Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors.

OBJECTIVES: CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. MATERIAL AND METHODS: We examined the frequencies of V249I and T280M among early-onset CAD patients (G1; n = 149; <50 years), late-onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47-93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein-C (HDL-C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non-carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). RESULTS: G1 patients had non-significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL-C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. CONCLUSIONS: There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early-onset CAD. Neither allele affected MI or lipid levels.

Relationship of the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and early-onset coronary artery disease.

BACKGROUND: The Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) gene has been associated with coronary artery disease (CAD) in some but not all studies. To determine the impact of the mutant Asp298 eNOS allele on the development of premature CAD, we examined the prevalence of this mutation in patients with early-onset CAD compared with those manifesting CAD later in life. If this mutation confers an increased risk of premature CAD, we hypothesized that the frequency of the homozygous mutation (Asp298Asp298) would be greater among the younger patient group. METHODS: A total of 299 patients with a history of myocardial infarction (MI) or angina pectoris plus angiographically documented CAD were studied. Patients were divided into 2 groups: group 1 (149 patients) included patients with CAD before the age of 50 years and group 2 (150 patients) included patients with a first presentation of CAD at >65 years old. Prevalence of eNOS Glu298 and Asp298 alleles was assessed by molecular analysis and compared for the 2 groups. RESULTS: There was no significant difference in the frequency of the mutant Asp298 allele between the 2 groups (G1: 42% vs G2: 42.7%, P =.79). The frequencies of the Glu298Glu298, Glu298Asp298, and Asp298Asp298 genotypes were similar in both groups (34.9%, 46.3%, and 18.8% for G1 and 29.3%, 56%, and 14.7% for G2, respectively, P =.29). CONCLUSIONS: Our study does not support the conclusion that the eNOS Asp298 allele contributes to the development of premature CAD.

Waiting for cardiac surgery: results of a risk-stratified queuing process.

BACKGROUND: The Queen Elizabeth II Health Sciences Centre uses a weekly peer-review conference of cardiovascular experts to prioritize each surgical case to 1 of 4 queues with the use of standardized criteria of coronary anatomy, stress test result, and symptoms. We examined the hazard of waiting as well as the impact of waiting on surgical outcomes. METHODS AND RESULTS: Analysis was performed for 2102 consecutive patients queued for CABG, aortic valve replacement, or CABG+aortic valve replacement between January 1, 1998, and December 31, 1999. Among 1854 patients undergoing surgery, median waiting times on the respective queues were as follows: in-house urgent group, 8 days; semiurgent A group, 37 days; semiurgent B group, 64 days; and elective group, 113 days. There were 13 deaths (12 cardiac) that occurred during the waiting period (0.7% of the patients). Of the 8.7% patients upgraded to a more urgent queue, 86.1% required hospitalization before surgery. Although female sex was not associated with prolonged waiting time, it was predictive of urgent status (P=0.001). The incidence of postoperative complications was 25.0%, and operative mortality was 2.86%. Both were more frequent among patients undergoing surgery early (P=0.01); however, this difference was attributable to the in-house urgent queue. The median length of stay was 7 days for all patients and was not affected by waiting time. CONCLUSIONS: Death and upgrades while the patients were waiting tended to occur early in the queuing process, and prolonged waiting was not associated with worse surgical outcomes. The cost of reducing waiting times could in part be offset by prevention of hospital admissions among upgraded patients.

Differences in ventricular septal motion between subgroups of patients with heart failure.

