Sarcomeric Mutations Research Articles

Myocardial DNA damage combined with genotype predicts heart failure outcome in various underlying diseases

Abstract Background Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure. Purpose To investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure from various etiologies; and to elucidate the relationships between genotypes and DNA damage, as well as their additive effect in prognosis prediction. Methods We performed immunostaining of DNA damage markers, poly(ADP-ribose) (PAR) and γ-H2A.X on biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. We calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at ∼1 year. The secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation. Whole-exome data from consenting patients were further analyzed to classify pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy-related genes. We compared the degree of DNA damage among different genotypes, and examined the additive effect of combining DNA damage markers and genotypes in predicting treatment response. Results The participants had a mean age of 56 years, of whom 72% were men. Among them, 55% achieved LVRR at ∼1 year. Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X when compared with those who did [%PAR, 11 (6–19) % vs. 2 (1–4) %, P < 0.001; %γ-H2A.X, 22 (11–40) % vs. 5 (2–9) %, P < 0.001] (Figure, left bottom). The receiver-operating characteristic (ROC) analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (area under the curve 0.87 and 0.85, respectively). Patients with lower %PAR or %γ-H2A.X had reduced long-term clinical events [PAR, hazard ratio 1.63 (95%CI 1.31- 2.01), P < 0.001; γ-H2A.X, 1.48 (1.27-1.72), P < 0.001] (Figure, left bottom). In addition, there was a strong negative correlation between the mean proportion of DNA damage marker positive nuclei and the probability of LVRR, across different underlying diseases (Figure, middle). Genotypes were identified in 105 patients (Figure, right top). Non-sarcomeric mutation (LMNA, etc) carriers presented with more pronounced DNA damage than sarcomeric mutation carriers (TTN, MYBPC3) (Figure, right bottom). Combination of genotypes and %γ-H2A.X augmented the area under the ROC for predicting 1-year LVRR to 0.90, from that of %γ-H2A.X alone at 0.85. Conclusions The degree of DNA damage accumulation in myocardial tissue differs by underlying diseases and genotypes, and determines the consequences of human heart failure. Assessment of DNA damage, especially when combined with genotype, is useful to predict treatment efficacy and prognosis of HFrEF patients with various underlying etiologies.graphical abstract

Assessment of Myocardial Work in sarcomere gene mutation carriers and overt hypertrophic cardiomyopathy

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease defined by unexplained hypertrophy and often characterized by diastolic and systolic dysfunction. In recent studies, HCM patients were found to have impaired left ventricular (LV) myocardial work (MW), a more load-independent parameter compared to global longitudinal strain (GLS). MW was never studied in sarcomere mutation carriers. Aim To compare MW between sarcomere mutation carriers, healthy controls and overt HCM. Methods A single centre study with a case-control design. The study population comprised 3 groups: overt HCM patients with a likely pathogenic/pathogenic sarcomere gene variant (n=51), carriers (n=51) and age and sex matched (to the carriers) healthy controls (n=32). All participants (pts) underwent a transthoracic echocardiogram including myocardial deformation analysis to calculate global longitudinal strain (GLS) and MW. MW was calculated from same-day non-invasive blood pressure evaluation. Global work index (GWI), Global constructive work (GCW), Global work efficiency (GWE) and Global wasted work (GWW) were obtained. Results GWI (1695mmHg% vs 1869mmHg%, p=0.001) and GCW (1993mmHg% vs 2244mmHg%, p<0.001) were lower in sarcomere mutation carriers compared to controls. LVEF and GLS were similar between the two groups (p=0.233). HCM pts were older (p<0.001), less likely female (p=0.01) and had a higher prevalence of cardiovascular (Cv) comorbidities, including hypertension (p<0.001), compared with sarcomere gene mutation carriers. Global work index (GWI) (1209mmHg%vs1695mmHg%), global constructive work (1456mmHg% vs 1993mmHg%, p<0.001) and global work efficiency (GWE) (89% vs 95%, p<0.001) were significantly lower in overt HCM compared with sarcomere mutation carriers. GWW was higher (117mmHg% vs 95mmHg%, p=0.006) in overt HCM. Conclusion In this study, we show for the first time that MW indexes were significantly worse in sarcomere gene mutation carriers compared to controls. GLS and MW indexes were also significantly different between overt HCM and sarcomere gene mutation carriers. These data suggest that MW is more sensitive to early changes than GLS and could play a major role in the evaluation and follow-up of sarcomere mutation carriers.

