Showing papers in "Jacc-Heart Failure in 2014"

Risk prediction in patients with heart failure: a systematic review and analysis.

Abstract: Objectives This study sought to review the literature for risk prediction models in patients with heart failure and to identify the most consistently reported independent predictors of risk across models. Background Risk assessment provides information about patient prognosis, guides decision making about the type and intensity of care, and enables better understanding of provider performance. Methods MEDLINE and EMBASE were searched from January 1995 to March 2013, followed by hand searches of the retrieved reference lists. Studies were eligible if they reported at least 1 multivariable model for risk prediction of death, hospitalization, or both in patients with heart failure and reported model performance. We ranked reported individual risk predictors by their strength of association with the outcome and assessed the association of model performance with study characteristics. Results Sixty-four main models and 50 modifications from 48 studies met the inclusion criteria. Of the 64 main models, 43 models predicted death, 10 hospitalization, and 11 death or hospitalization. The discriminatory ability of the models for prediction of death appeared to be higher than that for prediction of death or hospitalization or prediction of hospitalization alone (p = 0.0003). A wide variation between studies in clinical settings, population characteristics, sample size, and variables used for model development was observed, but these features were not significantly associated with the discriminatory performance of the models. A few strong predictors emerged for prediction of death; the most consistently reported predictors were age, renal function, blood pressure, blood sodium level, left ventricular ejection fraction, sex, brain natriuretic peptide level, New York Heart Association functional class, diabetes, weight or body mass index, and exercise capacity. Conclusions There are several clinically useful and well-validated death prediction models in patients with heart failure. Although the studies differed in many respects, the models largely included a few common markers of risk.

Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction.

Abstract: Objectives This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). Background Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. Methods Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry–based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. Results The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size–adjusted heart weight (p = 0.04). Conclusions Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial.

Abstract: Objectives This randomized controlled multicenter trial evaluated coenzyme Q10 (CoQ10) as adjunctive treatment in chronic heart failure (HF). Background CoQ10 is an essential cofactor for energy production and is also a powerful antioxidant. A low level of myocardial CoQ10 is related to the severity of HF. Previous randomized controlled trials of CoQ10 in HF were underpowered to address major clinical endpoints. Methods Patients with moderate to severe HF were randomly assigned in a 2-year prospective trial to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. The primary short-term endpoints at 16 weeks were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro–B type natriuretic peptide. The primary long-term endpoint at 2 years was composite major adverse cardiovascular events as determined by a time to first event analysis. Results A total of 420 patients were enrolled. There were no significant changes in short-term endpoints. The primary long-term endpoint was reached by 15% of the patients in the CoQ10 group versus 26% in the placebo group (hazard ratio: 0.50; 95% confidence interval: 0.32 to 0.80; p = 0.003) by intention-to-treat analysis. The following secondary endpoints were significantly lower in the CoQ10 group compared with the placebo group: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). In addition, a significant improvement of NYHA class was found in the CoQ10 group after 2 years (p = 0.028). Conclusions Long-term CoQ10 treatment of patients with chronic HF is safe, improves symptoms, and reduces major adverse cardiovascular events. (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]; ISRCTN94506234 )

Developing Therapies for Heart Failure With Preserved Ejection Fraction: Current State and Future Directions

Abstract: The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

Factors influencing the predictive power of models for predicting mortality and/or heart failure hospitalization in patients with heart failure.

Abstract: The present paper systematically reviews and compares existing prediction models in order to establish the strongest variables, models, and model characteristics in patients with heart failure predicting outcome To improve decision making accurately predicting mortality and heart-failure hospitalization in patients with heart failure can be important for selecting patients with a poorer prognosis or nonresponders to current therapy, to improve decision making MEDLINE/PubMed was searched for papers dealing with heart failure prediction models To identify similar models on the basis of their variables hierarchical cluster analysis was performed Meta-analysis was used to estimate the mean predictive value of the variables and models; meta-regression was used to find characteristics that explain variation in discriminating values between models We identified 117 models in 55 papers These models used 249 different variables The strongest predictors were blood urea nitrogen and sodium Four subgroups of models were identified Mortality was most accurately predicted by prospective registry-type studies using a large number of clinical predictor variables Mean C-statistic of all models was 066 ± 00005, with 071 ± 0001, 068 ± 0001 and 063 ± 0001 for models predicting mortality, heart failure hospitalization, or both, respectively There was no significant difference in discriminating value of models between patients with chronic and acute heart failure Prediction of mortality and in particular heart failure hospitalization in patients with heart failure remains only moderately successful The strongest predictors were blood urea nitrogen and sodium The highest C-statistic values were achieved in a clinical setting, predicting short-term mortality with the use of models derived from prospective cohort/registry studies with a large number of predictor variables

Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device.

