Maximal Wall Thickness Research Articles

Abstract 4118425: Prevalence and Spectrum of Pathogenic Genetic Variants in Korean Cardiomyopathy Patients: Insights from Next-Generation Sequencing

Background and Aim: Next-generation sequencing (NGS) is increasingly used to identify genetic variants associated with cardiomyopathies, which can aid in precise diagnosis and management. This study aimed to elucidate the prevalence and spectrum of pathogenic and likely pathogenic genetic variants in a cohort of Korean population diagnosed with different forms of cardiomyopathy. Methods: This retrospective study analyzed 122 patients diagnosed with cardiomyopathy at three tertiary hospitals in Korea, all of whom underwent NGS to identify genetic variants between December 2017 and October 2023. Detailed patient records, including clinical diagnoses, imaging results, and family histories, were reviewed to correlate genetic findings with phenotypic data. Results: Of the patients, 35 (28.7%) were found to have pathogenic or likely pathogenic variants, and 43 (35.2%) were found to have only variants of uncertain significance. Of the patients with pathogenic or likely pathogenic variants, 16 had hypertrophic cardiomyopathy (HCM) and 16 had dilated cardiomyopathy (DCM), while 3 remained with an uncertain clinical phenotype. In the HCM group, 16 patients exhibited variants predominantly in MYBPC3 (62.5%), followed by MYH7 (12.5%), and others such as TPM1, TNNI3, PRKAG2, and SCN5A (each 6.3%). Additionally, 43.8% of the HCM group had a familial history of sudden cardiac death or cardiomyopathy, with a mean left ventricular mass index (LVMi) of 148.3 ± 70.4 g/m2 and a mean maximal wall thickness of 17.7 ± 3.9 mm. The DCM group showed a different pattern, with TTN variants in 43.8%, LMNA in 18.8%, and others including MYBPC3, RBM20, TTN2, and KCNQ1 (each 6.3%). This group had a mean left ventricular ejection fraction (LVEF) of 27% and a LVMi of 119.7 g/m2. Conclusion: Our findings highlight significant genetic diversity in cardiomyopathies among Korean patients, with distinct genetic backgrounds observed in HCM and DCM. The high prevalence of specific mutations such as MYBPC3 in HCM and TTN in DCM could guide targeted genetic testing and personalized treatment strategies in these populations.

Multi-Principal Element Alloys for Fast Reactor Cladding Applications

Given the extensive list of multi-principal element alloys (MPEAs) within literature and the overwhelming number of alloys that can be made from only a handful of elements, this article proposes a methodology for prioritizing alloys for use as cladding within advanced reactors. This paper applies neutronic, mechanical, and chemical assessments to a collection of MPEAs available within literature for use as advanced reactor cladding. The results are compared to a reference design of HT9, a ferritic/martensitic steel, for employed in sodium-cooled fast reactor. Mechanical assessments determined pressure limits for a thin-walled tube pressure boundary, thus relating the material’s mechanical properties to a minimum acceptable wall thickness. Neutronic analyses reveal a maximum allowable wall thickness that a given material must meet to provide a level of neutronic economy that is equivalent to than that of HT9. Lastly, each alloying element is compared to typical fission products found in a fast reactor fuels to mitigate deleterious phenomena such as fuel-cladding chemical interactions (FCCI). These analyses indicate that Mo-Nb-Ti-V-based alloys are likely to be advantageous and that the inclusion of elements with a high neutronic penalty (e.g., Hf) could be considered with minimal consequences.

Optimization of Forming Parameters of Ti-3Al-2.5V Titanium Tubes by Differential Heating Push-Bending Based on a Modified Johnson−Cook Constitutive Model

This study addresses the challenges associated with the difficult formation and low quality of formed Ti-3Al-2.5V titanium alloy thin-walled tubes with small bending radii (r / D < 1.5, where r is the bending radius, D is the outer diameter of the tube) by proposing a differential heating push-bending (DHP-B) forming approach. Initially, the stress−strain curves of Ti-3Al-2.5V at various strain rates and temperatures were obtained through high-temperature uniaxial tensile tests. Subsequently, a modified Johnson−Cook (JC) model for Ti-3Al-2.5V within the temperature range of 25℃ to 800℃ was developed to enhance the accuracy of the finite element model. Based on the static implicit and dynamic explicit algorithms, a thermomechanically coupled finite element model for differential heating push-bending of titanium alloy thin-walled tubes has been established. Taking the heating temperature, friction coefficient, counterthrust force and rubber block thickness as the optimization parameters, the prediction model of the maximum wall thinning rate and thickening rate is obtained by using the response surface method, and the best parameter combination is obtained via the NSGA-II algorithm and the minimum distance selection method, which realizes the optimization of differential heating push-bending parameters, as verified by experiments in which the maximum wall-thinning rate is reduced to 9%, and the maximum wall thickness thickening rate is reduced to 14.2%, which improves the forming quality of the titanium tube.

Left atrial strain predicts adverse events in hypertrophic cardiomyopathy: preliminary results from a CMR study

