David E. Johnstone

Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure : a substudy of the studies of left ventricular dysfunction (SOLVD)

Neuroendocrine activation is known to occur in patients with congestive heart failure, but there is uncertainty as to whether this occurs before or after the presence of overt symptoms. In the Studies of Left Ventricular Dysfunction (SOLVD), a multicenter study of patients with ejection fractions of 35% or less, we compared baseline plasma norepinephrine, plasma renin activity, plasma atrial natriuretic factor, and plasma arginine vasopressin in 56 control subjects, 151 patients with left ventricular dysfunction (no overt heart failure), and 81 patients with overt heart failure before randomization. Median values for plasma norepinephrine (p = 0.0001), plasma atrial natriuretic factor (p less than 0.0001), plasma arginine vasopressin (p = 0.006), and plasma renin activity (p = 0.03) were significantly higher in patients with left ventricular dysfunction than in normal control subjects. Neuroendocrine values were highest in patients with overt heart failure. Plasma renin activity was normal in patients with left ventricular dysfunction without heart failure who were not receiving diuretics and was significantly increased (p less than 0.05) in patients on diuretic therapy. We conclude that neuroendocrine activation occurs in patients with left ventricular dysfunction and no heart failure. Neuroendocrine activation is further increased as overt heart failure ensues and diuretics are added to therapy.

Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.

