Features Of Hypertrophic Cardiomyopathy Research Articles

Identification of high-risk imaging features in hypertrophic cardiomyopathy using electrocardiography: A deep-learning approach

BackgroundPatients with hypertrophic cardiomyopathy (HCM) are at risk of sudden death, and individuals with ≥1 major risk markers are considered for primary prevention implantable cardioverter-defibrillators. Guidelines recommend cardiac magnetic resonance (CMR) imaging to identify high-risk imaging features. However, CMR imaging is resource intensive and is not widely accessible worldwide. ObjectiveThe purpose of this study was to develop electrocardiogram (ECG) deep-learning (DL) models for the identification of patients with HCM and high-risk imaging features. MethodsPatients with HCM evaluated at Tufts Medical Center (N = 1930; Boston, MA) were used to develop ECG-DL models for the prediction of high-risk imaging features: systolic dysfunction, massive hypertrophy (≥30 mm), apical aneurysm, and extensive late gadolinium enhancement. ECG-DL models were externally validated in a cohort of patients with HCM from the Amrita Hospital HCM Center (N = 233; Kochi, India). ResultsECG-DL models reliably identified high-risk features (systolic dysfunction, massive hypertrophy, apical aneurysm, and extensive late gadolinium enhancement) during holdout testing (c-statistic 0.72, 0.83, 0.93, and 0.76) and external validation (c-statistic 0.71, 0.76, 0.91, and 0.68). A hypothetical screening strategy using echocardiography combined with ECG-DL–guided selective CMR use demonstrated a sensitivity of 97% for identifying patients with high-risk features while reducing the number of recommended CMRs by 61%. The negative predictive value with this screening strategy for the absence of high-risk features in patients without ECG-DL recommendation for CMR was 99.5%. ConclusionIn HCM, novel ECG-DL models reliably identified patients with high-risk imaging features while offering the potential to reduce CMR testing requirements in underresourced areas.

Enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction in patient-specific induced pluripotent stem cell-derived cardiomyocytes with MYH7 mutation

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the β-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C.1063 G>A) heterozygous mutation(mutant-iPSC-CMs) and mutation-corrected isogenic iPSCs(control-iPSC-CMs) in the present study. Next, we compared phenotype of mutant-iPSC-CMs to that of control-iPSC-CMs, by assessing their morphology, hypertrophy-related genes expression, calcium handling, diastolic function and myofilament calcium sensitivity at days 15 and 40 respectively. Finally, to better understand increased myofilament Ca2+ sensitivity as a central mechanism of central pathogenicity in HCM, inhibition of calcium sensitivity with mavacamten can improveed cardiomyocyte hypertrophy. Mutant-iPSC-CMs exhibited enlarged areas, increased sarcomere disarray, enhanced expression of hypertrophy-related genes proteins, abnormal calcium handling, diastolic dysfunction and increased myofilament calcium sensitivity at day 40, but only significant increase in calcium sensitivity and mild diastolic dysfunction at day 15. Increased calcium sensitivity by levosimendan aggravates cardiomyocyte hypertrophy phenotypes such as expression of hypertrophy-related genes, abnormal calcium handling and diastolic dysfunction, while inhibition of calcium sensitivity significantly improves cardiomyocyte hypertrophy phenotypes in mutant-iPSC-CMs, suggesting increased myofilament calcium sensitivity is the primary mechanisms for MYH7 mutations pathogenesis. Our studies have uncovered a pathogenic mechanism of HCM caused by MYH7 gene mutations through which enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction. Correction of the myofilament calcium sensitivity was found to be an effective method for treating the development of HCM phenotype in vitro.

