Search

• Aficamten is a next-generation cardiac myosin inhibitor (CMI). • CMIs are a novel treatment for obstructive hypertrophic cardiomyopathy (oHCM). • We report the efficacy and safety of aficamten with disopyramide for refractory oHCM. • In cohort 3 of REDWOOD-HCM, aficamten plus disopyramide was well tolerated. • Patients showed improved left ventricular outflow-tract gradient and NYHA class. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.01.005 Byline: Aslan T. Turer (a), Kenneth W. Mahaffey (a), Kate L. Compton (c)(d), Robert M. Califf (a)(d), Kevin A. Schulman (b)(c) Abstract: Nonpublication of research results threatens the integrity of clinical research, but the extent of nonpublication and factors associated with publication remain poorly documented. We sought to examine rates of publication or presentation of research findings from multicenter clinical trials and determine what factors are associated with dissemination of results. Author Affiliation: (a) Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (b) Division of General Internal Medicine, Duke University Medical Center, Durham, NC (c) Center for Clinical and Genetic Economics, Duke University Medical Center, Durham, NC (d) Duke Clinical Research Institute, Duke University Medical Center, Durham, NC Article History: Received 3 October 2006; Accepted 9 January 2007

Objectives: The purpose of this study was to assess whether: 1) very small increases in troponin T, measured by a new highly sensitive cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis; and 2) serial changes can discriminate ischemia from other causes of cardiac troponin T (cTnT) release. Background: A new hs-cTnT assay offers greater sensitivity than current assays. Methods: Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple time points during and after incremental rapid atrial pacing. cTnT was quantified using both a standard and a pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary artery disease (CAD) and myocardial lactate release with pacing. Results: cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 15.6 pg/ml 60 min after termination of rapid atrial pacing (p < 0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 11.8 pg/ml, p < 0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n = 7) when compared with those without either marker (n = 5) (25.0 pg/ml vs. 10.2 pg/ml, p = 0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p = 0.50) changes were not different between groups. Conclusions: Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes. [ABSTRACT FROM AUTHOR]

Since the initial description of the phenomenon by Jennings et al 50 years ago, our understanding of the underlying mechanisms of reperfusion injury has grown significantly. Its pathogenesis reflects the confluence of multiple pathways, including ion channels, reactive oxygen species, inflammation, and endothelial dysfunction. The purposes of this review are to examine the current state of understanding of ischemia-reperfusion injury, as well as to highlight recent interventions aimed at this heretofore elusive target. In conclusion, despite its complexity our ongoing efforts to mitigate this form of injury should not be deterred, because nearly 2 million patients annually undergo either spontaneous (in the form of acute myocardial infarction) or iatrogenic (in the context of cardioplegic arrest) ischemia-reperfusion. [Copyright &y& Elsevier]

Intravenous diuretics are the cornerstone of management for patients hospitalized for heart failure. Physiologic data suggest that intermittent high-dose furosemide promotes neurohormonal activation, which a slow continuous infusion might remediate. However, the limited clinical data comparing dosing schemes are confounded. This study was a randomized, open-label, single-center trial of twice-daily bolus injection versus continuous infusion furosemide in patients hospitalized with heart failure and volume overload. The primary outcome was change in creatinine from admission to hospital day 3 or discharge. Twenty-one patients were randomized to bolus injection and 20 patients to continuous infusion. Baseline characteristics were balanced between study arms except for gender, with a mean age of 60 ± 15 years, a mean ejection fraction of 35 ± 19%, and a mean creatinine level of 1.9 ± 1.2 mg/dl. The mean doses of furosemide were similar between arms over the first 48 hours (162 ± 48 and 162 ± 52 mg/24 hours). None of the outcomes differed significantly between bolus and continuous dosing from admission to hospital day 3 or discharge (mean change in creatinine −0.02 vs 0.13 mg/dl, p = 0.18; urine output 5,113 vs 4,894 ml, p = 0.78; length of stay 8.8 vs 9.9 days, p = 0.69). All patients survived to discharge. In conclusion, there were no substantial differences between bolus injection and continuous infusion of equal doses of furosemide for the treatment of patients hospitalized with heart failure. Given the high prevalence of heart failure hospitalization and the disparate results of small studies regarding optimal dosing of loop diuretics to treat these patients, larger multicenter blinded studies are needed. [Copyright &y& Elsevier]

Objective: We examined the effect of body mass index on the association between revascularization strategy and survival in patients with coronary artery disease. Methods: Using the Duke Database for Cardiovascular Disease, we selected 22,877 patients who underwent cardiac catheterization from January 1986 to August 2004 and were found to have significant coronary artery disease. Patients were categorized into three coronary disease management groups: no revascularization, percutaneous coronary intervention, and coronary artery bypass surgery. Propensity scoring was used to control for coronary artery revascularization strategy. The relationship between body mass index, coronary disease treatment, and survival was assessed via Cox multivariable models adjusting for baseline demographic, clinical, and angiographic characteristics. Results: The median body mass index was 27.2 kg/m2 (24.4–30.4) in the overall cohort, 27.1 kg/m2 (24.1–30.3) in the no revacularization group, 27.4 kg/m2 (24.8–30.9) in the percutaneous intervention group, and 26.9 kg/m2 (24.4–30.1) in the coronary bypass group. Body mass index was a significant, but weak, predictor of revascularization, with higher indexes predicting lower rates of coronary bypass. Thirty-day survival did not differ across body mass indexes among treatment groups, but survival curves appeared to separate over longer-term follow-up. An inverted U-shaped survival function was noted across all time points after 30 days, with the lowest risk of death at a body mass index of approximately 26 kg/m2 (independent of revascularization strategy). Coronary bypass was associated with the highest survival at all later time points, whereas no revascularization was associated with the lowest. Conclusions: Extremes of body mass index are associated with lower long-term survival in patients with significant coronary disease. Revascularization, particularly with coronary bypass, is consistently associated with the best survival across the spectrum of body mass indexes. [Copyright &y& Elsevier]

