Purpose To generate high-resolution fibrosis maps using universal ventricular coordinates for spatial characterization of fibrotic patterns across disease severity in desmoplakin cardiomyopathy. Materials and Methods This retrospective study included patients with desmoplakin cardiomyopathy who underwent cardiac MRI between March 2012 and October 2024. Three-dimensional ventricular models were reconstructed from cine MRI acquisitions. Fibrosis identified at late gadolinium enhancement MRI was mapped to ventricular geometry using universal ventricular coordinates, enabling analysis within a common reference framework. Patients were classified as having mild, moderate, or severe disease based on fibrosis extent. Associations between fibrosis burden and left ventricular structural and functional metrics were evaluated using Tukey and Wald tests. Results Twenty-nine patients (mean age, 37.39 years [range, 10-77 years]; 20 female patients) were included. In mild disease, fibrosis was primarily located in the subepicardial midinferior region. With increasing fibrosis burden, moderate and severe disease demonstrated subepicardial circumferential involvement with a ringlike pattern in severe cases. Fibrosis burden correlated negatively with left ventricular ejection fraction (r = -0.80, P < .001) and positively with left ventricular end-diastolic volume index (r = 0.54, P = .002). Group comparisons showed significant differences between moderate and severe disease groups across all metrics (P < .05) but not between mild and moderate groups. Conclusion Use of universal ventricular coordinates enabled high-resolution mapping of fibrosis and demonstrated characteristic spatial patterns across disease severity in desmoplakin cardiomyopathy. Fibrosis was observed in nondilated ventricles, whereas higher fibrosis burden was associated with left ventricular dilatation and impaired systolic function. Keywords: Cardiomyopathies, Left Ventricle, Computer Applications-3D, MR Imaging Supplemental material is available for this article. © RSNA, 2026.

Background Desmosomal “hot‐phase” cardiomyopathy (HPC), characterized by bursts of myocardial inflammation mimicking acute myocarditis (AM), carries relevant risks of adverse outcomes. This study aimed to identify diagnostic “red flags” favoring HPC over AM. Methods Patients (n=134) receiving a first diagnosis of AM, proven by endomyocardial biopsy or cardiac magnetic resonance plus troponin elevation, were retrospectively identified at a referral center. HPC was defined by presence of pathogenic desmosomal gene variants (DGVs). Clinical, imaging, and electrical features were compared between HPC cases and controls with gene‐negative AM to identify red flags. Diagnostic algorithms were derived and tested in an external multicenter cohort of DGV carriers (n=30). Results Patients with HPC (n=22; 91% DSP+) were more frequently female (73% versus 24%, P<0.001) and younger than unmatched controls with AM (32±14 versus 41±14 years, P=0.007). When matched 1:1 by age, sex, and presentation, DGV carriers showed distinctive red flags: family history of cardiomyopathy/AM/sudden death; recurrent troponin peaks; persistent left ventricular systolic dysfunction; right ventricular involvement; ring‐like late gadolinium enhancement; late gadolinium enhancement persistence or extension; low QRS voltages; life‐threatening ventricular arrhythmias at <45 years; persistent >1000/24 hours ventricular ectopy; and recurrent nonsustained ventricular tachycardia. A “first‐contact” algorithm based on female sex and age <30 years achieved 77% accuracy, identifying 63% of DGV carriers in the external cohort. An alternative algorithm incorporating ring‐like late gadolinium enhancement, right ventricular involvement, and family history showed higher accuracy (93%) and yield (93%). Conclusions Myocarditis in DGV carriers predominantly affects young women. A red flag‐based approach improves recognition of desmosomal HPC over classic AM.

BACKGROUND:Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. METHODS:Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5x10(-5) in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2x) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. RESULTS:Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. CONCLUSIONS:This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

Background:Truncating variants in desmoplakin (DSPtv), are a leading cause of arrhythmogenic cardiomyopathy (ACM), often presenting with early fibrosis and arrhythmias disproportionate to systolic dysfunction. DSP is critical for cardiac mechanical integrity, linking desmosomes to the cytoskeleton to withstand contractile forces. While loss-of-function is implicated, direct evidence, both for DSP haploinsufficiency in human hearts and for the impact of mechanical stress on cardiomyocyte adhesion, has been limited, leaving the pathogenic mechanism unclear. Methods:We analyzed explanted human heart tissue from patients with DSPtv (N=3), titin truncating variants (TTNtv, N=5), and controls (N=5) using RNA-sequencing and mass spectrometry. We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harboring patient-derived or CRISPR-Cas9 engineered DSPtv to model a range of DSP expression levels. Using a 2D cardiac muscle bundle (CMB) platform enabling live visualization of cell junctions, we developed an assay to assess cell-cell adhesion upon heightened contractile stress in response to the contractile agonist endothelin-1. CRISPR-interference (CRISPRi) was used to confirm the role of DSP loss, and CRISPR-activation (CRISPRa) was tested for therapeutic rescue. Results:Compared to both control and TTNtv hearts, DSPtv human hearts exhibited reduced DSP at both the mRNA and protein level, as well as broadly disrupted desmosomal stoichiometry. Transcriptomic and proteomic analyses implicated cell adhesion, extracellular matrix, and inflammatory pathways. iPSC-CM models recapitulated DSP haploinsufficiency and desmosomal disruption. DSPtv CMBs showed normal baseline contractile function. However, they displayed marked cell-cell adhesion failure with contractile stress (75% failure vs. 8% in controls, p<0.001). Adhesion failure was prevented by the myosin inhibitor, mavacamten. CRISPRi-mediated DSP knockdown replicated this susceptibility to adhesion failure. Conversely, CRISPRa robustly increased DSP expression and rescued cell-cell adhesion failure in DSPtv CMBs (9% failure post-CRISPRa, p<0.001 vs. un-treated). Rescue occurred even when only the DSPII isoform was upregulated in a model with biallelic DSP transcript 1 loss of function. Conclusions:DSP haploinsufficiency is the major cause of DSP cardiomyopathy with a primary consequence of conferring vulnerability to cardiomyocyte cell-cell adhesion failure under heightened contractile stress. Transcriptional activation of DSP reverses this defect in preclinical models, establishing proof-of-concept for a potential therapeutic strategy in DSP cardiomyopathy.