Abstract 16516: CMR-ECG Imaging in Hypertrophic Cardiomyopathy Detects Electrophysiological Abnormalities Before Hypertrophy or ECG Changes

INTRODUCTION: In hypertrophic cardiomyopathy (HCM), ventricular arrhythmia associates with severity of LVH and scar, and presence vs absence of a sarcomeric gene mutation (G+LVH+ vs G-LVH+). Also, ECG changes in subclinical HCM (G+LVH-) signal increased risk of phenotype progression. HYPOTHESES: ECG Imaging (ECGI) can detect: i) subtle electrophysiological (EP) abnormalities in subclinical HCM (pre-LVH). ii) EP abnormalities related to genetic status (G+ vs G-LVH+) and structural changes (late gadolinium enhancement [LGE], max. wall thickness [MWT]) in overt disease. METHODS: 200 participant multicenter study: 70 G+LVH-, 51 G+LVH+, 53 G-LVH+ and 26 healthy volunteers (HV) underwent 12-lead ECG (to detect abnormal Q-waves, repolarization changes, LVH criteria) and CMR-ECGI computing epicardial unipolar electrograms (UEGs) to derive: activation time (AT), activation-recovery intervals (ARIc), spatial gradients (activation: G AT , repolarisation: G RT ) and fractionation. RESULTS: Compared to HV, G+LVH- had prolongation of AT (40.3±7.3 vs 35.4±6.1 ms p=0.003) and steeper G RT (mean: 1.12±0.27 vs 1.00±0.23 ms/mm p=0.042, max: 11.7±2.8 vs 10.0±1.9 ms/mm p=0.005). AT was prolonged even in G+LVH- with a normal 12-lead ECG (p<0.004). Compared to G+LVH-, G+LVH+ had similar AT but a more prolonged ARIc (275±29 vs 245±26 ms p<0.001). Compared to G-LVH+, G+LVH+ had similar MWT and LGE, but more signal fractionation (0.02±0.02 vs 0.01±0.03% UEGs with ≥2 deflections p=0.002). In overt HCM (all LVH+), MWT associated with AT ( r s 0.25 p=0.011) while LGE burden associated with G AT ( r s=0.27 p=0.006) and fractionation ( r s=0.22 p=0.025). CONCLUSION: Cardiac activation prolongation and repolarization abnormalities occur in subclinical HCM (before hypertrophy). Activation is prolonged even in subclinical HCM with normal 12-lead ECG. In overt HCM, ECGI abnormalities track adverse structural changes and reveal greater fractionation in those with a sarcomeric mutation.

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

Mechano-energetic efficiency in patients with hypertrophic cardiomyopathy with and without sarcomeric mutations.

Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomeric mutations which may affect myocardial mechano-energetic efficiency (MEE). We investigated the effects of sarcomeric mutations on MEE. A non-invasive pressure/volume (P/V) analysis was performed. We included 49 genetically screened HCM patients. MEEi was calculated as the ratio between stroke volume and heart rate normalized by LV mass. Fifty-seven percent (57%) HCM patients carried a sarcomeric mutation. Patients with and without sarcomeric mutations had similar LV ejection fraction, heart rate, LV mass, and LV outflow gradient. Younger age at diagnosis, family history of HCM, and lower MEEi were associated with presence of sarcomeric mutation (p = 0.017; p = 0.001 and p = 0.0001, respectively). Lower MEEi in HCM with sarcomeric mutation is not related to significant differences on filling pressure as shown on P/V analysis. Sarcomeric mutations determine a reduction of the LV pump performance as estimated by MEEi in HCM. Lower MEEi may predict a positive genetic analysis.

