Nihant BSC, Verdonschot JAJ, Bălan S
… +6 more, Thielecke E, Luiken JJFP, Nabben M, Heymans S, Breuer M, Adriaen ME
Circ Genom Precis Med
· 2026 Jul · PMID 42394617
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BACKGROUND: Dilated cardiomyopathy (DCM) is associated with shifts in cardiac metabolism. However, those shifts vary widely across patients, likely reflecting the diverse underlying causes of the disease. Identifying met...BACKGROUND: Dilated cardiomyopathy (DCM) is associated with shifts in cardiac metabolism. However, those shifts vary widely across patients, likely reflecting the diverse underlying causes of the disease. Identifying metabolic subtypes, or metabotypes, in DCM patients could help tailor treatments to patient needs. Hence, having a practical approach to identify these metabotypes would be a significant advance toward precision medicine in DCM. METHODS: We present a systems biology approach to uncover metabotypes directly from widely available transcriptomic data. We use in silico metabolic modeling methods that we have optimized for cardiac research to predict metabolic function activities from enzyme expression, followed by a hierarchical clustering approach. To demonstrate its power, we applied our method to publicly available cardiac data from end-stage DCM patients (N=164) and nonfailing controls (N=160). RESULTS: We identified 2 distinct metabotypes in end-stage DCM patients. These metabotypes are characterized by unique metabolic changes, notably in calcium handling, amino acid oxidation, and the pentose phosphate pathway. Strikingly, 1 DCM metabotype showed greater metabolic divergence from healthy controls, suggesting a greater metabolic contribution to its underlying etiology-even though disease severity was similar between the 2 identified DCM metabotypes. Further transcriptome-wide analysis revealed immune-related differences between metabotypes, suggesting an underlying interplay between inflammation, the immune response, and metabolism. CONCLUSIONS: Our results imply the presence of distinct metabotypes in end-stage DCM. Our systems biology approach offers an exciting opportunity to uncover novel insights into DCM, paving the way for a deeper understanding of its progression and heterogeneity.
Miras-Moreno S, Torres-Martos Á, Ruiz JR
… +5 more, Carter J, Abreu de Carvalho C, Aguilera CM, Piernas C, Martinez-Tellez B
Circ Genom Precis Med
· 2026 Jul · PMID 42394615
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BACKGROUND: Cardiorespiratory fitness (CRF) is a strong predictor of mortality and noncommunicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified 2 signatures of...BACKGROUND: Cardiorespiratory fitness (CRF) is a strong predictor of mortality and noncommunicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified 2 signatures of CRF (1 metabolomic and 1 proteomic) from UK Biobank participants who completed a risk-stratified submaximal cycle ergometer test, with CRF estimated from the heart rate response to incremental workload. METHODS: These signatures were validated in an independent sample of UK participants with data on metabolomics (n=354 222) and proteomics (n=29 961) to investigate prospective associations with all-cause mortality and noncommunicable diseases. Prospective associations were evaluated using Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, lifestyle factors (including smoking, alcohol intake, diet, and body mass index), and relevant medical history. RESULTS: Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed 2 novel signatures of CRF (1 metabolomic and 1 proteomic) that robustly reflect CRF levels (R: 0.50-0.60). Over an average of 9 years of follow-up, we observed 27 659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic signature of CRF was strongly associated with a 39% to 54% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (90% in both), cardiovascular disease (42%-47%), and colorectal cancer (33%-39%). Additionally, the proteomic signature of CRF was associated with a 17% lower risk of all-cause mortality, and with a 22% to 39% lower risk of type 2 diabetes and cardiovascular disease. CONCLUSIONS: Together, these findings indicate that circulating metabolites and proteins are associated with CRF and with subsequent risk of mortality and noncommunicable diseases.
