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Cardiac endothelial cells, regardless of whether they are from endocardial or from coronary (micro)vascular origin, directly modulate performance of the subjacent cardiomyocytes, resulting in control of the onset of ventricular relaxation and rapid filling of the heart. This review summarizes major features of the morphology, embryology, and comparative physiology of cardiac endothelial cells as well as the experimental observations on how cardiac endothelial cells affect the mechanical performance of the heart. As for the underlying mechanisms of the interaction between cardiac endothelial cells and cardiomyocytes, two working hypotheses have been postulated over the past years; (1) interaction mediated through a trans-endothelial physicochemical gradient for various ions (active blood-heart barrier), and (2) interaction mediated through the release by the cardiac endothelial cells of various cardioactive substances, eg, nitric oxide, endothelin, and prostacyclin. These two mechanisms may act in concert or in parallel.

Background: In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear., Methods: In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction., Results: The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol., Conclusions: These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.

Which patients with an acute myocardial infarction should be treated with an angiotensin-converting enzyme (ACE) inhibitor and when should this treatment be initiated? Combining pathophysiological evidence with the findings of large clinical trials, it is recommended that in the postinfarction setting ACE inhibitors should be given only to high risk patients, ie, patients with arterial hypertension, patients in Killip class II or III, patients with an acute anterior myocardial infarction, patients with left ventricular dysfunction and patients with a previous myocardial infarction. Treatment should be started as soon as it is considered safe.

Rats in which ligation of the left anterior descending (LAD) coronary artery did not result in an infarct visible to the naked eye have generally been called sham-operated controls and have been used to evaluate changes in the characteristics of the remaining viable myocardium of rats where myocardial infarction was present. Whether these sham-operated rats are equivalent to normal controls or whether they have been altered by the surgery is unknown. The purpose of this study was to evaluate potential differences in papillary muscle mechanical characteristics and responsiveness to beta-adrenergic stimulation in control, open-chest, sham-operated (aborted infarct), and infarct rats 4 weeks after surgery. Absence of significant myocardial damage was verified by morphologic examination in sham-operated hearts: myocardial infarction scar was 1.5 +/- 0.6% (mean +/- SE) of circumference, no infarct being transmural. Basal contractile indices were decreased in papillary muscles in infarct rats compared with the three other groups. The response in contractile indices of infarct muscles to isoproterenol was also less compared with the other three groups. However, although basal contractility was the same in muscles from sham-operated, open-chest, and controls, the responsiveness of sham-operated muscles to isoproterenol was less: change in total tension of 2.9 +/- 1.2% vs. 9.5 +/- 2.7% for controls and 9.3 +/- 2.4% for open-chest (p < 0.05). Percent change in maximum rate of tension development (+dT/dt) was also less in muscles from sham-operated versus control muscles (21 +/- 2 vs. 33 +/- 6%; p < 0.05). Twitch configuration changed similarly with isoproterenol in all four groups. Thus, although contractility is unaffected by sham operation, beta-adrenergic responsiveness of tension-generating indices is modified.

Purpose: To determine the prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with a history of myocardial infarction (MI) and cholesterol levels lower than 240 mg/dL., Materials and Methods: A cross-sectional analysis was conducted at baseline of 4159 participants in the Cholesterol and Recurrent Events (CARE) Study. Symptomatic diffuse atherosclerosis was defined as a history of MI plus lower extremity or cerebrovascular atherosclerosis or claudication by Rose questionnaire., Results: The prevalence of symptomatic diffuse atherosclerosis was 12.9%; 353 participants (8.5%) had lower extremity disease and 219 (5.3%) had cerebrovascular disease. After controlling for other variables, diffuse atherosclerosis was associated with age (Odds Ratio [OR] = 1.44 per ten-year increase), systolic blood pressure (OR = 1.13 per 10 mm Hg increase), a history of multiple myocardial infarctions (OR = 1.76), diabetes (OR = 1.76), hypertension (OR = 1.38), reduced exercise performance (OR = 1.55), current smoking status (OR = 2.87), and lower alcohol intake (OR = 0.97 per drink per week). There was no association with race, gender, or lipid levels., Conclusions: The presence of clinically evident diffuse atherosclerosis is common and is associated with several modifiable risk factors. Early identification of these individuals could affect treatment and clinical outcomes.

Interactions between the various cell types that make up the cardiovascular system are known to play an important role in maintaining homeostasis. One area about smooth muscle cells that has received little attention, despite the production of a wide variety of mediators by smooth muscle cells, is their effect on myocardial function. In this study, the myocardial contractile effects of four different types of dog aortic strips on rabbit papillary muscles were evaluated. Of these, medial vascular smooth muscle strips most consistently (65% of the time) produced a "vascular-derived contractile factor" (VDCF), which caused a 15% increase in isometric twitch tension and a 24% increase in isotonic twitch shortening with no change in twitch configuration. Endovascular strips with or without intact endothelium and complete aortic rings had less consistent effects. Vascular-derived contractile factor was stable after freezing at -80 degrees C, its activity was not modified by a broad spectrum peptidase, but it was heat-labile. The angiotensin II blocker, losartan, did not modify its effects. However, incubation with indomethacin did reduce, but did not eliminate, the contractile effects of vascular strips. The addition of alpha 1- and beta-blockers did not further modify the effects of VDCF. Endocardial endothelial removal increased the effects of VDCF. No correlation existed between endothelin levels and the contractile effects of vascular strips. It is concluded that VDCF is produced by the medial layer of large vessels but its exact cellular origin is uncertain. These findings expand the ever-increasing understanding of the inter-relationship between the structures that make up the cardiovascular system, and open the door to new studies evaluating the inter-relationship of vessels and myocardium.

It is known that endocardial endothelium (EE) modulates the performance of its subjacent myocardium. However, one species where these effects have been more difficult to describe is the rat. As the rat is a species which is used to evaluate the contractile effects of various pathologic conditions, a better appreciation of the contractile effects of EE and its modulatory role on the contractile effects of inotropic substances is important. In this study, the contractile effects of increasing extracellular calcium concentrations (0.7 mM to 3.25 mM) and phenylephrine (10(-7) to 10(-4) M) on rat papillary muscles with intact endocardial endothelium (EE on) and after endocardial endothelial removal (EE off) were assessed. At 0.7 mM extracellular calcium concentration, endocardial endothelial removal decreased all measured indices of myocardial performance (P < 0.05 EE on v EE off), except for maximum rate of unloaded muscle shortening (Vmax) which did not change, and decreased time to peak tension development (TTPT) as well as shortening of time to half tension decline from peak tension (RT1/2) shortening. Increasing extracellular calcium concentration from 0.7 mM to 3.25 mM caused all indices of myocardial performance and RT1/2 to increase more in muscles without EE, such that at 2.5 mM extracellular calcium all differences between EE on and EE off had disappeared. The only exception was TTPT which decreased with increasing extracellular calcium concentrations in muscles with EE on but increased in muscles with EE off. Again, at 2.5 mM extracellular calcium concentration differences in TTPT between EE on and EE off had disappeared. Except for minor differences on TTPT, increasing phenylephrine concentrations had similar contractile effects on muscles with EE on and EE off. These results indicate that EE modulates rat myocardial contraction and that these effects are best observed at lower extracellular calcium concentrations (0.7 mM). They also indicate that EE does not appear to significantly modulate the myocardial effects of alpha-adrenergic agonists in the rat.

