The Adaptive Right Ventricle in Eisenmenger Syndrome: Potential Therapeutic Targets for Pulmonary Hypertension?
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Pulmonary hypertension (PH) is a rare disease with significant mortality despite targeted therapies. Among patients with PH, both survival and functional class are more closely correlated with right ventricular (RV) function than with the degree of pulmonary artery pressure elevation or pulmonary vascular resistance. Unfortunately, the RV is usually exquisitely sensitive to increases in afterload associated with PH, and progressive RV failure is the typical clinical course among most patients over time. However, in the subset of PH patients with congenital heart disease and Eisenmenger syndrome, survival is prolonged and RV function is preserved compared to patients with primary PH. This functional superiority may be due to a persistent RV fetal phenotype as patients continue to have a biventricular hypertrophy pattern which mimics fetal cardiac morphology. We have utilized an ovine model of congenital heart disease to demonstrate superior RV function following acute afterload stimulus—a unique RV Anrep effect. Further, we have shown shared gene expression patterns in the fetal and CHD model RV. In the future, understanding the underlying mechanisms of RV adaptation in CHD and PH may yield novel therapeutic strategies for all patients with pulmonary hypertension.
KeywordsEisenmenger syndrome Pulmonary hypertension Right ventricle
Pulmonary arterial hypertension (PAH) is a rare but devastating disease that carries a significant burden of morbidity and mortality. Most investigations have focused on mechanisms that underlie abnormal pulmonary vascular reactivity and remodeling, which have led to the development of new therapies and improved survival. Similarly, much of the clinical evaluation of patients with PAH is based upon assessments of pulmonary arterial pressure and pulmonary vascular resistance. However, mortality is due to right ventricular (RV) failure, and there is growing recognition that indices of RV function in patients with PAH—including right atrial pressure and cardiac index—are correlated most closely with not only survival but also functional class [1, 2]. Interestingly, patients with PAH associated with CHD have better functional capacity and survival than patients with other forms of PAH despite equivalent pulmonary artery pressures and advanced pulmonary arteriopathy . However, the mechanisms that might account for this difference are unknown and have been the subject of limited investigation. Among patients with primary PH, there is considerable variability in indices of RV function (cardiac output and right atrial pressure) relative to pulmonary artery pressure elevation. There is a subpopulation of patients who retain an adaptive phenotype with concentric hypertrophy and preserved mechanical efficiency; accordingly, these patients have improved survival compared to patients with a “maladaptive” RV phenotype . A better understanding of preserved RV function in these patients might lead to novel therapeutic targets.
24.2 Improved Survival in Eisenmenger Syndrome
For decades, there has been a consistently observed survival advantage among patients with Eisenmenger syndrome compared to those with idiopathic PH or PH secondary to other causes . Despite equivalent elevations in PA pressure and pulmonary vascular resistance compared with patients with IPAH, these patients have lower right atrial pressures and higher cardiac output. Moreover, at a similar level of PAP elevation, patients with ES have superior echocardiographic features of RV function . Two major mechanisms for this observed survival benefit have been theorized. The presence of a communication at either the atrial or ventricular level (or both) allows right-to-left shunting of blood—a “pop-off”—preserving left-sided output during right ventricular failure. Another intriguing potential factor is persistence of a fetal RV phenotype due to the presence at birth of an unrestrictive post-tricuspid valve left-to-right shunt that applies systemic-level afterload to the RV. In this situation, the RV does not undergo the deconditioning that normally occurs as pulmonary vascular resistance decreases after birth and, thereby, may be better suited to function against an increasing afterload as pulmonary hemodynamics worsen [5, 7]. Interestingly, a recent multicenter study of predictive factors of survival in patients with ES found that those with pre-tricuspid lesions had worse survival . These data support the hypothesis that RV remodeling in the setting of high afterload associated with post-tricuspid CHD lesions confers additional benefit beyond right-to-left unloading through an intracardiac shunt.
24.3 Preserved Fetal Morphology in Eisenmenger Syndrome
24.4 Fetal Phenotype in Ovine CHD Model
24.5 The Adaptive RV Response to Acute Afterload—RV Anrep Effect
24.6 Potential Mechanisms of RV Anrep Effect
24.7 Future Directions and Clinical Implications
Preserved RV function among patients with Eisenmenger Syndrome remains a clinical observation without a clearly identified pathophysiologic mechanism. Although a preserved RV fetal phenotype in these ES patients seems a logical conclusion based on both cardiovascular development and preliminary animal data, this hypothesis remains unproven. As the mechanisms for preserved RV function in these circumstances is better defined, the next step will be targeting of these pathways in all patients with preserved RV function in the hopes of improving the survival and functional status of these patients.
This research was supported by grants from the National Institutes of Health (HL61284 to J.R.F. and 5T32HD049303-07 to J.R.F. and R.J.K.) and American Heart Association (14FTF19670001 to R.J.K.).
- 1.Voelkel NF, Quaife RA, Leinwand LA, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;114:1883–91. https://doi.org/10.1161/CIRCULATIONAHA.106.632208.CrossRefPubMedGoogle Scholar
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