Adult Congenital Heart Disease

Carvedilol Does Not Improve Exercise Performance in Fontan Patients: Results of a Crossover Trial

Carvedilol Does Not Improve Exercise Performance in Fontan Patients: Results of a Crossover Trial. Butts R, Atz AM, BaezHernandez N, Sutcliffe D, Reisch J, Mahony L. Pediatr Cardiol. 2021 Feb 14. doi: 10.1007/s00246-021-02565-6. Online ahead of print. PMID: 33585998   Take Home Points: Carvedilol does not improve exercise performance of patients with "good" Fontan. There is a decrease in heart rate at peak exercise accompanied by an increase in oxygen level post Carvedilol treatment.   Commentary from Dr. M.C. Leong (Kuala Lumpur, Malaysia), section editor of ACHD Journal Watch: Patients with heart failure have chronically elevated levels of neurohormones e.g., norepinephrine and epinephrine, which compensates for the reduced heart function and maintains cardiac output. However, chronic high levels of norepinephrine lead to overstimulation of the heart, hastening the process of heart failure (1). Beta-blocker has been shown to reduce cardiac remodeling caused by elevated circulating catecholamines. Patients with Fontan circuits were associated with elevated circulating neurohormones as a compensatory mechanism to chronic low cardiac output syndrome (2). Meanwhile, in the absence of a subpulmonic pump, it is unknown whether increasing the filling time of the systemic ventricle will potentially increase the cardiac output of Fontan circuit.   In this study, the authors aimed to investigate the role of adding a selective beta-blocker, Carvedilol on the cardiac output of patients with Fontan circulation by using exercise capacity as the endpoint. The study also aimed to assess the carvedilol adverse event profile and effect on chronotropic incompetence in Fontan patients.   This study is a randomized, double-blind, placebo-controlled crossover trial of oral Carvedilol in young adults and children with Fontan circulation. 23 beta-blocker naïve patients with good Fontan i.e., able to achieve an RER > 1.0 during exercise testing, low NT-proBNP of < 300 pg./mL, serum albumin > 2.0 g/dL, serum creatinine < 2.0 mg/dL, AST or ALT < 3 times upper limit of normal, hemoglobin < 18 g/dL or > 7 g/dL were recruited. The patients were prescribed Carvedilol or placebo over 12 weeks as described in Figure 1, followed by a 6-week washout, before the crossover. Cardiopulmonary exercise tests were performed at the end of the 12-week treatment before and after the crossover. A 10% change in peak VO2 was defined as a desired detectable difference in the change in peak VO2. Baseline characteristics of the patients were as shown in table 2.   The study showed that oxygen consumption at rest did not differ between treatment groups. There was a statistically significant decrease in diastolic blood pressure with Carvedilol and heart rate. The rest of the exercise parameters were not significantly different between the treatment groups (Table 3). The change in oxygen consumption at peak exercise did not differ between subjects taking carvedilol vs. placebo (Figure 2). Understandably, treatment with Carvedilol was associated with a decrease in heart rate at peak exercise accompanied by an increase in oxygen. level (Figures 3 and 4). The blood parameters demonstrated a similar non-remarkable difference; sans the clinically non-meaningful NT-proBNP change. This study showed that Carvedilol failed to improve the exercise capacity of patients with Fontan circulation. There is, however, a blunted chronotropic response with Carvedilol, a condition which although expected, was a worrying feature given the association of Fontan circulation with chronotropic incompetence. This along with the potential of side effects from the beta-blocker has cast concerns over its routine use in the absence of cardiac arrhythmia in this group of patients.   While this study was very well planned and executed, I find the selection of patients concerning. Beta-blocker works well in patients with biventricular physiology and heart failure. The study population was patients with good Fontan and minimal heart failure, and hence potentially reduced the response observed. Perhaps studying its effect on patients with failed Fontan circuits would be more meaningful. Ref:   Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 2013 Aug 30;113(6):739-53. Ohuchi H, Negishi J, Ono S, Miyake A, Toyota N, Tamaki W, Miyazaki A, Yamada O. Hyponatremia and its association with the neurohormonal activity and adverse clinical events in children and young adult patients after the Fontan operation. Congenit Heart Dis. 2011 Jul-Aug;6(4):304-12.   