Abstract: Objectives The aim of this study was to determine whether differences in continuous flow left ventricular assist devices (LVADs) may lead to differences in the von Willebrand profile and the occurrence of bleeding and thromboembolic events. Background The HeartMate II (Thoratec Corp., Pleasanton, California) and HeartWare Ventricular Assist Device (HVAD) (HeartWare, Inc., Framingham, Massachusetts) systems are the most frequently implanted LVADs worldwide. In all patients with an axial-flow HeartMate II, acquired von Willebrand syndrome (AvWS) due to the loss of large molecular weight multimers was found. The large molecular weight multimers of the von Willebrand factor (vWF) play a key role in primary hemostasis through interactions with platelets. Methods This was a retrospective study of the vWF profile and incidence of bleeding and thromboembolic events in 102 patients receiving the HeartMate II (n = 51) and HVAD (n = 51). Between January 2003 and December 2010, vWF testing was performed in 102 of 175 consecutive patients after LVAD implantation. Results AvWS was found in all patients, demonstrated by a decrease in the high molecular weight multimers of vWF to 30 ± 14% in HeartMate II patients and 34 ± 13% in patients with an HVAD. Significant predictors of vWF antigen included age (p = 0.011), number of days on the device (p = 0.035), C-reactive protein (p Conclusions AvWS developed in all patients after centrifugal or axial flow pump implantation. Different patterns of AvWS were seen between the devices as well as individually. However, the complication rates after implantation were similar.

Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.

Abstract: Objectives This analysis aimed to perform a head-to-head comparison of 3 of the promising biomarkers of cardiovascular (CV) outcomes in heart failure (HF)—soluble ST2 (sST2), growth differentiation factor (GDF)-15, and highly-sensitive troponin T (hsTnT)—and to evaluate the role of serial measurement of these biomarkers in patients with chronic HF. Background sST2, GDF-15, and hsTnT are strongly associated with CV outcomes in HF. Methods This post-hoc analysis used data from a study in which 151 patients with chronic HF due to left ventricular systolic dysfunction were followed up over 10 months. At each visit, N-terminal pro–B-type natriuretic peptide (NT-proBNP), sST2, GDF-15, and hsTnT were measured and any major CV events were recorded. Results Baseline values of all 3 novel biomarkers independently predicted total CV events even after adjusting for clinical and biochemical characteristics, including NT-proBNP, with the best model including all 3 biomarkers (p l 0.001). Adding serial measurement to the base model appeared to improve the model's predictive ability (with sST2 showing the most promise), but it is not clear whether this addition is a unique contribution. However, when time-dependent factors were included, only sST2 serial measurement independently added to the risk model (odds ratio: 3.64; 95% confidence interval: 1.37 to 9.67; p = 0.009) and predicted reverse myocardial remodeling (odds ratio: 1.22; 95% confidence interval: 1.04 to 1.43; p = 0.01). Conclusions In patients with chronic HF, baseline measurement of novel biomarkers added independent prognostic information to clinical variables and NT-proBNP. Only serial measurement of sST2 appeared to add prognostic information to baseline concentrations and predicted change in left ventricular function. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting (PROTECT)]; NCT00351390 ).

The burden of acute heart failure on U.S. emergency departments.

