3.6 mmHg, P = 0.003), pulmonary vascular resistance (2.1 ± 0.7 to 1.3 ± 0.5 WU/m2, P < 0.0001) and cardiac index (2.0 ± 0.3 to 2.9 ± 0.6 l/min/m2, P < 0.0001) significantly improved from preoperative evaluation to 1 year after the conversion, and these improvements were maintained during the entire follow-up period. Peak oxygen uptake remained unchanged from the preoperative evaluation (49.7 ± 11.5% predicted) to 1 year (52.5 ± 12.0%), 5 years (56.2 ± 9.6%) and 10 years (51.2 ± 9.4%) after conversion (P = 0.19). Conclusions: Owing to its anti-arrhythmic effect and Fontan pathway recruitment effect, TCPC conversion with an extracardiac conduit prevented the natural decline of exercise tolerance that is seen in classic Fontan patients.   Source: https://pubmed.ncbi.nlm.nih.gov/31883324/   

Broda CR, Castellanos DA, Pham TDN, Dreyer WJ, Opina AD, Ermis PR, Lam WW.World J Pediatr Congenit Heart Surg. 2020 May;11(3):364-365. doi: 10.1177/2150135119896557.PMID: 32294000   Abstract Fontan-associated protein-losing enteropathy is difficult to treat and associated with poor prognosis. Cardiac rehabilitation and exercise are thought to have beneficial effects for patients with Fontan circulation. We report the case of a young adult patient palliated to Fontan circulation, with a decade-long history of symptoms related to protein-losing enteropathy. At age 23 years, he appreciated an improvement in symptoms and laboratory values after cardiac rehabilitation and prescriptive exercise.   Source: https://pubmed.ncbi.nlm.nih.gov/32294000/   

Terol C, Kamphuis VP, Hazekamp MG, Blom NA, Ten Harkel ADJ.Pediatr Cardiol. 2020 May 4. doi: 10.1007/s00246-020-02355-6. Online ahead of print.PMID: 32363435   Abstract Surgical repair of Tetralogy of Fallot (ToF) is usually performed in the first months of life with low early postoperative mortality. During long-term follow-up, however, both right (RV) and left ventricular (LV) performances may deteriorate. Tissue Doppler imaging (TDI) and speckle tracking echocardiography (ST) can unmask a diminished RV and LV performance. The objective of the current study was to assess the cardiac performance before and shortly after corrective surgery in ToF patients using conventional, TDI and ST echocardiographic techniques. Thirty-six ToF patients after surgery were included. Transthoracic echocardiography including TDI and ST techniques was performed preoperatively and at hospital discharge after surgery (10 days to 4 weeks after surgery). Median age at surgery was 7.5 months [5.5-10.9]. Regarding the LV systolic function there was a significant decrease in interventricular septum (IVS) S' at discharge as compared to preoperatively (pre IVS S' = 5.4 ± 1.4; post IVS S' = 3.9 ± 1.2; p < 0.001) and in global longitudinal peak strain (GLS) (pre = - 18.3 ± 3.4; post = - 14.2 ± 4.1; p = 0.003); but not in the fractional shortening (FS). Both conventional and TDI parameters showed a decrease in diastolic function at discharge. Tricuspid Annular Plane Systolic Excursion and RV S' were significantly lower before discharge. When assessing the RV diastolic performance, only the TDI demonstrated a RV impairment. There was a negative correlation between age at surgery and postoperative LV GLS (R = - 0.41, p = 0.031). There seems to be an impairment in left and right ventricle performance at discharge after ToF corrective surgery compared to preoperatively. This is better determined with TDI and ST strain imaging than with conventional echocardiography.   Fig. 1 Longitudinal strain of a male patient with Tetralogy of Fallot: a before surgery (GLS − 17.1%) and b before discharge after surgery (GLS − 10.8%). GLS global longitudinal peak strain   source:https://pubmed.ncbi.nlm.nih.gov/32363435/

Patel MD, Dorfman AL, Yu S, Lowery R, Mahani MG, Agarwal PP, Christensen JT, Lu JC.Pediatr Cardiol. 2020 May 4. doi: 10.1007/s00246-020-02360-9. Online ahead of print.PMID: 32367305   Abstract Patients after the Ross procedure are at risk for right (RV) and left ventricular (LV) dysfunction due to neo-aortic and pulmonary dysfunction. While neo-aortic root dilatation has been related to LV dysfunction, the potential contributions of aortic stiffness and ventricular interactions have not been evaluated. Patients status post Ross procedure up to age 18 years with cardiac magnetic resonance (CMR) exam from 2007 to 2018 were retrospectively reviewed. Aortic pulse wave velocity (PWV) was calculated from phase contrast and angiogram images. RV and LV peak global longitudinal (GLS) and circumferential strain (GCS) were measured using tissue tracking software. Multivariable regression was performed for variables associated with parameters of LV function. In 58 patients (median age 20.5 years at CMR exam), male gender, longer time since Ross procedure, aortic root dilatation, and lower RV ejection