Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

BACKGROUND: Digitalis glycosides have been in clinical use in the treatment of congestive heart failure (CHF) for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was published in 1990, an update is required to include more current trials. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating CHF in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme inhibitors, and beta-blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with "CHF due to systolic dysfunction" vs. "CHF with preserved systolic function." SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) 2003 Issue 4, MEDLINE (1966 to December 2003) and EMBASE (1990 to December 2003) were searched. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were also searched from 1996-2003. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic CHF who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of CHF such as acute ischemic heart disease or myocarditis was present. DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were evaluated as a joint effort of the coauthors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials. MAIN RESULTS: Thirteen articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show that there is no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. REVIEWERS' CONCLUSIONS: The literature indicates that digitalis has a useful role in the treatment of patients with CHF who are in normal sinus rhythm.

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

BACKGROUND: Digitalis glycosides have been in clinical use in the treatment of congestive heart failure for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was recently published, an update is required to include more current trials. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating congestive heart failure in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme (ACE) inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with diastolic vs. systolic dysfunction. SEARCH STRATEGY: Electronic databases were searched between 1966 and 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996-2000. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic congestive heart failure who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure such as acute ischemic heart disease or myocarditis was present. DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were reviewed by one of the coauthors, and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, UK. MAIN RESULTS: Eleven articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 10 of these selected studies, were recorded and analyzed. The data show that there is no difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. REVIEWER'S CONCLUSIONS: The literature indicates that digitalis has a useful role in the treatment of patients with congestive heart failure who are in normal sinus rhythm.

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

BACKGROUND: Digitalis glycosides have been in clinical use in the treatment of congestive heart failure for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was recently published, an update is required to include more current trials. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating congestive heart failure in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, ACE inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with diastolic vs. systolic dysfunction. SEARCH STRATEGY: Electronic databases were searched between 1966 and 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996-2000. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic congestive heart failure who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure such as acute ischemic heart disease or myocarditis was present. DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were reviewed by one of the coauthors, and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, UK. MAIN RESULTS: Eleven articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon on 8, 4, and 10 of these selected studies, were recorded and analyzed. The data show that there is no difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. REVIEWER'S CONCLUSIONS: The literature indicates that digitalis has a useful role in the treatment of patients with congestive heart failure who are in normal sinus rhythm.

Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators.

In the Studies of Left Ventricular Dysfunction (LVD), enalapril or placebo was administered in a double-blind fashion to 6797 participants with ejection fraction < or = 0.35. During 40 months' average follow-up, 28.1% of participants randomized to enalapril reported side effects compared with 16.0% in the placebo group (p < 0.0001). Enalapril use was associated with a higher rate of symptoms related to hypotension (14.8% vs 7.1%, p < 0.0001), azotemia (3.8% vs 1.6%, p < 0.0001), cough (5.0% vs 2.0%, p < 0.0001), fatigue (5.8% vs 3.5%, p < 0.0001), hyperkalemia (1.2% vs 0.4%, p = 0.0002), and angioedema (0.4% vs 0.1%, p < 0.05). Side effects resulted in discontinuation of blinded therapy in 15.2% of the enalapril group compared with 8.6% in the placebo group (p < 0.0001). Thus enalapril is well tolerated by patients with LVD; however, hypotension, azotemia, cough, fatigue, and other side effects result in discontinuation of therapy in a significant minority of patients.

Incomplete, delayed functional recovery late after reperfusion following acute myocardial infarction: "maimed myocardium".