BACKGROUND: Septal systolic motion is determined by the end-diastolic trans-septal pressure gradient, and hence is load dependent. OBJECTIVE: To explore septal contribution to left ventricular (LV) systolic function in patients with heart failure. DESIGN: Echocardiograms were identified post hoc from normal subjects and a cohort of patients with heart failure. PATIENTS: Twelve normal subjects and 69 patients with heart failure and normal conduction or left bundle brance block (LBBB) were studied. METHODS: Parasternal short axis LV end-diastolic and end-systolic areas were traced. Using a floating centroid, 32 radial chords were constructed, and perecentage shortening from end-diastole to end-systole was calculated for each chord. MAIN RESULTS: Comparing heart failure with normal conduction and LBBB, LV end-diastolic area was similar (43+/-10 versus 45+/-12 cm(2) not significant), but stroke area was higher in normal conduction (7+/-4 versus 4+/-4cm(2), P<0.05) as was area ejection fraction (0.17+/-0.11 versus 0.10+/- 0.08, P<0.01). In normal subjects, the summed percentage shortening of 10 midseptal chords was similar to that of 10 midfreewall chords (256+/-16% versus 235+/-32%, not significant). In contrast, patients with heart failure and normal conduction had greater midseptal than midfreewall sum med chord shortening (113+/-18% versus 60+/-12%, P<0.05); patients with heart failure and LBBB had paradoxical septal motion (3+/-28, P<0.05 compared with normal conduction). CONCLUSIONS: Patients with heart failure and normal conduction have an enhanced septal contribution to LV systolic function compared with normal subjects. In heart failure with LBBB, this is lost and the area ejection fraction is lower. Strategies to optimize septal function in heart failure warrant further study.

Relation of genetic polymorphisms of apolipoprotein E, angiotensin converting enzyme, apolipoprotein B-100, and glycoprotein IIIa and early-onset coronary heart disease.

OBJECTIVE: Apolipoprotein E (APOE) E4, apolipoprotein B-100 (APOB) Q3611 allele, the angiotensin converting enzyme (ACE) deletion (D) allele and glycoprotein IIIa (GP3A) P33 mutant allele are reported to predispose to early-onset coronary heart disease (CHD). These associations were not all confirmed in more recent studies. To determine the impact of these alleles on CHD, we examined the prevalence of these mutations in patients presenting with early-onset CHD and compared them to those manifesting CHD later in life. The delayed-onset was considered a sign of longevity and would serve as a comparative group to assess prevalence of the biochemical and genetic risk factors. METHODS: 300 patients with a history of myocardial infarction or angina pectoris and angiographically documented CHD were studied. Patients were divided into two groups: group 1 (G1 = 150 patients) presenting with these findings under the age of 50 years; while group 2 (G2 = 150 patients) were patients presenting for the first time over the age of 65 years. Prevalence of the alleles of APOE, APOB, ACE and GP3A was assessed by molecular analysis. An association of any of these genotypes with early onset CHD could lead to a higher prevalence in the younger age group. RESULTS AND CONCLUSIONS: None of the suspected alleles namely APOB Q3611 [G1: 10.7% vs. G2: 9.0%, p = 0.57], ACE D (G1: 52.0% vs. G2: 49.7%, p = 0.57), or the GP3A P33 (G1: 17.3% vs. G2: 15.7%; p = 0.58) showed any significant difference between the two groups. Subjects with APOE E4 were more frequent in the younger age group (G1: 18.3% vs. G2: 13.7%; p = 0.047), while APOE E2 was more frequent in G2 (G2: 10.0% vs. G1: 2.7%; p = 0.0002). Multivariate analysis showed an odds ratio of APOE E2 allele in G1 of 0.27 with a confidence interval of 0.10-0.73.

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.

BACKGROUND: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. OBJECTIVE: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. DESIGN: Subset analysis of a randomized, controlled trial. SETTING: 80 hospitals and affiliates in the United States and Canada. PATIENTS: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). INTERVENTION: Pravastatin, 40 mg/d, or placebo. MEASUREMENTS: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. RESULTS: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. CONCLUSIONS: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.

Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease.

