Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Immune checkpoint inhibitor-related myocarditis: current understanding and potential diagnostic and therapeutic strategies.

INTRODUCTION: Myocarditis associated with immune checkpoint inhibitors presents with an often-severe clinical phenotype with arrhythmias and concurrent myositis. This condition tends to occur early after treatment onset and is associated with a high fatality rate. Diagnosis may be challenging, and treatment algorithms are still evolving. AREAS COVERED: This review will provide an overview of immune checkpoint inhibitor mechanism of action and how it relates to myocarditis pathophysiology, diagnostic algorithms and potential pitfalls, and emerging treatment approaches published until May 2023. We will focus on the state of the field and potential new directions in research and patient care. We will also provide consensus-based diagnostic and therapeutic algorithms endorsed by major societies. EXPERT OPINION: The field needs more evidence-based approaches to risk stratification so that therapy can be tailored toward less cardiotoxic alternatives in high-risk patients. For diagnostic and therapeutic approaches, data from animal models are unlikely to provide conclusive evidence given the complexity of the human immune system. We strongly invite practitioners in the field to contribute every case to the ongoing multicenter registries.

Assessing the Accuracy and Reliability of AI-Generated Medical Responses: An Evaluation of the Chat-GPT Model.

Background: Natural language processing models such as ChatGPT can generate text-based content and are poised to become a major information source in medicine and beyond. The accuracy and completeness of ChatGPT for medical queries is not known. Methods: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes/no) or descriptive answers. The physicians then graded ChatGPT-generated answers to these questions for accuracy (6-point Likert scale; range 1 - completely incorrect to 6 - completely correct) and completeness (3-point Likert scale; range 1 - incomplete to 3 - complete plus additional context). Scores were summarized with descriptive statistics and compared using Mann-Whitney U or Kruskal-Wallis testing. Results: Across all questions (n=284), median accuracy score was 5.5 (between almost completely and completely correct) with mean score of 4.8 (between mostly and almost completely correct). Median completeness score was 3 (complete and comprehensive) with mean score of 2.5. For questions rated easy, medium, and hard, median accuracy scores were 6, 5.5, and 5 (mean 5.0, 4.7, and 4.6; p=0.05). Accuracy scores for binary and descriptive questions were similar (median 6 vs. 5; mean 4.9 vs. 4.7; p=0.07). Of 36 questions with scores of 1-2, 34 were re-queried/re-graded 8-17 days later with substantial improvement (median 2 vs. 4; p<0.01). Conclusions: ChatGPT generated largely accurate information to diverse medical queries as judged by academic physician specialists although with important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Immune checkpoint inhibitors and their impact on liver enzymes and attenuation.

BACKGROUND: Immune related adverse events impacting the liver are common from immune checkpoint inhibitor (ICI) therapy; however, there is little data regarding the subclinical impact of ICIs on liver inflammation. The study aims to determine whether ICI therapy affects liver attenuation and liver enzymes in melanoma patients with and without hepatic steatosis. METHODS: A retrospective, cohort study was conducted of patients with advanced melanoma treated with ICI therapy who received serial PET-CT scans at the Vanderbilt University Medical Center (VUMC). Primary outcomes included: liver attenuation measured by PET-CT/non-contrast CT and liver enzymes. Hepatic steatosis was diagnosed by radiologists on clinical imaging. RESULTS: Among 839 patients with advanced melanoma treated with ICIs, 81 had serial PET-CT scans approximately 12 months apart and long-term survival; of these 11 patients had pre-existing steatosis/steatohepatitis. Overall, ICI was not associated with significant increases in liver enzymes in all patients; modest decreases in liver enzymes were observed in patients with pre-existing steatosis/steatohepatitis. Similarly, liver attenuation did not change from baseline to post-treatment (58.44 vs 60.60 HU, + 2.17, p = 0.055). CONCLUSIONS: ICIs may not chronically affect liver enzymes or liver attenuation, a non-invasive measure of liver fat content and inflammation, in the general population or in those with pre-existing steatosis/steatohepatitis.

High Sensitivity Troponin T and NT-proBNP in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy.

Retrospective studies suggest that chimeric antigen receptor T-cell (CAR T) therapy may lead to cardiac injury, but this has not been assessed systematically or prospectively. In this prospective study of 40 patients who received CAR T, we systematically measured high-sensitivity troponin T (hsTropT) and N-terminal pro-B natriuretic peptide (NTproBNP) at baseline and on day 1, days 7, and 21 after CAR T. Biomarker elevations with respect to timepoint and cytokine release syndrome (CRS) status were examined using repeated measure analysis of variance. hsTropT did not differ with time or with the presence of grade 2 CRS. Median hsTropT was 12.1 ng/L [interquartile range (IQR): 9.2, 20.1] at baseline, 13.1 ng/L (IQR: 9.6, 24.2) at day 1, 11.9 ng/L (IQR: 9.6, 18.0) at day 7, and 15.3 ng/L (10.8, 20.2) at day 21. In contrast, NTproBNP rose on day 1 (P Wilcox = 0.0002) and day 7 (P Wilcox = 2.7 × 10-5), and the degree of elevation differed by the presence of grade 2 CRS (P interaction = 0.002). Median NTproBNP was 179 pg/mL (IQR: 116, 325) at baseline, 357 pg/mL (IQR: 98, 813) at day 1, 420 pg/mL (IQR: 239, 1242) at day 7, and 177 pg/mL (IQR: 80, 278) at day 21. In conclusion, hsTropT l did not differ across timepoints after CAR T therapy, but NTproBNP rose at day 7, the prognostic implications of which should be the target of future research, as the indications for this therapy expand.

Abnormal Cardiac Repolarization After Seizure Episodes in Structural Brain Diseases: Cardiac Manifestation of Electrical Remodeling in the Brain?

