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The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

High-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predict heart failure (HF) in the general population. However, the interpretation of levels of these biomarkers as predictors of HF is uncertain among patients with CKD. Here, we investigated whether hsTnT and NT-proBNP are associated with incident HF among patients with CKD. In a prospective cohort analysis, we studied 3483 people with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study recruited from June of 2003 to August of 2008 who were free of HF at baseline. We used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident HF after adjustment for demographic factors, traditional cardiovascular risk factors, markers of kidney disease, pertinent medication use, and mineral metabolism markers. At baseline, hsTnT levels ranged from ≤5.0 to 738.7 pg/ml, and NT-proBNP levels ranged from ≤5 to 35,000 pg/ml. Compared with those who had undetectable hsTnT, participants in the highest quartile (>26.5 pg/ml) had a significantly higher rate of HF (hazard ratio, 4.77; 95% confidence interval, 2.49 to 9.14). Similarly, compared with those in the lowest NT-proBNP quintile (<47.6 pg/ml), participants in the highest quintile (>433.0 pg/ml) experienced a substantially higher rate of HF (hazard ratio, 9.57; 95% confidence interval, 4.40 to 20.83) [corrected]. In conclusion, hsTnT and NT-proBNP were strongly associated with incident HF among a diverse cohort of individuals with mild to severe CKD. Elevations in these biomarkers may indicate subclinical changes in volume and myocardial stress that subsequently contribute to clinical HF., (Copyright © 2015 by the American Society of Nephrology.)

Background: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol‐requiring protein 1 (IRE1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing., Methods and Results: Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced X‐box protein 1, a marker for IRE1‐endoribonuclease activity, were associated with decreased corin RNA. Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1's endoribonuclease activity and time‐dependent reductions in corin mRNA. In HL‐1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1‐RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1‐mediated corin mRNA degradation., Conclusions: These data support the hypothesis that endoplasmic reticulum stress‐mediated, IRE1‐dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro‐hormone processing in humans processing in humans with advanced systolic heart failure.

Background: Chronic kidney disease is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial, and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic, multicenter prospective observational study of patients with chronic kidney disease., Methods and Results: We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV; the gold standard index of large artery stiffness), brachial, and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed up to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. When compared with the lowest tertile, the hazard ratios among subjects in the middle and top CF-PWV tertiles were 2.33 (95% confidence interval, 1.37-3.97; P=0.002) and 5.24 (95% confidence interval, 3.22-8.53; P<0.0001), respectively. After adjustment for multiple confounders, the hazard ratios for the middle and top CF-PWV tertiles were 1.95 (95% confidence interval, 0.92-4.13; P=0.079) and 3.01 (95% confidence interval, 1.45-6.26; P=0.003), respectively. Brachial systolic and pulse pressure were also independently associated with incident hospitalized HF, whereas central pressures were less consistently associated with this end point. The association between CF-PWV and incident HF persisted after adjustment for systolic blood pressure., Conclusions: Large artery stiffness is an independent predictor of incident HF in chronic kidney disease, an association with strong biological plausibility given the known effects of large artery stiffening of left ventricular pulsatile load., (© 2014 American Heart Association, Inc.)

Objective: To characterise the trends in the left ventricular assist device (LVAD) implantation rates and outcomes between 2004 and 2011 in the Medicare population. Since the approval of the HeartMate II in 2008, the use of LVADs has steadily climbed. Given the increase in LVAD use, issues around discharge disposition, post-implant hospitalisations and costs require further understanding., Methods: We examined LVAD implantation rates and short-term and long-term outcomes among Medicare fee-for-service beneficiaries hospitalised for LVAD implantation. We also conducted analyses among survivors 1-year post-discharge to examine rehospitalisation rates. Lastly, we reported Centers for Medicare & Medicaid Services (CMS) payments for both index hospitalisation and rehospitalisations 1 year post-discharge., Results: A total of 2152 LVAD implantations were performed with numbers increasing from 107 in 2004 to 612 in 2011. The 30-day mortality rate decreased from 52% to 9%, and 1-year mortality rate decreased from 69% to 31%. We observed no change in overall length of stay, but post-procedure length of stay increased. We also found an increase in home discharge dispositions from 26% to 53%. Between 2004 and 2010, the rehospitalisation rate increased and the number of hospital days decreased. The adjusted CMS payment for the index hospitalisation increased from $188 789 to $225 697 over time but decreased for rehospitalisation from $60 647 to $53 630., Conclusions: LVAD implantations increased over time. We found decreasing 30-day and 1-year mortality rates and increasing home discharge disposition. The proportion of patients rehospitalised among 1-year survivors remained high with increasing index hospitalisation cost, but decreasing post-implantation costs over time.

Background: Although noninvasive positive pressure ventilation (NIPPV) for patients with acute decompensated heart failure was introduced almost 20 years ago, the variation in its use among hospitals remains unknown. We sought to define hospital practice patterns of NIPPV use for acute decompensated heart failure and their relationship with intubation and mortality., Methods and Results: We conducted a cross-sectional study using a database maintained by Premier, Inc., that includes a date-stamped log of all billed items for hospitalizations at >400 hospitals. We examined hospitalizations for acute decompensated heart failure in this database from 2005 to 2010 and included hospitals with annual average volume of >25 such hospitalizations. We identified 384 hospitals that encompassed 524 430 hospitalizations (median annual average volume: 206). We used hierarchical logistic regression models to calculate hospital-level outcomes: risk-standardized NIPPV rate, risk-standardized intubation rate, and in-hospital risk-standardized mortality rate. We grouped hospitals into quartiles by risk-standardized NIPPV rate and compared risk-standardized mortality rates and risk-standardized intubation rates across quartiles. Median risk-standardized NIPPV rate was 6.2% (interquartile range, 2.8%-9.3%; 5th percentile, 0.2%; 95th percentile, 14.8%). There was no clear pattern of risk-standardized mortality rates across quartiles. The bottom quartile of hospitals had higher risk-standardized intubation rate (11.4%) than each of the other quartiles (9.0%, 9.7%, and 9.1%; P<0.02 for all comparisons)., Conclusions: Substantial variation exists among hospitals in the use of NIPPV for acute decompensated heart failure without evidence for differences in mortality. There may be a threshold effect in relation to intubation rates, with the lowest users of NIPPV having higher intubation rates., (© 2014 American Heart Association, Inc.)

Hyperacute rejection is a rare but potentially catastrophic complication after cardiac transplantation. We describe an unusual case of hyperacute rejection due to preformed anti-donor antibodies despite a negative preoperative panel-reactive antibody (PRA) screen. An excellent outcome was achieved in this case and our strategy involving the use of CentriMag ventricular assist devices (VADs) for biventricular support during treatment with rituximab, intravenous immunoglobulin (IVIG), and plasmapheresis is illustrated.

