W H Wilson Tang

Yale University, New Haven, Connecticut, United States

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Publications (554)3627.51 Total impact

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    ABSTRACT: Objective: To study whether the temporal pattern of transient hyponatremia development in acute heart failure might provide insight into its pathophysiology and prognostic relevance. Methods: A post-hoc analysis of the ESCAPE and DOSE AHF studies was performed (n=716). Patients were stratified according to the temporal pattern of hyponatremia development: (1) no hyponatremia; (2) persistent hyponatremia; (3) decompensation hyponatremia disappearing with decongestive treatment; and (4) treatment-induced hyponatremia. Results: Transient decompensation versus no hyponatremia was associated with significantly elevated blood urea nitrogen/creatinine ratio (P-value<0.001), plasma renin activity (P-value<0.001), and plasma aldosterone levels (P-value<0.001) at baseline. Disease severity characteristics of such patients were intermediate between no and persistent hyponatremia. In contrast, patients with treatment-induced versus no hyponatremia had similar baseline characteristics, comparable natriuretic peptide levels, and both groups had little neurohumoral activation at baseline. Diuretic efficacy, defined as net fluid balance [mL] per 40 mg furosemide-equivalent dose administered, was lower in patients with persistent or treatment-induced hyponatremia versus decompensation hyponatremia or no hyponatremia, respectively. The former versus latter groups also had more pronounced neurohumoral activation with decongestive treatment. The risk for all-cause mortality [HR (95%CI) = 2.50 (1.50-4.19); P-value<0.001] and death or heart failure readmission [HR (95%CI) = 2.18 (1.60-2.97); P-value<0.001] was significantly elevated in patients with persistent versus no hyponatremia, with the risk of decompensation and treatment-hyponatremia situated in-between. Conclusions: Transient hyponatremia is prognostically relevant, but has a heterogeneous etiology according to its temporal pattern of development.
    No preview · Article · Feb 2016 · The American journal of medicine
  • Takeshi Kitai · W. H. Wilson Tang
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    ABSTRACT: Opinion statement: In patients with heart failure, an elevated heart rate is associated with worse cardiovascular outcomes and is increasingly recognized as a modifiable risk factor. Beta-blockers are the mainstay of therapy for heart failure. However, up-titration of beta-blockers in response to persistently elevated heart rate can be associated with increased risk of adverse reactions besides negative chronotropism. Recently, the specific heart rate-lowering agent, ivabradine, which acts by directly and selectively inhibiting the I f current in the sinoatrial node, generated renewed interest in potential benefits of pharmacologic modification of heart rate in heart failure. Several placebo-controlled, multicenter clinical trials showed the benefits of ivabradine in patients with angina and heart failure, which is largely confined to those with left ventricular systolic dysfunction. In addition, the other potential effects of ivabradine have been proposed.
    No preview · Article · Feb 2016 · Current Treatment Options in Cardiovascular Medicine
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    Frederik H. Verbrugge · Wilfried Mullens · W.H. Wilson Tang
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    ABSTRACT: Opinion statement: Diuretic resistance in acute heart failure has emerged as a powerful predictor of adverse outcome, which is often independent of underlying glomerular filtration rate (GFR). Metrics of diuretic efficacy differ in their accuracy, convenience, and biological plausibility, which should be taken into account when interpreting their results. Loop diuretic efficacy depends on adequate delivery of both the pharmacological agent itself and its substrate (i.e., sodium chloride) to the loop diuretic site of action at the luminal side of the thick ascending limb of Henle's loop. This requires an adequate dosing strategy, with higher doses needed when GFR is low. Importantly, the kidneys are able only to regulate the effective circulatory volume. Thus, specific problems of intravascular volume depletion and poor cardiac output with impaired renal perfusion should be addressed. Addition of thiazide-type diuretics should be considered when a progressive decrease in loop diuretic efficacy is observed with prolonged use (i.e., the braking phenomenon). Furthermore, thiazide-type diuretics are a useful addition in patients with low GFR to maximally boost fractional sodium excretion when nephron perfusion is poor. However, thiazide-type diuretics limit free water excretion and should be withheld in cases of hypotonic hyponatremia. Mineralocorticoid receptor antagonists (MRA) and acetazolamide are interesting options to increase loop diuretic efficacy, but further study is needed to assess whether improved diuretic efficacy also translates into clinical outcome benefits. Finally, ultrafiltration should be considered in patients with refractory diuretic resistance as persistent volume overload after decongestive treatment is associated with worse outcomes. Whether more upfront use of individually tailored ultrafiltration is superior to pharmacological therapy remains to be shown by adequately powered randomized clinical trials.