Diastolic dysfunction is a syndrome characterized by impaired ventricular filling. Abnormalities in diastolic function can generally be classified as being the result of abnormal relaxation or of abnormal compliance. Diastolic dysfunction is frequently present in patients with heart failure and it is occasionally the dominant or sole cause of symptoms. It is frequently the result of the convergence of factors such as advanced age, renal dysfunction, left ventricular hypertrophy and impaired coronary perfusion. A good history and physical examination are essential for the diagnosis of diastolic dysfunction. Because it uniquely allows for the noninvasive evaluation of mitral and pulmonary venous flow and provides critical information on the cause of diastolic dysfunction and on associated abnormalities, two-dimensional and Doppler echocardiography is the most useful tool in the comprehensive assessment of diastolic function. Treatment of diastolic dysfunction is difficult and should not only focus on controlling symptoms but also include attempts at resolving the underlying cause. Relief of myocardial ischemia, control of arterial hypertension and regression of ventricular hypertrophy are important objectives of treatment.

Objectives: This study sought to evaluate the in-hospital and postdischarge mortality of patients with an acute myocardial infarction in the 1990s., Background: The widespread implementation of therapeutic interventions that modify the natural history of coronary artery disease has led to changes in the profile and survival of patients with an acute myocardial infarction. Although data exist for selected subsets of patients with an acute myocardial infarction, at this time there is little recent prospective information on all patients presenting with an acute myocardial infarction, particularly for survival after hospital discharge., Methods: All patients < or = 75 years old presenting with an acute myocardial infarction between July 1, 1990 and June 30, 1992 at nine Canadian hospitals were prospectively evaluated and followed up for 1 year. From November 1991, patients of all ages were included. In two centers, recruitment continued until December 31, 1992. A total of 3,178 patients were recruited., Results: The in-hospital mortality rate of patients < or = 75 years old was 8.4%, and that at 1 year after hospital discharge was 5.3%. For patients of all ages recruited after November 1, 1991, the in-hospital mortality rate was 9.9% and 7.1% for 1 year after hospital discharge. For patients < or = 75 years old, age carried an independent in-hospital but no post discharge risk. Female patients had a twofold greater risk of dying in hospital. After hospital discharge, only 1.7% of patients < or = 75 years old and 1.9% of patients of all ages died of a presumed arrhythmic death. Premature ventricular contractions had no independent prognostic value. The relatively low in-hospital (5.3%) and postdischarge (6.1%) reinfarction rate may have contributed to improved survival. A greater reinfarction rate in patients >75 years old (17.4% vs. 9.6%, p < 0.001) may have contributed to their poorer outcome., Conclusions: One-year mortality after acute myocardial infarction continues to decrease, and changes in the prognostic value of traditional methods of risk stratification have occurred.

Although elevated plasma cholesterol levels represent a well-established and significant risk for developing atherosclerosis, there is a wide spectrum of cholesterol levels in patients with coronary artery disease (CAD). Most secondary prevention studies have generated convincing evidence that cholesterol reduction in patients with high cholesterol levels is associated with improved clinical outcome by reducing risk of further cardiovascular events. However, other risk factors may play a prominent role in the pathogenesis of coronary disease in the majority of patients with near-normal cholesterol values. The Cholesterol and Recurrent Events (CARE) study was designed to address whether the pharmacologic reduction of cholesterol levels with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who have survived an MI yet have a total cholesterol value < 240 mg/dl (< 6.2 mmol/liter). The other inclusion criteria for this study were age 21-75 years, low density lipoprotein (LDL) cholesterol levels of 115-174 mg/dl (3.0-4.5 mmol/liter), and fasting serum triglyceride levels < 350 mg/dl (< 4.0 mmol/liter). A total of 4,159 eligible consenting patients without other study exclusions were then randomly assigned to receive either pravastatin 40 mg daily or matching placebo in addition to their individualized conventional therapy. The trial was designed to have a median follow-up of 5 years. Study endpoints will be evaluated with respect to predefined subgroups according to baseline lipid values, age, gender, prior cardiovascular risk factors, and history.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: In patients with acute myocardial infarction (MI), early restoration of patency of the infarct-related artery (IRA) leads to preservation of left ventricular function and improved clinical outcome. However, there is evidence that the benefits associated with a patent IRA are out of proportion to the observed improvement in ventricular function and may result not only from salvage of ischemic myocardium but also from the opening of the IRA beyond a narrow postinfarct time window. The objectives of this study were (1) to assess the effect of IRA patency on outcome of patients after acute MI with left ventricular dysfunction while controlling for differences in left ventricular ejection fraction and the extent of coronary disease and (2) to determine the effect of angiotensin-converting enzyme (ACE) inhibitor therapy on patients with patent as well as occluded infarct arteries., Methods and Results: The Survival and Ventricular Enlargement (SAVE) study consisted of 2231 patients with a documented MI and a left ventricular ejection fraction < or = 40%. They were randomized to the ACE inhibitor captopril (50 mg TID) or placebo 3 to 16 days after MI and were followed for an average of 3.5 years. Left ventricular ejection fraction, measured with radionuclide left ventriculography, was repeated at the end of the follow-up period. The 946 patients in whom the patency of the IRA was established before randomization form the basis of this study. At cardiac catheterization averaging 4.2 days after infarction, 30.7% of patients had an initially occluded IRA. After revascularization, 162 of the 946 patients (17.1%) were left with an occluded IRA at the time of randomization. The 162 patients with persistently occluded IRAs and 784 with patent IRAs had similar clinical baseline characteristics, but those with occluded arteries had a slightly lower ejection fraction than the 784 patients with patent infarct arteries (30% versus 32%, P = .01). Cox proportional-hazards analyses showed that the independent predictors of all-cause mortality were hypertension (relative risk [RR] 1.94, P < .001), number of diseased coronary arteries (RR 1.68, P < .001), occluded IRA (RR 1.49, P = .039), ejection fraction (RR 1.36, P < .001), age (RR 1.10, P = .030), and use of beta-adrenergic receptor blocking agents (RR 0.60, P = .007). Independent predictors of a composite end point consisting of cardiovascular mortality, morbidity, or reduction of ejection fraction of > or = 9 units were occluded IRA (odds ratio [OR] 1.73, P = .002), hypertension (OR 1.71, P < .001), number of diseased vessels (OR 1.38, P < .001), ejection fraction (OR 1.18, P = .003), use of beta-adrenergic receptor blocking agents (OR 0.67, P = .007), and randomization to captopril (OR 0.70, P = .009)., Conclusions: IRA patency within 16 days after MI predicts a favorable clinical outcome, independent of the number of obstructed coronary arteries or of left ventricular function. The beneficial effect of ACE inhibition is independent of patency status of the IRA. These findings support the need for additional, prospective clinical trials of late reperfusion in MI patients.