Background: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study., Methods and Results: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN., Conclusions: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Cardiomyocytes release atrial natriuretic peptide (ANP) and B-type natriuretic peptide to stimulate processes that compensate for the failing heart by activating guanylyl cyclase (GC)-A. C-type natriuretic peptide is also elevated in the failing heart and inhibits cardiac remodeling by activating the homologous receptor, GC-B. We previously reported that GC-A is the most active membrane GC in normal mouse ventricles while GC-B is the most active membrane GC in failing ventricles due to increased GC-B and decreased GC-A activities. Here, we examined ANP and CNP-specific GC activity in membranes obtained from non-failing and failing human left ventricles and in membranes from matched cardiomyocyte-enriched pellet preparations. Similar to our findings in the murine study, we found that CNP-dependent GC activity was about half of the ANP-dependent GC activity in the non-failing ventricular and was increased in the failing ventricle. ANP and CNP increased GC activity 9- and 5-fold in non-failing ventricles, respectively. In contrast to the mouse study, in failing human ventricles, ANP-dependent activity was unchanged compared to non-failing values whereas CNP-dependent activity increased 35% (p=0.005). Compared with ventricular membranes, basal GC activity was reduced an order of magnitude in membranes derived from myocyte-enriched pellets from non-failing ventricles. ANP increased GC activity 2.4-fold but CNP only increased GC activity 1.3-fold. In contrast, neither ANP nor CNP increased GC activity in equivalent preparations from failing ventricles. We conclude that: 1) GC-B activity is increased in non-myocytes from failing human ventricles, possibly as a result of increased fibrosis, 2) human ventricular cardiomyocytes express low levels of GC-A and much lower levels or possibly no GC-B, and 3) GC-A in cardiomyocytes from failing human hearts is refractory to ANP stimulation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin-converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we investigated the relative early WRF-associated mortality rates in subjects randomized to ACE-I or placebo., Methods and Results: Subjects in the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337) were studied. The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary end point. In the overall population, early WRF was associated with increased mortality (adjusted hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; P=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR, 1.4; 95% CI, 1.1-1.8; P=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR, 1.0; 95% CI, 0.8-1.3; P=1.0; P=0.09 for the interaction). In patients who continued to receive study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR, 0.66; 95% CI, 0.5-0.9; P=0.018)., Conclusions: These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Background: An increased minute ventilation (VE)/carbon dioxide production (VCO2) relationship, an expression of ventilatory inefficiency (VI), is associated with increased morbidity and mortality in patients with left ventricular systolic dysfunction (LVSD). A direct link between VI and a specific cardiac abnormality has not been established., Methods: We analyzed cardiopulmonary exercise test (CPET) data from patients (N=83) with severe LVSD (ischemic and nonischemic; left ventricular ejection fraction [LVEF] 19%±7%) and at least moderate exercise intolerance. Subjects were stratified into two groups based on the (VE/VCO2 ratio at anaerobic threshold (VE/VCO2@AT) (group 1 VE/VCO2@AT≤34; group 2 VE/VCO2@AT>34). Clinical, CPET, echocardiographic, and hemodynamic data were compared between groups., Results: Group 2 subjects had lower exercise capacity (peak (VO2, 45.7%±11.8% vs 50.4±8.9% predicted; P<.05), with a significantly lower oxygen pulse (71.6%±24.5% vs 85.4±18.5% predicted) and maximum systolic BP (122±19 mm Hg vs 138±22 mm Hg; P<.001 for both), suggesting a more blunted stroke volume to exercise vs group 1. There were no differences in left ventricular (LV) size, LVEF, or mitral regurgitation between the two groups. In sharp contrast, group 2 had larger right ventricular (RV) dimensions (4.5±1.1 cm vs 3.9±0.8 cm) and more severe RV systolic dysfunction (RV fractional area change 26%±11% vs 33%±12%; tricuspid annular plane systolic excursion [TAPSE] 1.6±0.5 cm vs 2.0±0.5 cm; all P<.001) vs group 1. Multivariable analysis revealed that only TAPSE and Doppler-estimated pulmonary artery systolic pressure were independently associated with VE/VCO2@AT and the (VE/VCO2slope. The VE/VCO2@AT, VE/VCO2 slope, and TAPSE had nearly identical predictive value for death or transplant., Conclusions: The present study suggests that VI is a functional, noninvasive marker of more advanced right-sided heart dysfunction in patients with severe LVSD.