The objective of the current editorial is to introduce a new concept ("maimed myocardium") that we believe describes more accurately the incomplete, delayed recovery of LV function that may occur late after reperfusion after AMI. It has been demonstrated previously that myocardium remains viable for a prolonged period in many patients with nonsustained coronary occlusion, despite the occurrence of myocardial necrosis; late reperfusion may result in myocardial salvage in reversibly ischemic (stunned) segments (complete recovery) and in intensely injured (maimed) segments that display partial return of LV function over time (incomplete recovery). Clinically, the basis for maimed myocardium is the observation that delayed, LV functional recovery may occur in partially infarcted segments where there has been an antecedent ischemic insult of sufficient duration to result in some degree of myocardial necrosis. Certain acute coronary syndromes characterized by nonsustained coronary occlusion followed by spontaneous reperfusion (e.g., non-Q-wave AMI) or drug-induced reperfusion induced by the exogenous administration of thrombolytic therapy are associated with incomplete, delayed recovery of LV function as detected clinically by partial improvement in serial radionuclide-ejection measurement, enhanced metabolic integrity of cardiac tissue by F-18 deoxyglucose myocardial imaging, and scintigraphic findings of reverse thallium redistribution--findings that support the presence of partially viable myocardium that has been incompletely salvaged during reperfusion late after AMI. Experimentally, delayed LV functional recovery has been reported in animal models in which prolonged coronary occlusion (hours to days) followed by reperfusion is associated with late recovery of regional LV function in myocardial segments subtending border (stunned) zones and central infarct (maimed) zones. In studies in animals and human beings, postextrasystolic potentiation and pharmacologic inotropic interventions may augment maimed and stunned segments, although the magnitude of regional contractile reserve that can be unmasked with these interventions is quantitatively less in the maimed than in stunned segments. In summary, the propensity of intensely injured or partially infarcted LV segments to display intermediate functional recovery followed by reperfusion late after coronary occlusion suggests that even severely depressed but residually viable cardiac muscle can be salvaged incompletely over time.(ABSTRACT TRUNCATED AT 400 WORDS)

Dobutamine effects on systole and diastole in rats with myocardial infarction.

In this article, the authors attempt to determine the effect of catecholamine stimulation on the systolic and diastolic properties of the left ventricle (LV) in rats with chronic infarction. Male Sprague-Dawley rats underwent coronary artery ligation at 8-10 weeks of age. Baseline hemodynamics were measured 1-2 months after infarction. Dobutamine was administered in bolus injections of increasing concentrations, and peak hemodynamic response after each dose was recorded. Rats were divided into three groups: controls (n = 14), rats with infarct size less than 30% of LV (n = 13), and rats with infarct size at least 30% of LV (n = 9). Baseline hemodynamics were similar among the three groups. There was no significant difference in the maximal response of LV systolic pressure and heart rate between the three groups. Left ventricle +dP/dt increased with dobutamine in all three groups, but rats with infarct size of at least 30% had a significantly smaller increase above baseline as compared with control rats. In contrast, LV -dP/dt increased to a similar degree in all three experimental groups with dobutamine. Although hemodynamics can be affected by loading conditions in the intact animal, the magnitude of the change in +dP/dt with unaltered -dP/dt suggests that there is an impaired inotropic but not lusitropic response to catecholamine stimulation in rats with large chronic myocardial infarcts. The findings imply a differential effect of beta-agonist stimulation on systolic and diastolic properties of the heart.

Contraction band necrosis: its modification by the free radical scavenger N-2-mercaptopropionyl glycine.

Contraction band necrosis (CBN) may represent infarct extension from free radical generation during reperfusion. We sought to limit CBN with the free radical scavenger N-2-mercaptopropionyl glycine (MPG, 20 mg/kg). Sixteen chronically instrumented Beagles (8 control, and 8 MPG treated) underwent 90-min left anterior descending coronary artery (LAD) occlusion followed by 6-h reperfusion. Coronary blood flow (CBF) was measured by the radioactive microsphere technique. The dogs were killed, and the hearts were perfused with red and blue dyes to determine area at risk (AAR), stained with nitroblue tetrazolium for infarct localization, and sectioned for histologic analysis and BF measurements. In controls and MPG-treated animals, infarct/risk ratios were 40 +/- 5 and 38 +/- 6%, and epicardial collateral BFs were 0.21 +/- 0.037 and 0.15 +/- 0.034 ml/g/min, respectively (p = NS). Hemodynamic measurements did not differ between the two groups. However, CBN as a percentage of total infarct was reduced in controls (22 +/- 3%) as compared with MPG-treated animals (35 +/- 2%, p = 0.002). Thus, MPG altered the histologic composition of infarcts in this model, surprisingly increasing the amount of CBN without altering overall infarct size (IS). These results raise questions about the role of free radical scavengers in generation of CBN and suggest that a population of cells exists in which treatment with MPG may alter the mechanism of cell death.