The objective of this study was to evaluate the tension-frequency relationship in normal and cardiomyopathic myocardium from one species with a negative or biphasic relationship, the hamster, and one with a positive relationship, the dog. Left ventricular papillary muscles from 100-day-old normal Syrian and cardiomyopathic (CHF-147) hamsters and right ventricular papillary muscles or trabeculae from normal mongrel dogs and dog with pacing-induced heart failure were used for the study. Stimulation frequency was varied from 1 to 90/min and isometric contractions recorded at each frequency prior to and after the addition of phenylephrine 10 microM. A tension-frequency relationship at varying extracellular calcium concentrations (1.25, 2.5 and 5.0 mM) was also constructed in normal hamster myocardium. Ryanodine 1.2 microM was added to a bath with normal hamster muscles and a force-frequency relationship constructed prior to and after adding phenylephrine 10 microM. A calcium dose-response curve in normal and cardiomyopathic dog myocardium was also constructed. Normal and cardiomyopathic hamster myocardium had a biphasic tension-frequency relationship with the increase in tension during the second phase being greater in normal v cardiomyopathic hamster myocardium (0.66 +/- 0.19 v 0.12 +/- 0.03 g/mm2, P < 0.05). The initial decrease in tension in response to increasing stimulation frequency was markedly attenuated in normal hamster myocardium by increasing extracellular calcium concentration. Developed tension was eliminated at lower stimulation rates by ryanodine such that when developed tension did occur, it increased with increasing stimulation rates. The addition of phenylephrine to hamster myocardium modified the tension-frequency relationship of both normal and cardiomyopathic dog myocardium and their response to phenylephrine were similar. In each case, tension increased progressively with increasing stimulation rate. Although the absolute increase in tension caused by increasing extracellular calcium was less in cardiomyopathic dog myocardium, the percent increase in tension and shortening was greater. We conclude that the tension-frequency relationship of normal and cardiomyopathic hamster myocardium are biphasic, with the initial negative phase being the result of limitations of sarcoplasmic reticulum calcium handling. Phenylephrine modifies this relationship to a uniphasic positive one, likely by its effects on both the sarcolemma and the sarcoplasmic reticulum. Also, the tension-frequency relationship of normal and cardiomyopathic dog myocardium are similar and unmodified by phenylephrine.

The sexual abuses described in this article are occurring so frequently that they constitute a public health problem. Superficially they appear to be quite dissimilar because they involve individuals of different ages, different settings, and different power relationships. Basic to each of them, however, is an absence of consent by the victim and the misuse of power by the perpetrator in order to accomplish the abuse. We now have an adequate understanding of each of these abuses and it is now time to make a concerted effort to stop these abuses. This will require the combined efforts of the education of the public, improved identification of the abuses, treatment of the victims, and an appropriate criminal justice response combined with treatment of the perpetrator.

Objectives: This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation., Background: Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure., Methods: In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors., Results: By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations., Conclusions: Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Objectives: This observational study was done to describe the long term prognosis of patients presenting to an emergency room with decompensated heart failure and to determine the factors that influence their survival., Design: The routine clinical and laboratory characteristics of consecutive patients presenting to an emergency room with decompensated heart failure were documented and the patients followed for an average of 44 months (range 41 to 47)., Setting: One teaching hospital and one community-based hospital in Montreal, Quebec., Patients: A prospective cohort of 153 consecutive patients presenting to the emergency room with decompensated heart failure., Outcome Measures: Total mortality was the main outcome. Survival status was validated by the government health insurance board., Results: Survival was poor, with 61% dying within the 47-month follow-up. Univariate analysis revealed the following variables to be associated with decreased survival; low sodium (P < 0.001), decreased renal function (P < 0.001), prior hospitalization for decompensated heart failure (P < 0.001), intraventricular conduction defect (P < 0.002), failure despite prior use of angiotensin-converting enzyme (ACE) inhibitors (P < 0.005) and increased cardiac dimensions as determined by increased left ventricular end systolic diameter (P < 0.04). The multivariate analysis using the Cox proportional hazards model showed a prior admission for heart failure (relative risk [RR] 1.9 [P = 0.005], 95% confidence interval [CI] 1.2 to 2.9), hyponatremia (RR 2.1 [P = 0.005], 95% CI 1.2 to 3.5), presence of an intraventricular conduction delay (RR 1.9 [P = 0.003], 95% CI 1.2 to 2.9), and the cumulative required dose of intravenous furosemide (RR 1.7 [P = 0.03], 95% CI 1.1 to 2.8) to be associated with increased mortality. Patients with hyponatremia despite the use of ACE inhibitors were at greatest risk (RR 11.5 [P < 0.001], 95% CI 5.3 to 24.9)., Conclusions: This prospective observational study confirms that the long term prognosis of patients needing hospitalization for congestive heart failure remains poor. Readily available acute-phase clinical variables may assist in predicting prognosis.

Objectives: The purpose of this study was to determine whether the type and extent of ventricular remodeling after infarction influence inducibility of ventricular arrhythmias after infarction., Background: Although serious ventricular arrhythmias after infarction are related to ventricular dysfunction, the relation between inducibility of ventricular arrhythmias and ventricular remodeling remains incompletely understood., Methods: Rats that survived ligation of the left anterior descending coronary artery (n = 218) were randomized to receive placebo (saline solution) or captopril or propranolol therapy and were followed up for 5 weeks. Hemodynamic and neurohumoral blood measurements were obtained, and therapy was stopped. Two days later, susceptibility to ventricular arrhythmias was assessed by programmed electrical stimulation, and hearts were prepared for pathologic studies., Results: Placebo-treated rats with a large myocardial infarction had ventricular dysfunction, marked neurohumoral activation, ventricular enlargement (endocardial circumference 16 +/- 3 [mean +/- SD] to 20 +/- 4 mm, p < 0.05) and increased cardiac fibrosis (volume density of collagen 2.3 +/- 0.8% to 5.6 +/- 2.4%, p < 0.05). In many rats this resulted in easily inducible ventricular arrhythmias (inducibility quotient 4.9 +/- 2.2). Captopril attenuated the development of ventricular dysfunction, neurohumoral activation, ventricular hypertrophy and dilation (endocardial circumference 18 +/- 3 mm) and cardiac fibrosis (3.1 +/- 0.8%, p < 0.05). These modifications were accompanied by decreased inducibility of ventricular arrhythmias (inducibility quotient 1.1 +/- 2.0, p < 0.05). Propranolol did not prevent ventricular dysfunction, had variable effects on neurohumoral activation and led to increased ventricular dilation (endocardial circumference 25 +/- 4 mm, p < 0.05) and cardiac fibrosis (7.7 +/- 1.2%, p < 0.05). Nevertheless, these morphologic changes led to decreased inducibility of ventricular arrhythmias (inducibility quotient 2.2 +/- 2.5%, p < 0.05)., Conclusions: This study indicates that the inducibility of ventricular arrhythmias can be reduced as a result of markedly different effects on ventricular remodeling, indicating that the relation between ventricular remodeling, arrhythmias and survival is more complex than previously thought.

Heart failure is the only cardiovascular disorder which is increasingly prevalent in North America. Several large clinical trials have emerged within the past 10 years. The results from some of these trials have had a significant impact on the way congestive heart failure is recognized and treated. The objective of this review is not to review exhaustively all recent clinical trials in heart failure but to present the most important ones selected because of their impact on how one understands and treats congestive heart failure in 1993. The results, as well as some important pathophysiological considerations related to these trials, will be addressed.

This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.

Objectives: This study was conducted to evaluate the degree of neurohumoral activation around the time of hospital discharge after myocardial infarction., Background: Because pharmacologic interventions that block the effects of neurohumoral activation improve the prognosis after infarction, we hypothesized that widespread neurohumoral activation persists in some patients until at least the time of hospital discharge and that the determinants of activation vary from one system to another., Methods: Five hundred nineteen patients in the Survival and Ventricular Enlargement Study (SAVE) had plasma neurohormones measured before randomization at a mean of 12 days after infarction. All patients had left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt heart failure., Results: Although all neurohormones except epinephrine were increased compared with values in age-matched control subjects, plasma norepinephrine (301 +/- 193 vs. 222 +/- 87 pg/ml, p < 0.001), renin activity (3.0 +/- 3.7 vs. 1.2 +/- 1.2 ng/ml per h, p < 0.001), arginine vasopressin (1.9 +/- 6.9 vs. 0.7 +/- 0.3 pg/ml, p < 0.001) and atrial natriuretic peptide (75 +/- 75 vs. 21 +/- 9 pg/ml, p < 0.001) values ranged from normal to very high, indicating a wide spectrum of neurohumoral activation. Activation of one system did not correlate with activation of another. The clinical and laboratory variables most closely associated with neurohumoral activation were Killip class, left ventricular ejection fraction, age and use of diuretic drugs. The association between neurohumoral activation and clinical and laboratory variables varied from one neurohormone to another., Conclusions: Neurohumoral activation occurs in a significant proportion of patients at the time of hospital discharge after infarction. Which neurohormone is activated and which clinical and laboratory variables determine this activation vary from one neurohormone to another.