Background: Soluble ST2 reflects activity of an interleukin-33-dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches., Methods and Results: We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ≤22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B-type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017)., Conclusions: ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Background: The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease, with limited data on less advanced chronic kidney disease (CKD) stages., Methods: A total of 3,267 adult participants (50% non-Hispanic blacks, 46% women) with CKD from the Chronic Renal Insufficiency Cohort were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (n = 323) or those without electrocardiographic data (n = 22) were excluded. Atrial fibrillation was ascertained by a 12-lead electrocardiogram and self-report. Age-, sex-, and race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross-sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable-adjusted logistic regression analysis., Results: The mean estimated glomerular filtration rate was 43.6 (+/-13.0) mL/(min 1.73 m(2)). Atrial fibrillation was present in 18% of the study population and in >25% of those > or =70 years old. In multivariable-adjusted models, 1-SD increase in age (11 years) (odds ratio 1.27, CI 95% 1.13-1.43, P < .0001), male [corrected] sex (0.80, 0.65-0.98, P = .0303), smoking (former vs never) (1.34, 1.08-1.66, P = .0081), history of heart failure (3.28, 2.47-4.36, P < .001), and history of cardiovascular disease (1.94, 1.56-2.43, P < .0001) were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high-sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated glomerular filtration rate <45 mL/(min 1.73 m(2)) was associated with AF in an unadjusted model (1.35, 1.13-1.62, P = .0010), but not after multivariable adjustment (1.12, 0.92-1.35, P = .2710)., Conclusions: Nearly 1 in 5 participants in Chronic Renal Insufficiency Cohort, a national study of CKD, had evidence of AF at study entry, a prevalence similar to that reported among patients with end-stage renal disease and 2 to 3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: B-type natriuretic peptide (BNP) is produced as a biologically inactive prohormone (proBNP(1-108)), processed, and released as an inactive amino acid N-terminal fragment (proBNP(1-76)) and a biologically active carboxyl-terminal fragment (proBNP(77-108) or BNP32). We hypothesized that simultaneous assessment of proBNP(1-108) and active BNP32, as an index of natriuretic peptide processing efficiency, would improve risk stratification in patients with chronic systolic heart failure., Methods and Results: We quantified plasma proBNP(1-108) and BNP32 in 756 participants in the Penn Heart Failure Study, a prospective cohort of outpatients with predominantly systolic heart failure. Cox models were used to determine the association between biomarker level at the time of study entry and incident risk of adverse cardiovascular outcomes. A significant amount of unprocessed proBNP(1-108) circulates in patients with systolic heart failure (median, 271 pg/mL; interquartile range, 65 to 825). Higher levels of proBNP(1-108) were associated with an increased risk of all-cause death or cardiac transplantation (adjusted hazard ratio, 4.9; 95% CI, 2.5 to 9.7; P<0.001, comparing third versus first proBNP(1-108) tertile). ProBNP(1-108) provided additive information to BNP32 risk assessment, particularly in patients with BNP32 less than the median of 125 pg/mL (adjusted hazard ratio, 1.4; 95% CI, 1.2 to 1.8; P<0.001 per doubling of proBNP(1-108))., Conclusions: Circulating proBNP(1-108) is independently associated with an increased risk of adverse cardiovascular outcomes in ambulatory patients with chronic systolic heart failure. The combined assessment of BNP32 and proBNP(1-108) provides additional information in determining risk of adverse clinical outcomes, particularly in patients with low BNP32 values that might otherwise be reassuring to the clinician.

Left-ventricular hypertrophy (LVH) is one of the strongest independent predictors of cardiovascular morbidity and mortality in the general population. Although hypertension and obesity are well-established, independent risk factors for the development of LVH, they explain less than 25% to 50% of the variance of left ventricular mass (LVM) in humans. A substantial body of evidence suggests that there is a genetic basis to the observed inter-individual variability in the susceptibility to the development of LVH. Given the continuous relationship between LVM and cardiovascular morbidity and mortality, elucidating the genetic determinants of inter-individual differences in the susceptibility to LVH is of considerable public health importance. It promises the opportunity to identify high-risk individuals for targeted intervention and may identify novel therapeutic targets for improved prevention and treatment strategies.

Background: Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide (BNP) into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity. We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in blacks with systolic heart failure., Methods and Results: This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP(1 to 108)/processed BNP-32 was significantly higher (P=0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (relative risk 3.49; 95% CI, 1.45 to 8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes., Conclusions: We have identified a pharmacogenomic interaction in blacks with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed-dose combination isosorbide-dinitrate/hydralazine ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared with noncarriers.

