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OBJECTIVE: The purpose of this study was to address the timing of sudden death in advanced heart failure patients. BACKGROUND: Sudden death is a catastrophic event in cardiovascular disease. It has a circadian pattern prominent in the early AM, which has been thought to be due to a surge of sympathetic stimulation. We postulated that the distribution of events in advanced heart failure, with chronic sympathetic activation, would be more uniform implicating other potential mechanisms. METHODS: We analyzed data from Prospective Randomized Amlodipine Survival Trial (PRAISE). Sudden deaths were analyzed by time of death in 4-h and 1-h blocks for uniformity of distribution in the entire cohort, and in the prespecified ischemic and nonischemic stratum. Further analyses were undertaken in the treatment groups of amlodipine and placebo, and among those receiving background therapy of aspirin and warfarin. RESULTS: Sudden deaths in the overall cohort showed a nonuniform distribution with a PM peak but not an AM peak. The ischemic stratum also showed a PM peak, but sudden deaths within the nonischemic stratum were uniformly distributed. Neither amlodipine treatment nor aspirin or warfarin use altered the distribution. CONCLUSIONS: Sudden death in advanced heart failure did not show an AM peak, suggesting that circadian sympathetic activation did not strongly influence these events. The PM peak noted is likely complex in origin and was not affected by antiischemic or antithrombotic medications.

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BACKGROUND: A preliminary study suggested that the long-acting late-generation calcium-channel blocker amlodipine has favorable effects on exercise tolerance and is safe to use in heart failure, in contrast to earlier generation agents. The goal of 2 multicenter studies was to assess the effect of adjunctive therapy with amlodipine in addition to standard therapy on exercise capacity, quality of life, left ventricular function, and safety parameters in patients with heart failure and left ventricular systolic dysfunction. METHODS: Two large multicenter trials examining the effects of amlodipine on these parameters over a 12-week period of therapy were undertaken in patients with mild to moderate heart failure and left ventricular systolic dysfunction. A total of 437 patients with stable heart failure were studied in a randomized, double-blind, placebo-controlled prospective design. RESULTS: Amlodipine at a dose of 10 mg/day in addition to standard therapy in such patients was associated with no significant difference in change in exercise tolerance on a Naughton protocol compared with placebo in each trial. Among all patients taking amlodipine, exercise time increased 53 +/- 9 (SE) seconds; exercise time for those taking placebo increased 66 +/- 9 seconds (P = not significant). There were no significant differences in changes of quality of life parameters between amlodipine- and placebo-treated patients, and there were no significant differences in symptom scores or New York Heart Association classification between groups. Left ventricular function (measured as ejection fraction) improved 3. 4% +/- 0.5% in amlodipine-treated patients and 1.5% +/- 0.5% in placebo-treated patients (P =.007). There was no statistically significant excess of important adverse events (episodes of worsening heart failure in 10% amlodipine-treated vs 6.3% of placebo-treated patients) or differences in need for changes in background medication between groups. CONCLUSIONS: The addition of 10 mg of amlodipine per day to standard therapy in patients with heart failure is associated with no significant improvement in exercise time compared with placebo therapy over a 12-week period, and there was no increased incidence of adverse events. These data suggest that the addition of amlodipine to standard therapy in heart failure will not result in additional efficacy per se beyond standard therapy.

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Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

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BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

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Congestive heart failure is associated with chronotropic and inotropic hyporesponsiveness to adrenergic stimulation. A decrease in Gs alpha or an increase in Gi alpha is associated with a decrease in adenylyl cyclase activity. The current study assessed G proteins in response to treatment with direct-acting vasodilators and correlated changes in lymphocyte beta-adrenergic receptor components with changes in hemodynamic variables. Twenty-three patients with severe chronic congestive heart failure (New York Heart Association functional classes III and IV) were studied. Patients were grouped as responders (n = 10) or nonresponders (n = 13) on the basis of clinical assessment of functional status from questionnaires. Therapy was associated with an increase in cardiac index, a decrease in mean arterial pressure, and a decrease in systemic vascular resistance in all patients. Left ventricular filling pressure significantly decreased in responders (26 +/- 2 mm to 13 +/- 3 mm, p < 0.05) but did not change significantly in nonresponders. Similarly, mean right atrial pressure significantly decreased in responders (11 +/- 2 mm Hg to 4 +/- 1 mm Hg, p < 0.05) but did not change in nonresponders. Plasma norepinephrine increased significantly only in nonresponders (679 +/- 100 pg/ml to 1233 +/- 201 pg/ml, p < 0.05). Whereas lymphocyte beta-adrenergic receptor density and Gs did not significantly change, Gi increased after treatment only in the nonresponder group (23 +/- 5 to 51 +/- 11 fmol/mg, p < 0.05). A poor response to direct-acting vasodilators can be distinguished by reactive increases in plasma norepinephrine and lymphocyte Gi in the absence of a decrease in either left- or right-sided filling pressures.