Nitroprusside infusion improves arterial baroreflex control of heart rate in dogs with chronic congestive heart failure.

To determine if nitroprusside improves arterial baroreflex responsiveness in chronic congestive heart failure (CHF), we administered nitroprusside to 11 conscious dogs with pacing-induced CHF. Baroreflex sensitivity was determined by plotting the R-R interval against systolic aortic pressure after a bolus injection of phenylephrine (PE). At baseline, dogs with CHF had higher heart rate (HR), increased left atrial blood pressure (BP), and reduced left ventricular (LV) dP/dt as compared with 10 sham-operated normal animals. Baroreflex sensitivity index was significantly lower in CHF dogs, (8.3 +/- 1.3 ms/mm Hg) than normal dogs (25.1 +/- 1.2 ms/mm Hg, p < 0.001). Intravenous (i.v.) administration of nitroprusside (1 microgram/kg/min) to CHF dogs decreased left atrial BP (23 +/- 1-17 +/- 1 mm Hg) and HR (131 +/- 4-115 +/- 4 beats/min), but had no significant effect on either cardiac output (CO) or systolic aortic BP. This resulted in a 58% increase in baroreflex sensitivity index to 13.1 +/- 1.3 ms/mm Hg (p < 0.001); and the change correlated significantly with magnitude of decrease in left atrial BP (r = 0.884, p < 0.001) but not with the increase in R-R interval (r = 0.390, p > 0.10). In contrast, administration of nitroprusside sufficient to decrease left atrial BP (9.0 +/- 1.4-6.4 +/- 1.2 mm Hg) did not alter baroreflex sensitivity (26.4 +/- 3.4-26.4 +/- 3.9 ms/mm Hg) in 5 normal dogs. The results suggest that nitroprusside infusion increases arterial baroreflex sensitivity only in dogs with CHF and that this effect is probably functionally linked to the reductions of cardiac filling pressure.

Mechanical abnormalities in the rat ischemic heart failure model which lie downstream to cAMP production.

OBJECTIVE: We previously showed diminished inotropic responses to isoproterenol in uninfarcted posterior papillary muscles of rats with anterior wall infarcts comprising > or = 30% of the left ventricle. We have also shown that this occurs in the absence of beta-receptor downregulation. Our objective was to show a mechanical defect in the rat infarct model which is secondary to cellular defects downstream to cAMP production. METHODS: Sprague-Dawley rats were infarcted via coronary ligation. After 3 weeks, the uninfarcted papillary muscle was placed in a muscle bath and exposed to increasing concentrations of dibutyryl cAMP while contracting isometrically at 28 degrees C. RESULTS: The large infarct group showed evidence of right ventricular hypertrophy which was manifested by an increased right ventricular mass. No differences were found in baseline measurements of developed tension (DT); rate of tension development (dT/dt); rate of relaxation (-dT/dt); time to peak tension (TPT); and relaxation time (t1/2R). When these muscles were stimulated with dibutyryl cAMP, the large infarct group had a reduced inotropic response as measured by +dT/dt and TPT. No consistent abnormalities were noted in relaxation. The findings are similar to those we noted previously with isoproterenol stimulation. CONCLUSION: The impaired response to beta stimulation in uninfarcted myocardium from rats with large myocardial infarctions is due to cellular defects which lie downstream to cAMP production.

Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content.

