Remodeling In Hypertrophic Cardiomyopathy Research Articles

Abstract Tu089: p21 Regulates Hypertrophic Cardiomyopathy Remodeling By Inhibition of Cardiomyocyte Endoreplication

Background: We previously discovered that a murine model of hypertrophic cardiomyopathy had increased cardiomyocyte endoreplication and replication stress leading to increased DNA damage. Activation of DNA damage response pathways was associated with increased cardiomyocyte expression of the cyclin-dependent kinase inhibitor p21. However, the role of p21 on pathologic myocardial remodeling in hypertrophic cardiomyopathy is poorly understood. Methods: We utilized a murine model of hypertrophic cardiomyopathy that is deficient in cardiac myosin binding protein 3 (Mybpc3 -/- ). We used murine models deficient in p21 (Cdkn1a -/- ) or overexpressed p21 (Cdkn1a SUPER ) to determine the role of p21 on hypertrophic remodeling. Heart structure and function were evaluated by echocardiography. Flow cytometry and immunohistochemistry were used to measure cardiomyocyte DNA content and ploidy. Proteomics and biochemical assays were utilized to identify p21 target proteins. Results: We observed that there was an increased p21 expression in Mybpc3 -/- cardiomyocytes during the postnatal day 7 to 25 time interval. Elimination of p21 expression in Mybpc3 -/- animals (Cdkn1a -/- /Mybpc3 -/- ) caused increased myocardial hypertrophy (Table 1). Conversely, selective overexpression of p21 in cardiomyocytes (Cdkn1a SUPER /Mybpc3 -/- /Myh6Cre) led to reduced myocardial hypertrophy (Table 1). We discovered that isolated cardiomyocyte nuclei from Mybpc3 -/- mice with reduced p21 had increased polyploidy whereas overexpression of cardiomyocyte p21 led to reduced cardiomyocyte polyploidy (Table 1). Using both proteomics and targeted assays we discovered that cardiomyocyte p21 was binding to key cycle regulatory proteins to inhibit cardiomyocyte endoreplication and hypertrophic growth. Conclusions: Collectively, our results show that induction of p21 in hypertrophic cardiomyopathy reduces cardiomyocyte growth by inhibiting endoreplication.

Integrative analysis of transcriptome, DNA methylome and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions (DMRs) were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors (TFs), including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions (NDRs) in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening the fetal gene reprogramming in HCM.

“Interstitial fibrosis is associated with left atrial remodeling and adverse clinical outcomes in selected low-risk patients with hypertrophic cardiomyopathy”

BackgroundCardiovascular magnetic resonance (CMR) extracellular volume (ECV) allows non-invasive detection of myocardial interstitial fibrosis, which may be related to diastolic dysfunction and left atrial (LA) remodeling in hypertrophic cardiomyopathy (HCM). While the prognostic role of LGE is well-established, interstitial fibrosis and LA dysfunction are emerging novel markers in HCM. This study aimed to explore the interaction between interstitial fibrosis by ECV, LA morpho-functional parameters and adverse clinical outcomes in selected low-risk patients with HCM. Methods115 HCM patients and 61 matched controls underwent CMR to identify: i) interstitial fibrosis by ECV in hypertrophied left ventricular LGE-negative remote myocardium (r-ECV); ii) LA indexed maximum (LAVi max) and minimum (LAVi min) volumes, ejection fraction (LA-EF) and strain (reservoir εs, conduit εe and booster εa), by CMR feature-tracking. 2D-echocardiographic assessment of diastolic function was also performed within 6 months from CMR. A composite endpoint including worsening NYHA class, heart failure hospitalization, atrial fibrillation and all-cause death was evaluated at 2.3 years follow-up. HCM patients were divided into two groups, according to r-ECV values of controls. ResultsPatients with r-ECV ≥29% (n = 45) showed larger LA volumes (LAVimax 63 vs. 54 ml/m2, p < 0.001; LAVimin 43 vs. 28 ml/m2, p 〈0001), worse LA function (εs 16 vs. 28%, εe 8 vs. 15%, εa 8 vs. 14%, LA-EF 33 vs. 49%, all p < 0.001) and elevated Nt-proBNP (1115 vs. 382 pg/ml, p = 0.002). LA functional parameters inversely correlated with r-ECV (εs r = −0.54; LA-EF r = −0.46; all p < 0.001) and E/e' (εs r = −0.52, LA-EF r = −0.46; all p < 0.006). r-ECV ≥29% and LAVi min >30 ml/m2 have been identified as possible independent factors associated with the endpoint. ConclusionsIn HCM diffuse interstitial fibrosis detected by increased r-ECV is associated with LA remodeling and emerged as a potential independent predictor of adverse clinical outcomes, on top of the well-known prognostic impact of LGE.

