Associations of relative fat mass and BMI with all-cause mortality: Confounding effect of muscle mass.

OBJECTIVE: The study objective was to examine associations of relative fat mass (RFM) and BMI with all-cause mortality in the Dutch general population and to investigate whether additional adjustment for muscle mass strengthened these associations. METHODS: A total of 8433 community-dwelling adults from the PREVEND general population cohort (1997-1998) were included. Linear regression models were used to examine associations of RFM and BMI with 24-h urinary creatinine excretion, a marker of total muscle mass. Cox regression models were used to examine associations of RFM and BMI with all-cause mortality. RESULTS: The mean age of the cohort was 49.8 years (range: 28.8-75.7 years), and 49.9% (n = 4209) were women. In age- and sex-adjusted models, both RFM and BMI were associated with total muscle mass (24-h urinary creatinine excretion), and these associations were stronger with BMI (standardized beta [Sß]RFM : 0.29; 95% CI: 0.27-0.31 vs. SßBMI : 0.38; 95% CI: 0.36-0.40; pdifference < 0.001). During a median follow-up period of 18.4 years, 1640 deaths (19.4%) occurred. In age- and sex-adjusted models, RFM was significantly associated with all-cause mortality (hazard ratio per 1-SD [HRRFM ]: 1.16; 95% CI: 1.09-1.24), whereas BMI was not (HRBMI : 1.04; 95% CI: 0.99-1.10). After additional adjustment for muscle mass, associations of both RFM and BMI with all-cause mortality increased in magnitude (HRRFM : 1.24; 95% CI: 1.16-1.32 and HRBMI : 1.12; 95% CI: 1.06-1.19). Results were broadly similar in multivariable adjusted models. CONCLUSIONS: In the general population, a higher RFM was significantly associated with mortality risk, whereas a higher BMI was not. Adjusting for total muscle mass increased the strength of associations of both RFM and BMI with all-cause mortality.

Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF.

AIMS: We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND RESULTS: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin. CONCLUSIONS: In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.

Effects of a simple cardiac rehabilitation program on improvement of self-reported physical activity in atrial fibrillation - Data from the RACE 3 study.

BACKGROUND AND AIM: Physical inactivity is associated with an increased prevalence of atrial fibrillation (AF). We aim to evaluate whether cardiac rehabilitation (CR) motivates patients to become and stay physical active, and whether CR affects sinus rhythm maintenance and quality of life (QoL) in patients with persistent AF and moderate heart failure. METHODS: In the Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure study patients were randomized to conventional or targeted therapy. Targeted therapy contained next to optimal risk factor management a 3-month CR program, including self-reported physical activity and counseling. Successful physical activity was assessed in the targeted group, defined as activity of moderate intensity ≥ 150 min/week, or ≥ 75 min/week of vigorous intensity. AF was assessed at 1 year on 7-days Holter monitoring, QoL using general health, fatigue and AF symptom questionnaires. RESULTS: All 119 patients within the targeted group participated in the CR program, 106 (89%) completed it. At baseline 80 (67%) patients were successfully physical active, 39 (33%) were not. NTproBNP was lower in active patients. During 1-year follow-up physical active patients stayed active: 72 (90%) at 12 weeks, 72 (90%) at 1 year. Inactive patients became active: at 12 weeks 25 (64%) patients and 30 (77%) at 1 year. No benefits were seen on sinus rhythm maintenance and QoL for successful physical active patients. CONCLUSION: In patients with persistent AF and moderate heart failure participation in CR contributes to improve and to maintain physical activity.

A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure.

Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.

Sex-Based Differences in Unrecognized Myocardial Infarction.

