Per Hildebrandt

Plasma Adiponectin, Body Mass Index, and Mortality in Patients With Chronic Heart Failure

Background—Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. Methods and Results—In 195 CHF patients (age 69.3±10.2 years, BMI 27.3±5.2 kg/m2, left ventricular ejection fraction 30±8.9%, mean±SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (&bgr;=0.47, P<0.001), and both biomarkers were negatively associated with BMI (&bgr;=−0.43, P<0.001 for adiponectin and &bgr;=−0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, systolic blood pressure, left ventricular ejection fraction <25%, duration of CHF, and creatinine clearance) and for NT-proBNP, the hazard ratio of mortality for values in the 2 upper tertiles relative to the lowest tertile of adiponectin was 3.23 (P=0.032). BMI predicted mortality independently of clinical parameters of CHF severity (hazard ratio=0.63, P=0.012), but this association became insignificant after additional adjustment for NT-proBNP (hazard ratio=0.74, P=0.13). Conclusions—A high adiponectin level was a predictor of mortality, independent of risk markers of CHF severity, presumably because of its role as a marker for wasting. BMI was also associated with mortality, but a part of this relation may be mediated by adiponectin and NT-proBNP levels.

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure

BACKGROUND The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population

Objective: To identify potentially confounding variables for the interpretation of plasma N-terminal pro brain natriuretic peptide (NT-proBNP). Design: Randomly selected subjects filled in a heart failure questionnaire and underwent pulse and blood pressure measurements, ECG, echocardiography, and blood sampling. Setting: Subjects were recruited from four Copenhagen general practices located in the same urban area and were examined in a Copenhagen University Hospital. Patients: 382 women and 290 men in four age groups: 50–59 years (n = 174); 60–69 years (n = 204); 70–79 years (n = 174); and > 80 years (n = 120). Main outcome measures: Associations between the plasma concentration of NT-proBNP and a range of clinical variables. Results: In the undivided study sample, female sex (p < 0.0001), greater age (p < 0.0001), increasing dyspnoea (p = 0.0001), diabetes mellitus (p = 0.01), valvar heart disease (p = 0.002), low heart rate (p < 0.0001), left ventricular ejection fraction ⩽ 45% (p < 0.0001), abnormal ECG (p < 0.0001), high log10[plasma creatinine] (p = 0.0009), low log10[plasma glycosylated haemoglobin A1c] (p = 0.0004), and high log10[urine albumin] (p < 0.0001) were independently associated with a high plasma log10[plasma NT-proBNP] by multiple linear regression analysis. Conclusions: A single reference interval for the normal value of NT-proBNP is unlikely to suffice. There are several confounders for the interpretation of a given NT-proBNP concentration and at the very least adjustment should be made for the independent effects of age and sex.

Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure.

OBJECTIVES The purpose of the study was to investigate the effects of beta1-blockade on left ventricular (LV) size and function for patients with chronic heart failure. BACKGROUND Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects. METHODS In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function. RESULTS Decreases in both LV end-diastolic volume index (150 ml/m2 at baseline to 126 ml/m2 after six months, p = 0.007) and LV end-systolic volume index (107 ml/m2 to 81 ml/m2, p = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, p = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m2 to 160 g/m2 in the placebo group [p = 0.005] and 179 g/m2 to 164 g/m2 in the metoprolol CR/XL group [p = 0.011). CONCLUSIONS This study is the first randomized study to demonstrate that the beta1-blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.

Risk prediction is improved by adding markers of subclinical organ damage to SCORE