Reverse myocardial remodeling in hypertrophic cardiomyopathy: Little explored benefit of physical exercise

Reverse myocardial remodeling in hypertrophic cardiomyopathy: Little explored benefit of physical exercise

Abstract 18098: Prolonged Filtered QRS Duration on Signal Averaged Electrocardiogram is Associated With Structural Remodeling in Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy, electrical remodeling and fibrosis that lead to inhomogeneous ventricular depolarization and arrhythmias. Signal averaged ECG (SAECG) is useful for non-invasive risk stratification in ischemic cardiomyopathy. However, the association between SAECG and structural remodeling in HCM has not been investigated. Methods: We retrospectively studied 594 HCM patients from the Johns Hopkins HCM Registry, who underwent echocardiography and cardiac magnetic resonance (CMR) imaging within 12 months of SAECG or 12-lead ECG. Seventy-three patients underwent SAECG and were divided into 2 groups (Normal-SAECG, Abnormal-SAECG) based on filtered QRS duration and/or presence of late potentials . Results: Abnormal SAECG was seen in 50% of HCM patients (37/73). Of the 37 HCM patients with abnormal SAECG, 29 patients only had prolonged filtered QRS duration ( fQRS&gt; 114ms ), and 8 patients had prolonged fQRS duration as well as late potentials ( LAS40 &gt;38ms; RMS40 &lt;20μV). Mean fQRS and LAS40 were significantly higher in the Abnormal-SAECG group ( fQRS : 125.7 vs 107msec, p&lt;0.0001; LAS40 : 31.2 vs 22.9msec; p=0.002; RMS40 : 40 vs 54μV; p=0.07). HCM patients with abnormal SAECG also had 1) larger left atrial size (p=0.03), lower global LV peak systolic strain (p=0.04), systolic strain rate (p=0.008), early diastolic strain rate (p=0.01) by ECHO; 2) greater LV mass index (p=0.004) 3) Higher prevalence and amount of late gadolinium enhancement (LGE) reflecting LV-scar (p=0.045 and 0.01) by CMR; 4) higher prevalence of repolarization abnormalities on 12-lead ECG (p=0.02). Adverse outcomes (sustained-VT/VF, heart failure, death) were similar in the 2 groups. Filtered QRS duration (SAECG) was positively correlated with LV mass index (r=0.43, p=0.0002), QRS duration on 12-lead ECG (r=0.67, p=0.000), and negatively correlated with global LV early diastolic strain rate (r= -0.34, p=0.009) in our HCM cohort. Conclusion: In HCM, prolonged filtered QRS on SAECG reflects a greater degree of structural remodeling characterized by more LV hypertrophy, larger LA size, worse cardiac mechanics, and higher prevalence and amount of fibrosis.

