Biomedical subjects

Michael J Ackerman

Publications and source records attributed to Michael J Ackerman.

9 recordsLinked to original sources

PubMed2026

Prevalence and Prognostic Significance of Exercise-Accentuated J-Point Elevation in Brugada Syndrome.

BACKGROUND: The clinical significance of accentuation of precordial J-point elevation during exercise in Brugada syndrome (BrS) remains unclear. OBJECTIVES: This study sought to determine the prevalence and prognostic significance of accentuation of J-point elevation during exercise in a large single-center BrS cohort. METHODS: In this retrospective study, 141 consecutive patients referred for BrS evaluation (95 with type 1 BrS pattern-BrS1 cohort, 46 without type 1 pattern but with loss-of-function sodium voltage-gated channel alpha subunit 5 variants-SCN5A cohort) who underwent exercise stress testing (EST) from January 1, 2000, through October 31, 2025 were included. Two blinded cardiologists reviewed all tracings. An exercise-accentuated BrS phenotype was defined as J-point elevation increase ≥1 mm in V1/V2 during exercise. Cardiac events included arrhythmic syncope, cardiac arrest, and appropriate implantable cardioverter-defibrillator shocks. Firth penalized logistic regression was used for unadjusted and adjusted analyses. RESULTS: Overall, 41 patients (29%) demonstrated an exercise-accentuated BrS phenotype, emerging near peak exercise (median 90% age-predicted maximum heart rate). The phenotype was highly reproducible on serial testing (88% of follow-up ESTs). Exercise-accentuated phenotype was not associated with overall cardiac events (unadjusted OR: 1.83 [0.84-3.99]; P = 0.13; adjusted OR: 1.22 [0.47-3.21]; P = 0.69). However, it was strongly associated with exertion-triggered cardiac events (unadjusted OR: 10.50 [2.94-37.50]; P < 0.001; adjusted OR: 10.04 [2.76-36.53]; P < 0.001), independent of sex, exercise workload, and baseline type 1 pattern. Consistent results were noted in SCN5A variant-positive patients. CONCLUSIONS: Exercise-induced accentuation of J-point elevation reproducibly identifies a subset of BrS patients at risk for exertional cardiac events. These findings support the inclusion of EST in the evaluation of patients with a clinical diagnosis or genetic susceptibility to BrS and may inform exercise-related risk counseling.

Brugada syndrome↗

PubMed2026

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification.

BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Humans↗

PubMed2026

DENND3-p.R534S disrupts dyadic microdomain architecture to drive potentially pro-arrhythmic calcium and electrophysiologic instability.

AIMS: Inherited ventricular arrhythmias (VAs) frequently occur in the absence of pathogenic variants in canonical ion channel genes, suggesting alternative mechanisms of electrical instability. DENND3 is a guanine nucleotide exchange factor that regulates Rab GTPase-mediated trafficking, but its role in cardiac excitation-contraction coupling and membrane microdomain organization remains undefined. METHODS AND RESULTS: We studied induced pluripotent stem cell-derived cardiomyocytes generated from a CRISPR/CAS9-engineered ultra-rare DENND3-p.R534S variant-inserted line (previously identified in an idiopathic ventricular fibrillation pedigree) and matched isogenic controls. Multielectrode array recordings, live-cell calcium imaging, super-resolution imaging using expansion microscopy, and biochemical analyses were used to assess electrical activity, calcium handling, membrane architecture, and calcium release unit organization. Potentially therapeutic studies were performed using genetic and pharmacologic inhibition of Rab11b. DENND3-p.R534S induced pluripotent stem cell-derived cardiomyocytes exhibited multicellular electrical instability characterized by increased beat-to-beat variability, arrhythmic activity, conduction slowing, and prolonged excitation-contraction delay. These abnormalities were accompanied by heterogeneous and dyssynchronous calcium cycling despite preserved expression of major calcium-handling proteins. Super-resolution imaging revealed disruption of BIN1-dependent membrane architecture and nanoscale uncoupling of Cav1.2 and RyR2. Inhibition of Rab11b restored BIN1 organization, re-established dyadic coupling, normalized calcium cycling, and improved electrical stability. CONCLUSION: These findings support a model in which altered trafficking balance contributes to disruption of membrane microdomain organization, leading to dyadic uncoupling, calcium instability, and electrical dysfunction. Modulation of the Rab11b-mediated trafficking pathway restored structural and functional abnormalities, supporting the trafficking-associated pathway as a potential therapeutic target in DENND3-associated ventricular arrhythmia.

