Finn Gustafsson

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 .).

Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II).

OBJECTIVES This study investigated the influence of the mechanical blood pump HeartMate II (HMII) (Thoratec Corporation, Pleasanton, California) on blood coagulation and platelet function. BACKGROUND HMII is an implantable left ventricular assist device used for the treatment of heart failure. Patients treated with HMII have increased bleeding tendencies. METHODS We measured agonist-induced platelet aggregation in 16 patients on HMII support. RESULTS The von Willebrand factor (vWF)-dependent ristocetin-induced platelet aggregation was impaired in 11 of the 16 patients, of which 12 had experienced at least 1 minor or major bleeding episode. The impaired ristocetin-induced platelet aggregation was associated both with decreased specific activity of plasma vWF, presumably due to lack of high molecular weight vWF multimers, as well as with attenuated function of the platelets themselves. CONCLUSIONS The results imply that HMII treatment is associated with impaired platelet aggregation, which may contribute to an increased tendency to bleed.

Long-term survival in patients hospitalized with congestive heart failure: relation to preserved and reduced left ventricular systolic function

AIMS The purpose of this study was to evaluate the influence of left ventricular systolic function on the survival in a large consecutive cohort of patients hospitalized with congestive heart failure and to determine how left ventricular systolic function interacts with co-morbid conditions in terms of prognosis. METHODS AND RESULTS Analysis of survival data from 5491 patients admitted for new or worsening heart failure to 34 departments of cardiology or internal medicine in Denmark from 1993-1996 was carried out. A standardized echocardiogram was available for 95% of the patients, and left ventricular systolic function was estimated using wall motion index score. Follow-up time was 5-8 years. Patients with preserved systolic function were older, more frequently female, and had less evidence of ischemia than patients with systolic dysfunction. After 1 year, 24% of the patients had died. Low wall motion index was a potent independent predictor of death (risk ratio for one unit increase, 0.60 (0.56-0.64)), and was of greater prognostic significance in younger patients and patients with a history of myocardial ischemia. However, even in patients with preserved systolic function, mortality was high (1 year mortality, 19%). CONCLUSION In hospitalized heart failure patients, particularly in younger patients with ischemic heart disease, mortality risk is inversely related to left ventricular systolic function.

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.

Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II).

The incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients supported with a continuous-flow left ventricular assist device (LVAD) has not been investigated in detail. In 23 consecutive recipients of a HeartMate II, we analyzed the incidence of VT/VF during a total of 266 months of follow-up. Sustained VT or VF occurred in 52% of the patients, with the majority of arrhythmias occurring in the first 4 weeks after LVAD implantation. VT/VF requiring implantable cardioverter-defibrillator (ICD) shock or external defibrillation occurred in 8 patients and significant hemodynamic instability ensued in 3 patients. There were no clear predictors of VT/VF, and it is argued that prophylactic ICD implantation should be considered in patients supported with a continuous-flow LVAD.

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.

Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects. Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy.

OBJECTIVES The purpose of this study was to determine whether a diuretic effect may be detectable in patients treated with eplerenone, a mineralocorticoid receptor antagonist, as compared with placebo during the first month of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study) (n = 6,080) and whether this was associated with eplerenones beneficial effects on cardiovascular outcomes. BACKGROUND The mechanism of the survival benefit of eplerenone in patients with heart failure post-myocardial infarction remains uncertain. METHODS A diuretic effect was indirectly estimated by changes at 1 month that was superior to the median changes in the placebo group in body weight (-0.05 kg) and in the estimated plasma volume reduction (+1.4%). A potassium-sparing effect was defined as a serum potassium increase greater than the median change in the placebo group: +0.11 mmol/l. RESULTS In the eplerenone group, body weight (p < 0.0001) and plasma volume (p = 0.047) decreased, whereas blood protein and serum potassium increased (both, p < 0.0001), as compared with the placebo group, suggesting a diuretic effect induced by eplerenone, associated with a potassium-sparing effect. A diuretic effect, as defined by an estimated plasma volume reduction, was independently associated with 11% to 19% better outcomes (lower all-cause death, cardiovascular death or cardiovascular hospitalization, all-cause death or hospitalization, hospitalization for heart failure). Potassium sparing was also independently associated with 12% to 34% better outcomes. There was no statistically significant interaction between the observed beneficial effects of eplerenone (9% to 17%) on cardiovascular outcomes and potassium-sparing or diuretic effects. CONCLUSIONS Eplerenones beneficial effects on long-term survival and cardiovascular outcomes are independent from early potassium-sparing or diuretic effects, suggesting that mineralocorticoid receptor antagonism provides cardiovascular protection beyond its diuretic and potassium-sparing properties.

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 …

Determinants and Consequences of Renal Function Variations With Aldosterone Blocker Therapy in Heart Failure Patients After Myocardial Infarction Insights From the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

Background— We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results— Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of −1.4±0.3 mL · min−1 · 1.73 m−2 compared with placebo ( P 20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02–1.30; P =0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction 20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. Conclusions— In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes. # Clinical Perspective {#article-title-45}Background— We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results— Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of −1.4±0.3 mL · min−1 · 1.73 m−2 compared with placebo (P<0.0001), an effect that appeared within the first month (−1.3±0.4 mL · min−1 · 1.73 m−2) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR >20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02–1.30; P=0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction <35%, and use of eplerenone and loop diuretic. An early decline in eGFR by >20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. Conclusions— In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes.