Over the past decades, the approach to cardiomyopathies has deeply evolved. It has progressively transitioned from one predominantly based on clinical evaluation and conventional imaging towards an integrated and multidimensional approach that incorporates advanced imaging techniques, tissue characterization, and comprehensive genetic testing. In this perspective, the current classification of cardiomyopathies, from the European Society of Cardiology, has introduced the new entity of non-dilated left ventricular cardiomyopathy (NDLVC) that encompasses a spectrum of diseases from hypokinetic non-dilated forms [formerly called dilated cardiomyopathies (DCMs)] to non-hypokinetic non-dilated forms, characterized by left ventricular scar (previously called arrhythmogenic cardiomyopathies). However, the pivotal principle of the new classification is that the phenotype should be considered the starting point of a dynamic diagnostic pathway rather than its ultimate definition. Contemporary evaluation of patients with DCM and NDLVC requires a longitudinal and integrative perspective in which clinical features, imaging markers, and molecular data converge to refine disease characterization. Stated that, several aspects warrant further refinement. Arrhythmic risk stratification of DCM and NDLVC remains incompletely delineated, reflecting the complex and heterogeneous nature of the underlying arrhythmogenic substrate and its variable expression across different stages of the diseases. In addition, a proportion of patients remain genetically elusive despite extensive testing, underscoring the need for deeper molecular insights. At the same time, the expanding recognition of genotype-positive/phenotype-negative individuals introduces clinical scenarios that are not yet fully delineated, particularly with regard to surveillance strategies and preventive decision-making. This review paper aims to provide a structured and evidence-informed framework to guide personalized management of DCM and NDLVC, starting from the phenotype towards precision medicine.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced NAV3 expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.NEW & NOTEWORTHY This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

AIMS:Only limited epidemiological data exist from national or international prospective multicentre registries covering the whole spectrum of cardiogenic shock (CS) aetiologies. METHODS AND RESULTS:A national prospective multicentre observational study, CZECH-SHOCK, was conducted in 15 main tertiary care centres in Czechia over a 12 month period from March 2023 to February 2024. A total of 418 patients with a median age of 70 (interquartile range 59-76) years were enrolled. The majority of patients was males (69.6%). A newly developed heart failure was observed in 76.8% patients, and acute myocardial infarction complicated by CS was the most frequent cause of a CS episode (56.7%). Mechanical circulatory support devices were utilized in 28.2% of cases. A 30 day mortality was 39.5%. In a multivariate analysis, six independent factors were associated with a higher 30 day mortality: age [odds ratio (OR) per 10-year increase: 1.78, 95% confidence interval (CI): 1.45-2.19], history of coronary artery disease (OR: 2.38, 95% CI: 1.41-4.30), history of chronic obstructive pulmonary disease (OR: 2.58, 95% CI: 1.27-5.25), Society for Cardiovascular Angiography and Interventions class on admission (OR per one class increase: 1.64, 95% CI: 1.27-2.11), renal replacement therapy during in-hospital stay (OR: 2.46, 95% CI: 1.32-4.59), and new mechanical ventilation after admission (OR: 4.58, 95% CI: 2.50-8.39). CONCLUSION:Acute myocardial infarction complicated by CS still represents the most frequent cause of CS episodes. The in-hospital mortality of patients with CS remains high, despite frequent utilization of haemodynamic support and organ replacement therapies.