OBJECTIVE: In the presence of low serum folate, mutant 5,20-methylenetetrahydrofolate reductase (MTHFR + [A223V/C677T]) in the homozygous state (+/+), may predispose to higher plasma homocysteine (tHct) levels and coronary artery disease (CAD). To determine the impact of this relationship on predisposition to early-onset CAD, we examined the prevalence of the mutation and plasma tHct in patients with early-onset CAD and compared them to patients manifesting CAD later in life. METHODS: Three hundred patients with history of acute myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients consisted of two groups: group 1 (G1 = 150 patients) presenting with these findings under age 50; while group 2 (G2 = 150) presented for the first time over age 65 years. Prevalence of the MTHFR+ mutation was assessed by molecular analysis, and plasma tHct and folate were measured. An association of the +/+ genotype with early onset CAD could lead to its higher prevalence in the younger age group. RESULTS: There was no significant difference in the frequency of the (+/+) genotype between the two groups (G1: 11.3% vs. G2: 11.3%). However, patients with the (+/+) genotype in both groups had higher tHct when plasma folate was below the mean value (G1: p < 0.0001 while G2: p < 0.01). CONCLUSION: The mutant MTHFR genotype was not found to be a determining factor in early-onset CAD. Higher tHct values were obtained in the older age group, which is expected because other studies have shown that tHct levels increase with age. A significant relation was shown between MTHFR genotype and low folate status yielding high tHct levels in those with the (+/+) genotype. As this relation was seen in both groups, although to a lesser extent in the older G2, it does not explain the underlying cause of early-onset CAD.

Relation of HFE gene mutations, high iron stores and early onset coronary artery disease.

OBJECTIVE: To determine the impact of mutations in the HFE gene (human leukocyte antigen H) on predisposition to coronary artery disease (CAD) in patients not diagnosed with hereditary hemochromatosis. BACKGROUND: Elevated iron stores can predispose to acute myocardial infarction. Two mutations (C282Y and H63D) in the novel major histocompatibility complex (MHC) class 1 gene HFE were found in most patients with hereditary hemochromatosis causing high iron stores. The effect of these mutations on predisposition to CAD has not been investigated previously. METHODS: Three hundred patients with a history of myocardial infarction or angina pectoris and angiographically documented CAD were studied. Patients were divided into two groups: group 1 (150 patients), manifesting early onset CAD and presenting with these findings under age 50 years; and group 2 (150 patients), presenting for the first time over age 65 years. Prevalence of the C282Y and H63D mutations was assessed by molecular analysis, and plasma ferritin was measured immunochemically. RESULTS: There was no difference in the prevalence of homozygous, heterozygous or compound heterozygous (C282Y/H63D) states between the groups. Males in group 1 had higher plasma ferritin than those in group 2 (234 +/- 174 micrograms/L versus 136 +/- 103 micrograms/L, P < 0.0001), but this was not significantly different in females (75 +/- 54 micrograms/L versus 92 +/- 73 micrograms/L, P = 0.26). Ferritin remained higher in group 1 than in group 2 males after exclusion of mutation carriers (195 +/- 121 micrograms/L versus 109 +/- 76 micrograms/L, respectively, P < 0.0001), but did not change in females. CONCLUSIONS: Higher iron stores were found in males with early onset CAD. This association was not related to the C282Y or H63D mutation in HFE. It is suggested that association of the MHC locus with delayed onset CAD is probably unrelated to HFE in these patients, and that HFE mutations are not a major risk factor in the development of high iron stores in early onset CAD.

The relationship between cardiothoracic ratio and left ventricular ejection fraction in congestive heart failure. Digitalis Investigation Group.