Associated with technological progress in deoxyribonucleic acid and messenger ribonucleic acid profiling, advances in basic biology have led to a more complete and sophisticated understanding of interactions among genes, environment, and affected tissues in the setting of complex and heterogeneous conditions such as heart failure (HF). Ongoing identification of mutations causing hereditary hypertrophic and dilated cardiomyopathies has provided both pathophysiological insights and clinically applicable diagnostics for these relatively rare conditions. Genotyping clinical trial participants and genome-wide association studies have accelerated the identification of much more common disease- and treatment-modifying genes that explain patient-to-patient differences that have long been recognized by practicing clinicians. At the same time, increasingly detailed characterization of gene expression within diseased tissues and circulating cells from animal models and patients are providing new insights into the pathophysiology of HF that permit identification of novel diagnostic and therapeutic targets. In this rapidly evolving field, there is already ample support for the concept that genetic and expression profiling can enhance diagnostic sensitivity and specificity while providing a rational basis for prioritizing alternative therapeutic options for patients with cardiomyopathies and HF. Although the extensive characterizations provided by genomic and transcriptional profiling will increasingly challenge clinicians' abilities to utilize complex and diverse information, advances in clinical information technology and user interfaces will permit greater individualization of prevention and treatment strategies to address the HF epidemic.

Left ventricular ejection fraction (EF) is used to assess patients with heart failure (HF); however, frequent measurements are not cost-effective. Impedance cardiography (ICG) is a low-cost, noninvasive test that measures systolic time intervals and may be a method for detecting impaired vs intact EF. This study evaluated the relationship between EF by echocardiography or gated nuclear ventriculography and systolic time ratio (STR) by ICG in outpatients with chronic HF. A retrospective chart review identified 52 patients with EF and STR measured within 2 weeks. There was an inverse correlation between STR and EF (r=-0.54; P<.001). The area under the receiver operating characteristic curve for STR to identify reduced EF was 0.86. An EF < or =50% and STR > or =0.50 demonstrated 93% sensitivity and 85% specificity. STR was able to distinguish intact (>50%) from impaired EF (< or =50%). STR by ICG has the potential to be a reliable method to monitor ventricular function in chronic HF.

Corin is a cardiac serine protease that acts as the pro-atrial natriuretic peptide (ANP) convertase. Recently, 2 single-nucleotide polymorphisms (SNPs) (T555I and Q568P) in the human corin gene have been identified in genetic epidemiological studies. The minor I555/P568 allele, which is more common in African Americans, is associated with hypertension and cardiac hypertrophy. In this study, we examined the effect of T555I and Q568P amino acid substitutions on corin function. We found that corin frizzled-like domain 2, where T555I/Q568P substitutions occur, was required for efficient pro-ANP processing in functional assays. Mutant corin lacking this domain had 30+/-5% (P<0.01) activity compared to that of wild type. Similarly, corin variant T555I/Q568P had a reduced (38+/-7%, P<0.01) pro-ANP processing activity compared to that of wild type. The variant also exhibited a low activity (44+/-15%, P<0.05) in processing pro-brain natriuretic peptide (BNP). We next examined the biochemical basis for the loss of activity in T555I/Q568P variant and found that the zymogen activation of the corin variant was impaired significantly, as indicated by the absence of the activated protease domain fragment. This finding was confirmed in human embryonic kidney (HEK)293 cells and murine HL-1 cardiomyocytes. Thus, our results show that the corin gene SNPs associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity. Our data suggest that corin deficiency may be an important mechanism in hypertensive and heart diseases.

Background: The objective of the study was to evaluate racial differences in the prevalence of left ventricular (LV) dysfunction. Few data compare the relative frequency of reduced LV ejection fraction (EF) (LVEF) in blacks and whites. Because of the higher prevalence of risk factors for heart failure in blacks, including hypertension, obesity, and LV hypertrophy, we hypothesized that LV dysfunction would also be more common in this ethnic group., Methods: In the DHS, a probability-based sample of Dallas County, we performed cardiac magnetic resonance imaging on 1335 black and 858 white participants aged 30 to 67 years to measure LVEF and volumes. We compared the prevalence of reduced LV EF and distribution of ventricular volumes in the 2 ethnic groups., Results: The prevalence of a reduced LVEF, whether defined as < 50%, < 55%, or < 60%, did not appear to be different between black versus white women (P > or = .7 for each) or men (P > or = .4 for each). Similar findings were seen using a recently defined sex-specific threshold (men < 55% and women < 61%) for low EF (P = .1). Mean LV end-diastolic and end-systolic volumes indexed to body surface area were also comparable in black and white men (P > or = .3) and women (P > or = .1)., Conclusions: Despite having a higher prevalence of risk factors for heart failure, blacks as compared with whites did not have a higher prevalence of reduced LVEF in the general population.

