Combined use of direct renin inhibitor and carvedilol in heart failure with preserved systolic function

Hypotheses: Heart failure with preserved systolic function (HFPSF) has attained epidemic proportions; however evidence-based therapeutic interventions have not advanced despite continued research over the past three decades. We propose the combined use of direct renin inhibitor and carvedilol for this condition.

Rationale: The Renin Angiotensin Aldosterone System (RAAS) plays a central role in myocyte hypertrophy, fibrosis and ventricular remodeling which is responsible for the diastolic dysfunction in HFPSF. Rising serum aldosterone levels with age have been implicated as a cause of myocardial fibrosis in the elderly. The sole use of Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers is associated with angiotensin-II and aldosterone escape and increased plasma renin activity. Carvedilol is a novel third generation non-selective β-blocker. The use of combination therapy will facilitate in better blood pressure control, reduce afterload, improve ventricular relaxation, cause regression of ventricular remodeling/fibrosis, maintain atrioventricular synchrony and enhance cardio-metabolic profile. The individual benefits of direct renin inhibitor and carvedilol could plausibly have a supra-additive effect when used in combination. Besides this, carvedilol can further reduce generation of free radicals, decrease LDL oxidation, improve Doppler echo diastolic parameters and decrease cardiac norepinephrine and density of cardiac β-receptors.

Conclusion: Evidence suggests that patients with HFPSF are treated less aggressively as compared to patients with heart failure with systolic dysfunction. Aggressive therapy with concurrent use of direct renin inhibitor and carvedilol will help in improving outcomes in this vulnerable patient sub-population. No prior trial has evaluated the combined use of these drugs for the treatment of HFPSF.