Fibrosis In Hypertrophic Cardiomyopathy Research Articles

Myocardial bridging in obstructive hypertrophic cardiomyopathy: a risk factor for myocardial fibrosis.

Myocardial bridging (MB) is common in patients with hypertrophic cardiomyopathy (HCM). There are sparse data on the impact of MB on myocardial fibrosis in HCM. This study was designed to evaluate the relationship between MB and myocardial fibrosis in patients with obstructive HCM. In this cohort study, retrospective data were collected from a high-volume HCM center. Patients with obstructive HCM who underwent septal myectomy and preoperative cardiac magnetic resonance (CMR) were screened from 2011 to 2018. Finally, 492 patients were included in this study, with an average age of 45.7years. Of these patients, 76 patients had MB. MB occurred mostly in the left anterior descending artery (73/76). The global extent of late gadolinium enhancement (LGE) was correlated with the degree of systolic compression (r = 0.33, p = 0.003). Multivariable linear regression analysis revealed that the degree of systolic compression was an independent risk factor for LGE (β = 0.292, p = 0.007). The LGE fraction of basal and mid anteroseptal segments in patients with severe MB (compression ratio ≥ 80%) was significantly greater than that in patients with mild to moderate MB (compression ratio < 80%). During a median follow-up of 28 (IQR: 15-52) months, 15 patients died. Kaplan-Meier analysis did not identify differences in all-cause death (log-rank p = 0.63) or cardiovascular death (log-rank p = 0.72) between patients undergoing MB-related surgery and those without MB. MB with severe systolic compression was significantly associated with a high extent of fibrosis in patients with obstructive HCM. Concomitant myotomy or coronary artery bypass grafting might provide excellent survival similar to that of patients without MB. Identification of patients with severe MB and providing comprehensive management might help improve the prognosis of patients with HCM.

Expression of Circulating miR-21 and -29 and their Association with Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is characterized by myocardial hypertrophy, fibrosis, and sarcomeric disarray. To evaluate the expression levels of circulating miR-21 and -29 in patients with HCM and their association with clinical characteristics and myocardial fibrosis. In this case-control study, 27 subjects with HCM, 13 subjects with hypertensive cardiomyopathy, and 10 control subjects were enrolled. Evaluation of patients' functional capacity was made by the six-minute walk test. Echocardiographic measurements of left ventricle systolic and diastolic function were conducted. Cardiac magnetic resonance late gadolinium enhancement (LGE) -through a semiquantitative evaluation- was used in the assessment of myocardial fibrosis extent in HCM patients. The expression of miR-21 and -29 in peripheral blood samples of all patients was measured via the method of quantitative reverse transcription polymerase chain reaction. Circulating levels of miR-21 were higher in both hypertensive and HCM (p<0.001) compared to controls, while expression of miR-29 did not differ between the three studied groups. In patients with HCM and LGE-detected myocardial fibrosis in more than 4 out of 17 myocardial segments, delta CT miR-21 values were lower than in patients with myocardial LGE in 3 or fewer myocardial segments (2.71 ± 1.06 deltaCT vs. 3.50 ± 0.55 deltaCT, p=0.04), indicating the higher expression of circulating miR-21 in patients with more extensive myocardial fibrosis. MiR-21 was overexpressed in patients with HCM and hypertensive cardiomyopathy. Importantly, in patients with HCM, more extensive myocardial fibrosis was associated with higher levels of miR-21.

Inhibition of miR-199a-3p in a murine hypertrophic cardiomyopathy (HCM) model attenuates fibrotic remodeling

BackgroundHypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ∼1: 200–500 and predisposes individuals to heart failure and sudden death. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and resultsUsing high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured murine primary cardiac fibroblasts and analyzed the conditioned media by proteomics, we found that several extracellular matrix (ECM) proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially secreted (data are available via ProteomeXchange with identifier PXD042904). We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac fibroblasts drives upregulation of ECM gene expression, including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac fibroblasts. ConclusionsAltogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac fibroblasts. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

Abstract 15164: The Different Prognostic Values of T1 Mapping in Patients With Hypertrophic Cardiomyopathy

