Growth Differentiation Factor-15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy.

Background Heart failure (HF) has been increasing in prevalence, and a need exists for biomarkers with improved predictive and prognostic ability. GDF-15 (growth differentiation factor-15) is a novel biomarker associated with HF mortality, but no serial studies of GDF-15 have been conducted. This study aimed to investigate the association between GDF-15 levels over time and the occurrence of ventricular arrhythmias, HF hospitalizations, and all-cause mortality. Methods and Results We used a retrospective case-control design to analyze 148 patients with ischemic and nonischemic cardiomyopathies and primary prevention implantable cardioverter-defibrillator (ICD) from the PROSe-ICD (Prospective Observational Study of the ICD in Sudden Cardiac Death Prevention) cohort. Patients had blood drawn every 6 months and after each appropriate ICD therapy and were followed for a median follow-up of 4.6 years, between 2005 to 2019. We compared serum GDF-15 levels within ±90 days of an event among those with a ventricular tachycardia/fibrillation event requiring ICD therapies and those hospitalized for decompensated HF. A comparator/control group comprised patients with GDF-15 levels available during 2-year follow-up periods without events. Median follow-up was 4.6 years in the 148 patients studied (mean age 58±12, 27% women). The HF cohort had greater median GDF-15 values within 90 days (1797 pg/mL) and 30 days (2039 pg/mL) compared with the control group (1062 pg/mL, both P<0.0001). No difference was found between the ventricular tachycardia/fibrillation subgroup within 90 days (1173 pg/mL, P=0.60) or 30 days (1173 pg/mL, P=0.78) and the control group. GDF-15 was also significantly predictive of mortality (hazard ratio, 3.17 [95% CI, 2.33-4.30]). Conclusions GDF-15 levels are associated with HF hospitalization and mortality but not ventricular arrhythmic events.

CinE caRdiac magneTic resonAnce to predIct veNTricular arrhYthmia (CERTAINTY).

Better models to identify individuals at low risk of ventricular arrhythmia (VA) are needed for implantable cardioverter-defibrillator (ICD) candidates to mitigate the risk of ICD-related complications. We designed the CERTAINTY study (CinE caRdiac magneTic resonAnce to predIct veNTricular arrhYthmia) with deep learning for VA risk prediction from cine cardiac magnetic resonance (CMR). Using a training cohort of primary prevention ICD recipients (n = 350, 97 women, median age 59 years, 178 ischemic cardiomyopathy) who underwent CMR immediately prior to ICD implantation, we developed two neural networks: Cine Fingerprint Extractor and Risk Predictor. The former extracts cardiac structure and function features from cine CMR in a form of cine fingerprint in a fully unsupervised fashion, and the latter takes in the cine fingerprint and outputs disease outcomes as a cine risk score. Patients with VA (n = 96) had a significantly higher cine risk score than those without VA. Multivariate analysis showed that the cine risk score was significantly associated with VA after adjusting for clinical characteristics, cardiac structure and function including CMR-derived scar extent. These findings indicate that non-contrast, cine CMR inherently contains features to improve VA risk prediction in primary prevention ICD candidates. We solicit participation from multiple centers for external validation.

Clinical decision tool for CRT-P vs. CRT-D implantation: Findings from PROSE-ICD.