Abstract 18721: Increased Predisposition to Hypertrophic Cardiomyopathy in Mitochondria Gene CYP2E1 Rare Variant Carriers

Introduction: With a prevalence of up to 1 in 200, hypertrophic cardiomyopathy (HCM) is the most common monogenic hereditary cardiovascular disease. Previous studies have observed that mitochondrial dysfunction and mitochondria-associated metabolic remodeling are major metabolic features in HCM. However, the impact of mitochondrial gene mutations on HCM were poorly understood. Methods and Results: We selected 2272 mitochondrial genes from the Mitocarta database 3.0 and screened rare variants from the whole-exome sequencing data in 985 HCM patients (excluding patients with HCM phenotypes, including mitochondrial myopathy) and 759 non-HCM controls. We found that CYP2E1 rare variants were significantly enriched in HCM patients (OR = 9.56, Bonferroni corrected P = 0.001). Patients with or without CYP2E1 rare variants shared similar demographic and echocardiographic variables at baseline. With a median follow-up time of 5.31 years in 735 HCM patients, we revealed that HCM patients with CYP2E1 rare variants were more likely to experience myocardial infarction (HR 14.1, P < 0.001). Conclusion: We demonstrated that rare variants in the mitochondrial gene CYP2E1 might increase the risk of HCM onset and may be associated with the occurrence of myocardial infarction endpoints in HCM. We hypothesize that the mechanism is related to the extensive and complex mitochondrial metabolic processes in which CYP2E1 is involved. Our findings provided new evidence for the association between mitochondrial gene variants and HCM, and more multi-center evidence is needed to confirm this association in the future.

Phenotype variation of hypertrophic cardiomyopathy in carriers of the p.Arg870His pathogenic variant in the MYH7 gene

The review analyzes variability of clinical manifestations of p.Arg870His in the MYH7 gene, which is repeatedly registered in patients with hypertrophic cardiomyopathy (HCM). The analysis involves the data from scientific publications obtained as a search result in the PubMed, СlinVar, and eLibrary.ru databases, as well as authors’ own results. A wide range of phenotypic manifestations have been revealed in carriers of p.Arg870His, from the asymptomatic to severe course, rapid progression, and early death. The review considers possible factors that modify the effect of the pathogenic variant (i.e. dosage of the pathogenic variant, the presence of other unfavorable genetic variants, etc.). The importance of accumulating information on the clinical features of HCM in the carriers of specific gene variants is emphasized in order to clarify their pathogenicity and to identify factors modifying the clinical outcome, which is important for the choice of the treatment strategy for HCM.

Evidence of Advanced Pulmonary Vascular Remodeling in Obstructive Hypertrophic Cardiomyopathy With Pulmonary Hypertension

Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone. Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure? Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements. The HCM cohort (n= 7; mean ± SD age, 43 ± 18 years; 71%men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8mm, mean ± SD outflow tract gradient of 90 ± 30mmHg, median mPAP of 25mmHg (interquartile range [IQR], 6mmHg), median pulmonary artery wedge pressure (PAWP) of 16mmHg (IQR, 4mmHg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n= 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2%vs49.7 ± 12%; P< .001) and arterial wall fibrosis (11.5 ± 3.4mm vs21.0 ± 4.7mm; P< .0001), which correlated with mPAP (r= 0.84; P= .018), PAWP (r= 0.74; P= .05), and LV outflow tract gradient (r= 0.78; P= .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P= .008) in the HCM group, which correlated with mPAP (r= 0.81; P= .03) and LV outflow tract gradient (r= 0.83; P= .02). To the best of our knowledge, these data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction.

Subtypes and Mechanisms of Hypertrophic Cardiomyopathy Proposed by Machine Learning Algorithms.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited cardiac disease that results in left ventricular hypertrophy. Machine learning uses algorithms to study patterns in data and develop models able to make predictions. The aim of this study is to identify HCM subtypes and examine the mechanisms of HCM using machine learning algorithms. Clinical and laboratory findings of 143 adult patients with a confirmed diagnosis of nonobstructive HCM are analyzed; HCM subtypes are determined by clustering, while the presence of different HCM features is predicted in classification machine learning tasks. Four clusters are determined as the optimal number of clusters for this dataset. Models that can predict the presence of particular HCM features from other genotypic and phenotypic information are generated, and subsets of features sufficient to predict the presence of other features of HCM are determined. This research proposes four subtypes of HCM assessed by machine learning algorithms and based on the overall phenotypic expression of the participants of the study. The identified subsets of features sufficient to determine the presence of particular HCM aspects could provide deeper insights into the mechanisms of HCM.

LincRNA RMRP Regulates Phenylephrine-induced Cardiomyocyte Hypertrophy by Means of Targeting miR-1.