Left atrial remodeling in hypertrophic cardiomyopathy and Fabry disease: A CMR-based head-to-head comparison and outcome analysis

BackgroundHypertrophic cardiomyopathy (HCM) and Fabry disease cardiomyopathy (FD) are phenocopies, as they show left ventricular hypertrophy (LVH). The left atrium (LA) is emerging as a potential marker of disease severity in both cardiomyopathies. The present study compares HCM and FD cardiomyopathy with similar degree of LVH, exploring LA morpho-functional parameters and the correlates of clinical outcome. MethodsWe performed a comprehensive CMR-based comparison between 30 HCM and 30 FD patients matched on age, sex, BSA, LV mass and major cardiovascular risk factors affecting LA remodeling (arterial hypertension and diabetes). 30 healthy controls were also included. CMR feature tracking (CMR-FT) analysis, T1 mapping and conventional parameters were evaluated. Patients also underwent transthoracic echocardiography for LV diastolic function assessment. Clinical events at follow-up were collected (atrial and ventricular events, bradyarrhythmia, heart failure (HF) hospitalization and death). ResultsHCM patients showed greater LA remodeling compared to FD patients, namely higher LA end-systolic volume index (LAVi max), lower LA-ejection fraction (LA-EF) and worse reservoir (εs) and booster function (εa) (all p < 0.05). Accordingly, these parameters have demonstrated good potential for distinguishing between FD and HCM (AUC 0.68–0.73, all p < 0.05), with LAVi max being an independent predictor for HCM diagnosis (OR 1.07, 95%CI 1.011–1.132, p 0.02). Moreover, in HCM patients a significant association between εs and HF occurrence was observed at 2-year follow-up (OR 0.85, 95%CI 0.72–0.99, p 0.04). ConclusionsIn HCM, LA remodeling is greater than in FD cardiomyopathy with similar LVH, and reservoir strain is associated with HF at follow-up.

Altered coronary artery function, arteriogenesis and endothelial YAP signaling in postnatal hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a cardiovascular genetic disease caused largely by sarcomere protein mutations. Gaps in our understanding exist as to how maladaptive sarcomeric biophysical signals are transduced to intra- and extracellular compartments leading to HCM progression. To investigate early HCM progression, we focused on the onset of myofilament dysfunction during neonatal development and examined cardiac dynamics, coronary vascular structure and function, and mechano-transduction signaling in mice harboring a thin-filament HCM mutation. Methods: We studied postnatal days 7-28 (P7-P28) in transgenic (TG) TG-cTnT-R92Q and non-transgenic (NTG) mice using skinned fiber mechanics, echocardiography, biochemistry, histology, and immunohistochemistry. Results: At P7, skinned myofiber bundles exhibited an increased Ca2+-sensitivity (pCa50 TG: 5.97 ± 0.04, NTG: 5.84 ± 0.01) resulting from cTnT-R92Q expression on a background of slow skeletal (fetal) troponin I and α/β myosin heavy chain isoform expression. Despite the transition to adult isoform expressions between P7-P14, the increased Ca2+- sensitivity persisted through P28 with no apparent differences in gross morphology among TG and NTG hearts. At P7 significant diastolic dysfunction was accompanied by coronary flow perturbation (mean diastolic velocity, TG: 222.5 ± 18.81mm/s, NTG: 338.7 ± 28.07mm/s) along with localized fibrosis (TG: 4.36% ± 0.44%, NTG: 2.53% ± 0.47%). Increased phosphorylation of phospholamban (PLN) was also evident indicating abnormalities in Ca2+ homeostasis. By P14 there was a decline in arteriolar cross-sectional area along with an expansion of fibrosis (TG: 9.72% ± 0.73%, NTG: 2.72% ± 0.2%). In comparing mechano-transduction signaling in the coronary arteries, we uncovered an increase in endothelial YAP expression with a decrease in its nuclear to cytosolic ratio at P14 in TG hearts, which was reversed by P28. Conclusion: We conclude that those early mechanisms that presage hypertrophic remodeling in HCM include defective biophysical signals within the sarcomere that drive diastolic dysfunction, impacting coronary flow dynamics, defective arteriogenesis and fibrosis. Changes in mechano-transduction signaling between the different cellular compartments contribute to the pathogenesis of HCM.