Objectives: This study aimed to determine the impact of T1 mapping on cardiovascular magnetic resonance (CMR) on long-term adverse outcomes in patients with hypertrophic cardiomyopathy (HCM). Background: In patients with HCM, the prognostic value of native T1 and extracellular volume fraction (ECV) for sudden cardiac death (SCD) has not been well defined. Methods: Consecutive 663 participants with HCM who underwent CMR were recruited. The follow-up endpoints included heart failure (HF)-related death and SCD or aborted SCD. Results: During the median follow-up time of 44 months (interquartile range [IQR]: 23 to 65.5 months), 55 (8.3%) participants reached the endpoint including 37 (5.6%) with SCD or aborted SCD and 18 (2.7%) with HF-related death. On Cox proportional hazards regression multivariable analyses, native T1 but not ECV was independently associated with CD (hazard ratio [HR]: 1.00; 95% confidence interval[CI] : 1.00 to 1.01; P = 0.02), while native T1 (HR: 1.01; 95%CI: 1.00 to 1.01; P = 0.008) and ECV (HR:1.15 for every 1% increase; 95%CI: 1.05 to 1.26; P = 0.003) were both independently associated with HF-related death after the adjustment for left ventricular ejection fraction (LVEF) and LV late gadolinium enhancement (LGE) extent. Conversely, native T1(HR: 1.00; 95% CI: 1.00 to 1.01; P = 0.40) and ECV (HR: 1.01; 95% CI: 0.94 to 1.08; P = 0.81) were not associated with SCD after the adjustment for non-sustained ventricular tachycardia, history of syncope and LV LGE extent. Conclusions: In this study of patients with HCM, T1 mapping had distinct prognostic associations; native T1 and ECV were both independently associated with HF-related death, whereas T1 mapping was not independently associated with SCD or aborted SCD. These findings may indicate distinct implications for the management of left ventricular fibrosis in HCM.

Link between fibrosis-specific biomarkers and interstitial fibrosis in hypertrophic cardiomyopathy.

Cardiac fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and has proven unfavorable clinical significance. Replacement fibrosis is better known, and has already been studied on a larger scale, whereas interstitial fibrosis is less explored. We aimed to analyze relationship between serum biomarkers and interstitial fibrosis, as assessed with cardiac magnetic resonance (CMR) in HCM. We performed 3T CMR scans in 50 HCM patients to assess interstitial fibrosis as expressed by extracellular volume (ECV). In all patients, we determined levels of serum cardiac-specific (troponin T [TnT], N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) and fibrosis-specific (procollagen I C-terminal propeptide, procollagen III N-terminal propeptide, transforming growth factor β1, galectin 3) biomarkers. Patients were divided based on their median value of ECV. The final study population consisted of 49 patients. The median value of ECV in our cohort was 28.1%. Patients stratified according to median ECV differed in terms of several variables: body mass index, late gadolinium extent, NT-proBNP and galectin 3 levels (all P < 0.05). Cardiac biomarkers (TnT and NT-proBNP) and galectin 3 were significantly correlated with ECV (rS = 0.34; P = 0.02; rS = 0.39; P = 0.006; rS = 0.43; P = 0.002, respectively). Galectin 3 and body mass index were found to be independent predictors of ECV (odds ratio [OR], 2.29 [1.07-4.91]; P = 0.03; OR, 0.81 [0.68-0.97]; P = 0.02, respectively). Galectin 3 was an independent predictor of interstitial fibrosis in HCM patients expressed as elevated ECV values. The other fibrosis-specific biomarkers measured were not useful in detecting interstitial fibrosis in HCM. In addition, there was a positive correlation between classical cardiac biomarkers and interstitial fibrosis in HCM patients.

LV and LA mechanics in pediatric HCM : a CMR study of phenotype-genotype correlation