Abstract Background Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of major adverse cardiovascular events (MACE), however, current risk stratification methods are imperfect. Left atrial global longitudinal strain (LA GLS) is an increasingly acknowledged predictive parameter, yet its potential role in HCM is not well defined. Purpose This study aims to investigate the prognostic role of cardiac magnetic resonance (CMR)-derived LA GLS for the occurrence of MACE in patients with HCM. Methods A retrospective, single-centre, CMR study of HCM patients was conducted. Clinical data was collected from electronic medical record and CMR images were analysed by two blinded investigators. LA GLS was derived from CMR two-chamber cine images by a semiautomatic method, and was categorized according to its median value. The endpoint was a composite of MACE, including all-cause death, sudden cardiac death (SCD), sustained and non-sustained ventricular tachycardias (VT), appropriate implantable cardiac defibrillator (ICD) shocks, heart failure (HF) hospitalization, and new-onset atrial fibrillation (AF). Cox regression analysis was performed. The preliminary results of the study are now reported. Results A total of 54 HCM patients were included, mean age was 58.5 years ± 15.9 and 38.9% were female. Average maximal wall thickness (MWT) was 18.0 mm ± 3.9, 37% had left ventricular outflow obstruction (LVOTO) and 45.1% had positive late gadolinium enhancement (LGE). After a mean follow-up of 6.9 ± 3.0 years, 26 patients (48.1%) experienced the composite endpoint. Figure 1 shows the clinical and CMR differences according to the occurrence of MACE. LA GLS was significantly lower in patients with MACE compared to those without (26.5 ± 19% vs 36.7 ± 13%, p=0.026), with a moderate predictive value (AUC = 0.68, Figure 2A). Multivariate Cox regression analysis revealed that a decrease in LA GLS (HR 1.09 per each 1% decrease, 95% CI 1.03-1.15, p=0.002), the presence of LGE (HR 6.9, 95% CI 1.7-28, p=0.007), the presence of LVOTO (HR 3.4, 95% CI 1.12-10.2, p=0.031) and an increase in MWT (HR 1.23 per each 1mm increase, 95% CI 1.05-1.45, p=0.011) were independently associated with MACE. Among low-risk HCM patients (absence of LGE or LVOTO, or MWT below our median value), LA GLS had an additional prognostic role, and those with an LA GLS above the median value (LA GLS&amp;gt;29.7%) presented a remarkably favourable prognosis (Figure 2B-D). Conclusions CMR-derived LA GLS is a predictor of outcomes in HCM beyond established imaging prognostic factors. Particularly, LA GLS appears to be useful in risk-stratifying low-risk HCM patients: those with normal LA GLS show an excellent prognosis. If confirmed in larger studies, LA GLS could be used to individualise HCM management.Figure 2

First time evaluation of myocardium microRNA profile in Anderson-Fabry disease: implications in the pathological processes

Abstract Background Anderson Fabry disease (AFD) is an X-linked lysosomal disorder, characterized by progressive sphingolipid storage and organ dysfunction. Cardiac involvement is characterized by left ventricular hypertrophy, inflammation and fibrosis and is leading cause of mortality. MicroRNAs (miRNAs) are emerging as promising biomarkers in medicine, as they are dysregulated in many human diseases, offering opportunities to improve our understanding of disorders and discover new therapeutic targets. However, so far, only a few studies have evaluated the role of miRNAs in Fabry disease, and cardiac tissue miRNAs have never been assessed. Purpose To determine the specific tissue miRNA profile analyzing myocardial tissue of AFD patients and to evaluate their relationship with the severity of cardiac involvement. Methods 19 AFD patients (10 females [53%]; median age 53 years [IQR 43-63]) undergoing right ventricular endomyocardial biopsy (n=15) or surgical septal myectomy (n=4), standard cardiac magnetic resonance (1.5T, cines for maximum wall thickness (MWT) and indexed LV mass (LVMi) calculation) and high-sensitivity Troponin I (TnI) dosage were included and compared to 7 endomyocardial biopsies of controls. Myocardial samples were fixed in formalin and embedded in paraffin. RNA was extracted from 3-5 slides of tissue and used to generate small RNA libraries (Qiagen) for Next Generation Sequencing analysis on Illumina sequencer. Raw data were normalized and analyzed using DEseq2 pipeline. Correlations were performed using Pearson r; a p &amp;lt; 0.05 was considered statistically significant. Results In AFD group median MWT was 13 mm [IQR 8-17], LVMi was 72 g/m2 [IQR 46-97]. TnI was increased in 9 patients (47%) and NT-proBNP in 8 (42%). 6 patients were on specific AFD treatment. We identified 9 miRNAs differentially expressed in AFD patients compared to controls; miRPath analysis revealed that these miRNAs are associated to pathways involved in AFD pathogenesis (autophagy and mTOR signalling, HIF-1, apoptosis, TGF-beta signalling and inflammation) (figure 1). Moreover, we found 10 miRNAs that were differentially expressed in maximal wall thickness (&amp;lt;10 mm, 10-15 mm, &amp;gt;15 mm) groups (figure 2), in particular 3 miRNAs that progressively increased at the increasing of thickness. Among these miRNAs, miR-21-5p showed the strongest correlation with myocardial hypertrophy (r=0.869, p value&amp;lt;0.001 for MWT; r=0.905, p&amp;lt;0.001 for LVMi) and with cardiac damage (r=0.831, p&amp;lt;0.001 for TnI). Additionally, miR-21-5p had a modest correlation with age (r=0.518, p=0.05) and did not differ between patients on specific AFD treatment and patients not treated (p=0.660). Conclusions This study for the first time evaluated the myocardial miRNA profile in AFD patients and identified miR-21-5p as a cardiac biomarker correlating with clinical heart involvement, both in terms of left ventricular hypertrophy (MWT, LVMi) and myocardium damage (troponin).Figure 1Figure 2

Association between impaired left ventricular global longitudinal strain and B-type natriuretic peptide in obstructive hypertrophic cardiomyopathy