Cardiac hypertrophy is a feature of hypertrophic cardiomyopathy (HCM), which could lead to heart failure and other cardiovascular diseases. Cardiomyocyte hypertrophy (CH) is the primary characteristic of cardiac hypertrophy. Long noncoding RNA (lncRNA, lincRNA) plays an important role in CH. In this study, the expression of linc-RMRP and its correlation with cardiac hypertrophy were analyzed in cardiac tissues of patients with HCM. Real-time qPCR and western blotting measured the expressions of lincf-RMRP, miR-1, and hypertrophic marker genes. RNA pulldown and luciferase reporter gene assays were performed to validate the combination between linc-RMRP and miR-1. We confirmed that Linc-RMRP was upregulated in both cardiac hypertrophy tissues and phenylephrine (PE)-induced CH cells, and the cells presented hypertrophic features, enlarged cell surface area and volume, elevated total protein contents, and increased expressions of ANP, BNP, β-MHC, and activated p70S6K and 4EBP1. Bioinformatic analysis found that linc-RMRP directly bonds to miR-1. RNA pulldown, mutation, and luciferase reporter gene assays verified this combination. Silencing linc-RMRP significantly attenuated hypertrophic responses induced by PE while the expression of miR-1 was released. However, the transfection of miR-1 inhibitor reversed the effects of linc-RMRP knockdown exerted on PE-treated cardiomyocytes. In summary, our study identified the modulatory role linc-RMRP played in regulating PE-induced CH by means of binding miR-1, and this might provide a new target for cardiac hypertrophy therapy.

Index of microcirculatory resistance in the assessment of coronary microvascular dysfunction in hypertrophic cardiomyopathy

Introduction and objectivesCoronary microvascular dysfunction (CMD) is one of the most important pathophysiological features in hypertrophic cardiomyopathy (HCM). The index of microcirculatory resistance (IMR) is an invasive method to assess the coronary microcirculation. The aim was to assess CMD in patients with HCM by IMR. MethodsAdult patients with HCM without epicardial coronary artery disease underwent cardiac catheterization for the assessment of CMD by IMR (normal cut-off value ≤22.0) and coronary flow reserve (CFR) (normal cut-off value ≥2). Cardiovascular magnetic resonance (CMR) was performed to assess the ischemic burden by perfusion imaging during regadenoson-induced hyperemia, and the extent of myocardial fibrosis was assessed by late gadolinium enhancement (LGE), native T1 mapping and extracellular volume (ECV). ResultsFourteen patients were enrolled with a mean age of 62.8±6.2years, 8 (57.1%) males, of whom 9 (64.3%) had obstructive HCM. Using IMR, CMD was detected in 4 (29%) patients. Among four patients with an IMR>22.0, all had non-obstructive HCM and two had angina. CFR<2 was reported in eight patients (57%). Concordance between IMR and CFR (both normal or both abnormal) was verified in 6 patients (43%). Among four patients with IMR>22.0, perfusion defects were found in two of the three patients who underwent stress CMR. Increased ECV (>28%) was documented in two of the patients with IMR>22 and in three of the patients with IMR≤22.0. LGE was >15% in 2 of the patients with IMR>22 and in 4 with IMR≤22.0. ConclusionsIMR assessment in HCM is feasible and safe. Patients with abnormal IMR seemed to have more significant tissue abnormalities on CMR.

Commentary on the enigma of small vessel disease in hypertrophic cardiomyopathy: is invasive assessment of microvascular resistance a novel independent predictor of prognosis?

The key pathophysiological features in hypertrophic cardiomyopathy are ventricular hypertrophy, diastolic dysfunction, and abnormalities in the mitral valve apparatus, but coronary microvascular dysfunction and ischemia have also been described. The small vessel disease changes could be reflected in the invasive measurement of the index of microvascular resistance, with prognostic potential.