Abstract Funding Acknowledgements Type of funding sources: None. Background Paediatric hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death. The relationship between the genotype variation and phenotype expression has not been fully elucidated, with some studies showing association with an increased hypertrophy and MYH7 or multiple genetic variations. In HCM fibrosis and hypertrophy contribute to left ventricular (LV) mechanics’ alteration resulting in subendocardial dysfunction. The latter is associated with a decreased global longitudinal and radial strains (GLS, GRS), whereas epicardial thickening leads to preserved global circumferential strain (GCS) and LV twist. Children with HCM have reduced LA function, measurable by both volumetric and strain analysis and reduced LA mechanics are associated with poor exercise capacity. Feature tracking –cardiac magnetic resonance (FT-CMR) has enhanced the non-invasive assessment of myocardial deformation in HCM. The main aim of our study was to assess differences of LV and LA mechanics features on CMR between patients harbouring multiple pathogenic or likely pathogenic variants (MGv, n=16) or single genetic variations (SGv, n=35). Methods Our retrospective CMR study included 51 patients (1.7–18.8 years ago). CMR data were: LV and LA’s morphological values, late gadolinium enhancement (LGE) of LA and LV walls, LV feature tracking (FT) derived strain and LV twist (LVT). LV twist was calculated as the difference between basal and apical rotation. The LA feature FT derived strain, LA conduit function, reservoir function and pump function were computed. Results In MGv group, the indexed LV mass 108.8 +/-53.0 vs 74.3+/- 22.2 in SGv (p = 0.03). LGE was present in 51% patients of the whole cohort, with LGE in 64 % of MGv group. LV FT derived strain values and LA function were not statistically significant different between groups (MGv vs SGv: GLS −15.8+/−5.3 vs −18.7+/−4.8, GCS −27.8+/8 vs −31.1+/−8.6, GRS 44.7+/−24.6 vs 62.3+/−32). LVT was reduced in MGv group (0.04+/−7.6) vs (7.4+/−7.4) in SGv (p = 0.003). LA contractile function did not differ between the groups (MGv vs SGv: GLS LA 25.1+/−14.2 vs 27.6+/−13.5). LA reservoir, conduction and pump function did not differ between the groups. LVT was significantly correlated with the LA contractile function. An increased of LVT was associated with an increased LA GLS and EF (p = 0.011; p = 0.004). Conclusions Patients with multiple genetic variants have a greater LV mass and altered LV mechanics with reduced LV twist. This study gives insights in phenotype- genotype correlation in paediatric HCM and warrants larger longitudinal studies to assess its clinical significance.

Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM. Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n=15), and controls from hearts deemed unsuitable for transplantation (n=8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n=8-10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n=3) and examined using confocal microscopy. Lumican mRNA was increased threefold in HCM patients (P<0.05) and correlated strongly with expression of collagen I (R2 =0.60, P<0.01) and III (R2 =0.58, P<0.01). Lumican protein was increased by 40% in patients with HCM (P<0.01) and correlated with total (R2 =0.28, P=0.05) and interstitial (R2 =0.30, P<0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P<0.001), and lumican protein increased 20-fold (P<0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P<0.01; mice: +13%, P<0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (-15nm, P<0.05), overlapped more frequently with (+7.3%, P<0.05) and to a larger degree with (+5.6%, P<0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8nm, P<0.001), longer (+345.9nm, P<0.001), and fewer (-8.9%, P<0.001) collagen fibres. The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.

Identification of fibrosis in hypertrophic cardiomyopathy: a radiomic study on cardiac magnetic resonance cine imaging

ObjectivesHypertrophic cardiomyopathy (HCM) often requires repeated enhanced cardiac magnetic resonance (CMR) imaging to detect fibrosis. We aimed to develop a practical model based on cine imaging to help identify patients with high risk of fibrosis and screen out patients without fibrosis to avoid unnecessary injection of contrast.MethodsA total of 273 patients with HCM were divided into training and test sets at a ratio of 7:3. Logistic regression analysis was used to find predictive image features to construct CMR model. Radiomic features were derived from the maximal wall thickness (MWT) slice and entire left ventricular (LV) myocardium. Extreme gradient boosting was used to build radiomic models. Integrated models were established by fusing image features and radiomic models. The model performance was validated in the test set and assessed by ROC and calibration curve and decision curve analysis (DCA).ResultsWe established five prediction models, including CMR, R1 (based on the MWT slice), R2 (based on the entire LV myocardium), and two integrated models (ICMR+R1 and ICMR+R2). In the test set, ICMR+R2 model had an excellent AUC value (0.898), diagnostic accuracy (89.02%), sensitivity (92.54%), and F1 score (93.23%) in identifying patients with positive late gadolinium enhancement. The calibration plots and DCA indicated that ICMR+R2 model was well-calibrated and presented a better net benefit than other models.ConclusionsA predictive model that fused image and radiomic features from the entire LV myocardium had good diagnostic performance, robustness, and clinical utility.Key Points• Hypertrophic cardiomyopathy is prone to fibrosis, requiring patients to undergo repeated enhanced cardiac magnetic resonance imaging to detect fibrosis over their lifetime follow-up.• A predictive model based on the entire left ventricular myocardium outperformed a model based on a slice of the maximal wall thickness.• A predictive model that fused image and radiomic features from the entire left ventricular myocardium had excellent diagnostic performance, robustness, and clinical utility.