Abstract: Objectives The goal of this study was to examine 2006 to 2010 emergency department (ED) admission rates, hospital procedures, lengths of stay, and costs for acute heart failure (AHF). Background Patients with AHF are often admitted and are associated with high readmissions and cost. Methods We utilized Nationwide Emergency Department Sample AHF data from 2006 to 2010 to describe admission proportion, hospital length of stay (LOS), and ED charges as a surrogate for resource utilization. Results were compared across U.S. regions, patient insurance status, and hospital characteristics. Results There were 958,167 mean yearly ED visits for AHF in the United States. Fifty-one percent of the patients were female, and the median age was 75.1 years (interquartile range [IQR]: 62.5 to 83.7 years). Overall, 83.7% (95% confidence interval: 83.1% to 84.2%) were admitted; the median LOS was 3.4 days (IQR: 1.9 to 5.8 days). Comparing 2006 with 2010, there was a small decrease in median LOS (0.09 days), but the proportion admitted did not change. Odds of admission, adjusting for age, sex, hospital characteristic (academic and safety net status), and insurance (Medicare, Medicaid, private, self-pay/no charge) were highest in the Northeast. Median ED charges were $1,075 (IQR: $679 to $1,665) in 2006 and $1,558 (IQR: $1,018 to $2,335) in 2010. Patients without insurance were more likely to be discharged from the ED, but when admitted, were more likely to receive a major diagnostic or therapeutic procedure. Conclusions A very high proportion of ED patients with AHF are admitted nationally, with significant variation in disposition and procedural decisions based on region of the country and type of insurance, even after adjusting for potential confounding.

Cardiac Size and Sex-Matching in Heart Transplantation: Size Matters in Matters of Sex and the Heart

Abstract: Objective This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation. Background Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes. Methods We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHMrecipient – pHMdonor)/(pHMrecipient)]*100. Results The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p l 0.001), which remained robust in adjusted models (HR: 1.25; p = 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p = 0.02) but no difference in male patients (1-year HR, 1.00; p = 1.0). Conclusions Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation.

Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.

Abstract: Objectives The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. Background Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD). Methods Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product. Results Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p 95%) had significantly reduced peak stress MBF ( Conclusions Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.

Combined Neprilysin and Renin-Angiotensin System Inhibition for the Treatment of Heart Failure

Abstract: Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart Failure: The CUPID 2 Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b)

Abstract: Objectives Impaired cardiac isoform of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity is a key abnormality in heart failure patients with reduced ejection fraction. The CUPID 2 (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b) trial is designed to evaluate whether increasing SERCA2a activity via gene therapy improves clinical outcome in these patients. Background Intracoronary delivery of recombinant adeno-associated virus serotype 1 (AAV1)/SERCA2a improves intracellular Ca2+ handling by increasing SERCA2a protein levels and, as a consequence, restores systolic and diastolic function. In a previous phase 2a trial, this therapy improved symptoms, functional status, biomarkers, and left ventricular function, and reduced cardiovascular events in advanced heart failure patients. Methods CUPID 2 is a phase 2b, double-blind, placebo-controlled, multinational, multicenter, randomized event-driven study in up to 250 patients with moderate-to-severe heart failure with reduced ejection fraction and New York Heart Association functional class II to IV symptoms despite optimal therapy. Enrolled patients will be at high risk for recurrent heart-failure hospitalizations by virtue of having elevated N-terminal pro–B-type natriuretic peptide/BNP (>1,200 pg/ml, or >1,600 pg/ml if atrial fibrillation is present) and/or recent heart failure hospitalization. The primary endpoint of time-to-recurrent event (heart failure–related hospitalizations in the presence of terminal events [all-cause death, heart transplant, left ventricular assist device implantation or ambulatory worsening heart failure]) will be assessed using the joint frailty model. This ongoing trial is expected to complete recruitment in 2014, with the required number of 186 recurrent events estimated to occur by mid 2015. Results Available data indicate that calcium up-regulation by AAV1/SERCA2a gene therapy is safe and of potential benefit in advanced heart failure patients. Conclusions The CUPID 2 trial is designed to study the effects of this therapy on clinical outcome in these patients. (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b [CUPID-2b]; NCT01643330)

Cardiac rehabilitation improves functional capacity and patient-reported health status in patients with continuous-flow left ventricular assist devices: the Rehab-VAD randomized controlled trial.

