Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

AIMS: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers. METHODS: Study participants were stratified to G143E non-carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*h/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers. CONCLUSIONS: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.

Trandolapril, an angiotensin-converting enzyme inhibitor prodrug, needs to be activated by carboxylesterase 1 (CES1) in the liver to exert its intended therapeutic effect. A previous in vitro study demonstrated that the CES1 genetic variant G143E (rs71647871) abolished CES1-mediated trandolapril activation in cells transfected with the variant. This study aimed to determine the effect of the G143E variant on trandolapril activation in human livers and the pharmacokinetics (PKs) and pharmacodynamics (PDs) in human subjects. We performed an in vitro incubation study to assess trandolapril activation in human livers (5 G143E heterozygotes and 97 noncarriers) and conducted a single-dose (1 mg) PK and PD study of trandolapril in healthy volunteers (8 G143E heterozygotes and 11 noncarriers). The incubation study revealed that the mean trandolapril activation rate in G143E heterozygous livers was 42% of those not carrying the variant (p = 0.0015). The clinical study showed that, relative to noncarriers, G143E carriers exhibited 20% and 15% decreases, respectively, in the peak concentration (Cmax ) and area under the curve from 0 to 72 h (AUC0-72 h ) of the active metabolite trandolaprilat, although the differences were not statistically significant. Additionally, the average maximum reductions of systolic blood pressure and diastolic blood pressure in carriers were ~ 22% and 23% less than in noncarriers, respectively, but the differences did not reach a statistically significant level. In summary, the CES1 G143E variant markedly impaired trandolapril activation in the human liver under the in vitro incubation conditions; however, this variant had only a modest impact on the PK and PD of trandolapril in healthy human subjects.

Routine Postprocedure Chest Radiography Is Not Warranted After Right-Heart Catheterization.

PURPOSE: To determine whether routine postprocedure chest radiography is indicated to exclude pneumothorax after outpatient right heart catheterization with or without endomyocardial biopsy. METHODS: This HIPAA-compliant retrospective quality improvement cohort study was approved by the institutional review board. All outpatients from January 1, 2010, to July 1, 2017, who underwent routine postprocedure chest radiography after right heart catheterization with or without endomyocardial biopsy formed the study population (n = 6,036). Subjects were identified by electronic medical record query using Current Procedural Terminology codes. Pneumothorax prevalence was calculated by coded review of chest radiography reports. Size of pneumothorax (if present) and clinical outcome were determined, and 95% confidence intervals (CIs) were calculated. RESULTS: Most (99%) right heart catheterizations were performed using an internal jugular vein approach, as determined by a random sample of 100 subjects. The prevalence of pneumothorax on postprocedure chest radiography reports was 0.1% (7 of 6,036; 95% CI: 0.05%-0.24%). Three of these seven pneumothoraces were confirmed by repeat imaging within 1 hour to be false-positives (ie, no pneumothorax), resulting in a corrected pneumothorax rate of 0.07% (4 of 6,036; 95% CI: 0.00%-0.2%). The remaining four that reported pneumothoraces were less than 1 cm. No chest tubes were placed, and all subjects were discharged home without an unexpected escalation in the level of care. CONCLUSION: In a large cohort of over 6,000 subjects, pneumothorax after right heart catheterization utilizing an internal jugular vein approach was rare and when found was clinically insignificant. False-positives were common. Routine postprocedure chest radiography in this setting is not warranted and is being discontinued at the study institution.

Association of Donor Tricuspid Valve Repair With Outcomes After Cardiac Transplantation.