    Full-text · Article · Feb 2016 · Current Treatment Options in Cardiovascular Medicine
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    ABSTRACT: Background: Hypoalbuminemia is common in patients with chronic heart failure, and is a marker of disease severity associated with an adverse prognosis. Whether hypoalbuminemia contributes to (or is associated with) worse outcomes in AHF is unclear. We sought to determine the implications of low serum albumin in patients receiving decongestive therapies for acute heart failure (AHF). Methods: Baseline serum albumin levels were measured in 456 AHF subjects randomized in the DOSE-AHF and ROSE-AHF trials. We assessed the relationship between admission albumin levels (both as a continuous variable and stratified by median albumin [≥3.5 g/dL]) and worsening renal function [WRF], worsening heart failure [WHF], and clinical decongestion by 72 hours; 7-day cardiorenal biomarkers; and post-discharge outcomes. Results: The mean baseline albumin level was 3.5±0.5 g/dL. Albumin was not associated with WRF, WHF, or clinical decongestion by 72 hours. Furthermore, there was no association between continuous albumin levels and symptom change by visual analog scale or weight change by 72 hours. Albumin was not associated with 60-day mortality, rehospitalization or unscheduled emergency room visits. Conclusions: Baseline serum albumin levels were not associated with short-term clinical outcomes for AHF patients undergoing decongestive therapies. These data suggest serum albumin may not be a helpful tool to guide decongestion strategies.
    No preview · Article · Feb 2016 · Journal of cardiac failure
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    Preview · Article · Jan 2016 · Nature Communications
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    ABSTRACT: The purpose of this study is to investigate the impact of a reduction of hemoglobin (Hb) content in the erythrocytes as estimated by mean corpuscular hemoglobin concentration (MCHC) on long-term clinical outcomes in non-anemic patients with heart failure (HF). We prospectively enrolled 1,579 subjects with HF undergoing coronary angiography enrolled in the GeneBank study with 5-year follow-up of all-cause mortality. Levels of Hb and MCHC were assessed at enrollment and after 6 months of follow up. Anemia was defined as Hb levels <13 g/dL in males, and <12 g/dL in females. In our non-anemic cohort (n=785, 49.7%), mean Hb and median MCHC were 13.8±1.1 g/dL and 34.3 (interquartile range 33.6-35) g/dL, respectively. Non-anemic HF patients with lower MCHC had higher mortality risk (Quartiles 1 vs 4, Hazard ratio = 2.1, 95% confidence interval 1.4-3.3, p=0.001). In a subset of non-anemic patients with persistent normal Hb on follow-up (n=206), the mean time between baseline and follow up MCHC levels was 169.3±41.6 days. In comparison to patients with levels of MCHC above the first quartile (≥33.6 g/dL) on baseline and follow up, patients with persistently low MCHC (<33.6 g/dL) had a significantly increased mortality risk (log rank <0.001). All models remained significant even after adjusting for traditional cardiac risk factors, left ventricular ejection fraction, baseline Hb levels and mean corpuscular volume. In conclusion, relative hypochromia is an independent predictor of increased mortality risk in patients with HF, even in the setting of normal Hb levels.
    No preview · Article · Jan 2016
  • Gary S. Francis · G. Michael Felker · W.H. Wilson Tang
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    ABSTRACT: Circulating natriuretic peptide measurements have been used extensively over the past 15 years to diagnose and monitor patients with heart failure. We are still learning how complex the dynamics of natriuretic peptides can be in the interpretation of test results in individual patients. Although natriuretic peptide measurements are widely used in practice, there are questions regarding why these peptides may not necessarily track with blood volume or invasive hemodynamic measurements in individual patients. Interpretation of natriuretic peptide measurements will depend on many factors, including special patient populations, obesity, renal function, the state of congestion or decongestion, and whether patients are receiving specific therapies. Natriuretic peptide measurements have clearly revolutionized clinical care for patients with heart failure, but further research should provide insights to help use these measurements to individualize patient care beyond the current guidelines.