Abstract Background Left ventricular global longitudinal strain (LV-GLS) is considered valuable in explaining impaired left ventricular contractility in hypertrophic cardiomyopathy (HCM) with preserved ejection fraction and is associated with worse outcome. Elevated B-type natriuretic peptide (BNP) is a biomarker of increased LV wall stretch and a risk factor of heart failure, mortality, and other adverse cardiovascular events. However, relationship between GLS and BNP has not received sufficient attention in the obstructive variant of HCM. Purpose This study aimed to determine the association between echocardiographic LV-GLS and plasma BNP in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods A total of 145 consecutive patients (32% females) with symptomatic HOCM were enrolled in the retrospective study. HOCM was defined with a maximum end-diastolic wall thickness ≥15mm without other etiologies for LV hypertrophy, and peak LV outflow tract (LVOT) gradient ≥30mmHg. The echocardiographic parameters regarding LV geometry, loading conditions, and GLS were evaluated according to guidelines. Patients were divided into two groups according to absolute GLS values (greater or lower than median LV-GLS). Patient baseline clinical data, echocardiographic parameters, and BNP were compared. Univariate and multivariable regression analysis were applied to identify the independent determinator of LV-GLS. Results The median value of LV-GLS of this study cohort was -13.4%. Eighty-one patients (47.6±13.4 years-old) had a |GLS|≥13.4% and 64 individuals (48.7±12.6 years-old) had a |GLS|&amp;lt;13.4%. No differences were found in age, gender, physical examinations, LVEF, cardiovascular comorbidities, or active medications between the two groups, except for body mass index (BMI). Patients with |GLS|≥13.4% had statistically lower BMI (24.58±2.42 vs. 26.00±3.12kg/m², p=0.030). BNP was found significantly elevated in patients with |GLS|&amp;lt;13.4% when compared with individuals with |GLS|≥13.4% {median (IQR); 550.05 (214.50, 899.35) vs. 182.40 (78.90, 479.90)pg/mL, p=0.004}. In univariate regression analysis, decreased |GLS| was associated with male gender, maximum and mean LV wall thickness, peak LVOT gradient, reduced mitral annular e’ velocity, elevated BNP and cardiac troponin I. In multivariable regression analysis, GLS was found independently associated with mean LV wall thickness and BNP. Conclusions In patients with symptomatic HOCM with preserved ejection fraction, impaired LV-GLS was found to be associated with plasma BNP and mean LV wall thickness, independent of gender, age, loading conditions, LVEF, or LVOT gradient. Reduced GLS may be a more sensitive surrogate in assessing increased myocardial wall tension or stretch, rather than LV contractility in these patients. Therefore, the interpretation of GLS in HOCM should shift away from systolic interest toward emphasizing its potential value in risk stratification of diastolic heart failure with preserved LVEF.Figure 1

Determinants of right ventricular - pulmonary arterial uncoupling in hypertrophic cardiomyopathy

Abstract Background Right ventricular (RV) – pulmonary arterial (PA) coupling, assessed by echocardiography, is a non-invasive surrogate on how the RV is adapted to an increased afterload in the pulmonary circulation. In cases of exhaustion of compensatory RV remodeling, the ratio decreases and there is RV-PA uncoupling. Our objective was to identify what are the determinants of this parameter in patients with hypertrophic cardiomyopathy (HCM). Methods This prospective cohort study enrolled patients with HCM without obstructive epicardial coronary artery disease, that underwent a comprehensive evaluation. Echocardiography was used to assess RV-PA coupling as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP). In addition, coronary flow reserve in the left anterior descending artery (CFR_LAD) was also evaluated: diastolic coronary flow velocity was measured in basal conditions and in hyperemia and CFR was calculated as the ratio of hyperemic and basal peak diastolic flow velocities. This was used as a surrogate marker of coronary microvascular dysfunction. Cardiac magnetic resonance (CMR) was also performed to evaluate RV function (volumes and ejection fraction), and the extent of late gadolinium enhancement (LGE) in the left ventricle (LV). Results We enrolled 62 patients, with a mean age of 55 (15) years, 64% males. In 64% it was an asymmetrical septal hypertrophy phenotype, in 31% an apical hypertrophy, and in 27%, it was an obstructive HCM. Mean TAPSE/PASP was 0.556 (0.23) and median was 0.50. All patients had a normal LV ejection fraction. Univariable linear regression analysis showed that age, maximal wall thickness, E/E’, indexed left atrial volume (LAVi), CFR-LAD, %LGE and % hypoperfusion (by CMR) were correlated with RV-PA uncoupling. The HCM phenotype or the presence of obstruction were not associated with uncoupling. Multivariable stepwise linear regression analysis showed that the independent predictors of RV-PA uncoupling were age (b-estimate: - 0.180, p=0.009), LAVi (b-estimate: -0.645, p=&amp;lt;0.001), CFR-LAD (b-estimate: 0.183, p=0.011) and %LGE (b-estimate: -0.270, p=&amp;lt;0.001). Conclusion In patients with HCM, the presence of coronary microcirculation abnormalities and the extent of LGE in the LV are independent predictors of RV-PA uncoupling.

Prediction of family inheritance in non-sarcomeric hypertrophic cardiomyopathy using clinical variables and 12-lead electrocardiogram artificial intelligence models

Abstract Background Hypertrophic cardiomyopathy (HCM) can be familial even in the absence of a causative sarcomeric variant, justifying periodical screening of first-degree relatives. However, indiscriminate screening may burden low-risk individuals unnecessarily. The prevalence and predictors of familial disease in non-sarcomeric HCM remain inadequately characterized. Purpose Our study aims to develop a tailored approach to family screening based on index cases’ clinical profiles. By leveraging artificial intelligence (AI) models, we aim to predict the likelihood of family disease using pertinent clinical variables and electrocardiograms (ECGs) from the proband. Methods From January 2008 to June 2022, all probands diagnosed with HCM at our Heart Institute genetics clinic were included if they had i) negative genetic testing for a (likely) pathogenic variant in a sarcomeric gene and ii) ≥1 first- or second-degree relative screened for HCM. The outcome was the presence of family disease defined as left ventricular wall thickness ≥13mm or verified autopsy report confirming HCM. Predictors of family disease were assessed at the first genetic clinic visit and considered age, sex, hypertension, and echocardiography metrics (maximal wall thickness, septal morphology, outflow tract obstruction at rest or Valsava). Using 12-lead ECGs and clinical variables, we used machine learning to train two distinct AI models. Model A utilized ECG signals only to train a ResNet model, while Model B used both ECGs and selected clinical variables (below 0.2 alpha level in logistic regressions) to train a random forest model to predict family disease. We performed evaluations at both ECG-level (one ECG used per patient) and patient-level (all available ECGs used in a patient) and we present individual and ensemble model performance. Results Among 356 families with sarcomere-negative HCM, 106 (30%) were familial. Probands were aged 53 ± 16 years, 30% female, 36% with a diagnosis of hypertension and 43% with peak outflow tract obstruction ≥30mmHg. In univariable logistic regressions, family disease was associated with age at diagnosis (OR 0.89 per 5-year, P=0.003), hypertension (OR 0.60, P=0.046) and obstruction (OR 0.52, P=0.013). The ensemble AI model, which integrated clinical and ECG data, achieved an AUC of 0.82 (95% CI: [0.795, 0.848]). It demonstrated a specificity of 0.891 (95% CI: [0.867, 0.913]) and a negative predictive value of 0.798 (95% CI: [0.772, 0.823]). When comparing ECG-level and patient-level data (1 to 10 ECGs per patient), the models consistently achieved AUC values between 0.78 and 0.81, indicating stable performance across various data subsets. Conclusion The prevalence of family inheritance in sarcomere-negative HCM can be accurately predicted using AI models that integrate clinical variables and 12-lead ECG data. This approach could enable tailored screening strategies based on the likelihood of family disease.