Circ Genom Precis Med
· 2026 Jul · PMID 42394602
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Clinical genetic testing is now the standard of care for cardiomyopathy, guiding risk stratification, clinical management, and earlier diagnosis in family members. Yet, a large proportion of the genetic basis of cardiomy...Clinical genetic testing is now the standard of care for cardiomyopathy, guiding risk stratification, clinical management, and earlier diagnosis in family members. Yet, a large proportion of the genetic basis of cardiomyopathy remains incompletely explained. Prior efforts to identify genetic causes of cardiomyopathy have largely focused on coding DNA sequence, which accounts for only 3% of the human genome, leaving the noncoding regulatory sequence space relatively unexplored. A confluence of emerging technologies is now transforming our capability to identify and interpret noncoding variants. This review summarizes the field's current knowledge of how noncoding variants influence the development of cardiomyopathy, both from the standpoint of rare Mendelian disease variants and population-level risk alleles. In addition, we describe how new technologies have enabled systematic identification and prioritization of regulatory regions that govern gene expression. Beyond identification of regulatory regions, we discuss how causal testing of variants is now possible at an unprecedented scale through massively parallel reporter assays, allowing both detailed mapping of these regions and efficient validation of variants discovered through genome-wide association studies. Finally, we review deep learning approaches that hold the potential for genome-wide noncoding variant interpretation. Together, this review highlights strategies for large-scale interpretation of noncoding variants while also demonstrating the clear need for extension of clinical variant adjudication workflows to the noncoding genome to fully take advantage of increasingly available whole-genome sequencing data.
Muller SA, Murray B, Tichnell C
… +14 more, Salavati A, Loh P, Carrick RT, Cox M, van der Harst P, Cramer MJ, Oerlemans MIFJ, Gasperetti A, Asatryan B, Zimmerman S, van Tintelen JP, Calkins H, James CA, Te Riele ASJM
BACKGROUND: Current guidelines recommend regular screening for first-degree relatives of gene-elusive arrhythmogenic right ventricular cardiomyopathy (ARVC) patients using a similar regimen as for genotype-positive/pheno...BACKGROUND: Current guidelines recommend regular screening for first-degree relatives of gene-elusive arrhythmogenic right ventricular cardiomyopathy (ARVC) patients using a similar regimen as for genotype-positive/phenotype-negative relatives. However, the multifactorial nature of gene-elusive ARVC may necessitate a different approach. This study aimed to determine the yield of cardiac screening in first-degree relatives of ARVC probands without a validated genetic cause. METHODS: We included all first-degree relatives of probands who (1) met the 2010 Task Force Criteria, (2) underwent next-generation sequencing that included all genes with at least moderate evidence for ARVC causation per Clinical Genome Resource appraisal (validated ARVC genes), and (3) had no pathogenic/likely pathogenic (P/LP) variants identified in these genes. The primary and secondary end points were definite ARVC by the 2010 Task Force Criteria and ventricular arrhythmia, respectively. RESULTS: We included 44 relatives (39.0 [22.3-45.8] years; 36% male) from 24 families. In 4 (17%) families, a P/LP variant was identified in a different cardiomyopathy/arrhythmia gene (, , , ). Overall, 10 (23%) relatives had definite ARVC at baseline evaluation. Of the 20 relatives without definite ARVC who had follow-up available, 8/20 (40%) relatives progressed to definite ARVC during 9.0 (5.8-14.4) years of follow-up. No statistical difference in the yield of baseline screening or serial evaluation between relatives from families with a P/LP variant and relatives from families without a P/LP variant was observed. Of the 27 relatives who had follow-up available, ventricular arrhythmia was observed in 2/27 (7%) relatives and occurred 6.3 and 13.8 years after definite ARVC diagnosis. Both of those relatives were from families without a P/LP variant. CONCLUSIONS: These findings highlight the importance of managing first-degree relatives of ARVC probands without a validated genetic cause similarly to genotype-positive ARVC relatives. Furthermore, using a broad cardiomyopathy and arrhythmia gene panel in ARVC probands, rather than limiting testing to validated ARVC genes alone, is warranted.