    No preview · Article · Jan 2016 · Journal of the American College of Cardiology
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    ABSTRACT: Chromosome position 9p21 encodes three-tumor suppressors p16INK4a, p14ARF, and p15INK4b, and the long non-coding RNA ANRIL (antisense noncoding RNA in the INK4 locus). The rs11515 single nucleotide polymorphism in the p16INK4a/p14ARF 3′ untranslated region is associated with glioblastoma, melanoma, and other cancers. This study investigated the frequency and effect of rs11515 genotypes in breast cancer. Genomic DNA samples from 400 women (200 with and 200 without a diagnosis of breast cancer) were genotyped for the rs11515 major © and minor (G) alleles. The rs11515 polymorphism was also investigated in 108 heart tissues to test for tissue specific effects. Four 9p21 transcripts, p16INK4a, p14ARF, p15INK4b, and ANRIL were measured in breast tumors and myocardium using quantitative PCR. Heterozygotes (CG genotype) were more frequent in women with breast cancer compared to the control population (P = 0.0039). In those with breast cancer the CG genotype was associated with an older age (P = 0.016), and increased lymph node involvement (P = 0.007) compared to homozygotes for the major allele (CC genotype). In breast tumors the CG genotype had higher ANRIL (P = 0.031) and lower p16INK4a (P = 0.006) expression compared to the CC genotype. The CG genotype was not associated with altered 9p21 transcripts in heart tissue. In breast cancer the rs11515 CG genotype is more frequent and associated with a more aggressive tumor that could be due to increased ANRIL and reduced p16INK4a expression. The absence of associations between rs11515 genotypes and 9p21 transcripts in heart tissue suggests this polymorphism has tissue or disease specific functions.
    Full-text · Article · Jan 2016 · Frontiers in Oncology
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    ABSTRACT: Aims: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure. Methods and results: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18-1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52). Conclusion: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area.
    No preview · Article · Jan 2016 · European Journal of Heart Failure
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    ABSTRACT: Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure is strongly and independently associated with worsening renal function. Our objective was to determine whether SBP reduction or titration of oral neurohormonal antagonists during acute decompensated heart failure treatment negatively influences diuresis and decongestion. Methods and Results-SBP reduction was evaluated from admission to discharge in consecutive acute decompensated heart failure admissions (n=656). Diuresis and decongestion were examined across a range of parameters, such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4±19.4 mm Hg, and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with worsening renal function (odds ratio, 1.9; 95% confidence interval, 1.2-2.9; P=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (odds ratio, 2.0; 95% confidence interval, 1.3-3.2; P=0.002). However, SBP reduction did not negatively affect diuresis or decongestion (P≥0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in >50% of admissions and was associated with a modest additional reduction in blood pressure (≤5.6 mm Hg). Notably, worsening renal function was not increased, and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists. Conclusions-Despite a higher rate of worsening renal function, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline-recommended titration of chronic oral medication during acute decompensated heart failure hospitalization may not be antagonistic to the short-term goal of decongestion.
    No preview · Article · Jan 2016 · Circulation Heart Failure
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    ABSTRACT: Background: Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed. Methods and results: Based on well-established renal physiological principles, an equation was derived to predict net sodium output using a spot urine sample obtained 1 or 2 hours after loop diuretic administration. This equation was then prospectively validated in 50 acute decompensated heart failure patients using meticulously obtained timed 6-hour urine collections to quantify loop diuretic-induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2-4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91; P<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (area under the curve =0.95, 95% confidence interval 0.89-1.0; P<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66; P<0.001) and lesser ability to predict poor natriuretic response (area under the curve =0.76, 95% confidence interval 0.63-0.89; P=0.002). Conclusions: In patients being treated for acute decompensated heart failure, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.
