Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure.

BACKGROUND: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. METHODS: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. RESULTS: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]. CONCLUSIONS: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

The role of beta-blockers in preventing sudden death in heart failure.

Sudden death accounts for one third to one half of the deaths in patients with heart failure. Recent studies using beta-adrenergic blockers in patients with reduced systolic function and heart failure symptoms have shown significant reductions in overall mortality rates. This article discusses the role of beta-blockers in preventing sudden death in these patients. Six large beta-blocker trials in patients with heart failure have been published to date, with a combined relative risk reduction for sudden death of 38% (confidence interval [CI] 0.53-0.23; P < .001). Although dependent on a nonmechanistic definition of sudden death, the clinical trials of beta-blockers to date have shown that they significantly reduce the risk of sudden death in patients with heart failure. Future studies are required to define the role of other heart failure therapies in the context of this new standard of care.

Radio frequency heating of chronic ovine infarct leads to sustained infarct area and ventricular volume reduction.

OBJECTIVE: Myocardial infarct expansion and subsequent left ventricular remodeling are associated with increased incidence of congestive failure and mortality. Collagen is known to denature and contract when heated above 65 degrees C. We therefore tested the hypothesis that radio frequency heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and left ventricular volume. METHODS: Thirteen male Dorset sheep underwent surgical coronary artery ligation. At least 14 weeks later, animals were randomized to either radio frequency infarct heating (95 degrees C) with application of a restraining patch or a sham operation. Before treatment, after treatment, and 10 weeks later, left ventricular volume was measured with transdiaphragmatic echocardiography and myocardial infarct area was measured with an array of sonomicrometry crystals. RESULTS: Radio frequency infarct heating causes an acute decrease of 34% (-215 +/- 82 mm(2); P =.0002) in infarct area at end-diastole that is maintained at 10 weeks (-144 +/- 79 mm(2); P =.0002). Radio frequency infarct heating causes a downward trend in end-diastolic left ventricular volume measured by echocardiography of 20% (-15.7 +/- 6.3 mL; P = no significant difference) and end-systolic left ventricular volume of 32% (-17.1 +/- 9.8 mL; P =.09), which are significantly decreased at 10 weeks (-13.6 +/- 22.3 mL; P =.007 and -15.3 +/- 21.9 mL; P =.008, respectively). Radio frequency infarct heating causes an acute improvement in systolic function (P <.001), a sustained increase in left ventricular ejection fraction (+0.11%; P =.06), and preserved stroke volume. CONCLUSION: Radio frequency heating of chronic left ventricular myocardial infarct causes a sustained reduction in infarct area and left ventricular volume. This technique may beneficially reverse infarct expansion and left ventricular remodeling after myocardial infarction.

Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators.

BACKGROUND: Ventricular arrhythmias are a frequent finding in congestive heart failure (CHF) patients and a cause of concern for physicians caring for them. Previous studies have reached conflicting conclusions regarding the importance of ventricular arrhythmias as predictors of sudden death in patients with CHF. This study examined the independent predictive value of ventricular arrhythmias for sudden death and all-cause mortality in PROMISE (Prospective Randomized Milrinone Survival Evaluation). METHODS AND RESULTS: Ventricular arrhythmias were analyzed and quantified by use of prespecified criteria on baseline ambulatory ECGs from 1080 patients with New York Heart Association (NYHA) class III/IV symptoms and a left ventricular ejection fraction

Beta-adrenergic blocker mortality trials in congestive heart failure.

Many of the current discussions of beta-adrenergic blocker therapy in patients with congestive heart failure have used fairy tales to describe the evolution of this treatment from contraindication to standard of care. This article reviews the early studies that initiated this revolution in heart failure therapy and discusses the major mortality trials that have demonstrated that these agents improve survival and limit the progression of congestive heart failure. These major trials have used 1 of 4 beta blockers (metoprolol, bisoprolol, carvedilol, or bucindolol) in varying study designs with different patient populations. Each trial had different objectives and limitations, and these are described in the context of their impact on proving a survival benefit. In addition, the specific effect of beta-blocker therapy on sudden death in patients with heart failure is briefly discussed. The weight of these trials suggests that beta-adrenergic blocker therapy can save 1 life of every 35 patients treated in patients with mild-to-moderate heart failure. The data are compelling and the techniques for "starting low and going slow" with titrations have been well documented.