Myocytes, Cardiac↗

PubMed2026

Incidence of Atrial and Ventricular Arrhythmias in Patients With Titin Truncating Variants Across the Ventricular Morphofunctional Phenotypic Spectrum.

BACKGROUND: Titin truncating variants (TTNtvs), the most common genetic cause of dilated cardiomyopathy (DCM), are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD), suggesting they can cause arrhythmias before development of overt ventricular cardiomyopathy. OBJECTIVES: This study sought to compare the incidence of atrial and ventricular arrhythmias (VAs) between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, nondilated left ventricular cardiomyopathy (NDLVC), and DCM. METHODS: A retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with pathogenic/likely pathogenic TTNtvs. Patients were classified as having G+/P- disease, NDLVC, or DCM using the 2023 European Society of Cardiology guideline for cardiomyopathies. The incidence of AF, sustained VA, appropriate defibrillator therapies, SCA, and SCD was ascertained from medical records. RESULTS: Among 253 TTNtv-positive patients (mean age of 45 ± 16 years; 59% male), 54 (21%) were G+/P-, 49 (20%) were NDLVC, and 150 (59%) were DCM. During a median follow-up of 3.8 years at our institution, new-onset AF was seen in 67 patients (26% of those at risk). There was no significant difference in survival from new-onset AF in patients with NDLVC (HR: 3.29; 95% CI: 0.71-15.3; P = 0.13), although DCM was associated with worse AF-free survival (HR: 4.86; 95% CI: 1.17-20.1; P = 0.03). New-onset VAs were seen in 44 (17%) patients during follow-up, including SCA in 12 (5%) patients. There was no association between NDLVC (HR: 0.71; 95% CI: 0.19-2.69; P = 0.62) and DCM (HR: 0.97; 95% CI: 0.37-2.54; P = 0.95) phenotypes compared with G+/P- patients. Cardiac transplantation was done in 14 (6%) patients, and 6 (2%) died of cardiac causes, including 2 cases of SCD. CONCLUSIONS: When stratified by morphofunctional phenotype, there was no difference in VAs across morphofunctional phenotypes in patients with TTNtvs. This highlights that patients with TTNtvs may be at risk of SCA/SCD even without overt ventricular cardiomyopathy. The risk of new-onset AF was highest in patients with DCM but was seen at all phenotypic stages during follow-up.

arrhythmia↗

PubMed2026

Clinical characteristics and prognostic impact of multiple pathogenic variants across the genetic spectrum of arrhythmogenic and dilated cardiomyopathies.

BACKGROUND: Arrhythmogenic and dilated cardiomyopathies (ACM and DCM, respectively) are genetically heterogeneous disorders of the right and/or left ventricles associated with an increased risk of major arrhythmic events (MAE) and end-stage heart failure (ESHF). In arrhythmogenic right ventricular cardiomyopathy (ARVC), the presence of >1 pathogenic or likely pathogenic (P/LP) variant is associated with worse outcomes. Whether this phenomenon occurs for non-desmosomal arrhythmogenic left ventricular cardiomyopathy (ALVC)/DCM genes is unknown. OBJECTIVE: This study aimed to evaluate the impact of single vs multiple P/LP variants on arrhythmic and heart failure outcomes across the ACM/DCM genetic spectrum. METHODS: We retrospectively analyzed 1054 genotype-positive patients with ≥1 P/LP variant in a definitive or strong evidence ARVC- or ALVC/DCM-causative gene. Primary endpoints were MAE (sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy, and sudden cardiac death) and ESHF (transplant or heart failure death). RESULTS: Of the 1054 patients, 27 (3%) harbored >1 P/LP variants (21 with ≥1 ALVC/DCM gene; 6 with >1 ARVC gene). MAE occurred in 20% of single-variant patients compared with 48% and 50% of those with >1 P/LP variants in ≥1 ALVC/DCM- and >1 ARVC-susceptibility gene(s), respectively. ESHF occurred in 9%, 29%, and 17% of patients, respectively. On adjusted analysis, >1 P/LP variants in ≥1 ALVC/DCM-susceptibility (MAE hazard ratio [HR], 2.46 [1.28-4.72]; P = .01 and ESHF HR, 3.15 [1.35-7.37], P = .01) and >1 ARVC-susceptibility gene(s) (MAE HR, 2.67 [1.28-8.72], P = .03) were independent predictors of the primary endpoints. CONCLUSION: Multiple P/LP variants confer an increased risk of arrhythmic events and heart failure across the ACM/DCM spectrum.