BACKGROUND: Tricuspid regurgitation after cardiac transplantation is associated with worse clinical outcomes. This study sought to determine the association of donor tricuspid valve repair (dTVR) with outcomes after cardiac transplantation. METHODS: Patients who underwent cardiac transplantation between January 20, 2002, and December 31, 2016, were included. Multivariable Cox regression modeling was performed to determine the association between dTVR and the composite outcome of death, posttransplant TVR, kidney transplant after cardiac transplant, or chronic dialysis, and included propensity scoring to control for baseline differences in likelihood of undergoing dTVR. RESULTS: The analysis included 330 patients, with 173 (52.4%) undergoing dTVR. dTVR performance varied by surgeon and also increased over time, with 71 (83.5%) performed during January 1, 2011, to November 30, 2013. Transplant year and surgeon were significantly associated with the baseline likelihood of undergoing dTVR. Although fewer composite outcomes occurred in the dTVR vs no dTVR group (39 [22.5%] vs 56 [36.4%], p = 0.006), dTVR was not significantly associated with the composite outcome in multivariable modeling. Lower risk for the composite outcome was associated with greater number of biopsies during the first posttransplant year, whereas higher risk was associated with more high-grade biopsy specimens and higher creatinine. CONCLUSIONS: There was no significant benefit or harm with regards to the composite of death, posttransplant TVR, or dialysis associated with dTVR.

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms.

Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency >0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs, including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), were loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. In addition, A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs, includingL40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), significantly reduced CES1 protein and/or mRNA expression levels in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of the human liver. Neither CES1 expression nor activity was affected by the two haplotypes. In summary, this study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1.

Comparing the Effectiveness of an Axial and a Centrifugal Left Ventricular Assist Device in Ventricular Unloading.

Centrifugal (CFG) and axial flow (AX) left ventricular assist devices have different hydrodynamic properties that may impact the effectiveness of left ventricular unloading. We sought to determine whether patients implanted with the HeartWare HVAD (CFG) and HeartMate II (AX) had a similar degree of hemodynamic support by comparing parameters measured using echocardiography and right heart catheterization. Using our prospectively collected database, we identified 268 patients implanted with the AX and 93 with the CFG. Demographic characteristics were similar between groups. AX patients had a significantly lower INTERMACS score. Baseline ventricular dimension, mitral regurgitation, right ventricular systolic pressure, right atrial pressure, mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance were similar. Wedge pressure was higher, and left ventricular ejection fraction was lower at baseline in the AX. After implantation, there was a greater reduction of right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, and left ventricular internal diameter during diastole in the AX cohort. After implantation, cardiac output by Fick calculation showed a greater improvement in the AX group. These results demonstrate that both AX and CFG devices resulted in left ventricular unloading; however, AX devices may offer advantages in the magnitude of left ventricular unloading, which could have implications in myocardial recovery or reduction in pulmonary vascular resistance before transplantation.

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation.

Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

Relation of serum uric acid to cardiovascular disease.

This review summarizes recent published literature on the association between serum uric acid and cardiovascular disease, a relationship which is complex and not fully elucidated. Uric acid may be a marker for risk, a causative agent in cardiovascular disease, or both. Various biologic factors can influence serum uric acid levels, and serum uric acid level itself is closely related to conditions such as hypertension, dyslipidemia, obesity, and impaired glucose metabolism, that contribute to cardiovascular disease pathophysiology. Serum uric acid levels have been found to be associated with adverse outcomes, including mortality, in the general population. In addition, serum uric acid is associated with increased risk for incident coronary heart disease, heart failure, and atrial fibrillation. In the setting of established systolic heart failure, serum uric acid is positively associated with disease severity and mortality risk. Whether targeting treatment based on uric acid levels might affect clinical outcomes is still being studied.

Vitamin D receptor genetics on extracellular matrix biomarkers and hemodynamics in systolic heart failure.