Background Cardiomyocytes require the HSP70 (heat shock protein 70) chaperone BiP (binding immunoglobulin protein) to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase FICD (FIC domain protein adenylyl transferase) is increasingly recognized to regulate BiP activity through the posttranslational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown.Methods We assessed 6-month and 12-month-old wild-type and FICD knockout mice in a transverse aortic constriction hypertrophy paradigm. We determined cardiac function and injury using echocardiography, histological stainings, and biochemical approaches. In complementary assays, we used isolated neonatal wild-type and FICD knockout cardiomyocytes and cardiac fibroblasts to quantitatively assess cell-type specific adaptations in proteostasis and ER stress responses.Results We find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response and impairs BiP interaction with FAM134B, an ER-selective autophagy receptor, thus limiting ER-selective autophagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent unfolded protein response induction and ER-selective autophagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue.Conclusions Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPR ER ) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPR ER induction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

Background and Aims Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. Methods All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. Results Eight hundred patients [40.3 +/- 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 +/- 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF <= 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF <= 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). Conclusions Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF <= 50%, and myocardial injury events.

Background and Aims Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. Methods Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). Results In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. Conclusions The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach. Structured Graphical Abstract The desmoplakin risk score provides individualized predictions of 5-year ventricular arrhythmia risk in patients with pathogenic/likely pathogenic (P/LP) desmoplakin variants based on five readily available clinical risk factors (www.dsp-risk.com). The desmoplakin risk score demonstrated strong discrimination of ventricular arrhythmia risk (c-statistic .79 during external validation) and accurately stratifies patients into low- (0%-5% risk at 5 years), intermediate- (5%-20% risk at 5 years), and high-risk (>20% risk at 5 years) groups for the purposes of guiding primary prevention implantable cardiac defibrillator decision-making. DSP, desmoplakin; LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular contraction; RV, right ventricular; VA, ventricular arrhythmia.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by replacement of ventricular myocardium with fibrofatty tissue, predisposing the patient to ventricular arrhythmias and/or sudden cardiac death. Most cases of ACM are associated with pathogenic variants in genes that encode desmosomal proteins, an important cell-to-cell adhesion complex present in both the heart and skin tissue. Although ACM was first described as a disease predominantly of the right ventricle, it is now acknowledged that it can also primarily involve the left ventricle or both ventricles. The original right-dominant phenotype is traditionally diagnosed using the 2010 task force criteria, a multifactorial algorithm divided into major and minor criteria consisting of structural criteria based on two-dimensional echocardiographic, cardiac MRI, or right ventricular angiographic findings; tissue characterization based on endomyocardial biopsy results; repolarization and depolarization abnormalities based on electrocardiographic findings; arrhythmic features; and family history. Shortfalls in the task force criteria due to the modern understanding of the disease have led to development of the Padua criteria, which include updated criteria for diagnosis of the right-dominant phenotype and new criteria for diagnosis of the left-predominant and biventricular phenotypes. In addition to incorporating cardiac MRI findings of ventricular dilatation, systolic dysfunction, and regional wall motion abnormalities, the new Padua criteria emphasize late gadolinium enhancement at cardiac MRI as a key feature in diagnosis and imaging-based tissue characterization. Conditions to consider in the differential diagnosis of the right-dominant phenotype include various other causes of right ventricular dilatation such as left-to-right shunts and variants of normal right ventricular anatomy that can be misinterpreted as abnormalities. The left-dominant phenotype can mimic myocarditis at imaging and clinical examination. Additional considerations for the differential diagnosis of ACM, particularly for the left-dominant phenotype, include sarcoidosis and dilated cardiomyopathy. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Transesophageal echocardiography (TEE) has become a routine diagnostic and monitoring technique during cardiac surgery. However, contraindications to TEE may warrant a preoperative multidisciplinary discussion of the relative risks and benefits of the procedure, among which is a history of esophagectomy. Consensus guidelines consider TEE indicated for cardiac surgeries involving heart valves or the thoracic aorta but consider a prior esophagectomy as a relative contraindication. 1 Hahn R.T. Abraham T. Adams M.S. et al. Guidelines for performing a comprehensive transesophageal echocardiographic examination: recommendations from the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists. J Am Soc Echocardiogr. 2013; 26: 921-964 Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar The safety, prevalence, and imaging ability of TEE in cardiac surgery patients with a history of bariatric surgery have been described elsewhere, but no data exist for those with esophagectomy. 2 Kelava M. Koprivanac M. Alfirevic A. et al. Safety of transesophageal echocardiography for cardiac surgery in patients with histories of bariatric surgery. J Am Soc Echocardiogr. 2020; 33: 130-132 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Whereas the benefit of TEE in cardiac surgery is well documented, information regarding the imaging quality and gastric injury rate of TEE in esophagectomy patients is lacking. 3 MacKay E.J. Neuman M.D. Fleisher L.A. et al. Transesophageal echocardiography, mortality, and length of hospitalization after cardiac valve surgery. J Am Soc Echocardiogr. 2020; 33: 756-762.e1 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar A qualification of clinical benefit versus risks of TEE during cardiac surgery in patients with prior esophagectomy would aid in clinical decision-making, and as such we sought to qualify (1) the quality of TEE images obtained in these patients; (2) adverse events related to probe placement; and (3) cardiac anesthesiologist opinions and experiences related to such cases.

Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20’s nuclear localization in RBM20-DCM patients.

Background Aortic root dilatation and aortic insufficiency can occur in patients with prior conotruncal defect surgery, the Ross procedure, and connective tissue disease (CTD). Valve-sparing aortic root replacement (VSRR) is an excellent choice for these young patients. We present the outcomes of young patients undergoing VSRR by congenital heart surgeons at a single center. Methods A single center retrospective chart review from April 2008 – April 2021 was performed. Patients with aortic root and valve pathology who underwent VSRR were identified. A total of 49 patients were identified by using the hospital surgical database. Three VSRR techniques were utilized during the study period; aortic valve-sparing root remodeling (Group 1, 7 patients), aortic valve-sparing root reimplantation (Group 2, 32 patients), and a modified root remodeling procedure utilizing a geometric annuloplasty ring (Group 3, 10 patients). Patient characteristics, post-VSRR echocardiogram studies and need for intervention, and survival were analyzed. Results Long-term survival after VSRR is excellent with only one death related to cardiac causes. Valve degeneration remains a concern with 13 patients (26%) requiring subsequent aortic valve replacement over the study period. Risk factors for aortic valve reintervention were the aortic root remodeling technique, mild or greater immediate post-operative aortic insufficiency and higher post-operative mitral insufficiency. Follow-up was significantly longer in Group 1 patients compared to Groups 2 and 3. Conclusions Valve-sparing aortic root replacement is safely performed by congenital heart surgeons in a heterogeneous patient population. Valve degeneration remains a concern and greater than trivial post-operative aortic insufficiency should prompt further attempts at valve repair or replacement.

Introduction: Genetic hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition primarily due to pathogenic variants in sarcomere genes, often with marked clinical variability. We hypothesized that this variability may, in part, be due to additive effects from low penetrance sarcomere variants that would otherwise be dismissed due to high population prevalence. Methods: Low-penetrance HCM-associated sarcomere gene variants were identified by meeting a threshold for enrichment in HCM (ascertained from the Sarcomeric Human Cardiomyopathy Registry, SHaRe) versus the general population (ascertained from the Genome Aggregation Database, gnomAD), defined by an odds ratio (OR) >5, and a population prevalence greater than the most common autosomal dominant pathogenic HCM variant, MYBPC3 R502W (4x10 -5 ). Clinical variables and time-event analyses were performed from SHaRe . Results: A total of 507 unique sarcomere gene variants were present in 6384 individuals with genetic testing. Ten putative low-penetrance variants were identified in the genes MYBPC3 (N=2), TNNT2 (N=1), TNNI3 (N=2), and MYH7 (N=5) with a combined OR of 12.7 (range 5.8 - 28.4). These variants had a population prevalence of 4.02x10 -5 to 3.5x10 -4 . Family members of low-penetrance variant carriers were less likely to have HCM (35/171, 20%) than those of MYBPC3 R502W carriers (44/113, 39%, p<0.005). Age of diagnosis was older in patients with isolated low-penetrance variants than those with pathogenic variants (42 ± 19 vs 37 ± 18, p=0.005). Composite adverse events were less likely in patients with isolated low-penetrance variants than typical pathogenic sarcomere variants, but the risk was additive with both present (see Figure). Conclusions: A subset of low-penetrance sarcomere gene variants are tolerated in the general population at higher than expected proportions for HCM and may exert an additive pathogenic effect. These findings support an oligogenic risk model of HCM.

In May 2019, Michigan Medicine launched a new high-sensitivity troponin T (hsTnT) assay for inpatient utilization. Although widely used and studied internationally, the utilization of inpatient hsTnT in the United States is less ubiquitous and its implications on medical decision-making are less