The challenge of risk stratification in hypertrophic cardiomyopathy: Clinical, genetic and imaging insights from a quaternary referral centre

BackgroundHypertrophic cardiomyopathy (HCM) is the commonest genetic cardiomyopathy and may result in sudden cardiac death (SCD). Clinical risk stratification scores are utilised to estimate SCD risk and determine potential utility of a primary prevention implantable cardioverter defibrillator (ICD). MethodsPatients with a confirmed diagnosis of HCM from a quaternary HCM service were defined according to clinical characteristics, genetic profiles and cardiac imaging results. European Risk-SCD score and American Heart Association / American College of Cardiology (AHA/ACC) Score were calculated. The primary outcome was cardiac arrest. Results380 patients with HCM were followed up for a median of 6.4 years. 18 patients (4.7%) experienced cardiac arrest, with predictive factors being younger age (37.2 vs 54.4 years, p = 0.0041), unexplained syncope (33.3% vs 9.4%, p = 0.007), non-sustained ventricular tachycardia (50.0% vs 12.7%, p < 0.0001), increased septal thickness (21.5 vs 17.5 mm, p = 0.0003), and presence of a sarcomeric gene mutation (100.0% vs 65.8%, p = 0.038). The Risk-SCD and AHA/ACC scores had poor agreement (kappa coefficient 0.38). Risk-SCD score had poor sensitivity (44.4%), classifying 55.6% of patients with cardiac arrest as low-risk but was highly specific (93.7%). AHA/ACC risk score did not discriminate between groups significantly. 20 patients (5.3%) died, with most >60-year-olds having a non-cardiac cause of death (p = 0.0223). ConclusionThis study highlights limited (38%) agreement between the Risk-SCD and AHA/ACC scores. Most cardiac arrests occurred in ostensibly low or medium-risk patients under both scores. Appropriate ICD selection remains challenging. Incorporating newer risk markers such as HCM genotyping and myocardial fibrosis quantification by cardiac MRI may assist future risk refinement.

Hypertrophic Cardiomyopathy Diagnosis and Treatment in High- and Low-Income Countries: A Narrative Review.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac condition characterized by unexplained left ventricular hypertrophy without a hemodynamic cause. This condition is prevalent in the United States, resulting in various clinical manifestations, including diastolic dysfunction, left ventricular outflow obstruction, cardiac ischemia, and atrial fibrillation. HCM is associated with several genetic mutations, with sarcomeric mutations being the most common and contributing to a more complex disease course. Early diagnosis of HCM is essential for effective management, as late diagnosis often requires invasive treatments and creates a substantial financial burden.Disparities in HCM diagnosis and treatment exist between high-income and low-income countries. High-income countries have more resources to investigate and implement advanced diagnostic and treatment modalities. In contrast, low-income countries face challenges in accessing diagnostic equipment, trained personnel, and affordable medications, leading to a lower quality of life and life expectancy for affected individuals. Diagnostic tools for HCM include imaging studies such as 2D echocardiography, cardiovascular magnetic resonance (CMR), and electrocardiograms (ECGs). CMR is considered the gold standard but remains inaccessible to a significant portion of the world's population, especially in low-income countries. Genetics plays a crucial role in HCM, with numerous mutations identified in various genes. Genetic counseling is essential but often limited in low-income countries due to resource constraints. Disparities in healthcare access and adherence to treatment recommendations exist between high-income and low-income countries, leading to differences in patient outcomes. Addressing these disparities is essential to improve the overall management of HCM on a global scale. In conclusion, this review highlights the complex nature of HCM, emphasizing the importance of early diagnosis, genetic counseling, and access to appropriate diagnostic and therapeutic interventions. Addressing healthcare disparities is crucial to ensure that all individuals with HCM receive timely and effective care, regardless of their geographic location or socioeconomic status.

Association between left atrial myopathy and sarcomere mutation in patients with hypertrophic cardiomyopathy: insights into left atrial strain by MRI feature tracking.