INTRODUCTION: Vitamin D deficiency has been associated with the development of myocardial hypertrophy and inflammation. These findings suggest that vitamin D status and vitamin D receptor (VDR) genomics may play a role in myocardial fibrosis. The aim of this pilot study was to determine the association between vitamin D levels, VDR polymorphisms, and biomarkers of left ventricular remodeling and hemodynamics. METHODS: In a cross-sectional pilot study, patients with ejection fraction (EF) <40% (and New York Heart Association ≥ II) undergoing right heart catheterization were included in the study. Blood was collected for determination of 25-hydroxyvitamin D level (antibody competitive immunoassay), VDR genotypes (BsmI, ApaI, TaqI, and FokI), and biomarkers (N-terminal propeptide of collagen type III [PIIINP], matrix metalloproteinase 2, and galectin 3). The vitamin D genotypes were determined through the use of pyrosequencing. RESULTS: A total of 30 patients with a mean EF of 17% ± 8% were enrolled. There was a significant association between the BsmI C allele, ApaI G allele, and TaqI A allele, which formed a haplotype block (CGA) for analysis. There were no differences in baseline parameters between patients with the VDR haplotype block (n = 20) and those without (n = 10). Individual genotypes were not associated with any biomarker or hemodynamics. Patients with the CGA haplotype demonstrated significantly higher log PIIINP values (1.74 ± 0.32 mcg/mL vs 1.36 ± 0.31 mcg/mL, P = .0041). When evaluating vitamin D levels below and above the median level (19 ng/mL), there was no significant difference between these 2 groups in regard to biomarker levels for left ventricular remodeling. CONCLUSION: This study has shown that a biomarker for collagen type III synthesis, PIIINP, was associated with the CGA haplotype of BsmI, ApaI, and TaqI single nucleotide polymorphisms on the VDR. These findings suggest that VDR genetics may play a role in myocardial fibrosis in patients with systolic heart failure.

Effect of obesity on in-hospital treatment for acute coronary syndrome complicated by new-onset heart failure.

OBJECTIVE: Obesity has been associated with superior outcomes in heart failure (HF) and acute coronary syndrome (ACS). Although patients with new-onset HF after ACS are at a high risk, they may receive less aggressive treatment. It is unknown whether treatment practices are biased by BMI. METHODS AND RESULTS: Consecutive patients without previous HF, who were hospitalized with ACS, and had left ventricular ejection fraction less than 40% or clinical HF were analyzed to assess the utilization of evidence-based treatment by BMI. BMI was categorized into normal (18.5 to <25 kg/m), overweight (25 to <30 kg/m), and obese (≥30 kg/m) groups. Multivariable logistic regression models were performed to examine the association of BMI with undergoing cardiac catheterization, and discharge on ß-blocker or angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Analysis included 461 patients. There were no significant differences among BMI groups in performance of cardiac catheterization or discharge on ACE inhibitor/ARB or ß-blocker. Compared with normal, neither overweight nor obese BMI was significantly associated with cardiac catheterization [overweight: odds ratio (OR) 1.49, 95% confidence interval (CI) 0.82-2.72, P=0.2; obese: OR 1.75, 95% CI 0.92-3.33, P=0.09], or discharge on ACE inhibitor/ARB (overweight: OR 0.70, 95% CI 0.40-1.21, P=0.7; obese: OR 0.69, 95% CI 0.39-1.23, P=0.2), or ß-blocker (overweight: OR 1.24, 95% CI 0.69-2.21, P=0.5; obese: OR 1.13, 95% CI 0.62-2.07, P=0.7). CONCLUSION: Among patients with new-onset HF complicating ACS, there were no significant differences in evidence-based treatment practices by BMI.

The effect of continuous infusion loop diuretics in patients with acute decompensated heart failure with hypoalbuminemia.