BACKGROUND: Exercise training improves contractile function and can reduce arrhythmia burden after a myocardial infarction (MI). How exercise modifies the proarrhythmic status is uncertain. METHODS: In this study, rats 6...BACKGROUND: Exercise training improves contractile function and can reduce arrhythmia burden after a myocardial infarction (MI). How exercise modifies the proarrhythmic status is uncertain. METHODS: In this study, rats 6 weeks post-MI were randomized to an 8-week high-intensity exercise program (MI-EX) or to a sedentary control group (MI-SED) and compared with a sedentary sham group (Sham-SED). After the exercise program, in vivo and ex vivo programmed electrical stimulation was performed on the rat hearts. Subsequently, optical mapping was conducted to electrophysiologically characterize the MI hearts. RESULTS: Exercise significantly improved maximal oxygen uptake (O; MI-EX, 67 mL·min·kg versus MI-SED, 47 mL·min·kg). In vivo cardiac stimulation protocols indicated reduced inducibility of ventricular arrhythmias in MI-EX compared with MI-SED. This anti-arrhythmic effect was retained ex vivo in Langendorff-perfused hearts. Optical mapping of the noninfarcted left ventricle indicated a prolonged average action potential (AP) duration at 4.5 Hz pacing frequency in both MI groups compared with Sham-SED. As pacing frequency increased (6.5 Hz and ≈8 Hz), AP duration remained significantly longer in the MI-SED group but decreased in the MI-EX group, demonstrating a negative frequency dependency. Spatial heterogeneity of AP duration in the noninfarcted left ventricle area was increased post-MI but was significantly reduced following exercise. Optical AP recorded from the remnant myocardium within the scar showed similar AP duration characteristics at low stimulation frequencies, but AP upstroke time was shorter in the MI-EX group compared with MI-SED. CONCLUSIONS: Post-MI exercise was associated with electrophysiological changes in both the noninfarcted region and the remnant myocardium within the scar. These changes suggest a mechanism for the anti-arrhythmic effects of exercise following MI.
BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function ar...BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS: Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS: Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%-28.4%; =0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (-1.01 versus -3.48 mL/min per 1.73 m per year; <0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%-24.2%]; =0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22-0.78]; =0.006; interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17-0.66]; =0.002, interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS: Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03458130. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03536767. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03860935. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04988386.
Marcinkiewicz AM, Shanbhag A, Chareonthaitawee P
… +29 more, Zhang W, Al-Jilaihawi H, Zaid R, Cadet S, Ramirez G, Lemley M, Yi J, Hijazi W, Builoff V, Liang JX, Calsavara VF, Einstein AJ, Miller E, Feher A, Ruddy TD, Le VT, Mason S, Knight S, Alexanderson E, Carvajal-Juarez I, Slipczuk L, Travin MI, Rosamond TL, Wopperer S, Berman DS, Dey D, Di Carli M, Miller RJH, Slomka PJ
BACKGROUND: Aortic enlargement is a powerful predictor of dissection and rupture, yet it is rarely evaluated during routine myocardial perfusion imaging, despite the widespread availability of computed tomography (CT) at...BACKGROUND: Aortic enlargement is a powerful predictor of dissection and rupture, yet it is rarely evaluated during routine myocardial perfusion imaging, despite the widespread availability of computed tomography (CT) attenuation correction scans. The aim of this study was to determine whether fully automated, opportunistically derived, artificial intelligence-based aortic measurements from myocardial perfusion imaging CT attenuation correction scans are associated with adverse outcomes in a large multicenter cohort. METHODS: Computed tomography attenuation correction scans from patients undergoing positron emission tomography/CT and single-photon emission CT/CT myocardial perfusion imaging across 10 centers were included. A deep learning model automatically segmented the thoracic aorta, and a postprocessing algorithm extracted maximum ascending and descending diameters. The aortic size index (1) was calculated by indexing the diameter to body surface area. RESULTS: A total of 29 339 patients (56% male; median age, 66 years [interquartile range, 58-75 years]) were included. Over a median follow-up of 3.5 years (interquartile range, 1.9-5.0 years), 5083 (17.3%) patients died. Median ascending and descending aortic size index values were 1.8 cm/m (interquartile range, 1.6-2.0) and 1.5 cm/m (interquartile range, 1.4-1.6), respectively, with an increase with age and higher values in females. Elevated aortic size index thresholds (ascending >2.2 cm/m; descending >1.6 cm/m) were significantly associated with increased all-cause mortality (ascending: adjusted hazard ratio, 1.16 [95% CI, 1.07-1.26], <0.001; descending: adjusted hazard ratio, 1.23 [95% CI, 1.14-1.31]; <0.001). Notably, the prognostic value of an abnormal aortic size index persisted independent of age, sex, and perfusion abnormalities. CONCLUSIONS: Artificial intelligence can unlock previously unused information within routine myocardial perfusion imaging CT attenuation correction scans by rapidly and automatically quantifying aortic size at scale. Opportunistic aortic measurements derived from CT attenuation correction may serve as an adjunctive risk biomarker and could add prognostic value to standard myocardial perfusion imaging without additional imaging or radiation.