Abstract: Objectives This study examined the effects of a cardiac rehabilitation (CR) program on functional capacity and health status (HS) in patients with newly implanted left ventricular assist devices (LVADs). Background Reduced functional capacity and HS are independent predictors of mortality in patients with heart failure. CR improves both, and is related to improved outcomes in patients with heart failure; however, there is a paucity of data that describe the effects of CR in patients with LVADs. Methods Enrolled subjects (n = 26; 7 women; age 55 ± 13 years; ejection fraction 21 ± 8%) completed a symptom-limited cardiopulmonary exercise test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), a 6-min walk test (6MW), and single-leg isokinetic strength test before 2:1 randomization to CR versus usual care. Subjects in the CR group underwent 18 visits of aerobic exercise at 60% to 80% of heart rate reserve. Within-group changes from baseline to follow-up were analyzed with a paired t-test, whereas an independent t-test was used to determine differences in the change between groups. Results Within-group improvements were observed in the CR group for peak oxygen uptake (10%), treadmill time (3.1 min), KCCQ score (14.4 points), 6MW distance (52.3 m), and leg strength (17%). Significant differences among groups were observed for KCCQ, leg strength, and total treadmill time. Conclusions Indicators of functional capacity and HS are improved in patients with continuous-flow LVADs who attend CR. Future trials should examine the mechanisms responsible for these improvements, and if such improvements translate into improved clinical outcomes. (Cardiac Rehabilitation in Patients With Continuous Flow Left Ventricular Assist Devices:Rehab VAD Trial [RehabVAD]; NCT01584895 )

Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure

Abstract: Objectives The aim of this study was to determine whether biomarkers of myocardial stress and fibrosis improve prediction of the mode of death in patients with chronic heart failure. Background The 2 most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of the mode of death may facilitate treatment decisions. The relationship between amino-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown. Methods HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized controlled trial of exercise training versus usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause-specific Cox proportional hazards modeling, and interaction testing was used to measure differential associations between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP. Results After a median follow-up period of 2.5 years, there were 155 deaths: 49 from pump failure, 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk for both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death, but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure. Conclusions Clinical predictors along with NT-proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers.

Understanding the heterogeneity in volume overload and fluid distribution in decompensated heart failure is key to optimal volume management: role for blood volume quantitation.

Abstract: Objectives This study sought to quantitate total blood volume (TBV) in patients hospitalized for decompensated chronic heart failure (DCHF) and to determine the extent of volume overload, and the magnitude and distribution of blood volume and body water changes following diuretic therapy. Background The accurate assessment and management of volume overload in patients with DCHF remains problematic. Methods TBV was measured by a radiolabeled-albumin dilution technique with intravascular volume, pre-to-post–diuretic therapy, evaluated at hospital admission and at discharge. Change in body weight in relation to quantitated TBV was used to determine interstitial volume contribution to total fluid loss. Results Twenty-six patients were prospectively evaluated. Two patients had normal TBV at admission. Twenty-four patients were hypervolemic with TBV (7.4 ± 1.6 liters) increased by +39 ± 22% (range, +9.5% to +107%) above the expected normal volume. With diuresis, TBV decreased marginally (+30 ± 16%). Body weight declined by 6.9 ± 5.2 kg, and fluid intake/fluid output was a net negative 8.4 ± 5.2 liters. Interstitial compartment fluid loss was calculated at 6.2 ± 4.0 liters, accounting for 85 ± 15% of the total fluid reduction. Conclusions TBV analysis demonstrated a wide range in the extent of intravascular overload. Dismissal measurements revealed marginally reduced intravascular volume post-diuretic therapy despite large reductions in body weight. Mobilization of interstitial fluid to the intravascular compartment with diuresis accounted for this disparity. Intravascular volume, however, remained increased at dismissal. The extent, composition, and distribution of volume overload are highly variable in DCHF, and this variability needs to be taken into account in the approach to individualized therapy. TBV quantitation, particularly serial measurements, can facilitate informed volume management with respect to a goal of treating to euvolemia.