Left atrial (LA) myopathy, characterized by LA enlargement and mechanical dysfunction, is associated with worse prognosis in hypertrophic cardiomyopathy (HCM) while the impact of sarcomere mutation on LA myopathy remains unclear. We aimed to assess the association between LA myopathy and sarcomere mutation and to explore the incremental utility of LA strain in mutation prediction. A total of 105 consecutive HCM patients (mean age 47.8 ± 11.9years, 71% male) who underwent HCM-related gene screening and cardiac MRI were retrospectively enrolled. LA volume, ejection fraction and strain indices in reservoir, conduit, and booster-pump phases were investigated respectively. Fifty mutation-positive patients showed higher LA maximal volume index (59.4 ± 28.2 vs 43.8 ± 18.1mL/m2, p = 0.001), lower reservoir (21.3 ± 7.9 vs 26.2 ± 6.6%, p < 0.001), and booster-pump strain (12.1 ± 5.4 vs 17.1 ± 5.0%, p < 0.001) but similar conduit strain (9.2 ± 4.5 vs 9.1 ± 4.5%, p = 0.909) compared with mutation-negative patients. In multivariate logistic regression, LA booster-pump strain was associated with sarcomere mutation (odds ratio = 0.86, 95% confidence interval: 0.77-0.96, p = 0.010) independent of maximal wall thickness, late gadolinium enhancement, and LA volume. Furthermore, LA booster-pump strain showed incremental value for mutation prediction added to Mayo II score (AUC 0.798 vs 0.709, p = 0.024). In HCM, mutation-positive patients suffered worse LA enlargement and worse reservoir and booster-pump functions. LA booster-pump strain was a strong factor for sarcomere mutation prediction added to Mayo II score. The independent association between sarcomere mutation and left atrial mechanical dysfunction provide new insights into the pathogenesis of atrial myopathy and is helpful to understand the adverse prognosis regarding atrial fibrillation and stroke in mutation-positive patients. • In patients with hypertrophic cardiomyopathy, left atrial (LA) reservoir and booster-pump function, but not conduit function, were significantly impaired in mutation-positive patients compared with mutation-negative patients. • LA booster-pump strain measured by MRI-derived feature tracking is feasible to predict sarcomere mutation with high incremental value added to Mayo II score.

The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye.

Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy. A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes. The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease. Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.

Evidence for microstructural alteration and microvascular disease in subclinical and overt hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation - Clinical Research Training Fellowship Background Disarray and microvascular disease (MVD) are implicated in adverse events in hypertrophic cardiomyopathy (HCM). Advances in CMR permit quantification of microstructural indices reflecting disarray, and microvascular disease. As novel myosin inhibitors provide promise for disease modification, early and disease-specific biomarkers are a rapidly emerging clinical priority. Purpose Using latest imaging techniques, we investigated MVD and disarray in 3 HCM groups: overt disease, either genotype positive (G+LVH+) or negative (G-LVH+), and subclinical HCM (G+LVH-), exploring relationships to electrical changes and genetic substrate. Methods A 207 subject, multi-centre consortium: 102 patients with overt HCM (52 G+LVH+, 50 G-LVH+), 77 subclinical (G+LVH-) and 28 matched healthy volunteers (HV). All underwent ECG, quantitative perfusion (measuring myocardial blood flow (MBF), perfusion reserve (MPR) and perfusion defects) and cardiac diffusion tensor imaging (cDTI) to investigate for evidence of disarray, measured as fractional anisotropy (FA – the directional variability of diffusion, reflecting myocyte disarray), mean diffusivity (MD – reflecting myocyte packing and intra- and extracellular volume) and absolute second eigenvector angle (E2A –measuring orientation of sheetlets, functional units of myocytes that re-orientate to facilitate wall-thickening). Results Compared to HV, overt HCM had evidence of microstructural alteration (lower FA (suggestive of disarray), higher MD and higher E2A, all p&amp;lt;0.001) and MVD (lower stress MBF and MPR p&amp;lt;0.001). Compared to G+LVH+, G-LVH+ had elevated E2A (64.4°(58.7–66.5) vs 60.1°(55.6–63.7 p = 0.006)). Perfusion defects were found in all G+ but not all G- overt disease (100%(52/52) vs 82%(41/50) p = 0.001). Compared to HV, subclinical HCM (G+LVH-) had evidence of microstructural alteration (lower FA suggestive of disarray, higher MD and higher E2A, all p&amp;lt;0.001) and MVD (reduced stress MBF (2.43±0.52 vs 2.77±0.62ml/g/min p = 0.006) with perfusion defects in 29% (vs 0 HV p = 0.001)). Microstructural markers and MVD were independently associated, in both overt and subclinical disease (overt: E2A and stress MBF: β=-0.29, p = 0.002; subclinical: those with perfusion defects (vs without) had lower FA &amp; higher E2A). Disarray markers and MVD independently associated with pathological ECG abnormalities in both overt and subclinical disease, after adjustment for degree of fibrosis and LVH (overt: FA odds ratio (OR) for abnormal ECG=3.2, p = 0.014; stress MBF OR=2.8, p = 0.013; subclinical: FA OR=3.4, p = 0.006, MPR OR=4.0 p = 0.008). Conclusions In Hypertrophic Cardiomyopathy, sarcomere mutation carriers without hypertrophy have microstructural alterations and microvascular disease that are detectable, correlate, and associate with pathological ECG changes. These are more prominent once LVH is present, with genotype positive and genotype negative overt disease patients having differing phenotypes.