fraction (EF) were associated with decreased LV EF. There was no association with LV late gadolinium enhancement or neo-aortic or conduit regurgitation. LV GCS and GLS also correlated with RV GCS, RV GLS and PWV. In multivariable analysis, the relation of RV and LV systolic function, but not aortic measurements, remained significant. In conclusion, in long-term follow-up after pediatric Ross procedure, RV function rather than aortic root size or aortic stiffness most closely relates to LV function. Ventricular interactions may impact decision-making on timing of conduit intervention, which could differ from established criteria in populations with only aortic or pulmonary valve disease. Further study is warranted to evaluate possible association with clinical outcome.   source:https://pubmed.ncbi.nlm.nih.gov/32367305/   

Turley TN, O'Byrne MM, Kosel ML, de Andrade M, Gulati R, Hayes SN, Tweet MS, Olson TM.JAMA Cardiol. 2020 May 6:e200872. doi: 10.1001/jamacardio.2020.0872. Online ahead of print.PMID: 32374345   Abstract Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, setting, and participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main outcomes and measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.   Source: https://pubmed.ncbi.nlm.nih.gov/32374345/   

Spearman AD, Gupta A, Pan AY, Gronseth EI, Thirugnanam K, Gudausky TM, Foerster SR, Ramchandran R.Semin Thorac Cardiovasc Surg. 2020 May 7:S1043-0679(20)30053-8. doi: 10.1053/j.semtcvs.2020.03.004. Online ahead of print.PMID: 32387780   Abstract To improve our understanding of pulmonary arteriovenous malformations in univentricular congenital heart disease, our objective was to identify the effects of hepatic vein and superior vena cava constituents on lung microvascular endothelial cells independent of blood flow. Paired blood samples were collected from the hepatic vein and superior vena cava in children 0-10 years old undergoing cardiac catheterization. Isolated serum was subsequently used for in vitro endothelial cell assays. Angiogenic activity was assessed using tube formation and scratch migration. Endothelial cell survival was assessed using proliferation (BrdU incorporation, cell cycle analysis) and apoptosis (caspase 3/7 activity, Annexin-V labeling). Data were analyzed using Wilcoxon signed-rank test and repeated measures analysis. Upon incubating lung microvascular endothelial cells with 10% patient serum, hepatic vein serum increases angiogenic activity (tube formation, P = 0.04, n = 24; migration, P< 0.001, n = 18), increases proliferation (BrdU, P < 0.001, n = 32; S-phase, P = 0.04, n = 13), and decreases apoptosis (caspase 3/7, P < 0.001, n = 32; Annexin-V, P = 0.04, n = 12) compared to superior vena cava serum. Hepatic vein serum regulates lung microvascular endothelial cells by increasing angiogenesis and survival in vitro. Loss of hepatic vein serum signaling in the lung microvasculature may promote maladaptive lung microvascular remodeling and pulmonary arteriovenous malformations.   Source: https://pubmed.ncbi.nlm.nih.gov/32387780/   

Kaemmerer H, Gorenflo M, Huscher D, Pittrow D, Apitz C, Baumgartner H, Berger F, Bruch L, Brunnemer E, Budts W, Claussen M, Coghlan G, Dähnert I, D'Alto M, Delcroix M, Distler O, Dittrich S, Dumitrescu D, Ewert R, Faehling M, Germund I, Ghofrani HA, Grohé C, Grossekreymborg K, Halank M, Hansmann G, Harzheim D, Nemes A, Havasi K, Held M, Hoeper MM, Hofbeck M, Hohenfrost-Schmidt W, Jurevičienė E, Gumbienè L, Kabitz HJ, Klose H, Köhler T, Konstantinides S, Köestenberger M, Kozlik-Feldmann R, Kramer HH, Kropf-Sanchen C, Lammers A, Lange T, Meyn P, Miera O, Milger-Kneidinger K, Neidenbach R, Neurohr C, Opitz C, Perings C, Remppis BA, Riemekasten G, Scelsi L, Scholtz W, Simkova I, Skowasch D, Skride A, Stähler G, Stiller B, Tsangaris I, Vizza CD, Vonk Noordegraaf A, Wilkens H, Wirtz H, Diller GP, Grünig E, Rosenkranz S.J Clin Med. 2020 May 13;9(5):E1456. doi: 10.3390/jcm9051456.PMID: 32414075 Free article.   Take Home Points:   Adults with congenital heart disease and pulmonary hypertension have better survival compared to those with idiopathic pulmonary arterial hypertension Treatment patterns changed over time, with more patients receiving combination targeted pulmonary arterial hypertension therapy Despite the lack of evidence, some patients with congenital heart disease and pulmonary hypertension continued to receive anticoagulant and antiplatelets   Commentary from Dr. MC Leong (Kuala Lumpur), section editor of ACHD Journal Watch:  The COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) registry is a prospective European registry of all patients with various forms of pulmonary hypertension. It started in Dresden, Germany in July 2007 and soon grew to include 49 pulmonary hypertension centers across 11 European countries. Understandably, the majority of the centers are from Germany. The registry has since collected some 8200 adult patients and become one of the largest pulmonary hypertension registries.   