Left ventricular failure is the final common pathway for a wide spectrum of myocardial insults, including systemic hypertension and myocardial infarction. Although left ventricular hypertrophy is an adaptive response to pressure and volume overload, this process becomes maladaptive if left untreated and pathologic cardiac hypertrophy then becomes an important and independent risk factor for the development of heart failure. Despite its importance, the transition from hypertrophy to heart failure in humans is poorly understood. The focus of treatment should be prevention of heart failure and other cardiovascular events, such as stroke and atrial fibrillation. When heart failure is present, treatment with medical and device therapy is then focused on improving functional capacity, increasing survival, and preventing progression to end-stage heart failure.

Corin activates pro-A-type naturetic peptide and pro-B-type naturetic peptide into biologically active molecules. We recently identified a minor allele in the corin gene defined by 2 highly linked single nucleotide polymorphisms (T555I and Q568P), which was associated with hypertension in blacks. Because of the direct antihypertrophic effects of the natriuretic peptide system, we hypothesized that the minor corin I555(P568) allele would be associated with an enhanced hypertrophic response to pressure overload. The relationship between systolic blood pressure and indexed left ventricular mass, derived from cardiac MRI, was analyzed in the Dallas Heart Study as a function of corin allele status. The Multi-Ethnic Study of Atherosclerosis was used as a validation cohort. All of the analyses were limited to self-identified blacks without treatment for hypertension. In addition, we genotyped 2114 markers highly informative for African ancestry in the Dallas Heart Study and derived a covariate representing African ancestry for multivariate models. In adjusted analysis, the corin I555(P568) allele was an independent predictor of left-ventricular mass in subjects with elevated systolic blood pressure. Linear spline regression analysis confirmed a significant interaction (P=0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure >120 mm Hg, and this nonlinear interaction was replicated in the Multi-Ethnic Study of Atherosclerosis. In the Dallas Heart Study, the corin I555(P568) allele was also associated with an increased odds for prevalent left ventricular hypertrophy in the presence of untreated hypertension. These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension.

Background: Cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-sparing cyclosporine-free induction regimen consisting of the early administration basiliximab, an interleukin-2 receptor monoclonal antibody, followed by the late initiation of cyclosporine on post-operative Day 4., Methods: Between September 1998 and December 1999, we treated 25 patients at risk for post-operative renal dysfunction (high-risk basiliximab group) with the new induction regimen and another 33 patients not at risk (low-risk CsA group) for renal dysfunction with our standard cyclosporine protocol. We identified a historical control group (1996 through 1998) of 32 patients at risk for renal dysfunction (high-risk CsA group) who had received our standard cyclosporine protocol., Results: The increase in serum creatinine levels after transplantation was less in the high-risk basiliximab group (-0.1 +/- 0.7) than in the high-risk CsA group (0.5 +/- 1.0, p < 0.02) and comparable to the low-risk CsA group (0.03 +/- 0.6). The basiliximab protocol did not increase rejection; the percentage of rejection episodes was high-risk basiliximab, 0; high-risk CsA, 13; and low-risk CsA, 3 (p = .13)., Conclusion: Basiliximab induction therapy allows delayed initiation of cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.

Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (P<0.001), fat-free mass (P=0.002), or height2.7 (P<0.001) was 2- to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (P<0.001 when left ventricular hypertrophy was indexed to body surface area or height2.7 and P=0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2- to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.

