Vasopressin receptor antagonists in heart failure

Abstract

There is ample evidence that arginine vasopressin (AVP) is a component of the neurohormonal response to congestive heart failure (CHF). Furthermore, AVP might play a role in the development, progression and worsening of CHF. Because of the need for further improvement in the treatment of CHF, randomized clinical trials were conducted to assess the efficacy and safety of non-peptide AVP receptor antagonists in patients with CHF. In pivotal trials of three non-peptide AVP receptor antagonists, these compounds improved the fluid status, osmotic balance and hemodynamics of patients with CHF. These studies support the approval of this class of agents for the symptomatic treatment of CHF, but long-term studies are required to demonstrate their role in the outcome and quality of life of these patients.

Introduction

Congestive heart failure (CHF) is a growing medical problem with significant morbidity and mortality rates despite the use of complex medical treatments combining diuretics, digitalis, inhibitors/blockers of the renin–angiotensin–aldosterone system, and β-adrenergic receptor blockers [1^•]. Close to five million Americans are afflicted with CHF, and heart failure is the reason for at least 20% of all hospitalizations among patients over the age of 65 years [2^•]. In CHF patients, the annual mortality rate is 8–10%, the quality of life is poor and hospital stays are frequent. Each year, an estimated 500 000 new cases of CHF are diagnosed in the USA, and CHF-related complications result in one million hospital admissions and 40 000 deaths per year. Thus, there is a need to develop additional therapies to improve the outcome of CHF patients in terms of their quality of life and survival 3., 4..

In CHF, various neurohormonal systems (e.g. sympathetic nervous system, rennin–angiotensin–aldosterone system, endothelin, cytokines and arginine vasopressin [AVP]) are activated to maintain arterial pressure and circulatory homeostasis [2^•]. However, excessive activation of these systems can lead to increased cardiac preload through water and sodium retention, peripheral vasoconstriction, reduced renal blood flow and cardiac remodeling. This situation fuels a vicious cycle that worsens CHF, but which could be interrupted by specific blockers of these systems.

The neurohypophysial antidiuretic hormone AVP regulates free water reabsorption, body fluid osmolality, blood volume, blood pressure, cell contraction, cell proliferation and adrenocorticotropic hormone secretion via the stimulation of specific G-protein-coupled receptors currently classified into V₁-vascular receptor (V₁R), V₂-renal receptor (V₂R) and V₃-pituitary receptor (V₃R) subtypes. Each of these has distinct pharmacological profiles and intracellular second messengers [5]. Circulating levels of AVP are often elevated during the progression and/or exacerbation of CHF in response to various non-osmotic stimuli, including low arterial pressure and diminished effective arterial volume [6^•]. This stimulation of AVP secretion can occur despite low plasma osmolality and hyponatremia. For example, in the Studies of Left Ventricular Dysfunction (SOLVD) population (ejection fraction of ≤ 35%), patients with asymptomatic left ventricular dysfunction had higher AVP levels (mean median plasma AVP=2.2 pg/ml) than did control patients (mean median plasma AVP=1.8 pg/ml), whereas patients with symptomatic mild-to-moderate CHF had even higher AVP levels (mean median plasma AVP=3.0 pg/ml) [7]. Sustained AVP release can worsen CHF through V₁R-mediated vasoconstriction and V₂R-mediated water retention. Furthermore, activation of V₁R subtypes in the myocardium can lead to hypertrophy; stimulation of V₃R subtypes can result in adrenocorticotropic hormone-mediated aldosterone secretion and subsequent sodium reabsorption. In the Survival and Ventricular Enlargement (SAVE) population of post-myocardial infarction patients with left ventricular dysfunction, AVP levels one month after infarction were independently associated with long-term cardiovascular outcomes, including heart failure, recurrent myocardial infarction and death [8].

Accordingly, blockade of AVP receptors might prove beneficial in the treatment of CHF [9]. Recently, orally active non-peptide AVP receptor antagonists were developed following the random screening of chemical entities and optimization of lead compounds [10^•]; these were studied in experimental and human CHF.