Faculty Bibliography

BACKGROUND:Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality. Existing data on cardiac structure and function in HFpEF suggest significant heterogeneity in this population. METHODS AND RESULTS/RESULTS:Echocardiograms were obtained from 935 patients with HFpEF (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial before initiation of randomized therapy. Average age was 70±10 years, 49% were women, 14% were of African descent, and comorbidities were highly prevalent. Centralized quantitative analysis in a blinded core laboratory demonstrated a mean left ventricular ejection fraction of 59.3±7.9%, with prevalent concentric left ventricular remodeling (34%) and hypertrophy (43%), and left atrial enlargement (53%). Diastolic dysfunction was present in 66% of gradable participants and was significantly associated with greater left ventricular hypertrophy and a higher prevalence of left atrial enlargement. Doppler evidence of pulmonary hypertension was present in 36%. At least 1 measure of structural heart disease was present in 93% of patients. CONCLUSIONS:Patients enrolled in TOPCAT demonstrated heterogeneous patterns of ventricular remodeling, with high prevalence of structural heart disease, including left ventricular hypertrophy and left atrial enlargement, in addition to pulmonary hypertension, each of which has been associated with adverse outcomes in HFpEF. Diastolic function was normal in approximately one third of gradable participants, highlighting the heterogeneity of the cardiac phenotype in this syndrome. These findings deepen our understanding of the TOPCAT trial population and expand our knowledge of the diversity of the cardiac phenotype in HFpEF. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

BACKGROUND:This study evaluated the effectiveness of using trained volunteer staff in reducing 30-day readmissions of congestive heart failure (CHF) patients. METHODS:From June 2010 to December 2010, 137 patients (mean age 73 years) hospitalized for CHF were randomly assigned to either: an interventional arm (arm A) receiving dietary and pharmacologic education by a trained volunteer, follow-up telephone calls within 48 hours, and a month of weekly calls; or a control arm (arm B) receiving standard care. Primary outcomes were 30-day readmission rates for CHF and worsening New York Heart Association (NYHA) functional classification; composite and all-cause mortality were secondary outcomes. RESULTS:Arm A patients had decreased 30-day readmissions (7% vs 19%; P < .05) with a relative risk reduction (RRR) of 63% and an absolute risk reduction (ARR) of 12%. The composite outcome of 30-day readmission, worsening NYHA functional class, and death was decreased in the arm A (24% vs 49%; P < .05; RRR 51%, ARR 25%). Standard-care treatment and hypertension, age ≥65 years and hypertension, and cigarette smoking were predictors of increased risk for readmissions, worsening NYHA functional class, and all-cause mortality, respectively, in the multivariable analysis. CONCLUSIONS:Utilizing trained volunteer staff to improve patient education and engagement might be an efficient and low-cost intervention to reduce CHF readmissions.

Erythropoietin (EPO) was hypothesized to mitigate reperfusion injury, in part via mobilization of endothelial progenitor cells (EPCs). The REVEAL trial found no reduction in infarct size with a single dose of EPO (60,000 U) in patients with ST-segment elevation myocardial infarction. In a substudy, we aimed to determine the feasibility of cryopreserving and centrally analyzing EPC levels to assess the relationship between EPC numbers, EPO administration, and infarct size. As a prespecified substudy, mononuclear cells were locally cryopreserved before as well as 24 and 48-72 h after primary percutaneous coronary intervention. EPC samples were collected in 163 of 222 enrolled patients. At least one sample was obtained from 125 patients, and all three time points were available in 83 patients. There were no significant differences in the absolute EPC numbers over time or between EPO- and placebo-treated patients; however, there was a trend toward a greater increase in EPC levels from 24 to 48-72 h postintervention in patients receiving ≥30,000 U of EPO (P = 0.099 for CD133(+) cells, 0.049 for CD34(+) cells, 0.099 for ALDH(br) cells). EPC numbers at baseline were inversely related to infarct size (P = 0.03 for CD133(+) cells, 0.006 for CD34(+) cells). Local whole cell cryopreservation and central EPC analysis in the context of a multicenter randomized trial is feasible but challenging. High-dose (≥30,000 U) EPO may mobilize EPCs at 48-72 h, and baseline EPC levels may be inversely associated with infarct size.

Anomalous origin of the right coronary artery (RCA) from the pulmonary artery is a rare entity. The current recommendation is corrective operation even in asymptomatic patients when this cardiac malformation is found. We report a case of a 21-year-old male who initially presented with ST elevations. After surgical repair with re-implantation of the RCA to the aorta, he was found to have an acute thrombus in his left circumflex and several months later developed a thrombus in the proximal left anterior descending artery. We propose that the change from a hyperkinetic high flow state to a slow flow state in the setting of inadequate coronary flow reserve and endothelial function predisposed our patient to thrombus formation in the persistently dilated coronary arteries. It is expected that restoration of normal flow pattern in all coronary arteries will result in normalization of perfusion, decrease in feeding artery size, and return of endothelial function. Because this anomaly is rare, limited information exists on the effects of the procedure on myocardial perfusion. These findings raise the question of whether re-implantation of the anomalous artery is truly the superior approach.