Background: Despite their known benefits, beta-blockers (BBL) are not yet widely prescribed for heart failure, especially in the primary care setting. We wanted to identify patient characteristics that could guide primary care physicians in deciding whether they or a cardiologist should initiate BBL. A second objective was to determine the tolerability of BBL in clinical practice., Methods: A retrospective chart review was conducted on a consecutive series of 551 patients with systolic dysfunction referred to a heart failure clinic in an urban public hospital. Patient responses to BBL were stratified into three categories: favorable (improvement of left ventricular ejection fraction by serial echocardiography), unfavorable (development of decompensated heart failure), or neither. Tolerability of BBL was assessed by the need to permanently discontinue BBL., Results: Of 551 patients, 363 (66%) tolerated BBL. Among patients who had BBL initiated in the clinic, 48 had a favorable response, 34 had an unfavorable response, and 57 had neither a favorable or unfavorable response, as defined. A lower systolic blood pressure and higher diuretic dose were associated with development of decompensated heart failure as compared to improvement of ejection fraction., Conclusions: A majority of patients with heart failure in an urban public hospital can tolerate BBL. Easily measurable characteristics such as lower systolic blood pressure and higher diuretic dose may assist primary care physicians in triaging patients for referral to cardiologists for beta-blocker initiation.

Background: Emerging data suggest that diabetes mellitus is a risk factor for the progression of established heart failure only in those patients with ischemic cardiomyopathy. Whether diabetes mellitus is a risk factor for the progression from asymptomatic left ventricular systolic dysfunction to symptomatic heart failure in patients with left ventricular dysfunction of an ischemic cause is not known., Methods: We performed a retrospective analysis of 2821 patients with asymptomatic left ventricular systolic dysfunction from the Studies of Left Ventricular Dysfunction (SOLVD) Prevention trial. We used adjusted survival analysis to examine the effects of ischemic heart disease and diabetes mellitus on 3 prespecified study end points: (1) development of heart failure (HF) symptoms, (2) HF hospitalization, and (3) death or development of symptoms., Results: There is a statistically significant interaction between the cause of left ventricular systolic dysfunction and diabetes mellitus on the risk of development of heart failure symptoms (P = .020). Patients with ischemic cardiomyopathy and diabetes had an increased risk of progression to symptomatic heart failure (HR = 1.56, P < .001), hospitalization for heart failure (HR = 2.16, P < .001), and death or development of symptoms (HR = 1.50, P < .001), compared with patients with ischemic cardiomyopathy without diabetes. In contrast, diabetes was not associated with an increased risk of reaching these end points in patients with nonischemic cardiomyopathy., Conclusions: Diabetes mellitus is a risk factor for the progression from asymptomatic left ventricular systolic dysfunction to symptomatic heart failure, but this risk appears to be confined to those patients with ischemic cardiomyopathy.

Objectives: Our aim in this study was to determine whether increased left ventricular mass (LVM) is a risk factor for the development of a reduced left ventricular ejection fraction (LVEF)., Background: Prior studies have shown that increased LVM is a risk factor for heart failure but not whether it is a risk factor for a low LVEF., Methods: As part of the Cardiovascular Health Study, a prospective population-based longitudinal study, we performed echocardiograms upon participant enrollment and again at follow-up of 4.9 +/- 0.14 years. In the present analysis, we identified 3,042 participants who had at baseline a normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram), and at follow-up a measurable LVEF. The frequency of the development of a qualitatively depressed LVEF on two-dimensional echocardiography, corresponding approximately to an LVEF <55%, was analyzed by quartiles of baseline LVM. Multivariable regression determined whether LVM was independently associated with the development of depressed LVEF., Results: Baseline quartile of echocardiographic LVM indexed to body surface area was associated with development of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in quartile 3, and 14.1% in quartile 4 [p < 0.001]). A similar relationship was seen in the subgroup of participants without myocardial infarction (p < 0.001). In multivariable regression that adjusted for confounders, both baseline echocardiographic (p < 0.001) and electrocardiographic (p < 0.001) LVM remained associated with development of depressed LVEF., Conclusions: Increased LVM as assessed by electrocardiography or echocardiography is an independent risk factor for the development of depressed LVEF.

The progression from concentric left ventricular (LV) hypertrophy to heart failure has not been well defined. Of 159 predominantly hypertensive African-American patients with LV hypertrophy and a normal ejection fraction (EF), 28 (18%) developed a reduced EF after a median follow-up of approximately 4 years. Risk factors for this outcome included a history of coronary artery disease, pulmonary edema seen on a chest x-ray, or a subsequent myocardial infarction.

