Quantitative differences in the hemodynamic effects of captopril and nitroprusside in severe chronic heart failure

The hemodynamic effects of oral captopril and intravenous nitroprusside were compared in 15 patients with severe chronic congestive heart failure. At doses of both drugs titrated so as to produce similar decreases in systemic vascular resistance in each patient, nitroprusside produced substantially greater increases in cardiac index (+0.67 versus +0.31 liters/min/m2, p less than 0.01) but smaller decreases in mean arterial pressure (-18.4 versus -11.0 mm Hg, p less than 0.01) than did captopril. This finding was due to a significant decrease in heart rate with captopril (-7 beats/min, p less than 0.01) which was not seen with nitroprusside, since changes in stroke volume index with both drugs were similar. Nitroprusside produced a decrease in pulmonary arteriolar resistance quantitatively similar to the decrease in systemic vascular resistance, but the decrease in pulmonary arteriolar resistance with captopril was not significant. Despite similar decreases in systemic resistance, captopril produced a greater decrease in left ventricular filling pressure (-10.2 versus -6.9 mm Hg, p less than 0.01) but a smaller decrease in mean right atrial pressure (-3.1 versus -5.3 mm Hg, p less than 0.01) than did nitroprusside. Thus, captopril has actions independent of its systemic vasodilator effects which account for the quantitative differences observed in its hemodynamic responses compared with those of nitroprusside in patients with severe chronic heart failure. These differences support experimental evidence that angiotensin, in addition to its direct systemic arterial vasoconstrictor actions, exerts positive chronotropic effects and alters ventricular compliance but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature.     

Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure

The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodilator and inotropic therapy for severe chronic heart failure: passion and skepticism

Although substantial progress has been made in the last 5 years in the development of vasodilator and inotropic drugs for the management of patients with severe chronic heart failure, much of the enthusiasm that surrounded the introduction of many of these agents has subsequently been tempered by reports of drug failure or adverse reactions. In this review and analysis, currently available vasodilator and inotropic agents are critically and comparatively evaluated to assess their respective advantages and limitations. It is apparent that the ability of most of these drugs to produce substantial clinical benefits in patients with severe heart failure has probably been overstated. Therapy fails to achieve the desired clinical results all too frequently, possibly as the result of: the choice of an ineffective drug; the administration of an effective drug in subtherapeutic doses; the administration of an effective drug to improperly selected patients; the failure of initial hemodynamic benefits to be sustained; the occurrence of severe or serious adverse reactions; and the failure to alter concomitant therapy appropriately. The present analysis indicates that there is no uniformly effective or safe vasodilator or inotropic drug for patients with severe heart failure; all agents have important limitations. Of the available therapeutic choices, however, long-term converting enzyme inhibition appears to produce more consistent hemodynamic and clinical benefits with an acceptable degree of adverse reactions than other pharmacologic approaches for the management of these severely ill patients.     

Failure of low doses of amrinone to produce sustained hemodynamic improvement in patients with severe chronic congestive heart failure

Although amrinone produces acute hemodynamic improvement in patients with severe chronic congestive heart failure (CHF), it has not produced clinical benefits in long-term controlled trials. To determined if the administration of subtherapeutic doses of amrinone may account for its lack of efficacy in these studies, the dose requirements of the drug were investigated in 30 patients with severe CHF. Doses of 100 mg of oral amrinone produced moderate increases in cardiac index (0.35 liters/min/m2) and decreases in pulmonary capillary wedge pressure (6.8 mm Hg) and systemic vascular resistance (16%) (all p less than 0.01); these effects, however, were short-lived (less than 2.5 hours). Doses of 200 mg of oral amrinone produced marked increases in cardiac index (0.56 liters/min/m2) and substantial decreases in left ventricular filling pressure (9.9 mm Hg) and systemic vascular resistance (30%) (all p less than 0.01), and these effects persisted for longer than 4 hours. Only 4 patients showed hemodynamic responses with 100 mg of the drug that were sufficiently marked and long-lasting to merit chronic therapy, whereas 28 patients had such a response with the 200-mg dose. When 200 mg of amrinone was administered orally every 8 hours, sustained hemodynamic benefits were seen for 48 hours. However, 16 of 22 patients who received 600 mg of the drug daily for more than 1 week had intolerable adverse reactions that required drug withdrawal. In conclusion, hemodynamically effective doses of amrinone (600 mg/day) cannot be tolerated for long periods by most patients with severe chronic CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Provocation of myocardial ischemic events during initiation of vasodilator therapy for severe chronic heart failure: Clinical and hemodynamic evaluation of 52 consecutive patients with ischemie cardiomyopathy

