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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.

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 4.03pg/ml (HR = 1.7 (1.1,2.9)) and hemoglobin (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

We proposed and tested a novel electrocardiogram marker of risk of ventricular arrhythmias (VAs).Digital orthogonal electrocardiograms were recorded at rest before implantable cardioverter-defibrillator (ICD) implantation in 508 participants of a primary prevention ICDs prospective cohort study (mean ± SD age, 60 ± 12 years; 377 male [74%]). The sum magnitude of the absolute QRST integral in 3 orthogonal leads (SAI QRST) was calculated. A derivation cohort of 128 patients was used to define a cutoff; a validation cohort (n = 380) was used to test a predictive value.During a mean follow-up of 18 months, 58 patients received appropriate ICD therapies. The SAI QRST was lower in patients with VA (105.2 ± 60.1 vs 138.4 ± 85.7 mV ms, P = .002). In the Cox proportional hazards analysis, patients with SAI QRST not exceeding 145 mV ms had about 4-fold higher risk of VA (hazard ratio, 3.6; 95% confidence interval, 1.96-6.71; P.0001) and a 6-fold higher risk of monomorphic ventricular tachycardia (hazard ratio, 6.58; 95% confidence interval, 1.46-29.69; P = .014), whereas prediction of polymorphic ventricular tachycardia or ventricular fibrillation did not reach statistical significance.High SAI QRST is associated with low risk of sustained VA in patients with structural heart disease.

Current noninvasive surrogates of cardiac involvement in myotonic muscular dystrophy have low positive predictive value for sudden death. We hypothesized that the cardiac MR signal-to-noise ratio variance (SNRV) is a surrogate of the spatial heterogeneity of myocardial fibrosis and correlates with electrocardiography changes in myotonic muscular dystrophy. The SNRV for contrast enhanced cardiac MR images was calculated over the entire left ventricle in 43 patients with myotonic muscular dystrophy. All patients underwent standard electrocardiography, and a subset of 23 patients underwent signal averaged electrocardiography. After correcting for body mass index, age, and ejection fraction, SNRV was predictive of QRS duration on standard electrocardiography (1.35-msec increased QRS duration/unit increase in SNRV, P < 0.001). SNRV was also predictive of the low-amplitude late-potential duration (1.49-msec increased low-amplitude late-potential duration/unit increase in SNRV, P < 0.001). Ten-fold cross-validation yielded an area under the receiver operating characteristic curve of 0.87 for the predictive value of SNRV for QRS duration greater than 120 msec. The SNRV of the left ventricle is associated with QRS prolongation, likely due to late depolarization of tissue within islands of patchy fibrosis. The association of SNRV with future clinical events warrants further study.

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.

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 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 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.

Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with

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.

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.

Implantable cardioverter-defibrillators (ICDs) reduce arrhythmic sudden death in patients with systolic heart failure [(1)][1]. Interestingly, ICD therapies [(2,3)][2] are associated with an increased risk of death. The reasons for this increased mortality risk remain poorly understood. We studied

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: NCT 00733590.

T helper responses are critical for a productive immune response but an inappropriate response results in inflammatory and autoimmune disorders. The tyrosine kinase ITK has been shown to regulate the development of Th2 responses. Here, we show that ITK regulates Th1/Th17 responses as well. We find that Itk-/- mice are more susceptible to infection by Th1 inducing intracellular pathogen T. gondii, with generation of fewer antigen specific Th1 cells in vivo and fewer effector cells ex vivo upon antigen re-challenge. Transfer of WT CD4+ T cells confers protection against infection in Itk-/- mice. Furthermore, WT but not Itk-/- CD4+ T cells can promote the survival of Rag-/- mice infected by T. gondii. Additionally, the absence of ITK is protective during Th1/Th17 mediated Experimental Autoimmune Encephalomyelitis (EAE) with fewer pathogenic Th1 and Th17 effector cells in the periphery. Furthermore, transfer of Itk-/- CD4+ T cells into Tcra-/- mice results in lower severity of EAE compared to mice that receive WT cells suggesting that Itk-/- CD4+ T cells are intrinsically less pathogenic. Finally, using mice that express an analog sensitive mutant of ITK (ITKas) we show that temporally inhibiting the kinase activity of ITK with a genetically selective small-molecule inhibitor impairs development of Th1, Th2, and Th17 lineages. This work has implications for understanding ITK as a therapeutic target for Th2 mediated inflammatory and Th1/Th17 mediated autoimmune disorders.

For the obligate intracellular parasite, Toxoplasma gondii, elucidating its initial interactions with host cells and their parasitophorous vacuole membrane (PVM) is important for better understanding T. gondii infection. In many cell types, recycling endosomal (RE) trafficking often contributes to plasma membrane remodeling during processes such as phagocytosis. Previously, we characterized RE trafficking in RBL-2H3 mast cells and demonstrated IgE/antigen-stimulated outward trafficking of FITC-cholera toxin B (CTxB) bound to GM1 on RE membranes. When these cells are infected with virulent Type I strain tachyzoites, we find that invading parasites have an accumulation of FITC-CTxB on the PVM at early times after infection. This response is substantially enhanced when FITC-CTxB labels the RE pool in addition to the plasma membrane, providing evidence that RE membranes contribute to the nascent PVM. Consistent with earlier studies, IgE bound to its receptor at the plasma membrane shows no detectable accumulation at the PVM during this early stage (first hour) of infection. Under these conditions, antigen-stimulated degranulation is substantially inhibited, suggesting that parasitic infection interferes with normal signaling responses in these cells. Our ongoing research aims to further investigate the possible link between the PVM and RE trafficking and the potential immunomodulatory effects of T. gondii on infected mast cell signaling.