BACKGROUND:Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF. METHODS AND RESULTS/RESULTS:Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6±9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m2; and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7-16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%. CONCLUSIONS:TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00094302.

BACKGROUND:The benefit of oral anticoagulation therapy with warfarin for stroke prevention in atrial fibrillation (AF) is directly dependent on the quality of anticoagulation (QoA), which in the US is provided predominantly in the community setting. With the emergence of new oral anticoagulation agents, the current QoA needs to be assessed. OBJECTIVES/OBJECTIVE:The purpose of our study is to define the QoA with warfarin in patients with nonvalvular AF who are managed exclusively in community practices, and to compare the quality in the community setting with the quality demonstrated in the recent large randomized control trials. In addition, this study will assess the differences in the QoA based on cardiology vs primary care practices. METHODS:This is a retrospective, observational, multi-center study of 392 patients with AF in the community who were initiated on anticoagulation with warfarin for stroke prevention. International Normalized Ratio (INR) values were collected over a one-year period and the QoA was expressed as time in therapeutic range (TTR) calculated by the linear interpolation method. RESULTS:One hundred patients from cardiology practices and 292 patients from primary care were studied. During the one-year period, the overall mean TTR was 56.7%. The TTR in the primary care vs cardiology practices was 55.3% vs. 60.8% (p=0.02). Both practices had similar percent of time below therapeutic range, 29.8% vs. 29.2%. However, the primary care practice patients were above the therapeutic range 15% of the time vs. 10% in cardiology (p<0.001). There were one death secondary to intracranial bleed and one major bleed in the primary care group. There were no strokes during the study period in either group. CONCLUSION/CONCLUSIONS:The QoA with warfarin, as assessed by TTR, in the current community setting remains suboptimal, and there has been little to no improvement in current clinical practices. TTR should be considered when assessing the recent comparative studies evaluating novel pharmacologic agents to warfarin for the treatment of AF. SUBJECT AREAS: Arrhythmias, preventive cardiology, anticoagulation, thromboembolism, cardiovascular disease risk factors.

The p38 mitogen-activated protein kinase (MAPK) is a nexus point in inflammation, sensing, and stimulating cytokine production and driving cell migration and death. In acute coronary syndromes, p38MAPK inhibition could stabilize ruptured atherosclerotic plaques, pacify active plaques, and improve microvascular function, thereby reducing infarct size and risk of subsequent cardiac events. The SOLSTICE trial is randomized, double-blind, placebo-controlled, parallel group, multicenter phase 2a study of 535 patients that evaluates the safety and efficacy of losmapimod (GW856553), a potent oral p38MAPK inhibitor, vs placebo in patients with non-ST-segment elevation myocardial infarction expected to undergo an invasive strategy. The coprimary end points are reduction in high-sensitivity C-reactive protein at 12 weeks and reduction in infarct size as assessed by troponin area under the curve at 72 hours. A key secondary end point is 72-hour and 12-week B-type natriuretic peptide levels as a measure of cardiac remodeling and ventricular strain. The primary safety assessments are serious and nonserious adverse events, results of liver function testing, and major adverse cardiac events. Cardiac magnetic resonance imaging (N = 117) and coronary flow reserve (N = 13) substudies will assess the effects of losmapimod on infarct size, myocardial function, and coronary vasoregulation. Information gained from the SOLSTICE trial will inform further testing of this agent in larger clinical trials.

BACKGROUND:Detecting and quantifying the severity of mitral regurgitation is essential for risk stratification and clinical decision-making regarding timing of surgery. Our objective was to assess specific visual parameters by cine-magnetic resonance imaging (MRI) in the determination of the severity of mitral regurgitation and to compare it to previously validated imaging modalities: echocardiography and cardiac ventriculography. METHODS:The study population consisted of 68 patients who underwent a cardiac MRI followed by an echocardiogram within a median time of 2.0 days and 49 of these patients who had a cardiac catheterization, median time of 2.0 days. The inter-rater agreement statistic (Kappa) was used to evaluate the agreement. RESULTS:There was moderate agreement between cine MRI and Doppler echocardiography in assessing mitral regurgitation severity, with a kappa value of 0.47, confidence interval (CI) 0.29-0.65. There was also fair agreement between cine MRI and cardiac catheterization with a kappa value of 0.36, CI of 0.17-0.55. CONCLUSION/CONCLUSIONS:Cine MRI offers a reasonable alternative to both Doppler echocardiography and, to a lesser extent, cardiac catheterization for visually assessing the severity of mitral regurgitation with specific visual parameters during routine clinical cardiac MRI.