PURPOSE: Hypoalbuminemia is believed to decrease diuretic effectiveness and contribute to diuretic resistance that is observed in patients with nephrotic syndrome. Hypoalbuminemia is also seen in patients with acute decompensated heart failure (ADHF). However, the role of hypoalbuminemia on the effectiveness of continuous infusion diuretics in patients with ADHF is not known. METHODS: To evaluate hypoalbuminemia (albumin ≤ 3 g/dL) and diuretic effectiveness, we performed a retrospective study in 162 patients admitted to a tertiary care center for treatment of ADHF over a 3-year period. All patients received continuous infusion diuretic for at least a 2-day time period. RESULTS: A total of 33 patients were determined to have hypoalbuminemia. Average net urine output over a 2-day study period was similar between patients with and without hypoalbuminemia (-1462 ± 1734 vs -1233 ± 1560 mL, P = .46, respectively). In addition, diuretic doses (furosemide equivalent/24 hours) were similar between the 2 groups (788 ± 671 vs 778 ± 713 mg, P = .91, respectively) as was baseline serum creatinine (1.6 ± 0.6 vs 1.6 ± 0.6 mg/dL, P = .5, respectively). CONCLUSION: Overall, hypoalbuminemia did not decrease the diuretic effectiveness when measured by the net urine output in patients receiving continuous infusion diuretics for the treatment of ADHF.

Association between bilirubin and mode of death in severe systolic heart failure.

The bilirubin level has been associated with worse outcomes, but it has not been studied as a predictor for the mode of death in patients with systolic heart failure. The Prospective Randomized Amlodipine Evaluation Study (PRAISE) cohort (including New York Heart Association class IIIB-IV patients with left ventricular ejection fraction <30%, n = 1,135) was analyzed, divided by bilirubin level: ≤0.6 mg/dl, group 1; >0.6 to 1.2 mg/dl, group 2; and >1.2 mg/dl, group 3. Multivariate Cox proportional hazards models were used to determine the association of bilirubin with the risk of sudden or pump failure death. Total bilirubin was entered as a base 2 log-transformed variable (log2 bilirubin), indicating doubling of the bilirubin level corresponding to each increase in variable value. The higher bilirubin groups had a lower ejection fraction (range 19% to 21%), sodium (range 138 to 139 mmol/L), and systolic blood pressure (range 111 to 120 mm Hg), a greater heart rate (range 79 to 81 beats/min), and greater diuretic dosages (range 86 to 110 furosemide-equivalent total daily dose in mg). The overall survival rates declined with increasing bilirubin (24.3, 31.3, and 44.3 deaths per 100 person-years, respectively, for groups 1, 2, and 3). Although a positive relation was seen between log2 bilirubin and both pump failure risk and sudden death risk, the relation in multivariate modeling was significant only for pump failure mortality (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82, p = 0.0004), not for sudden death mortality (hazard ratio 1.21, 95% confidence interval 0.98 to 1.49, p = 0.08). In conclusion, an increasing bilirubin level was significantly associated with the risk of pump failure death but not for sudden death in patients with severe systolic heart failure.

Association of implantable defibrillator therapy risk with body mass index in systolic heart failure.

OBJECTIVES: To determine whether risk for implantable cardioverter-defibrillator (ICD) therapy varies by body mass index (BMI) in systolic heart failure (HF). BACKGROUND: It is unknown whether obesity increases sudden death risk in patients with systolic HF. METHODS: Secondary analysis of patients with HF, left ventricular ejection fraction ≤0.40 and ICD (N = 464) was performed using Cox regression modeling to assess risk for first delivered ICD therapy, with patients grouped by BMI (kg/m(2)): normal (18.5 to <25), overweight (25 to <30), and obese (≥30). RESULTS: Overweight patients, compared with patients with normal BMI, had greater adjusted risk for first ICD therapy (HR 1.66; 95% CI 1.02-2.71; P = 0.04), whereas obese BMI was not associated with risk for first ICD therapy. CONCLUSIONS: There was an inverted U-shaped relationship between BMI and risk for first ICD therapy among systolic HF patients, with highest risk in overweight BMI.

Changes in serial B-type natriuretic peptide level independently predict cardiac allograft rejection.