Association of NT-proBNP and hs-cTnT with Imaging Markers of Diastolic Dysfunction and Focal Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

Serum biomarkers such as N-terminal prohormone of the brain natriuretic peptide (NT-proBNP) and cardiac troponins are elevated in patients with hypertrophic cardiomyopathy (HCM). At present, it is not clear if these markers are associated with distinct clinical alterations in HCM, such as left ventricular hypertrophy, outflow tract obstruction, myocardial fibrosis and/or diastolic dysfunction (DD), which are associated with adverse cardiovascular outcome. Here we evaluate the association of NT-proBNP and high sensitivity cardiac troponin T (hs-cTnT) to a variety of cardiac imaging parameters in HCM patients in a multivariable regression analysis. This retrospective cross-sectional study included 366 HCM patients who underwent transthoracic echocardiography (TTE), 218 of whom also obtained cardiovascular magnetic resonance (CMR) to assess focal myocardial fibrosis by LGE. Multivariable regression analyses revealed the strongest association of the DD parameters E/E′ mean and E/E′ septal with NT-proBNP (b = 0.06, 95%-CI [0.05–0.07], p < 0.001, R2 = 0.28; b = 0.08, 95%-CI [0.06–0.1], p < 0.001, R2 = 0.25) and LGE size showed the strongest association with hs-cTnT (b = 0.20, 95%-CI [0.15–0.24], p < 0.001, R2 = 0.28). This study indicates that NT-proBNP and hs-cTnT are associated with structural and functional alterations in HCM. NT-proBNP is a stronger predictor for DD, while hs-cTnT is associated with the extent of focal myocardial fibrosis. Both biomarkers might be useful in the diagnostic procedure in addition to imaging parameters.

Noncontrast T1ρ dispersion imaging is sensitive to diffuse fibrosis: A cardiovascular magnetic resonance study at 3T in hypertrophic cardiomyopathy

PurposeTo determine the sensitivity of a noncontrast T1 dispersion cardiovascular magnetic resonance technique for detecting diffuse fibrosis in hypertrophic cardiomyopathy (HCM). MethodsThirty-two adult HCM patients and ten age- and gender-matched healthy volunteers were prospectively included in this study. Patients and controls underwent cine, T1ρ-mapping, and pre- and post-contrast T1-mapping imaging using a 3-T magnetic resonance system. Myocardial extracellular volume fraction (ECV) maps were obtained using pre- and post-contrast T1 maps to determine reference values for diffuse fibrosis. Myocardial T1ρ and T1ρ dispersion maps called myocardial fibrosis index (mFI) maps provided 570 myocardial segments for Pearson or Spearman correlation analysis. The left ventricle myocardia of the HCM patients were divided into 16 segments that were further classified as either normal-thickness myocardium (<15 mm) (HCM-N) or hypertrophic myocardium (≥15 mm) (HCM-H). ResultsECV and mFI values increased progressively on a per-segment basis from healthy controls to the HCM-N group and then to the HCM-H group (ECV: 27.4 ± 2.8% vs. 31.1 ± 4.2% vs. 37.6 ± 6.9%, respectively [P < 0.0001]; mFI: 6.1 ± 0.9 ms vs. 8 ± 1.9 ms vs. 11 ± 3.3 ms, respectively [P < 0.0001]). There was a strong positive correlation between the segmented ECV and the mFI (r = 0.878). The mFI was equally or significantly better than the ECV for differentiating fibrosis content in HCM-N and HCM-H according to their receiver operating characteristic curves. ConclusionA T1ρ dispersion imaging mFI can sensitively detect diffuse myocardial fibrosis in HCM, even in HCM-N.

