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BackgroundHospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V"2) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care.Methods and ResultsPatients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled.ConclusionTolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes.

Background:: The determinants of exercise performance are multifactorial and incompletely understood in patients with symptomatic left ventricular (LV) dysfunction, with much less information regarding asymptomatic LV dysfunction. This study assessed the hemodynamics and neurohormonal factors influencing exercise performance in patients with LV ejection fractions @?0.35, both symptomatic and asymptomatic, enrolled in Studies of LV Dysfunction. Methods and Results:: We studied 103 patients enrolled prospectively in Studies of LV Dysfunction before randomized therapy; 38 were symptomatic and 65 had no or minimal symptoms. By using rest-exercise gated equilibrium radionuclide ventriculography and cuff blood pressure, we assessed the heart rate, LV and right ventricular (RV) volumes and ejection fractions, total peripheral resistance, the LV peak systolic pressure/end systolic volume ratio as an index of contractility, and plasma renin and norepinephrine at rest and during maximal graded supine bicycle ergometer exercise. Changes between rest and exercise were evaluated as indices of cardiovascular reserve. The cumulative workload ranged from 120 to 2,100 watt-min. At rest, the LV ejection fraction was 0.30 in asymptomatic patients and 0.25 in symptomatic patients, respectively (P < .0004). During exercise, asymptomatic patients had greater increases in heart rate, systolic blood pressure, LV ejection fraction, and cardiac output than symptomatic patients (P @? .05). Combining all patients, the strongest univariate correlates of exercise workload were the ability to increase heart rate (r = 0.70), the pressure/volume ratio (r = 0.63), and systolic blood pressure (r = 0.55), and to decrease the total peripheral resistance (r = -0.47) with moderate correlations for the ability to increase LV and RV ejection fractions (r = 0.33 and 0.35, respectively) (P < .0008). By multivariate analysis, workload was modeled best by the changes in four factors: heart rate, systolic blood pressure, and the LV and RV ejection fractions (R^2 = 0.54, P < .001). Conclusion:: Exercise performance and its hemodynamics differed in patients with symptomatic and asymptomatic LV dysfunction. Rather than features at rest, the reserve capacities for increasing heart rate, systolic blood pressure, and the LV and RV ejection fractions were the predominant cardiac mechanisms related to greater exercise performance.

Patients with heart failure and left ventricular systolic dysfunction exhibit increased adrenergic activity but blunted adrenergic responsiveness. We studied patients enrolled in the Studies of Left Ventricular Dysfunction, examining exercise responses of heart rate (HR) and plasma norepinephrine (PNE). Eighty-seven patients were studied before randomization; 65 of these were examined 1 year after randomization to placebo or enalapril. Compared with prevention trial (asymptomatic) patients, patients in the treatment trial (symptomatic) had higher resting HR and PNE levels and less increase in HR with a greater increase in PNE with exercise. Acute administration of enalapril increased the resting HR in patients in the prevention trial only but had no significant effect on PNE. After 1 year of therapy, patients in the prevention trial exhibited no change. Within the treatment trial, the placebo group displayed both a higher peak PNE and increase in PNE with exercise than did the enalapril group, whose HR response was maintained in spite of a reduction of exercise PNE. We conclude that (1) compared with asymptomatic patients, symptomatic patients with reduced left ventricular ejection fraction manifest greater resting and exercise adrenergic activity, with blunted HR response; and (2) in symptomatic patients, 1 year of enalapril treatment effected an augmented HR response to adrenergic stimulation, supporting an interaction between the renin/angiotensin and adrenergic nervous systems. Normalization of adrenergic tone and response likely contributes to the benefits of long-term angiotensin-converting enzyme inhibitor therapy. (Am Heart J 1997;134: 37-43.)