P1 NEW TREATMENT STRATEGIES IN PATIENTS WITH SENILE CARDIAC AMYLOIDOSIS

Abstract We present the case of a 75 year–old man, diabetic, dyslipidemic, hypertensive, previous ischemic heart disease, AF, previous hospitalizations for heart failure, who underwent cardiology evaluation for worsening dyspnea (NYHA class II–III), swallen ankles and elevated BNP levels (900 pg/ml). The patient suffered from sensory–motor polyneuropathy diagnosed with EMG and ENG. Echocardiographic evaluation: severe concentric hypertrophy of the left ventricle (SIV 18 mm, PP 17 mm), granular sparkling and EF 50%, left atrium dilatation, light–moderate mitral regurgitation, moderate tricuspid regurgitation with PAPS 40–45 mmHg. Circumferential pericardial effusion (12 mm). Moreover, we noticed a decreased longitudinal contractive function of the left ventricle (TDI e‘, a’, e s’ &amp;lt;5 cm/s e absolute GLS &amp;lt; 15%), speckle–tracking ‘cherry on the top‘ and restrictive diastolic pattern. •ECG: low QRS voltage and increased wall thickness (&amp;gt;12 mm). •Laboratory: (SPIE and UPIE) no monoclonal protein present. •Bone scintigraphy: grade 3 cardiac uptake. •Cardiac MRI: asymmetric hypertrophy of the left ventricle with moderate biventricular systolic dysfunction. Subendocardial late gadolinium enhancement. •Genetic testing: no sarcomeric or TTS gene mutations. All findings were suggestive for senile cardiac amyloidosis (ATTR wt), the patient was discharged from the hospital with optimized medical therapy for heart failure and follow up was prescribed. After 3 months from the first diagnosis we added Tafamidis to the therapy (ESC indications class IB). ATTR–ACT, published on ‘New England Journal of Medicine’ showed that Tafamis is superior to placebo in reducing the combination of all–cause mortality and cardiovascular–related hospitalizations. Tafamidis was also associated with a significant reduction in the decline in functional capacity (as measured by the 6–minute walk test) and the decline in quality of life (as measured by the KCCQ–OS) at month 30, with differences first observed at 6 months. Tafamidis was well–tolerated, with a safety profile comparable to placebo. Follow–up: 6 months later the introduction of Tafamidis, the patient has not needed other hospitalizations for heart failure, well tolerates the drug with a subjective symptom reduction and remarkable improvement in quality of life.