Blunted coronary flow velocity reserve is associated with impairment in systolic function and functional capacity in hypertrophic cardiomyopathy

BackgroundCoronary microvascular dysfunction constitutes an important pathophysiological feature in hypertrophic cardiomyopathy (HCM).We aimed to assess the association between impaired coronary flow velocity reserve (CFVR) and ventricular systolic function and functional capacity. MethodsEighty-three patients with HCM were enrolled in this prospective cohort study. Patients underwent echocardiogram to evaluate ventricular performance and CFVR in the left anterior descending artery (LAD) and posterior descending artery (PD). Diastolic coronary flow velocity was measured in basal conditions and in hyperemia. CFVR was calculated as the ratio of hyperemic and basal peak diastolic flow velocities. Functional capacity was evaluated by cardiopulmonary exercise testing (CPET). The link between CFVR and biventricular systolic function and peak VO2 was studied. ResultsAge was 55.0(14.4)years, 50 patients (60%) were male; 59 patients (71%) had nonobstructive HCM. Mean CFVR LAD was 1.81(0.49) and CFVR PD was 1.73(0.55). Lower CFVR PD was associated with impaired global longitudinal strain (GLS) 2D (β-estimate:-3.240,95%CI:-4.634;-1.846, p < 0.001), GLS 3D (β-estimate:-2.559,95%CI:-3.932;-1.186, p < 0.001) and area strain (β-estimate:-3.044,95%CI:-5.373;-0.716, p = 0.011). Lower values of CFVR PD related to worse global work index (β-estimate:267.824,95%CI:75.964;459.683, p = 0.007), global constructive work (β-estimate:217.300,95%CI:38.750;395.850, p = 0.018) and global work efficiency (β-estimate:5.656,95%CI:2.229;9.084, p = 0.002). Impaired CFVR LAD (β-estimate:2.826, 95%CI:0.913;4.739, p = 0.004) and CFVR PD (β-estimate:2.801,95%CI:0.657;4.945, p = 0.011) were associated with lower TAPSE. Lower values of CFVR LAD (β-estimate:2.580, 95%CI:0.169;4.991, p = 0.036) and CFVR PD (β-estimate:3.163, 95%CI: 0.721;5.606, p = 0.012) were associated with worse peak VO2. ConclusionLower CFVR was associated with impairment in biventricular systolic function parameters and functional capacity assessed by pVO2.

Anatomical-MRI Correlations in Adults and Children with Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is the most frequent hereditary cardiovascular disease and the leading cause of sudden cardiac death in young individuals. Advancements in CMR imaging have allowed for earlier identification and more accurate prognosis of HCM. Interventions aimed at slowing or stopping the disease’s natural course may be developed in the future. CMR has been validated as a technique with high sensitivity and specificity, very few contraindications, a low risk of side effects, and is overall a good tool to be employed in the management of HCM patients. The goal of this review is to evaluate the magnetic resonance features of HCM, starting with distinct phenotypic variants of the disease and progressing to differential diagnoses of athlete’s heart, hypertension, and infiltrative cardiomyopathies. HCM in children has its own section in this review, with possible risk factors that are distinct from those in adults; delayed enhancement in children may play a role in risk stratification in HCM. Finally, a number of teaching points for general cardiologists who recommend CMR for patients with HCM will be presented.