Although hydralazine provokes myocardial ischemie events in hypertensive patients not in heart failure by producing reflex tachycardia, the frequency of and mechanisms underlying ischemie events when this drug is administered as a vasodilator agent to patients with heart failure is unknown. The responses to hydralazine in 52 consecutive patients with severe chronic heart failure secondary to coronary artery disease were reviewed. Twelve patients (23 percent) had 16 ischemie events during the initial administration of hydralazine (angina at rest in 12 and myocardial infarction in 4); these generally occurred in the absence of significant tachycardia and hypotension. Thirty-five of the 52 patients received nitroprusside (8 of whom had ischemie events with hydralazine), but this drug provoked ischemia in only 1 of the 35 although it resulted in greater decreases in systemic arterial pressure than occurred with hydralazine. In patients with an ischemie event only with hydralazine, left ventricular filling pressure decreased 14.6 mm Hg with nitroprusside but only 3.9 mm Hg with hydralazine (probability [p] < 0.01). Provocation of ischemia with hydralazine may therefore be due to the relative preservation of elevated left ventricular preload with this drug, since ischemie events are not common with nitroprusside despite greater decreases in systemic pressures.     

Efficacy of captopril in low-renin congestive heart failure: importance of sustained reactive hyperreninemia in distinguishing responders from nonresponders

To determine the efficacy of converting-enzyme inhibition in patients with low-renin congestive heart failure (CHF), the long-term hemodynamic and clinical responses to captopril were evaluated in 26 consecutive patients with severe, chronic CHF whose pretreatment plasma renin activity (PRA) was less than 2 ng/ml/hour. After 2 to 8 weeks of continuous treatment with captopril, 14 patients (54%) showed long-term hemodynamic benefits, of whom 13 (50%) improved clinically by at least 1 New York Heart Association functional class. To distinguish responders from nonresponders, patients were grouped based on the presence or absence of sustained reactive hyperreninemia (PRA during chronic therapy greater than 4 ng/ml/hour). After 2 to 8 weeks of therapy with captopril, 14 patients had sustained reactive hyperreninemia. Their cardiac index increased by 0.33 liters/min/m2 (p less than 0.01), left ventricular filling pressure decreased by 12.6 mm Hg (p less than 0.001), mean right atrial pressure decreased by 4.9 mm Hg (p less than 0.001) and systemic vascular resistance decreased by 529 dyne s cm-5 (p less than 0.001). Twelve of these 14 patients improved clinically. Twelve other patients had no reactive increase in PRA, and these patients showed no significant improvement in any hemodynamic variable after 2 to 8 weeks of treatment with captopril; only 1 of the 12 patients improved clinically (p less than 0.001 between groups). The 2 groups were otherwise similar with regard to pretreatment demographic, hemodynamic and hormonal variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and clinical effects of combined verapamil and propranolol therapy in angina pectoris

Because of their common negative chronotropic and inotropic effects, combined therapy of beta-adrenergic blocking drugs and calcium channel antagonists has long been feared to produce synergistic cardiodepressant effects. To evaluate whether such fears are justified when such therapy is used in patients with angina pectoris, five hemodynamic and clinical studies were reviewed. These studies indicated that in patients with preserved ventricular function treated with low or moderate doses of propranolol, verapamil produced little change in cardiac performance; this finding was not significantly different from the effects of verapamil in the absence of beta-blockade. In patients receiving large doses of propranolol, verapamil produced modest but significant cardiodepressant effects; these could be avoided by withdrawal of propranolol for 24 hours. Adverse reactions, when they occurred, were primarily hemodynamic rather than electrophysiologic.Short-term (48 hours) and long-term (4 weeks) randomized controlled trials, which objectively evaluated exercise tolerance in patients with angina pectoris, demonstrated that combined therapy of verapamil and propranolol was superior not only to placebo but also to either drug alone. In patients with preserved left ventricular function, the incidence of adverse effects with combined therapy was small (less than 10%) but increased to 25% in patients with poor left ventricular performance (ejection fraction less than 30%). Combined therapy of nifedipine and propranolol also produced adverse hemodynamic and clinical reactions.Combined therapy of beta-adrenergic and calcium channel antagonists can provide substantial clinical benefits for patients with angina pectoris who remain symptomatic with either agent used alone. Because adverse effects can occur, however, patients being considered for such treatment need to be carefully selected and observed.     

Differences in hemodynamic effects of nitroprusside and prazosin in severe chronic congestive heart failure: evidence for a direct negative chronotropic effect of prazosin.