Anderson-Fabry disease patients with anatomical heart hypertrophy express a higher degree of electrocardiographic hypertrophy compared to hypertrophic cardiomyopathy patients

Abstract Background Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease that has progressively gained attention due to the availability of specific therapeutic options. Heart involvement is of critical prognostic significance and differential diagnosis with Hypertrophic Cardiomyopathy (HCM) is as challenging as it is crucial to provide the patient with the appropiate treatment. Purpose To describe ECG features in AFD patients according to the presence of anatomical hypertrophy and compare them with matched HCM patients. Methods One-hundred-sixty-two AFD patients were recruited in the present multicentre study cohort and divided into 2 groups according to the presence (Group A, n=111) or the absence (Group B, n=51) of anatomical hypertrophy. Group A patients were then compared with a matched cohort of HCM patients (n=111) with the use of Propensity Score Martching relatively to sex, age and maximal wall thickness. Results AFD patients with cardiac hypertrophy, compared with matched HCM patients with the same indexed cardiac mass at echocardiography [151 (124-211) vs 145 (123-182) g/m2; p=0.1675], showed on the surface electrocardiogram a higher degree of electrical hypertrophy expressed as increased total QRS score [204 (158-271) vs 177 (138-221) mm; p=0.0004] and R wave amplitude in aVL ≥ 11 mm [51 (45.9%) vs 25 (22.5%); p&amp;lt;0.0001], whereas they did not differ with respect to Sokolow-Lyon index [31 (18-44) vs 32 (22-40) mm; p=0.518] and Cornell index [19 (12-25) vs 17 (12-24) mm; p=0.5]. Furthermore, AFD patients featured wider QRS complexes [110 (100-134) vs 100 (90-106) ms; p&amp;lt;0.0001] and a higher prevalence of Right Bundle Branch Block (RBBB), both complete [25 (22.5%) vs 3 (2.7%); p&amp;lt;0.0001] and incomplete [17 (15.4%) vs 2 (1.8); p&amp;lt;0.0001], as well as non specific intraventricular block [14 (12.6%) vs 4 (3.6%); p&amp;lt;0.0001]. Conclusions Our cohort of Anderson-Fabry patients, compared with HCM patients with the same indexed cardiac mass at echocardiography matched by age, sex and wall thickness, featured a higher degree of electrocardiographic hypertrophy expressed as increased total QRS score and R wave amplitude in aVL, whereas it did not differ with respect to Sokolow-Lyon and Cornell indexes. These findings may prove beneficial in achieving earlier the diagnosis of AFD, enabling clinicians to initiate swiftly and without delay the specific disease modifying therapies available.Electrocardiographic differencesTotal QRS Score AFD vs HCM

Adverse prognostic implications of increased left ventricular force in hypertrophic cardiomyopathy

Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force &amp;gt; median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (&amp;lt;3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (&amp;gt;7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Impaired myocardial energetics in both sarcomere positive and negative HCM are linked to arrhythmic risk

Abstract Background Impaired myocardial energetics play a pivotal role in the complex pathophysiology of hypertrophic cardiomyopathy (HCM), and are thought to be mediated by energy-costly sarcomeric mutations and mitochondrial dysfunction (1). Two thirds of HCM patients, however, do not possess pathogenic sarcomeric mutations (2) and instead develop the condition due to a combination of increased polygenic susceptibility and comorbidities. Whether energetic impairment, a target of novel HCM treatments (e.g., myosin modulators such as Mavacamten), similarly affects sarcomere mutation positive (Sarc+) and negative (Sarc-) HCM remains unclear, as does the association between impaired energetics and markers of arrhythmic risk such as hypertrophy severity, cardiac function and non-sustained ventricular tachycardia (NSVT). This study aimed to investigate differences in resting myocardial energetics between Sarc+ and Sarc- HCM by measuring the phosphocreatine-to-adenosine triphosphate (PCr/ATP) ratio using phosphorus magnetic resonance spectroscopy (31P-MRS) and explore the association between impaired energetics and markers of arrhythmic risk in HCM. Methods We recruited one hundred (100) participants (80 non-obstructive HCM patients and 20 age- and sex-matched controls). Myocardial energetics were assessed using 31P-MRS to measure the PCr/ATP ratio. Cardiac magnetic resonance (CMR) imaging including cine, T1 (ShMOLLI), quantitative pixel-wise perfusion mapping (3) and late gadolinium enhancement (LGE) imaging was also performed. In addition, HCM patients underwent 7-day ECG monitoring to document NSVT episodes (3 beats ≥120 bpm). Results HCM patients had impaired myocardial energetics (PCr/ATP ratio) relative to controls (HCM 1.64±0.36 vs controls 1.97±0.32 p&amp;lt;0.001). PCr/ATP ratios did not differ between Sarc+ and Sarc- HCM even after adjustment for confounders including age, hypertrophy and fibrosis burden (Sarc+ 1.64 [1.50-1.78] vs Sarc- 1.64 [1.52-1.77], p=0.993). PCr/ATP ratio showed no correlation with maximum wall thickness (p=0.257), left ventricular ejection fraction (p=0.727) or myocardial perfusion reserve (p=0.851), but did inversely correlate with global longitudinal strain (r=-0.3, p=0.025). Reduced PCr/ATP was associated with presence of fibrosis (LGE+ 1.58±0.35 vs LGE- 1.79±0.37 p=0.025) and with NSVT, independent of age or fibrosis burden (NSVT+ 1.54 [1.40-1.67] vs NSVT- 1.73 [1.62-1.86], p=0.046). Conclusion Myocardial energetics are similarly impaired in Sarc+ and Sarc- HCM, and are independently associated with impaired contractility, greater fibrosis severity and heightened arrhythmic risk. Our findings provide novel mechanistic insights into the potentially favourable response of HCM patients to energy-sparing myosin modulator therapies irrespective of genotype and highlight the potential for cardiac energetics to serve as a marker of arrhythmic risk.