Objective: The aim was to evaluate age related changes in myocardial contractility and alpha 1 adrenergic responsiveness in myocardium from normal and cardiomyopathic hamsters., Methods: 50 male cardiomyopathic hamsters (CHF 147) and 45 golden Syrian hamsters were killed at 30, 50, 100, 200, or 300 days of age. Left ventricular papillary muscles were isolated and mounted in an isolated bath and isometric, isotonic, and unloaded contractions were recorded during a phenylephrine dose-response curve. The effects of increasing stimulation rate from 6 to 45 x min-1 and of increasing temperature from 29 degrees C to 35 degrees C before and after the addition of phenylephrine were verified in 100 day old hamsters., Results: At 30 days of age, tension generation and shortening indices were similar in both strains. Thereafter, contractility increased in normal hamsters, to reach a peak at 50 d which was maintained until 300 d, when a slight decrease occurred. In cardiomyopathic hamsters, contractility increased more slowly, such that by 50 d tension was lower than in normals, at 15.8(SEM 1.9) v 26.5(2.2) mN.mm-2 (p < 0.01). This decrease persisted until 200 d, when it normalised and then decreased again by 300 d. The response of normal and cardiomyopathic muscles to phenylephrine was similar at 30 days of age. Thereafter, the response of cardiomyopathic muscles decreased more than in normals. This decrease was accompanied by a rightward shift in the dose-response curve. Increasing stimulation rate had no effect under basal conditions; however, once phenylephrine was added it caused tension to increase in cardiomyopathic muscles instead of decreasing, thereby rendering the relative effects of phenylephrine at 45 stimuli.min-1 similar in both groups., Conclusions: Force generating and shortening indices in normal and cardiomyopathic hamster myocardium are similarly immature at 30 days of age. Normal myocardium reaches its full potential by 50 d, but cardiomyopathic myocardium does not reach it until 200 d, and it decreases thereafter. A decrease in alpha 1 adrenergic responsiveness in cardiomyopathic myocardium at lower stimulation rates can be reversed by increasing the stimulation rate.

Endocardial endothelium has been shown to modulate the contractile characteristics and alpha-1-adrenergic responsiveness of its adjacent myocardium. This study was designed to evaluate whether this was also the case in the pacing-overdrive model of heart failure in the dog, a model in which changes in contractile characteristics and changes in alpha-1-adrenergic responsiveness similar to those caused by endocardial endothelial removal, occur prior to endocardial endothelial removal. Pacing-overdrive heart failure caused a decrease in total tension (TT) (5.1 +/- 0.5 g/mm2 in controls to 2.2 +/- 0.4 g/mm2 in pacing-overdrive, P < 0.01) and twitch configuration (time to 1/2 tension decline [RT1/2] 659 +/- 23 to 517 +/- 41 ms P < 0.01) to occur in isolated papillary muscles. Endocardial endothelial removal in control muscles caused similar but less marked changes (TT to 3.8 +/- 0.3 g/mm2, and RT1/2 to 563 +/- 21 ms). Endocardial endothelium removal also decreased TT (to 1.6 +/- 0.3 g/mm2) and RT1/2 (459 +/- 28 ms) in pacing-overdrive muscles indicating that even in this model of heart failure, endocardial endothelium continued to modulate the contractile characteristics of its adjacent myocardium. The addition of phenylephrine caused proportionately similar changes in contractile characteristics in both control and pacing-overdrive muscles prior to and after endocardial endothelial removal. However, in control muscles, endocardial endothelial removal caused a rightward shift in phenylephrine concentration-response curve (EC50 0.6 +/- 0.2 x 10(-6)M to 3.4 +/- 1.0 x 10(-6)M, P < 0.05). Pacing-overdrive muscles already had a rightward shift (EC50 = 4.1 +/- 1.0 x 10(-6)M) prior to endocardial endothelium removal, such that endocardial endothelial removal caused no further shift in EC50 (2.8 +/- 1.0 x 10(-6)M) indicating that the decrease in alpha-1-adrenergic responsiveness in this model was endocardial endothelium dependent. Taken together, these results suggest that the direct modulating effects of the endocardial endothelium on its adjacent myocardium are not necessarily related to its modulatory role on the myocardial effects of circulating substances in the plasma and, that in heart failure, the decrease in alpha-1-adrenergic responsiveness that occurs is related to endocardial endothelium dysfunction.

Objectives: This observational study was done to describe the characteristics, hospital course and short term prognosis of patients presenting to an emergency room with decompensated heart failure and to determine the parameters influencing the length of their hospital stay., Design: The routine clinical and laboratory characteristics of consecutive patients presenting to an emergency room with decompensated heart failure were documented and the patients followed for six months., Setting: One teaching hospital and one community-based hospital in Montreal, Quebec., Patients: A prospective cohort of 153 consecutive patients presenting to the emergency room with decompensated heart failure. Follow-up was by clinic visit and telephone survey at one, three and six months. Follow-up was 100%., Measures of Outcome: Length of hospital stay, in-hospital mortality, readmissions and after hospital discharge deaths were measured., Results: The average length of hospital stay was 6.2 days with a skewed distribution ranging from one to 56 days. A multivariate analysis showed that the length of hospital stay was associated with increasing left atrial size (P < 0.05), an ischemic etiology of the heart failure (P < 0.03) and a slow response to diuretic therapy (P < 0.001). This mathematical model accounted for only a small amount of hospital stay variability (R2 = 0.22). Six month mortality and morbidity of these patients was high, with 23% dying and 30% readmitted for heart failure, but was independent of the duration of the initial hospitalization., Conclusions: This prospective study confirms that the hospital course for congestive heart failure is shortening. The six month prognosis of patients presenting to an emergency room for decompensated heart failure is poor and appears independent of the length of hospital stay.

Background: There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care., Methods: To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction., Results: In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P < 0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P < 0.001), as were revascularization procedures before randomization (31 percent vs. 12 percent, P < 0.001). During an average follow-up of 42 months, these procedures were also performed more commonly in the United States than in Canada. These differences were not associated with any apparent difference in mortality (22 percent in Canada and 23 percent in the United States) or rate of reinfarction (14 percent in Canada and 13 percent in the United States), but there was a higher incidence of activity-limiting angina in Canada than in the United States (33 percent vs. 27 percent, P < 0.007)., Conclusions: The threshold for the admission of patients to a coronary care unit or for the use of invasive diagnostic and therapeutic interventions in the early and late periods after an infarction is higher in Canada than in the United States. This is not associated with any apparent difference in the rate of reinfarction or survival, but is associated with a higher frequency of activity-limiting angina.

