Overt Hypertrophic Cardiomyopathy Research Articles

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

CMR 4-145 - Pro-arrhythmic Electrophysiological Abnormalities in Subclinical and Overt Hypertrophic Cardiomyopathy; Insights from CMR-ECGI

CMR 4-145 - Pro-arrhythmic Electrophysiological Abnormalities in Subclinical and Overt Hypertrophic Cardiomyopathy; Insights from CMR-ECGI

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

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

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

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

Abstract 13421: Meta-Analysis of Penetrance in Genetic Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is clasically caused by pathogenic or likely pathogenic (P/LP) variants in genes encoding sarcomeric proteins (G+) leading to left ventricular hypertrophy (LVH). Aim: To contrast cross-sectional penetrance in clinical and population studies, and to determine the phenotypic conversion (% of G+ developing LVH during follow-up) in longitudinal studies ( Figure 1 ). Methods: A systematic literature search was performed. Pooled penetrance (with 95% confidence intervals [CIs]) and phenotypic conversion were calculated with random effects generalized linear mixed model meta-analyses. Calculations were made for each gene and across all genes. Meta-regression was employed to explore sex-related differences. Results: In cross-sectional clinical studies, after excluding probands, penetrance across all genes in relatives carrying P/LP variants identified during cascade screening was 58% (95% CI [53,64]). Penetrance varied from ~32% for myosin light chain 3 to ~65% for myosin heavy chain 7 ( MYH7 ) and troponin T ( TNNT2 ). The mean age of HCM onset was 38 years (95% CI [36, 40]) across all genes, but studies including a higher % of males reported a later age of onset. In contrast, penetrance in population studies was ~10-15%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in the UK Biobank. In longitudinal clinical studies, the pooled phenotypic conversion was 15% (95% CI [8,27]) over an average of ~7 years of follow up, starting from a mean age of ~16 years across all genes. However, it varied from ~12% for myosin binding protein C to ~23% for MYH7 . Conclusions: The penetrance is 5-7-fold higher in a clinical context compared to incidental identification in population studies, suggesting important but currently undefined factors that modify disease expression. More longitudinal studies are needed to improve understanding of penetrance and identify drivers of the transition from genetic susceptibility to overt HCM

Angiotensin receptor blockers in patients with hypertrophic cardiomyopathy: A comparison of VANISH and INHERIT randomized trials

To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P=.4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.

Circulated TGF-β1 and VEGF-A as Biomarkers for Fabry Disease-Associated Cardiomyopathy.

Fabry disease (FD) is a lysosomal disorder caused by α-galactosidase A deficiency, resulting in the accumulation of globotriaosylceramide (Gb-3) and its metabolite globotriaosylsphingosine (Lyso-Gb-3). Cardiovascular complications and hypertrophic cardiomyopathy (HCM) are the most frequent manifestations of FD. While an echocardiogram and cardiac MRI are clinical tools to assess cardiac involvement, hypertrophic pattern variations and fibrosis make it crucial to identify biomarkers to predict early cardiac outcomes. This study aims to investigate potential biomarkers associated with HCM in FD: transforming growth factor-β1 (TGF-β1), TGF-β active form (a-TGF-β), vascular endothelial growth factor (VEGF-A), and fibroblast growth factor (FGF2) in 45 patients with FD, categorized into cohorts based on the HCM severity. TGF-β1, a-TGF-β, FGF2, and VEGF-A were elevated in FD. While the association of TGF-β1 with HCM was not gender-related, VEGF was elevated in males with FD and HCM. Female patients with abnormal electrocardiograms but without overt HCM also have elevated TGF-β1. Lyso-Gb3 is correlated with TGF-β1, VEGF-A, and a-TGF-β1. Elevation of TGF-β1 provides evidence of the chronic inflammatory state as a cause of myocardial fibrosis in FD patients; thus, it is a potential marker of early cardiac fibrosis detected even prior to hypertrophy. TGF-β1 and VEGF biomarkers may be prognostic indicators of adverse cardiovascular events in FD.

Systolic anterior motion of the anterior mitral valve leaflet begins in subclinical hypertrophic cardiomyopathy.

Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM. Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008). Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.

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

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

Abstract 15004: Characterization of Hypertrophic Cardiomyopathy Caused by Mutations in Four and a Half Lim Domains 1 Gene

Background: Mutations in Four and Half Lim domain 1 ( FHL1 ), an X-chromosome gene, have been described in rare cases of Hypertrophic Cardiomyopathy (HCM), mainly associated with myopathy. The current knowledge of the outcome of HCM caused by FHL1 mutations relies only on isolated case series. Objective: We aim to establish the prevalence of FHL1 mutations in a large population with overt HCM and clinically characterize HCM patients carrying FHL1 pathogenic and likely pathogenic genetic variants. Methods: From a total population of 794 HCM patients from 3 Referral Centers for hereditary cardiomyopathies, 349 HCM probands, who tested negative for sarcomeric mutations, were genetically screened by using Next Generation Panels including FHL1 . Moreover, all patients underwent personal and family history collection, physical examination, 12-lead electrocardiogram and echocardiography; while Cardiac Magnetic Resonance (CMR) was performed in a subgroup. Clinical and genetic data of FHL1 mutation carriers from our cohort were pooled with those of 52 FHL1 positive HCM cases from literature. Results: We identified 2 FHL1 pathogenic and 2 likely pathogenic variants (1 missense: c.764G&gt;C; 2 duplications: c.762dup and c.599dupT; and 1 deletion: c.210delG) in 6 HCM probands (0.8% of all HCM and 1.7 % of non sarcomeric HCM). As shown in Fig.1 A, pooled analysis suggested that clinical phenotype of FHL1-HCM was characterized by early-onset, severe diastolic dysfunction independently from the degree of hypertrophy and fibrosis at CMR (Fig 1 B), high sudden death risk, increased incidence of atrial fibrillation and evolution toward heart failure requiring heart transplantation, and variable skeletal muscle involvement. Conclusions: HCM patients carrying FHL1 mutations present with a worse prognosis as compared with the classic sarcomeric-HCM. A better characterization of these patients is needed for a personalized preventive and therapeutic approach.

Natural history of hypertrophic cardiomyopathy in cats from rehoming centers: The CatScan II study.

The natural history of hypertrophic cardiomyopathy (HCM) in cats has been mainly studied in cats referred for suspected heart disease, which can skew the results towards cats with clinical signs. Few data are available on factors associated with development of HCM in cats. (1) Clinical variables can predict which cats will develop HCM; (2) HCM in cats not referred for suspected heart disease is associated with a low rate of cardiovascular events. One hundred seven cats from rehoming centers without a history of clinical signs of cardiac or systemic disease at the time of adoption. Prospective longitudinal study. After rehoming, shelter cats were reexamined for serial echocardiograms. Cox regression analysis was used to identify predictors of development of HCM in cats that were normal at baseline. Adverse cardiovascular events including heart failure, thromboembolism, or sudden death were recorded. Cats were monitored for a median of 5.6 [1.2-9.2] years. At baseline, 68/107 cats were normal, 18/107 were equivocal and 21/107 had HCM. Nineteen cats developed HCM during the study period. The factors at baseline associated with increased hazard of developing HCM were lower left atrial fractional shortening, higher left ventricular fractional shortening, and higher body weight. Cardiovascular events were observed in 21% of cats with HCM. Cardiovascular events were common in cats with HCM from a rehoming center study sample. Lower left atrial systolic function appears to precede overt HCM.

Use of advanced echocardiographic modalities to discriminate preclinical HCM mutation carriers from non-carriers