To compare the hemodynamic effects of prazosin and nitroprusside in patients with severe congestive heart failure, nine patients with heart failure refractory to conventional therapy received oral prazosin and intravenous nitroprusside administered so as to produce a similar decrease in left ventricular filling pressure in each patient. By this comparison, both drugs produced similar decreases in mean right atrial pressure, mean pulmonary arterial pressure and systemic and pulmonary vascular resistance. However, with nitroprusside, cardiac index increased more (+0.97 versus +0.73 liters/min per m2, P less than 0.01) and mean arterial pressure decreased less (-13.7 versus -18.3 mm Hg, P less than 0.05) than with prazosin. Both drugs produced similar changes in stroke volume index (+11.7 cc/beat per m2 with nitroprusside and +12.5 with prazosin) and stroke work index (+8.1 g-m/m2 with nitroprusside and +6.6 with prazosin). Therefore, the differences in the hemodynamic responses observed with the two agents were due to the significantly greater decrease in heart rate with prazosin (-8 beats/min) than with nitroprusside (-2 beats/min, P less than 0.05). These clinical data support experimental evidence suggesting that there is a significant negative chronotropic action of prazosin independent of its peripheral vascular effects.     

Coronary flow studies in patients with left ventricular hypertrophy of the hypertensive type. Evidence for an impaired coronary vascular reserve

Increased myocardial blood flow occurs in ventricular hypertrophy, but flow per 100 grams of myocardium remains normal. The increase in flow may be obtained at the expense of the existing coronary vascular reserve or by an increase in the vascular bed. The coronary vascular reserve was studied by analyzing the hyperemic reaction to selective injection of contrast agent into the coronary arteries in 25 patients: a control group (9 patients) with chest pain syndrome, normal coronary arteries and a normal left ventricle (Group I) and 16 patients with aortic stenosis, left ventricular hypertrophy and normal coronary arteries (Group II). The hyperemic response in Groups I and II was 73.3 +/- 2.2 and 65.8 +/- 9.1 percent, respectively (difference not significant). Group II was subdivided into two groups: Group IIA had five patients with a left ventricular mass of less than 200 g (mean 158.8 +/- 25.9); this group had a hyperemic response of 102.3 +/- 9.9 percent. Group IIB had 11 patients with a left ventricular mass of more than 200 g (mean 308.9 +/- 22.5) and a hyperemic response of 49.27 +/- 10.42 percent. The hyperemic response was correlated with the diastolic left ventricular-aortic gradient (r = +0.64, p less than 0.001), left ventricular mass (r = -0.51, p less than 0.01) and aortic diastolic pressure (r = +0.636, p less than 0.001). Group I had a left ventricular mass similar to that of Group IIA (124.9 +/- 9 and 158.8 +/- 26 g, respectively) but a lower hyperemic response (73.3 +/- 2 and 102.3 +/- 10 percent, respectively). These data suggest that severe left ventricular hypertrophy is associated with a reduction in coronary vascular reserve; it is speculated that this decrease in the vascular reserve capacity may be related to the ischemic component of hypertrophic heart disease.     

Systematic analysis of contrast echocardiograms

Contrast echocardiography was first described in 1968. Since then, many reports have described clinical and experimental uses for the technique. Contrast echocardiography is performed at least occasionally in most echocardiography laboratories, but most physicians use this technique merely to determine the presence of a shunt or, more rarely, for structure identification. Contrast echocardiography can provide much more information. Some different types of information available from contrast echocardiographic records are discussed, including timing of contrast appearance within the cardiac cycle, relative timing of appearance in different cardiac structures, relative intensity of contrast opacification, cyclical changes in contrast opacification, negative contrast effect, slope of contrast trajectories on M-mode contrast echocardiography, and clearance times.     

Diagnosing tricuspid regurgitation by direct imaging of the regurgitant flow in the right atrium using contrast echocardiography

To determine whether tricuspid regurgitation (TR) can be diagnosed by direct imaging of regurgitant flow in the right atrium (RA) using contrast echocardiography, echocardiography was performed in 35 patients using peripheral intravenous injections of 5% dextrose solution. Fifteen patients had TR judged by v-wave synchronous contrast appearance on the inferior vena cava echogram (a previously validated method for diagnosing TR), 5 of whom had clinically obvious TR. Twenty patients had no TR on inferior vena cava contrast echocardiography, 9 of whom were normal volunteers. On subsequent blind review, 13 of the 15 patients with TR were correctly identified on the basis of the regurgitant contrast flow just posterior to the tricuspid valve in the RA. Of the 20 without TR, 19 were correctly identified and there was 1 false-positive result. Using different criteria for the diagnosis (insisting on imaging of flow across the tricuspid valve in systole), another blinded observer correctly diagnosed only 8 of the 15 patients as having TR, but had no false-positive results. To avoid false-positive results, it is important to realize that there are 2 regions where retrograde flow can normally be seen in the RA: (1) briefly at the onset of systole coincident with tricuspid valve closure, and (2) in the posterior RA, as distinct from the anterior RA area just behind the tricuspid valve where TR is diagnosed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic and pharmacologic determinants of vasodilator response: A conceptual framework for rational drug therapy for chronic heart failure