Background: Medical practice patterns change in response to a variety of stimuli, one of which may be the publication of the results of randomized clinical trials. We assessed the temporal association between the publication of clinical trials on myocardial infarction and changes in treatment practices for this disorder., Methods: We analyzed the use of aspirin before and after myocardial infarction and that of calcium antagonists after myocardial infarction in 2231 survivors of myocardial infarction enrolled in the Survival and Ventricular Enlargement (SAVE) study over a three-year period (from January 1987 through January 1990). The proportion of patients using these treatments was analyzed before and after the publication dates of three clinical trials: the Physicians' Health Study, published in January 1988, which supported the use of aspirin to prevent a first myocardial infarction; the Second International Study of Infarct Survival (ISIS-2), published in August 1988, which supported the use of aspirin after myocardial infarction; and the Multicenter Diltiazem Postinfarction Trial, published in August 1988, which reported a deleterious effect of diltiazem in some patients after myocardial infarction., Results: The use of aspirin before myocardial infarction increased from 16.2 percent to 23.9 percent between January 1987 and January 1990 (P less than 0.001). Enrollment in the study after the publication of the Physicians' Health Study independently predicted aspirin use before myocardial infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85). The use of aspirin after myocardial infarction increased from 38.8 percent to 71.9 percent (P less than 0.001) during the three-year study period. Enrollment in the study after the publication of ISIS-2 independently predicted the use of aspirin after myocardial infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76). The use of calcium antagonists after myocardial infarction decreased from 57.1 percent to 33.1 percent (P less than 0.001) during the study period. Enrollment in the study after the publication of the Multicenter Diltiazem Postinfarction Trial independently predicted the use of calcium antagonists after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57)., Conclusions: These observations suggest that randomized clinical trials have a measurable influence on medical practice patterns.

The expression of preproenkephalin A (ppENK) gene was investigated in the rat heart, following the onset of myocardial infarction induced by ligation of the left anterior descending coronary artery. The relative abundance of ppENK mRNA and the level of enkephalins were measured by Northern blot analysis and radioimmunoassay, respectively, in the ventricles from control-unoperated, sham-operated, and operated rats. Three hours after the surgery, a comparison between rats with infarction and sham-operated rats revealed that the relative abundance of ppENK mRNA and the level of enkephalins were increased three- to four- and two- to three-fold, respectively, in the ventricles of rats with infarction. No difference was observed between rats with infarction and sham-operated rats 24 h after the surgery, or between rats with infarction compared at time intervals of 3 and 24 h following the surgery. The abundance of the ppENK mRNA in the polysomal fraction of the ventricular septum was also measured 3 h after the surgery and found to be threefold higher in rats with infarction as compared with sham-operated rats. These results indicate that the level of enkephalins rapidly increases in the ventricles of rats following myocardial infarction, and that this higher level may be ascribed to a stimulation of the local synthesis of enkephalins.

Objective: To evaluate the mechanisms by which the angiotensin converting enzyme (ACE) inhibitor captopril may modify the presence of ventricular arrhythmias in patients with chronic heart failure., Patients: Forty-seven patients with chronic stable congestive heart failure., Methods: Twenty-four hour Holter monitoring was done prior to and after one month of therapy with the ACE inhibitor captopril. In a first group of 25 patients, changes in the incidence of ventricular arrhythmias were correlated with changes in cardiac hemodynamics (assessed invasively). In a second group of 22 patients, changes in ventricular arrhythmias were correlated with changes in echocardiographic measurements. In all patients serum potassium was kept constant, and changes in exercise tolerance and serum noradrenaline levels were assessed prior to and after captopril., Results: One month of captopril therapy caused an improvement in cardiac hemodynamics and in exercise tolerance. It also led to a tendency for improved echocardiographic measurements and serum noradrenaline levels, similar to those already published by others. However, no change in the incidence or severity of ventricular arrhythmias was detected. No correlation could be found between changes in ventricular arrhythmias and any of the variables measured., Conclusions: As the only obvious difference between this and previous studies that documented a decrease in ventricular arrhythmias when ACE inhibitors were started in patients with congestive heart failure is a lack of change in serum potassium in this study, the current results suggest that the major antiarrhythmic effect of ACE inhibitors in patients with congestive hear failure is the result of their potassium sparing effects.

Patients with congestive heart failure have abnormal coronary hemodynamics, characterized by decreased coronary sinus oxygen content, increased coronary sinus blood flow and increased myocardial oxygen consumption. To evaluate their prognostic importance, the clinical characteristics and systemic and coronary hemodynamics were related to survival in 91 patients with severe congestive heart failure and decreased ejection fraction (25.5 +/- 10% [mean +/- SD]). In 69 patients congestive heart failure was due to or secondary to coronary artery disease (group 1) and in 22 it was due to idiopathic dilated cardiomyopathy (group 2). Five patients were in functional class II, 48 in class III and 38 in class IV. The median survival time was 20.7 months. As assessed with the Cox proportional hazards model, coronary sinus oxygen content was most strongly associated with a poor prognosis. On the basis of a comparison between the lowest (coronary sinus oxygen content less than or equal to 4.44 vol%) and highest quintile (coronary sinus oxygen content greater than 4.44 vol%), a low coronary sinus oxygen content was associated with a 2.34-fold increased risk of dying (95% confidence interval, 1.31 to 4.08). A low systolic blood pressure and a high diastolic pulmonary artery pressure were also significantly associated with increased mortality. Patients in the subgroup with a low coronary sinus oxygen content had values for functional class, ejection fraction and systemic hemodynamics similar to those of patients in the subgroup with high coronary sinus oxygen content. It is concluded that a low coronary sinus oxygen content indicative of noncompensated metabolic demand suggests a poor prognosis in patients with severe congestive heart failure.

alpha-Adrenergic agonists have been shown to increase the tension developed by myocardial muscle. However, their effects on the maximum velocity of unloaded muscle shortening (Vmax) have not been rigorously examined. In this study, the contractile effects of the alpha-adrenergic agonist phenylephrine were examined in the presence of propranolol in papillary muscles of two species, the dog and the rabbit. In rabbit papillary muscles studied at physiological calcium concentrations (1.25 mM), phenylephrine increased all indices of contractility (Vmax, tension, and maximum rate of tension developed (dT/dt)) starting at 10(-8) M. The percent increase in Vmax (121 +/- 8%) was less than that of tension (188 +/- 20%, p less than 0.05) and dT/dt (262 +/- 35%, p less than 0.01). These findings occurred at both 29 and 35 degrees C and were inhibited by adding 10(-5) M prazosin. Increasing extracellular calcium concentration from 1.25 to 15 mM caused changes in twitch configuration that were significantly different from those of phenylephrine. Calcium increased all indices of contractility more than did phenylephrine. This was particularly true for dT/dt (502 +/- 82 vs. 262 +/- 35% for phenylephrine, p less than 0.01). Nonetheless, the ratio of increase in tension to increase in Vmax under both experimental conditions was similar (the increase in Vmax was 64% of that of tension with phenylephrine and 69% with increased calcium). At 1.25 mM calcium, the increase in contractility caused by phenylephrine was much smaller in dog myocardium as compared with rabbit myocardium. Rather, the effects of phenylephrine on dog myocardium studied at 1.25 mM calcium resembled that of rabbit myocardium studied at 15 mM calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have indicated that patients with an acute myocardial infarction have marked activation of all neurohumoral systems on admission to the hospital. This activation begins to subside within the first 72 hours so that by 7-10 days, all plasma neurohormones have returned to normal. The only documented exceptions were found to occur in patients with left ventricular dysfunction and overt heart failure, where both plasma renin activity and atrial natriuretic peptide were increased, and in patients with left ventricular dysfunction but no overt heart failure, where only atrial natriuretic peptide was increased. Although these studies suggest that neurohumoral activation rarely occurs at the time of hospital discharge, they were small and may have missed an important subgroup of patients with persistent neurohumoral activation. In the Survival and Ventricular Enlargement (SAVE) study, 522 patients had plasma neurohumoral levels measured at a mean of 12 days postinfarction. All SAVE patients had left ventricular dysfunction (left ventricular ejection fraction less than or equal to 40%), but no overt heart failure. In this group of patients, all neurohumoral levels (plasma renin activity, norepinephrine, arginine vasopressin, and atrial natriuretic peptide) were found to be increased compared with age-matched control subjects. These results indicate that, in fact, a subgroup of patients without overt heart failure has persistent neurohumoral activation at the time of hospital discharge postinfarction, and that this activation involves several neurohumoral systems. Since patients with persistent neurohumoral activation postinfarction are likely those most at risk of developing complications and the ones most likely to benefit from pharmacologic interventions blunting the effects of neurohumoral activation, measurement of predischarge neurohumoral levels may be useful.