We used the rapid ventricular pacing model to examine myocardial norepinephrine (NE) uptake kinetics in congestive heart failure. Dogs subjected to pacing at 225 beats/min for 8 wk developed heart failure as evidenced by elevated left atrial pressure, depressed first derivative of left ventricular pressure with respect to time, and depressed cardiac output compared with dogs paced at 100 beats/min for 8 wk. Fast-paced dogs also exhibited an elevated plasma NE and reduced myocardial NE content. Myocardial NE uptake kinetics and interstitial NE concentration were measured in vivo using a triple-isotope intracoronary tracer technique. The rate constant of neuronal uptake of NE was significantly depressed in the fast-paced animals (0.224 +/- 0.027 vs. 0.725 +/- 0.097 s-1, P < 0.001), while the interstitial NE concentration was significantly increased in the heart (1.12 +/- 0.15 vs. 0.17 +/- 0.07 ng/ml, P < 0.001). Myocardial beta-adrenoceptor density was significantly reduced in the fast-paced animals (49 +/- 7 vs. 86 +/- 6 fmol/mg, P < 0.001), and there was a significant inverse correlation between beta-adrenoceptor density and interstitial NE concentration. Thus we conclude that excess myocardial interstitial NE content contributes to the abnormalities in the beta-adrenoceptor system.

Effects of metoprolol on left ventricular function in rats with myocardial infarction.

To study the effect of beta-receptor-blocking agents in an animal model of left ventricular (LV) dysfunction, we measured LV performance in vivo and in vitro in 69 rats with or without metoprolol (M) treatment 3 wk after left coronary arterial ligation or sham operation. Rats were divided into six groups including control (C) and M noninfarct (C-N and M-N), C and M small infarct (C-S and M-S), and C and M large infarct (C-L and M-L). LV function was measured as slope of change in systolic vs. diastolic pressure (pressure-function curve) during pressor response after administration of a bolus of phenylephrine (5 micrograms/kg i.v.). Reduction of LV function was noted in C-L compared with C-N and C-S (slope of pressure-function curve 3.3 +/- 0.3 vs. 11.0 +/- 1.9 and 11.9 +/- 2.3, respectively) and in M-L compared with M-N and M-S rats (slope of 5.5 +/- 1.4 vs. 11.3 +/- 2.0 and 12.1 +/- 1.4, respectively). There was no significant difference between C and M rats, although there was a trend toward partial correction of the pressure-function curves in M-L compared with C-L rats. In muscle bath preparations the uninfarcted LV posterior papillary muscle from shams and rats with small infarcts showed a dose-related increase in peak rate of tension development with isoproterenol stimulation, but this response was lacking in both C-L and M-L. Tissue assays showed no change in beta-receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term effects of naloxone on hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure.

OBJECTIVES: The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing. BACKGROUND: We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role n mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial. METHODS: We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RR interval. RESULTS: Plasma beta-endorphin levels were elevated in dogs with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure. CONCLUSIONS: The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.

Role of converting enzyme inhibitors in the treatment of heart failure.

Treatment with angiotensin-converting enzyme inhibitors has proved to be effective in relieving symptoms of congestive heart failure. With recognition of the high mortality rate that accompanies heart failure, the question has arisen whether angiotensin-converting enzyme inhibitors may also improve survival. Early trials of the vasodilator combination hydralazine plus nitrates (V-HeFT trial) showed a strong trend toward a reduction in mortality, and a subsequent trial of the angiotensin-converting enzyme inhibitor enalapril in a population of patients with end-stage heart failure (CONSENSUS trial) showed a highly significant reduction in the mortality. The SOLVD trial was begun in 1986 to determine whether enalapril could reduce morbidity and mortality in patients with mild to moderate congestive failure (primarily New York Heart Association classes II and III), as well as in asymptomatic patients with a low ejection fraction. This report presents the results in patients with symptoms of congestive failure who were studied in the SOLVD treatment trial. A total of 2,569 patients were recruited into the trial, with an average follow-up period of 41.4 months. There was a 16% reduction in mortality in the enalapril-treated group compared with that of patients receiving placebo (p = 0.0036), as well as a 26% reduction in the combined end point of death plus hospital admission for congestive failure (p < 0.0001). Compared with placebo, enalapril significantly reduced the incidence of death due to progressive heart failure but apparently had no effect on sudden death. The results clearly indicate that the angiotensin-converting enzyme inhibitor enalapril can reduce both morbidity and mortality in symptomatic congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.

BACKGROUND: It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure. METHODS: Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months. RESULTS: There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P less than 0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group; vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P less than 0.001). CONCLUSIONS: The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril.