The relationship between serum lumican levels and myocardial fibrosis in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young individuals and an important cause of heart failure at any given age. Lumican, is an indicator of fibrosis and has been studied in various cardiac conditions. In this study, we aimed to evaluate the relation between serum Lumican levels and presence and extent of myocardial fibrosis in HCM. Methods The patients diagnosed with HCM between June 2022 and March 2023 were enrolled consecutively in this prospective study. Age and gender-matched healthy individuals formed control group. Additionally, HCM patients divided into two groups according to extent of late gadolinium enhancement (LGE). Results A total of 114 patients (62.3% male, 54.5±9.4 mean age) were enrolled in this prospective study. 64 patients formed HCM (+) and 50 patients formed HCM (-) group. The HCM (+) group is divided into two groups as LGE (+) and LGE (-) according to LGE involvement. Serum Lumican [p=0.018, β: 1.561, OR (95% CI): 1.080-2.257], NT-proBNP [p=0.043, β: 1.209, OR (95% CI): 1.079-2.527] and maximum wall thickness (MWT) [p=0.033, β: 1.322, OR (95% CI): 1.023-1.707] were revealed as independent risk factors associated with LGE by multivariate logistic regression analysis (Figure 1). ROC curve analysis was performed to identify the optimal cut-off value and calculate area under the curve (AUC) for Lumican, troponin (Tn) and NT-proBNP in order to predict the presence and extent of LGE in patients with HCM. A cut off value of 9.06 for Lumican was associated with 67.8% sensitivity and 65.5% specificity in prediction of LGE. A cut-off value of 932.4 for NT-proBNP was associated with 60% sensitivity, 60% specificity in prediction of LGE. Conclusion Myocardial fibrosis is one of the important mechanisms in HCM pathophysiology. Although LGE on cardiac magnetic resonance imaging(CMR) allows comprehensive evaluation of myocardial fibrosis, the support of diagnosis with a biomarker would be beneficial in clinical practice.Our study revealed that serum Lumican level is an independent predictor of severe LGE in HCM patients. Lumican can be used in addition to CMR for evaluating extence of myocardial fibrosis in HCM patients and may help clinicians in guiding follow-up and treatment.

Hemodynamic effects of right and biventricular pacing during exercise in hypertrophic obstructive cardiomyopathy

Abstract Background One third of patients with hypertrophic cardiomyopathy present with dynamic left ventricular outflow tract obstruction (LVOTO), referred to as hypertrophic obstructive cardiomyopathy (HOCM). Symptomatic treatment aims at reducing LVOTO with either medications, invasive septal reduction, or pacing. The importance of pacing site is unclear, and effects of pacing during physical activity have not been investigated. Purpose To determine the effect of right ventricular (RV) and biventricular (BiV) pacing, respectively, on LVOTO and cardiac output (CO) during exercise in patients with HOCM. Methods Patients with symptomatic HOCM, sinus rhythm, and no bundle branch block, scheduled for alcohol septal ablation (ASA), were eligible for inclusion. The day before ASA, we placed temporary pacing leads in the right atrium, the RV apex, and on the left ventricle’s lateral wall via the coronary sinus. LVOTO was assessed by echocardiography, and CO was measured by thermodilution with a pulmonary artery catheter. Patients performed supine cycling for 2 minutes until heart rate (HR) increased ≥20 bpm. We measured LVOTO and CO in sinus rhythm, and during cycling with atrial sensed RV pacing, and atrial sensed BiV pacing. The order of pacing sites was randomized, and the personnel performing echocardiography and CO measurements were blinded to the order of pacing. Results We included six patients (54±15 years) with a mean maximal left ventricular wall thickness of 16.7±1.8 mm. Resting LVOTO was 55.7±30.9 mmHg. The figures show LVOTO and CO in sinus rhythm (HR 85±10 bpm), RV pacing (HR 90±10 bpm), and BiV pacing (HR 91±9 bpm) during supine cycling. The LVOTO declined from 56±34 mmHg in sinus rhythm to 27±12 mmHg and 25±5 mmHg respectively for atrial sensed RV and BiV pacing. CO remained unchanged during sinus rhythm (9.0±1.2 L/min), atrial sensed RV pacing (9.0±1.7 L/min), and BiV pacing (8.9±1.5 L/min). Conclusion In this ongoing study evaluating cardiac pacing in HOCM, preliminary data indicate that both RV and BiV pacing are effective in reducing LVOTO during exercise, without compromising CO.