The association between cardiac mr feature tracking strain and myocardial late gadolinium enhancement in patients with hypertrophic cardiomyopathy

Aim Hypertrophic cardiomyopathy (HCM) is a relatively common, heritable cardiomyopathy, and cardiac magnetic resonance (CMR) studies have been performed previously to evaluate different aspects of the disease. However, a comprehensive study, including all four cardiac chambers and analysis of left atrial (LA) function, is missing in the literature. The aim of this retrospective study was to analyze CMR-feature tracking (CMR-FT) strain parameters and atrial function of HCM patients and to investigate the association of these parameters with the amount of myocardial late gadolinium enhancement (LGE).Material and Methods In this retrospective, cross-sectional study, we analyzed the CMR images (CMRI) of 58 consecutive patients, who from February 2020 to September 2022 were diagnosed with HCM at our tertiary cardiovascular center. Patients who were younger than 18 yrs or who had moderate or severe valvular heart disease, significant coronary artery disease, previous myocardial infarction, suboptimal image quality, or with contraindication to CMR were excluded. CMRI was performed at 1.5 T with a scanner, and all scans were assessed by an experienced cardiologist and then re-assessed by an experienced radiologist. SSFP 2-, 3- and 4‑chamber, short axis views were obtained and left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), and mass were measured. LGE images were obtained using a PSIR sequence. Native T1 and T2 mapping and post-contrast T1 map sequences were performed and each patient's myocardial extracellular volume (ECV) was calculated. LA volume index (LAVI), LA ejection fraction (LAEF), LA coupling index (LACI) were calculated. The complete CMR analysis of each patient was performed with CVI 42 software (Circle CVi, Calgary, Canada), off-line.Results The patients were divided into two groups, HCM with LGE (n=37, 64 %) and HCM without LGE (n=21, 36 %). The average patient age in the HCM patients with LGE was 50.8±14 yrs and 47±12.9 yrs in the HCM patients without LGE. Maximum LV wall thickness and basal antero-septum thickness were significantly higher in the HCM with LGE group compared to the HCM without LGE group (14.8±3.5 mm vs 20.3±6.5 mm (p&lt;0.001), 14.2±3.2 mm vs 17.3±6.1 mm (p=0.015), respectively). LGE was 21.9±31.7 g and 15.7±13.4 % in the HCM with LGE group. LA area (22.2±6.1 vs 28.8±11.2 cm2; p=0.015) and LAVI (28.9±10.2 vs 45.6±23.1; p-0.004) were significantly higher in the HCM with LGE group. LACI was doubled in the HCM with LGE group (0.2±0.1 vs 0.4±0.2; p&lt;0.001). LA strain (30.4±13.2 vs 21.3±16.2; p-0.04) and LV strain (15.2±3 vs 12.2±4.5; p=0.012) were significantly decreased in the HCM with LGE group.Conclusion This study sheds light on the CMR-FT differences between HCM with and without LGE. We found a greater burden of LA volume but significantly lower LA and LV strain in the LGE patients. These findings highlight further the LA and LV remodeling in HCM. Impaired LA function appears to have physiological significance, being associated with greater LGE. While our CMR-FT findings support the progressive nature of HCM, beginning with sarcomere dysfunction to eventual fibrosis, further studies are needed to validate these results in larger cohorts and to evaluate their clinical relevance.

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce. Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration. Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.

Sarcomere dynamics simulations to uncover mechanisms in hypertrophic cardiomyopathy.

Mutations in the beta myosin heavy chain (MYH7) can cause hypercontractility and cardiac remodeling in hypertrophic cardiomyopathy (HCM), but the mechanisms of specific mutations can be difficult to predict. Many mutations change intrinsic rates of myosin activity and their force sensitivity, which can dynamically alter chemo-mechanical cycle events and resultant force generation during cardiac contraction. Our team's multiscale approach enables measurement of the kinetics and force generation in purified myosin proteins, isolated myofibrils, and single and multicellular human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) platforms. Computational modeling can integrate results across these scales and provide additional insights into the individual and combinatorial effects of different changes in myosin kinetics. We have previously used a continuum model to highlight the significance of dysregulation of the super relaxed state of myosin driving hypercontractility in hiPSC-CMs with the P710R mutation. Sensitivity analysis also supported variable myofibril density and sarcomeric organization as a source of population heterogeneity in the force generating capacity of individual hiPSC-CMs. In our ongoing studies, we are leveraging computational modeling to compare the predicted and measured effects of HCM mutations in our different experiments. We have incorporated the measured changes in unloaded myosin to predict force generation after isometric maximal calcium activation (myofibril measurements) and twitch stimulation in single hiPSC-CMs on gels of physiologic stiffness. Additional simulations with spatially explicit models enable more direct prediction of the impact of heterogeneous mixtures of myosins with different molecular profiles and on cooperativity effects associated with the transmission of tension along the length of a sarcomere. Finally, we have visualized the strain profiles of individual sarcomeres in contracting myofibrils in live cells and are correlating these measurements to our simulations. These studies will give new insights into the key biophysical drivers of HCM.