BACKGROUND: Left ventricular ejection fraction (EF) is a valuable prognostic index in patients with congestive heart failure (CHF). Although EF can be readily measured, many clinicians use roentgenographic heart size as a clue to differentiate systolic from diastolic dysfunction, even in the absence of solid supportive data. OBJECTIVE: To test the hypothesis that the cardiothoracic ratio (CTR) measured from the chest roentgenogram can be used to estimate left ventricular EF in individuals with CHF. METHODS: To answer this question, the database of the Digitalis Investigation Group trial was used. The CTR, determined using the Danzer method, and quantitative EF, measured locally using angiographic, radionuclide, or 2-dimensional echocardiographic techniques, were compared in 7476 patients with clinical CHF (New York Heart Association functional classes I-IV) due to acquired left-sided cardiac disease of ischemic, hypertensive, idiopathic, and alcohol-related causes. RESULTS: Mean (+/-SD) CTR for the cohort was 0.53+/-.07. Mean (+/-SD) EF was 31.7%+/-12.2%. A weak, negative correlation between CTR and EF was observed (r=-0.176). Similar findings were obtained when the results were stratified by cause of CHF, presence of clinically defined right ventricular dysfunction, and method of EF measurement. Categorical analysis failed to yield a CTR cutoff point that facilitated useful segregation of individuals with an EF greater than 35% or 35% and below; greater than 40% or 40% and below; and greater than 45% or 45% and below in any patient group. CONCLUSIONS: Although a weak, negative correlation exists between CTR and EF, this relationship does not allow for accurate determination of systolic function in individual patients with CHF. Considering the morbidity and mortality associated with CHF, and the clinical implications of systolic function in this syndrome, direct measurement of EF is recommended.

Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators.

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.

Preliminary assessment of patients' opinions of queuing for coronary bypass graft surgery at one Canadian centre.

OBJECTIVES: To explore psychological and socioeconomic concerns of patients who queued for coronary artery bypass surgery and the effectiveness of support existing in one Canadian cardiovascular surgical center. DESIGN: Standardised questionnaire and structured interview. SETTING: Victoria General Hospital, Halifax, Nova Scotia. SUBJECTS: 100 consecutive patients awaiting non-emergency bypass surgery. RESULTS: Most patients (96%) found the explanation of findings at cardiac catheterisation and the justification given for surgery satisfactory. However, 84 patients complained that waiting for surgery was stressful and 64 registered at least moderate anxiety. Anger over delays was expressed by 16%, but only 4% thought that queuing according to medical need was unfair. Economic hardship, attributed to delayed surgery, was declared by 15 patients. This primarily affected those still working--namely, blue collar workers and younger age groups. Only 41% of patients were satisfied with existing institutional supports. Problems related mainly to poor communication. CONCLUSIONS: Considerable anxiety seems to be experienced by most patients awaiting bypass surgery. Better communication and education might alleviate some of this anxiety. Economic hardship affects certain patient subgroups more than others and may need to be weighed in the selection process. A more definitive examination of these issues is warranted.

Managed delay for coronary artery bypass graft surgery: the experience at one Canadian center.

OBJECTIVES: This study sought to assess the impact of delaying coronary artery bypass surgery at one Canadian academic tertiary referral center. BACKGROUND: Universal access to medical services in Canada comes at the expense of waiting lists whose impact has been incompletely assessed. METHODS: A prospective, observational study of all residents of Nova Scotia and Prince Edward Island accepted for bypass surgery between 1 April 1992 and 31 October 1992 was undertaken to determine 1) whether triage guidelines were being followed; and 2) the incidence of cardiac death, nonfatal myocardial infarction and worsening symptoms associated with delayed operation. The analysis had 90% power to detect a mortality rate of > or = 3% (alpha 0.05). RESULTS: Of 423 patients referred, 35% were triaged as urgent, 9.7% as semiurgent A, 39% as semiurgent B and 16.3% as elective, with no age or gender bias identified. Operation occurred at < or = 1 week in 25%, < or = 1 month in 47%, and >6 months in 1.4%. There were no nonfatal myocardial infarctions, but five cardiac deaths occurred (1.2%). Of 275 patients not initially classified as urgent, 12.4% required reclassification to higher priorities because of worsening symptoms; none had perioperative myocardial infarction or died. One in four patients queued longer than target waiting times. Only 4% of patients considered prioritization on the basis of medical need unfair, but 64% experienced at least moderate anxiety. CONCLUSION: This triage system equitably stratified patients to a queue. Deaths were rare and could not be attributed to the triage process. Patients with worsening clinical status were safely accommodated with earlier waiting times, but concerns remain regarding excessive waiting times and patient anxiety.

Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators.

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-converting 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 < 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Maximizing the benefits of thrombolytic therapy for acute myocardial infarction.

Thrombolytic therapy is a huge advance in the management of acute myocardial infarction (AMI). The results of large clinical trials over the past 9 years have unequivocally demonstrated its benefit: of every 1000 patients treated 30 will be saved, at a cost of two cases of nonfatal cerebral hemorrhage and seven of noncerebral major hemorrhage. The concurrent use of acetylsalicylic acid increases the benefit of thrombolytic therapy. Sales figures for thrombolytic agents indicate that their use in Canada is less than optimal and lags behind that in several European countries. Major educational efforts are needed to promote awareness of the efficacy of thrombolytic therapy and of optimal approaches for maximizing its potential benefit for patients with AMI.

Diagnosis and management of heart failure. Canadian Cardiovascular Society.

Many of the recommendations presented in this consensus report are summarized in Figure 2. All patients with known or suspected heart failure should undergo a detailed history and physical examination. Other causes for the symptoms and/or clinical signs indicative of heart failure should be excluded. Routine biochemical tests, as well as a standard chest x-ray and ECG, should be performed on all patients with heart failure. Precipitating or aggravating causes of heart failure should be eliminated. Patients with potentially surgically correctable lesions, such as constrictive pericarditis, valvular disease or left ventricular aneurysm, should be referred for cardiological evaluation and the appropriate surgery. Patients with ischemic induced heart failure should be assessed for possible revascularization by either angioplasty or bypass surgery. Pending clinical findings and the degree of systolic or diastolic dysfunction present, determined by noninvasive tests, the panel made recommendations concerning the choice of various therapeutic agents. These clinical guidelines have been developed for practising physicians who manage patients with heart failure. The process by which consensus recommendations were developed by the Canadian Cardiovascular Society was based on the principle that guidelines have the best chance of succeeding if they are developed by those who will be using them. Strategies that ensure physicians are aware of the current guidelines, and that their implementation leads to measurable improvement in the diagnosis and management of patients with heart failure must be developed. Consensus reports represent an ongoing process which is subject to revision when further conclusive evidence is obtained by ongoing and future clinical trials.

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators.

OBJECTIVES: This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS: From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS: There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS: Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril: the Studies of Left Ventricular Dysfunction. The SOLVD Investigators.

OBJECTIVES: This study was performed to assess the quality of life of patients with left ventricular dysfunction for up to 2 years after randomization to enalapril or placebo. BACKGROUND: Previous reports have documented that survival of patients with congestive heart failure can be extended by the angiotensin-converting enzyme inhibitor enalapril. However, it is unknown whether enalapril has a long-term favorable impact on the quality of life in patients with heart failure. METHODS: A brief quality of life questionnaire assessing the quality of life was administered at baseline and at 6 weeks, 1 year and 2 years of follow-up to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). Participants had an ejection fraction < or = 0.35, no other serious illnesses and either symptomatic heart failure (treatment trial, n = 2,465) or asymptomatic left ventricular dysfunction (prevention trial, n = 2,560). RESULTS: Among the 14 scales of quality of life, better scores at one or more follow-up intervals were noted in 6 scales in the treatment trial and in 1 scale in the prevention trial among patients assigned to enalapril. Consistent superiority with enalapril at two consecutive follow-up intervals was noted in the treatment trial for social functioning and dyspnea but for no scale in the prevention trial. However, an average of 40% of quality of life responses were missing at 2 years of follow-up because of death or failure to complete the questionnaire. In the treatment trial, survivors with more severe heart failure were less likely to complete the questionnaire. CONCLUSIONS: Modest benefits in quality of life for > or = 1 year occurred when patients with left ventricular dysfunction and symptomatic heart failure were treated with enalapril. No apparent beneficial or adverse effect on quality of life was observed with enalapril in asymptomatic patients with left ventricular dysfunction.

Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.

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 approximately 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 taking many medications in relation to severity of congestive heart failure symptoms and ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)