Sitagliptin Use in Patients With Diabetes and Heart Failure: A Population-Based Retrospective Cohort Study

Abstract: Objectives The study objective was to evaluate the effects of sitagliptin in patients with type 2 diabetes (T2D) and heart failure (HF). Background There is uncertainty in the literature about whether dipeptidyl peptidase (DPP)-4 inhibitors cause harm in patients with HF and T2D. Methods We analyzed data from a national commercially insured U.S. claims database. Patients with incident HF were identified from individuals with T2D initially treated with metformin or sulfonylurea and followed over time. Subjects subsequently using sitagliptin were compared with those not using sitagliptin in the 90 days before our primary outcome of all-cause hospital admission or death using a nested case-control analysis after adjustment for demographics and clinical and laboratory data. HF-specific hospital admission or death also was assessed. Results A total of 7,620 patients with diabetes and incident HF met our inclusion criteria. Mean (SD) age was 54 years (9), and 58% (3,180) were male. Overall, 887 patients (12%) were exposed to sitagliptin therapy (521 patient years of exposure) after incident HF. Our primary composite endpoint occurred in 4,137 patients (54%). After adjustment, sitagliptin users were not at an increased risk for the primary endpoint (7.1% vs. 9.2%, adjusted odds ratio [aOR]: 0.84, 95% confidence interval [CI]: 0.69 to 1.03) or each component (hospital admission 7.5% vs. 9.2%, aOR: 0.93, 95% CI: 0.76 to 1.14; death 6.9% vs. 9.3%, aOR: 1.16, 95% CI: 0.68 to 1.97). However, sitagliptin use was associated with an increased risk of HF hospitalizations (12.5% vs. 9.0%, aOR: 1.84, 95% CI: 1.16 to 2.92). Conclusions Sitagliptin use was not associated with an increased risk of all-cause hospitalizations or death, but was associated with an increased risk of HF-related hospitalizations among patients with T2D with pre-existing HF.

Effect of Rosuvastatin on Repeat Heart Failure Hospitalizations: The CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure)

Abstract: Objectives This study sought to examine the effect of statin therapy hospitalizations for heart failure (HFH) in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial. Background HFH is an important, frequently recurrent event. Conventional time-to-first event analyses do not take account repeat events. We used a number of statistical approaches to examine the effect of treatment on first and repeat HFH in the CORONA trial. Methods In the CORONA trial, 5,011 patients ≥60 years of age with chronic New York Heart Association functional classes II to IV systolic heart failure resulting from ischemia were randomized to receive rosuvastatin or placebo. Poisson, Andersen-Gill, and negative binomial methods (NB) were used to analyze the effect of rosuvastatin on HFH, and the NB and a parametric joint frailty model (JF) were used to examine this effect while accounting for the competing risk of cardiovascular (CV) death. Rosuvastatin/placebo rate ratios were calculated, both unadjusted and adjusted. Results A total of 1,291 patients had 1 or more HFH (750 of these had a single HFH only), and there were a total of 2,408 HFHs. The hazard ratio for the conventional time-to-first event analysis for HFH was 0.91 (95% confidence interval [CI]: 0.82 to 1.02, p = 0.105). In contrast, the NB on repeat hospitalizations gave an unadjusted RR (RR) for HFH of 0.86 (95% CI: 0.75 to 0.99, p = 0.030), adjusted 0.82 (95% CI: 0.72 to 0.92, p = 0.001), and after including CV death as the last event, adjusted RR of 0.85 (95% CI: 0.77 to 0.94, p = 0.001). The JF gave an adjusted RR of 0.82 (95% CI: 0.73 to 0.92, p = 0.001). Similar results were found in analyses of all CV hospitalizations and all-cause hospitalizations. Conclusions When repeat events were included, rosuvastatin was shown to reduce the risk of HFH by approximately 15% to 20%, equating to approximately 76 fewer admissions per 1,000 patients treated over a median 33 months of follow-up. Including repeat events could increase the ability to detect treatment effects in heart failure trials.