With an aging U.S. population and a declining physician supply, the care of critically ill patients will soon be reaching a level of crisis. At the same time, the evidence continues to mount in support of intensivist staffing to improve both patient outcomes and resource utilization in intensive care units (ICUs). Whereas the vast majority of medical and surgical ICUs are staffed by physicians trained in critical care medicine, that is not commonly the case in coronary care units (CCUs) in this country. Despite that, the breadth and diversity of comorbidities in patients that occupy our CCU beds is continuously growing. No longer is the CCU merely an observation unit for peri-infarction complications, but rather it has truly become an ICU for patients with cardiovascular disease. With this in mind, there becomes a growing need for intensivist-trained cardiologists and a push for the development of critical care training pathways in our cardiovascular fellowship programs. [Copyright &y& Elsevier]

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: −40 ± 27 mm Hg, and −43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (−36 ± 27 mm Hg and −53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (−6% ± 7.5% and −12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM. [Display omitted] [ABSTRACT FROM AUTHOR]

Adiponectin is a key component in multiple metabolic pathways. Studies evaluating associations of adiponectin with clinical outcomes in older adults have reported conflicting results. We investigated the association of adiponectin with mortality and cardiovascular disease (CVD) morbidity in a young, multiethnic adult population. We analyzed data from participants in the Dallas Heart Study without baseline CVD who underwent assessment of total adiponectin from 2000 to 2002. The primary outcome of all-cause mortality was assessed over median 10.4 years of follow-up using multivariable-adjusted Cox proportional hazards models. Secondary outcomes included CVD mortality, major adverse cardiovascular and cerebrovascular events (MACCE), and heart failure (HF). The study cohort included 3,263 participants, mean age 43.4 years, 44% women, and 50% black. There were 184 deaths (63 CVD), 207 MACCE, and 46 HF events. In multivariable models adjusted for age, gender, race, hypertension, diabetes, smoking, high-density lipoprotein cholesterol-C, hyperlipidemia, high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and body mass index, increasing adiponectin quartiles were positively associated with all-cause mortality Q4 versus Q1 (hazard ratio [HR] = 2.27; 95% confidence interval [CI] 1.47, 3.50); CVD mortality Q4 versus Q1 (HR = 2.43; 95% CI 1.15, 5.15); MACCE Q4 versus Q1 (HR = 1.71; 95% CI 1.13, 2.60); and HF Q4 versus Q1 (HR = 2.95; 95% CI 1.14, 7.67). Findings were similar with adiponectin as a continuous variable and consistent across subgroups defined by age, gender, race, obesity, diabetes, metabolic syndrome, or elevated high-sensitivity C-reactive protein. In conclusion, higher adiponectin was associated with increased mortality and CVD morbidity in a young, multiethnic population. These findings may have implications for strategies aimed at lowering adiponectin to prevent adverse outcomes. [ABSTRACT FROM AUTHOR]

Background Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. Objectives This study sought to determine the relationship between adipose tissue distribution and incident hypertension. Methods Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). Results Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m 2 ), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). Conclusions Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort. Background: Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans. Methods: A total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index. Results: Median BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = −0.08; p < 0.0001) and liver fat (beta coefficient = −0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations. Conclusions: Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides. [Copyright &y& Elsevier]

Previous studies have identified cardiac troponin I (cTnI) as an important marker in pulmonary hypertension (PH) prognosis. However, traditional assays are limited by poor sensitivity, even among patients at high risk. cTnI was measured in 255 PH patients using a new highly sensitive (hs) assay. Other measures included demographics, creatinine, 6-minute walk distance, hemodynamics, cardiac magnetic resonance imaging, and B-type natriuretic peptide level. The association between cTnI and survival was assessed using Kaplan-Meier analysis and Cox regression. cTnI was detectable with the hs assay in 95% of the patients with a median level of 6.9 pg/ml (IQR 2.7e12.6 pg/ml). Higher cTnI levels associated with higher levels of B-type natriuretic peptide, shorter 6-minute walk distance, and more severe hemodynamic and cardiac magnetic resonance imaging abnormalities. During a median follow-up of 3.5 years, 60 individuals died. Unadjusted event rates increased across higher cTnI quartiles (3, 5, 13, 17 events/100 person-years, respectively, p trend = 0.002). cTnI in the fourth (vs first) quartile remained associated with death in a final stepwise multivariable model that included clinical variables and hemodynamics (adjusted hazard ratio 5.3, 95% confidence interval 1.8e15.6). In conclusion, cTnI levels, detectable with a novel hs assay, identify patients with PH who have more severe hemodynamic and cardiac structural abnormalities and provide novel and independent prognostic information. This hs assay has the potential to detect more at-risk patients and improve current risk-stratification algorithms. [ABSTRACT FROM AUTHOR]