Automated deep learning approach for identifying etiologies of hypertrophic phenocopies by echocardiography

Abstract Background Left ventricular hypertrophy (LVH) is an indicator of poor prognosis across various cardiovascular diseases and is developed by various etiologies. Transthoracic echocardiography (TTE) is the most available cardiac imaging tool to detect LVH. However, it is still challenging to differentiate three non-ischemic cardiomyopathies which frequently presenting LVH: Fabry cardiomyopathy (FC), hypertrophic cardiomyopathy (HCM), and cardiac amyloidosis (CA) from morphology or cardiac function evaluated by TTE. Purpose We aimed to develop stepwise deep learning models to differentiate FC, HCM, and CA using radiomics extracted from TTE. Methods We conducted a retrospective cohort study between 2011 and 2022 in Taiwan. Patients with left ventricular (LV) mass index≥95g/m² in women or ≥115g/m² in men, or the maximal LV wall thickness≥13mm on echocardiography were enrolled. The TTE automatic processing models included four steps: image quality assessment, view classification, auto-segmentation of interventricular septum (IVS), and dynamic radiomics analysis. One echocardiographic study was scanned per patient, and each study contains multiple cardiac cycles. One sample was extracted from each cycle and all samples were evaluated by image quality assessment and view classification model that based on VGG16. Samples with apical four (A4C) and apical five chamber (A5C) views were retained for following steps. Manual contouring of the septal region served as the ground truth for auto-segmentation based on U-Net. The last step was the extraction of dynamic radiomic features from IVS and the dynamic radiomic features were analyzed using an LSTM model to differentiate three hypertrophic cardiomyopathies. Results There were 103 patients with FC, 96 patients with HCM, and 49 patients with CA in this study. Patients with CA were older and had lower LV ejection fraction (EF) than those with FC or HCM (age: 65.8±9.7 vs. 59.3±11.1 vs. 58.6±14.2 years, P=0.002; LVEF: 56.6±10.8 vs. 61.9±8.8 vs. 64.5±8.3%, P&amp;lt;0.001). In addition, patient with FC had larger LV mass index than those with HCM or CA. (Fig. 2A) The details of the performances of four stepwise models were provided in Figure 2 (B-F). The image quality assessment and view classification models achieved accuracies of 91.7% and 95.2%, respectively. The auto-segmentation had the median Dice score as 0.88 for contouring IVS. The results indicated that deep learning algorithms had great ability to recognize different views with proper image quality, and could contour the IVS adequately. The accuracy of dynamic radiomics-based LSTM model to differentiate three hypertrophic phenocopies was 74.5%. Conclusion We developed an automatic process with four stepwise models for analyzing the radiomics of IVS on TTE to differentiate FC, HCM and CA with the modest performance by LSTM model. The developed automatic models may provide potential implications to identify various etiologies LVH in the future.Figure 1-Workflow of this studyFigure 2-Performances of stepwise models

Effectiveness of contemporary risk stratification in patients with hypertrophic cardiomyopathy: a pilot study

Abstract Introduction Risk stratification and primary prevention of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) is a challenging discipline. When using current stratification systems, there is always a compromise between sensitivity and specificity. Objective In our pilot study, we sought to determine the incidence of SCD and the effectiveness of stratification systems, i.e., the ESC HCM Risk-SCD score and the system of individual major risk factors (RF) according to ACC/AHA in patients followed in an expert center. Methods Patients with HCM were risk-stratified and followed for 10 ± 8 years at the referral HCM center. Results Five hundred and five patients were stratified, and 71 (14%) were implanted with a cardioverter-defibrillator (ICD) based on risk stratification. ICD patients were stratified at age 39 ± 17 years, of which 26 (35%) were women, maximal left ventricular wall thickness (MLWT) was 23 ± 7 mm, and left atrial dimension (LA) 46 ± 7 mm. During follow-up, 12 (17%) patients had ≥ 1 appropriate ICD therapy at age 46 ± 19 years. Patients with ≥ 1 appropriate ICD therapy had an average 5-year ESC score of 1.8 ± 0.4% and an average ACC/AHA major RF of 1.4 ± 0.8, MLWT 25 ± 6 mm, LA 47 ± 7 mm. None of the ICD patients died of SCD. Five (7%) patients suffered from ICD complications, including 4 (6%) inappropriate shock, and one patient experienced infective endocarditis requiring system extraction. During follow-up, 118 (23%) patients died, of which 28 (6%) from HCM-related causes, 12 (2%) from stroke, 11 (2%) from advanced heart failure, one perioperatively (myectomy) and 4 (1%) patients died suddenly (SCD). The mean age of SCD patients at the time of stratification was 59 ± 14 years; all were male, MLWT 18 ± 5 mm, LA 49 ± 2 mm, mean ESC score 2.0 ± 0.9%, and three (75%) had no RF present according to ACC/AHA. The ESC HCM Risk-SCD score was markedly less sensitive (sensitivity 56%; 95% CI 21-86) but more specific (specificity 98%; 95% CI 96-99) than the ACC/AHA approach (sensitivity 77%; 95% CI 46-95; and specificity 71%; 95% CI 67-75) (Figure). Conclusion With current risk stratification, albeit imperfect, SCD is rare in HCM patients managed at an expert center.