    No preview · Article · Jan 2016 · Circulation Heart Failure
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    ABSTRACT: Background: The aim of this analysis was to determine the long-term prognostic value of lower serum chloride in patients with stable chronic heart failure. Electrolyte abnormalities are prevalent in patients with chronic heart failure. Little is known regarding the prognostic implications of lower serum chloride. Methods and results: Serum chloride was measured in 1673 consecutively consented stable patients with a history of heart failure undergoing elective diagnostic coronary angiography. All patients were followed for 5-year all-cause mortality, and survival models were adjusted for variables that confounded the chloride-risk relationship. The average chloride level was 102±4 mEq/L. Over 6772 person-years of follow-up, there were 547 deaths. Lower chloride (per standard deviation decrease) was associated with a higher adjusted risk of mortality (hazard ratio 1.29, 95% confidence interval 1.12-1.49; P<0.001). Chloride levels net-reclassified risk in 10.4% (P=0.03) when added to a multivariable model (with a resultant C-statistic of 0.70), in which sodium levels were not prognostic (P=0.30). In comparison to those with above first quartile chloride (≥101 mEq/L) and sodium (≥138 meq/L), subjects with first quartile chloride had a higher adjusted mortality risk, whether they had first quartile sodium (hazard ratio 1.35, 95% confidence interval 1.08-1.69; P=0.008) or higher (hazard ratio 1.43, 95% confidence interval 1.12-1.85; P=0.005). However, subjects with first quartile sodium but above first quartile chloride had no association with mortality (P=0.67). Conclusions: Lower serum chloride levels are independently and incrementally associated with increased mortality risk in patients with chronic heart failure. A better understanding of the biological role of serum chloride is warranted.
    Full-text · Article · Jan 2016 · Circulation Heart Failure
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    ABSTRACT: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. Methods and Results-We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. Conclusions-Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.
    No preview · Article · Jan 2016 · Circulation Heart Failure
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    ABSTRACT: Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. Methods and Results-C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO-or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. Conclusions-Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline→TMAO pathway contribute to increased heart failure susceptibility.
    No preview · Article · Jan 2016 · Circulation Heart Failure
  • Roy S. Small · W.H. Wilson Tang

    No preview · Article · Jan 2016 · Circulation Heart Failure
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    ABSTRACT: Aims: We aimed to characterize abnormal liver function tests in patients with heart failure (HF), as they are commonly encountered yet poorly defined. Methods and results: We used data from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) to characterize associations with baseline liver function tests (LFTs). Each LFT was analysed as both a continuous and dichotomous variable (normal vs. abnormal; bilirubin >1.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >35 mmol/L). Logistic regression assessed the association of LFTs and 30-day all-cause mortality and heart failure (HF) rehospitalization, and Cox proportional hazards assessed the association with 180-day all-cause mortality among patients alive at a 30-day landmark. In ASCEND-HF, 4228 (59%) had complete admission LFT data. Of these, 42% had abnormal bilirubin, 22% had abnormal ALT, and 30% had abnormal AST. Patients with abnormal LFTs were younger, had lower body mass index, and lower left ventricular ejection fraction. In multivariable models, increased total bilirubin was associated with increased 30-day mortality or HF rehospitalization [hazard ratio (HR) 1.17 per 1 mg/dL increase, 95% confidence interval (CI) 1.04, 1.32; P = 0.012], but not with an increase in 180-day mortality (HR 1.10, 95% CI 0.97, 1.25; P = 0.13) per 1 mg/dl increase. Compared with normal bilirubin levels, abnormal bilirubin was associated with increased 30-day mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54; P = 0.048) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62; P = 0.007). We found no association with AST or ALT and outcomes. Conclusion: Greater than 40% of patients hospitalized with acute HF had abnormal LFTs. After multivariable adjustment, only elevated bilirubin was independently associated with worse clinical outcomes and may represent an important prognostic variable.
    No preview · Article · Dec 2015 · European Journal of Heart Failure
  • Justin L Grodin · Jeffrey M Testani · W H Wilson Tang

    No preview · Article · Dec 2015 · Journal of the American College of Cardiology
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    ABSTRACT: Aims: Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes. Methods and results: We measured plasma ET-1 at baseline, 48-72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9-10] pg/mL at baseline, 6.3 (IQR 4.9-8.1) pg/mL at 48-72 h, and 5.9 (IQR 4.7-7.9) pg/mL at 30 days (P < 0.001). Baseline and 48-72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.001 and HR 1.5, 95% CI 1.2-1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48-72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03-2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis. Conclusion: We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP.