BACKGROUND: Despite positive associations with rejection, the clinical value of B-type natriuretic peptide (BNP) monitoring in heart transplant recipients has not been established. We sought to determine the predictive value of changes in serial BNP level for identifying patients with acute allograft rejection. METHODS: BNP, hemodynamics and biopsies were obtained for 205 transplant recipients who underwent a total of 4,007 endomyocardial biopsy procedures. Samples analyzed were collected ≥ 180 days post-transplant, without evidence of rejection on the immediately preceding biopsy. Using a repeated-measures multivariate model, we assessed the association of change in BNP with Grade ≥ 3A (2R) rejection. We also determined predictive values of various cut-off thresholds of change in serial BNP levels to predict Grade ≥ 3A rejection. RESULTS: There were 47 episodes of Grade ≥ 3A rejection among the 1,350 samples analyzed. Median change in serial BNP (ΔBNP) for those with Grade ≥ 3A rejection was 20 pg/ml (IQR -26 to 169 pg/ml) and among those with Grade <3A rejection was -4 pg/ml (IQR -34 to 22 pg/ml, p = 0.003). On multivariate analysis, ΔBNP remained the most potent independent predictor of Grade ≥ 3A rejection (p = 0.001). ΔBNP >100 pg/ml predicted increased risk of Grade ≥ 3A rejection (OR = 5.3, p < 0.001) with high specificity (93.3%) and positive predictive value (13.0%) and excellent negative predictive value (97.3%). CONCLUSIONS: Change in serial BNP level is an independent predictor of cardiac allograft rejection. With wide availability, rapid turnaround, low cost, favorable positive predictive value and excellent negative predictive value, serial BNP monitoring has several advantages for non-invasive monitoring of heart transplant recipients for acute cardiac allograft rejection.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure.

BACKGROUND: Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. METHODS: The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. RESULTS: A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). CONCLUSION: Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

Association of obesity and survival in systolic heart failure after acute myocardial infarction: potential confounding by age.

AIMS: To determine the association between obesity and outcomes in post-acute myocardial infarction (AMI) patients with systolic heart failure (HF). METHODS AND RESULTS: Of the 6632 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) participants, 6611 had data on baseline body mass index (BMI) and 6561 had BMI > or = 18.5 kg/m(2). Of these, 1573 were obese (BMI > or = 30 kg/m(2)) and 4988 were non-obese (BMI 18.5-29.9 kg/m(2)). Propensity scores for obesity, estimated for each patient, were used to assemble a cohort of 1519 pairs of obese and non-obese patients who were balanced on 65 baseline characteristics. All-cause mortality occurred in 13.7 and 13.8% of matched obese and non-obese patients, respectively, during 16 months of median follow-up [matched hazard ratio (HR) for obesity 0.98; 95% confidence interval (CI) 0.79-1.21; P = 0.831]. Before matching, the obese group was younger (mean age, 62 vs. 64 years; P < 0.0001) and had more women (37 vs. 26%; P < 0.0001). The paradoxical pre-match association between obesity and reduced mortality (unadjusted HR 0.82; 95% CI 0.70-0.95; P = 0.008) disappeared when adjusted for age alone (age-adjusted HR 0.91; 95% CI 0.78-1.06; P = 0.206) but not for gender alone (gender-adjusted HR 0.79; 95% CI 0.68-0.92; P = 0.003). Obesity had no association with mortality in 1573 pairs of age-matched obese and non-obese patients (age-adjusted HR 0.94; 95% CI 0.77-1.13; P = 0.484). CONCLUSION: In post-AMI patients with systolic HF, obesity provides no independent intrinsic survival benefit. The paradoxical unadjusted survival associated with obesity is largely explained by the younger age of obese patients.

Relation of body mass index to mortality after development of heart failure due to acute coronary syndrome.

Several studies have suggested that obesity may be associated with a survival advantage in heart failure (HF). The duration of HF likely influences disease severity and may introduce lead-time bias into analyses of outcomes. The aim of this study was to analyze a cohort in which the exact time of HF onset could be determined: patients in the University of Michigan subset of the acute coronary syndromes (ACS) database of the Global Registry of Acute Coronary Events (GRACE) who developed new-onset HF (no history of HF and left ventricular ejection fraction or=30 kg/m(2)). Underweight patients (BMI