Why do the kidneys release renin in patients with congestive heart failure? A nephrocentric view of converting-enzyme inhibition.
Explore the source record for details and available documents.
Acute Kidney Injury↗
Biomedical subjects
M Packer
Publications and source records attributed to M Packer.
Do vasodilators prolong life in heart failure?
Explore the source record for details and available documents.
Enalapril↗
Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure.
Congestive heart failure is the most important predisposing factor to the occurrence of sudden death in patients with cardiovascular disease. As left ventricular dysfunction deteriorates and symptoms of heart failure become evident, ambulatory ventricular arrhythmias become increasingly frequent and complex, and sudden cardiac death becomes an increasingly common occurrence. When the left ventricular ejection fraction has declined to less than 30 percent and symptoms of heart failure become refractory to treatment with digitalis and diuretics, 35 to 50 percent of patients will die of a lethal cardiac arrhythmia within three years. A number of factors interact to determine the occurrence of malignant ventricular arrhythmias in patients with congestive heart failure. Myocardial fibrosis and enhanced left ventricular wall stress may alter the electrophysiologic properties of the myocardium, but these factors may not be sufficient to explain the development of lethal rhythm disturbances. Neurohormonal activation may exacerbate the frequency and complexity of ambulatory arrhythmias in these patients, but such activation can persist for long periods without fatal electrophysiologic sequelae. Recent investigations suggest that electrolyte depletion may provide an important immediate precipitating cause for the occurrence of fatal ventricular tachyarrhythmias in the patient with severe left ventricular dysfunction whose susceptibility is markedly heightened by preexisting structural, hemodynamic, or neurohormonal factors. Further work is needed to determine if prophylactic therapy directed at preventing electrolyte depletion can favorably modify the long-term outcome of these severely ill patients.
Arrhythmias, Cardiac↗
Hemodynamic effects of BTS 49465, a new long-acting systemic vasodilator drug, in patients with severe congestive heart failure.
The hemodynamic effects of BTS 49465, a new oral, direct-acting systemic vasodilator drug, were investigated in 10 patients with severe chronic congestive heart failure. One to 2 hours after the administration of 1.5 mg/kg orally, BTS 49465 produced significant increases in cardiac index, stroke volume index, and stroke work index (26%, 27%, and 23%, respectively, p less than 0.01 to 0.001) and marked decreases in left ventricular filling pressure (-12.6 mm Hg, 44%), mean pulmonary artery pressure (-13.2 mm Hg, 31%), and mean right atrial pressure (-7.7 mm Hg, 63%), all p less than 0.001, without significant changes in heart rate. These hemodynamic responses were accompanied by notable declines in systemic vascular resistance (-28%, p less than 0.001) and pulmonary arteriolar resistance (-24%, p less than 0.05). These effects persisted throughout the 24-hour period of observation. The decline in left ventricular filling pressure in our patients ranged in magnitude from 8 to 21 mm Hg, and varied linearly and directly with pretreatment values for left ventricular filling pressure (r = 0.69). The decrease in systemic vascular resistance ranged in magnitude from 3% to 40% and varied linearly and directly with pretreatment values for systemic vascular resistance (r = 0.85). These data indicate that BTS 49465, a new oral, direct-acting vasodilator agent, exerts balanced cardiocirculatory effects in patients with severe chronic heart failure, which may be sustained with once-daily oral administration.
Administration, Oral↗
Influence of diabetes mellitus on changes in left ventricular performance and renal function produced by converting enzyme inhibition in patients with severe chronic heart failure.