Jones O, Linton N, Bissett S
… +23 more, Koutsoftidis S, Kay J, Wu H, Chow JJ, Qureshi N, Baykaner T, Zaman J, Lewalter T, Demircali A, Zheng Q, Heaney F, Jose I, Malcolme-Lawes L, Koa-Wing M, Lim B, Arnold A, Peters N, Keene D, Ng FS, Whinnett Z, Temelkuran B, Drakakis E, Kanagaratnam P
BACKGROUND: Conventional activation mapping of atrial fibrillation (AF) during clinical procedures is limited by low-amplitude, fractionated electrograms and cycle length variability. The Tau20-RETROmapping stimulator-re...BACKGROUND: Conventional activation mapping of atrial fibrillation (AF) during clinical procedures is limited by low-amplitude, fractionated electrograms and cycle length variability. The Tau20-RETROmapping stimulator-recorder system (TauRhythm Therapies, United Kingdom) is an investigational device used to identify nonpulmonary vein AF drivers by real-time, high-density activation mapping of uniform wavefronts during AF. We validated the accuracy of the system and applied it to left atrial mapping for evidence of AF drivers. METHODS: Left atrial geometry was acquired using a 3-dimensional electroanatomic mapping system with high-density mapping catheters (CARTO 3 with Optrell, or EnSite X with HD Grid). Electrograms were recorded for 30 seconds at multiple left atrial sites. The Tau20-RETROmapping system generates activation maps of organized wavefronts. System performance was manually validated against randomly sampled local electrograms using a grid sweep of thresholds to identify Pareto-optimal parameters in sinus rhythm, atrial pacing, atrial tachycardia (AT), and AF. The system was then applied to identify putative driver activation patterns during persistent AF. RESULTS: We studied 24 patients undergoing pulmonary vein isolation for AF. Six patients presented in sinus rhythm or AT, in whom the system demonstrated a sensitivity of 100.0% (95% CI, 80.5%-100.0%) and a specificity of 100.0% (85.2%-100.0%). Eighteen patients were mapped in AF: the system had a sensitivity of 94.4% (86.2%-98.4%) and a specificity of 97.1% (89.9%-99.6%) when identifying organized AF wavefronts, and accurately identified the earliest activation in 89.6% (79.7%-95.7%) of waves. Stable propagation originating from the left atrial appendage (LAA) was observed in 3/18 patients, while 8/18 demonstrated competing propagation toward and away from the LAA. Conduction away from the LAA was detected along the anterior (8/18 patients), lateral (8/18 patients), and posterior (7/18 patients) walls. No propagation near the LAA was observed in 6/18 patients. CONCLUSIONS: The Tau20-RETROmapping system enables real-time activation mapping of AF, with the most convincing driver-like areas being identified around the LAA.
Gotschy A, Cammann VL, Schweiger V
… +20 more, Schlenker R, Di Vece D, Károlyi M, Nguyen TH, Horowitz JD, Kobayashi Y, Kato K, Meder B, Pasquini A, Galea N, Fedele E, Calò L, Kozerke S, Ruschitzka F, Crea F, Lüscher TF, Manka R, Ghadri JR, Templin C, Galiuto L
BACKGROUND: The pathogenesis of Takotsubo syndrome (TTS) is poorly understood, but differences in outcome depending on the triggering factor imply differences in the pathophysiology. Beyond the established trigger-based...BACKGROUND: The pathogenesis of Takotsubo syndrome (TTS) is poorly understood, but differences in outcome depending on the triggering factor imply differences in the pathophysiology. Beyond the established trigger-based InterTAK (International Takotsubo Registry) classification, the newly proposed distinction between primary and secondary TTS aims to differentiate emotionally primed heart dysfunction from TTS driven by direct myocardial injury. To explore these potential differences, we utilized cardiovascular magnetic resonance imaging to assess left ventricular function, myocardial edema, and myocardial injury across the InterTAK classification and between primary and secondary TTS. METHODS: For this multicenter cohort study, 110 patients (95% female, age 66±12 years) from the InterTAK registry were included who received cardiovascular magnetic resonance 3 (interquartile range, 2-5) days after symptom onset. Cardiovascular magnetic resonance included assessment of myocardial function, edema (T2-weighted spin-echo and T2-mapping when available), and late gadolinium enhancement. RESULTS: No significant differences were observed in left ventricular volumes, function, or mass across the 3 InterTAK groups or between primary and secondary TTS. Patients with emotional triggers exhibited significantly larger myocardial edema (72% versus 60% for physical triggers; <0.01), supported by higher T2-mapping values in a subset of 22 patients with T2-mapping. In multivariable regression, only emotional trigger (<0.01) and the absence of coronary artery disease (=0.04) were independently associated with the extent of myocardial edema. Secondary TTS showed a higher prevalence of focal or patchy late gadolinium enhancement (primary 19%, secondary 54%; <0.01). In multivariable logistic regression, secondary TTS (<0.01) and early cardiovascular magnetic resonance (=0.02) were associated with the presence of any late gadolinium enhancement. CONCLUSIONS: TTS due to emotional stress is associated with larger myocardial edema, and secondary TTS exhibited late gadolinium enhancement more frequently, indicative of direct myocardial damage. These findings suggest that emotionally primed heart dysfunction and direct myocardial injury contribute to TTS pathophysiology to varying extents, influenced by both the triggering factor and preexisting conditions.