Three fourths of deaths from myocardial infarction occur in patients older than 65 years of age, making cardiovascular disease the leading cause of death in older persons [1, 2]. Older patients, despite their high risk for cardiovascular death, are less likely to receive cardioprotective medications or interventions [3-15] or to be enrolled in clinical trials that test potentially beneficial treatments [3]. Although much information is available on serum cholesterol as a predictor of coronary artery disease in younger patients, as well as on the benefits of reduction of serum cholesterol levels, the role of cholesterol in coronary artery disease in older patients is less clear. Elevated cholesterol levels do not strongly predict coronary events in older patients [16-23]; thus, the need for cholesterol screening and treatment in older persons has generated much divergent opinion [22-31]. Recent analysis of a cohort of older persons (mean age, 80 years) strongly suggested that concomitant disease or debilitation was associated with low blood cholesterol levels and was responsible for the reduced ability of serum cholesterol levels to predict the incidence of coronary events. After adjustment for low serum iron and albumin levels and exclusion of events in the first year of follow-up, serum cholesterol levels became a significant predictor of coronary death [32]. Without this adjustment, no such association was seen [32]. Almost all trials of cholesterol treatment have excluded patients who were 65 years of age or older. The National Cholesterol Education Panel guidelines [33] therefore extrapolated findings from the treatment of younger patients in their recommendations for treating older patients, noting the considerable potential for absolute risk reduction given the high incidence of cardiovascular events in older patients. More recently, researchers observed that simvastatin treatment of hypercholesterolemic patients with coronary artery disease reduced recurrent major coronary events in the subset of patients who were 65 to 70 years of age at study entry [34]. However, information is needed on the effect of lipid treatment in older patients who have had myocardial infarction and have average cholesterol levels; most patients who have had myocardial infarction have cholesterol values in the average, not elevated, range [35-37]. The Cholesterol and Recurrent Events (CARE) trial [38] investigated whether reducing average cholesterol levels by using pravastatin in patients who have had myocardial infarction would prevent recurrent cardiac events. It showed that in patients with average cholesterol levels, pravastatin therapy reduced the risk for coronary death or recurrent myocardial infarction by 24% (P = 0.003), reduced the risk for fatal and nonfatal myocardial infarction by 25% (P = 0.006), reduced the risk for coronary artery bypass grafting and angioplasty by 27% (P < 0.001), and reduced the risk for stroke by 31% (P = 0.03) [38]. It also reported that patients who were older than the median age of 59 years had a reduced rate of coronary death, nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty. Of the 4159 patients in the CARE trial, 1283 (31%) were 65 to 75 years of age at baseline; these patients are eligible for retirement health care (Medicare) benefits in the United States. We report on the effect of pravastatin on individual cardiovascular events in these older patients, including myocardial infarction, coronary artery bypass grafting, angioplasty, and stroke, as well as on overall hospitalization for cardiovascular disease. Methods Study Design and Patients The design and results of the CARE trial have been described in detail elsewhere [38, 39]. The study was a randomized, double-blind, placebo-controlled trial with a planned average follow-up of 5 years. Patients were recruited from 80 participating centers in the United States and Canada. Institutional review board approval was obtained for investigation of human participants. Patients were eligible if they had had an acute myocardial infarction 3 to 20 months before randomization; were 21 to 75 years of age; and had plasma total cholesterol levels less than 6.2 mmol/L (240 mg/dL), low-density lipoprotein (LDL) cholesterol levels of 3.0 to 4.5 mmol/L (115 to 174 mg/dL), and fasting triglyceride levels less than 4.0 mmol/L (350 mg/dL). The diagnosis of myocardial infarction was confirmed by the MI Confirmation Core Laboratory, which evaluated reports of changes in serum creatine kinase levels, electrocardiographic evidence, and clinical symptoms [38, 39]. Plasma lipids were measured at least 2 months after discharge from hospitalization for the index myocardial infarction. Women were required to be postmenopausal or surgically sterile. All participants received dietary counseling according to the National Cholesterol Education Program Step 1 guidelines. After the screening visits were completed, eligible patients returned for a randomization visit, during which they were assigned to receive either pravastatin (40 mg/d) or identically appearing placebo by means of a telephone call from a clinical center to the Data Coordinating Center. The patient was the unit of randomization, randomization was stratified within each clinical center, and the allocation schedule was generated by computer. The code for treatment assignment was maintained only at the Data Coordinating Center. The primary trial outcome was fatal coronary artery disease or confirmed nonfatal myocardial infarction. For the primary analysis of the treatment effects in subgroups, we used an expanded end point (death from coronary artery disease, nonfatal myocardial infarction, angioplasty, or coronary artery bypass grafting), called major coronary events. Statistical Analysis All analyses were done on an intention-to-treat basis. P values (all of which were two-sided) less than 0.05 were deemed statistically significant. Baseline characteristics in the two treatment groups were determined by using the standard z-test for continuous variables and chi-square tests for categorical variables [40]. All hypothesis testing and risk reductions (with their CIs) were assessed by using the Cox proportional-hazards model. Kaplan-Meier survival curves for the control and pravastatin groups were calculated [41]. The relative risk reduction was calculated as 1 the hazard ratio. The upper and lower bounds of the 95% CIs for the relative risk reductions were applied to the rates in the placebo group to compute the CI for absolute risk reduction, and these bounds were inverted to provide the CIs for the number of patients needed to treat to prevent an event. To determine whether imbalances in risk factors at baseline could have affected the estimates of risk reduction attributable to therapy, we performed subsidiary multivariate analyses that included the following covariates: age, sex, baseline lipid levels, smoking, diabetes, hypertension, and left ventricular ejection fraction. Potential clinical center effects were assessed by including 79 indicator variables to denote the 80 clinical centers in the Cox proportional-hazards analysis. We used SAS software, version 6.12 (SAS Institute, Cary, North Carolina), to execute all analyses. Role of the Study Sponsor The CARE trial was an investigator-initiated study proposed to and funded by Bristol-Myers Squibb. The data were collected and analyzed by and are now maintained at the Coordinating Center, University of Texas School of Public Health. The sponsor is entitled to comment on manuscripts before submission. The authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor, a member of the Executive Committee of the trial, was contractually required to fund the study until its conclusion. The sponsor maintained information on adverse events and other trial data, as required by federal regulations. Results Screening and Exclusion before Randomization From a total of 11 207 patients identified from records in hospitals and ambulatory practices for possible inclusion in the CARE trial, 3244 (29%) were at least 65 years of age (hereafter referred to as older patients). Of these 3244 older patients, 1139 (35%) qualified for the trial. An additional 144 patients reached the age of 65 years between their screening date and randomization; thus, 1283 older patients were randomly assigned in the CARE trial. A similar percentage of the patients younger than 65 years of age (hereafter referred to as younger patients)-39% (3020 patients)-qualified for the trial. Older patients were less likely than younger patients to be ineligible because of elevated total cholesterol, LDL cholesterol, or triglyceride levels (8% and 12%, respectively). However, older patients were more likely than younger patients to be ineligible because criteria for myocardial infarction were not met (61% and 53%, respectively) (P < 0.05 for all comparisons). Baseline Characteristics The median follow-up was 5 years (25th and 75th percentiles, 4.3 and 5.4 years). The mean age of the older patients was 69 years at randomization (25th and 75th percentiles, 66 and 73 years) and 74 years at the end of the trial. Baseline coronary risk factors significantly differed between the two age groups (Table 1). Older patients more frequently were female (18% compared with 12% of younger patients), had hypertension (48% compared with 40%), and had diabetes (19% compared with 12%). In addition, they were more likely to have had a second previous myocardial infarction (21% compared with 15%) and less frequently were current smokers (12% compared with 24%), had ever smoked (70% compared with 81%), or had a family history of coronary artery disease (33% compared with 44%) (P < 0.05 for all comparisons). Table 1. Baseline Characteristics of Patients Younger Than 65 Years of Age and Those 65