AbstractAimsRecent‐onset dilated cardiomyopathy (RODCM) is characterized by heterogeneous aetiology and diverse clinical outcomes, with scarce data on genotype–phenotype correlates. Our aim was to correlate individual RODCM genotypes with left ventricular reverse remodelling (LVRR) and clinical outcomes.Methods and resultsIn this prospective study, a total of 386 Czech RODCM patients with symptom duration ≤6 months underwent genetic counselling and whole‐exome sequencing (WES). The presence of pathogenic (class 5) or likely pathogenic (class 4) variants in a set of 72 cardiomyopathy‐related genes was correlated with the occurrence of all‐cause death, heart transplantation, or implantation of a ventricular assist device (primary outcome) and/or ventricular arrhythmia event (secondary outcome). LVRR was defined as an improvement of left ventricular ejection fraction to >50% or ≥10% absolute increase, with a left ventricular end‐diastolic diameter ≤33 mm/m2 or ≥10% relative decrease. Median follow‐up was 41 months. RODCM was familial in 98 (25%) individuals. Class 4–5 variants of interest (VOIs) were identified in 125 (32%) cases, with 69 (18%) having a single titin‐truncating variant (TTNtv) and 56 (14%) having non‐titin (non‐TTN) VOIs. The presence of class 4–5 non‐TTN VOIs, but not of TTNtv, heralded a lower probability of 12‐month LVRR and proved to be an independent baseline predictor both of the primary and the secondary outcome. The negative result of genetic testing was a strong protective baseline variable against occurrence of life‐threatening ventricular arrhythmias. Detection of class 4–5 VOIs in genes coding nuclear envelope proteins was another independent predictor of both study outcomes at baseline and also of life‐threatening ventricular arrhythmias after 12 months. Class 4–5 VOIs of genes coding cytoskeleton were associated with an increased risk of life‐threatening ventricular arrhythmias after baseline assessment. A positive family history of dilated cardiomyopathy alone only related to a lower probability of LVRR at 12 months and at the final follow‐up.ConclusionsRODCM patients harbouring class 4–5 non‐TTN VOIs are at higher risk of progressive heart failure and life‐threatening ventricular arrhythmias. Genotyping may improve their early risk stratification at baseline assessment.

McDonagh TA, M Metra, M Adamo, Gardner RS, A Baumbach, M Böhm, H Burri, J Butler, J Čelutkienė, O Chioncel, Cleland JGF, Crespo-Leiro MG, D Farmakis, M Gilard, S Heymans, Hoes AW, T Jaarsma, Jankowska EA, M Lainscak, Lam CSP, Lyon AR, McMurray JJV, A Mebazaa, R Mindham, C Muneretto, Piepoli MF, S Price, Rosano GMC, F Ruschitzka, Skibelund AK, McDonagh TA, M Metra, M Adamo, Gardner RS, A Baumbach, M Böhm, H Burri, J Butler, J Čelutkienė, O Chioncel, Cleland JGF, Crespo-Leiro MG, D Farmakis, M Gilard, S Heymans, Hoes AW, T Jaarsma, Jankowska EA, M Lainscak, Lam CSP, Lyon AR, McMurray JJV, A Mebazaa, R Mindham, C Muneretto, Piepoli MF, S Price, Rosano GMC, F Ruschitzka, Skibelund AK, Jan Krejčí, Lenka Špinarová, Jiří Pařenica, Anna Chaloupka, Jiří Veselý

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 −7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionaly abnormal in the absence of a disease sufficient to cause this abnormality such as coronary artery disease, hypertension, valvular or congenital heart disease. According to the phenotype expresion cardiomyopathies are divided into dilated, hypertrophic, restrictive, arrhytmogenic and unclassified cardiomyopathies (noncompaction and tako-tsubo cardiomyopathy). The same phenotypic expression may include etiologically different forms of the disease, and at the same time phenotypic expression may change in many cardiomyopathies in the course of illness. For each type of cardiomyopathy, we further distinguish the familial (genetic) form and the acquired form. The clinical manifestation of the disease includes symptoms of heart failure, with reduced, mildly reduced or preserved ejection fraction, symptoms resulting from a number of arrhythmias and extracardiac symptoms, but in some cases symptoms may not be presented for a relatively long time. The disease can lead to significant morbidity and mortality if not detected and treated early, especially in young people who are frequently affected. Significant developments in diagnostic and treatment methods have led to an improvement in the prognosis of patients with cardiomyopathies in recent years.

