Angiotensin Receptor Blockade and Exercise Capacity in Adults With Systemic Right Ventricles

Abstract

Background-Pharmacological blockade of the renin-angiotensin system improves exercise tolerance in patients with left ventricular dysfunction, yet its impact on patients with systemic right ventricles (RVs) remains unknown. Methods and Results-A multicenter, randomized, double-blind, placebo-controlled, crossover clinical trial was performed to assess the effects of losartan on exercise capacity and neurohormonal levels in patients with systemic RVs. Of 29 patients studied (age, 30.3Ϯ10.9 years), 21 had transposition of the great arteries with a Mustard baffle, and 8 had congenitally corrected transposition of the great arteries. Baseline values were as follows: V O 2 max, 29.8Ϯ5.6 mL · kg Ϫ1 · min Ϫ1 (73.5Ϯ12.9% predicted value); RV ejection fraction, 41.6Ϯ9.3%; N-terminal pro brain natriuretic peptide (NT-proBNP), 257.7Ϯ243.4 pg/mL (normal Ͻ125 pg/mL); and angiotensin II, 5.7Ϯ4.9 pg/mL (normal Ͻ5.0 pg/mL). Comparing losartan to placebo showed no differences in V O 2 max (29.9Ϯ5.4 versus 29.4Ϯ6.2 mL · kg Ϫ1 · min Ϫ1 ; Pϭ0.43), exercise duration (632.3Ϯ123.0 versus 629.9Ϯ140.7 seconds; Pϭ0.76), and NT-proBNP levels (201.2Ϯ267.8 versus 229.7Ϯ291.5 pg/mL; Pϭ0.10), despite a trend toward increased angiotensin II levels (15.2Ϯ13.8 versus 8.8Ϯ12.5 pg/mL; Pϭ0.08). Conclusions-In adults with systemic RVs, losartan did not improve exercise capacity or reduce NT-proBNP levels.Minimal baseline activation of the renin-angiotensin system may explain this lack of benefit and imply an alternative pathophysiological mechanism for the progressive ventricular dysfunction and impaired exercise capacity observed in such patients. Key Words: angiotensin Ⅲ exercise Ⅲ transposition of great vessels P atients with congenitally corrected transposition of the great arteries (L-TGA) or intra-atrial baffle repair for complete transposition of the great arteries (D-TGA) function with a morphological right ventricle (RV) supporting a systemic circulation. Overall, excellent long-term survival is reported, with most young adults remaining symptom free. 1,2 However, long-term sequelae include progressive RV dilatation, systolic ventricular dysfunction, 2-5 impaired exercise tolerance, 6,7 arrhythmias, 1,2,5 and sudden death, 1 raising concern over the suboptimal capacity of the RV to endure against a systemic afterload.In both symptomatic and asymptomatic patients with left ventricular (LV) dysfunction, pharmacological blockade of the renin-angiotensin system (RAS) improves LV filling pressures, 8 -10 cardiac index, 8,9 exercise tolerance, 8 -12 and overall survival. [13][14][15] Results of such studies are often extrapolated to patients with systemic RVs, and therapy frequently is empirically initiated. However, beneficial effects of inhibiting the RAS in patients with systemic RVs have not yet been demonstrated. This study therefore was designed to assess the effects of losartan on exercise capacity and neurohormonal levels in adults with systemic RVs. Methods Study PopulationThe study population was derived from patients having L-TGA or ...

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

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“…RVH and RVF are a major cause of morbidity and mortality in patients with pulmonary hypertension and represent long-term risks for patients with surgically corrected congenital heart diseases such as tetralogy of Fallot, L-transposition of the great arteries, and hypoplastic left heart (4,34). Standard treatments for LVF (ACE inhibitors, ␤-blockers) have shown limited success in RVF (22,54), suggesting fundamental cellular-level differences between the RV and LV. The two ventricles derive embryologically from different heart fields (19) and manifest differences in calcium handling, inotropy, and patterns of gene expression in response to stress (7,37,67,69).…”

Rheumatic “Taussig-Bing Heart”: A Case Report

“…Medical management with diuretics, afterload reduction with angiotensin converting enzyme inhibitors such as captopril and digoxin (inotropic) is adapted for the failing systemic right ventricle [40], depending on the severity of associated malformations [41]. The role of angiotensin receptor blocker with losartan was evaluated and found to have no improvement in exercise capacity and no reduction in neurohormonal levels in patients with systemic right ventricle [42]. Beta blockers did not improve outcome in a randomized trial included pediatric patients with systemic RV dysfunction [43] and must be used cautiously in ccTGV patients as they may precipitate AV block, but an improvement in systemic ventricular function occurred after carvedilol (a vasodilatory beta blocker) administration in a 80-year old woman with ccTGV [44], Aggressive medical treatment with afterload reduction is indicated for patients with ventricular enlargement and early symptoms.…”

Ventricular Assist Devices in Patients with Systemic Right Ventricular Failure due to Congenitally Corrected Transposition of the Great Arteries

“…Although there are no randomized control trials in this patient population, evidence based therapies in heart failure with reduced ejection fraction have been applied, which include angiotensin converting enzyme inhibitor or angiotensin II receptor blocker and beta-blocker therapies [14][15][16][17][18][19]. There is no evidence for digoxin; however, it can be used.…”