Abstract 371: Prevalence and Spectrum of Thin Filament Mutations in 1025 Patients with Hypertrophic Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Melissa L Will ◽  
Andrew P Landstrom ◽  
J. Martijn Bos ◽  
Bernard J Gersh ◽  
Steve R Ommen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin I ◽  
Mutational Analysis ◽  
Troponin T ◽  
Cohort Analysis ◽  
Left Ventricular ◽  
Septal Curvature

Background Recently, genetic testing for sarcomeric hypertrophic cardiomyopathy (HCM) became a commercially available diagnostic test involving analysis of 8 HCM-associated myofilament genes, four of which encode thin filament proteins - TNNT2- encoded cardiac troponin T, TPM1 -encoded alpha tropomyosin, TNNI3- encoded cardiac troponin I, and ACTC- encoded cardiac actin. Compared to the two most common subtypes of sarcomeric HCM, much less is known about the prevalence and spectrum of thin filament HCM. Methods Comprehensive open reading frame/splice site mutational analysis of these 4 thin filament-encoding genes was performed, using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, on the largest assembled cohort of unrelated patients (N = 1025, 61% male, 49 ± 18 years at diagnosis, maximal left ventricular wall thickness, LVWT, 22.3 ± 7 mm) with clinically diagnosed HCM that were seen at the Mayo Clinic. Results Nineteen distinct missense mutations, involving conserved residues and absent in 600 reference alleles, were identified in 36 of 1025 patients (3.5%) including TNNT2 (16 patients), TNNI3 (12), TPM1 (7) and ACTC (1). Among these 36 patients with thin filament-HCM, their average age at diagnosis was 33.2 ± 16 years and the average LVWT was 21 ± 8 mm. Eighteen patients (50%) had evidence for familial HCM and 13% had a positive history for sudden cardiac death. Only 13 patients (36%) had a reverse septal curvature by echocardiography. Instead, 12 patients (34%) had either sigmoidal or neutral septal contours and 9 patients (25%) had apical variant-HCM. Conclusion Here, we present the largest cohort analysis of thin filament HCM to date and detail the prevalence and spectrum of HCM-associated mutations in these 4 genes. Compared to the strong association between reverse septal curvature and thick filament HCM, the septal morphology associated with thin filament HCM was quite varied. Contrary to published estimates of the frequency of troponin T-HCM (5 – 10%) and the other subtypes of thin filament HCM, the prevalence of thin filament HCM was very low in this cohort. If confirmed in other cohorts, a revised cascade for HCM genetic testing should be considered.

scholarly journals Mavacamten rescues increased myofilament calcium sensitivity and dysregulation of Ca2+ flux caused by thin filament hypertrophic cardiomyopathy mutations

2020 ◽  
Vol 318 (3) ◽  
pp. H715-H722 ◽  
Author(s):  
Alexander J. Sparrow ◽  
Hugh Watkins ◽  
Matthew J. Daniels ◽  
Charles Redwood ◽  
Paul Robinson
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin I ◽  
Troponin T ◽  
Thick Filament ◽  
Calcium Sensitivity ◽  
Calcium Handling ◽  
Cellular Models

Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor. NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.

Abstract 4845: Hypertrophic Cardiomyopathy due to Sarcomere Gene Mutations is Associated with More Severe Derangement of Microvascular Function Compared to Myofilament Negative Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Iacopo Olivotto ◽  
Francesca Girolami ◽  
Michael J Ackerman ◽  
Roberto Sciagra ◽  
Stefano Nistri ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Thin Filament ◽  
Troponin I ◽  
Genetic Test ◽  
Troponin T ◽  
Gene Mutations ◽  
Thick Filament ◽  
Microvascular Function ◽  
Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

scholarly journals Reversed Septal Curvature Is Associated with Elevated Troponin Level in Hypertrophic Cardiomyopathy

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Renata Rajtar-Salwa ◽  
Tomasz Tokarek ◽  
Paweł Petkow Dimitrow
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Troponin I ◽  
High Sensitivity ◽  
Ventricular Outflow Tract ◽  
Left Ventricular ◽  
Septal Thickness ◽  
Left Ventricular Outflow ◽  
Echocardiographic Parameters ◽  
Ischemic Events ◽  
Septal Curvature

The aim of study was to compare patients with hypertrophic cardiomyopathy divided according to septal configuration assessed in a 4-chamber apical window. The study group consisted of 56 consecutive patients. Reversed septal curvature (RSC) and non-RSC were diagnosed in 17 (30.4%) and 39 (69.6%) patients, respectively. Both RSC and non-RSC groups were compared in terms of the level of high-sensitivity troponin I (hs-TnI), NT-proBNP (absolute value), NT-proBNP/ULN (value normalized for sex and age), and echocardiographic parameters, including left ventricular outflow tract gradient (LVOTG). A higher level of hs-TnI was observed in RSC patients as compared to the non-RSC group (102 (29.2-214.7) vs. 8.7 (5.3-18) (ng/l), p = 0.001 ). A trend toward increased NT-proBNP value was reported in RSC patients (1279 (367.3-1186) vs. 551.7 (273-969) (pg/ml), p = 0.056 ). However, no difference in the NT-proBNP/ULN level between both groups was observed. Provocable LVOTG was higher in RSC as compared to non-RSC patients (51 (9.5-105) vs. 13.6 (7.5-31) (mmHg), p = 0.04 ). Furthermore, more patients with RSC had prognostically unfavourable increased septal thickness to left LV diameter at the end diastole ratio. Patients with RSC were associated with an increased level of hs-TnI, and the only trend observed in this group was for the higher NT-proBNP levels. RSC seems to be an alerting factor for the risk of ischemic events. Not resting but only provocable LVOTG was higher in RSC as compared to non-RSC patients.

