Features Of Hypertrophic Cardiomyopathy Research Articles

Microvascular dysfunction contributes to atrial fibrillation in hypertrophic cardiomyopathy, a multimodality study

Abstract Background Microvascular dysfunction (MVD) constitutes one of the most important pathophysiological features in hypertrophic cardiomyopathy (HCM). Chronic and recurrent myocardial ischemia potentially contributes to arrhythmic risk, namely to atrial fibrillation (AF). Purpose To analyze the impact of MVD in the occurrence of AF in HCM patients (P), assessed by coronary flow velocity reserve (CFVR) on echocardiography (echo) and ischemia on cardiovascular magnetic resonance (CMR). Methods Prospective study, which enrolled HCM P without obstructive epicardial coronary artery disease, who underwent stress echo and stress CMR. By echo, the evaluation of CFVR in the left anterior descending (LAD) artery was performed in apical three chambers view. Diastolic coronary flow velocity was measured in basal conditions and in hyperemia, induced by adenosine perfusion (0.14 mg/kg/min intravenously, during 2 minutes). CFVR was calculated as the ratio of hyperemic to basal peak diastolic flow velocities. On CMR, perfusion imaging was acquired during regadenoson-induced hyperemia. To quantify the ischemic burden, the myocardium was divided into 32 subsegments (16 AHA segments subdivided into an endocardial and epicardial layer, excluding segment 17) and the ischemic burden was calculated as the number of involved subsegments, assigning 3% of myocardium to each subsegment. Late gadolinium enhancement (LGE) was quantified used the 6 standard deviation method. Kaplan Meyer curves were performed to evaluate the impact of CFVR, ischemia, left atrial volume and LGE in the occurrence of atrial fibrillation during the follow up. Results 73P were enrolled, 47 (64%) males, mean age 54.3(14.8) years. 19 P (26%) had obstructive HCM, mean maximal wall thickness (MWT) was 20.1(4.6)mm, left ventricular (LV) mass 96.9(30.6)g/m2, LV ejection fraction 71.6(8.4)%, left atrial volume (LAV) 47.0(16.8)ml/m2, CFVR LAD 1.8(0.4), ischemic burden 22.5(17.1)% of LV. During the follow up of 54.6(7.8) months (minimum 42months, maximum 80months), P with more severe microvascular dysfunction (CFVR LAD<2.0 and ischemia ≥18% of LV) had significant higher incidence of atrial fibrillation (figure 1). P with CFVR LAD≥2.0 and LAV≤34ml/m2 had significantly less AF comparing to P with CFVR LAD<2.0 and LAV>34ml/m2. Interestingly, P with only one of this risk factors had similar incidence of AF, pointing toward a similar impact of microvascular dysfunction and LA dilatation. Although LGE is a well-known surrogate marker of disease severity, extension of the ischemia seemed to play a more important role in AF development, as patients with ischemia ≥ 18% of LV and LGE < 15% had more AF than P with ischemia < 18% of LV and LGE ≥ 15%. Conclusion Microvascular dysfunction and consequent ischemic burden were linked to AF, which likely reflects advanced disease, involving atrial myocardium beyond LV myocardium, contributing for atrial dysfunction and arrhythmogenicity. Figure 1

Mitral regurgitation in obstructive hypertrophic cardiomyopathy: assessing the impact of mavacamten

Abstract Background Hypertrophic cardiomyopathy (HCM) is a genetic cardiac condition that leads to a hypercontractile state. This, as well as other features of HCM, such as abnormal mitral valve morphology and septal protrusion can lead to left ventricular outflow tract (LVOT) obstruction. Mitral regurgitation (MR) is a frequent finding in patients with hypertrophic cardiomyopathy (HCM), usually due to systolic anterior motion (SAM) of the mitral valve. Patients with outflow obstruction can present with a myriad of symptoms. With the introduction of myosin inhibitors such as mavacamten, reductions in the LVOT gradient and improvement in symptoms has been well documented. However, the impact on SAM and SAM-mediated MR has not been well explored. Objectives We aimed to evaluate whether mavacamten resulted in a change in SAM and subsequently a change in mitral regurgitation, in patients with obstructive HCM from baseline following a period of established mavacamten pharmacotherapy. Methods Transthoracic echocardiography (TTE), which is used to facilitate the safe prescription and monitoring of mavacamten therapy, was retrospectively analysed. Severity of mitral regurgitation (graded as 0-4 to delineate trivial, mild, moderate, moderate to severe and severe disease), grade of SAM (0-3) and LVOT gradients were documented, with baseline studies compared to the most recent follow up scan for the patient in question. MR severity was based on the visual impression of the reporting sonographer, and was reviewed by an imaging cardiologist. Patients had undergone between 4 and 24 weeks of mavacamten pharmacotherapy depending on their time of enrolment into the mavacamten clinic. Concurrent changes in NT-pro BNP were also evaluated. Results 24 patients (female n=4; male n = 20) in the mavacamten clinic underwent retrospective analysis of their echocardiographic parameters. Improvement in the severity of MR occurred in 75% of patients (n=18; p<0.001). In 39% of these patients, severity improved by 2 grades or more. Systolic anterior motion of the mitral valve was downgraded in 75% of patients (n=18; p<0.001), with an improvement by 2 grades or more in 42% of individuals. Mavacamten therapy resulted in a reduction in LVOT gradient at rest (-28.96± 5.124mmHg P=<0.0001) and with Valsalva (-60.95± 7.551mmHg P=<0.0001). Furthermore, a significant reduction in serum NT-proBNP levels was demonstrated from baseline (-975.2± 7.551ng/L P=<0.0001). 1 patient had to discontinue therapy at 4 weeks primarily due to a drop in left ventricular ejection fraction. Conclusion In patients with obstructive HCM, mavacamten resulted in a significant reduction in SAM-mediated mitral regurgitation, with corresponding falls in LVOT gradients. Cardiac myosin inhibitor scanning protocols should include detailed mitral valve assessment, to allow accurate evaluation of both SAM-dependent and SAM-independent MR mechanisms. Severity of mitral regurgitation. Change in grade of SAM.