Arrhythmogenic cardiomyopathy↗

PubMed2026

Beyond ion channel dysfunction: Integration of the transcriptome and proteome from patient-specific re-engineered cardiac cells, and population-level QT genome-wide association study reveals broad cellular dysfunction.

BACKGROUND: Congenital long QT syndrome (LQTS) is a cardiac channelopathy with increased risk of cardiac-triggered syncope/seizures, sudden cardiac arrest, and sudden cardiac death. OBJECTIVE: This study aimed to describe the transcriptomic and proteomic profiles in patient-derived inducible pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of the 3 canonical genotypes of congenital LQTS: LQT1, LQT2, and LQT3 and integrate these omics-level findings with each other and with population/clinical level QT-genome-wide association study (GWAS) data. METHODS: LQT1, LQT2, LQT3 and respective isogenic control iPSC-CMs were cultured, and RNA and protein samples were collected. RNA sequencing and mass spectrometry-enabled proteomic analysis was performed. PrediXcan analysis was performed using QT GWAS summary statistics and transcriptome expression data. Differential gene and protein expression and ingenuity pathway analysis (IPA) was performed comparing each LQT genotype with its respective isogenic control. RESULTS: 1645 differentially expressed genes (DEGs) were identified; 13 were altered in all 3 LQTS genotypes. IPA analysis of DEGs revealed 301 altered pathways; 47 were altered in all LQTS genotypes. Proteomic analysis identified 2561 differentially expressed proteins (DEPs); 30 were altered in all 3 genotypes. IPA analysis of DEPs identified 646 altered pathways. 306 genes/proteins were identified as significantly altered in both the transcriptome and proteome; pathway analysis of these 301 genes identified 201 altered pathways. 7 pathways were altered in all 3 LQTS genotypes in both the transcriptome and proteome. Integration of the population-level PrediXcan results and the cardiomyocyte-derived omics results identified multiple shared pathways. CONCLUSION: Multi-omics analysis of LQTS and integration of omics results with QT GWAS data reveals that primary LQTS-causative ion channel defects precipitate secondary alterations in a wide range of cellular pathways. Our findings suggest more broad molecular level changes throughout the cell. This study lays the foundation for further exploration of broad cellular changes resulting from ion channel disturbances and how they contribute to disease mechanism.

Humans↗

PubMed2026

Risk stratification in short QT syndrome: Findings from a pooled analysis.

BACKGROUND: In long QT syndrome, longer QT intervals indicate increased arrhythmic risk, and a rate-corrected QT interval (QTc) of ≥500 ms denotes high risk. Establishing similar associations in short QT syndrome (SQTS) remains elusive. OBJECTIVE: This study aimed to demonstrate that shorter QT intervals denote a higher risk of malignant arrhythmias in SQTS and to define the "high-risk" QTc value in SQTS. METHODS: Pooled analysis of patients treated in our institutions or those reported in the literature revealed 162 patients with SQTS and known symptomatic status; 57 of them (35.2%) had arrhythmic symptoms (sudden death, cardiac arrest, or malignant syncope). RESULTS: There was a significant inverse association between the QTc and arrhythmic symptoms (with a median QTc of 315.0 ms [interquartile range 300.5-338.0] among symptomatic patients vs 330.0 ms [interquartile range 312.5-355.0] among asymptomatic patients; P = .0023). Receiver operator characteristics analysis showed that shorter QTc values were associated with a higher risk (area under the curve 0.64 ± 0.04; P = .0024). When patients were grouped by QTc range, most of those with a QTc of ≤320 ms had malignant arrhythmic symptoms, whereas the reverse was true for those with a QTc of ≥320 ms. Male patients were overrepresented in the SQTS cohort and more so in the subgroup with malignant symptoms. CONCLUSION: This pooled analysis of patients with SQTS demonstrates that, among patients with congenital SQTS, a shorter QTc is associated with a higher risk of malignant ventricular arrhythmias. A QTc shorter than 320 ms correlates with a higher arrhythmic risk. Men seem to be at higher risk.