Diabetes mellitus is frequently accompanied by specific abnormalities of the renin-angiotensin system, but it is not known whether these alterations modify the response to converting enzyme inhibition. To evaluate this possibility, 129 patients with severe chronic heart failure were treated with captopril or enalapril for one to three months, while doses of digoxin and diuretics were kept constant; 35 patients had diabetes mellitus. Prior to therapy, diabetic patients had lower plasma renin activity (3.4 +/- 0.5 versus 7.0 +/- 1.1 ng/ml/hour) than did nondiabetic control subjects (p less than 0.05); yet the initial hemodynamic response to captopril was similar in both groups. Plasma renin activity predicted the hypotensive response to the first dose of captopril in nondiabetic control subjects (r = 0.70, p less than 0.001) but not in diabetic patients (r = 0.29). During long-term treatment with captopril or enalapril, both diabetic and nondiabetic patients had similar increases in cardiac index and decreases in mean arterial pressure and systemic vascular resistance. Diabetic patients, however, showed larger reductions in left ventricular filling pressure (-13.8 versus -9.1 mm Hg, p less than 0.02) and mean right atrial pressure (-6.2 versus -3.9 mm Hg, p less than 0.05) than did nondiabetic subjects; this was accompanied by a notable decline in body weight in diabetic patients only. Renal function remained unaltered during converting enzyme inhibition in nondiabetic patients, but deteriorated significantly in diabetic patients, as reflected by a marked increase in serum creatinine concentration (1.7 +/- 0.1 to 2.1 +/- 0.1 mg/dl, p less than 0.001). In conclusion, despite lower pretreatment plasma renin activity, diabetic patients with severe chronic heart failure demonstrated improvement during long-term converting enzyme inhibition to a degree similar to (if not greater than) that seen in nondiabetic control subjects, but were more susceptible to the development of functional renal insufficiency than their nondiabetic counterparts. These differences are explicable by abnormalities of renin/aldosterone synthesis and angiotensin-mediated vasoregulation that are known to be present in the diabetic state.
Adult↗
Prognostic importance of the immediate hemodynamic response to nifedipine in patients with severe left ventricular dysfunction.
To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances. Groups 1 (hemodynamic improvement) and 2 (hemodynamic deterioration) were similar with respect to all demographic variables and pretreatment left ventricular performance (cardiac index, left ventricular filling pressure and systemic vascular resistance). Yet, the 1 year actuarial survival in patients in Group 1 was substantially better than that in patients in Group 2 (67 versus 23%, p = 0.009). Group 2, however, had higher values for plasma renin activity (17.7 +/- 6.0 versus 4.3 +/- 1.4 mg/ml per h, p less than 0.05), lower values for serum sodium concentration (134.6 +/- 1.2 versus 139.2 +/- 0.6 mEq/liter, p less than 0.05) and higher values for mean right atrial pressure (15.8 +/- 2.0 versus 7.9 +/- 1.4 mm Hg, p less than 0.01) than did patients in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure.
To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
How should we judge the efficacy of drug therapy in patients with chronic congestive heart failure? The insights of six blind men.
Explore the source record for details and available documents.
Diuretics↗
Can we expect vasodilator therapy to prolong life in patients with congestive heart failure?
Recent evidence from the Veterans Administration Vasodilator Heart Failure Trial supports the prophylactic use of a combination of hydralazine and isosorbide dinitrate to prolong life in patients with congestive heart failure. The clinical utility of such a combination vasodilator regimen may be limited, however, by its high frequency of adverse reactions, the lack of evidence that such a regimen enhances exercise tolerance, the inconvenience of taking a large number of tablets daily for a prophylactic indication, and the dearth of clinical experience combining hydralazine-nitrate with agents that may be clinically indicated to produce long-term symptomatic benefits (i.e., converting-enzyme inhibitors). Controlled evidence in animals and uncontrolled evidence in humans suggest that converting-enzyme inhibitors may also favorably modify prognosis, perhaps by antagonizing the deleterious actions of endogenous neurohormonal systems. Trials (presently in progress) are designed to evaluate the hypothesis that converting-enzyme inhibitors exert beneficial effects on the survival of patients with congestive heart failure comparable to those reported with hydralazine and isosorbide dinitrate.
Drug Therapy, Combination↗
Converting-enzyme inhibition in the management of severe chronic congestive heart failure: physiologic concepts.