scholarly journals Atomic resolution probe for allostery in the regulatory thin filament

2016 ◽  
Vol 113 (12) ◽  
pp. 3257-3262 ◽  
Author(s):  
Michael R. Williams ◽  
Sarah J. Lehman ◽  
Jil C. Tardiff ◽  
Steven D. Schwartz
Keyword(s):  
Binding Site ◽  
Human Disease ◽  
Calcium Binding ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin I ◽  
Troponin T ◽  
Calcium Binding Site

Calcium binding and dissociation within the cardiac thin filament (CTF) is a fundamental regulator of normal contraction and relaxation. Although the disruption of this complex, allosterically mediated process has long been implicated in human disease, the precise atomic-level mechanisms remain opaque, greatly hampering the development of novel targeted therapies. To address this question, we used a fully atomistic CTF model to test both Ca2+ binding strength and the energy required to remove Ca2+ from the N-lobe binding site in WT and mutant troponin complexes that have been linked to genetic cardiomyopathies. This computational approach is combined with measurements of in vitro Ca2+ dissociation rates in fully reconstituted WT and cardiac troponin T R92L and R92W thin filaments. These human disease mutations represent known substitutions at the same residue, reside at a significant distance from the calcium binding site in cardiac troponin C, and do not affect either the binding pocket affinity or EF-hand structure of the binding domain. Both have been shown to have significantly different effects on cardiac function in vivo. We now show that these mutations independently alter the interaction between the Ca2+ ion and cardiac troponin I subunit. This interaction is a previously unidentified mechanism, in which mutations in one protein of a complex indirectly affect a third via structural and dynamic changes in a second to yield a pathogenic change in thin filament function that results in mutation-specific disease states. We can now provide atom-level insight that is potentially highly actionable in drug design.

scholarly journals Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing

2020 ◽  
Vol 9 (6) ◽  
pp. 1636
Author(s):  
Damiano Magrì ◽  
Vittoria Mastromarino ◽  
Giovanna Gallo ◽  
Elisabetta Zachara ◽  
Federica Re ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Risk Stratification ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Troponin T ◽  
Cardiopulmonary Exercise Testing ◽  
Peak Oxygen Uptake ◽  
Variant Of Uncertain Significance ◽  
Cardiopulmonary Exercise

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.

Abstract 810: Impact of Elevated Plasma Matrix Metalloproteinase-2 on Prognosis in Hypertrophic Cardiomyopathy: Evidence from Long-Term Follow-Up of Genotyped Patients

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Eiichi Masuta ◽  
Hidekazu Ino ◽  
Noboru Fujino ◽  
Katsuharu Uchiyama ◽  
Kenshi Hayashi ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Troponin T ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiac Events ◽  
Group A ◽  
Group B

Background: Previous studies suggest that production of matrix metalloproteinase-2 (MMP-2) which is responsible for cardiac remodeling could determine prognosis of hypertrophic cardiomyopahty (HCM). However, few data exist regarding the importance of MMP-2 production in clinical settings. Therefore, we determined MMP-2 levels correlated to prognosis in HCM with sarcomere gene mutations. Methods and Results: Echocardiography and determination of plasma MMP-2 levels by enzyme-linked immunoassay were simultaneously performed in 31 HCM patients (22 women, mean age 56±12 years) with sarcomere protein gene mutation including 22 for cardiac troponin I, 5 for cardiac myosin binding-protein C, 3 for cardiac troponin T and 1 for beta-myosin heavy chain. Major cardiac events such as hospitalization due to congestive heart failure or ventricular fibrillation and mortality were prospectively examined for follow-up period of 48.4±29.1 months. When patients were divided into two groups (Group A: MMP-2 ≥800 ng/ml n=16 and Group B: MMP-2<800ng/ml n=15), there was no differences in mean age (59.4±11.7 year vs 53.1±11.3 year, p=0.13). On echocardiograms, interventricular septal thickness in group A (11.7±4.2 mm) was smaller than that in group B (15.9±4.8 mm, p<0.05) and percent fractional shortening (FS) was significantly impaired in group A (24.8±12.5%) in comparison with that in group B (37.7±8.1%, p=0.002). There was negative correlation between the MMP-2 levels and FS (p<0.001, r=0.76). The frequency of cardiac events was significantly higher in group A (10 patients of 16 patients) than in group B (1 patient of 15 patients, p=0.0012). Importantly, 5 patients of group A died, although none of groupB patients did (p=0.018). Conclusion: These results demonstrate that the high plasma concentration of MMP-2 (≥800 ng/ml) could be a predictor of prognosis in HCM with sarcomere mutations probably through reflecting impaired left ventricular function.

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