Baseline demographics   This study looks at the subset of 680 (8.3% from the total patients in the registry) adult patients (median age: 44 years, range 18-87 years and 66.6% females) in the registry with congenital heart disease. The median age of the patient is comparatively higher than the mean age of other registries of patients with congenital heart disease (CHD). This registry included 7 patients who were palliated with a Fontan circuit and received targeted pulmonary arterial hypertension (PAH) medications. Patient demographics and baseline characteristics of these patients were summarized in Table 1. Of the 680 patients, 487 (71.6%) patients had cardiac catheterization to confirm the diagnosis of pulmonary hypertension. The rest of the patients were diagnosed through non-invasive investigations. Figure 1. showed the age distribution of this cohort of patients.   Types of congenital heart disease   Simple lesions such as ventricular septal defects (29.3%) and patent ductus arteriosus (5.9%) constitute the majority of the cases. Atrial septal defects constitute 27.4% of all patients. 264 patients had their congenital heart disease operated. A summary of the types of congenital heart disease was tabulated in table 4.      Medication and treatment strategies   600 (88.2%) patients received targeted PAH therapy. 389 (65%) received endothelin receptor antagonists while 353 (59%) received phosphodiesterase type-5 inhibitors. Tables 2 & 3 showed the treatment characteristics and the distribution of targeted PAH medications used in different types of PAH in this cohort. 80 patients with Eisenmenger syndrome were treatment-naïve. These patients, according to the authors, were younger and had milder clinical symptoms. Treatment pattern changed over time. In the initial period, monotherapy was seen in the majority of patients (70% of total patients). After a median observation time of 45.3 months, more patients (50%) were on combination therapy in all groups except for patients with Fontan palliation (Figure 3). This was in line with the emergence of recent studies demonstrating the effects of goal-targeted therapy as well as combination therapies towards improved survival. The use of anticoagulants or platelet was varied. It was interesting to note that 13.4% of patients with Eisenmenger were on antiplatelets as there is no reliable data to support the beneficial effects of antiplatelet in this group of patients (Figure 4). There was also a substantial amount of patients receiving vitamin K or novel anticoagulants.       Survival   Of the 511 patients who received targeted PAH therapy, 91 died during the 5-year follow-up period, compared to 41 deaths in 1326 patients with idiopathic PAH. Patients with CHD had a better 5-year survival compared to patients with idiopathic PAH (Figure 5). Among patients with Eisenmenger syndrome, those with a simple CHD had a better survival compared to those with complex CHD (81% vs 64% survival at 5-year, p=0.063). These findings were in accord with previous studies.   This is an audit of a large registry. Like many multi-center registries, it is a mammoth task to validate all the data that is being entered and hence there may be inherent error in the data entry. The authors should be commended for being able to verify registry data in up to 70% of the participating centers. Pulmonary hypertension in CHD is often not easy to group and analyze. For example, patients with atrial septal defect and PAH may be classified as a simple lesion but the underlying pathogenesis is complex and often associated with idiopathic form of PAH. To include these patients in the simple lesion group and analyze their survival with other truly simple lesions changes the survival trajectory. Also, patients with single ventricle physiology with and without palliation may have a different cause of death. Patients with fenestrated Fontan circuits have complex physiology preventing accurate assessment of its pulmonary hypertension. Lastly, time 0 in survival curves in patients with CHD and pulmonary hypertension usually arbitrarily taken as the date the patients are included into the registry. Often, patients with bad disease would have died prior to being included into the registry and by natural selection, the survived patients are the ones with better and more stable disease. This gives the false impression that patients with CHD and pulmonary hypertension have better survival than patients of other causes of pulmonary hypertension. It will be interesting to see the “real” survival curve of this group of patients if time 0 be taken during infancy or childhood when the pulmonary hypertension starts to develop.  

