Chim C. Lang

Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study

BACKGROUND Obesity is a major risk factor for cardiovascular disease, but the most predictive measure for different ethnic populations is not clear. We aimed to assess whether markers of obesity, especially waist-to-hip ratio, would be stronger indicators of myocardial infarction than body-mass index (BMI), the conventional measure. METHODS We did a standardised case-control study of acute myocardial infarction with 27 098 participants in 52 countries (12,461 cases and 14,637 controls) representing several major ethnic groups. We assessed the relation between BMI, waist and hip circumferences, and waist-to-hip ratio to myocardial infarction overall and for each group. FINDINGS BMI showed a modest and graded association with myocardial infarction (OR 1.44, 95% CI 1.32-1.57 top quintile vs bottom quintile before adjustment), which was substantially reduced after adjustment for waist-to-hip ratio (1.12, 1.03-1.22), and non-significant after adjustment for other risk factors (0.98, 0.88-1.09). For waist-to-hip ratio, the odds ratios for every successive quintile were significantly greater than that of the previous one (2nd quintile: 1.15, 1.05-1.26; 3rd quintile: 1.39; 1.28-1.52; 4th quintile: 1.90, 1.74-2.07; and 5th quintiles: 2.52, 2.31-2.74 [adjusted for age, sex, region, and smoking]). Waist (adjusted OR 1.77; 1.59-1.97) and hip (0.73; 0.66-0.80) circumferences were both highly significant after adjustment for BMI (p<0.0001 top vs bottom quintiles). Waist-to-hip ratio and waist and hip circumferences were closely (p<0.0001) associated with risk of myocardial infarction even after adjustment for other risk factors (ORs for top quintile vs lowest quintiles were 1.75, 1.33, and 0.76, respectively). The population-attributable risks of myocardial infarction for increased waist-to-hip ratio in the top two quintiles was 24.3% (95% CI 22.5-26.2) compared with only 7.7% (6.0-10.0) for the top two quintiles of BMI. INTERPRETATION Waist-to-hip ratio shows a graded and highly significant association with myocardial infarction risk worldwide. Redefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of myocardial infarction attributable to obesity in most ethnic groups.

Effect of Metformin on Mortality in Patients With Heart Failure and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre-dispensed prescribing database for the population of Tayside, Scotland (population ∼400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean ± SD 75.4 ± 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 ± 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 ± 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 ± 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial.

QT dispersion and sudden unexpected death in chronic heart failure

Death in chronic heart failure (CHF) can be from progression of disease or sudden and unexpected. We have attempted to identify factors that predict sudden death in CHF. We followed up 44 patients with CHF for 12-50 (mean 36) months. 4 patients died of non-cardiovascular causes and were excluded from analysis. There were 7 sudden deaths (symptoms for less than 1 h in a previously stable patient) and 12 from progressive CHF. Patients who died of progressive CHF had lower left-ventricular ejection fractions and higher concentrations of atrial natriuretic factor than the 21 survivors, but there were no differences in these variables between survivors and those who died suddenly. However, the sudden death group had significantly (p < 0.05) greater inter-lead variability in the QT interval on the electrocardiogram (QT dispersion; 98.6 [95% CI 79.1-118] ms1/2) than survivors (53.1 [41.9-64.3] ms1/2) or the group who died from progressive CHF (66.7 [51.8-81.6] ms1/2). QT dispersion is a marker of myocardial electrical instability. The association of increased QT dispersion with sudden death suggests that patients at high risk of such death could be identified by means of this simple, reproducible test. This group might benefit from more intensive treatment.

Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure

Background—Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. Methods and Results—Twenty-six anemic patients aged 57±11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [&OV0312;o2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of &OV0312;o2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P <0.05). There were significant increases in hemoglobin (11.0±0.5 to 14.3±1.0 g/dL, P <0.05), peak &OV0312;o2 (11.0±1.8 to 12.7±2.8 mL · min−1 · kg−1, P <0.05) and exercise duration (590±107 to 657±119 s, P <0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. Conclusion—EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in &OV0312;o2 is increased oxygen delivery from increased hemoglobin concentration.

Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease

In chronic heart failure, a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor only partially suppresses aldosterone despite the fact that aldosterone has many harmful effects independent of angiotensin II. These possible harmful effects of aldosterone are magnesium loss, increased cardiac sympathetic activity, and increased ventricular arrhythmias. We have therefore assessed whether adding the aldosterone antagonist, spironolactone, to a loop diuretic and ACE inhibitor reverses any of these potentially harmful effects of residual aldosterone. In a preliminary animal study, we found that exogenous aldosterone reduced myocardial norepinephrine uptake by 24% in anesthetized rats in vivo. In our main study, 42 patients with New York Heart Association II to III congestive heart failure were randomized to spironolactone (50 to 100 mg/day, titrated to blood pressure and plasma potassium) or placebo in a double-blind fashion. Our principal finding is that cardiac norepinephrine uptake as assessed by 123I-metaiodobenzylguanidine scintigraphy increased with spironolactone (p < 0.01). Spironolactone also elevated plasma magnesium (p < 0.05), reduced urinary magnesium excretion (p < 0.05), and caused a reduction in ventricular arrhythmias on 24-hour ambulatory electrocardiography (p < 0.05). Spironolactone increased plasma renin activity, plasma aldosterone (p < 0.01), 24-hour urinary sodium excretion (p < 0.05), and urinary sodium/potassium ratio (p < 0.01). Echocardiographic-determined measurements of left ventricular systolic and diastolic function were unaltered by spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial

Summary Background Experimental evidence suggests that xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris. We ascertained whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina. Methods 65 patients (aged 18–85 years) with angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. We used computer-generated randomisation to assign patients to allopurinol (600 mg per day) or placebo for 6 weeks before crossover. Our primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain. We did a completed case analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 82040078. Findings In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211–408) from a baseline of 232 s (182–380), and placebo increased it to 249 s (200–375; p=0·0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31–58). Allopurinol increased median total exercise time to 393 s (IQR 280–519) from a baseline of 301 s (251–447), and placebo increased it to 307 s (232–430; p=0·0003); the point estimate was 58 s (95% CI 45–77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189–382) to 304 s (222–421), and placebo increased it to 272 s (200–380; p=0·001); the point estimate was 38 s (95% CI 17–55). No adverse effects of treatment were reported. Interpretation Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischaemic drug for patients with angina. Funding British Heart Foundation.

Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program.

Background— We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ejection fraction (LVEF). Methods and Results— In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL · min−1 · 1.73 m−2 compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin. Conclusions— Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING Cytokinetics Inc.

Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.

OBJECTIVE--The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). DESIGN--Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. SETTING--Coronary care unit of a teaching hospital. PATIENTS--75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. MAIN OUTCOME MEASURES--Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. RESULTS--Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). CONCLUSION--Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.

Hemodynamic Exercise Testing A Valuable Tool in the Selection of Cardiac Transplantation Candidates

BACKGROUND Peak exercise oxygen consumption (Vo2), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise Vo2 can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis. METHODS AND RESULTS Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22 +/- 7%; mean peak Vo2, 12.9 +/- 3.0 mL. min-1.kg-1). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (P < .0001). Survival in patients with peak Vo2 of > 14 mL.min-1.kg-1 (88%) was not different from that of patients with peak Vo2 of < or = 14 mL.min-1.kg-1 (79%) (P = NS). However, survival was worse in patients with peak Vo2 of < or = 10 mL.min-1.kg-1 (52%) versus those with peak Vo2 of > 10 mL.min-1.kg-1 (89%) (P < .0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak Vo2 dichotomized at 10 mL. min-1.kg-1 (risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak Vo2 of < or = 10 mL.min-1.kg-1 had an extremely poor 1-year survival rate (38%). CONCLUSIONS Both CO response to exercise and peak exercise Vo2 provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.