Valvular heart disease in pregnancy. A contemporary perspective.

Valvular heart disease may have a significant impact on the course and outcome of pregnancy with implications for fetal as well as maternal health. Optimally, serious symptomatic valvular heart disease should be detected and treated before pregnancy. Whether a pregnant woman is known to have valvular heart disease or is diagnosed during pregnancy, it is imperative that she is managed by an experienced multidisciplinary team. Although medical therapy may alleviate symptoms of heart failure in some patients, definitive intervention either with percutaneous balloon valvuloplasty or with surgical valve replacement may be necessary.

Effect of left ventricular sphericity on the evolution of ventricular dysfunction in rats with diffuse isoproterenol-induced myocardial necrosis.

BACKGROUND: Previous studies in heart failure have suggested that increased left ventricular (LV) sphericity is a precursor to hemodynamic deterioration, although these studies have predominantly used models with segmental damage due to coronary vessel occlusion and have only made baseline assessments of LV function. The purpose of this study was to examine the relationship between LV geometry and hemodynamic compromise through time in heart failure due to graded, diffuse myocardial injury with a patent coronary circulation. METHODS AND RESULTS: Rats received two injections of either 0, 85, 170, or 340 mg/kg isoproterenol. At 2, 6, and 16 weeks after injection, baseline hemodynamics, peak pressure-generating (aortic occlusion) and flow-generating (Tyrode's volume loading) capacities, and ventricular pressure-volume curves, dimensions, and histological scoring were measured. Increased LV sphericity preceded deterioration in baseline cardiac output, although it was the most powerful correlate of the dose-dependent decreases in peak cardiac output and ejection fraction. Time-dependent increases in pressure-generating capacity at a given volume were also due to compensatory increases in LV sphericity. The extent of right ventricular damage was also a strong correlate of peak flow-generating capacity. CONCLUSIONS: This study demonstrates that isoproterenol-induced myocardial necrosis resulted in progressive hemodynamic dysfunction of the left ventricle which most closely correlated with alterations in LV geometry. Although increases in LV sphericity preceded decrements in baseline function, techniques that assessed peak LV function demonstrated that increased LV sphericity was directly correlated with decreased peak flow-generating capacity, underscoring the clinical importance of these geometric alterations.

Neurohumoral mechanisms in heart failure: a central role for the renin-angiotensin system.

Congestive heart failure (CHF) is often the result of a progressive deterioration in cardiac function associated with marked alterations in peripheral physiology. The neurohumoral mechanisms involved in these alterations have the paradoxical role of serving simultaneously as adaptive, compensatory changes and as major contributing elements in the progression of CHF. This review discusses some of the clinical and experimental data that describe the time course of these neurohumoral mechanisms, with an emphasis on the renin-angiotensin system (RAS). The central role of the RAS in the pathophysiology of heart failure is discussed in relation to its interaction with other neurohumoral systems, its role in the peripheral vascular alterations, and its role in the myocardial alterations in CHF. In addition, these effects are discussed in the context of both the circulating and local RAS and the ability of pharmacologic interventions that modulate the RAS to modify the course of CHF favorably, especially the angiotensin-converting enzyme (ACE) inhibitors. An understanding of the intricate interactions of these neurohumoral mechanisms in CHF has already led to the development of therapies that reduce morbidity and mortality and provides the basis for continuing advances in the treatment of CHF.

Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs.

Endothelin (ET) is a potent vasoconstrictor that may be involved in a number of cardiovascular disorders, although its role in normal hemodynamics remains unclear. Twenty-two anesthetized open-chest dogs were instrumented for measurement of systemic and pulmonary hemodynamics, cardiac output, coronary blood flow, and cardiac contractility. Big ET induced peripheral and coronary vasoconstriction, which occurred before significant elevations in plasma ET and which was nearly completely blocked by bosentan, a new nonpeptidic mixed (ETA and ETB) ET receptor antagonist. Bosentan also prevented the peripheral dilatation caused by the specific ETB receptor agonist, sarafotoxin S6c, but did not prevent the peripheral vasoconstriction induced by angiotensin II. Bosentan alone had no significant hemodynamic effect in the normal anesthetized dog, although it did induce a reactive increase in the plasma level of ET-1 and ET-3. This study demonstrates that, despite blocking both ETA and ETB receptors, bosentan alone had no hemodynamic effect, suggesting that ET does not play a major role in the normal hemodynamic status of anesthetized dogs.

Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan).

BACKGROUND: Endothelin (ET) is a potent vasoconstrictor, and its concentration is increased in patients with heart failure. The purpose of this study was to investigate the role of endothelin in heart failure by use of a rat model. METHODS AND RESULTS: Experiments were performed on rats at 1 through 16 weeks after sham operation or coronary artery ligation. Rats with left ventricular end-diastolic pressures > 15 mm Hg were considered to have chronic heart failure (CHF), while the others were considered to have uncomplicated myocardial infarction (MI). There were increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham, 20 +/- 0.5 pg/mL, n = 45; CHF, 31 +/- 2 pg/mL, n = 50; P < .001) and transient increases in ET-3 concentrations at week 1 in both the MI and CHF groups. There were no significant increases in big ET-1 concentrations, suggesting an increased conversion of ET-1 from big ET-1 in the CHF group. At weeks 2 through 8, oral administration of the mixed (ETA and ETB) endothelin receptor antagonist bosentan significantly decreased mean arterial pressure in conscious CHF rats, an effect that increased over time. Furthermore, bosentan had an additive effect to the angiotensin-converting enzyme inhibitor cilazapril. CONCLUSIONS: Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan. Therefore, endothelin antagonists may be useful therapeutic agents in the treatment of CHF.

Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats.

The purpose of the present study was to gain a better understanding of the relation between ventricular remodeling and heart failure by assessing the adaptation of the heart through time to graded myocardial injury in the presence of a patent coronary circulation. Left ventricular (LV) remodeling is a dynamic response of the heart to injury and a critical component in the development of heart failure. However, most previous studies have been in the presence of an occluded coronary vessel, which may in itself effect remodeling. Male Wistar rats received two subcutaneous injections of either 0, 85, 170, or 340 mg isoproterenol per kilogram of body weight. At 2, 6, and 16 weeks after injection, LV pressure, the pressure-volume relation, and histology were assessed. The graded myocardial necrosis produced in isoproterenol-treated rats was associated with dose-dependent increases in LV end-diastolic pressure, volume indexes, and global diastolic wall stress. In the higher dose groups, the LV continued to enlarge after 2 weeks, resulting in a further reduction in the ratio of LV mass to volume and a persistent rise in diastolic wall stress. These progressive changes in LV structure were associated with an increase in long-term mortality in rats from the intermediate- and high-isoproterenol dose groups. The present study in rats demonstrates that diffuse isoproterenol-induced myocardial necrosis results in a progressive enlargement of the LV cavity that is out of proportion to mass, a finding similar to that observed in discrete myocardial infarction.

The evolving role of angiotensin-converting enzyme inhibition in heart failure: expanding the protective envelope.

Congestive heart failure (CHF) continues to be a major cause of morbidity and mortality; in the United States alone, CHF afflicts 4 million patients, representing about 2% of the adult population; causes or contributes to more than 250,000 deaths yearly; and is the principal or secondary diagnosis in 6% of all hospital discharges. After the discovery of angiotensin-converting enzyme (ACE) inhibitors as potent antihypertensive agents, an increased understanding of the pathophysiology of CHF, in addition to the recognition of heart failure as a process that evolves through time, led to the use of these agents in patients with CHF. Subsequently, a series of multicenter trials systematically explored the role of ACE-inhibitor therapy in heart failure. The purpose of this review is to discuss some of these trials and to describe the answers that they provide to the following questions: Are vasodilators beneficial in the treatment of severe heart failure? Are ACE inhibitors beneficial in mild-to-moderate heart failure? Which vasodilator regimen (ACE inhibitors or hydralazine/isosorbide dinitrate) is more effective? Finally, are ACE inhibitors beneficial in asymptomatic patients at risk of heart failure?

Increased vascular responsiveness to norepinephrine in rats with heart failure is endothelium dependent. Dissociation of basal and stimulated nitric oxide release.