BACKGROUND: Cardiac resynchronization therapy (CRT) devices reduce mortality through pacing-induced cardiac resynchronization and implantable cardioverter defibrillator (ICD) therapy for ventricular arrhythmias (VAs). Whether certain factors can predict if patients will benefit more from implantation of CRT pacemakers (CRT-P) or CRT defibrillators (CRT-D) remains unclear. METHODS AND RESULTS: We followed 305 primary prevention CRT-D recipients for the two primary outcomes of HF hospitalization and ICD therapy for VAs. Serum biomarkers, electrocardiographic and clinical variables were collected prior to implant. Multivariable analysis using Cox-proportional hazards model was used to fit the final models. Among 282 patients with follow-up outcome data, 75 (26.6%) were hospitalized for HF and 31 (11%) received appropriate ICD therapy. Independent predictors of HF hospitalization were atrial fibrillation (HR = 1.8 (1.1,2.9)), NYHA class III/IV (HR = 2.2 (1.3,3.6)), ejection fraction <20% (HR = 1.7 (1.1,2.7)), HS-IL6 >4.03pg/ml (HR = 1.7 (1.1,2.9)) and hemoglobin (<12g/dl) (HR = 2.2 (1.3,3.6)). Independent predictors of appropriate therapy included BUN >20mg/dL (HR = 3.0 (1.3,7.1)), HS-CRP >9.42mg/L (HR = 2.3 (1.1,4.7)), no beta blocker therapy (HR = 3.2 (1.4,7.1)) and hematocrit ≥38% (HR = 2.7 (1.03,7.0)). Patients with 0-1 risk factors for appropriate therapy (IR 1 per 100 person-years) and ≥3 risk factors for HF hospitalization (IR 23 per 100-person-years) were more likely to die prior to receiving an appropriate ICD therapy. CONCLUSIONS: Clinical and biomarker data can risk stratify CRT patients for HF progression and VAs. These findings may help characterize subgroups of patients that may benefit more from the use of CRT-P vs. CRT-D systems. TRIAL REGISTRATION: ClinicalTrials.gov NCT00733590.

Changes in Follow-Up Left Ventricular Ejection Fraction Associated With Outcomes in Primary Prevention Implantable Cardioverter-Defibrillator and Cardiac Resynchronization Therapy Device Recipients.

BACKGROUND: Heart failure patients with primary prevention implantable cardioverter-defibrillators (ICD) may experience an improvement in left ventricular ejection fraction (LVEF) over time. However, it is unclear how LVEF improvement affects subsequent risk for mortality and sudden cardiac death. OBJECTIVES: This study sought to assess changes in LVEF after ICD implantation and the implication of these changes on subsequent mortality and ICD shocks. METHODS: We conducted a prospective cohort study of 538 patients with repeated LVEF assessments after ICD implantation for primary prevention of sudden cardiac death. The primary endpoint was appropriate ICD shock defined as a shock for ventricular tachyarrhythmias. The secondary endpoint was all-cause mortality. RESULTS: Over a mean follow-up of 4.9 years, LVEF decreased in 13.0%, improved in 40.0%, and was unchanged in 47.0% of the patients. In the multivariate Cox models comparing patients with an improved LVEF with those with an unchanged LVEF, the hazard ratios were 0.33 (95% confidence interval: 0.18 to 0.59) for mortality and 0.29 (95% confidence interval: 0.11 to 0.78) for appropriate shock. During follow-up, 25% of patients showed an improvement in LVEF to >35% and their risk of appropriate shock decreased but was not eliminated. CONCLUSIONS: Among primary prevention ICD patients, 40.0% had an improved LVEF during follow-up and 25% had LVEF improved to >35%. Changes in LVEF were inversely associated with all-cause mortality and appropriate shocks for ventricular tachyarrhythmias. In patients whose follow-up LVEF improved to >35%, the risk of an appropriate shock remained but was markedly decreased.

Predictors of mortality, LVAD implant, or heart transplant in primary prevention cardiac resynchronization therapy recipients: The HF-CRT score.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality among individuals with dyssynchronous systolic heart failure (HF). However, patient outcomes vary, with some at higher risk than others for HF progression and death. OBJECTIVE: To develop a risk prediction score incorporating variables associated with mortality, left ventricular assist device (LVAD) implant, or heart transplant in recipients of a primary prevention cardiac resynchronization therapy-defibrillator (CRT-D). METHODS: We followed 305 CRT-D patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators for the composite outcome of all-cause mortality, LVAD implant, or heart transplant soon after device implantation. Serum biomarkers and electrocardiographic and clinical variables were collected at implant. Multivariable analysis using the Cox proportional hazards model with stepwise selection method was used to fit the final model. RESULTS: Among 305 patients, 53 experienced the composite endpoint. In multivariable analysis, 5 independent predictors ("HF-CRT") were identified: high-sensitivity C-reactive protein >9.42 ng/L (HR = 2.5 [1.4, 4.5]), New York Heart Association functional class III/IV (HR = 2.3 [1.2, 4.5]), creatinine >1.2 mg/dL (HR = 2.7 [1.4, 5.1]), red blood cell count <4.3 × 10(6)/µL (HR = 2.4 [1.3, 4.7]), and cardiac troponin T >28 ng/L (HR = 2.7 [1.4, 5.2]). One point was attributed to each predictor and 3 score categories were identified. Patients with scores 0-1, 2-3, and 4-5 had a 3-year cumulative event-free survival of 96.8%, 79.7%, and 35.2%, respectively (log-rank, P < .001). CONCLUSION: A simple score combining clinical and readily available biomarker data can risk-stratify CRT patients for HF progression and death. These findings may help identify patients who are in need of closer monitoring or early application of more aggressive circulatory support.