The functional integrity of the beta-adrenergic stimulatory pathway in a rabbit model of heart failure induced by long-term adriamycin treatment was investigated. Adriamycin-induced cardiomyopathy was produced in 46 rabbits by injecting 0.75 mg/kg of adriamycin, three times per week, for a period of 11 weeks. Biochemical studies performed on isolated membrane preparations revealed a 40 and 55% decrease in basal adenylyl cyclase activity in the left and right ventricles of the adriamycin treated rabbits, respectively. Furthermore, the Vmax of forskolin stimulation was significantly lower in both ventricles with no change in Kact. The Vmax of 5'-guanylylimidodiphosphate stimulation of the stimulatory guanylyl nucleotide binding protein Gs and beta-adrenergic receptor stimulation by isoproterenol were also significantly decreased (42%) in both ventricles of the adriamycin-treated rabbits with no change in Kact. Despite the decrease in receptor-mediated cyclic AMP production, no decrease in beta-adrenergic receptor population was found. Mechanical studies on the isolated right ventricular papillary muscle revealed a decrease in baseline total tension (3.1 +/- 0.4 g/mm2 to 1.8 +/- 0.2 g/mm2) and dT/dt (15.1 +/- 1.6 g/mm2 s to 7.9 +/- 0.8 g/mm2 s) in the adriamycin-treated rabbits. Furthermore, tension generation and dT/dt response to increasing concentrations of forskolin or isoproterenol were both significantly lower in the adriamycin-treated rabbits as compared to normal. We suggest that a decrease in the activity of the adenylyl cyclase component of the beta-adrenergic stimulatory pathway is largely responsible for the decrease in cyclic AMP generation in the adriamycin-treated rabbits. This defect may play an important role in the decrease of contractility in this model of heart failure.

To better understand the mechanism of nitrate tolerance in patients with congestive heart failure, 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion, mean arterial pressure had returned to baseline values and there was a significant increase in ventricular filling pressures and systemic vascular resistance compared with values after 1 h of treatment. The simultaneous infusion of N-acetylcysteine had no effect on these changes. Although a strict fluid restriction of 1.5 liters/day was maintained for 1 week before and throughout the study, after 24 h of nitroglycerin infusion there was a significant and similar degree of hemodilution whether nitroglycerin was infused alone (9.1 +/- 4.3%) or with N-acetylcysteine (8.7 +/- 4.1%). This hemodilution corresponded to an increase in intravascular volume of 745 +/- 382 ml, most of which occurred during the 1st h. Plasma renin activity increased and plasma atrial natriuretic peptide decreased during the infusion. The results of this study suggest that nitrate tolerance is multifactorial. In addition to the previously described pharmacologic tolerance to the effect of nitroglycerin on vascular smooth muscle, a capillary fluid shift from the extravascular to intravascular space appears to be involved, especially during the 1st h of the infusion. A third mechanism, reflex neurohumoral activation, also seems to contribute to the genesis of nitroglycerin tolerance.

Tolerance to the continuous intravenous infusion of nitroglycerin is thought to be largely the result of a decrease in vascular responsiveness, possibly due to intra-smooth muscle sulfhydryl group depletion. Another mechanism proposed to contribute to tolerance is nitroglycerin-induced reflex neurohumoral activation resulting in vasoconstriction and sodium and water retention. It has been proposed that the sulfhydryl group-containing angiotensin converting enzyme (ACE) inhibitor captopril may be useful in preventing tolerance to nitroglycerin by repleting sulfhydryl groups and by decreasing reflex neurohumoral activation. However, by decreasing renal perfusion pressure, the combination of captopril and nitrates could also lead to renal dysfunction. The objectives of this study were to determine whether captopril prevented or significantly reduced hemodynamic tolerance to a 72 h infusion of nitroglycerin, and to determine whether the combination of nitroglycerin and captopril caused deterioration of renal function. Nineteen patients with congestive heart failure received nitroglycerin (1.5 micrograms/kg/min) alone (n = 11) or in combination with oral captopril (63 +/- 8 mg/day) (n = 8). In both groups, partial hemodynamic tolerance developed within the first 24 h of nitroglycerin infusion. Nitroglycerin therapy, with or without captopril, did not affect plasma adrenaline, noradrenaline, aldosterone or arginine vasopressin. However, plasma renin activity increased and atrial natriuretic peptide decreased in both groups, these changes being significant after 1 h of infusion but gradually returning towards baseline, in both groups, over the next 71 h. The nitroglycerin infusion did not alter body weight, urine output, creatinine clearance or fractional sodium excretion in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether a 72-hour infusion of nitroglycerin produces hemodynamic improvement in patients with severe congestive heart failure and to assess the contributing role of various possible causes of hemodynamic tolerance to nitroglycerin, 19 patients received an infusion of nitroglycerin 1.5 micrograms/kg/min for 72 hours. In a subgroup of patients (n = 10), there was an increase in stroke work index and a decrease in ventricular filling pressures throughout the infusion and even after it was discontinued. Tolerance to the hemodynamic effects of nitroglycerin was partially reversed 8 hours after the infusion was stopped. Neurohumoral changes occurred but appeared to play only a minor role in the development of nitroglycerin tolerance. However, hematocrit fell 9 +/- 5%, which suggests that an increased intravascular volume contributed to tolerance. In summary: (1) a 72-hour infusion of nitroglycerin improves ventricular function in some patients with severe heart failure; (2) volume shifts from the extravascular to the intravascular compartments may, at least in part, be responsible for nitroglycerin tolerance; and (3) reflex neurohumoral activation may also play a small role in nitrate tolerance.

Study Objective: The aim was to assess myocardial, electrophysiological, and adrenergic changes caused by chronic administration of doxorubicin., Design: Doxorubicin induced cardiotoxicity was produced in three groups of rabbits by injecting doxorubicin 0.75 mg.kg-1 three times a week for 7, 9 and 11 weeks. There were 36 controls. All studies were conducted within 16 to 36 h after the last injection. Histological, mechanical, and action potential changes produced by doxorubicin were examined in vitro. The effects of doxorubicin on beta adrenergic receptors and cyclic adenosine monophosphate (AMP) generation in myocardial membrane preparations were also evaluated., Experimental Material: 145 New Zealand white rabbits, 2.4-2.7 kg, were used. After excision of the heart, a papillary muscle was used for mechanical studies, a portion of the septum for intracellular action potential studies, and the rest of the heart for histological or biochemical studies., Measurements and Results: Histological studies showed widespread myocardial damage that became more severe as the cumulative doses increased. Right ventricular papillary muscles of doxorubicin treated rabbits had lower total tension (1.5 v 3.3 g.mm-2 for controls, p less than 0.05) and dT/dt, shorter contraction duration, and lower velocity of shortening than the control muscles under all loading conditions. The changes progressed as the cumulative doxorubicin dose increased. Action potential duration was shorter in the doxorubicin treated groups (APD50 = 76 v 62 ms for controls, p less than 0.01), although resting action potential amplitude was normal. Tension-frequency response (6-36 stimuli.min-1) and response to increasing calcium concentrations (2.54-6.32 mM) were attenuated in the doxorubicin group. Percent change in tension and dT/dt in response to noradrenaline (50 microM), isoprenaline (20 microM), or dibutyryl cyclic AMP (40 mM), was increased in the doxorubicin group v controls (300-600% v 100-200% respectively), despite chronic increase in circulating catecholamines, depletion of myocardial catecholamines, and no change in beta adrenergic receptor number or affinity. The apparent increase in beta adrenergic responsiveness in the doxorubicin group may have been partly due to decreased basal cyclic AMP production (13 v 31 pMol.mg-1 protein.min-1, p less than 0.01), although maximum catecholamine stimulated cyclic AMP production was only mildly decreased (251 v 315 pMol.mg-1 protein.min-1, p less than 0.05). CONCLUSIONS - The subacute effects of chronic doxorubicin become progressively more marked as the cumulative dose increases, and there are significant differences in the myocardial characteristics between this chronic model and other models of heart failure. These differences may be related to the cytotoxic effects of doxorubicin on membranes and membrane bound enzymes.