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.

Genetic Basis of Hypertrophic Cardiomyopathy in Cats.

Hypertrophic cardiomyopathy (HCM) is a common cardiovascular condition in cats, affecting yth males and females of all ages. Some breeds, such as Ragdolls and Maine Coons, can develop HCM at a young age. The disease has a wide range of progression and severity, characterized by various pathological changes in the heart, including arteritis, fibrous tissue deposition, and myocardial cell hypertrophy. Left ventricular hypertrophy, which can restrict blood flow, is a common feature of HCM. The disease may persist into old age and eventually lead to heart failure and increased diastolic pressure. The basis of HCM in cats is thought to be genetic, although the exact mechanisms are not fully understood. Mutations in sarcomeric proteins, in particular myosin-binding protein C (MYBPC3), have been identified in cats with HCM. Two specific mutations, MYBPC3 [R818W] and MYBPC3 [A31P], have been classified as 'pathogenic'. Other variants in genes such as MYBPC3, TNNT2, ALMS1, and MYH7 are also associated with HCM. However, there are cases where cats without known genetic mutations still develop HCM, suggesting the presence of unknown genetic factors contributing to the disease. This work aims to summarise the new knowledge of HCM in cats and the alterations in cardiac tissue as a result of genetic variants.

Studying Pathogenetic Contribution of a Variant of Unknown Significance, p.M659I (c.1977G > A) in MYH7, to the Development of Hypertrophic Cardiomyopathy Using CRISPR/Cas9-Engineered Isogenic Induced Pluripotent Stem Cells.

Hypertrophic cardiomyopathy (HCM) is a cardiovascular pathology that is caused by variants in genes encoding sarcomere-associated proteins. However, the clinical significance of numerous variants in HCM-associated genes is still unknown. CRISPR/Cas9 is a tool of nucleotide sequence editing that allows for the unraveling of different biological tasks. In this study, introducing a mutation with CRISPR/Cas9 into induced pluripotent stem cells (iPSCs) of a healthy donor and the directed differentiation of the isogenic iPSC lines into cardiomyocytes were used to assess the pathogenicity of a variant of unknown significance, p.M659I (c.1977G > A) in MYH7, which was found previously in an HCM patient. Using two single-stranded donor oligonucleotides with and without the p.M659I (c.1977G > A) mutation, together with CRISPR/Cas9, an iPSC line heterozygous at the p.M659I (c.1977G > A) variant in MYH7 was generated. No CRISPR/Cas9 off-target activity was observed. The iPSC line with the introduced p.M659I (c.1977G > A) mutation in MYH7 retained its pluripotent state and normal karyotype. Compared to the isogenic control, cardiomyocytes derived from the iPSCs with the introduced p.M659I (c.1977G > A) mutation in MYH7 recapitulated known HCM features: enlarged size, elevated diastolic calcium level, changes in the expression of HCM-related genes, and disrupted energy metabolism. These findings indicate the pathogenicity of the variant.

Proteomic Characterisation of Heart Failure Reveals a Unique Molecular Phenotype for Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ischaemic cardiomyopathy (ISCM) and dilated cardiomyopathy (DCM) for identification of protein and pathway targets that could support the development of better diagnostic and treatment options for HCM. A high-throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart-failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Differentially expressed proteins unique to HCM were identified based on an observed fold change of ≥1.5 or ≤0.67 and q-value ≤ 0.05. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.

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.