Clinical and serum-based markers are associated with death within 1 year of de novo implant in primary prevention ICD recipients.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with <1-year life expectancy. OBJECTIVES: The aim of this study was to develop a risk prediction score for 1-year mortality in patients with primary prevention ICDs and to determine the incremental improvement in discrimination when serum-based biomarkers are added to traditional clinical variables. METHODS: We analyzed data from the Prospective Observational Study of Implantable Cardioverter-Defibrillators, a large prospective observational study of patients undergoing primary prevention ICD implantation who were extensively phenotyped for clinical and serum-based biomarkers. We identified variables predicting 1-year mortality and synthesized them into a comprehensive risk scoring construct using backward selection. RESULTS: Of 1189 patients deemed by their treating physicians as having a reasonable 1-year life expectancy, 62 (5.2%) patients died within 1 year of ICD implantation. The risk score, composed of 6 clinical factors (age ≥75 years, New York Heart Association class III/IV, atrial fibrillation, estimated glomerular filtration rate <30 mL/min/1.73 m(2), diabetes, and use of diuretics), had good discrimination (area under the curve 0.77) for 1-year mortality. Addition of 3 biomarkers (tumor necrosis factor α receptor II, pro-brain natriuretic peptide, and cardiac troponin T) further improved model discrimination to 0.82. Patients with 0-1, 2-3, 4-6, or 7-9 risk factors had 1-year mortality rates of 0.8%, 2.7%, 16.1%, and 46.2%, respectively. CONCLUSION: Individuals with more comorbidities and elevation of specific serum biomarkers were at increased risk of all-cause mortality despite being deemed as having a reasonable 1-year life expectancy. A simple risk score composed of readily available clinical data and serum biomarkers may better identify patients at high risk of early mortality and improve patient selection and counseling for primary prevention ICD therapy.

Protein biomarkers identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillators: findings from the Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSE-ICD).

BACKGROUND: Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality, but the benefits are heterogeneous. Current risk stratification based on left ventricular ejection fraction has limited discrimination power. We hypothesize that biomarkers for inflammation, neurohumoral activation, and cardiac injury can predict appropriate shocks and all-cause mortality in patients with primary prevention ICDs. METHODS AND RESULTS: The Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSe-ICD) enrolled 1189 patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was an ICD shock for adjudicated ventricular tachyarrhythmia. The secondary end point was all-cause mortality. After a median follow-up of 4.0 years, 137 subjects experienced an appropriate ICD shock and 343 participants died (incidence rates of 3.2 and 5.8 per 100 person-years, respectively). In multivariable-adjusted models, higher interleukin-6 levels increased the risk of appropriate ICD shocks. In contrast, C-reactive protein, interleukin-6, tumor necrosis factor-α receptor II, pro-brain natriuretic peptide (pro-BNP), and cardiac troponin T showed significant linear trends for increased risk of all-cause mortality across quartiles. A score combining these 5 biomarkers identified patients who were much more likely to die than to receive an appropriate shock from the ICD. CONCLUSIONS: An increase in serum biomarkers of inflammation, neurohumoral activation, and myocardial injury increased the risk for death but poorly predicted the likelihood of an ICD shock. These findings highlight the potential importance of serum-based biomarkers in identifying patients who are unlikely to benefit from primary prevention ICDs. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov; Unique Identifier: NCT00733590.

Outcomes in African Americans undergoing cardioverter-defibrillator implantation for primary prevention of sudden cardiac death: findings from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD).

