Heart failure in systemic right ventricle: Mechanisms and therapeutic options

Abstract

d-loop transposition of the great arteries (d-TGA) and congenitally corrected transposition of the great arteries (cc-TGA) feature a right ventricle attempting to sustain the systemic circulation. A systemic right ventricle (sRV) cannot support cardiac output in the long run, eventually decompensating and causing heart failure. The burden of d-TGA patients with previous atrial switch repair and cc-TGA patients with heart failure will only increase in the coming years due to the aging adult congenital heart disease population and improvements in the management of advanced heart failure. Clinical data still lags behind in developing evidence-based guidelines for risk stratification and management of sRV patients, and clinical trials for heart failure in these patients are underrepresented. Recent studies have provided foundational data for the commencement of robust clinical trials in d-TGA and cc-TGA patients. Further insights into the multifactorial nature of sRV failure can only be provided by the results of such studies. This review discusses the mechanisms of heart failure in sRV patients with biventricular circulation and how these mediators may be targeted clinically to alleviate sRV failure.

Keywords: atrial switch repair; congenital heart disease; congenitally corrected transposition of the great arteries; dextro-transposition of the great arteries; heart failure; pediatric cardiology; systemic right ventricle; tricuspid regurgitation.

FIGURE 1

Tricuspid regurgitation, myocardial fibrosis, perfusion defects, and ventricular dyssynchrony all play a role in sRV failure. These four mechanisms may be highly interlinked. Studies have shown that ventricular dyssynchrony results from hypertrophy, ischemia, and heart failure. Cardiac fibrosis is also a significant predictor of ventricular dyssynchrony. These observations hint at a highly interlinked pathophysiology of sRV failure. We created the figure with biorender.com.

FIGURE 2

Myocardial fibrosis is detected in many sRV patients and increases the risk of adverse cardiac outcomes such as heart failure. Cardiac fibroblast and myofibroblast activation is an essential mediator of fibrosis in left ventricular fibrosis, but this remains to be demonstrated in sRV. TGF-β secretion by myofibroblasts sets up a positive feedback loop that promotes tissue fibrosis. Abnormalities in MMP:TIMP ratio may also result in dysregulated collagen turnover. Lastly, neurohormonal activation is detected in sRV patients: aldosterone, angiotensin II, epinephrine, and norepinephrine are elevated in sRV patients and stimulate collagen production in the myocardium. However, clinical trials thus far have failed to show a beneficial effect of inhibiting the sympathetic and RAAS systems in sRV patients. We created the figure with biorender.com.

FIGURE 3

Myocardial ischemia and an impaired coronary flow reserve is independently associated with cardiac dysfunction and heart failure in systemic LV and sRV failure. sRV patients also show impaired vascular reactivity to adenosine (a vasodilator) during stress. A hypertrophied sRV may effectively outgrow its blood supply, creating an oxygen demand and supply mismatch and consequent ischemia. The RV is usually supplied throughout all phases of the cardiac cycle, but this may change in sRV, as some reports hypothesize that sRV perfusion is diastole-dependent, causing ischemia. Therefore, myocardial ischemia in sRV may be ischemia in sRV may be explained by various mechanisms, some of which may be amenable to treatment. We created the figure with biorender.com.