Humans↗

PubMed2026

Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young.

AIMS: Calcium release channel deficiency syndrome (CRCDS) results from loss-of-function (LOF) variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) without abnormalities on a stress electrocardiogram (ECG). Undetected CRCDS may underlie idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). We aimed to determine the prevalence of potential CRCDS-causative RYR2 variants in IVF and SUDY. METHODS AND RESULTS: We reviewed clinical evaluation and RYR2 genetic analysis of 169 IVF patients and 279 SUDY victims. Only ultra-rare (<0.005% in gnomAD) nonsynonymous RYR2 variants were considered potentially pathogenic. Among IVF patients, 6/169 (3%) overall-and 6/67 (9%) with exertion-related SCA-harboured an RYR2 variant and represent potential CRCDS cases. All exhibited normal resting and stress ECGs. Genetic analysis revealed six distinct RYR2 variants, two previously characterized as LOF. In SUDY, 31/279 victims (11%) had a RYR2 variant (30 unique variants), predominantly observed in exertion-related SCD 20/83 (24%) vs. rest-related 11/196 (6%). Of the 14 SUDY victims with functionally characterized RYR2 variants, five (2% of total cohort) had a LOF variant; among the 56 exertion-related SUDY cases, four (7%) had a LOF variant. CONCLUSION: CRCDS may account for 3% of IVF overall and 9% of exertion-related SCA in IVF. Ultra-rare RYR2 variants may underlie up to 11% of SUDY, with 65% of RYR2-positive cases occurring during exertion. LOF-RYR2 variants may contribute to ≥7% of exercise-associated SUDY. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.

Humans↗

PubMed2025

The clinical and electrocardiographic phenotype of patients with genotype-negative long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a genetic heart disease that increases the risk of ventricular arrhythmias and sudden cardia arrest. Despite advances in genetic testing, a small subset of patients with LQTS remain genetically elusive. OBJECTIVE: This study aimed to determine the prevalence and clinical characteristics of patients with a phenotype of LQTS but without a genotype. METHODS: This study aimed to identify phenotype-positive, genotype-negative patients with LQTS seen at Mayo Clinic (2000-2024). Retrospective data included demographics, clinical evaluations, electrocardiograms, and genetic results. Diagnosis adhered to established criteria, and genotype-negative LQTS was defined by the absence of pathogenic variants despite clinical presentation. RESULTS: The study included 1829 patients with LQTS. Of these, 1706 (93%) had pathogenic or likely pathogenic variants, and 95 patients (5%) had upgraded clinical variants of uncertain significance, leaving 32 (1.7%) with negative genetic tests. Among the genotype-negative patients, 17 underwent next-generation sequencing, identifying a genetic cause in 6 cases (0.3% of the total). The mean age at diagnosis for the remaining 26 patients was 25 ± 15 years, with 76% being women and an average initial corrected QT of 498 ± 41 ms. Fourteen patients (53%) experienced cardiac events prior to diagnosis, and 11 (44%) received an implantable cardioverter-defibrillator. The mean follow-up period was 8 ± 7 years. CONCLUSION: Genotype-negative LQTS accounted for < 2% of our cohort, highlighting diagnostic and management challenges. Comprehensive clinical evaluation and advanced genetic testing remain essential for accurate diagnosis and care.

Humans↗