Detecting Regional Fibrosis in Hypertrophic Cardiomyopathy: The Utility of Myocardial Strain Based on Cardiac Magnetic Resonance

The value of myocardial strain for reflecting fibrosis in patients with hypertrophic cardiomyopathy (HCM) on cardiac magnetic resonance (CMR) has not been definite. We aim to explore whether there are underlying non-contrast parameters to evaluate myocardial fibrosis and screen which may be the best. We retrospectively included 127 HCM patients (89 men; average age 46.6 ± 15.6 years) and 30 healthy controls (20 men; average age 52.0 ± 13.2 years) who have undergone late gadolinium enhancement (LGE) CMR. Next, 127 HCM patients were divided randomly into two sets including training cohort and validation cohort. Strain and imaging parameters were measured and analyzed statistically. Based on univariate and multivariate analysis, segmental circumferential strain (SCS) (p < 0.001) and maximal wall thickness (MWT) (p < 0.001) may differentiate myocardial segments with or without LGE as significant biomarkers for both sets. The area under the curve (AUC) was 0.803 (95% CI 0.785-0.820) for SCS and 0.777 (95% CI 0.759-0.795) for MWT to identify myocardial fibrosis. When combining SCS >-13.9% and MWT >16.4mm, the specificity of the model (AUC=0.779; 95% CI 0.760-0.796) achieved the highest 93.9%, with a sensitivity of 61.8%. Strain analysis in HCM holds promise for myocardial fibrosis detection and SCS is the best strain parameter based on CMR. Nevertheless, the model of combining SCS and MWT could achieve the highest specificity for fibrotic diagnosis.

Feature-tracking cardiac magnetic resonance method: a valuable marker of replacement fibrosis in hypertrophic cardiomyopathy.

PurposeLeft ventricular (LV) replacement fibrosis is a marker of adverse cardiac events in hypertrophic cardiomyopathy (HCM). We aimed to assess the efficacy of the feature-tracking cardiac magnetic resonance (FT-CMR) in the detection of LV replacement fibrosis.Material and methodsFifty-one patients with HCM (51% female, mean age = 21 ± 5.2 years) and significant myocardial hypertrophy, who underwent CMR between February 2018 and December 2019 were enrolled. Functional and 3D FT-CMR parameters were measured. LV global longitudinal strain, global radial strain (GRS), and global circumferential strain (GCS) were recorded. The percentage of enhanced myocardial mass was calculated. Univariate and multivariate regression analyses were performed to determine the predictors of fibrosis. A p-value of less than 0.05 was considered significant.ResultsThe mean enhanced mass percentage was 15.2 ± 10.53%. Among LV volumetric parameters, end-systolic and end-diastolic volume indices predicted fibrosis (fitness [F] = 8.11 and p = 0.006 vs. F = 6.6 and p = 0.012, correspondingly). The univariate linear regression demonstrated that GCS and GRS predicted total enhanced mass (%) (F = 12.29 and p = 0.001 vs. F = 7.92 and p = 0.007, respectively). After the inclusion of all volumetric and deformation parameters, the multivariate analysis identified the model of a combination of LV end-diastolic volume index (LV EDVI) and LV GCS as a robust predictor of the fibrosis percentage (F = 8.86 and p = 0.005).ConclusionsNon-contrast CMR parameters including LV GCS and LV EDVI are valuable markers of replacement fibrosis in HCM patients with notable myocardial hypertrophy.

A Novel miRNA Screen Identifies miRNA-4454 as a Candidate Biomarker for Ventricular Fibrosis in Patients with Hypertrophic Cardiomyopathy.

(1) Background: Left ventricular hypertrophy, myocardial disarray and interstitial fibrosis are the hallmarks of hypertrophic cardiomyopathy (HCM). Access to the myocardium for diagnostic purposes is limited. Circulating biomolecules reflecting the myocardial disease processes could improve the early detection of HCM. Circulating miRNAs have been found to reflect disease processes in several cardiovascular diseases. (2) Methods: We quantified circulating miRNA molecules in the plasma of 24 HCM and 11 healthy controls using the Human v3 miRNA Expression Assay Kit Code set (Nanostring Tech., Seattle, WA, USA) and validated differentially expressed miRNAs using RT-PCR. (3) Results: In comparison to healthy controls, the levels of six miRNAs (miR-1, miR-3144, miR-4454, miR-495-3p, miR-499a-5p and miR-627-3p) were higher in the plasma of HCM patients than healthy individuals (p < 0.05). Of these, higher levels of miR-1, miR-495 and miR-4454 could be validated by real-time PCR. In addition, elevated miR-4454 levels were significantly correlated with cardiac fibrosis, detected by magnetic resonance imaging in HCM patients. (4) Conclusions: Circulating miR-1, miR-495-3p and miR-4454 levels are elevated in the plasma of HCM patients. To the best of our knowledge, this is the first report showing a correlation between miR-4454 levels and cardiac fibrosis in HCM. This suggests miR-4454 as a potential biomarker for fibrosis in these patients.