Oxygen Uptake Efficiency Slope is Strongly Correlated to VO2peak Long-Term After Arterial Switch Operation

Oxygen Uptake Efficiency Slope is Strongly Correlated to VO2peak Long-Term After Arterial Switch Operation. Terol Espinosa de Los Monteros C, Van der Palin RLF, Hazekamp MG, Rammeloo L, Jongbloed MRM, Blom NA, Harkel ADJT. Pediatr Cardiol. 2021 Feb 1. doi: 10.1007/s00246-021-02554-9. Online ahead of print. PMID: 33527171   Take Home Points: In children and young adults post arterial switch operation in this single centre, unblinded study of cardiopulmonary exercise (CPEX) and echocardiography in 48 patients discovered: Left and right longitudinal peak strain on echo was reduced. Peak oxygen uptake (VO2peak) was reduced compared to age/sex matched healthy controls. Mean oxygen uptake efficiency slope (OUES) was reduced compared to age/sex matched healthy controls. There was a positive correlation between VO2peak and OUES. There was no correlation between CPEX variables and left ventricular echo parameters. The authors conclude that OUES may be a valuable tool in assessing post arterial switch patients, particularly those who cannot obtain maximal effort.   Commentary by Dr. Simon MacDonald (London, UK), section editor of ACHD Journal Watch: Impaired exercise tolerance is described in patients post arterial switch. This may be due to chronotropic incompetence, pulmonary artery narrowing, coronary abnormalities and ventricular dysfunction, and other sequalae post surgery. In assessing exercise capacity, CPEX with measurement of maximal oxygen consumption (VO2peak) is taken to be the gold standard.   However, not all patient groups can reach maximal exercise due to such things as motivational aspects, learning disability or physical disability. Submaximal exercise parameters could thus be useful in this setting and inform practice. It is known that ventilatory efficiency (VE/VCO2slope) and oxygen uptake efficiency slope (OUES) can be useful, with OUES already been shown in healthy people and some congenital heart patients over a wide age range to correlate with VO2peak. This was the first description of the correlation in patients post arterial switch.   The authors examined 48 patients with TGA with both intact ventricular septum and ventricular septal defect post arterial switch operation (ASO). They performed CPEX testing, a physical activity score and a transthoracic echocardiogram. CPEXs were performed on a cycle ergometer on a continuous incremental protocol, only including tests with a peak RER of ≥1.00. Tests were compared to a reference range for normal children. Weekly exercise behaviour was converted into a MET score.   The study group was predominantly male (75%), with ASO performed in the first week of life and median age at follow-up 16 years (interquartile range 13-18).   All of the patients exercised to exhaustion with RER>1.0, with results showed below (Table 2 in article)   Female patients had lower VO2peak and OUES compared to males. No correlation was found between CPEX results and echo ventricular function findings.     The authors examined relationship between VO2peak and OUES, in a combined data set of all the patients, with a positive correlation found (Figure 4 from paper below):     Patients were young, predominantly male, with the ASO procedure being performed around a particular surgical era, echo rather than MRI was used to assess ventricular function and it was a single centre study.   The authors conclude that patients post arterial switch have diminished exercise capacity and there is a correlation between VO2peak and OUES. This correlation may be helpful in some patients who fail to reach maximal exercise during CPEX testing, giving an exercise capacity assessment to guide management.   


Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation

Incidence, Predictors, and Mortality in Patients With Liver Cancer After Fontan Operation. Ohuchi H, Hayama Y, Nakajima K, Kurosaki K, Shiraishi I, Nakai M. J Am Heart Assoc. 2021 Feb 16;10(4):e016617. doi: 10.1161/JAHA.120.016617. Epub 2021 Feb 4. PMID: 33538186 Free PMC article.   Take Home Points: Incidence of Liver Cancer (LC) increases markedly following Fontan surgery, particularly >30 years later. Routine liver ultrasound, liver fibrosis indices and AFP and annual change in liver function tests should all be assessed as part of routine surveillance. Mortality is high if LC is diagnosed after the development of symptoms. Hepatocellular carcinoma is the most common but not the only type of LC that develops in patients with a Fontan circulation. Commentary by Dr. Helen Parry (Leeds, UK), section editor of ACHD Journal Watch:   Introduction: Fontan-associated liver disease (FALD) is an important non-cardiac complication in patients who have had Fontan surgery. This may take the form of hepatic fibrosis, cirrhosis and liver cancer.   Objectives: To assess the following variables in patients with a Fontan circulation: Incidence of liver cancer (LC) Predictors of LC Current management of LC Prognosis after diagnosis of LC Method: This was a single-centre study in Osaka, Japan. Patients with a Fontan circulation were followed up between 2005 and 2019. Patients were assessed 6 months after surgery and on a 5-yearly basis thereafter. Assessment included: Liver ultrasound Assessment of liver fibrosis through calculation of the aspartate transaminase (AST) to platelets ratio (APRI), calculation of the Fib-4 score and the Forns index. Alpha-fetoprotein (AFP) Albumin, creatinine, bilirubin, alanine transaminase (ALT), gamma GT and INR All patients were concomitantly screened for viral hepatitides. Patients were then classed as low, intermediate or high risk as per table 1:   Risk of advanced liver fibrosisAPRIFib-4 scoreForns indexAFPLow <0.50<1.30<4.2<10ng/mlIntermediate 0.50-1.501.30-2.674.2-6.9NAHigh >1.50>2.67>6.9>10ng/ml   Diagnosis of LC was made pathologically on all confirmed cases. Chi- squared and Fisher’s exact test were used to assess the degree of liver abnormalities demonstrated on ultrasound versus the incidence of LC. Cox proportional hazard regression modelling was used to predict the association between the above clinical factors and new onset LC. Results: Three-hundred and thirty nine patients were identified and followed up as above. All patients were free of LC at 10 years post-Fontan surgery, 98.4% at 20 years and 94.3% at 30 years. The incidence is shown below.   Number of years since Fontan operationIncidence (%)Amongst n=10-200.429420-300.43130>308.8321   Assessment of fibrosis according to APRI, Fib-4 score and Forns index was performed on 267 patients (79%). Fourteen patients underwent evaluation for the presence of LC following concerning results in the above investigations: 3 of these presented with symptoms, 6 had a significant sized space occupying lesion on ultrasound and 5 had raised AFP. Ten of these patients had LC based on histopathology: 8 hepatocellular carcinoma, 1 intrahepatic cholangiocarcinoma and one combined hepatocellular cholangiocarcinoma. The youngest of these patients was 14 years old, all other patients were over 18 years of age. Four of these patients died during the follow up period including all 3 patients who had symptoms at the time of presentation. The table below shows the treatment.   Type of treatmentN=Transarterial chemoembolization (TACE)2Radiofrequency ablation (RFA)1TACE and RFA combined1Surgical resection4Hospice referral2   Patient age, number of years following Fontan surgery, increase in BMI, higher NYHA classification, abnormal live function tests, greater degree of annual change in assessment if fibrosis, APRI, Fib-4 score, AFP levels and the degree of abnormality demonstrated on ultrasound were all independent predictors of LC (p<0.05). Positive aspects of the study: Highlights the importance of FALD and the importance of regular monitoring. The initial sample size of patients with a Fontan circulation was relatively large. The study was not limited to adult patients, paediatric patients were included (the youngest patient who developed LC was 14 years old) Negative aspects of the study: The number of patients who developed LC (n=10) was very small The number of patients followed up beyond 30 years after surgery was very small (n=21) and this was a small proportion of the total number included in the study. Reasons for this were not provided. Only 79% of patients included in the study had fibrosis indices calculated, why was this so low? Certain factors were not taken into account such as alcohol intake or sub-type of the Fontan circulation, e.g., Atrio-pulmonary, lateral tunnel, extra-cardiac. Comment: Five yearly liver assessment seems relatively infrequent in Fontan patients. Most places would do this every 1-2 years.