Verlee M, Hitzert MM, van Loon RL
… +17 more, Muiño Mosquera L, De Groote K, De Backer J, Demulier L, Meerschaut I, Jongbloed JDH, Vos YJ, Douwes JM, Neijzen RL, Dooijes D, Breur JMPJ, De Vogelaere E, Vermeulen G, Symoens S, Coucke P, Kerstjens-Frederikse WS, Callewaert B
Circ Genom Precis Med
· 2026 Jul · PMID 42381626
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BACKGROUND: Virtual panel analysis (VPA) of exome data is a common approach for the molecular diagnosis of congenital heart disease (CHD). However, differences in gene panel composition and patient inclusion criteria lim...BACKGROUND: Virtual panel analysis (VPA) of exome data is a common approach for the molecular diagnosis of congenital heart disease (CHD). However, differences in gene panel composition and patient inclusion criteria limit the evaluation of its diagnostic utility. This study aims to assess the diagnostic yield of VPA in a cohort of patients with CHD across 3 academic centers. METHODS: We collected clinical data including phenotypic features and family history, from 853 probands with CHD who underwent VPA analysis at the Center for Medical Genetics Ghent (525 probands; 471 genes), the University Medical Center Groningen (195 probands; 345 genes), and the University Medical Center Utrecht (133 probands; 55 genes). We evaluated the diagnostic yield by comparing the 3 centers with respect to panel composition and clinical presentation. RESULTS: The Center for Medical Genetics Ghent reported a higher diagnostic yield (9.9%) compared with the University Medical Center Groningen (7.2%) and the University Medical Center Utrecht (5.3%). In all centers, the diagnostic yield was higher in patients presenting with a syndromic constellation and did not differ significantly between the sporadic and familial cases. In 1.7% of the 536 nonsyndromic probands, a molecular cause was identified that typically is associated with syndromic CHD. Twelve genes showed likely pathogenic or pathogenic variants in multiple patients and contributed to 56.2% of the identified causes. CONCLUSIONS: We report an overall diagnostic yield of VPA for CHD of 8.6%, to which only a few genes contribute significantly, highlighting the complex origin of CHD. Since panel size, gene panel content, and local practices largely affect the diagnostic yield, we propose a (minimum) core gene panel for suspected isolated CHD, as well as a coordinated testing strategy for CHD to improve diagnosis and counseling and to catalyze collaborative efforts.