Abstract Background It is a challenging goal to identify which family members of patients with hypertrophic cardiomyopathy (HCM) will subsequently develop HCM. Previous studies evaluating the utility of two-dimensional conventional Doppler echocardiography in HCM families with a known pathogenic variant identified on genetic testing have been unable to reliably distinguish preclinical genotype-positive, phenotype-negative (G+P−) individuals from their healthy genotype-negative, phenotype-negative (G−P−) relatives. Purpose To determine if advanced echocardiographic modalities can discriminate preclinical HCM mutation carriers (G+P−) from non-carriers (G−P−). Methods A total of 199 participants who had undergone genetic testing from HCM families with a known pathogenic variant were included in the study: 39 G−P−; 58 G+P− and 102 overt HCM patients (G+P+). Speckle tracking echocardiography (STE) and colour M-mode were performed on all participants and longitudinal, circumferential and radial strain, and torsion were compared. Results Patients with overt HCM had the highest septal, posterior wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest global longitudinal, circumferential and radial strain, and tissue Doppler-derived myocardial systolic and diastolic velocities. Comparing G−P− and G+P− individuals, there were no significant differences in LV cavity size, wall thickness, LVOT gradient, LVEF and tissue Doppler-derived myocardial systolic and diastolic velocities. However, G+P− individuals had significantly higher peak apical rotation, peak twist and colour M-mode flow propagation velocity (Vp). Multivariate linear regression identified two independent predictors (peak apical rotation and Vp), and a regression equation (using multivariate linear regression) {Mutation carrier prediction value = (0.210×peak apical rotation) − (0.002×Vp) + 0.156; r=0.655)} was derived which allowed reliable discrimination of G+P- individuals with a sensitivity of 95.2% and specificity of 94.1% at the optimal cut-off. Conclusion In HCM family members without overt HCM, peak apical rotation and Vp provide good sensitivity and specificity for identifying mutation carriers and may be a clinically useful early marker of HCM before the onset of hypertrophy. Future longitudinal studies involving larger cohorts are required to validate these findings. Funding Acknowledgement Type of funding sources: None.

Prognostic significance of left atrial strain in sarcomere gene variant carriers without hypertrophic cardiomyopathy.

BackgroundGenetic testing of relatives of hypertrophic cardiomyopathy (HCM) patients has led to a large group of genotype‐positive, phenotype‐negative (G+/Ph−) subjects. Prediction of progression to overt HCM in these subjects is challenging. While left atrial (LA) strain is reduced in HCM patients it is currently unknown whether this parameter can be used to predict HCM phenotype progression.MethodsThis study includes 91 G+/Ph− subjects and 115 controls. Standard echocardiographic parameters as well as left ventricular global longitudinal strain (LV GLS) and LA reservoir strain (LASr) were assessed for each patient. Logistic and Cox proportional hazard regression analyses were used to investigate predictors of G+/Ph− status and HCM during follow‐up.ResultsIndependent predictors of G+ status included pathological Q waves (OR 1.60 [1.15–2.23], p < .01), maximal wall thickness (MWT: OR 1.10 [1.07–1.14], p < .001), mitral inflow E wave (OR 1.06 [1.02–1.10, p = .001), A wave (OR 1.06 [1.03–1.10], p < .001), LV GLS (OR .96 [.94–.98], p < .001), and LASr (OR .99 [.97–.99], p = .03). In univariable Cox regression analysis, male sex (HR 2.78 [1.06–7.29], p = .04), MWT (HR 1.72 [1.14–2.57], p = .009) and posterior wall thickness (HR 1.65 [1.17–2.30], p = .004) predicted HCM during a median follow‐up of 5.9 [3.2–8.6] years, whereas LASr did not (HR .95 [.89–1.02], p = .14). There were no significant predictors of HCM after multivariable adjustment.ConclusionLASr is significantly impaired in G+/Ph− subjects and is an independent predictor of G+/Ph− status, but did not predict HCM development during follow‐up.

Genetic relevance and determinants of mitral leaflet size in hypertrophic cardiomyopathy