Beta-2 adrenergic stimulators, a class of drugs which has been used for a long time in the treatment of bronchial asthma and in tocolysis, have recently become part of the therapeutic arsenal for congestive heart failure. Their action seems to be essentially vasodilator, although they do have a mild positive inotropic effect. In the short term, they improve the cardiac output and they decrease the peripheral vascular resistance. Their long term haemodynamic effects are still controversial. However, their are some arguments in favour of the persistence of the beneficial effects observed in the short term. They have a contradictory action on the capacity for exercise; one study states that they improve exercise capacity and another study finds that they do not. Their action on the length of survival is still unknown. Some reports suggest that they may aggravate ventricular arrhythmias. At the moment, then, this class of drugs is only used experimentally in congestive heart failure. We need to wait for the results of larger studies on the long-term benefits, the exercise capacity and the survival. Possible side effects also need to be studied in more detail.

Reviewed here are the data from 34 patients given prazosin for chronic intractable heart failure. In 13 patients in whom hemodynamics were measured after the fifth 3 mg dose of prazosin was given, no attenuation was found. The cardiac index increased from 1.77 +/- 0.13 to 2.5 +/- 0.13 liters/min/m2 (p less than 0.001), and the pulmonary capillary wedge pressure decreased from 31,46 +/- 1.56 to 23.54 +/- 1.11 mg Hg (p less than 0.001). During long-term follow-up (15.9 +/- 1.5 months) the administration of spironolactone proved to be very useful. Within three months of starting prazosin therapy, none of the 15 patients discharged on a regimen of spironolactone needed readmission for edema, but 11 of the 13 patients discharged without a spironolactone regimen did. The addition of spironolactone or an increase in furosemide to the therapeutic regimen was helpful but a change to hydralazine was not. We concluded that prazosin causes short-term hemodynamic and long-term clinical improvement in patients with intractable heart failure; that spironolactone helps to prevent clinical attenuation but that more detailed studies are required to better characterize the attenuation to vasodilators seen in patients with congestive heart failure.

We attempted to alter the inherited myocardial damage and loss of contractility of the cardiomyopathic Syrian hamster (strain U-MX7-1) by giving cardiac drugs that altered intracellular calcium and myocardial workload. Thirty-seven 21-day-old cardiomyopathic and thirty-seven 21-day-old normal hamsters were divided into five groups each: verapamil-, propranolol-, digoxin-, hydralazine-, and saline-injected. On their 90th day of life, the hamsters were killed. Of the five cardiomyopathic groups, only verapamil reduced myocardial damage. When both "control" and cardiomyopathic hamsters were treated with saline, digoxin, or propranolol, the cardiomyopathic hamsters had significantly less contractile force, maximal rate of force development, and maximum velocity of unloaded shortening. When both groups were treated with verapamil or hydralazine, there were no significant group differences in the indices of contractility. However, when saline-treated cardiomyopathic hamsters were compared with drug-treated cardiomyopathic hamsters, only verapamil preserved myocardial contractility. There was also a weak correlation between the Vmax and the actin-activated ATPase activity of the cardiomyopathic hamsters (r = 0.63, P less than 0.001). We conclude that verapamil helped protect the myocardium of genetically cardiomyopathic hamsters against structural damage, and helped preserve myocardial contractility.

To evaluate myocardial catecholamine balance in heart failure, systemic hemodynamics, coronary sinus blood flow, and arterial and coronary sinus venous norepinephrine (NE) and epinephrine (E) concentrations were determined in 30 patients with chronic left ventricular failure (CHF), and in 25 patients with angina pectoris (AP) but without heart failure. In the group with CHF, stroke work index was lower (CHF 20 +/- 9, AP 53 +/- 13 g-m/m2, p less than 0.001) and pulmonary capillary wedge pressure higher (CHF 28 +/- 8, AP 11 +/- 4 mm Hg, p less than 0.001), indicating depressed left ventricular function. Coronary sinus blood flow was similar in 2 groups (CHF 97 +/- 70, AP 73 +/- 32 ml/min, difference not significant). In the group with CHF, arterial (634 +/- 582 pg/ml) and coronary sinus venous (1,038 +/- 1,014 pg/ml) NE concentrations were significantly higher than in the group with AP (arterial 185 +/- 135, coronary sinus 231 +/- 167 pg/ml, p less than 0.001). The net myocardial NE release in patients with CHF was approximately 20 times higher than that in patients with AP (CHF 38,548 +/- 48,622, AP 2,245 +/- 10,242 pg/min, p less than 0.001). Arterial E and myocardial E uptake was similar in both groups. Although mechanisms for increased myocardial net NE release remains unknown, it probably represents enhanced cardiac sympathetic tone in response to heart failure.

The objective of this study was to assess the hemodynamic and neurohumoral (plasma renin activity, aldosterone, epinephrine, norepinephrine, vasopressin, and atrial natriuretic peptide) determinants of systemic vascular resistance in 35 patients with stable congestive heart failure. In the supine position, although activation of the various neurohumoral systems tended to occur in the same patients, there was little correlation between activation of any of the neurohumoral systems, as reflected by circulating levels, and systemic vascular resistance. There was also little correlation between changes in circulating neurohormones and changes in either mean arterial pressure or systemic vascular resistance in the standing position. Acutely reducing the activity of the renin-angiotensin system with the use of captopril did not improve the correlation between other neurohumoral and hemodynamic variables. In fact there was no correlation between the effects of acute captopril therapy and baseline renin values. These results support the concept that activation of one or another vasoconstrictor neurohumoral system varies from patient to patient and that the effects of their activation are tempered by activation of parallel vasodilator systems and by attenuation of neurohormone release and effector organ response.

The long-term efficacy and potential side effects of oral sympathomimetic amines in the treatment of advanced congestive heart failure remain controversial. We studied the acute and chronic hemodynamic and arrhythmogenic effects of the beta-2 agonist, salbutamol, 6 mg by mouth four times/day, in 20 patients with NYHA classes III to IV congestive heart failure. Acutely, salbutamol increased the cardiac index (1.9 to 2.3 L/min/m2, p less than 0.01) and heart rate (92 to 97 bpm, p less than 0.01) while it decreased pulmonary capillary wedge pressure (35 to 31 mm Hg, p less than 0.01). Salbutamol increased the number of patients having episodes of ventricular tachycardia from two to six and increased the number of episodes of ventricular tachycardia from 2 to 27. Once salbutamol was discontinued, no further episodes of ventricular tachycardia occurred in these six patients. Six patients did not have long-term hemodynamic studies because of serious arrhythmias and two died. In the 12 patients who had long-term studies, the initial beneficial hemodynamic effects of salbutamol were maintained. Thus, although salbutamol may have beneficial long-term hemodynamic effects, it may cause serious arrhythmias in patients predisposed to develop arrhythmias.