Introduction: Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous etiology and diverse clinical outcomes. Hypothesis: We hypothesized that the genotype of RODCM might correlate with left ventricular reverse remodeling (LVRR) and long-term clinical outcomes. Methods: A total of 386 RODCM patients (pts) [age 44±12 years, 277 males (72%), familial in 98 pts (25%)] with a history of symptoms less than six months underwent whole-exome sequencing (WES) where likely-pathogenic and pathogenic (class 4-5) disease-causing variants were identified. LVRR was defined as an improvement in left ventricular ejection fraction to >50% or ≥10% absolute increase, with left ventricular end-diastolic diameter ≤33 mm/m2 or ≥10% relative decrease. In this prospective study, the primary outcome was the first event of all-cause death, heart transplantation or ventricular assist device. The secondary outcome included sudden cardiac death, resuscitated cardiac arrest or treated ventricular tachyarrhythmias. Results: WES detected class 4-5 titin truncated variants ( TTNtv ) in 69 pts (19%), class 4-5 non-titin variants (non- TTN ) (Figure) in 56 pts (14%), variants of unknown significance only in 103 pts (27%) and a negative result in 158 pts (40%). At 12 months, LVRR was assessed in 359 pts and was present in 171 pts (48%). Carriers of class 4-5 non- TTN variants developed LVRR less frequently than subjects with other genetic testing results (28% vs. 51%, p˂0.01). During a median follow-up of 55 months, the primary and secondary outcomes occurred in 79 pts (20%) and 50 pts (13%), respectively. Carriers of class 4-5 non- TTN variants had an increased risk of both primary [HR 2.36 (95% CI 1.32-4.20), p˂0.01] and secondary [HR 3.08 (95% CI 1.42-6.67), p˂0.01] outcomes as compared with genotype-negative pts. In multivariable models, genotype remained a strong predictor of both types of outcome. Conclusions: Among RODCM patients, carriers of class 4-5 non- TTN variants have an increased risk of death and progressive heart failure, and a higher long-term burden of life-threatening ventricular arrhythmias compared to genotype-negative subjects. Funding: Supported by the research grant of the Ministry of Health, Czech Republic: [NV19-08-00122] and IPO 00023001.

Left ventricular (LV) involvement in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is not evaluated in the revised Task Force Criteria, possibly leading to underdiagnosis. This study explored the diagnostic role of myocardial native T1 mapping in patients with ARVC and their first-degree relatives. Thirty ARVC patients (47% males, mean age 45 ± 27 years) and 59 first-degree relatives not meeting diagnostic criteria underwent CMR with native T1 mapping. C MR was abnormal in 26 (87%) patients with ARVC. The right ventricle was affected in isolation in 13 (43%) patients. Prior to T1 mapping assessment, 2 (7%) patients exhibited isolated LV involvement and 11 (36%) patients showed features of biventricular disease. Left ventricular involvement was manifest as detectable LV late gadolinium enhancement (LGE) in 12 out of 13 cases. According to pre-specified inter-ventricular septal (IVS) T1 mapping thresholds, 11 (37%) patients revealed raised native T1 values including 5 out of the 17 patients who would otherwise have been classified as exhibiting a normal LV by conventional imaging parameters. Native septal T1 values were elevated in 22 (37%) of the 59 first-degree relatives included. Biventricular involvement is commonly observed in ARVC; native myocardial T1 values are raised in more than one third of patients, including a significant proportion of cases that would have been otherwise classified as exhibiting a normal LV using conventional CMR techniques. The significance of abnormal T1 values in first-degree relatives at risk will need validation through longitudinal studies.

AIMS:Danon disease (DD) is a rare X-linked disorder caused by mutations in the lysosomal-associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20-40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non-ischemic cardiomyopathy, who reached AHF and were younger than 40 years. METHODS AND RESULTS:The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre-transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, * P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, ** P = 0.002) were significantly more frequent in DD female patients. CONCLUSIONS:Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.