BackgroundWhether mitral leaflet elongation is a primary phenotype of hypertrophic cardiomyopathy (HCM) is controversial. We investigated the genetic relevance and determinants of mitral leaflet size by performing extensive gene analyses in patients with HCM.MethodsAnterior mitral leaflet (AML) lengths were measured in HCM patients (n = 211) and age- and sex-matched controls (n = 30) using echocardiography with hemodynamic and chamber geometric assessments. We analyzed 82 nuclear DNA (8 sarcomeric genes, 74 other HCM-associated genes) and mitochondrial DNA. Cardiac magnetic resonance imaging (CMR) was performed in the 132 HCM patients.ResultsAverage indexed AML was significantly longer for HCM than for controls (17.2 ± 2.3 vs. 13.3 ± 1.6 mm/m2, P < 0.001). Average AML length correlated with body surface area (BSA), left ventricular (LV) end-systolic volume (P < 0.001) and LV mass by CMR (P < 0.001). Average indexed AML by BSA of pure-apical HCM was significantly shorter than other typed HCM (16.6 ± 2.0 vs. 17.4 ± 2.4 mm/m2, P = 0.025). Indexed AML was independently correlated with left atrial wall stress. The thin filament mutation group showed larger average AML (31.9 ± 3.8 vs. 29.6 ± 3.8 mm, P = 0.045), but this was not significant with the indexed value. No difference in AML size among subgroups was observed based on the presence of sarcomere protein or mitochondria-related gene variants (P > 0.05).ConclusionAML elongation was a unique finding of HCM. However, the leaflet size was more related to chamber geometry and hypertrophy pattern rather than genetic factors within overt HCM.

P890Gene carriers of hypertrophic cardiomyopathy, what to expect over time

Abstract Background Data on the natural history of genotype positive/phenotype negative (G+/P-) hypertrophic cardiomyopathy (HCM) patients identified as a part of genetic cascade screening in different age groups is limited. Purpose To describe the rate of conversion to overt HCM phenotype in G+/P- subjects in relation with the age who were identified in a specialized clinic in a single center. Methods We retrospectively identified 56 consecutive HCM G+/P− subjects followed in our center specialized clinic between Jan 2012-Jan 2019. Demographics, family history of sudden cardiac death (SCD) and presence of symptoms were collected. All of them underwent baseline investigations including ECG, echocardiogram and/or cardiac magnetic resonance (CMR) and 24 hour monitor at baseline and during follow up. Overt HCM phenotype was defined as left ventricular hypertrophy (LVH) ≥13mm in the echocardiogram or CMR. Results We identified 56 HCM G+/P− subjects from 34 different families. 22 subjects were ≤18 years old with a mean age of 11.6±0.9 years (IQR [P25-P75] 9–16 years) and 32 subjects were &gt;18 years old with a mean age of 38.1±2.2 years (IQR [P25-P75] 27–48 years). Mean time of follow up was 35.2±34.4 months (IQR [P25-P75] 4.25–50.25 years). 60.7% (34) of them were female and 82.1% (46) were of Caucasian ethnicity. Most of the subjects with no evidence LVH were asymptomatic but small number had symptoms, 8.9% (5), and 3.6% (2) were treated with betablockers for palpitations. Family history of SCD was present in 57.1% (32) of the subjects and 35.7% (20) had a relative with an implantable cardiac defibrillator (ICD). MYBPC3 gene mutations were identified in 62.5% (35) of subjects, followed by MYH7 gene mutation in 23.2% (13) of the cases. None of the subjects under 18 year old developed HCM during the period of observation, however 7 subjects (21.9%), mean age 48.6±10.5 years, 71.4% (5) females, showed progression to HCM in the &gt;18 years old group. All of them had pathogenic MYBPC3 gene variants. No differences were found in gender, ethnicity, symptoms or family history of SCD in the G+/P− vs HCM group. There were no differences on the presence of ECG abnormalities and no episodes of NSVT were recorded in any of the groups. Baseline E/e' values of those with new HCM vs G+/P− were higher (8.2±3.3 vs 5.6±1.7, p=0.014). Conclusions In our cohort, rate of progression to HCM phenotype was 21.9% of &gt;18 years old HCM G+/P- subjects. The mean age at the time of developing the phenotype was 48.6±10.5 years old and all the patients were asymptomatic for cardiac symptoms. Echocardiographic E/e' values were increased. This data supports the need of life long follow up of this group of patients with ongoing clinical evaluation. Acknowledgement/Funding ESC clinical grant

Left Ventricular Strain Is Abnormal in Preclinical and Overt Hypertrophic Cardiomyopathy: Cardiac MR Feature Tracking.

