R. Cogswell

Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. Bridging integrator 1 (BIN1) is a membrane-associated protein important to cardiomyocyte homeostasis and is downregulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing secondary to ARVC. OBJECTIVE To determine whether plasma BIN1 levels can be used to measure disease severity in patients with ARVC. METHODS We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to correlate with cardiac functional status and predict ventricular arrhythmias. RESULTS Mean plasma BIN1 levels were decreased in patients with ARVC with heart failure (15 ± 7 vs 60 ± 17 in patients without heart failure, P <.05; the plasma BIN1 level was 60 ± 10 in non-ARVC normal controls). BIN1 levels correlated inversely with number of previous ventricular arrhythmia (R = -.47; P <.05), and low BIN1 levels correctly classified patients with advanced heart failure or ventricular arrhythmia (receiver operator curve area under the curve of 0.88 ± 0.07). Low BIN1 levels also predicted future ventricular arrhythmias (receiver operator curve area under the curve of 0.89 ± 0.09). In a stratified analysis, BIN1 levels could predict future arrhythmias in patients without severe heart failure (n = 20) with an accuracy of 82%. In the 7 patients with ARVC with serial blood samples, all of whom had evidence of disease progression during follow-up, plasma BIN1 levels decreased significantly (a decrease of 63%; P <.05). CONCLUSIONS Plasma BIN1 level seems to correlate with cardiac functional status and the presence or absence of sustained ventricular arrhythmias in a small cohort of patients with ARVC and can predict future ventricular arrhythmias.

Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival

BACKGROUND The Registry to Evaluate Early and Long-Term Pulmonary Arterial (PAH) Hypertension Disease Management (REVEAL) model was designed to predict 1-year survival in patients with PAH. Multivariate prediction models need to be evaluated in cohorts distinct from the derivation set to determine external validity. In addition, limited data exist on the utility of this model in the prediction of long-term survival. METHODS REVEAL model performance was assessed to predict 1-year and 5-year outcomes, defined as survival or composite survival or freedom from lung transplant, in 140 patients with PAH. RESULTS The validation cohort had a higher proportion of human immunodeficiency virus (7.9% vs 1.9%, p < 0.0001), methamphetamine use (19.3% vs 4.9%, p < 0.0001), and portal hypertension PAH (16.4% vs 5.1%, p < 0.0001) compared with the development cohort. The C-index of the model to predict survival was 0.765 at 1 year and 0.712 at 5 years of follow-up. The C-index of the model to predict composite survival or freedom from lung transplant was 0.805 and 0.724 at 1 and 5 years of follow-up, respectively. Prediction by the model, however, was weakest among patients with intermediate-risk predicted survival. CONCLUSIONS The REVEAL model had adequate discrimination to predict 1-year survival in this small but clinically distinct validation cohort. Although the model also had predictive ability out to 5 years, prediction was limited among patients of intermediate risk, suggesting our prediction methods can still be improved.

Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction

Pulmonary hypertension (PH) secondary to heart failure with preserved ejection fraction (HFpEF) is an increasingly recognized cause of PH due to an emerging epidemic of HFpEF. The mechanisms underlying the pathogenesis of PH in HFpEF are not well established, but the presence of PH and right ventricular dysfunction in HFpEF is associated with worse prognosis. Currently, it is unclear whether PH is just a marker of underlying disease severity or whether it could be a target of treatment in HFpEF. Although PH-HFpEF and pulmonary arterial hypertension share several clinical characteristics, the evidence supporting the use of pulmonary arterial hypertension-specific therapies in PH-HFpEF is limited. Here, we review the disease classification, epidemiology, proposed pathophysiology, and treatments for PH-HFpEF. Our limited understanding highlights an urgent need for more research to elucidate the pathogenesis of PH in HFpEF and to develop novel therapies for this challenging syndrome.