Natural history and patterns of current practice in heart failure

Abstract A total of 6,273 consecutive relatively unselected patients with heart failure or left ventricular dysfunction, or both (mean age 62 ± 12 years, mean ejection fraction 31 ± 9%), were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry over a period of 14 months. All patients were followed up for vital status and hospital admissions at 1 year. Ischemic heart disease was the underlying cause of failure or dysfunction in ≈70% of patients, whereas hypertensive heart disease was considered to be primarily involved in only 7%. There were striking differences in the etiology of heart failure among blacks and whites: 73% of whites had an ischemic etiology of failure versus only 36% of blacks; 32% of blacks had a hypertensive condition versus only 4% of whites. The total 1-year mortality rate was 18%; 19% of patients had hospital admissions for heart failure and 27% either died or had a hospital admission for congestive heart failure during the 1st year of follow-up. Factors related to 1-year mortality or hospital admission for congestive heart failure included age, ejection fraction, diabetes mellitus, atrial fibrillation and female gender. There was no difference in mortality associated with congestive heart failure among blacks and whites, but hospital admissions for heart failure were more frequent in blacks. Digitalis and diuretic agents were the drugs most often used in these patients, who were often making many medications in relation to severity of congestive heart failure symptoms and ejection fraction. Surprisingly, angiotensin-converting enzyme inhibitors were taken by only 30% of patients, and a substantial number were treated by drugs controversial in the presence of left ventricular dysfunction and heart failure, such as calcium channel antagonists and antiarrhythmic or beta-adrenergic blocking agents.

Prognostic Significance of Plasma Norepinephrine in Patients With Asymptomatic Left Ventricular Dysfunction

BACKGROUND Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction. METHODS AND RESULTS PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions < or = 35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients owing to study design. Using the Cox proportional hazards model that included left ventricular ejection fraction, New York Heart Association functional class, age, sex, treatment assignment to placebo or enalapril, and cause of heart failure, we examined whether these neurohormones predicted all-cause mortality, cardiovascular mortality, hospitalization for heart failure, development of heart failure, or development of ischemic events (myocardial infarction or unstable angina). PNE was the strongest predictor of clinical events in this patient population. PNE levels above the median of 393 pg/mL were associated with a relative risk of 2.59 (P = .002) for all-cause mortality, 2.55 (P = .003) for cardiovascular mortality, 2.55 (P = .005) for hospitalization for heart failure, 1.88 (P = .002) for development of heart failure, 1.92 (P = .001) for ischemic events, and 2.59 (P = .005) for myocardial infarction. PNE remained the most powerful predictor for all-cause mortality and ischemic events when the analysis included only the patients with histories of ischemic left ventricular dysfunction. The increases in other neurohormonal levels were not useful in predicting the subsequent development of clinical events. CONCLUSIONS Increased PNE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortalities and development of clinical events related to the onset of heart failure or acute ischemic syndromes. Thus, measurement of PNE may be a possible early marker for assessment of disease progression in patients with left ventricular dysfunction, and modulating the release or effect of PNE may lead to improved prognosis and/or a reduction in morbidity.