Background Abnormal cardiac repolarization is observed in patients with epilepsy and can be associated with sudden death. We investigated whether structural brain abnormalities are correlated with abnormal cardiac repolarizations in patients with seizure or epilepsy. Methods and Results We retrospectively analyzed and compared 12-lead ECG parameters following seizures between patients with and without structural brain abnormalities. A total of 96 patients were included: 33 women (17 with and 16 without brain abnormality) and 63 men (44 with and 19 without brain abnormality). Brain abnormalities included past stroke, chronic hematoma, remote bleeding, tumor, trauma, and postsurgical state. ECG parameters were comparable for heart rate, PR interval, and QRS duration between groups. In contrast, corrected QT intervals evaluated by Fridericia, Framingham, and Bazett formulas were prolonged in patients with brain abnormality compared with those without (women: Fridericia [normal versus abnormal], 397.4±32.7 versus 470.9±48.9; P=0.002; Framingham, 351.0±40.1 versus 406.2±46.1; P=0.002; Bazett, 423.8±38.3 versus 507.7±56.6; P<0.0001; men: Fridericia, 403.8±30.4 versus 471.0±47.1; P<0.0001; Framingham, 342.7±36.4 versus 409.4±45.8; P<0.0001; Bazett, 439.3±38.6 versus 506.2±56.8; P<0.0001). QT dispersion and Tpeak-Tend intervals were comparable between groups. We also observed abnormal ST-segment elevation in 5 patients. Importantly, no patients showed fatal arrhythmias during or after seizures. Conclusions Our study demonstrated that brain abnormalities can be associated with abnormal cardiac repolarization after seizures, which might be a manifestation of electrophysiological remodeling in the brain.

Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells.

BACKGROUND: Telethonin (TCAP) is a Z-disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. TCAP is shown to modulate α-subunit of the human cardiac sodium channel (hNav 1.5) by direct interactions. Several TCAP variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes. METHODS: Mutational analyses for TCAP were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J-wave pattern ECG. Using patch-clamp techniques, electrophysiological characteristics of hNav 1.5 were studied in HEK-293 cells stably expressing hNav 1.5 and transiently transfected with wild-type (WT) or variant TCAP. RESULTS: We identified two TCAP variants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J-wave pattern ECG. No patient had variant hNav 1.5. Patch-clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT-TCAP (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward-shifted by 5 mV in cells expressing p.E49K compared with WT-TCAP. Voltage dependency of activation was not leftward-shifted by p.R153H, while voltage dependency of steady-state inactivation was leftward-shifted by p.E49K. CONCLUSIONS: We found two TCAP variants in the patients with BrS, J-wave pattern ECG, and ARVC that can cause loss-of-function of the hNav 1.5 in heterologous expression systems. Our observation suggests that these variants might impair INa and be associated with the patients' electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.

Drug-induced fatal arrhythmias: Acquired long QT and Brugada syndromes.

Since the early 1990s, the concept of primary "inherited" arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes.

A Novel SCN5A Mutation Associated with Drug Induced Brugada Type ECG.

BACKGROUND: Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias. OBJECTIVE: To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome. METHODS: Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study. Genetic screening using direct sequencing identified a novel SCN5A variant, p.V1328M. Electrophysiological parameters of WT and p.V1328M and their effects on drug pharmacokinetics were studied using the patch-clamp method. RESULTS: Whole-cell sodium current densities were similar for WT and p.V1328M channels. While p.V1328M mutation did not affect the voltage-dependence of the activation kinetics, it caused a positive shift of voltage-dependent steady-state inactivation by 7 mV. The tonic block in the presence of pilsicainide was similar in WT and p.V1328M, when sodium currents were induced by a low frequency pulse protocol (q15s). On the contrary, p.V1328M mutation enhanced pilsicainide induced use-dependent block at 2 Hz. (Ki: WT, 35.8 µM; V1328M, 19.3 µM). CONCLUSION: Our study suggests that a subclinical SCN5A mutation, p.V1328M, might predispose individuals harboring it to drug-induced Brugada Syndrome.

Amiodarone inhibits apamin-sensitive potassium currents.

BACKGROUND: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. OBJECTIVE: To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells. METHODS: We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. RESULTS: Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 ± 0.25 µM with 1 µM intrapipette Ca(2+)). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6 ± 3.1% of IKAS induced with 1 µM intrapipette Ca(2+) (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+)-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+) (n = 4), and 16.4±4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+) dependent inhibition of I KAS. CONCLUSION: Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.

Heterogeneous upregulation of apamin-sensitive potassium currents in failing human ventricles.

BACKGROUND: We previously reported that IKAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca(2+) activated K(+) (SK2) channel and apamin-sensitive K(+) currents (IKAS) are upregulated in failing human ventricles. METHODS AND RESULTS: We studied 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non-HF group). IKAS and action potential were recorded with patch-clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 µmol/L Ca(2+) concentration, IKAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non-HF group (n=8, P=0.008). IKAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca(2+) dependency of IKAS in HF myocytes was shifted leftward compared to non-HF myocytes (Kd 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (-0.9% and 7.3%) in non-HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3-fold higher in HF than in non-HF. CONCLUSIONS: There is heterogeneous upregulation of IKAS densities in failing human ventricles. The midmyocardial layer shows lower IKAS densities than epicardial and endocardial layers of cells. Increase in both Ca(2+) sensitivity and SK2 protein expression contributes to the IKAS upregulation.

Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.

BACKGROUND: Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. METHODS AND RESULTS: Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. CONCLUSIONS: ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5.

Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.

RATIONALE: Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). OBJECTIVE: We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles. METHODS AND RESULTS: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 µmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002). CONCLUSIONS: Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.