Abstract 12273: Correlation Between Aortic Strain and Native T1 Value in Hypertrophic Cardiomyopathy

Introduction: Aortic stiffness is related to impairment of left ventricular (LV) function and LV remodeling. Myocardial ischemia and fibrosis in hypertrophic cardiomyopathy (HCM) cause ventricular arrhythmia and sudden cardiac death. Magnetic resonance imaging (MRI) can evaluate aortic stiffness and LV function noninvasively. Aortic strain shows the possibility for the assessment of the aortic status and T1 mapping allows the assessment of diffuse myocardial fibrosis. Hypothesis: We assessed the hypothesis that aortic strain is correlated with native T1 values in HCM patients. Methods: Thirty-six HCM patients (mean age : 64±2 years) and forty control subjects (mean age : 58±3 years) with no history of coronary artery disease were examined using a 3T MRI. Cross-sectional aortic areas of the descending aorta were measured and aortic strain was calculated as follows: aortic strain (%) = (maximum aorta area - minimum aorta area)/minimum aorta area х 100. Native T1 values were measured as an averaged T1 values in the septum of 3 short-axis slices of base-to-apex left ventricle myocardium. LV ejection fraction (LVEF), left atrium (LA) dimension and E/e’ were measured by echocardiography. Results: LVEF showed no significant differences between HCM patients and control subjects (66.2±1.1% vs. 64.5±1.0%, p=0.2488). LA dimension and E/e’ in HCM patients were significantly higher than control subjects (LA dimension: 38.3±1.1mm vs 34.9±0.85mm, p=0.0155, E/e’: 13.4±0.95 vs 9.2±0.42, p&lt;0.0001). Native T1 values and aortic strain of the descending aorta in HCM patients were significantly lower than those in control subjects (native T1 values: 1254±8ms vs 1208±8ms, p&lt;0.0001, aortic strain: 7.95±0.66% vs 12.92±1.27%, p=0.0012). Multiple linear regression analysis revealed that aortic strain was correlated with age (β=-0.370, p=0.0014) and native T1 values (β=-0.244, p=0.0448). Conclusions: In HCM patients, aortic strain of the descending aorta was significantly decreased compared to control subjects and correlated with native T1 values. Aortic strain may be a promising factor for myocardial fibrosis in HCM patients.

Patterns of Replacement Fibrosis in Hypertrophic Cardiomyopathy.

Background Myocardial replacement fibrosis is one of the major histologic features of hypertrophic cardiomyopathy (HCM), but its characteristics have not been well delineated. Purpose To clarify the characteristics of replacement fibrosis in HCM and to evaluate the prognostic value of the regional extent of fibrosis. Materials and Methods This prospective study evaluated participants with HCM who underwent contrast-enhanced cardiac MRI from March 2011 to April 2019. For each participant, global and 16-segment extent of late gadolinium enhancement (LGE) in the left ventricle (LV) at cardiac MRI was analyzed. The primary end point was all-cause death. Results Among the 798 study participants enrolled (median age, 49 years [interquartile range {IQR}: 38-59 years]; 508 men), 588 (74%) underwent whole-exome sequencing. Thirty-five participants (4%) experienced death from any cause during a median follow-up of 2.9 years (IQR: 1.5-4.7 years). Spearman analysis showed weak correlations between the extent of LGE and wall thickness (LGE of global LV and maximal LV wall thickness, r = 0.35 [P < .001]; LGE and thickness of septum, r = 0.30 [P < .001]). In the 16-segment model, the distribution of LGE was visually inhomogeneous and higher in the basal anterior, basal septal, midanterior, and midseptal regions (P < .001). This similar distribution of LGE was observed in participants with asymmetric septal hypertrophy, those with apical HCM, participants positive for mutation and those negative for mutation, and participants with MYH7 and MYBPC3 mutations. Cox analysis indicated that both the global extent of LGE (adjusted hazard ratio = 1.68 per 10% increase in LGE; P < .001) and the regional extent of LGE (ie, basal, midventricular, and apical regions of LV when on the short-axis view; septum, anterior free wall, inferior free wall, and lateral free wall when on the long-axis view) were associated with adverse outcomes. Conclusion In hypertrophic cardiomyopathy, myocardial replacement fibrosis weakly correlated with hypertrophy, was inhomogeneous and asymmetric, and was predominantly distributed in the interventricular septal wall and anterior free wall at the basal and mid levels. Greater extent of fibrosis was associated with poor prognosis, regardless of its location in the left ventricle. © RSNA, 2021 See also the editorial by Hanneman in this issue.