AIMS It is unclear whether subclinical vascular damage adds significantly to Systemic Coronary Risk Evaluation (SCORE) risk stratification in healthy subjects. METHODS AND RESULTS In a population-based sample of 1968 subjects without cardiovascular disease or diabetes not receiving any cardiovascular, anti-diabetic, or lipid-lowering treatment, aged 41, 51, 61, or 71 years, we measured traditional cardiovascular risk factors, left ventricular (LV) mass index, atherosclerotic plaques in the carotid arteries, carotid/femoral pulse wave velocity (PWV), and urine albumin/creatinine ratio (UACR) and followed them for a median of 12.8 years. Eighty-one subjects died because of cardiovascular causes. Risk of cardiovascular death was independently of SCORE associated with LV hypertrophy [hazard ratio (HR) 2.2 (95% CI 1.2-4.0)], plaques [HR 2.5 (1.6-4.0)], UACR > or = 90th percentile [HR 3.3 (1.8-5.9)], PWV > 12 m/s [HR 1.9 (1.1-3.3) for SCORE > or = 5% and 7.3 (3.2-16.1) for SCORE < 5%]. Restricting primary prevention to subjects with SCORE > or = 5% as well as subclinical organ damage, increased specificity of risk prediction from 75 to 81% (P < 0.002), but reduced sensitivity from 72 to 65% (P = 0.4). Broaden primary prevention from subjects with SCORE > or = 5% to include subjects with 1% < or = SCORE < 5% together with subclinical organ damage increased sensitivity from 72 to 89% (P = 0.006), but reduced specificity from 75 to 57% (P < 0.002) and positive predictive value from 11 to 8% (P = 0.07). CONCLUSION Subclinical organ damage predicted cardiovascular death independently of SCORE and the combination may improve risk prediction.

N-Terminal Pro Brain Natriuretic Peptide Is Inversely Related to Metabolic Cardiovascular Risk Factors and the Metabolic Syndrome

We wanted to investigate the relationship of N-terminal pro brain natriuretic peptide (Nt-proBNP) to metabolic and hemodynamic cardiovascular (CV) risk factors in the general population. From a population-based sample of 2656 people 41, 51, 61, or 71 years of age, we selected 2070 patients without previous stroke or myocardial infarction who did not receive any CV, antidiabetic, or lipid-lowering treatment in 1993 to 1994. Traditional CV risk factors, 24-hour blood pressures, left ventricular (LV) mass, and ejection fraction by echocardiography, pulse wave velocity, urine albumin/creatinine ratio (UACR), and serum Nt-proBNP were measured in 1993 to 1994. The metabolic syndrome was defined in accordance with the definition of the European Group for the Study of Insulin Resistance (EGIR). Higher log(Nt-proBNP) was in multiple regression analysis related to female gender (&bgr;=−0.37), older age (&bgr;=0.32), higher clinic pulse pressure (&bgr;=0.20), lower serum total cholesterol (&bgr;=−0.15), lower LVEF (&bgr;=−0.08, all P<0.001), lower log(serum insulin) (&bgr;=−0.07), lower log(plasma glucose) (&bgr;=−0.06, both P<0.01, lower log(serum triglyceride) (&bgr;=−0.06), lower body mass index (&bgr;=−0.05); lower heart rate (&bgr;=−0.05), higher logUACR (&bgr;=0.04, all P<0.05) and higher log(LV mass index) (&bgr;=0.04, P=0.07), adjusted R2=0.35, P<0.001). The metabolic syndrome was associated with lower Nt-proBNP (35 pg/mL versus 48 pg/mL; P<0.001) and shifted the positive relationship between pulse pressure and Nt-proBNP to the right (ie, higher blood pressure for a given level of Nt-proBNP). The metabolic syndrome was associated with lower Nt-proBNP levels and shifted the positive relationship between Nt-proBNP and pulse pressure to the right, creating a possible link between the metabolic syndrome and hypertension.

Quantification of aortic regurgitation by magnetic resonance velocity mapping

The use of magnetic resonance (MR) velocity mapping in the quantification of aortic valvular blood flow was examined in 10 patients with angiographically verified aortic regurgitation. MR velocity mapping succeeded in identifying and quantifying the regurgitation in all patients, and the regurgitant volume determined with MR velocity mapping agreed well with the grade obtained by aortic root angiography (p < 0.02). The accuracy in quantification of the aortic valvular flow rate was demonstrated by a significant correlation between the stroke volume (ml) measured by MR velocity mapping and calculated from MR imaging of the left ventricular end-diastolic and end-systolic volumes in eight patients (Y = 0.89 x X + 11, r = 0.97, p < 0.001). This finding was confirmed by a good agreement between the net cardiac output (L/min) quantified with MR velocity mapping and simultaneous 125I-indicator dilution measurement in all subjects (Y = 0.89 x X + 0.08, r = 0.82, p < 0.01). In conclusion, MR velocity mapping may be used as a noninvasive tool in the quantification of aortic regurgitation.

Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction

Abstract OBJECTIVES This study evaluated the efficacy of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril in diabetic patients with left ventricular dysfunction after acute myocardial infarction (AMI). BACKGROUND Patients with diabetes mellitus have a high mortality following AMI, probably due to a high risk of congestive heart failure and reinfarction. Because ACE inhibition effectively reduces progression of heart failure, it could be particularly beneficial in diabetic patients after AMI. METHODS The study is a retrospective analysis using data from the Trandolapril Cardiac Evaluation (TRACE) study, which was a randomized, double-blind, placebo-controlled trial of trandolapril in 1,749 patients with AMI and ejection fraction ≤35%. The mean follow-up time was 26 months. RESULTS A history of diabetes was found in 237 (14%) of the 1,749 patients. Treatment with trandolapril resulted in a relative risk (RR) of death from any cause for the diabetic group of 0.64 (95% confidence interval 0.45 to 0.91) versus 0.82 (0.69 to 0.97) for the nondiabetic group. In the diabetic group, trandolapril reduced the risk of progression to severe heart failure markedly (RR, 0.38 [0.21 to 0.67]), and no significant reduction of this end point was found in the nondiabetic group. CONCLUSIONS The ACE inhibition after myocardial infarction complicated by left ventricular dysfunction appears to be of considerable importance in patients with diabetes mellitus by saving lives and substantially reducing the risk of progression to severe heart failure.

Valve area and cardiac output in aortic stenosis: Quantification by magnetic resonance velocity mapping☆

Valve area and cardiac output were determined with magnetic resonance (MR) velocity mapping in 12 patients with aortic stenosis. Heart catheterization, Doppler echocardiography, and indicator dilution were performed for comparison. Left ventricle could be catheterized in only nine patients; in these cases, MR measured a mean valve area of 1.2 cm2 compared with 0.9 cm2 derived from catheterization data, with a mean difference of 0.2 cm2 between the 2 methods. The limits of agreement were [0.0, +0.5] cm2, less in patients with an important degree of concomitant regurgitation. In the whole material, MR measured a mean area of 1.1 cm2 compared with 1.2 cm2 derived from Doppler echocardiography data, with a mean difference of 0.1 cm2 and [-0.5, +0.6] cm2 as limits of agreement. In 11 patients the cardiac output was quantified by MR to a mean of 4.9 L/min and by indicator dilution to 5.0 L/min, with a mean difference of 0.2 L/min, and [-0.6, +0.8] L/min as limits of agreement. In addition, MR offers the major advance of simultaneous quantification of regurgitant volume in cases of concomitant regurgitation. In conclusion, because the two important prognostic determinants in aortic stenosis--the valvular area and the cardiac output--may be quantified, MR has potential to become a clinical tool in assessment of severity in aortic stenosis.

Hyperkalaemia and impaired renal function in patients taking spironolactone for congestive heart failure: retrospective study

Spironolactone reduces disease and death in patients with severe congestive heart failure and is well tolerated with regard to renal function and serum potassium concentrations.1 Guidelines recommend taking spironolactone in addition to angiotensin converting enzyme inhibitors and β blockers,2 3 but since spironolactone can lead to renal dysfuction or hyperkalaemia, we followed up a cohort of patients taking spironolactone to identify predictors of harmful effects. We selected 125 consecutive patients from the congestive heart failure outpatient clinic of Frederiksberg University Hospital, Copenhagen (table).4 We included only patients with a left ventricular ejection fraction (LVEF) of no more than 45% or patients who were taking spironolactone. We started 65 patients on spironolactone; 60 patients were already taking spironolactone when they were referred. We measured blood electrolytes at baseline and then every two months. The study started in September 1999 …