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) reduce the risk of death in patients with left ventricular dysfunction. Little is known regarding the benefit of this therapy in African Americans (AAs). OBJECTIVE: The purpose of this study was to determine the association between AA race and outcomes in a cohort of primary prevention ICD patients. METHODS: We conducted a prospective cohort study of patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end-point was appropriate ICD shock defined as a shock for rapid ventricular tachyarrhythmias. The secondary end-point was all-cause mortality. RESULTS: There were 1189 patients (447 AAs and 712 non-AAs) enrolled. Over a median follow-up of 5.1 years, a total of 137 patients experienced an appropriate ICD shock, and 343 died (294 of whom died without receiving an appropriate ICD shock). The multivariate adjusted hazard ratio (95% confidence interval) comparing AAs vs non-AAs were 1.24 (0.96-1.59) for all-cause mortality, 1.33 (1.02, 1.74) for all-cause mortality without receiving appropriate ICD shock, and 0.78 (0.51, 1.19) for appropriate ICD shock. Ejection fraction, diabetes, and hypertension appeared to explain 24.1% (10.1%-69.5%), 18.7% (5.3%-58.0%), and 13.6% (3.8%-53.6%) of the excess risk of mortality in AAs, with a large proportion of the mortality difference remaining unexplained. CONCLUSION: In patients with primary prevention ICDs, AAs had an increased risk of dying without receiving an appropriate ICD shock compared to non-AAs.

Prospective observational study of implantable cardioverter-defibrillators in primary prevention of sudden cardiac death: study design and cohort description.

BACKGROUND: Primary-prevention implantable cardioverter-defibrillators (ICDs) reduce total mortality in patients with severe left ventricular systolic function. However, only a minority of patients benefit from these devices. We designed the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) to identify risk factors and enhance our understanding of the biological mechanisms that predispose to arrhythmic death in patients undergoing ICD implantation for primary prevention of sudden death. METHODS AND RESULTS: This is a multicenter prospective cohort study with a target enrollment of 1200 patients. The primary end point is ICD shocks for adjudicated ventricular tachyarrhythmias. The secondary end point is total mortality. All patients undergo a comprehensive evaluation including history and physical examination, signal-averaged electrocardiograms, and blood sampling for genomic, proteomic, and metabolomic analyses. Patients are evaluated every 6 months and after every known ICD shock for additional electrocardiographic and blood sampling. As of December 2011, a total of 1177 patients have been enrolled with more nonwhite and female patients compared to previous randomized trials. A total of 143 patients have reached the primary end point, whereas a total of 260 patients died over an average follow-up of 59 months. The PROSE-ICD study represents a real-world cohort of individuals with systolic heart failure receiving primary-prevention ICDs. CONCLUSIONS: Extensive electrophysiological and structural phenotyping as well as the availability of serial DNA and serum samples will be important resources for evaluating novel metrics for risk stratification and identifying patients at risk for arrhythmic sudden death. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Unique Identifier: NCT00733590.

Experimental evaluation of the elastic determinants of myocardial function in vivo.

Shortening of myocardial fibers occurs following force development in those fibers. The extent, speed and timing of shortening are determined by kinetics and extent of force. However, shortening is also influenced by the elastance/viscosity of the muscle tissue, because that determines the coupling between force and shortening. In the in vivo dog heart, we estimated that coupling by measuring local myocardial force and fiber shortening independently under various conditions. We determined the effect of positive and negative inotropy (by intracoronary injection of dobutamine and acetylcholine, respectively), and of dysfunctional contraction produced by local ischemia/reperfusion and BDM. Under baseline and both positive and negative intropy, most shortening occurred during systole, and dobutamine increased the proportion of total shortening in early systole from 45.8 +/- 8.5% to 74.9 +/- 9.6%. During reperfusion following ischemia, shortening in early systole was markedly reduced to 16.5 +/- 2.9; BDM caused a similar reduction to 16.5 +/- 8.1. Most of the shortening occurred during early diastole (53.0 +/- 6.8 for reperfusion, and 54.0 +/- 10.3 for BDM). These effects were all reversible. It is concluded that energetic efficiency is greatly affected by the elastic properties coupling force and shortening. Thus appropriate analysis of muscle function must take into account the changeable elastic properties of the tissue-both force and shortening, and their interaction must be considered.