Reckmann J, Milting H, Voß S
… +13 more, Radukic MT, Klag F, Flottmann F, Lütkemeyer A, Groß J, Gärtner A, Landwehr S, Anselmetti D, Hoyer A, Müller KM, Gummert J, Walhorn V, Brodehl A
Circ Genom Precis Med
· 2026 Jul · PMID 42381621
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BACKGROUND: The gene encodes the IF (intermediate filament) protein desmin, which connects different multiprotein complexes, such as the cardiac desmosomes, and is highly important for the structural integrity of cardio...BACKGROUND: The gene encodes the IF (intermediate filament) protein desmin, which connects different multiprotein complexes, such as the cardiac desmosomes, and is highly important for the structural integrity of cardiomyocytes. Pathogenic mutations cause filament assembly defects leading to cardiomyopathies. However, most variants listed in genetic disease databases are currently classified as variants of unknown significance. Here, we characterized 21 different variants of unknown significance and 18 additional proline variants, localized in a highly conserved stretch at the C terminus of the desmin coil-2 subdomain. METHODS: We inserted desmin variants via site-directed mutagenesis and investigated the filament assembly in transfected cell lines and cardiomyocytes derived from induced pluripotent stem cells by confocal microscopy. In addition, we purified recombinant wild-type and mutant desmin and analyzed the filament formation by atomic force microscopy. Coexpression with wild-type desmin delivered by adeno-associated virus was used to model the heterozygous status of cardiomyopathy patients. RESULTS: Twelve variants of unknown significance formed cytoplasmic aggregates, which were likewise verified by atomic force microscopy. Of note, these 12 variants disturb the filament assembly even when coexpressed with wild-type desmin. Using a proline screen, we showed that proline residues localized at nearly each of the positions in this stretch cause filament assembly defects. By modeling the tetrameric structure of desmin, we demonstrated that specific heptad positions, as well as positions of intramolecular and intermolecular ion bridge sites, are particularly susceptible to mutations that promote desmin aggregation. CONCLUSIONS: In summary, our study demonstrated that the highly conserved stretch at the C terminus of the coil-2 subdomain is a hotspot region, where several pathogenic mutations cause an aberrant desmin aggregation. Based on our molecular data, we suggest reclassifying the aggregate-forming variants as likely pathogenic mutations rather than variants of unknown significance. Our study may have relevance for the genetic counseling of cardiomyopathy patients with similar variants.
Walsh MN, Kober L, Sliwa K
… +19 more, Adamo M, Agarwal A, Banerjee A, Bozkurt B, Cikes M, Damasceno A, Desai AS, Felker GM, Hogan G, Kinugawa K, Kittleson M, Lam CSP, McDonagh T, Metra M, Mullens W, Ribeiro ALP, Vaughn Y, Vest A, Joint American Heart Association (AHA)/American College of Cardiology (ACC)/European Society of Cardiology (ESC)/World Heart Federation (WHF) Task Force for the Universal Definition of Heart Failure in collaboration with the Heart Failure Society of America (HFSA), the Heart Failure Association (HFA) of the European Society of Cardiology, and the Japanese Heart Failure Society (JHFS)
Circulation
· 2026 Jun · PMID 42366997
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Heart failure (HF) remains a pressing health concern, with rising prevalence globally. Subjectivity and ambiguity in the definition of HF and its antecedent stages have limited research, global surveillance, and preventi...Heart failure (HF) remains a pressing health concern, with rising prevalence globally. Subjectivity and ambiguity in the definition of HF and its antecedent stages have limited research, global surveillance, and prevention programs. To address this, several cardiac societies and foundations convened to standardize the definition of HF in 2021 and designated stage B or pre-HF to identify individuals at risk of developing HF. In subsequent years, substantial progress and changes have been made in aspects of preventing HF, improving HF diagnosis and management, and recognizing the importance of the affected individual's voice. Global differences and disparities in HF are better understood, as are causes and comorbidities leading to differences in care, which are also influenced by access to care. This consensus document presents the Second Universal Definition of Heart Failure, aiming to standardize terminology and facilitate a uniform approach for clinicians, researchers, health systems, and policymakers. In this definition, the classification of HF phenotypes moves away from rigid left ventricular ejection fraction cutoffs, instead grouping HF into reduced, preserved, and improved ejection fraction categories to better reflect clinical realities. A universal classification of HF causes is also proposed. The document also addresses the dynamic trajectories of HF-improvement, remission, and recovery-and highlights the impact of social determinants and geographic variation on HF risk and outcomes. By providing a comprehensive, standardized framework for HF definition and classification, this document seeks to improve prevention, early detection, and management of HF worldwide, ultimately enhancing patient care and advancing global cardiovascular health.