Arroyo-Rodríguez C, Fritche-Salazar JF, Posada-Martínez EL, Arías-Godínez JA, Ortiz-León XA, Calvillo-Arguelles O, Ruiz-Esparza ME, Sandoval JP, Sierra-Lara D, Araiza-Garaygordobil D, Picano E, Rodríguez-Zanella H. Int J Cardiovasc Imaging. 2020 Apr;36(4):595-604. doi: 10.1007/s10554-019-01753-z. Epub 2020 Jan 1. PMID: 31894525 Similar articles Select item 31894524   Abstract To investigate the role of right ventricular free wall strain (RVFWSL) to predict low functional capacity in repaired tetralogy of Fallot (rTOF). We prospectively enrolled 33 patients with rTOF with moderate to severe PR who underwent rest and peak exercise echocardiography on a semisupine cycloergometer. Conventional function and strain imaging parameters of both ventricles were measured. Patients performing < 7 METS were defined to have low functional capacity. Logistic regression was used to identify parameters associated with low functional capacity. Eleven patients (33.3%) had low functional capacity. These patients were shorter (height 155 ± 7 vs 163 ± 9 cm, p = 0.023), more frequently female (27.3 vs 72.7%, p = 0.024) and had history of Blalock-Taussig shunt (45.5 vs 9.1%, p = 0.027). On multivariate analysis RVFWSL was the only predictor of low functional capacity OR 1.39 (CI 95%, 1.06-1.83., p = 0.018) per % change. A RVFWSL < 17% (absolute value) had an AUC of 0.785, sensitivity of 81.8% and specificity of 77.3% to predict low functional capacity. Right ventricular free wall strain is an independent predictor of low functional capacity in repaired tetralogy of Fallot with moderate to severe PR. A value < 17% might be useful in deciding when to perform pulmonary valve replacement, when functional capacity cannot be objectively measured.   source:https://pubmed.ncbi.nlm.nih.gov/31894525

Kuijpers JM, Vaartjes I, Bokma JP, van Melle JP, Sieswerda GT, Konings TC, Bakker-de Boo M, van der Bilt I, Voogel B, Zwinderman AH, Mulder BJM, Bouma BJ. Int J Cardiol. 2020 Apr 1;304:39-42. doi: 10.1016/j.ijcard.2019.11.114. Epub 2019 Nov 18. PMID: 31767384 Similar articles Select item 31894525   Abstract Background: Coronary artery disease (CAD) will increasingly determine outcome in the aging adult congenital heart disease (CHD) population. We aimed to determine sex-specific incidence of CAD in adult CHD patients throughout adulthood, compared to the general population. Methods and results: We followed 11,723 adult CHD patients (median age 33 years; 49% male; 57% mild, 34% moderate, 9% severe CHD) from the Dutch CONCOR registry, and two age-sex-matched persons per patient from the general population for first CAD event in national registers (period 2002-2012). Incidence rates were estimated using smoothed hazard functions. CAD risk during follow-up, stratified by CHD severity, was compared using proportional subdistribution hazards regression. In ACHD patients, 103 CAD events (43 women) occurred over 60,456 person-years. Rates per 1000person-years increased from 0.3(95% confidence interval: 0.1-0.6) at age 20 to 5.8(3.7-8.9) at 70 years in female, and from 0.5(0.3-1.0) to 7.8(5.1-11.8) in male patients. Compared to the general population, relative risk was 12.0(2.5-56.3) in women and 4.6(1.7-12.1) in men aged 20 years. Relative risk declined with age, remaining significant up to age ~65 years in women and ~50 years in men. In patients with mild, moderate and severe CHD, CAD risk was 1.3(0.9-1.9), 1.6(1.0-2.5) and 2.9(1.3-6.9) times increased compared to the general population, respectively. Conclusions: We found increased CAD risk in adult CHD patients, with greater relative risk at younger age, in women and those with more severe CHD. These results underline the importance of screening for and treatment of CAD risk factors in these patients.   source:https://pubmed.ncbi.nlm.nih.gov/31767384