T1 mapping by cardiovascular magnetic resonance (CMR) is an accurate tool to assess myocardial extracellular space with wider clinical applications in the aetiological characterization of cardiomyopathies. The aims of the study were to explore a possible role of myocardial T1 mapping in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and in first-degree relatives at risk and to investigate the possible relationship between left ventricular (LV) involvement at CMR and ECG features. Thirty patients with ARVC (47% males, mean age 42±22 years) and 59 first-degree relatives who did not fulfil ARVC diagnostic Task Force criteria, underwent full diagnostic work-up including CMR with native and post-contrast T1 mapping. The CMR was abnormal in 26 (86%) patients with ARVC. The RV was affected in isolation in 13 (43%) patients. Prior to T1 mapping assessment, 2 (7%) patients exhibited isolated LV involvement and 11 (36%) patients showed features of biventricular disease. Left ventricular involvement was manifested as detectable LV late gadolinium enhancement (LGE) in 12 out of 13 cases. According to pre-specified septal T1 mapping thresholds, 11 (37%) patients showed abnormally high native T1 values. Myocardial T1 mapping was higher than normal in 5 (17%) patients who would have been classified as exhibiting a normal LV by conventional imaging. The proportion of patients with abnormal T1 values was similar in patients with or without LGE. Myocardial T1 mapping was higher than normal in 22 (37%) of the 59 first-degree relatives. Native and/or post contrast myocardial T1 values are raised in almost half of patients with ARVC and in a similar proportion of unaffected first-degree relatives. T1 mapping offers the potential for early detection of LV involvement in patients with ARVC and in first-degree relatives at risk. Type of funding source: None

Dilated cardiomyopathy and myocarditis are associated with an increased risk of cardiac arrhythmias. They represent one of the leading causes of sudden cardiac death in young athletes <35 years of age. Cardiac adaptation to an intense physical exercise is by itself linked to an array of electric, morphologic and functional changes comprising what is known as athletic heart. Discrimination of this physiologic adaptation from pathological findings is essential for risk stratification. The aim of this work is an overview of the current knowledge in differential diagnostics of dilated cardiomyopathy and myocarditis from the athletic heart, identification of individuals in high risk of sudden cardiac death, and a summary of recommendations regarding sports activity.

Dilatacni kardiomyopatie a myokarditida jsou spojeny se zvýseným rizikem srdecnich arytmii a jsou jednou z hlavnich přicin nahle srdecni smrti sportovců mladsich 35 let. Adaptace srdce na intenzivni fyzickou zatěž je sama o sobě spojena s řadou elektrických, morfologických a funkcnich změn pod obrazem tzv. atletickeho srdce. Odliseni fyziologicke adaptace od patologickeho nalezu je zcela zasadni pro rizikovou stratifikaci. Cilem teto prace je shrnuti soucasných poznatků v diferencialni diagnostice dilatacni kardiomyopatie a myokarditidy od atletickeho srdce, identifikace jedinců ve vysokem riziku nahle srdecni smrti a shrnuti doporuceni ve vztahu ke sportovni aktivitě. © 2020, CKS.

Dilatacni kardiomyopatie a myokarditida jsou spojeny se zvýseným rizikem srdecnich arytmii a jsou jednou z hlavnich přicin nahle srdecni smrti sportovců mladsich 35 let. Adaptace srdce na intenzivni fyzickou zatěž je sama o sobě spojena s řadou elektrických, morfologických a funkcnich změn pod obrazem tzv. atletickeho srdce. Odliseni fyziologicke adaptace od patologickeho nalezu je zcela zasadni pro rizikovou stratifikaci. Cilem teto prace je shrnuti soucasných poznatků v diferencialni diagnostice dilatacni kardiomyopatie a myokarditidy od atletickeho srdce, identifikace jedinců ve vysokem riziku nahle srdecni smrti a shrnuti doporuceni ve vztahu ke sportovni aktivitě. © 2020, CKS.