Renal insufficiency is an independent powerful predictor of morbidity and mortality in a number of cardiovascular disorders. A number of retrospective analyses of large heart failure trials have shown that even mild renal insufficiency has powerful negative predictive power in patients with both mild and severe heart failure. We discuss the available data on the prognostic value of mild renal insufficiency in heart failure, as well as possible mechanisms of this phenomenon. Future research should focus on its possible pathophysiology.

The importance placed on the physical examination in the assessment of patients with cardiovascular disorders appears to be declining, perhaps in part due to a paucity of data showing its value in the modern era. To determine whether the physical examination provides important prognostic information in patients with chronic heart failure, the authors performed a post-hoc analysis of 2479 participants from the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial. The presence of elevated jugular venous pressure and a third heart sound at baseline were each associated with subsequent heart failure hospitalization, the composite end point of death or heart failure hospitalization, and pump-failure death, independently of many other markers of disease severity. The subgroup of patients with at least one of these two physical examination findings was at increased risk for all-cause mortality. The authors believe that additional studies assessing the prognostic value of the physical examination should be conducted and, if favorable, likely would lead to a renewed interest in the physical examination.

Purpose: To determine the independent prognostic value of a third heart sound (S(3)) and elevated jugular venous pressure in patients with asymptomatic left ventricular dysfunction., Methods: We performed a post hoc analysis of 4102 participants from the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial. In that trial, participants with asymptomatic or minimally symptomatic left ventricular dysfunction (New York Association class I or II, left ventricular ejection fraction < or =0.35, no treatment for heart failure) were allocated randomly to enalapril or placebo and followed for a mean (+/- SD) of 34 +/- 14 months. The presence of an S(3) and elevated jugular venous pressure was ascertained by physical examination at study enrollment. We used multivariate proportional hazards models to determine whether these physical examination findings were associated with the development of heart failure, a prespecified endpoint of the SOLVD prevention trial., Results: At baseline, 209 subjects (5.1%) had an S(3) and 70 (1.7%) had elevated jugular venous pressure. Heart failure developed in 1044 subjects (25.5%). After adjusting for other markers of disease severity, an S(3) was associated with an increased risk of heart failure (relative risk [RR] = 1.38; 95% confidence interval [CI]: 1.09 to 1.73; P = 0.007) and the composite endpoint of death or development of heart failure (RR = 1.34; 95% CI: 1.09 to 1.64; P = 0.005). Elevated jugular venous pressure was also associated with these outcomes in multivariate models., Conclusion: The physical examination provides prognostic information among patients with asymptomatic or minimally symptomatic left ventricular dysfunction.

Objectives: This study was undertaken to determine whether enalapril had comparable efficacy in black and white patients with asymptomatic left ventricular dysfunction (ALVD) in preventing the development of symptomatic heart failure (HF)., Background: Recent studies have suggested that black patients with HF due to systolic dysfunction may derive less benefit than white patients with HF when treated with the same medication., Methods: This is a post hoc analysis of the 4,054 black and white participants of the Studies of Left Ventricular Dysfunction Prevention Trial., Results: Randomization to enalapril was associated with a comparable reduction in the relative risk of the development of symptomatic HF in black (relative risk [RR] 0.67, 95% confidence interval [CI] 0.49, 0.92, p = 0.01) and white patients (RR 0.61, 95% CI 0.53, 0.70, p < 0.001). Treatment with enalapril was also associated with a comparable reduction in the risk of the development of HF requiring medical therapy and the composite end point of death or development of HF in black and white patients. Black as compared with white patients with ALVD were at increased risk of the development of symptomatic HF (RR 1.81, 95% CI 1.51, 2.17, p < 0.001) despite adjustment for available measures of disease severity., Conclusions: Despite the increased absolute risk in black patients compared with white patients for the progression of ALVD, enalapril was equally efficacious in reducing the risk of progression of ALVD in these two ethnic groups.