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

Abstract: Objectives The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of Background Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. Methods GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of Conclusions The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840 )

Characterization of a Novel Symptom of Advanced Heart Failure: Bendopnea

Abstract: Objectives This study sought to examine the frequency and hemodynamic correlates of shortness of breath when bending forward, a symptom we have termed “bendopnea.” Background Many heart failure patients describe bendopnea such as when putting on their shoes. This symptom has not previously been characterized. Methods We conducted a prospective study of 102 subjects with systolic heart failure referred for right-heart catheterization. Time to onset of bendopnea was measured prior to catheterization. Forty-six subjects also underwent hemodynamic assessment when sitting and bending. Hemodynamic profiles were assigned on the basis of whether pulmonary capillary wedge pressure (PCWP) was ≥22 mm Hg and cardiac index (CI) was ≤2.2 l/min/m 2 . Results Bendopnea was present in 29 of 102 (28%) subjects with median (25th, 75th percentiles) time to onset of 8 (7, 11) seconds. Subjects with bendopnea had higher supine right atrial pressure (RAP) (p = 0.001) and PCWP (p = 0.0004) than those without bendopnea but similar CI (p = 0.2). RAP and PCWP increased comparably in subjects with and without bendopnea when bending, but CI did not change. In those with, versus without, bendopnea, there was more than a 3-fold higher frequency of a supine hemodynamic profile consisting of elevated PCWP with low CI (55% vs. 16%, respectively, p l 0.001) but no association with a profile of elevated PCWP with normal CI (p = 0.95). Conclusions Bendopnea is mediated via a further increase in filling pressures during bending when filling pressures are already high, particularly if CI is reduced. Awareness of bendopnea should improve noninvasive assessment of hemodynamics in subjects with heart failure.

Is Heart Rate Important for Patients With Heart Failure in Atrial Fibrillation

Abstract: Objectives This study sought to investigate the relationship between resting ventricular rate and mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm (SR) or atrial fibrillation (AF). Background Slower heart rates are associated with better survival in patients with CHF in SR, but it is not clear whether this is true for those in AF. Methods We assessed 2,039 outpatients with CHF and LVEF ≤50% undergoing baseline assessment, of whom 24% (n = 488) were in AF; and 841 outpatients reassessed after attempted treatment optimization at 1 year, of whom 22% (n = 184) were in AF. Cox proportional hazards models were used to assess the relationships between heart rate and survival in patients with CHF and AF or sinus rhythm. We analyzed heart rate and rhythm data recorded at the baseline review and after 1-year follow-up. Proportional hazards assumptions were checked by Schoenfeld and Martingale residuals. Results The median survival for those in AF was 6.1 years (interquartile range [IQR]: 5.3 to 6.9 years) and 7.3 years (IQR: 6.5 to 8.1 years) for those in SR. In univariable analysis, patients with AF had a worse survival (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.08 to 1.47; p = 0.003) but after covariate adjustment, survival rates were similar. After adjusting Cox regression models, there was no association between heart rate (per 10 beats/min increments) and survival in patients with AF before (HR: 0.94, 95% CI: 0.88 to 1.00, p = 0.07) or after (HR: 1.00, 95% CI: 0.99 to 1.00, p = 0.84) therapy optimization. For patients in SR, higher heart rates were associated with worse survival, both before (HR: 1.10, 95% CI: 1.05 to 1.15, p Conclusions In patients with CHF and a reduced LVEF, slower resting ventricular rate is associated with better survival for patients in SR but not for those with AF.

Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in Myocardial Repair

Abstract: Objectives This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. Background Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. Methods In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. Results Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. Conclusions CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms.

Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.

Abstract: Objectives: The purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicine in improving functional status of patients with stable chronic hear...

Changes of Natriuretic Peptides Predict Hospital Admissions in Patients With Chronic Heart Failure: A Meta-Analysis

Abstract: Objectives The goal of this study was to explore the association between changes in B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) plasma levels and risk of hospital admission for heart failure (HF) worsening in patients with chronic HF. Background The relationship between BNP and NT-proBNP plasma levels and risk of cardiovascular events in patients with chronic HF has been previously demonstrated. However, it is unclear whether changes in BNP and NT-proBNP levels predict morbidity in patients with chronic HF. Methods The MEDLINE, Cochrane, ISI Web of Science, and SCOPUS databases were searched for papers about HF treatment up to August 2013. Randomized trials enrolling patients with systolic HF, assessing BNP and/or NT-proBNP at baseline and at end of follow-up, and reporting hospital stay for HF were included in the analysis. Meta-regression analysis was performed to test the relationship between BNP and NT-proBNP changes and the clinical endpoint. Sensitivity analysis was performed to assess the influence of baseline variables on results. Egger's linear regression was used to assess publication bias. Results Nineteen trials enrolling 12,891 participants were included. The median follow-up was 9.5 months (interquartile range: 6 to 18 months), and 22% of patients were women. Active treatments significantly reduced the risk of hospital stay for HF worsening. In meta-regression analysis, changes in BNP and NT-proBNP were significantly associated with risk of hospital stay for HF worsening. Results were confirmed by using sensitivity analysis. No publication bias was detected. Conclusions In patients with HF, reduction of BNP or NT-proBNP levels was associated with reduced risk of hospital stay for HF worsening.