Background Myocardial infarction is an important cause of morbidity and mortality in both men and women. Atypical or the absence of symptoms, more prevalent among women, may contribute to unrecognized myocardial infarctions and missed opportunities for preventive therapies. The aim of this research is to investigate sex-based differences of undiagnosed myocardial infarction in the general population. Methods and Results In the Lifelines Cohort Study, all individuals ≥18 years with a normal baseline ECG were followed from baseline visit till first follow-up visit (≈5 years, n=97 203). Individuals with infarct-related changes between baseline and follow-up ECGs were identified. The age- and sex-specific incidence rates were calculated and sex-specific cardiac symptoms and predictors of unrecognized myocardial infarction were determined. Follow-up ECG was available after a median of 3.8 (25th and 75th percentile: 3.0-4.6) years. During follow-up, 198 women experienced myocardial infarction (incidence rate 1.92 per 1000 persons-years) compared with 365 men (incidence rate 3.30; P<0.001 versus women). In 59 (30%) women, myocardial infarction was unrecognized compared with 60 (16%) men (P<0.001 versus women). Individuals with unrecognized myocardial infarction less often reported specific cardiac symptoms compared with individuals with recognized myocardial infarction. Predictors of unrecognized myocardial infarction were mainly hypertension, smoking, and higher blood glucose level. Conclusions A substantial proportion of myocardial infarctions are unrecognized, especially in women. Opportunities for secondary preventive therapies remain underutilized if myocardial infarction is unrecognized.

Genome-wide studies of heart failure and endophenotypes: lessons learned and future directions.

Heart failure (HF) is a complex clinical syndrome resulting from structural or functional impairments of ventricular filling or ejection of blood. HF has a poor prognosis and the burden to society remains tremendous. The unfulfilled expectation is that expanding our knowledge of the genetic architecture of HF will help to quickly advance the quality of risk assessment, diagnoses, and treatment. To date, genome-wide association studies (GWAS) of HF have led to disappointing results with only limited progress in our understanding and tempering the earlier expectations. However, the analyses of traits closely related to HF (also called 'endophenotypes') have led to promising and novel findings. For example, GWAS of NT-proBNP levels not only identified variants in the NNPA-NPPB locus but also substantiated data suggesting that natriuretic peptides in itself are associated with a lower risk of hypertension and HF. Many other genetic associates currently await experimental follow-up in which genes are prioritized based on bioinformatic analyses and various model organisms are employed to obtain functional insights. Promising genes with identified function could later be used in personalized medicine. Also, targeting specific pathogenic gene mutations is promising to protect future generations from HF, such as recently done in human embryos carrying the cardiomyopathy-associated MYBPC3 mutation. This review discusses the current status of GWAS of HF and its endophenotypes. In addition, future directions such as functional follow-up and application of GWAS results are discussed.

Effect of Metformin on Renal Function After Primary Percutaneous Coronary Intervention in Patients Without Diabetes Presenting with ST-elevation Myocardial Infarction: Data from the GIPS-III Trial.

PURPOSE: The association between metformin use and renal function needs further to be elucidated since data are insufficient whether metformin affects renal function in higher risk populations such as after ST-elevation myocardial infarction (STEMI). METHODS: We studied 379 patients included in the GIPS-III trial in which patients without diabetes or renal dysfunction, who underwent primary percutaneous coronary interventions (PCI) for STEMI, were randomized to metformin 500 mg or placebo twice daily for four months. At baseline and at seven scheduled visits up to four months after PCI, estimated glomerular filtration rate (eGFR) was determined (2582 values). Contrast-induced acute kidney injury (CI-AKI) was defined as an increase in serum creatinine of ≥0.3 mg/dl or 25 % rise within 48 h after PCI. RESULTS: At all visits, the mean eGFR was similar in patients randomized to metformin or placebo. Over the four month period, mixed-effect repeated-measures model analysis showed a least-squares mean ± standard error change in eGFR of -5.9±0.8 ml/min/1.73 m2 in the metformin group and −7.1 ±0.8 ml/min/1.73 m2 in the control group (P=0.27 for overall interaction). The incidence of CI-AKI was 14.8 %; 29 (15.2 %) patients in the metformin group versus 27 (14.4 %) controls (P=0.89). After adjustment for covariates, metformin treatment was not associated with CI-AKI (odds ratio: 0.96, 95%CI 0.52−1.75, P=0.88). CONCLUSION: We conclude that initiation of metformin shortly after primary PCI has no adverse effect on renal function in patients without diabetes or prior renal impairment, further providing evidence of the safety of metformin use after myocardial infarction and subsequent contrast exposure.