BACKGROUND: Endothelial dysfunction and abnormal vascular responsiveness to vasoconstrictors may play an important role in chronic heart failure (CHF). The purpose of our study was to (1) evaluate whether the vascular response to norepinephrine is abnormal in a rat model of heart failure; (2) investigate the role of alpha 1- and alpha 2-adrenergic receptors; and (3) assess the contribution of the endothelium, and specifically endothelium-derived nitric oxide, to this response. METHODS AND RESULTS: Concentration-response curves of rat thoracic aortic rings were studied in isolated organ baths at 1 week after coronary artery ligation. In CHF rats, norepinephrine-induced contractions were increased in intact rings compared with rings from sham rats, despite decreased contraction in denuded rings. Decreased alpha 1-receptor sensitivity was demonstrated by the increased EC50 of methoxamine in endothelium-denuded rings from CHF rats, although maximal responses to KCl contraction were also decreased in CHF. There was no difference in the vascular response to clonidine, and acetylcholine-mediated relaxations were preserved in CHF rats, suggesting normal stimulated nitric oxide release. However, nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester, as well as measurements of basal cGMP, demonstrated that basal nitric oxide release was decreased in CHF rats. CONCLUSIONS: This study demonstrates that the increased vascular responsiveness to norepinephrine in intact vessels from rats with heart failure is the result of decreased basal nitric oxide release and suggests that the dissociation of basal and stimulated nitric oxide release may play a pathophysiology role at an early stage of heart failure.

Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries.

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor. To investigate the in vivo effects of ETB receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ETB agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 microgram caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 micrograms caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ETB receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.

Temporal evolution of endothelial dysfunction in a rat model of chronic heart failure.

OBJECTIVES: The goal of this study was to investigate the evolution of endothelial dysfunction and plasma renin activity in a rat model of heart failure. BACKGROUND: Endothelial dysfunction has been demonstrated in heart failure and may play a significant role in this pathophysiologic process. Studies have also suggested a physiologic interaction between the renin-angiotensin system and endothelium-derived relaxing factor. However, the evolution of endothelial dysfunction and plasma renin activity in heart failure has not been studied to date. METHODS: Endothelium-dependent and -independent relaxations were studied at 1, 4 and 16 weeks after coronary artery ligation in a rat model of heart failure. Thoracic aortic rings were placed in isolated organ baths and acetylcholine and sodium nitroprusside concentration response curves were generated. Plasma renin activity was assessed at each time point. RESULTS: Aortic rings from rats with heart failure demonstrated no evidence of endothelial dysfunction at week 1, although progressive rightward shifts in the acetylcholine curves and decreasing maximal relaxation over time compared with findings in sham-operated control rats were evident at weeks 4 and 16. The sodium nitroprusside curves were not different between rats with heart failure and sham-operated rats. Plasma renin activity was elevated at week 1 and progressively increased through week 16, even though it correlated poorly with endothelial dysfunction. CONCLUSIONS: This study suggests that endothelial dysfunction in heart failure is a progressive time-dependent process that probably plays a minor role early in heart failure. Although plasma renin activity increased significantly in rats with heart failure, it was poorly predictive of endothelial dysfunction.

Hemodynamic variability and circadian rhythm in rats with heart failure: role of locomotor activity.

Heart rate variability is known to be decreased by heart failure; however, the influences of concomitant diseases, changes in activity level, evolution through time, and abnormalities in the circadian rhythm are unknown. This study evaluated the influence of these factors by assessing hemodynamic variability in rats with heart failure (n = 8) and sham-operated controls (n = 8) through telemetric monitoring of heart rate, blood pressure, and locomotor activity for 8 wk. Hemodynamic variability was assessed by the standard deviation as well as hourly standard deviations and coefficients of variation of these variables over 48 h at 2, 4, and 8 wk after myocardial infarction. The circadian rhythm was investigated through power spectral analysis. Heart failure was associated with marked decreases in heart rate and mean arterial pressure variability and circadian rhythm without any differences in activity and no change through time. Heart failure in rats due to myocardial infarction in the absence of any confounding diseases is associated with marked abnormalities in hemodynamic variability and circadian rhythm independent of locomotor activity.