Purpose To evaluate myocardial strain and circumferential transmural strain difference (cTSD; the difference between epicardial and endocardial circumferential strain) in a genotyped cohort with hypertrophic cardiomyopathy (HCM) and to explore correlations between cTSD and other anatomic and functional markers of disease status. Left ventricular (LV) dysfunction may indicate early disease in preclinical HCM (sarcomere mutation carriers without LV hypertrophy). Cardiac MRI feature tracking may be used to evaluate myocardial strain in carriers of HCM sarcomere mutation. Materials and Methods Participants with HCM and their family members participated in a prospective, multicenter, observational study (HCMNet). Genetic testing was performed in all participants. Study participants underwent cardiac MRI with temporal resolution at 40 msec or less. LV myocardial strain was analyzed by using feature-tracking software. Circumferential strain was measured at the epicardial and endocardial surfaces; their difference yielded the circumferential transmural strain difference (cTSD). Multivariable analysis to predict HCM status was performed by using multinomial logistic regression adjusting for age, sex, and LV parameters. Results Ninety-nine participants were evaluated (23 control participants, 34 participants with preclinical HCM [positive for sarcomere mutation and negative for LV hypertrophy], and 42 participants with overt HCM [positive for sarcomere mutation and negative for LV hypertrophy]). The average age was 25 years ± 11 and 44 participants (44%) were women. Maximal LV wall thickness was 9.5 mm ± 1.4, 9.8 mm ± 2.2, and 16.1 mm ± 5.3 in control participants, participants with preclinical HCM (P = .496 vs control participants), and participants with overt HCM (P < .001 vs control participants), respectively. cTSD for control participants, preclinical HCM, and overt HCM was 14% ± 4, 17% ± 4, and 22% ± 7, respectively (P < .01 for all comparisons). In multivariable models (controlling for septal thickness and log-transformed N-terminal brain-type natriuretic peptide), cTSD was predictive of preclinical and overt HCM disease status (P < .01). Conclusion Cardiac MRI feature tracking identifies myocardial dysfunction not only in participants with overt hypertrophic cardiomyopathy, but also in carriers of sarcomere mutation without left ventricular hypertrophy, suggesting that contractile abnormalities are present even when left ventricular wall thickness is normal. © RSNA, 2018 Online supplemental material is available for this article.

Transcriptome Analysis of Cardiac Hypertrophic Growth in MYBPC3-Null Mice Suggests Early Responders in Hypertrophic Remodeling

Rationale: With a prevalence of 1 in 200 individuals, hypertrophic cardiomyopathy (HCM) is thought to be the most common genetic cardiac disease, with potential outcomes that include severe hypertrophy, heart failure, and sudden cardiac death (SCD). Though much research has furthered our understanding of how HCM-causing mutations in genes such as cardiac myosin-binding protein C (MYBPC3) impair contractile function, it remains unclear how such dysfunction leads to hypertrophy and/or arrhythmias, which comprise the HCM phenotype. Identification of early response mediators could provide rational therapeutic targets to reduce disease severity. Our goal was to differentiate physiologic and pathophysiologic hypertrophic growth responses and identify early genetic mediators in the development of cardiomegaly in the cardiac myosin-binding protein C-null (cMyBP-C-/-) mouse model of HCM.Methods and Results: We performed microarray analysis on left ventricles of wild-type (WT) and cMyBPC-/- mice (n = 7 each) at postnatal day (PND) 1 and PND 9, before and after the appearance of an overt HCM phenotype. Applying the criteria of ≥2-fold change, we identified genes whose change was exclusive to pathophysiologic growth (n = 61), physiologic growth (n = 30), and genes whose expression changed ≥2-fold in both WT and cMyBP-C-/- hearts (n = 130). Furthermore, we identified genes that were dysregulated in PND1 cMyBP-C-/- hearts prior to hypertrophy, including genes in mechanosensing pathways and potassium channels linked to arrhythmias. One gene of interest, Xirp2, and its protein product, are regulated during growth but also show early, robust prehypertrophic upregulation in cMyBP-C-/- hearts. Additionally, the transcription factor Zbtb16 also shows prehypertrophic upregulation at both gene and protein levels.Conclusion: Our transcriptome analysis generated a comprehensive data set comparing physiologic vs. hypertrophic growth in mice lacking cMyBP-C. It highlights the importance of extracellular matrix pathways in hypertrophic growth and early dysregulation of potassium channels. Prehypertrophic upregulation of Xirp2 in cMyBP-C-/- hearts supports a growing body of evidence suggesting Xirp2 has the capacity to elicit both hypertrophy and arrhythmias in HCM. Dysregulation of Xirp2, as well as Zbtb16, along with other genes associated with mechanosensing regions of the cardiomyocyte implicate stress-sensing in these regions as a potentially important early response in HCM.