MicroRNAs as Biomarkers in Hypertrophic Cardiomyopathy: Current State of the Art.

Hypertrophic Cardiomyopathy (HCM) is the most common inherited Cardiomyopathy. The hallmark of HCM is myocardial fibrosis that contributes to heart failure, arrhythmias and sudden cardiac death. Currently, there are no reliable serum biomarkers for the detection of myocardial fibrosis, while cardiac magnetic resonance (CMR) is an imaging technique to detect myocardial fibrosis. MicroRNAs (miRNAs) have been increasingly suggested as biomarkers in cardiovascular diseases. However, in HCM there is as yet no identified and verified specific circulating miRNA signature. We conducted a review of the literature to identify the studies that indicate the possible roles of miRNAs in HCM. From studies in transgenic mice with HCM, miR-1, -133 may identify HCM in the early asymptomatic phase. Human miR-29a could be used as a circulating biomarker for detection of both myocardial hypertrophy and fibrosis in HCM, while it could also have a possible additional role in discrimination of hypertrophic obstructive cardiomyopathy from non-obstructive HCM. Additionally, miR-29a-3p is associated with diffuse myocardial fibrosis in HCM, while miR-1-3p could discriminate end-stage HCM from dilated cardiomyopathy and left ventricle dilation. Another role of miRNAs could also be the contribution in the differential diagnosis between HCM and phenocopies. Moreover, miRNA- targeted therapy (miR-133 mimics) is promising in inhibiting cardiac hypertrophy, but this is still in the early stages. A more reliable and specific signature of miRNAs is expected with forthcoming studies in samples from HCM patients and correlation of miRNAs with CMR and serum markers of fibrosis may implicate novel diagnostic and therapeutic pathways.

Genetic regulation of myocardial fibrosis in hypertrophic cardiomyopathy

Abstract Background Myocardial fibrosis is a common feature of hypertrophic cardiomyopathy (HCM) but its pathophysiology has yet to be elucidated. Purpose In this study, we used a multiplex approach to examine the genetic regulation of pathways associated with fibrosis in patients undergoing septal myectomy. Methods Myocardial tissue was collected at time of surgical intervention. Control biopsy samples were obtained from the left ventricular free wall from structurally normal hearts during autopsy following non-cardiac related death. Tissue was either snap frozen in liquid nitrogen and subsequently stored at −80 degrees or collected in RNA laterTM and frozen 24 hours later at −80 degrees. Total RNA was extracted from HCM tissue samples using the Qiagen RNeasy fibrous tissues mini kit and from control samples using mirVana isolation kit (Ambion), according to the manufacturer's protocol. Quantitative PCR (qPCR) was performed on the extracted RNA using a RT. Profiler™ Human finrosis PCR Array. Results The study cohort comprised 22 HCM samples and 5 controls. The relative regulation of genes involved in myocardial fibrosis in patients with HCM compared to controls is shown in figure 1. In patients with HCM, there was increased expression of genes involved in collagen synthesis. A significant two-fold upregulation in type III procollagen mRNA was observed relative to controls (p=0.013) with a similar trend identified for type I procollagen (1.5 fold up-regulation, p=0.081). The gene expression of MMP3 (−1.5 fold, p=0.029) and MMP8 (−1.8, p=0.002) which are involved in collaged degradation were downregulated in the HCM group. The gene expression of pro-fibrotic mediators TGF-β2 (4.8 fold, p=0.008) and CCN2 (2.9 fold, p=0.021) was also significantly elevated. Within the HCM group, there was a correlation between the fold regulation of TGF-β1 (r=0.570, p=0.006; r=0.528, p=0.012), TGF-β2 (r=0.569, p=0.006; r=0.514, p=0.014) and TGF-β3 (r=0.738, p&amp;lt;0.001; r=0.496, p=0.019) to gene regulation of type I and III procollagens respectively. The expression of BMP-7 which has been shown to reduce myocardial fibrosis by antagonising TGF- β mediated endothelial – mesothelial transformation of fibroblasts was also down-regulated in HCM (−3.8, p=0.015). Conclusions Genetic expression of procollagen is significantly upregulated in patients with HCM relative to controls. TGF-β and CCN2 mediated signalling appear to be key mediators in promoting collagen expression. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Heart Hospital Charitable Grant, UK Figure 1. Gene expression in HCM