Ghosh RM, Griffis HM, Glatz AC, Rome JJ, Smith CL, Gillespie MJ, Whitehead KK, O'Byrne ML, Biko DM, Ravishankar C, Dewitt AG, Dori Y. J Am Heart Assoc. 2020 Apr 7;9(7):e015318. doi: 10.1161/JAHA.119.015318. Epub 2020 Mar 30. PMID: 32223393 Free Article Similar articles Select item 32200729 Take Home Points: Nearly a third of patients developed complications in the first 6 months post Fontan completion. This was mainly driven by prolonged pleural effusions, readmission or unplanned cardiac catheterization. Prolonged cross-clamp time and prolonged bypass time emerged as risk factors for early Fontan morbidity. The presence and severity of AV valve regurgitation did not influence early outcomes. The presence of a type 3 or type 4 lymphatic drainage pattern on MRI (T2 -weighted) was associated with higher early failure rates (Odds ratio 6.28). Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch:  Recent studies implicated the role of lymphatic congestion in the pathogenesis of both protein-losing enteropathy and plastic bronchitis in patients with the Fontan circulation resulting in late Fontan failure. The role of lymphatic drainage in the development of early Fontan complications is not well described. This is a single center retrospective study at a tertiary paediatric center in the US, describing the prevalence and cause of early post-Fontan morbidity.   All patients who underwent a Fontan operation from June 2012 to July 2017 were included. Those presenting for a Fontan take-down, those for Fontan revision or those with a Kawashima operation, were excluded. Lymphatic patterns were characterized using T2-weighted images. Patterns included 4 types:   Type 1: Little or no abnormalities of the thoracic duct Type 2: Enhancement of the supraclavicular area and dilatation and/or tortuosity of the thoracic duct Type 3: Enhancement of mediastinal and supraclavicular area Type 4: enhancement extending from the mediastinum into the lung parenchyma   The primary outcome was a composite of early Fontan complications (within 6 months of surgery) including death, Fontan take-down, ECMO, chest drain >14 days, cardiac catheterization, re-admission, heart transplant listing. Fontan failure is characterized into 4 groups: structural failure, pump failure, pleural (non-chylous) effusions despite lack of pump or structural failure, and lastly lymphatic failure – usually presenting with chylothorax or plastic bronchitis.     Two hundred and thirty-eight patients were included in the study; 58 developed early Fontan complications (25.7%) – only 2 deaths occurred. Mean age at surgery was 3.4±1.7 years. An extra-cardiac fenestrated Fontan was present in 81% of the cohort.   The presence of a systemic RV (81% vs 67%, p0.047), a longer bypass time (median time 69.5 vs 64 minutes, p=0.025) and a longer cross-clamp time (median time 29 vs 25 min, p=0.002) was associated with a higher rate of early post-Fontan complications.  The presence and severity of atrio-ventricular valve regurgitation did not have an effect on early outcomes.   Fontan failure was attributed to structural failure in 20 patients (35%), and to pump failure in 8 patients (14%). The presence of severe Fontan complications was only 4%.  Fifteen patients (21.5%) had prolonged effusions and 15 patients (21.5%) had lymphatic failure as evidenced by plastic bronchitis or chylous effusions.   One hundred and ninety-five patients (82%) had pre-Fontan MRI’s. The systemic-pulmonary arterial collateral (APC) burden was quantified and expressed as a percentage of the total aortic flow. Of the 51 patients with a >35%  APC burden, 43 had collateral embolization prior to Fontan completion. Only 126 patients had the correct T2 weighted sequences to establish lymphatic flow patterns: 39 had type 1, 41 had type 2, 35 had type 3. Only 7 had type 4 – thus rather rare.     Forty- three percent of those with type 3 pattern and all of those with the type 4 pattern developed early complications. Type 3 and type 4 patterns were combined and regarded as high-grade lymphatic abnormalities.     Type 3 and 4 combined subtended an odds-ratio of 6.05 (95% CI 2.10-17.46, p=0.001) for developing complications compared to those with a type 1 pattern. When controlling for a morphological RV, bypass and cross-clamp time, the odds ratio was 6.28 (95% CI 2.13 – 18.5, p=0.001) for developing early Fontan complications.  