    No preview · Article · Dec 2015 · European Journal of Heart Failure
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    ABSTRACT: Background: Patients with moderate-to-severe chronic kidney disease (CKD) are poorly represented in clinical trials of cardiac resynchronization therapy (CRT). Objectives: This study sought to assess the real-world comparative effectiveness of CRT with defibrillator (CRT-D) versus implantable cardioverter-defibrillator (ICD) alone in CRT-eligible patients with moderate-to-severe CKD. Methods: We conducted an inverse probability-weighted analysis of 10,946 CRT-eligible patients (ejection fraction <35%, QRS >120 ms, New York Heart Association functional class III/IV) with stage 3 to 5 CKD in the National Cardiovascular Data Registry (NCDR) ICD Registry, comparing outcomes between patients who received CRT-D (n = 9,525) versus ICD only (n = 1,421). Outcomes were obtained via Medicare claims and censored at 3 years. The primary endpoint of heart failure (HF) hospitalization or death and the secondary endpoint of death were assessed with Cox proportional hazards models. HF hospitalization, device explant, and progression to end-stage renal disease were assessed using Fine-Gray models. Results: After risk adjustment, CRT-D use was associated with a reduction in HF hospitalization or death (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.78 to 0.91; p < 0.0001), death (HR: 0.85; 95% CI: 0.77 to 0.93; p < 0.0004), and HF hospitalization alone (subdistribution HR: 0.84; 95% CI: 0.76 to 0.93; p < 0.009). Subgroup analyses suggested that CRT was associated with a reduced risk of HF hospitalization and death across CKD classes. The incidence of in-hospital, short-term, and mid-term device-related complications did not vary across CKD stages. Conclusions: In a nationally representative population of HF and CRT-eligible patients, use of CRT-D was associated with a significantly lower risk of the composite endpoint of HF hospitalization or death among patients with moderate-to-severe CKD in the setting of acceptable complication rates.
    No preview · Article · Dec 2015 · Journal of the American College of Cardiology
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    ABSTRACT: Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with ΔcGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans.
    No preview · Article · Nov 2015 · Journal of Cardiovascular Translational Research

Publication Stats

11k Citations
3,627.51 Total Impact Points


  • 2016
    • Yale University
      New Haven, Connecticut, United States
  • 2008-2015
    • Metropolitan Heart and Vascular Institute
      Minneapolis, Minnesota, United States
    • Lerner Research Institute
      • Department of Cellular and Molecular Medicine
      Cleveland, Ohio, United States
    • Rede Sarah de Hospitais de Reabilitação
      Brasília, Federal, Brazil
  • 2003-2015
    • Cleveland Clinic
      • • Department of Cell Biology
      • • Department of Cardiovascular Medicine
      • • Department of Cardiology
      Cleveland, Ohio, United States
  • 2014
    • Henry Ford Hospital
      Detroit, Michigan, United States
    • Cleveland State University
      Cleveland, Ohio, United States
  • 2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • MetroHealth Medical Center
      Cleveland, Ohio, United States
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 2005-2013
    • Case Western Reserve University
      • Division of Cardiovascular Medicine
      Cleveland, Ohio, United States
  • 2012
    • NCI-Frederick
      Фредерик, Maryland, United States
    • Baylor College of Medicine
      Houston, Texas, United States
    • Cleveland Clinic Laboratories
      Cleveland, Ohio, United States
    • Universiteit Hasselt
      • Faculty of Medicine and Life Sciences
      Flanders, Belgium
  • 2011
    • Allegheny General Hospital
      Pittsburgh, Pennsylvania, United States
  • 1999-2011
    • Stanford Medicine
      • Division of Cardiovascular Medicine
      Stanford, California, United States
  • 2009
    • Western Sydney University
      • School of Nursing and Midwifery
      Sydney, New South Wales, Australia
  • 2007
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
    • VA San Diego Healthcare System
      San Diego, California, United States
  • 2004
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • University of Texas Southwestern Medical Center
      • Department of Internal Medicine
      Dallas, Texas, United States
  • 2001-2004
    • Stanford University
      • Division of Cardiovascular Medicine
      Palo Alto, California, United States