Imaging predictors of adverse prognosis in fabry disease cardiomyopathy: a systematic review and meta-analysis

Abstract Background Cardiac involvement represents the main cause of death in patients with Fabry disease (FD). Echocardiography and Cardiac Magnetic Resonance (CMR) have an established diagnostic role, but their prognostic value remains unresolved. This systematic review and meta-analysis sought to assess the prognostic implications of imaging parameters in FD. Methods PubMed, ClinicalTrials.gov, Embase and Cochrane Library databases were searched for studies published from inception through to October 1, 2023. Full-length original papers including FD patients undergoing baseline imaging assessment and clinical follow-up were selected. Pre-defined study outcomes were a cardiovascular endpoint and a composite clinical endpoint. A meta-analysis of the studies investigating the effect of single imaging parameters on a pre-specified cardiovascular endpoint and a separate analysis on a pre-specified composite clinical endpoint were performed to obtain the pooled estimates for the association between the imaging parameters and the study outcome. The study protocol was registered in PROSPERO. Results Thirteen studies including 1,399 FD patients (44.8% males) were selected. At pooled analysis, late gadolinium enhancement (HR 4.39; 95% CI 2.5-7.71), left atrium volume indexed (HR 1.02 per ml/m2; 95% CI 1.01-1.04), E/e’ (HR 1.14 per unit increase; 95% CI 1.08-1.21), left ventricular (LV) mass indexed (HR 1.014 per mg/m2; 95% CI 1.006-1.023), maximum LV wall thickness (HR 1.19 per mm, 95% CI 1.04-1.36), LV-global longitudinal strain (HR 1.2 per unit increase; 95% CI 1.2-1.27), were significantly associated with the cardiovascular endpoint, whereas T1-mapping (p=0.115) and LV-ejection fraction (p=0.305) were not. T1-mapping was associated with the composite endpoint (HR 0.986 per msec increase; 95% CI 0.976-0.997). Meta-regression analysis did not show any significant interaction between each of the potential effect modifiers. Conclusion This meta-analysis demonstrates a robust prognostic value regarding several imaging parameters in FD, specifically indexes of LV mass and wall thickness, diastolic dysfunction, LV-GLS, and LGE presence. These findings support multimodality cardiovascular imaging, including CMR, in FD disease patients to predict long-term prognosis and call for longitudinal multicentre studies to develop multi-modality-imaging derived risk-score algorithms.

A direct comparison of non-invasive blood markers of liver fibrosis as associates of cardiovascular risk. The Athens cardiometabolic registry

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). This risk increases further with advanced liver fibrosis. To date, non-invasive tests (NIT) for liver fibrosis risk have not been established as diagnostic or prognostic biomarkers of CVD. Purpose The purpose of the study was to compare NIT of liver fibrosis with respect to their associations with vascular injury and cardiovascular (CV) events. Methods Individuals without clinically overt CVD and patients with CVD (total n=1,692), consecutively recruited in the Athens Cardiometabolic Registry, were analysed in this study. We retrospectively evaluated the association of NIT (i.e. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), BARD score) with indices of subclinical arterial injury (i.e. carotid wall thickness and atherosclerotic plaque for subclinical atherosclerosis, pulse wave velocity (PWV), for arterial stiffness) and the incidence of CV events. Patients were followed-up for CV events for a median time of 39 months. Results Elevated FIB-4 (&amp;gt;2.67) was associated with vascular damage [adjusted odds ratio (aOR)=2.97, 95% confidence intervals (CI)= 1.71-5.78 for maximal wall thickness (maxWT) and aOR=4.58, 95% CI=2.44-8.60 for PWV] across the entire study population, including those with or without clinically overt CVD. NFS&amp;gt; 0.675 showed similar associations but lacked significant correlation with arterial stiffness in coronary artery disease patients. FIB-4&amp;gt; 2.67 and BARD&amp;gt; 2 were associated with increased risk of the composite endpoint of CV death, acute myocardial infarction, or coronary revascularization [adjusted hazard ratio, (aHR)=2.00, 95% CI= 1.12-3.55 and aHR=3.36, 95% CI=1.03-11.0 for FIB-4 (n=842) and BARD (n=887) respectively]. FIB-4 and BARD as continuous variables confered incremental prognostic value compared to European Systematic Coronary Risk Evaluation 2 (SCORE2). Conclusion In a population with a wide range of cardiometabolic risk, FIB-4 was associated with both markers of atherosclerotic disease and arterial stiffness as well as with adverse CV events. These data support further investigation of FIB-4 as a biomarker of CV risk.

Fabry cardiomyopathy: myocardial fibrosis, inflammation and reduced mannose6phosphate receptors cause low accessibility to enzyme therapy

Abstract Background Clinical impact of enzyme replacement therapy (ERT) on advanced Fabry disease cardiomyopathy (FDCM) appears limited. Purpose Clarify the pathologic mechanisms responsible of ERT inefficacy in the advanced FDCM. Methods Ten male patients with advanced FDCM (echocardiographic maximal wall thickness 19.3 ± 2.1 mm) underwent left ventricular endomyocardial biopsy before and 4 hours after beta-agalsidase infusion. Comparative studies between pre and post infusion samples included: histology and electron microscopy; assessment of myocardial alpha-galactosidase A activity; immunohistochemistry for alpha-galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; Ultrastructural immunogold analysis with anti-alpha-galactosidase A ab. Western Blot (WB) quantification of mannose-6-phosphate receptors (M6Pr). Controls were surgical left ventricular biopsies from patients with mitral stenosis. Results Histologic and Ultrastructural evaluation showed no removal of storage material while myocardial fibrosis was 9.8 ± 6.8 vs 3.8 ± 2.0 of controls and virus-negative lymphocytic inflammation was observed in 7 out of 10 patients. At Ultrastructural immunogold analysis, Myocardial alpha-galactosidase A activity increased in post infusion samples by overall 1.89-fold. Alpha-galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in post-infusion samples. Immunogold particles increased by 1.33-fold remaining far from normal controls (86.9 ± 6.6). Protein analysis showed M6Pr in advanced FDCM to be 81% lower than in normal heart. Conclusions Our study shows a low accessibility to ERT of cardiomyocytes affected by advanced FDCM. It is sustained by myocardial fibrosis, inflammation and severe down-regulation of M6Pr. Figure Legend Histologic and ultrastructural and mannose6phosphate receptors characteristics of patients with severe Fabry Disease Cardiomyopathy. Panel A shows severe cellular glycolipid infiltration associated with diffuse interstitial fibrosis (Masson trichrome, 100x). Panel B reveals an overlapping lymphocytic CD45Ro+ myocardial inflammation with focal necrosis of adjacent cardiomyocytes. Insert(i), Ultrastructural detail showing vacuoles (black arrows) to consist of myelin bodies,( scale bar=3μm). Panel C (upper) Western blot analysis of all 10 patients of Mannose-6-phosphate Receptor, molecular weight 275 Kd. Alpha sarcomeric actin (43 kDa) was used as a loading control. (Panel C -lower) Panel D: Graphs document western blot of Mannose-6-phosphate Receptor, in all 10 patients with severe FDCM showing 3-fold lower of Mannose-6-phosphate Receptor values in patients versus normal heart (4.830 ± 1116,724 vs 14.737± 1145,386; p &amp;lt; 0.001).