Early Assessment of Myocardial Fibrosis of Hypertrophic Cardiomyopathy with Native-T1-Mapping-Based Deep Learning: A Preliminary Study

To explore the diagnostic performance of deep learning (DL) model in early detection of the interstitial myocardial fibrosis using native T1 maps of hypertrophic cardiomyopathy (HCM) without late gadolinium enhancement (LGE). Sixty HCM patients and 44 healthy volunteers who underwent cardiac magnetic resonance were enrolled in this study. Each native T1 map was labeled according to its LGE status. Then, native T1 maps of LGE (-) and those of the controls were preprocessed and entered in the SE-ResNext-50 model as the matrix for the DL model for training, validation and testing. A total of 241 native T1 maps were entered in the SE-ResNext-50 model. The model achieved a specificity of 0.87, sensitivity of 0.79, and area under curve ( AUC) of 0.83 ( P<0.05) in distinguishing native T1 maps of LGE (-) from those of the controls in the testing set. The DL model based on SE-ResNext-50 could be used for identifying native T1 maps of LGE (-) with relatively high accuracy. It is a promising approach for early detection of myocardial fibrosis in HCM without the use of contrast agent.

Efficacy of Novel Noncontrast Cardiac Magnetic Resonance Methods in Indicating Fibrosis in Hypertrophic Cardiomyopathy.

Objective In hypertrophic cardiomyopathy (HCM), myocardial fibrosis is routinely shown by late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) imaging. We evaluated the efficacy of 2 novel contrast-free CMR methods, namely, diffusion-weighted imaging (DWI) and feature-tracking (FT) method, in detecting myocardial fibrosis. Methods This cross-sectional study was conducted on 26 patients with HCM. Visual and quantitative comparisons were made between DWI and LGE images. Regional longitudinal, circumferential, and radial strains were compared between LGE-positive and LGE-negative segments. Moreover, global strains were compared between LGE-positive and LGE-negative patients as well as between patients with mild and marked LGE. Results All 3 strains showed significant differences between LGE-positive and LGE-negative segments (P < 0.001). The regional longitudinal and circumferential strain parameters showed significant associations with LGE (P < 0.001), while regional circumferential strain was the only independent predictor of LGE in logistic regression models (OR: 1.140, 95% CI: 1.073 to 1.207, P < 0.001). A comparison of global strains between patients with LGE percentages of below 15% and above 15% demonstrated that global circumferential strain was the only parameter to show impairment in the group with marked myocardial fibrosis, with borderline significance (P=0.09). A review of 212 segments demonstrated a qualitative visual agreement between DWI and LGE in 193 segments (91%). The mean apparent diffusion coefficient was comparable between LGE-positive and LGE-negative segments (P=0.51). Conclusions FT-CMR, especially regional circumferential strain, can reliably show fibrosis-containing segments in HCM. Further, DWI can function as an efficient qualitative method for the estimation of the fibrosis extent in HCM.

Fibrosis in hypertrophic cardiomyopathy: role of novel echo techniques and multi-modality imaging assessment

Hypertrophic cardiomyopathy (HCM) represents one of the primary cardiomyopathies and may lead to heart failure and sudden cardiac death. Among various histologic features of the disease examined, assessment of myocardial fibrosis may offer valuable information, since it may be considered the common nominator for all HCM connected complications. Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) has emerged as the reference noninvasive method for visualizing and quantifying myocardial fibrosis in patients with HCM. T1 mapping, a promising new CMR technique, may provide an advantage over conventional LGE-CMR, by permitting a more valid quantification of diffuse fibrosis. On the other hand, echocardiography offers a significantly more portable, affordable, and easily accessible solution for the study of fibrosis. Various echocardiographic techniques ranging from integrated backscatter and contrast-enhanced ultrasound to two- (2D) or three-dimensional (3D) deformation and shear wave imaging may offer new insights into substrate characterization in HCM. The aim of this review is to describe thoroughly all different modalities that may be used in everyday clinical practice for HCM fibrosis evaluation (with special focus on echocardiographic techniques), to concisely present available evidence and to argue in favor of multi-modality imaging application. It is essential to understand that the role of various imaging modalities is not competitive but complementary, since the information provided by each one is necessary to illuminate the complex pathophysiologic pathways of HCM, offering a personalized approach and treatment in every patient.