Prevalence and Progression of Late Gadolinium Enhancement in Children and Adolescents With Hypertrophic Cardiomyopathy.

Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ≈60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. In addition, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM. CMR scans from 195 patients ≤21 years of age were analyzed in an observational, retrospective study, including 155 patients with overt HCM and 40 sarcomere mutation carriers without left ventricular (LV) hypertrophy. The extent of LGE was quantified by measuring regions with signal intensity >6 SD above nulled remote myocardium. Patients were 14.3±4.5 years of age at baseline and 68% were male. LGE was present in 70 (46%) patients with overt HCM (median extent, 3.3%; interquartile range, 0.8-7.1%), but absent in mutation carriers without LV hypertrophy. Thirty-one patients had >1 CMR (median interval between studies, 2.4 years; interquartile range, 1.5-3.2 years). LGE was detected in 13 patients (42%) at baseline and in 16 patients (52%) at follow-up CMR. The median extent of LGE increased by 2.4 g/y (range, 0-13.2 g/y) from 2.9% (interquartile range, 0.8-3.2%) of LV mass to 4.3% (interquartile range, 2.9-6.8%) ( P=0.02). In addition to LGE, LV mass and left atrial volume, indexed to body surface area, and z score for LV mass, as well, increased significantly from first to most recent CMR. LGE was present in 46% of children and adolescents with overt HCM, in contrast to ≈60% typically reported in adult HCM. In the subset of patients with serial imaging, statistically significant increases in LGE, LV mass, and left atrial size were detected over 2.5 years, indicating disease progression over time. Further prospective studies are required to confirm these findings and to better understand the clinical implications of LGE in pediatric HCM.

Intrinsic mitral valve alterations in hypertrophic cardiomyopathy sarcomere mutation carriers.

Mitral valve (MV) abnormalities are recognized features of hypertrophic cardiomyopathy (HCM), and there is preliminary evidence suggesting they are intrinsic phenotypic manifestations of sarcomere mutations, present in mutation carriers without left ventricular (LV) hypertrophy (subclinical HCM). However, further study is required to characterize the nature of these changes and their functional impact. Thus, we performed comprehensive echocardiographic analysis of MV structure and function on a genotyped population. MV and papillary muscle echocardiographic parameters were measured in 192 genotyped individuals, including 50 overt HCM, 79 subclinical HCM, and 63 mutation-negative, healthy relatives as normal controls. Compared to controls, subclinical HCM subjects had elongated anterior MV leaflets relative to LV end-diastolic volume index (0.57 ± 0.02 vs. 0.51 ± 0.02 mm/mL/m2, P = 0.013) and anteriorly displaced papillary muscles [decreased papillary-septal separation (31.1 ± 0.7 vs. 34.2 ± 0.9 mm, P = 0.004) and relative antero-posterior position ratio of the papillary muscles (0.67 ± 0.01 vs. 0.71 ± 0.01, P = 0.011]. Similar findings were identified comparing overt HCM to controls. These MV changes were associated with an increased prevalence of systolic anterior motion (SAM) of the MV amongst subclinical HCM subjects. Sarcomere mutations are associated with primary abnormalities of the MV apparatus, specifically excess anterior leaflet length relative to LV cavity size and anterior displacement of the papillary muscles; both features predisposing to SAM. These abnormalities appear to be early phenotypic consequences of sarcomere mutations, observed in mutation carriers with normal LV wall thickness.