Beta-adrenoceptor and adenylate cyclase function in the infarct model of rat heart failure.

In order to determine the possible etiology for diminished inotropic responsiveness to catecholamines in the infarction model of chronic congestive heart failure in rats, we studied beta-adrenoceptor number and site-specific stimulated adenylate cyclase activity in noninfarcted left ventricular tissue of rats at 3 months after ligation of the left coronary artery. Rats were divided into sham, small infarct, and large infarct groups according to infarct size. The large infarct groups showed increased right ventricle to body weight ratio (0.93 +/- 0.07 mg/g for the large infarcts vs 0.52 +/- 0.02 and 0.54 +/- 0.02 mg/g for the shams and small infarcts, respectively). Beta-Adrenoceptor number among the groups was similar (shams, 27 +/- 1 fmol/mg; small infarcts, 26 +/- 1 fmol/mg; and large infarcts, 29 +/- 1 fmol/mg), as was Kd (20 +/- 1 pmol, 18 +/- 2 pmol, and 18 +/- 2 pmol, respectively). Site-specific stimulation of adenylate cyclase using isoproterenol, Gpp(NH)p, forskolin, and MnCl2 revealed no significant differences among the groups. We conclude that this system is not responsible for the altered inotropic responsiveness to catecholamines seen in this model.

Initial blood pressure response to enalapril in hospitalized patients (Studies of Left Ventricular Dysfunction [SOLVD]).

Studies of Left Ventricular Dysfunction (SOLVD) is a randomized trial of enalapril versus placebo in reducing mortality in patients with cardiac dysfunction (defined as left ventricular ejection fraction less than or equal to 35%). Before randomization, patients at risk for hypotension were hospitalized for a test dose of 2.5 mg of enalapril administered orally at baseline and again 12 hours later. As of February 1989, 89 of 7,539 (1.2%) patients had been studied during hospitalization. Baseline systolic and diastolic blood pressures were 115 +/- 18 and 73 +/- 10 mm Hg, respectively. After enalapril, systolic blood pressure decreased slightly but significantly 8 to 20 hours after the initial dose (mean reduction 8 to 11 mm Hg). In this highly selected group of 89 patients, symptoms relating to decrease in blood pressure were noted in 13 (15%). It is emphasized that most patients with cardiac dysfunction readily tolerate enalapril. However, the agent should be administered with caution to patients with advanced congestive failure and diminished baseline blood pressure, owing to a significant incidence of symptomatic hypotension.

Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction.

BACKGROUND: Short-term cholesterol feeding has been shown to affect vasomotor tone and increase infarct size in anesthetized rabbits. The purpose of the study was to determine whether acute hypercholesterolemia reduced collateral flow to ischemic myocardium and increased infarct size in the awake dog. METHODS AND RESULTS: Acute myocardial infarction was produced in awake dogs by a 4-hour left anterior descending coronary artery occlusion followed by 6-hour reperfusion after either a cholesterol-supplemented diet (n = 14) or a control diet of dog chow (n = 15) for 10 days. Infarct size was determined using nitroblue tetrazolium staining. In two subgroups, a 15-minute transient occlusion of the left anterior descending coronary artery was produced before the diet treatments and was compared with occlusion after diet treatments, so that the effects of hypercholesterolemia of collateral flow could be determined by paired comparisons. Cholesterol feeding increased plasma cholesterol to 288 +/- 52 mg/dl, which was twofold to threefold that in the control group (127 +/- 35 mg/dl), but had no effects on baseline systemic hemodynamics and myocardial blood flow. Coronary artery occlusion produced similar increases in heart rate, mean aortic pressure, left atrial pressure, and plasma norepinephrine in both groups of animals. However, cholesterol feeding reduced collateral flow to ischemic myocardium and increased infarct size, compared with the control group. The infarct size correlated with ischemic myocardial blood flow in both groups, but the slopes of regression lines relating the two variables did not differ between the two groups. CONCLUSIONS: Short-term, diet-induced hypercholesterolemia increased infarct size in awake dogs. This change results, at least in part, from a decrease in collateral blood flow to ischemic myocardium during coronary artery occlusion.