Global and regional left ventricular response to bicycle exercise in coronary artery disease: Assessment by quantitative radionuclide angiocardiography

Abstract The left ventricular response to bicycle exercise was evaluated in 60 patients with coronary artery disease and in 13 normal control subjects. Left ventricular ejection fraction, mean normalized ejection rate and regional wall motion were determined using first-pass radionuclide angiocardiograms obtained at rest and again during peak graded bicycle exercise. All normal subjects demonstrated improved left ventricular function with exercise. Left ventricular ejection fraction increased significantly from 67 ± 3 per cent (mean ± SE) at rest to 82 ± 4 per cent with exercise (p −1 to 6.53 ± 0.42 sec −1 (p The major determinant of an abnormal left ventricular response to exercise was the presence or absence of electrocardiographic evidence of myocardial ischemia. Left ventricular ejection fraction decreased or remained the same with exercise in all patients with coronary artery disease and electrocardiographic ischemia. New regional wall motion abnormalities were detected in 20 of these patients. In this group, the left ventricular ejection fraction decreased from 66 ± 2 per cent at rest to 58 ± 2 per cent with exercise (p −1 ; exercise 3.34 ± 0.22 sec −1 , p > 0.05). Of the 30 patients with coronary artery disease who exercised to symptom-limiting fatigue without electrocardiographic ischemia, 18 demonstrated compromised left ventricular reserve with exercise. Twelve of the remaining patients with coronary artery disease had normal left ventricular reserve, in eight of whom ventricular function was completely normal both at rest and during exercise. In this group exercised to fatigue, the left ventricular ejection fraction increased from 53 ± 4 per cent at rest to 58 ± 2 per cent with exercise (p −1 to 3.67 ± 0.39 sec −1 (p

Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study

Background—Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure. Methods and Results—We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (P <0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87;P <0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91;P =0.024 for interaction of group by treatment). Conclusion—Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.

Anatomy of human extrinsic cardiac nerves and ganglia

The anatomy of the human extrinsic cardiac nerves and ganglia was reinvestigated because descriptions of human cardiac innervation vary, detailed analyses of subhuman mammalian cardiac innervation reveal considerable similarities among species and the anatomic pattern of cardiac innervation observed in subhuman mammals differs significantly from those described for humans. The presence of a consistent pattern of cardiac innervation in subhuman mammals raised the question as to whether a similar pattern exists in humans. To investigate this, the cervical and thoracic autonomic nerves and ganglia were dissected in 13 embalmed and 10 autopsy cadavers. All major sympathetic cardiopulmonary nerves were found to arise from the stellate ganglia and the caudal halves of the cervical sympathetic trunks below the level of the cricoid cartilage. These sympathetic cardiopulmonary nerves usually consisted of 3 nerves on the right side and 4 on the left. In contrast to widely accepted reports, no sympathetic cardiopulmonary nerves were found to arise from the superior cervical ganglia or the thoracic sympathetic trunks inferior to the stellate ganglia. Parasympathetic cardiopulmonary nerves were found to arise from the recurrent laryngeal nerves and the thoracic vagi immediately distal to them. These nerves interconnected with sympathetic cardiopulmonary nerves anterior and posterior to the main pulmonary artery to form the ventral and dorsal cardiopulmonary plexuses. These plexuses contained relatively large discrete nerves as well as smaller interconnections. Emerging from these plexuses to innervate the ventricles were 3 distinct relatively large cardiac nerves, the right and left coronary cardiac nerves and the left lateral cardiac nerve. In addition to these 3 major nerves, small cardiac nerves arose from the plexuses and the thoracic vagi. Histologic examination of representative dissections confirmed the presence of neural tissue and identified the locations of neuronal cell bodies in these structures. Cell bodies were located in the nodose, superior cervical, middle cervical, stellate and thoracic sympathetic ganglia. The middle cervical ganglia varied in size and number. Neuronal cell bodies were found in the cervical and thoracic sympathetic trunks and in small mediastinal ganglia located along the courses of the cardiopulmonary and cardiac nerves. Marked similarities exist between the anatomy of the cardiopulmonary nerves and ganglia of humans and baboons.