Pulmonary Arterial Compliance Improves Rapidly after Left Ventricular Assist Device Implantation

Pulmonary artery compliance (PAC) contributes to right ventricular (RV) afterload, is decreased in the setting of increased left ventricular (LV) filling pressures, and may be an important component of World Health Organization (WHO) group II pulmonary hypertension (PH). Left ventricular assist device (LVAD) implantation can rapidly change LV filling, but its relationship with PAC is unknown. Right heart catheterization was performed preoperatively, postoperatively (between 48 and 72 hours), and >30 days post-LVAD implantation in a cohort of 64 patients with end-stage systolic heart failure. Within 72 hours, LVAD implantation was associated with an increase in PAC (2.0—3.7 ml/mm Hg, p < 0.0001), a decrease in pulmonary vascular resistance (3.5—1.7 Wood units, p < 0.0001). Pulmonary arterial compliance did not increase further at the >30 post-LVAD time point (3.7 ± 1.7 to 3.6 ± 0.44 ml/mm Hg, p = 0.44). Pulmonary artery compliance improves rapidly after LVAD implantation. This suggests that more permanent changes in the pulmonary vascular bed may not be responsible for the abnormal PAC observed in WHO group II PH.

Performance of the REVEAL pulmonary arterial hypertension prediction model using non-invasive and routinely measured parameters

BACKGROUND The REVEAL model for pulmonary arterial hypertension (PAH) uses 19 predictors to calculate a 1-year survival probability and can be repeated over time. It is currently unclear which of the 19 variables are the most essential for serial REVEAL score calculation. We aimed to identify high-yield predictors in the REVEAL score and hypothesized that the model could be simplified considerably without compromising performance. METHODS REVEAL scores were calculated in a cohort of 140 PAH patients (Full REVEAL Model). Scores were then recalculated excluding all right heart catheterization and pulmonary function test data (Simple Model) and again using only PAH type, New York Heart Association class, brain natriuretic peptide, renal function and right atrial pressure by echocardiogram (Clinical Model). The models were then tested for the ability to predict 1-year outcomes and the performance of the models was compared. RESULTS The c indices of the models to predict 1-year survival were not statistically different from one another (Full REVEAL Model: 0.765; Simple Model: 0.759; Clinical Model: 0.745; p = 0.92). For the composite outcome of survival or freedom from lung transplant at 1 year, the models were again not statistically different from one another (c indices: Full REVEAL Model: 0.805; Simple Model: 0.809; Clinical Model: 0.785; p = 0.73). CONCLUSIONS The original, Full REVEAL Model appeared to have comparable performance after selectively limiting the number of predictors. There is opportunity to re-evaluate large-registry PAH data to identify a limited number of high-yield variables and to develop a simplified, clinical model.

How to Develop and Implement a Specialized Heart Failure with Preserved Ejection Fraction Clinical Program

Heart failure with preserved ejection fraction (HFpEF), a highly prevalent and complex clinical syndrome with high morbidity and mortality, is often unrecognized and not optimally treated. Clinical trials for HFpEF have been plagued by low enrollment, and clinicians often approach HFpEF patients with “therapeutic nihilism” given the perceived lack of available therapies based on the disappointing results of these prior trials. Due to these challenges, we have pioneered the successful creation of dedicated, specialized HFpEF clinical programs. Here, we discuss (1) the rationale for the development of a specialized HFpEF clinical program; (2) strategies for the systematic identification of HFpEF patients; (3) a standardized diagnostic and therapeutic approach; (4) validation of the HFpEF clinical program paradigm; (5) staffing and reimbursement considerations; (6) HFpEF clinical trial enrollment; and (7) challenges and future directions for HFpEF clinical programs. We conclude that it is feasible to create HFpEF clinical programs that fulfill the major unmet need of identifying and caring for patients with HFpEF. These clinics are essential for confirming the HFpEF diagnosis, providing standardized treatment, and facilitating clinical trial enrollment. It is our hope that the information provided here will encourage others to establish their own specialized HFpEF programs, thereby allowing for comprehensive care for these complex patients.