Strain-volume loops for assessment of diastolic function in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Diastolic function assessment in patients with hypertrophic hearts and preserved ejection fraction (EF) is a rather challenging task, necessitating the introduction of new parameters. Strain-volume loops (SVLs), based on simultaneous frame-by-frame strain and volume changes’ recordings acquired by means of three-dimensional (3D) speckle tracking imaging, is an innovative tool which has been applied in various substrates. The ability of SVLs to assess diastolic function in hypertrophic cardiomyopathy (HCM) has not been investigated until now. Purpose Aim of this study was to investigate potential correlations between SVLs, traditional diastolic function indices and phenotypic features of HCM (thickness, obstruction and fibrosis) that may also reflect myocardial "stiffness". Methods We included 40 HCM patients (54.1 ± 14.3 years, 82.5% male, maximum wall thickness 19.3 ± 4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography (panel A) and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build an SVL. Peak of radial, longitudinal and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), strain to end-diastolic volume (EDV) ratios (Rs/V, Ls/V, Cs/V) as well as the extent of systolic-diastolic uncoupling (difference between systolic and diastolic strain for the same volume) were computed for the analysis. Left atrial volume index (LAVI), E/E’ and tricuspid regurgitation velocity (TRvel) were measured to define diastolic dysfunction (DD) stage. Burden of fibrosis was evaluated by LGE extent in CMR slices. Results All HCM patients had preserved EF (60.5 ± 5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO &amp;gt; 30 mm Hg at rest). Mean LV mass index was 78.9 ± 14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2 ± 4.5% of LV mass. Concerning SVLs the following values were recorded for radial (Rsp 30.8 ± 9.8%, RsSl 0.4 ± 0.13 and Rs/V 0.25 ± 0.09), longitudinal (Lsp -9.4 ± 3.7%, LsSl 0.12 ± 0.06 and Ls/V 0.08 ± 0.04) and circumferential deformation (Csp -14.2 ± 3.5%, CsSl 0.18 ± 0.05 and Cs/V 0.11 ± 0.03). Traditional isolated diastolic indices (E/E’, LAVI, TRvel and DD stage) did not present significant correlations with SVL parameters or HCM phenotypic features. However, potentially "stiffer" hearts (combination of increased LVMI and fibrosis) presented a leftward transition of longitudinal SVLs, which also became wider (greater uncoupling) (panel B). Conclusions Traditional diastolic indices show modest only correlations with SVLs or HCM phenotypic characteristics, necessitating new approaches to DD of HCM patients. SVLs seem to be a promising-innovative tool for indirect assessment of myocardial "stiffness" and diastolic function. Abstract Figure.

Differential Diagnosis of Thick Myocardium according to Histologic Features Revealed by Multiparametric Cardiac Magnetic Resonance Imaging.

Left ventricular (LV) wall thickening, or LV hypertrophy (LVH), is common and occurs in diverse conditions including hypertrophic cardiomyopathy (HCM), hypertensive heart disease, aortic valve stenosis, lysosomal storage disorders, cardiac amyloidosis, mitochondrial cardiomyopathy, sarcoidosis and athlete’s heart. Cardiac magnetic resonance (CMR) imaging provides various tissue contrasts and characteristics that reflect histological changes in the myocardium, such as cellular hypertrophy, cardiomyocyte disarray, interstitial fibrosis, extracellular accumulation of insoluble proteins, intracellular accumulation of fat, and intracellular vacuolar changes. Therefore, CMR imaging may be beneficial in establishing a differential diagnosis of LVH. Although various diseases share LV wall thickening as a common feature, the histologic changes that underscore each disease are distinct. This review focuses on CMR multiparametric myocardial analysis, which may provide clues for the differentiation of thickened myocardium based on the histologic features of HCM and its phenocopies.

Deleterious Rare Desmosomal Variants Contribute to Hypertrophic Cardiomyopathy and Are Associated With Distinctive Clinical Features.

Deleterious rare variants in genes encoding desmosome proteins have been identified as the essential basis of arrhythmogenic cardiomyopathy (ACM) and detected in dilated cardiomyopathy, but the relationship between deleterious rare desmosomal variants and hypertrophic cardiomyopathy (HCM) remains unknown. Whole exome sequencing was performed in 1000 patients with HCM and 761 non-HCM controls to search for deleterious rare variants in genes encoding desmosomal proteins including PKP2, JUP, DSC2, DSG2, and DSP. Clinical phenotypes were assessed in patients with HCM, and patients with deleterious rare desmosomal variants underwent evaluation of ACM revised Task Force Criteria. A total of 27 deleterious rare desmosomal variants were present in 24 (2.4%) patients with HCM and 5 (0.66%) controls. The variants were more prevalent in the patients with HCM than in the controls (P= 0.004). The majority of patients possessing deleterious rare desmosomal variants could not be diagnosed as ACM. Moreover, the patients with deleterious rare desmosomal variants possessed several distinctive clinical features compared with patients without such variants, including a higher incidence of nonsustained ventricular tachycardia (29.2% vs 4.5%, P < 0.001), left bundle branch block (33.3% vs 1.6%, P < 0.001), and right ventricular involvement for an HCM phenotype (29.2% vs 0.30%, P < 0.001). We screened deleterious rare desmosomal variants in a large HCM case-control cohort and found deleterious rare desmosomal variants can be relevant to HCM. Moreover, our data indicated deleterious rare desmosomal variants were associated with distinctive clinical features of HCM. These findings require validation in other HCM cohorts.