Charting a roadmap for heart failure biomarker studies.

Abstract: Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers.

Long-term outcomes after medical and invasive treatment in patients with hypertrophic cardiomyopathy.

Abstract: Objectives The aim of this study was to determine the long-term outcomes (all-cause mortality and sudden cardiac death [SCD]) after medical therapy, alcohol septal ablation (ASA), and myectomy in patients with hypertrophic cardiomyopathy (HCM). Background Therapy-resistant obstructive HCM can be treated both surgically and percutaneously. But there is no consensus on the long-term effects of ASA, especially on SCD. Methods This study included 1,047 consecutive patients with HCM (mean age 52 ± 16 years, 61% men) from 3 tertiary referral centers. A total of 690 patients (66%) had left ventricular outflow tract gradients ≥ 30 mm Hg, of whom 124 (12%) were treated medically, 316 (30%) underwent ASA, and 250 (24%) underwent myectomy. Primary endpoints were all-cause mortality and SCD. Kaplan-Meier graphs and Cox regression models were used for statistical analyses. Results The mean follow-up period was 7.6 ± 5.3 years. Ten-year survival was similar in medically treated patients (84%), ASA patients (82%), myectomy patients (85%), and patients with nonobstructive HCM (85%) (log-rank p = 0.50). The annual rate of SCD was low after invasive therapy: 1.0%/year in the ASA group and 0.8%/year in the myectomy group. Multivariate analysis demonstrated that the risk for SCD was lower after myectomy compared with the ASA group (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p = 0.04) and the medical group (hazard ratio: 2.3; 95% confidence interval: 1.0 to 5.2; p = 0.04). Conclusions Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk of patients after myectomy was lower than after ASA or in the medical group.

Association of obesity in early adulthood and middle age with incipient left ventricular dysfunction and structural remodeling: the CARDIA study (Coronary Artery Risk Development in Young Adults).

Abstract: Objectives The goal of this study was to investigate the relationship of body mass index (BMI) and its 25-year change to left ventricular (LV) structure and function Background Longstanding obesity may be associated with clinical cardiac dysfunction and heart failure Whether obesity relates to cardiac dysfunction during young adulthood and middle age has not been investigated Methods The CARDIA (Coronary Artery Risk Development in Young Adult) study enrolled white and black adults ages 18 to 30 years in 1985 to 1986 (Year-0) At Year-25, cardiac function was assessed by conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography (STE) Twenty-five–year change in BMI (classified as low: Results The mean BMI was 244 kg/m2 in 3,265 participants included at Year-0 Change in BMI adjusted for risk factors was directly associated with incipient myocardial systolic dysfunction assessed by STE (High-High: β-coefficient = 067; Low-High: β-coefficient = 035 for longitudinal peak systolic strain) and diastolic dysfunction assessed by TDI (High-High: β-coefficient = −074; Low-High: β-coefficient = −045 for e′) and STE (High-High: β-coefficient = −006 for circumferential early diastolic strain rate) Greater BMI was also significantly associated with increased LV mass/height (High-High: β-coefficient = 2611; Low-High: β-coefficient = 1187) Conclusions Longstanding obesity from young adulthood to middle age is associated with impaired LV systolic and diastolic function assessed by conventional echocardiography, TDI, and STE in a large biracial cohort of adults age 43 to 55 years

Association of cardiorespiratory fitness with left ventricular remodeling and diastolic function: the Cooper Center Longitudinal Study.