Abstract 10095: Association of Plasma Adiponectin and Leptin Levels With All-Cause Mortality and New-Onset Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death in the young. The current models to predict ventricular tachycardia/fibrillation (VT/VF) and mortality perform poorly. Adipokines are secreted from the adipose tissue and regulate cardiac inflammation, fibrosis, and hypertrophy. Among the adipokines, adiponectin and leptin are related to cardiac remodeling in HCM. The present study examined the association of plasma adiponectin and leptin levels with all-cause mortality and VT/VF in patients with HCM. Hypothesis: Plasma adiponectin and leptin levels at enrollment are associated with all-cause mortality and VT/VF in patients with HCM. Methods: We performed a multicenter prospective cohort study of patients with HCM. We measured plasma adiponectin and leptin levels at enrollment. The outcome was a composite of all-cause mortality and new-onset VT/VF. After dividing the cohort into four groups according to the adiponectin and leptin levels, we compared the risk of the outcome event using the Cox proportional hazards model adjusting for age, body mass index, left atrium diameter, and maximum left ventricular wall thickness, using the largest group as a reference. Results: During a median follow-up of 3.3 years, the outcome event occurred in 37 out of 402 patients. The four groups divided by adiponectin and leptin levels had different risks of the outcome event (log-rank P &lt;0.001). The Cox proportional hazards model revealed that the High-Adiponectin, Low-Leptin group had a significantly higher risk (adjusted HR 5.02, 95% CI 1.63-15.47, P =0.005. Figure ) compared with the reference (Low-Adiponectin, High-Leptin) group. Conclusions: The combination of high plasma adiponectin and low leptin levels is independently associated with mortality and new-onset VT/VF in patients with HCM. These adipokines have a potential to become novel biomarkers for risk stratification in HCM to improve the current prediction models.

RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy.

Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM. Interventricular septum myectomies from patients with obstructive HCM (n=20) and donors' hearts (CTRL, discarded for technical reasons, n=7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile. We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls. We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Differential Expression of microRNAs in Hypertrophied Myocardium and Their Relationship to Late Gadolinium Enhancement, Left Ventricular Hypertrophy and Remodeling in Hypertrophic Cardiomyopathy.

Background: Differential expression has been found in a variety of circulating miRNAs in patients with hypertrophic cardiomyopathy (HCM). However, study on myocardial miRNAs is limited and a lot of miRNAs were not studied in previous studies. Methods: Twenty-one HCM patients and four patients who died from non-cardiovascular diseases were prospectively recruited for our study. A total of 26 myocardial tissues were collected, which were stored in liquid nitrogen immediately for miRNA detection using the Agilent Human miRNA Microarray Kit. All HCM patients underwent cardiovascular magnetic resonance (CMR) examination before surgery and cvi42 software was used to analyze cardiac function and myocardial fibrosis. Results: Compared with the control group, the expression of 22 miRNAs was found to be significantly increased in the HCM group, while 46 miRNAs were found to be significantly decreased in the HCM group. The expression levels of hsa-miR-3960 and hsa-miR-652-3p were significantly correlated with left ventricular mass index (r = 0.449 and 0.474, respectively). Meanwhile, Hsa-miR-642a-3p expression was positively correlated to the quantification of late gadolinium enhancement (r = 0.467). Conclusions: Our study found that 68 myocardial miRNAs were significantly increased or decreased in the HCM group. Myocardial miRNA levels could be used as potential biomarkers for LV hypertrophy, fibrosis and remodeling.