Performance of the REVEAL model in WHO Group 2 to 5 pulmonary hypertension: Application beyond pulmonary arterial hypertension

BACKGROUND The majority of patients with pulmonary hypertension (PH) have non-pulmonary arterial hypertension PH (non-PAH PH) or multifactorial PH. The REVEAL score was designed to predict 1-year survival in patients with pulmonary arterial hypertension (PAH) only. It is unknown whether this model is applicable to a more general population of PH patients. METHODS Both newly diagnosed and previously diagnosed patients with PH of any etiology (n = 200) were enrolled in an observational cohort between the years 2003 and 2009. REVEAL scores were assessed for the ability to predict 1-year survival in the following groups: (1) PAH; (2) non-PAH PH; (3) multifactorial PH; and (4) the entire cohort. RESULTS Of the 200 patients, 126 (63%) had PAH, 32 (16%) had non-PAH PH and 42 (21%) had multifactorial PH. The concordance indices for the model when applied to the various groups were: PAH, 0.72; non-PAH PH, 0.97; multifactorial PH, 0.77; and entire cohort, 0.775. Observed and predicted survivals of the entire cohort according to model-assigned risk strata were not statistically different from one another (p = 0.60), suggesting adequate model calibration. CONCLUSIONS The REVEAL survival prediction model for PAH has comparable performance when applied to a broad population of PH patients. The data suggest that the model may have utility in PH patients in general, subject to validation in a larger cohort.

Gastrointestinal Bleeding during Continuous-Flow Left Ventricular Assist Device Support is Associated with Lower Rates of Cardiac Transplantation.

Gastrointestinal bleeding (GIB) remains a significant problem after continuous-flow left ventricular assist device (CF-LVAD) implantation. We hypothesized that the subsequent need for blood transfusions in patients with GIB may reduce rates of cardiac transplantation. We performed a retrospective review of 232 patients implanted with the HeartMate II (HM II) CF-LVAD from June 2005 through May 2013 at our center to determine risk factors for GIB and assess its effect on cardiac transplantation. Over a total LVAD follow-up time of 364 person-years, 62 GIB episodes occurred in 49 patients (27%), for an event rate of 0.45 gastrointestinal bleeds/patient-year of LVAD support. Women made up 15% of our cohort, yet contributed 29% of the GIB (p = 0.06). Survival at 6 month, 1 year, and 2 years was not statistically different in patients who developed GIB and those who did not (77% vs 78%, 74% vs 71%, and 61% vs 54%, respectively). In transplant-eligible patients, GIB was associated with a 27% lower rate of cardiac transplantation (rate ratio 0.73, p < 0.05). Although the mechanism behind this finding is unclear, GIB appears to be linked to higher transfusion rates, which may cause the development of subsequent allosensitization.

High prevalence of subclinical cerebral infarction in patients with heart failure with preserved ejection fraction

Undetected atrial fibrillation (AF) may be common in the heart failure with preserved ejection fraction (HFpEF) population, and failure to detect this may lead to the missing of opportunities to prevent associated subclinical cerebral infarctions (SCIs) and cognitive decline.

Substance abuse at the time of left ventricular assist device implantation is associated with increased mortality

BACKGROUND Advanced heart failure teams are often faced with the decision of whether or not to offer a left ventricular assist device (LVAD) to patients who have end-stage heart failure and recent or ongoing substance abuse. The outcomes of these patients after LVAD implantation are unknown. METHODS Baseline predictors and outcomes were collected and analyzed from patients with active substance abuse and a cohort of patients without active substance abuse matched for age, INTERMACS profile and year of implantation. The primary outcome was all-cause mortality. Secondary outcomes included rates of listing for cardiac transplantation, transplantation and chronic drive-line infection. RESULTS The cohort consisted of 20 consecutive LVAD recipients with active substance abuse and 40 recipients without active substance abuse. During a median follow-up period of 2.3 years (IQR 1.4 to 3.6), the substance abuse group had 3.2 times the rate (hazard) of death compared with a matched cohort (HR 3.2, 95% CI 1.2 to 8.0, p < 0.05). Furthermore, the rate of listing for transplant was 69% lower (rate ratio 0.31, p < 0.0005), rate of cardiac transplant was 89% lower (rate ratio 0.11, p < 0.0005), and risk of chronic drive-line infection was 5.4 times higher (rate ratio 5.4, p < 0.0005) in the substance abuse group. CONCLUSIONS Active substance abuse in patients who received an LVAD was associated with increased mortality and overall poor outcomes. Larger scale data will be needed to confirm these findings and to inform decision-making in this population.