Nasilli G, Lin X, Swiatlowska P
… +10 more, Meraviglia V, Pérez-Hernández M, Zhang M, Sanchez-Alonso JL, Bellin M, Gorelik J, Rothenberg E, Casini S, Delmar M, Remme CA
BACKGROUND: Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duch...BACKGROUND: Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy. METHODS: Isolated ventricular cardiomyocytes from mice with cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (plakophilin-2), as well as -c.2013delC, and isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes were incubated for 2 to 4 hours with compounds known to decrease microtubule detyrosination (parthenolide, 10 µmol/L; EpoY, 20 µmol/L) or vehicle (dimethyl sulfoxide). Immunocytochemistry, mechano-scanning ion conductance microscopy, patch-clamp analysis, and stochastic optical reconstruction microscopy were performed. RESULTS: Cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 cardiomyocytes displayed increased microtubule detyrosination and membrane stiffness, which were both attenuated by parthenolide treatment. Parthenolide significantly increased whole-cell sodium current density in cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes, with macropatch measurements demonstrating that this increase occurred both at the intercalated disc and lateral membrane. Stochastic optical reconstruction microscopy analysis revealed that parthenolide increased cardiac sodium channel cluster density at the intercalated disc of cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes. In contrast, parthenolide had no effect on sodium current, cardiac sodium channel cluster size, or density in cardiomyocytes from control mice. -c.2013delC human-induced pluripotent stem cell-derived-cardiomyocytes displayed increased microtubule detyrosination and reduced sodium current compared with isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes, which were both prevented by parthenolide and EpoY. CONCLUSIONS: Increased microtubule detyrosination secondary to loss of PKP2 impacts cardiomyocyte (dys)function beyond the desmosome, contributing to both electrical and mechanical alterations in the setting of arrhythmogenic cardiomyopathy. Our findings identify microtubule detyrosination as a novel therapeutic target in pathophysiological conditions, such as arrhythmogenic cardiomyopathy, aimed at improving both contractile and electrical function.
Lindman BR, Gillam LD, Perpetua EM
… +17 more, Elmariah S, Otto CM, Scherrer-Crosbie M, O'Gara PT, Leon MB, Mack M, Thourani V, Gluckman TJ, Dauerman HL, Tanguturi V, Aksoy O, O'Kane S, Linn D, Jessup M, Fonarow GC, Yancy CW, Vemulapalli S
Circulation
· 2026 Jun · PMID 42360276
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BACKGROUND: Undertreatment and delayed treatment of aortic stenosis (AS) are common, both of which are associated with increased mortality. Historically, assessment of quality for AS care has focused on peri- and postpro...BACKGROUND: Undertreatment and delayed treatment of aortic stenosis (AS) are common, both of which are associated with increased mortality. Historically, assessment of quality for AS care has focused on peri- and postprocedural outcomes. The American Heart Association Target: AS registry is the first national registry to provide data and evaluate quality for upstream processes of care for patients with AS. METHODS: Randomly selected patients from 2023 and 2024 with moderate or severe AS from 58 sites in the Target: AS registry were included. The 2 primary quality measures were (1) timely diagnosis (percentage of patients with an echocardiogram consistent with possible severe AS who had all assessments to clarify AS severity and symptoms within 30 days) and (2) timely treatment (percentage of patients with a Class I indication for aortic valve replacement treated within 90 days). Secondary measures included documentation of key echocardiographic parameters in the report, clinical recommendations in the echocardiogram report summary, multidisciplinary heart valve team evaluation, guideline-based performance of multimodality testing, and timely surveillance echocardiograms. RESULTS: Among 8097 patients, 47% were women, 7% Black, 6% Hispanic, and 3% Asian. Timely diagnosis occurred in 54% in 2023, improving to 61% in 2024 (=0.027) with gaps caused by lack of timely symptom assessment (23% [2023]; 16% [2024]), lack of stroke volume index (35% [2023]; 18% [2024]), or lack of timely multimodality testing (87% [2023]; 75% [2024]). Among those with a Class I indication for aortic valve replacement, timely treatment occurred in 82% (2023) versus 85% (2024) (=NS). Multidisciplinary heart valve team evaluation occurred in 78% (2023) versus 84% (2024) (=0.008). Key findings in the echocardiography report were documented in 83% (2023) and 85% (2024) (=NS), but a clinical recommendation was included in <10% of the time. Timely surveillance echocardiograms for moderate (2 years) and severe AS (1 year) were not performed in ~40% of patients. CONCLUSIONS: The national American Heart Association Target: AS registry demonstrates opportunities for improvement in timely diagnosis, surveillance, and treatment for patients with AS at participating centers. By providing an infrastructure to measure performance and identify best practices, the Target: AS registry has the potential to elevate and optimize care and patient outcomes.