Coronary microvascular dysfunction in hypertrophic cardiomyopathy – impact from tissue characteristics to clinical manifestations

Abstract Background Coronary microvascular dysfunction (CMD) is an important pathophysiological feature in hypertrophic cardiomyopathy (HCM). Purpose This study investigated the role of CMD in tissue characteristics, left ventricular (LV) systolic performance and clinical manifestations in HCM. Methods This prospective study enrolled patients with HCM without obstructive epicardial coronary artery disease. Each patient underwent cardiovascular magnetic resonance (CMR) including parametric mapping, perfusion imaging during regadenoson-induced hyperemia, late gadolinium enhancement (LGE) and three-dimensional longitudinal, circumferential and radial strains analysis. Electrocardiogram and 24 hours Holter recording were performed to assess arrhythmias. Results 75P were enrolled, 47 (63%) males, mean age 54.6 (14.8) years; 51 patients (68%) had non obstructive HCM, mean maximum wall thickness (MWT) was 20.2 (4.6)mm, LV ejection fraction 71.6 (8.3)%, ischemic burden 22.5 (16.9)% of LV. Greater MWT was associated the severity of ischemia (β-estimate: 1.809, 95% CI: 1.073; 2.545; p&amp;lt;0.001). Ischemic burden was strongly associated with higher values of native T1 (β-estimate: 9.018, 95% CI: 4.721, 13.315; p&amp;lt;0.001). An association between ischemia and the extent of LGE was found (β-estimate: 2.02, 95% CI: 0.93, 3.10; p&amp;lt;0.001). Ischemia in ≥21% of LV was associated with LGE &amp;gt;15% (AUC 0.766, sensitivity 0.724, specificity 0.659). In multivariable analysis, in the overall population, MWT and LGE were independently associated with ischemia, however the evidence of association between ischemia and extent of LGE became weaker (β-estimate: 1.070, 95% CI: −0.106; 2.245; p=0.074). In subgroup analysis, the association between ischemia and LGE remained significant in individuals with MWT 15–20mm, non-obstructive HCM, female and age &amp;lt;40 years. The severity of ischemia was not associated with markers of LV systolic function, namely LVEF, longitudinal, radial and circumferential strain A strong evidence of association was found between ischemia and atrial fibrillation/flutter (AF/AFL) (OR: 1.481, 95% CI: 1.020,2.152; p=0.039), but no association was verified with non-sustained ventricular tachycardia. Conclusion In HCM, CMD is related to the severity of LV hypertrophy. Ischemia secondary to CMD promotes fibrosis and is associated with an increase in the odds of AF/ALF. Funding Acknowledgement Type of funding sources: None.

Utility of volume-strain loops in diastolic function assessment of patients with hypertrophic cardiomyopathy

Abstract Background Diastolic function assessment in patients with hypertrophic hearts and preserved ejection fraction (EF) is a rather challenging task. Combined plotting of deformation parameters against other indices, especially left ventricular (LV) volume, may reflect diastolic function components of the hypertrophic myocardium. Purpose Aim of this study was i) to apply strain-volume loops (SVLs) in hypertrophic cardiomyopathy (HCM) patients based on simultaneous frame-by-frame strain and volume changes' recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to investigate potential correlations between these loops, traditional diastolic function indices and phenotypic features of HCM (thickness, obstruction and fibrosis) that may also reflect myocardial “stiffness”. Methods We included 40 HCM patients (54.1±14.3 years, 82.5% male, maximum wall thickness 19.3±4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build an SVL. Peak of radial, longitudinal and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), strain to end-diastolic volume (EDV) ratios (Rs/V, Ls/V, Cs/V) as well as the extent of systolic-diastolic uncoupling (difference between systolic and diastolic strain for the same volume) (panel A) were computed for the analysis. Left atrial volume index (LAVI), E/E' and tricuspid regurgitation velocity (TRvel) were measured to define diastolic dysfunction (DD) stage. Burden of fibrosis was evaluated by LGE extent in CMR slices. Results All HCM patients had preserved EF (60.5±5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO&amp;gt;30 mm Hg at rest). Mean LV mass index was 78.9±14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2±4.5% of LV mass. Concerning SVLs the following values were recorded for radial (Rsp 30.8±9.8%, RsSl 0.4±0.13 and Rs/V 0.25±0.09), longitudinal (Lsp −9.4±3.7%, LsSl 0.12±0.06 and Ls/V 0.08±0.04) and circumferential deformation (Csp −14.2±3.5%, CsSl 0.18±0.05 and Cs/V 0.11±0.03). Traditional isolated diastolic indices (E/E', LAVI, TRvel and DD stage) did not present significant correlations with SVL parameters or HCM phenotypic features. However, potentially “stiffer” hearts (combination of increased LVMI and fibrosis) presented a leftward transition of longitudinal SVLs, which also became wider (greater uncoupling) (panel B). Conclusions Traditional diastolic indices show modest only correlations with SVLs or HCM phenotypic characteristics, necessitating new approaches to DD of HCM patients. SVLs seem to be a promising-innovative tool for indirect assessment of myocardial “stiffness” and diastolic function. Funding Acknowledgement Type of funding sources: None. Figure 1