[Experiences of combined heart-lung transplantations in the University Medical Center Groningen]. / Ervaringen met gecombineerde hart-longtransplantatie in het Universitair Medisch Centrum Groningen.

OBJECTIVE: Reporting the results of combined heart-lung transplantation in the University Medical Center Groningen (UMCG), the Netherlands. DESIGN: Retrospective study. METHOD: Data were retrieved of patients who underwent a combined heart-lung transplantation in the UMCG between December 1996 and December 2007. Demographic, clinical and other relevant characteristics were recorded, as well as post-transplantation morbidity and mortality. RESULTS: The study group consisted of 14 patients (3 men and 11 women) with a mean age of 41 years. Indications for heart-lung transplantation were: congenital heart disease complicated by pulmonary hypertension (6 patients), idiopathic pulmonary hypertension with severe right ventricle failure (4 patients), lung fibrosis with severe right ventricle failure (1 patient), cystic fibrosis with systolic left ventricle failure (1 patient), pulmonary hypertension after thoracic radiation and chemotherapy (1 patient) and re-transplantation after lung-transplant failure (1 patient). The mean waiting time prior to operation was approximately 1.5 years. 9 of the 14 patients (64%) underwent such a marked clinical deterioration during the waiting period that they were given a 'very high urgency status' for transplantation. Almost half of patients became dependent on supplementary intravenous inotropics during the waiting period. At the end of the study 6 of the 14 patients (43%) were alive, with a mean survival period of 58 months (range: 6-132). Infection was the cause of death in 4 of the 8 patients. Of the 8 deceased patients, 4 were underweight preoperatively (BMI < 18.5 kg/m2) and were cachectic. This was the case in only 1 of the 6 surviving patients. CONCLUSION: A combined heart-lung transplantation is a rare operation in the Netherlands. The waiting time in this study was long and the post-transplantation mortality was high. Underweight (cachexia), a sign of a poor clinical condition, appears to be associated with mortality.

Mortality and preoperative cardiac function in vascular amputees: an N-terminal pro-brain natriuretic peptide (NT-proBNP) pilot study.

OBJECTIVE: To determine preoperative ventricular function in vascular amputees by measuring N-terminal pro-brain natriuretic peptide (NT-proBNP) and to analyse the relationship between NT-proBNP levels and 30-day postoperative mortality. DESIGN: Prospective pilot study. SUBJECTS AND METHODS: In 19 patients planned for a lower limb amputation for non-reconstructable peripheral arterial disease NT-proBNP was measured the day before amputation. RESULTS: Four amputees died within 30 days after the amputation. In 17 of 19 patients NT-proBNP values were found more than 2 standard deviations above the age corrected reference value. Pre-amputation NT-proBNP levels did not differ significantly between non-survivors and survivors (P = 0.162). CONCLUSION: Preoperative NT-proBNP levels are not significantly related to 30-day mortality after lower limb amputation procedure. Preoperative NT-proBNP levels are very high, indicating that serious ventricular dysfunction may be present in vascular amputees.

High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics.

BACKGROUND: Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression. METHODS AND RESULTS: The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications. Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event. CONCLUSIONS: This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction disease.

The feasibility of repeated left ventricular ejection fraction analysis with sequential single-dose radionuclide ventriculography.

OBJECTIVE: Repeated left ventricular ejection fraction (LVEF) analyses with sequential single-dose radionuclide ventriculography might be an interesting technique for monitoring the effect of positive inotropic interventions. The aim of the study was to assess the reproducibility of LVEF measurement with planar radionuclide ventriculography within 3 h, using a standard single dose of radioactive tracer. METHODS: Sixteen patients underwent routine planar radionuclide ventriculography with a standard dose of 500 MBq of [Tc]pertechnetate and returned after 3 h for a repeat planar radionuclide ventriculography without administration of additional tracer. RESULTS: The average initial LVEF was 35.1+/-18.6%-point (range, 12%-point to 68%-point). The mean difference of the LVEF between the initial planar radionuclide ventriculography and the repeat planar radionuclide ventriculography was 2.8%+/-6.3% (range, -11.8% to 13.3%, P=NS). The correlation between both measurements was significant with a correlation coefficient of 0.995 (P<0.01). Bland-Altman analysis revealed a mean LVEF difference of 0.94%-point between the baseline planar radionuclide ventriculography and the repeat planar radionuclide ventriculography (95% confidence interval: -2.7%-point to 4.5%-point). The visual wall motion assessment showed excellent reproducibility, with a kappa-statistic of 0.98. CONCLUSION: Repeated radionuclide ventriculography with a 3 h interval using a single standard dose of 500 MBq of [Tc]pertechnetate is highly reproducible and will be useful for monitoring the effect of positive inotropic interventions.