Evidence from the experimental and clinical laboratory suggests that the heart failure state is characterized not only by an excessive degree of systemic vasoconstriction but also by an exaggerated neurohormonal response to the decline in cardiac performance. Therapeutic interventions directed only at the first abnormality may serve to exacerbate the second, and thus may fail to produce long-term hemodynamic and clinical benefits. Converting-enzyme inhibitors successfully antagonize both homeostatic malfunctions, and thus are among the few vasodilators that have been shown to produce consistent circulatory and symptomatic improvement in patients with severe chronic heart failure in controlled clinical trials; the responses to treatment with these agents have been superior to those seen during therapy with placebo or other vasodilator drugs. Furthermore, experimental and clinical evidence suggests that converting-enzyme inhibitors exert favorable effects on the survival of patients with severe heart failure; this potential has now been confirmed in a large-scale, multicenter, placebo-controlled trial. Despite its benefits, converting-enzyme inhibition may be accompanied by adverse circulatory and metabolic reactions (symptomatic hypotension, renal insufficiency, and potassium retention), which are predictable consequences of interference with the homeostatic role of angiotensin II in low-output states.
Angiotensin-Converting Enzyme Inhibitors↗
Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure.
Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.
Adult↗
Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure.
Support for the concept that neurohormonal mechanisms play an important role in determining the survival of patients with severe chronic heart failure is derived from two lines of evidence: circulating levels of neurohormones are markedly elevated in patients who have a poor long-term prognosis and the survival of high-risk patients may be favorably modified by treatment with specific neurohormonal antagonists. Plasma norepinephrine is a major prognostic factor in patients with severe chronic heart failure, the most markedly elevated levels being observed in patients with the most unfavorable long-term prognosis. Data from uncontrolled studies suggest that low-dose beta-blockade may improve the survival of patients with dilated cardiomyopathy. Similar trends were noted in the Beta-Blocker Heart Attack Trial, in which patients with congestive heart failure before or accompanying their acute myocardial infarction experienced a significant reduction in sudden death when treated with beta-blockers. In contrast, there appeared to be little selective benefit in patients without heart failure, who presumably had low circulating levels of catecholamines. Similarly, serum sodium concentration is a major prognostic factor in patients with severe chronic heart failure, the shortest survival being observed in patients with the most severe hyponatremia. The poor long-term outcome of hyponatremic patients appears to be related to the marked elevation of plasma renin activity in these individuals, since (in retrospective studies) hyponatremic patients appeared to fare significantly better when treated with converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II formation. In contrast, there appeared to be no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low. These data suggest that neurohormonal systems may exert a deleterious effect on the survival of some patients with severe chronic heart failure, which may be favorably modified by long-term treatment with specific neurohormonal antagonists.
Adrenergic beta-Antagonists↗
Adaptive and maladaptive actions of angiotensin II in patients with severe congestive heart failure.
The renin-angiotensin system appears to have evolved millions of years ago as a primary attempt to preserve circulatory homeostasis at a time when the principal cause of a low cardiac output was intravascular volume depletion. Angiotensin II supported systemic BP by direct systemic vasoconstriction, by facilitating the central and peripheral effects of the sympathetic nervous system, by promoting renal sodium retention by the production of aldosterone, and by increasing total body water by enhancing thirst and the synthesis of vasopressin. In addition, angiotensin II evolved as an important mechanism to preserve the glomerular filtration rate in low-flow states. These actions of angiotensin II were beneficial when the system first evolved, but its activation in patients with heart failure not only fails to reverse the low-output state but further exacerbates loading conditions in the left ventricle, thereby leading to worsening heart failure. Moreover, increased levels of angiotensin II cause heightened sympathetic nervous activity, potassium depletion, and hyponatremia, each of which can lead to further clinical deterioration. Therefore, activation of the renin-angiotensin system in heart failure might appear (at first) to be a maladaptive response. Recent evidence, however, suggests that this hormonal system continues (even in heart failure) to carry out the primary functions for which it was designed. Angiotensin II plays an important role in preserving systemic BP and in preserving the glomerular filtration rate as renal artery pressure and renal blood flow decline; in addition, by stimulating the synthesis of aldosterone, the renin-angiotensin system provides an important role for potassium disposal.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Survival in congestive heart failure during treatment with drugs with positive inotropic actions.
