Robert N. Doughty

Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial

Objective To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. Design Randomised, placebo controlled trial. Setting Academic medical centre in an urban setting in New Zealand. Participants 1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo. Main outcome measures Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death. Results Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49). Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone. Trial registration Australian Clinical Trials Registry ACTRN 012605000242628.

Immunoreactive amino‐terminal pro‐brain natriuretic peptide (NT‐PROBNP): a new marker of cardiac impairment

Human brain natriuretic peptide‐32 (BNP) (i.e. proBNP(77–108)), the mature form of BNP and secreted predominantly by the cardiac ventricle, is formed from a high molecular weight precursor, proBNP(1–108). We have recently identified the aminoterminal form proBNP(1–76) (NT‐proBNP) in human plasma but its source, metabolism and production in circulatory disorders are unknown. We have investigated the relationship between immunoreactive (IR) NT‐proBNP and BNP‐32 in normal and hypertensive subjects and in patients with cardiac impairment, as well as the regional plasma concentrations in patients undergoing routine cardiac catheterization.

Left Ventricular Remodeling With Carvedilol in Patients With Congestive Heart Failure Due to Ischemic Heart Disease

Objectives. The aim of this study, a substudy of the Australia–New Zealand trial of carvedilol in patients with heart failure due to ischemic heart disease, was to determine the effects of this treatment on left ventricular size and function with the use of quantitative two-dimensional (2D) echocardiography. Background. Beta-adrenergic blocking drugs have been shown to improve left ventricular ejection fraction in patients with heart failure due to either ischemic heart disease or idiopathic dilated cardiomyopathy. However, the effects of such treatment on left ventricular size remain uncertain. Methods. One hundred twenty-three patients from 10 centers in New Zealand and Australia participated in the 2D echocardiographic substudy. Echocardiography was performed before randomization and was repeated after 6 and 12 months of treatment. Left ventricular end-diastolic and end-systolic volumes were measured from apical four- and two-chamber views with the use of a modified Simpson’s rule method. Results. After 12 months, heart rate was 8 beats/min lower in the carvedilol than in the placebo group, whereas left ventricular end-diastolic and end-systolic volumes were increased in the placebo group but reduced in the carvedilol group. At 12 months, left ventricular end-diastolic volume index was 14 ml/m2less in the carvedilol than in the placebo group (p = 0.0015); left ventricular end-systolic volume index was 15.3 ml/m2less (p = 0.0001), and left ventricular ejection fraction was 5.8% greater (p = 0.0015). Conclusions. In patients with heart failure due to ischemic heart disease, carvedilol therapy for 12 months reduced left ventricular volumes, increased left ventricular ejection fraction and prevented progressive left ventricular dilation. These changes demonstrate a beneficial effect of carvedilol on left ventricular remodeling in heart failure. The observed changes may explain in part the improved clinical outcomes produced by treatment with carvedilol. (J Am Coll Cardiol 1997;29:1060–6) © 1997 by the American College of Cardiology

Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies

AIMS Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF). METHODS AND RESULTS The MAGGIC meta-analysis includes individual data on 39 372 patients with HF, both reduced and preserved left-ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin-receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively. CONCLUSION In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org. The score has the potential for widespread implementation in a clinical setting.

Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy.

Background—The CAPRICORN trial has shown that carvedilol improved outcome in patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors. The aim of this substudy was to determine the effects of carvedilol on left ventricular remodeling in this patient group. Methods and Results—Patients entering the CAPRICORN trial from 13 centers in New Zealand, Australia, and Spain were recruited for this echocardiographic substudy. In 127 patients, quantitative 2D echocardiography was performed according to a standard protocol before randomization and repeated after 1, 3, and 6 months of treatment with carvedilol or placebo. Left ventricular volumes, ejection fraction (Simpson’s method), and wall motion score index were determined in a blinded analysis at the Core Echo Laboratory. At 6 months, left ventricular end systolic volume was 9.2 mL less in the carvedilol group than in the placebo group (P =0.023), and left ventricular ejection fraction was 3.9% higher (P =0.015). Left ventricular end diastolic volume and wall motion score index were not statistically different between the 2 groups at 6 months. Conclusions—In patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors, carvedilol had a beneficial effect on ventricular remodeling, which may, in part, mediate the substantial clinical beneficial effects of carvedilol in this patient population.

Neurohumoral Prediction of Benefit From Carvedilol in Ischemic Left Ventricular Dysfunction

BACKGROUND Plasma neurohormones were analyzed for prediction of adverse outcomes and response to treatment in 415 patients with ischemic left ventricular dysfunction randomly assigned to receive carvedilol or placebo. METHODS AND RESULTS Atrial natriuretic peptide, brain natriuretic peptide (BNP), or norepinephrine (NE) levels above the group median were associated with increased mortality rates and heart failure. On multivariate analysis, both BNP and NE interacted with treatment to predict death or heart failure independent of age, New York Heart Association class, and left ventricular ejection fraction. For placebo, supramedian levels of BNP were associated with 3-fold the mortality rate of inframedian levels (20/104; 19% vs 6/99; 6%; P<0.01). For carvedilol, mortality rate was comparable in these 2 subgroups (12/109; 11% vs 8/94; 9%; NS). Corresponding rates for heart failure were 29/104 (28%) versus 3/99 (3%; P<0.001) for placebo and 16/109 (15%) versus 7/94 (7%; NS) for carvedilol. High NE levels did not predict additional benefit from carvedilol, which significantly reduced heart failure admissions only in those with NE levels below the median (13.1% to 4. 0%; P<0.01). In the 23% of the study population with supramedian BNP but inframedian levels of NE, carvedilol reduced hospital admission with heart failure by >90% (P<0.001). CONCLUSIONS Carvedilol reduced mortality rates and heart failure in those with higher pretreatment BNP levels but lesser activation of plasma NE. Neurohumoral profiling may guide introduction of beta-blockade in heart failure.

Physician-Directed Patient Self-Management of Left Atrial Pressure in Advanced Chronic Heart Failure

Background— Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure. Methods and Results— Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P=0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P=0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% (P<0.001). There were improvements in New York Heart Association class (−0.7±0.8, P<0.001) and left ventricular ejection fraction (7±10%, P<0.001). Doses of angiotensin-converting enzyme/angiotensin-receptor blockers and &bgr;-blockers were uptitrated by 37% (P<0.001) and 40% (P<0.001), respectively, whereas doses of loop diuretics fell by 27% (P=0.15). Conclusions— Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Uptake of self-management strategies in a heart failure management programme

Multidisciplinary heart failure programs including patient education and self‐management strategies such as daily recording of body weight and use of a patient diary decrease hospital readmissions and improve quality of life. However, the degree of uptake of individual components of these programs and their contribution to patient benefit are uncertain.

Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction an individual patient meta-analysis: Meta-analysis research group in echocardiography acute myocardial infarction

Background— Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved. We undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI. Methods and Results— Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20; P<0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF. The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (<39%) and lowest (9%) in patients with the highest LVEF (>53%; P<0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (P=0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome. Conclusions— Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.