Sex-related differences in left ventricular remodeling and outcome after alcohol septal ablation in hypertrophic obstructive cardiomyopathy: insights from cardiovascular magnetic resonance imaging

BackgroundAlcohol septal ablation (ASA) has been proven to reverse left ventricular (LV) remodeling in hypertrophic cardiomyopathy (HCM). However, there are no studies on the effect of sex on LV remodeling after ASA. We aimed to investigate whether sex differences affect the process of LV remodeling and outcome after ASA.MethodsA total of 107 patients with obstructive HCM (54 men and 53 women, mean age 51 ± 8 years) were recruited. Cardiovascular magnetic resonance (CMR) was performed at baseline and 16 months after ASA. The extent of late gadolinium enhancement (LGE) was measured.ResultsWomen had a higher indexed LV mass and smaller indexed LV end-systolic volumes than men at the time of ASA. After ASA, both men and women exhibited a regression of LV mass, and the percentage of mass regression was greater in men than women (15.3% ± 4.3% vs. 10.7% ± 1.8%, p < 0.001). In multivariable analysis, male sex, higher reduction of LV outflow tract (LVOT) gradient and lower baseline LV mass index were independently associated with greater LV mass regression after ASA. Kaplan–Meier analysis showed significantly higher cardiovascular events in women than in men (p = 0.015). Female sex [hazard ratio (HR) 3.913, p = 0.038] and LV mass preablation (HR, 1.019, p = 0.010) were independent predictors of cardiovascular outcomes.ConclusionsMales with HCM had favorable reverse remodeling with greater LV mass regression post-ASA than female patients. This favorable LV reverse remodeling might provide a mechanistic explanation for the survival advantage in men.

PO-691-08 ASSESSING THE MECHANISTIC ROLE OF DIFFUSE FIBROSIS TOWARDS ARRHYTHMOGENESIS IN HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in the young and is a significant cause of SCD in adults. Myocardial fibrosis takes the form of both dense (focal) and diffuse fibrosis, with histopathological evidence showing diffuse fibrosis as the hallmark feature of the disease. Diffuse fibrosis, however, is not well captured by standard LGE-CMR and its contribution to arrhythmogenic propensity in HCM patients has never been assessed before. We introduce information from post-contrast T1 mapping, a quantitative and parametric imaging modality to represent the extensive diffuse fibrotic remodeling in HCM. To investigate the mechanistic role of diffuse fibrosis towards arrhythmogenesis with personalized, image-based models of fibrotic remodeling. In this retrospective study, we reconstructed 3D left ventricular models using contrast-enhanced LGE-MRI from 26 HCM patients, but with only 13 having experienced VA. We incorporated parametric post-contrast T1 mapping to define new, personalized thresholds of the LGE-MRI signal intensity to delineate regions of non-fibrotic myocardium, and diffuse and dense fibrosis at the tissue level. At the cellular level, we incorporated HCM-specific cell remodeling (Fig A). Rapid pacing was used to assess VA inducibility from the personalized distributions of diffuse fibrosis. Clinical characteristics, amount of fibrotic remodeling, and distribution of hypertrophy were not significantly associated with clinical VA (Fig B). T1-based thresholding increased the amount of diffuse fibrosis to 40.5 ± 9.4% from 8.9 ± 9.4% achieved by standard LGE-MRI thresholding (p<0.0001), but the amount of dense scar did not change significantly (3.8 ± 2.3 vs 3.2 ± 1.3, p=0.30). An average of 1.5 [0-3] unique VAs were induced in models reconstructed from patients with clinical VA compared to 0.3 [0-2] in models reconstructed from patients without clinical VA (p<0.001). Overall, one or more VA was induced in 11/13 models with clinical VA compared to 2/13 without clinical VA. The arrhythmogenic propensity of the ventricular substrate with diffuse fibrosis is patient-specific; it is not the amount of fibrosis, but its distribution (shape and location) that determines inducibility of arrhythmia.