Retrospective studies have shown that patients with severe chronic heart failure who receive long-term treatment with positive inotropic agents have a high mortality rate, but in the absence of controlled trials it remains unclear whether the high incidence of fatal cardiovascular events in these patients is related to treatment or to the severity of the underlying disease. Most of the evidence that suggests a detrimental effect of positive inotropic therapy on survival remains circumstantial. The pooling of data from long-term studies of patients after an acute myocardial infarction suggests that use of digitalis may be associated with an unfavorable effect on survival. The prolonged administration of intravenous or oral catecholamines is associated with a high mortality rate, which may not be seen in similar patients treated conventionally. The presence of intrinsic sympathomimetic activity appears to neutralize the benefits of beta-blockade during the first year after an acute myocardial infarction; treatment with such agents after the first year may increase mortality. Long-term treatment with phosphodiesterase inhibitors is associated with a high mortality rate, which exceeds that reported in earlier years with vasodilator therapy. Nevertheless, most of these studies of positive intropic agents were not performed to evaluate the issue of survival and did not randomly assign patients to treatment groups. Hence, we do not know that the patients entered into these studies were truly comparable to their proposed control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiotonic Agents↗
Calcium-channel blockade in the management of severe chronic congestive heart failure: a bridge too far.
Because vasodilator therapy has become an established approach to the treatment of patients with severe chronic heart failure, there has been increasing interest in the use of the calcium channel-blocking drugs in the management of this disorder. This approach has particular appeal because approximately 60% of patients with heart failure have severe left ventricular dysfunction associated with coronary artery disease, and left ventricular systolic and diastolic performance in these patients may improve after interventions directed at improving myocardial blood flow. Unfortunately, all available calcium channel-blocking drugs possess potent negative inotropic effects; these are normally offset in patients without heart failure by activation of the sympathetic nervous system. Patients with severe left ventricular dysfunction, however, are exquisitely dependent on the transmembrane transport of calcium for maintenance of contractile function and show marked attenuation of adrenergic reflexes, which can no longer serve a homeostatic support function; hence, such patients are likely to experience notable cardiodepressant effects after calcium-channel blockade. In clinical trials, although some patients with severe chronic heart failure have been reported to benefit from short-term calcium-channel blockade, the hemodynamic benefits seen are modest compared with those from conventional vasodilator drugs, and little long-term improvement has been observed in randomized, double-blind trials. In addition, 10% to 40% of patients who receive short- and long-term therapy with verapamil, nifedipine, and diltiazem show evidence of serious hemodynamic or clinical deterioration.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Prolonging life in patients with congestive heart failure: the next frontier. Introduction.
Explore the source record for details and available documents.
Heart Failure↗
Comparison of captopril and enalapril in patients with severe chronic heart failure.
To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.
Adult↗
Comparative hemodynamic and clinical effects of long-term treatment with prazosin and captopril for severe chronic congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy.
Short- and long-term hemodynamic and clinical responses to sequential therapy with prazosin (15 mg/day for 3 to 12 weeks) and captopril (75 to 300 mg/day for 2 to 15 weeks) were compared in 22 patients with severe chronic congestive heart failure. First doses of prazosin produced marked increases in cardiac index and stroke volume index (p less than 0.01), but these effects were lost during long-term treatment. First doses of captopril produced only modest increases in both variables, but these persisted without attenuation during prolonged therapy. Both drugs produced immediate decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure and systemic vascular resistance; these changes became significantly attenuated (p less than 0.01) with prazosin but not with captopril. At the end of treatment, stroke volume index was significantly higher and right and left ventricular filling pressures were significantly lower with captopril than with prazosin (p less than 0.05 to 0.01). Only 8 of the 22 patients (36%) treated with prazosin benefited clinically, whereas 14 of 19 patients (74%) treated with captopril felt that they had improved (p less than 0.05). These differences could not have been predicted by comparing responses to first doses of the 2 drugs. These findings indicate that the choice of 1 vasodilator drug over another in patients with congestive heart failure should be based on studies that compare their long-term rather than short-term hemodynamic and clinical effects.
Adult↗