C16 NONCOMPACTION OF VENTRICULAR MYOCARDIUM AND X–LINKED RECESSIVE ICHTYOSIS

Abstract Noncompact left ventricle is a rare congenital cardiomyopathy characterized by numerous ventricular trabeculae separated by deep intertrabecular recesses. It can occur in isolation or in association with neuromuscular disorders and congenital heart defects. The cause is not known but it is thought to be due to the arrest of the normal maturation process of the myocardium. Among the responsible mutations are taffazzine, ZASP and distrobrevin. It can manifest as left ventricular dilatation and dysfunction, arrhythmias, thromboembolic events, and sepsis. The echocardiogram is the investigation of first choice. Magnetic resonance allows you to more precisely distinguish compact and non–compact layers, thrombi and myocardial fibrosis. Clinical case A 19–year–old patient came for syncope. She presented with midfacial hypoplasia, cupped ears, synophrium, high palate, ichthyosis, small hands, and scarring from Achilles tendon lengthening. She denied a family history of cardiovascular disease and sudden cardiac death. Karyotype analysis showed karyotype 46Y, –X, + der t (X; Y) (p22.2; q11.1), with a chromosome derived from the X;Y translocation (a feature already known in the mother and in several maternal relatives ). Coronary angiography, electroencephalogram and brain MRI were within limits. Echocardiogram and MRI showed non–compact myocardium at the left ventricular apex and mild ventricular dysfunction with areas of anterior and posterior dyssynergia (Fig. 1). The ECG showed high QRS voltages. The Holter ECG showed numerous supraventricular extrasystoles even in pairs and runs, rare PVCs, and nocturnal pauses of up to 3 seconds. The patient underwent genetic screening by NGS for sarcomeric mutations which resulted negative. Subsequent genetic analysis showed deletion in two chromosomal regions that could be interpreted as pathogenic (chromosomal region Xp22.33 containing the SHOX gene and involving the deleted locus in Leri–Weill dyschondrosteosis and in the Xp22.33p22.31 region containing the STS gene involving the locus deleted in X–linked recessive ichthyosis) and a duplication in the chromosomal region Yq11.221q11.23 of uncertain significance. Conclusions After review of the scientific literature, the association of the illustrated complex deletion and translocation with non–compact myocardium represents a new finding, worthy of being explored in genetically affected patients.

Contribution of artificial intelligence and left atrial strain in the prediction of sudden cardiac death in hypertrophic cardiomyopathy. Results of a multicentric cohort

Sudden cardiac death (SCD) remains a serious outcome in hypertrophic cardiomyopathy (HCM), with an estimated incidence of 1%/year. Its risk prediction stays challenging for clinicians. Implantation of cardioverter-defibrillator is recommended with a strong level of evidence when the HCM risk score is over 6%. However, the ESC HCM risk score is criticized for its moderate diagnostic performance (C-index 0,70), and its low sensibility. Recent studies suggest that low PALS (peak atrial longitudinal strain) is associated with poor prognosis in HCM. Artificial intelligence, wich is experiencing an unprecedented boom, may be an interesting tool in association to left atrial strain in Prognostication. This preliminar study aimed to evaluate the value of the left atrial strain coupled with artificial inteligence algorythm in the prediction of suddent cardiac death in hypertrophic cardiomyopathy. This restrospective multi-center cohort (Marseille la Timone, Bordeaux and Rennes) included 431 patients with sarcomeric HCM from 2007 to 2018. The average follow-up time was 57 months. The primary endpoint was all cause death, ventricular arythmias, recovered SCD and internal electric shock. Analyses were entrusted to the LIS laboratory specialized in Computer Science at Aix-Marseille University. Sixty-six percent of men composed the cohort with a mean age of 52 ± 16 yo. Sarcomeric mutations were found in 52% of them, the mean left ventricular ejection fraction was 63 ± 16, 23% had significant ventricular obstruction. The mean PALS was 25 ± 12%. In the multivariate analysis, PALS 4 chamber, left ventricular global longitudinal strain and syncope were associated with the primary endpoint, (respectivly HR 2,48 IC95% [1,09–5,63]; P 0,030; HR 1,13 IC95% [1,03–1,25]; P 0,012; HR 0,95 IC95% [0,92–0,99]; P: 0.023). The random Forrest algorithm was able to successfully classify the patient (occurrence of primary endpoint or not) in 92,2% of the cases. Left atrial strain coupled with the Random Forrest algorithm could offer an interesting implementative value for the prediction of sudden cardiac death in hypertrophic cardiomyopathy. Further analysis are required to define its sensibility and specificity.

A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies.

In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding mutant proteins of the sarcomere. We recently reported an upregulation of elements in the Notch signalling cascade in cardiomyocytes derived from human inducible pluripotent stem cells expressing a TNNT2 variant encoding cardiac troponin T (cTnT-I79N+/-), which induces hypertrophy, remodelling, abnormalities in excitation-contraction coupling and electrical instabilities (Shafaattalab S et al. 2021 Front. Cell Dev. Biol. 9, 787581. (doi:10.3389/fcell.2021.787581)). Our search of the literature revealed the novelty of this finding and stimulated us to discuss potential connections between the Notch signalling pathway and familial cardiomyopathies. Our considerations focused on the potential role of these interactions in arrhythmias, microvascular ischaemia, and fibrosis. This finding underscored a need to consider the role of Notch signalling in familial cardiomyopathies which are trigged by sarcomere mutations engaging mechano-signalling pathways for which there is evidence of a role for Notch signalling with crosstalk with Hippo signalling. Our discussion included a role for both cardiac myocytes and non-cardiac myocytes in progression of HCM and DCM. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Pathogenic BCS1L Mutation Resulting in Hypertrophic Cardiomyopathy: A Unique Presentation of Nuclear Mitochondrial Disease.