Comparison of mitral regurgitation severity assessments based on magnetic resonance imaging and echocardiography in patients with hypertrophic cardiomyopathy

Mitral regurgitation (MR), which is one of the factors responsible for heart failure symptoms and the development of atrial fibrillation, is an important feature of hypertrophic cardiomyopathy (HCM), and its presence affects which treatment options are chosen. Although cardiac magnetic resonance imaging (MRI) is considered the reference standard for assessing the regurgitant volume (RV) and fraction (RF), echocardiography is the most common method for assessing MR severity. Accordingly, the aim of this study was to compare the results of echocardiography and cardiac MRI for assessing MR severity in a cohort of patients with HCM. MR severity was assessed in 53 patients using cardiac MRI by determining the mitral RV (MRV) and mitral RF (MRF). The results were graded according to thresholds recommended in current guidelines. MR severity assessed by echocardiography was graded by integrating indices of severity. Greater than mild MR, as assessed using echocardiography, was present in 22 patients (41.5%) with HCM and in none of the control patients (p = 0.001). In all, 31 patients (58.5%) had no more than mild MR. When MR severity was assessed using different methods, either moderate (kappa = 0.44, 95% confidence interval = 0.21–0.67), poor or no agreement was found between MRI-derived and echocardiography-derived grades. HCM patients with echocardiography-derived moderate and severe MR had similar median MRVs and MRFs (p = 0.59 and p = 0.11, respectively). In HCM patients, cardiac MRI and echocardiography were at most in modest agreement in assessing MR severity. Importantly, echocardiography-derived moderate and severe MR were not distinguishable by either MRV or MRF.

Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers.

BackgroundImpaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype‐positive, left ventricular hypertrophy‐negative).Methods and ResultsA single center, case‐control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre‐phenotypic features of HCM. Individuals with genotype‐positive, left ventricular hypertrophy‐negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH‐fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype‐positive, left ventricular hypertrophy‐negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m2, P=0.03), lower left ventricular end‐systolic volume (21.0±6.9 versus 26.7±6.2 mm/m2, P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826).ConclusionsRegional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Molecular Genetic Basis of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.

MRI of the Heart in Obstructive Hypertrophic Cardiomyopathy: Scanning Protocol, Visualization, Clinical Significance (review of the Literature with Own Clinical Observations)

Hypertrophic cardiomyopathy (HCM) defined by wall thickness ≥ 15 mm in one or more left ventricular myocardium segments, according to the results of any imaging technique that is not explained solely due to increased pressure load. For decades, echocardiography has been the first-line method in the diagnosis of HCM. This is due to its availability, low cost, and informative content. However, due to the high spatial resolution and volumetric nature of image acquisition, magnetic resonance imaging (MRI) has advantages over other diagnostic techniques. Currently, cardiac MRI is becoming the method of choice in diagnostics and management in patients with HCM. This article presents the possibilities of MR imaging in patients with HCM and demonstrates the typical phenotypes and some morphological characteristics of HCM according to our research protocols conducted on a MR scanner with a 1,5 T magnetic field strength. In addition, the article shows the clinical significance of MRI for the management of patients with HCM.