Differences in Atrial Remodeling in Hypertrophic Cardiomyopathy Compared to Hypertensive Heart Disease and Athletes' Hearts.

Background: Hypertrophic cardiomyopathy (HCM), hypertensive heart disease (HHD) and athletes’ heart share an increased prevalence of atrial fibrillation. Atrial cardiomyopathy in these patients may have different characteristics and help to distinguish these conditions. Methods: In this single-center study, we prospectively collected and analyzed electrocardiographic (12-lead ECG, signal-averaged ECG (SAECG), 24 h Holter ECG) and echocardiographic data in patients with HCM and HHD and in endurance athletes. Patients with atrial fibrillation were excluded. Results: We compared data of 27 patients with HCM (70% males, mean age 50 ± 14 years), 324 patients with HHD (52% males, mean age 75 ± 5.5 years), and 215 endurance athletes (72% males, mean age 42 ± 7.5 years). HCM patients had significantly longer filtered P-wave duration (153 ± 26 ms) and PR interval (191 ± 48 ms) compared to HHD patients (144 ± 16 ms, p = 0.012 and 178 ± 31, p = 0.034, respectively) and athletes (134 ± 14 ms, p = 0.001 and 165 ± 26 ms, both p < 0.001, respectively). HCM patients had a mean of 4.9 ± 16 premature atrial complexes per hour. Premature atrial complexes per hour were significantly more frequent in HHD patients (27 ± 86, p < 0.001), but not in athletes (2.7 ± 23, p = 0.639). Left atrial volume index (LAVI) was 43 ± 14 mL/m2 in HCM patients and significantly larger than age- and sex-corrected LAVI in HHD patients 30 ± 10 mL/m2; p < 0.001) and athletes (31 ± 9.5 mL/m2; p < 0.001). A borderline interventricular septum thickness ≥13 mm and ≤15 mm was found in 114 (35%) HHD patients, 12 (6%) athletes and 3 (11%) HCM patients. Conclusions: Structural and electrical atrial remodeling is more advanced in HCM patients compared to HHD patients and athletes.

Correlation between markers of fibrosis and myocardial remodeling in patients with various course of hypertrophic cardiomyopathy

Aim. To assess the relationship between fibrosis markers and structural and functional parameters in patients with various types of hypertrophic cardiomyopathy (HCM).Material and methods. This prospective comparative non-randomized study included 49 patients with HCM. Patients were divided into 3 groups according to the disease course: group 1 — stable course (n=12; men, 8 (67%), mean age ‒ 41±12 years); group 2 — progressive course (n=26; men, men, 16 (61%). mean age — 57±11 years); group 3 — patients with atrial fibrillation (AF) (n=11; men, 4 (36%), mean age — 63±6 years). Patients underwent standard clinical and paraclinical investigations. The levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined in all patients using enzyme-linked immunosorbent assay in blood serum.Results. In all patients with HCM, elevated levels of MMP-9 and TIMP-1 are noted compared to the reference values. In group 1, the MMP-9 level [Me (Q1; Q3)] was 226 (201;271) ng/ml; TIMP-1 — 410 (267;488) ng/ml; in group 2, the MMP-9 level was 236 (187;285) ng/ml; TIMP-1 — 421 (321;499) ng/ml. In the course with AF, the MMP-9 level was 260 (228;296) ng/ml, while TIMP-1 — 381,5 (305;466) ng/ml; no significant difference was revealed (p=0,59; p=0,90, respectively). A correlation was found between age and MMP-9 levels, as well as between MMP-9 levels and left atrial volume (p=0,034; p=0,035, respectively).Conclusion. The high activity of matrix metalloproteinases and their tissue inhibitors reflects enhanced fibrosis and myocardial remodeling in HCM, which is especially characteristic of patients with AF.