Abstract: Objectives This study sought to compare the cross-sectional associations between fitness and echocardiographic measures of cardiac structure and function. Background Cardiorespiratory fitness is inversely associated with heart failure risk. However, the mechanism through which fitness lowers heart failure risk is not fully understood. Methods We included 1,678 men and 1,247 women from the Cooper Center Longitudinal Study who received an echocardiogram from 1999 to 2011. Fitness was estimated by Balke protocol (in metabolic equivalents) and also categorized into age-specific quartiles, with quartile 1 representing low fitness. Cross-sectional associations between fitness (in metabolic equivalents) and relative wall thickness, left ventricular end-diastolic diameter indexed to body surface area, left atrial volume indexed to body surface area, left ventricular systolic function, and E/e′ ratio were determined using multivariable linear regression analysis. Results Higher levels of mid-life fitness (metabolic equivalents) were associated with larger indexed left atrial volume (men: beta = 0.769, p Conclusions Low fitness is associated with a higher prevalence of concentric remodeling and diastolic dysfunction, suggesting that exercise may lower heart failure risk through its effect on favorable cardiac remodeling and improved diastolic function.

Impact of Cardiovascular Events on Change in Quality of Life and Utilities in Patients After Myocardial Infarction: A VALIANT Study (Valsartan In Acute Myocardial Infarction)

Abstract: Objectives The objective of this study was to determine the impact of nonfatal cardiovascular (CV) events on changes in health-related quality of life (HRQL) Background There is limited understanding of the impact of nonfatal CV events on long-term changes in HRQL in survivors of myocardial infarction (MI) Methods The VALIANT (Valsartan In Acute Myocardial Infarction) trial enrolled 14,703 patients post-MI complicated by Killip class II or higher (scale measuring heart failure severity post-MI ranging from class I to IV) and/or reduced ejection fraction The HRQL substudy included 2,556 (174%) patients who completed the EQ-5D with 5 questions, with responses mapped to utility weight on a scale of 0 to 1 and a visual analog scale (VAS) ranging from 0 (worst) to 100 (best) imaginable health state EQ-5D was administered at baseline and 6, 12, 20, and 24 months The trajectory of EQ-5D scores was developed by using linear mixed effects regression models with calculation of deviation from this trajectory after nonfatal CV events Patients who died before the next EQ-5D assessment were excluded Results Over a 2-year period, 597 patients experienced a nonfatal CV event and survived to have another EQ-5D assessment Their baseline EQ-5D scores were lower than patients without a subsequent nonfatal CV event (VAS 610 ± 19 vs 682 ± 18 [p Conclusions MI survivors suffering a CV event experienced significantly worse HRQL than their previous trajectory, suggesting that generic instruments can be responsive to nonfatal events Reduction in nonfatal CV events may affect longitudinal changes in HRQL

Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.

Abstract: Objectives The aim of this study was to describe the method used to perform electrogram-guided EMB and correlate electrogram characteristics with pathological and clinical outcomes. Background Endomyocardial biopsy (EMB) is valuable in determining the underlying etiology of a cardiomyopathy. The sensitivity, however, for focal disorders, such as lymphocytic myocarditis and cardiac sarcoidosis (CS), is low. The sensitivity of routine fluoroscopically guided EMB is low. Abnormal intracardiac electrograms are seen at sites of myocardial disease. However, the exact value of electrogram-guided EMB is unknown. Methods We report 11 patients who underwent electrogram-guided EMB for evaluation of myocarditis and CS. Results Of 40 total biopsy specimens taken from 11 patients, 19 had electrogram voltage 5 mV signified normal myocardium with no significant diagnostic yield. Biopsy results guided therapy in all patients, including 5 with active myocarditis or CS, all of whom subsequently received immunosuppressive therapy. There were no procedural complications. Conclusions In patients with suspected myocarditis or CS, electrogram-guided EMB targeting sites with abnormal or low-amplitude electrograms may increase the diagnostic yield for detecting abnormal pathological findings.

Obesity, subclinical myocardial injury, and incident heart failure.

Abstract: Objectives: The study sought to evaluate the association of obesity with a novel biomarker of subclinical myocardial injury, cardiac troponin T measured with a new high-sensitivity assay (h...