Dynamic exercise changes in venous pressure and liver stiffness in Fontan patients: effects of Treprostinil

Dynamic exercise changes in venous pressure and liver stiffness in Fontan patients: effects of Treprostinil.

Possner M, Chaudhry A, Dillman JR, Urbina EM, Gao Z, McCoy C, Faust M, Rossiter HB, Powell AW, Mays W, Veldtman G.

Cardiol Young. 2021 Jan 28:1-7. doi: 10.1017/S1047951121000159. Online ahead of print.

PMID: 33504408

 

Take Home Points:

  • A marked dissociation between peripheral venous pressure augmentation (average rise ~ 88%) and liver stiffness rise (up to 30%) during incremental exercise was observed; this suggests intrinsic compensatory mechanisms shelter the liver from acute haemodynamic shifts in Fontan patients.
  • Treprostinil, an inhaled prostacyclin analogue, failed to attenuate venous pressure and liver stiffness responses to exercise.

 

Dr. Timothy Roberts

 

Commentary by Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: The Fontan circulation results in chronic venous pressure overload which is thought to contribute to Fontan-associated liver disease. During exercise, systemic venous pressure rises markedly without a similar augmentation of cardiac output. Inhaled pulmonary vasodilators have garnered interest as a therapy to improve Fontan haemodynamics by lowering systemic venous pressure and improving systemic ventricular pre-load and thus cardiac output. The aims of this study were:

 

  1. To assess liver stiffness at rest and immediately following maximal exercise.
  2. To measure the acute venous pressure responses to maximal incremental and constant work rate exercise; and
  3. To assess the effects of an inhaled prostacyclin analogue, Treprostinil, on systemic venous pressure responses, exercise endurance, and aerobic capacity as well as ultrasound-derived liver stiffness pre- and post-exercise.

This was a substudy to a larger prospective, randomised, double-blind, placebo-controlled cross-over trial examining the effects of inhaled Treprostinil on exercise endurance in young adults with a non-failing Fontan circulation. Inclusion criteria were age 18 years or older, and history of a Fontan palliation. Exclusion criteria were clinically unstable patients, Fontan pathway or intracardiac obstruction, ventricular dysfunction (EF < 40 %), uncontrolled arrhythmias, inability to perform exercise testing, obesity (BMI > 35), pregnancy or breast-feeding, and ongoing pulmonary vasodilator treatment. The primary outcome was change in liver stiffness measured using ultrasound sheer wave elastography following maximal exercise. Secondary outcomes included change in venous pressure at peak exercise, and changes in venous pressure, liver stiffness and exercise parameters in response to inhaled Treprostinil during and following incremental maximal exercise.

 

Figure 1 (below) illustrates the study protocol:

 

Fifteen patients were recruited, of which 14 completed the study and were included in the final results. Mean age was 27.7 +/- 8.1, 64% were female, and BMI 24 +/- 3.4. Underlying anatomy included tricuspid atresia (n=4), double inlet left ventricle (2), pulmonary atresia (2), and hypoplastic left heart syndrome (6). Most Fontan palliation types were lateral tunnel (n=9), with 2 atrio-pulmonary and 3 extra-cardiac Fontan type.

 

Liver sheer wave speed increased in 11 of 14 patients immediately after exercise (figure 2). The relative increase in sheer wave speed was 29 +/- 40 % on placebo and 22 +/- 32 % on Treprostinil (p=0.54). No significant correlation was seen with liver sheer wave speed and systemic venous pressure at peak exercise.

 

 

Peripheral venous pressures increased acutely during incremental (12.1 +/- 2.4 vs 22.6 +/- 8.0 mmHg, p < 0.001) and constant work rate exercise (12.5 +/- 2.5 vs. 23.4 +/- 5.2 mmHg, p < 0.001) on placebo. Treprostinil did not reduced venous pressures at rest nor at peak exercise during the incremental work rate exercise test (figure 3). There was no significant difference in VO2peak with placebo or Treprostinil (24.6 +/- 9.04 vs. 23.4 +/- 6.67 ml/kg/min, p = 0.19). Exercise endurance was significantly lower after inhalation of Treprostinil compared with placebo (5.19 +/- 0.89 vs. 5.82 +/- 1.23 minute, p = 0.02).

 

 

The observed “uncoupling” of venous pressure and liver stiffness may be explained by alterations in splanchnic blood flow precipitated by exercise. The authors suggest that exercise may acutely moderate hepatic inflow through diminished portal venous and hepatic arterial inflow and that this may relatively constrain acute hepatic congestion. Liver compliance may also vary between patients, mediated by perisinusoidal fibrosis that limits and contains the ability of increased blood flow to augment liver stiffness.

 

Study limitations include the small sample size, selection bias for well-functioning Fontan patients, lack of liver cirrhosis assessment, and absence of direct measurement of pulmonary vascular resistance. While Treprostinil failed to alter venous pressure and liver stiffness responses, its haemodynamic effect in a “sicker” Fontan population remains unknown and may warrant further assessment.

 

 

Atarim

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