Effect of long-term Enalapril therapy on neurohormones in patients with left ventricular dysfunction

Abstract The aim of this study was to compare the long-term effects of treatment with enalapril or placebo on plasma neurohormones in patients with left ventricular (LV) dysfunction. Elevated neurohormonal levels are associated with increased mortality in patients with congestive heart failure. Multiple studies have shown that angiotensin-converling enzyme inhibitors decrease mortality and morbidity in these patients. In Studies of Left Ventricular Dysfunction (SOLVD), enalapril significantly reduced mortality in patients with symptomatic LV dysfunction (treatment trial). In contrast, in patients with asymptomatic LV dysfunction (prevention trial), there was no significant reduction in mortality with enalapril therapy. The effect of enalapril was examined in 333 prevention trial and 129 treatment trial patients. Plasma norepinephrine (NE) and plasma renin activity were measured in these patients at baseline, and at 4 and 12 months of follow-up. In a subset of these patients, atrial natriuretic peptide (ANP) and arginine vasopressin were also measured. Analysis of covariance models were used to determine the effect of enalapril on each neurohormone. Participants in the treatment trial had significantly higher neurohormonal levels when compared with those in the prevention trial or normal control subjects. In the treatment trial, patients taking enalapril had a greater decrease in plasma NE levels than patients taking placebo (p

Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery

Background— Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. Methods and Results— The Ischemia Management with Accupril post–bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (≤7 days) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction ≥40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio 1.15, 95% confidence interval 0.92 to 1.42, P=0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P=0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG. Conclusions— In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk.

Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD).

The Studies of Left Ventricular Dysfunction (SOLVD) trials were designed to evaluate the effects of enalapril on long-term mortality in patients with severe left ventricular (LV) dysfunction. Patients with LV ejection fractions less than or equal to 0.35 and symptoms of congestive heart failure (CHF) were enrolled in the treatment trial, whereas those with no history of overt CHF and taking no treatment directed for LV dysfunction were enrolled in the prevention trial. The baseline clinical characteristics of SOLVD patients were compared to characterize differences between patients in these 2 separate but concurrent trials. From over 70,000 patients screened with LV dysfunction, 4,228 patients were enrolled in the prevention trial and 2,569 patients in the treatment trial. Ischemic heart disease was the primary cause of LV dysfunction in both prevention (83%) and treatment (71%) trial patients. Prior myocardial infarction was present in 80% of the prevention and 66% of the treatment trial patients (p less than 0.001). In the prevention trial, infarction was recent (less than or equal to 6 months) in 27% patients and remote (greater than 6 months) in 57% patients. Treatment trial patients had proportionately more women (20 vs 13%; p less than 0.001) and non-Caucasians (20 vs 14%; p less than 0.001), as well as the coexisting risk factors of hypertension (42 vs 37%; p less than 0.001) and diabetes (26 vs 15%; p less than 0.001) than did prevention trial patients. Clinical characteristics of patients in both trials were influenced by the gender and race of enrolled patients. Similarly, coronary artery bypass surgery was performed less often in women and non-Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)