MiRNA-Regulated Pathways for Hypertrophic Cardiomyopathy: Network-Based Approach to Insight into Pathogenesis.

Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. The wide spread of high-throughput sequencing casts doubt on its monogenic nature, suggesting the presence of mechanisms of HCM development independent from mutations in sarcomeric genes. From this point of view, HCM may arise from the interactions of several HCM-associated genes, and from disturbance of regulation of their expression. We developed a bioinformatic workflow to study the involvement of signaling pathways in HCM development through analyzing data on human heart-specific gene expression, miRNA-target gene interactions, and protein–protein interactions, available in open databases. Genes regulated by a pool of miRNAs contributing to human cardiac hypertrophy, namely hsa-miR-1-3p, hsa-miR-19b-3p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-93-5p, hsa-miR-133a-3p, hsa-miR-155-5p, hsa-miR-199a-3p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-451a, and hsa-miR-497-5p, were considered. As a result, we pinpointed a module of TGFβ-mediated SMAD signaling pathways, enriched by targets of the selected miRNAs, that may contribute to the cardiac remodeling in HCM. We suggest that the developed network-based approach could be useful in providing a more accurate glimpse on pathological processes in the disease pathogenesis.

Novel Myosin-Based Therapies in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is the most common genetic disease of myocardium and is recognized to have substantial clinical impact including sudden cardiac death, arrhythmias, and heart failure. Historically medical therapies have been used in hypertrophic cardiomyopathy (HCM) with limited prospective randomized data to support their effectiveness. In this review, we discuss a novel class of drug that inhibits myosin (myo-blocker) which was developed to precisely target the mechanism of HCM in detail. We discuss and contextualize the clinical trial results for mavacamten, positioning it in the therapeutic landscape as well as presenting future questions and further developments to be made in this area. Many sarcomeric mutations driving hypertrophic cardiomyopathy seem to have a primary effect of causing hypercontractility which may drive many secondary problems such as structural remodeling, arrhythmias, and further contractile deficits. Myo-blockers such as the first-in-class mavacamten are small molecules that specifically target myosin to decrease contractility and have been developed to precisely ameliorate the hypercontractile mechanism of HCM. Mavacamten has been shown in large, randomized, double-blind clinical trials to have benefit generally in improving symptoms, decreasing LV outflow tract obstruction, and promoting beneficial remodeling in HCM with obstructive physiology.

Elevation of high-sensitivity cardiac troponin T and left ventricular remodelling in hypertrophic cardiomyopathy.

AimsHypertrophic cardiomyopathy (HCM) is generally associated with mild disability and normal life expectancy. On the other hand, once the end‐stage phase of HCM characterized by left ventricular (LV) ejection fraction < 50% is established, patients with this subtype have a poor prognosis. This study clarifies the clinical parameters associated with progression to end‐stage HCM.Methods and resultsWe retrospectively studied 157 HCM patients (age 59.9 ± 14.2 years, 104 men) with preserved LV systolic function in whom subsequent echocardiographic data were obtained for a period of >1 year. HCM progressed to end‐stage HCM in 13 patients (8.3%) of the 157 patients during a mean follow‐up period of 6.3 ± 2.8 years. Compared with patients who did not reach end‐stage HCM at the last evaluation, patients with progression to the end‐stage phase had lower ejection fraction, larger LV size, more enlarged left atrial diameter, longer follow‐up period, and higher frequency of an elevated concentration of high‐sensitivity cardiac troponin T (hs‐cTnT; >0.014 ng/mL) at registration. Multivariate analysis revealed that elevated hs‐cTnT was a significant predictor independent of lower LV ejection fraction for progression to end‐stage HCM. Furthermore, in patients with elevated hs‐cTnT levels, LV ejection fraction became significantly lower, LV end‐diastolic diameter increased, and LV wall thickness decreased during the follow‐up period, whereas those parameters did not change in the normal hs‐cTnT group.ConclusionsIn patients with HCM, an elevated hs‐cTnT was associated with progression of LV remodelling, and this biomarker can be useful for predicting progression to the end‐stage phase.