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BACKGROUND: Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients. METHODS AND RESULTS: In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy. CONCLUSIONS: These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients.

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Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system, the angiotensin-converting enzyme and the angiotensin II receptor. Recent work, however, has led to the development of agents that directly inhibit renin, the proximal step in the cascade. In this study, we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by using enalkiren, a primate-selective, dipeptide renin inhibitor, which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 +/- 0.3 to 2.3 +/- 0.1 liter/min/m2) and stroke volume index (26 +/- 3 to 34 +/- 4 ml/m2) and decreases in left ventricular filling pressure (31 +/- 3 to 25 +/- 3 mm Hg), mean right atrial pressure (15 +/- 1 to 13 +/- 2 mm Hg), heart rate (78 +/- 5 to 72 +/- 6 beats/min) and systemic vascular resistance (2,199 +/- 594 to 1,339 +/- 230 dynes.s.cm-5) (all p less than 0.01 to 0.05). These observations indicate that renin inhibition produces hemodynamic benefits in patients with chronic CHF and could potentially provide a novel approach to interfering with the renin-angiotensin system in patients with this disorder.

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Angiotensin converting enzyme (ACE) inhibitors are the only therapeutic agents used in the treatment of chronic heart failure that have been shown to both improve symptoms and prolong life. These agents produce long-term haemodynamic and clinical benefits in about 60-65% of patients. The only reliable means of determining which patients are most likely to respond favourably to treatment is by a therapeutic trial; the response cannot be predicted by demographic factors, pretreatment left ventricular function or plasma renin activity. In addition to their symptomatic benefits, ACE inhibitors reduce the mortality of patients with chronic heart failure, possibly by decreasing ventricular wall stress and decreasing the frequency and complexity of ventricular arrhythmias. The most serious adverse effects of treatment, hypotension, functional renal insufficiency and potassium retention, occur most commonly in patients with the most advanced disease [New York Heart Association (NYHA) class III and IV heart failure] and when efforts are made to block the formation of angiotensin (Ang) II continuously (as with the use of long-acting ACE inhibitors). The unique characteristics of the ACE inhibitors support their use as first-line agents in patients with chronic heart failure.

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Adrenergic hyporesponsiveness in congestive heart failure has been understood previously in terms of a reduction in beta-adrenergic receptors. We have examined another hypothesis, one that states the stimulatory guanine nucleotide regulatory protein (Gs) that couples the beta-adrenergic receptor to adenylate cyclase activity is also decreased in congestive heart failure. In addition to the 40% decrease in lymphocyte beta-adrenergic receptors in patients in congestive heart failure (5.9 +/- 0.7 vs. 9.7 +/- 1.4 fmol/mg, p less than 0.05), we found an 80% decrease in levels of Gs compared with age- and sex-matched healthy control subjects (72.5 +/- 19 vs. 376 +/- 73 fmol/mg, p less than 0.05). Myocardial Gs levels correlated significantly with lymphocyte Gs levels. We also assessed the hypothesis that reductions in beta-adrenergic receptors and in Gs are reversible after successful therapy with angiotensin converting enzyme inhibitors. Treatment with either captopril or lisinopril was associated with clinical improvement, an increase in beta-adrenergic receptor density (from 5.5 +/- 0.7 to 8.7 +/- 1.5 fmol/mg), and a twofold increase in Gs levels (p less than 0.05). Thus, the data are compatible with Gs serving as an adaptable and reversible regulator of the adrenergic response in congestive heart failure. In view of the fact that Gs is a transducing element common to all hormones that stimulate cyclic adenosine 5'-monophosphate production, the observations could extend to other abnormal neurohumoral mechanisms in congestive heart failure.

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Cardiopulmonary exercise testing is a noninvasive tool whose clinical value is not yet widely recognized. The technique involves breath-by-breath measurement of respiratory gas exchange during a symptom-limited exercise test, with determination of maximal oxygen uptake and anaerobic threshold. These measurements serve as objective, reproducible indices of exercise capacity that can be applied to the management of various clinical problems. In addition, by permitting simultaneous assessment of circulatory and ventilatory reserves, the test can be especially helpful in the differential diagnosis of exertional dyspnea and fatigue. This paper reviews the physiology of gas exchange, the limitations of standard exercise tests, and the methodology and clinical applications of cardiopulmonary exercise testing.

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