Mild preoperative renal dysfunction as a predictor of long-term clinical outcome after coronary bypass surgery.

BACKGROUND: Renal dysfunction is a prognostic marker in patients with cardiovascular disease. However, no long-term follow-up studies on the influence of mild renal dysfunction on mortality in patients undergoing coronary bypass grafting have been reported. Therefore, we aimed to identify the significance of preoperative (mild) renal dysfunction as a long-term predictor of clinical outcome after coronary bypass surgery. METHODS: In 358 patients who underwent isolated saphenous vein aorta-coronary artery bypass grafting, estimated glomerular filtration rates were calculated with the Cockroft-Gault equation (GFRc). Patients were categorized into 2 groups (group 1, GFRc >71.1 mL x min (-1) x 1.73 m (-2) ; group 2, GFRc <71.1 mL x min (-1) x 1.73 m (-2) ). Multivariate Cox proportional hazard analyses were performed to determine the independent prognostic value of GFRc. RESULTS: During a median follow-up of 18.2 years, 233 patients (65.1%) died. Patients who died had lower GFRc and were older. Multivariate analysis demonstrated that total mortality in patients with lower GFRc was significantly increased (lower GFRc group vs normal GFRc group: hazard ratio, 1.44; P = .019). Lower GFRc was also an independent predictor of cardiac mortality (hazard ratio, 1.51; P = .032). No significant differences were observed between groups in the occurrence of myocardial infarction and the need for reintervention. CONCLUSIONS: Our study demonstrates that after long-term follow-up, preoperative mild renal dysfunction is an independent predictor of long-term (cardiac) mortality in patients who undergo coronary artery bypass grafting.

Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL).

BACKGROUND: Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. METHODS AND RESULTS: Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER (P=0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P=0.33). CONCLUSIONS: The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

Renal function as a predictor of prognosis in chronic heart failure.

The incidence of chronic heart failure (CHF) has been increasing, particularly because of the aging of the population and the improved survival of patients with coronary artery disease. Therefore, the current pathophysiological and clinical considerations in the diagnosis and treatment of CHF will need further improvement in terms of cardiovascular risk profiling, preventive measures, earlier intervention, and patient-tailored disease management. To date, the role of the kidney in CHF is mainly considered within the context of excessive salt and water retention, due to reduced renal blood flow. However, recent data indicate that the kidney may play a more decisive role in the progression and prognosis of the disease. It has been demonstrated that renal function is independently associated with an increased risk for all-cause mortality and cardiovascular morbidity. Furthermore, moderate renal insufficiency is a common phenomenon in this patient population and, for example, left ventricular ejection fraction, glomerular filtration rate, and New York Health Association class are not only prognostically important but are also acting independently, and support the hypothesis that cardiac function, clinical status, and renal function represent, in part, different prognostic entities of CHF. It could be questioned why an impaired renal function adds prognostic risk to develop CHF? A subclinically decreased renal function is unlikely to be the direct cause. Renal function is known to correlate with a variety of cardiovascular risk factors. Similar risk factors could contribute to the pathogenesis of intrarenal disease. Furthermore, a large number of metabolic abnormalities are related to impaired renal function and induce myocardial dysfunction and damage. Finally, neurohormonal activation is apparent in patients with chronic heart failure. Angiotensin II, the central product of the renin-angiotensin system, may play a central role in the pathophysiology and progression of cardiovascular and renal diseases. In conclusion, to prevent cardiovascular morbidity and mortality, new therapeutic strategies might be triggered by focussing on increasing our knowledge concerning adaptive and maladaptive mechanisms of the kidney involved in CHF.