Prolonged ventricular activation time as a novel biomarker identifying burn-out phase of hypertrophic cardiomyopathy

Abstract Background Patients with hypertrophic cardiomyopathy (HCM) classically have preserved systolic function and decreased left ventricular end-diastolic volume. However, in a small sub-population, patients paradoxically develop systolic dysfunction, left ventricular dilatation, and ventricular wall thinning, which is known as end-stage hypertrophic cardiomyopathy or "burned-out cardiomyopathy’. Although an electrocardiogram (ECG) is a pivotal tool in HCM, its role in the detection of burned-out HCM has not been investigated. Purpose We assessed the ventricular activation time (VAT), an ECG marker of the duration of ventricular depolarization, as a predictive tool in the detection of the HCM burn-out phase. Methods We prospectively studied consecutive patients diagnosed with HCM via echocardiography at our medical center between 2017 and 2022. The ECG, along with echocardiography, was performed on the same day as the diagnosis. VAT was measured in milliseconds between the onset of the QRS complex to the peak or R wave on the V5 and V6 precordial ECG lead. HCM burn-out phase was supported when the left ventricular ejection fraction (LVEF) was below 50%, measured with echocardiography. Statistical analysis was performed using the SPSS software. Results Forty-five patients with HCM were studied, and their mean age was 51, while 78% (35/45) were male. Echocardiography data upon diagnosis revealed a mean maximum wall thickness of 19 (±3mm) and a mean left ventricular ejection fraction of 65% (±5%). Left ventricular outflow obstruction was present in 31% (14/45). During the study, 24% (11/45) presented atrial fibrillation, 44% (20/45) had an ICD implantation, and 22% (10/45) progressed to the burn-out phase of HCM. HCM patients who presented atrial fibrillation (63±31 vs. 46±14msec, p=0.018) or burn-out phase (65±32 vs. 46±13msec, p=0,009) had a significantly higher VAT than those subsets without. Notably, there was a significant positive relationship between VAT a burn-out phenotype (r=0,385, p=0.009). HCM patients with greater VAT also had a significantly higher risk of presenting a larger left atrial diameter (r=0,295, p=0.048), an increased left ventricular end-diastolic diameter (r=0.306, p=0.041), and a trend of presenting a lower LVEF (r=-0,262, p=0.082). Finally, we revealed a positive relationship between VAT and atrial fibrillation incidence (r=0,352, p=0.018). Conclusion Prolongation of VAT predicts the incidence of burn-out stage in patients with HCM and atrial fibrillation. Therefore, it seems to be a promising, inexpensive ECG marker for HCM progression and severity. Our findings emphasize the pivotal role of the ECG as a useful and inexpensive tool in the diagnostic follow-up of HCM.

Extracellular vesicles characterization in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a genetic disorder, diagnosed according to the presence of phenotypical traits of the myocardium. A specific biomarker which can associate with the severity of HCM is lacking. Extracellular Vesicles (EVs), nanoparticles released by cells into biological fluids, hold promise as accessible diagnostic tools, as their abundance and molecular composition can reflect the severity of cardiac diseases (Rizzuto 2024). We aim at characterising plasma-derived EVs isolated from 28 HCM patients and 18 healthy volunteers (CTR). Methods The whole cohort underwent transthoracic echocardiography, whereas magnetic resonance and exome sequencing was performed on HCM patients. EVs were isolated via ultracentrifugation from plasma of both groups. Quantitative and qualitative assessments of EVs were performed by nanoparticle tracking analysis, transmission electron microscopy, Western blot, targeted (Olink) and untargeted (nLC-MS/MS) proteomics and FACS analysis. Plasma-derived EV subpopulations were characterised according to their cellular origin. Data are expressed as median and interquartile range (25th, 75th). Results Most patients were male (68% HCM and 66% CTR) with a median age of 58 (49-69) years (HCM) and 47 (44-52) (CTR). Among HCM patients, missense mutations in the MYH7 gene were the most identified. The median maximum wall thickness (WTMax) in HCM was 16 mm (15-19) vs 8 mm (7-9) in CTR. The isolated EVs expressed tetraspanins (CD9, CD63 and CD81), Alix and β-integrin and showed an intact phospholipid bilayer of 100 nm in size. EV concentration was reduced in HCM vs CTRL, respectively 2.8*109 EV/ml/cell count (2*109-4*109) and 4.6*10⁹ EV/ml/cell count (3*109-6*109). Among 15 plasma-derived EV subpopulations studied, those released from platelets (CD41a) and activated platelets (CD62P and CD40L) were increased in HCM patients vs CTR by 1.7 fold. Negative associations were found between E/e’, parameter of diastolic function, and cardiomyocyte-derived EVs (r= -0.2658), and between left ventricle ejection fraction and platelet-derived EVs (r=-0.2189); a positive correlation was found between WTMax and EVs derived from activated endothelial cells (r=0.2330). The proteomic analysis of EVs shows an enrichment in proteins related to platelets adhesion and inflammation in HCM patients. Conclusions HCM patients present a peculiar phenotypic pattern of EVs that may associate with diagnostic clinical features of HCM.