A 21-year-old man with sensorineural hearing loss and glaucoma presented with severely limited exercise capacity since childhood. He was found to have biventricular concentric hypertrophy with greatest wall thickening at the posterior and lateral walls of the left ventricle apex (1.7 cm) and the free wall of the right ventricle (1.1 cm). There was no inducible left ventricular outflow tract obstruction. Metabolic testing revealed marked lactic aciduria (1,650.1 μmol/mmol creatinine) and plasma lactate (3.9 mmol/L). A sarcomeric hypertrophic cardiomyopathy gene panel was unremarkable, but mitochondrial gene analysis revealed a homozygous c.385G>A (p.Gly129Arg) pathogenic mutation in the BCS1L gene. This gene is responsible for an assembly subunit of cytochrome complex III in the respiratory transport chain and is the rarest respiratory chain defect. This gene has not frequently been implicated in cardiomyopathy. Mitochondrial hypertrophic cardiomyopathy is more rare than hypertrophic cardiomyopathy resulting from sarcomeric mutations and is more likely to be symmetric, less frequently results in left ventricular outflow tract obstruction, and is more likely to progress to dilated cardiomyopathy. Evidence-based screening protocols have not been established; treatment follows guideline-directed medical therapy for congestive heart failure, including evaluation for heart transplantation. This report expands the phenotype of the BCS1L mutation and suggests that affected patients may need screening for underlying cardiomyopathy.

Multi-scale modeling will unravel connections between sarcomeric mutations and cardiomyopathies

Multi-scale modeling will unravel connections between sarcomeric mutations and cardiomyopathies

HCM and DCM associated TNNT2 sarcomeric variants induce nucleus remodeling in human iPSC-CMs.

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are associated with sarcomeric protein mutations in thick- and thin-filament genes, particularly in the gene TNNT2, which encodes cardiac troponin T (cTnT). Mutations in cTnT can lead to altered contractility dynamics and a high incidence of sudden cardiac death. Human-induced pluripotent stem cells cardiomyocytes (hiPSC-CMs) model offers an effective method to investigate cardiac diseases in vitro. We analyze morphological and functional alterations in two common mutations associated with HCM and DCM, cTnT I79N and cTnT R141W, respectively. We performed experiments in physiologically relevant microenvironment and in the presence of two clinically relevant drugs to treat cardiomyopathies, mavacamten and omencativ mercabil. Cellular characterization confirmed successful maturation of cardiomyocytes and altered contractility consistent with human phenotypes. Stiffer microenvironment determined potential physiological conditions of our model to the human system. In addition, cardiomyocytes under constant physical influence respond to microenvironmental changes, such as energetic metabolism, signal transduction and propagation of electrical stimuli. Through mechanotransduction, the sarcomeric contractility is translated intracellularly to other organelles, including the nucleus. We analyze the mechanical effect of altered sarcomeric contraction, due to TNNT2 mutations, on the nuclear morphology and stiffness of hiPSC-CMs. We observed altered nuclear circularity, aspect ratio and area. We also observed alterations in the nucleus stiffness and protein expression for both HCM and DCM, with opposite effects. Drug treatment showed promising results for the model to correct both contractility and nuclear stiffness. Increased or diminished contractility imposed by TNNT2 pathogenic variants can trigger nuclear remodeling, potentially compromising cellular structure and composition. This supports that sarcomeric variants associated with cardiomyopathy plays a role in cardiomyocyte mechanotransduction.

A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young’s Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key ‘linker’ sites in this schema that may represent potential therapeutic targets.

The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye.

Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy. A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes. The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease. Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.

Sarcomeric gene variants among Indians with hypertrophic cardiomyopathy: A scoping review.

Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.