This article has attempted to summarize the increasing number of pharmacologic and physiologic variables that are being recognized as important determinants in the response to vasodilator therapy in patients with severe chronic heart failure. It is apparent that a careful consideration of many factors is necessary before proper selection of a specific drug can be made for a specific patient, since not all patients with refractory heart failure demonstrate beneficial hemodynamic and clinical responses to all agents. Each patient presents us with a unique set of physiologic variables; each drug has its own advantages and limitations. Identification of those subgroups of patients most likely to benefit from a specific agent or combination of agents is a major goal for future research. Although a number of hemodynamic variables can be made to improve acutely with a wide variety of vasodilator drugs, well tolerated sustained meaningful clinical benefits are probably observed in relatively few patients. Rational and successful vasodilator therapy is possible only through a highly individualized approach.     

Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction

It has previously been shown that analysis of coronary morphology can separate unstable from stable angina. An eccentric stenosis with a narrow neck or irregular borders, or both, is very common in patients who present with acute unstable angina, whereas it is rare in patients with stable angina. To extend these observations to myocardial infarction, the coronary morphology of 41 patients with acute or recent infarction and nontotally occluded infarct vessels was studied. For all patients, 27 (66%) of 41 infarct vessels contained this eccentric narrowing, whereas only 2 (11%) of 18 noninfarct vessels with narrowing of 50 to less than 100% had this lesion (p less than 0.001). In addition, a separate group of patients with acute myocardial infarction who underwent intracoronary streptokinase infusion were also analyzed in similar fashion. Fourteen (61%) of 23 infarct vessels contained this lesion after streptokinase infusion compared with 1 (9%) of 11 noninfarct vessels with narrowing of 50 to less than 100% (p less than 0.01). Therefore, an eccentric coronary stenosis with a narrow neck or irregular borders, or both, is the most common morphologic feature on angiography in both acute and recent infarction as well as unstable angina. This lesion probably represents either a disrupted atherosclerotic plaque or a partially occlusive or lysed thrombus, or both. The predominance of this morphology in both unstable angina and acute infarction suggests a possible link between these two conditions. Unstable angina and myocardial infarction may form a continuous spectrum with the clinical outcome dependent on the subsequent change in coronary supply relative to myocardial demand.     

Spectrum of exercise thallium-201 myocardial perfusion imaging in patients with chest pain and normal coronary angiograms.

Twenty-seven consecutive patients with chest pain and no significant obstructive coronary lesions on arteriography were studied with thallium-201 myocardial imaging during exercise and at rest. Fifteen of the patients had typical and 12 atypical angina pectoris. All underwent treadmill exercise electrocardiographic testing; the results were abnormal in 10 patients (37 percent), normal in 14 (52 percent) and uninterpretable in 3 (11 percent). The exercise and resting thallium-201 myocardial images were normal in 23 patients (85 percent); the results of exercise testing were normal in 12 of these patients, abnormal in 8 and uninterpretable in 3. Four patients had a perfusion defect on exercise thallium-201 myocardial imaging; the defect filled in by 4 hours in two patients but persisted in the other two. In contrast, when thallium-201 myocardial imaging was performed in 28 consecutive patients with angiographic coronary artery disease, only 5 patients (16 percent) had normal exercise and resting thallium-201 myocardial images. Therefore, thallium-201 myocardial imaging offers a more effective means of identifying patients with chest pain and no obstructive coronary artery disease than the clinical history or the exercise electrocardiographic test, or both. However, 15 percent of these patients will have abnormal exercise thallium-201 myocardial images because of factors that have not yet been identified.     

Hemodynamic effects of captopril in patients with severe chronic heart failure

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 ± 0.14 to 2.28 ± 0.30 liters/min/m² (p < 0.05) while pulmonary capillary wedge pressure decreased from 22.7 ± 2.0 to 14.7 ± 4.7 mm Hg (p < 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 ± 6.7 to 71.2 ± 12.0 mm Hg (p < 0.001) and from 1,909 ± 246 to 1,362 ± 347 dynes-s-cm⁵ (p < 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = ?0.82, p < 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).