We studied 56 right ventricular papillary muscles isolated from cats to determine whether the direct mechanical effects of contrast media are due to their pharmacologic action or to the hyperosmolality caused by them. A 10% solution of Renografin-76 abruptly decreased force 22% below control, then slowly increased it to 22% above control. To elucidate these changes we also studied: (1) Renografin-60 (lower concentration of diatrizoate); (2) meglumine and diatrizoate; (3) meglumine alone; (4) diatrizoate sodium; (5) ethylene diamine tetra-acetic acid (EDTA) (same concentration as in Renografin-76); (6) sucrose to increase osmolality; and (7) Amipaque (metrizamide), a contrast medium without meglumine or diatrizoate. All solutions containing meglumine, and EDTA alone decreased force. Diatrizoate sodium also decreased force initially, presumably due to the high sodium concentration. Meglumine alone decreased force abruptly and substantially. In contrast, metrizamide and 100 mmol sucrose only increased force. Thus, the abrupt decrease in force was caused by the pharmacologic action of meglumine, EDTA, or high sodium in the contrast media, whereas the slow increase in force was caused by hyperosmolality.

The renal hemodynamic and neurohumoral determinants of sodium and water excretion abnormalities were studied in 66 patients with severe chronic congestive heart failure. Abnormalities were not closely related to any one variable but were the result of the convergence of a number of determinants. The most important determinants for sodium excretion were activation of the renin-angiotensin system and ventricular function; and the most important for water excretion were plasma vasopressin, plasma norepinephrine, and renal and ventricular functions. In a subgroup of patients, neurohumoral overactivation led to severe sodium and water excretion abnormalities and to increased furosemide requirements. A 17-month follow-up of all 66 patients showed a less favorable clinical course for this subgroup even when compared with hemodynamically matched patients.

Congestive heart failure was induced in rabbits by a chronic treatment with a low dose of adriamycin (0.75 mg/kg intravenously 3 times per week for 11 weeks). Twenty-four to 48 h after the last injection, adriamycin-treated rabbits had a three-fold increase in plasma norepinephrine, a seven-fold increase in plasma epinephrine, a 19 +/- 8% increase in heart rate, and a 54 +/- 10% decrease in the total tension generated by their isolated papillary muscles, when compared with normal age-matched controls. This demonstrated the occurrence of the cardiomyopathy and heart failure. The effect of adriamycin on myocardial and diaphragmatic protein synthesis was examined in vivo after a 1-h infusion with [3H]leucine and in vitro after a 2-h incubation of right ventricular papillary muscle with [3H]leucine. The rate of in vivo [3H]leucine incorporation into total protein was increased in the heart of the adriamycin-treated rabbits. The increases were 60 +/- 16% in the left ventricle, 49 +/- 18% in the septum, 32 +/- 18% in the right ventricle, and 66 +/- 16% in the atria. A similar increase was observed when measuring the rate of [3H]leucine incorporation into myosin, a myofibrillar protein, and when the rate of [3H]leucine incorporation into total protein was measured in vitro in papillary muscle. In contrast, the rate of [3H]leucine incorporation into total protein of the diaphragm was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cough and wheezing are common findings in left heart failure. However, it is still questionable whether nonallergic bronchial hyperresponsiveness, the hallmark of asthma, is also associated with this condition. In 12 subjects with acute decompensation of chronic postischemic LV failure, we assessed the PC20 methacholine during an episode of acute LV failure and after five to 15 days of intensive diuretic therapy. Weight, arterial blood gases, plethysmographic lung volumes, and expiratory flows were also measured on both visits. Extravascular lung water was estimated indirectly with a radiologic score. During acute decompensation, six subjects had significant airway obstruction and eight had a PC20 less than or equal to 16 mg/ml (significant bronchial hyperresponsiveness). After diuretic therapy, subjects improved significantly, losing an average of 2.2 kg, but they still had chronic LV failure and evidence of an obstructive breathing defect. Although mean PC20 was unchanged, three subjects had significantly improved PC20 after treatment. We conclude that: (1) left ventricular failure is often associated with mild bronchial hyperresponsiveness, although it is not excluded that smoking and the resulting possibility of bronchial obstruction can also play some role; and (2) acute treatment does not generally alter bronchial responsiveness to methacholine, suggesting that chronic LV failure can cause chronic changes to the airways.

The oral angiotensin-converting enzyme inhibitor captopril (CPT) produces beneficial hemodynamic and clinical responses in patients with chronic congestive heart failure (CHF). Cardiac output and stroke volume increase, along with a decrease in pulmonary capillary wedge pressure, indicating improved left ventricular function. During maintenance CPT therapy, the beneficial hemodynamic and clinical effects appear to be sustained. Improved left ventricular pump function with CPT is associated with decreased metabolic cost, as myocardial oxygen consumption consistently decreases in proportion to the decrease in myocardial oxygen demand. Myocardial ischemia occurs infrequently, as is evident from the abnormal myocardial lactate metabolism. Hypotension appears to be the major adverse effect, particularly after the first dose. However, with dose titration and the use of a smaller initial dose, a marked precipitous fall in blood pressure can be avoided in the majority of patients. Thus, CPT may prove to be a useful agent in the vasodilator therapy of chronic CHF.

The acute effects of captopril in three groups of patients with coronary artery disease were studied: 25 patients with congestive heart failure; 8 patients with hypertension; and 14 normotensive patients with angina, and systolic arterial pressure greater than 120 mmHg, but no evidence of heart failure. Systemic haemodynamics were assessed by balloon-tipped thermodilution catheter and coronary haemodynamics were assessed by thermodilution catheter in the coronary sinus. Despite significantly different baseline haemodynamic values, captopril decrease systolic arterial pressure without increasing heart rate in all three groups, thereby decreasing double-product, a major determinant of myocardial work. Coronary blood flow and myocardial oxygen consumption decreased similarly in all groups and decreased in parallel to double-product, while coronary vascular resistance and transmyocardial oxygen difference did not change except for a slight decrease in transmyocardial oxygen difference in those patients with congestive heart failure. Transmyocardial lactate extraction increased insignificantly. These findings suggest that captopril may improve metabolic balance in various types of patients with coronary artery disease and that it does this by decreasing myocardial oxygen demand.

We investigated the hemodynamic and inotropic effects of the new class III antiarrhythmic drug melperone. In eight pentobarbital-anesthetized dogs, the effects of intravenous melperone 0.5, 2.5, and 12.5 mg/kg-1 were tested. During atrial pacing we measured cardiac output (CO), mean aortic blood pressure (MAP), right (RV) and left (LV) ventricular pressures, and LV dP/dt. In six RV papillary muscles isolated from cats and suspended in a muscle bath containing Krebs-Henseleit solution, we studied the direct effects of melperone 10(8)-5 X 10(-5) M. Administration of melperone decreased total peripheral resistance, MAP, RV and LV systolic and end-diastolic pressures, while CO remained unchanged. Melperone increased LV dP/dtmax. The contractile force (F) and dF/dtmax of the isolated ventricular muscle preparations increased slightly with increasing concentrations of melperone, up to 10(-5) M. In conclusion, melperone has vasodilator and slight positive inotropic effects in addition to its class III antiarrhythmic effect.