Tran D, D'Ambrosio P, Verrall CE, Attard C, Briody J, D'Souza M, Fiatarone Singh M, Ayer J, d'Udekem Y, Twigg S, Davis GM, Celermajer DS, Cordina R. J Am Heart Assoc. 2020 Apr 21;9(8):e015639. doi: 10.1161/JAHA.119.015639. Epub 2020 Apr 15. PMID: 32290749 Free Article Similar articles Select item 32315058   Take Home Points:   In this relatively healthy group of Fontan patients, low skeletal muscle mass was associated with reduced exercise capacity, ventricular dysfunction, and compensatory erythrocytosis as a marker of cyanosis. BMI overestimates skeletal muscle mass and underestimates adiposity in Fontan patients.   Commentary by Dr. Maan Jokhadar (Atlanta), section editor of ACHD Journal Watch:  The Fontan circulation is associated with elevated central venous pressure, low cardiac output, and cyanosis. These abnormalities increase the risk of heart failure, arrhythmias, thromboembolic events, hepatic fibrosis, and protein using the neuropathy, to name a few. Prior studies have described role of skeletal muscle as a “muscle pump” that increases venous return and augments pulmonary blood flow, which improves cardiac output and improves exercise capacity in Fontan patients.   Cardiac dysfunction can cause neurohormonal derangement and associated skeletal muscle loss and myopenia. There is also a complicated and often paradoxical interrelationship between obesity and heart failure (obesity paradox) with obese patients more likely to develop heart failure but obese patients with heart failure having improved survival. Data are mixed regarding the presence of the obesity paradox failure in Fontan patients.   Derek Tran and colleagues from Sydney, Australia performed a cross-sectional study of 28 Fontan patients who were prospectively recruited. The mean age was 26 with a near even split between male and female and 57% had a systemic left ventricle.  Extracardiac Fontan was present in 50%, lateral tunnel in 39%, and 11% (3 patients) with atriopulmonary Fontan. The median BMI was 22.4 kg/m2. Participants had dual energy x-ray absorptiometry (DXA) to assess Appendicular lean mass index (ALMI) Z score and total percent body fat (%BF). They also underwent cardiopulmonary stress testing, echocardiography, handgrip strength assessment, and biochemical assessments. This was a relatively healthy group with exclusion criteria that included NYHA class III-IV, major intellectual or physical disability, or current pregnancy.   - Fontan associated myopenia ( Z score: -2 or lower) :  11 patients (39%) - Less pronounced skeletal muscle mass deficit (Z score: between -2 and -1) : 8 patients (29%) - Normal range muscle mass (Z score: higher than -1) was present in only 9 patients (32%)   All participants with normal range skeletal muscle mass had normal ventricular systolic function. Whereas 80% participants with ventricular dysfunction had skeletal myopenia. Males had lower %BF. High adiposity was present in 32%, moderate adiposity and 14%, 50% had normal range adiposity, and 4% (1) had low adiposity. There were 3 patients who had both Fontan associated myopenia and high adiposity.   Vitamin D deficiency was not associated with myopenia. Above normal range PTH was present in 40%, even though only 7 patients had low vitamin D. Blood leptin was increased and 70% of patients, reflecting elevated adiposity.   ALMI was strongly associated with exercise capacity as measured by peak VO2. Fontan associated myopenia was strongly associated with reduced peak handgrip. There was no difference in spirometry measures between normal and reduced muscle mass groups.   This is the first study to characterize body composition using DXA in Fontan patients. This clinically stable group showed low skeletal muscle mass and adiposity predisposition, which can be unrecognized when looking at BMI alone. BMI may overestimate skeletal muscle mass and underestimate adiposity in Fontan patients. Low skeletal muscle mass was associated with reduced exercise capacity, ventricular dysfunction, and compensatory erythrocytosis as a marker of cyanosis. About two thirds of participant had reduced muscle mass.  ALMI was independently associated with absolute peak VO2. Grip strength was positively associated with muscle mass and was lower in patients with Fontan associated myopenia.   Ventricular systolic dysfunction was associated with low muscle mass, which could be due to peripheral “muscle pump” impairment reducing venous return, pulmonary blood flow, and cardiac output. Ventricular dysfunction can also cause myopenia due to myriad physiologic and neurohormonal mechanisms.   Based in DXA analysis of Fontan patients, reduced muscle mass and increased adiposity is common.   Given that reduced muscle mass is associated with ventricular dysfunction and reduced exercise capacity, additional study is needed to determine the therapeutic strategies and potentially substantial benefits of building lean muscle mass in these patients.