The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers

Ho, Carolyn Y.; Day, Sharlene M.; Colan, Steven D.; Russell, Mark W.; Towbin, Jeffrey A.; Sherrid, Mark V.; Canter, Charles E.; Jefferies, John L.; Murphy, Anne M.; Cirino, Allison L.; Abraham, Theodore P.; Taylor, Matthew R.G.; Mestroni, Luisa; Bluemke, David A.; Jarolím, Petr; Shi, Lei; Sleeper, Lynn A.; Seidman, Christine E.; Orav, E. John

doi:10.1001/jamacardio.2016.5670

Cited by 56 publications

(51 citation statements)

References 29 publications

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“…Compared to controls, HCM CMTs exhibited a 79-121% increased maximum contraction velocity (fig.2A, B), but without changes in contraction time (fig.2C). Relaxation half-time (t 1/2 ) was prolonged (fig.2D), which further supports that impaired relaxation is a consequence of HCM thick filament mutations, which has also been documented in HCM patients 23 . These kinetic changes are distinct from kinetic changes induced by omecamtiv mecarbil 24 , a direct myosin activator that prolongs contraction time.…”

Section: Resultssupporting

confidence: 79%

A contraction stress model of hypertrophic cardiomyopathy due to thick filament sarcomere mutations

Cohn

Thakar

Lowe

et al. 2018

Preprint

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18860-837-2048 (t) | travis.hinson@jax.org 19 20 Thick filament sarcomere mutations are the most common cause of hypertrophic cardiomyopathy (HCM), 21 a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear 22 mechanisms. We engineered an isogenic panel of four human HCM induced pluripotent stem cell (iPSc) 23 models using CRISPR/Cas9, and studied iPSc-derived cardiomyocytes (iCMs) in 3-dimensional cardiac 24 microtissue (CMT) assays that resemble in vivo cardiac architecture and biomechanics. HCM mutations 25 result in hypercontractility in association with prolonged relaxation kinetics in proportion to mutation 26 pathogenicity but not calcium dysregulation. RNA sequencing and protein expression studies identified 27 that HCM mutations result in p53 activation secondary to increased oxidative stress, which results in 28 increased cytotoxicity that can be reversed by p53 genetic ablation. Our findings implicate 29 hypercontractility as an early consequence of thick filament mutations, and the p53 pathway as a 30 molecular marker and candidate therapeutic target for thick filament HCM. 31 32 35 hypertrophy (LVH) with preserved systolic contractile function 2 . In young athletes, HCM manifests as a 36 common cause of sudden cardiac death; while in adults, HCM is associated with heart failure that may 37 progress to require cardiac transplantation 3 . Over the last few decades, the genetic basis of HCM has been 38 demonstrated by inheritance of autosomal dominant mutations in components of the force-producing 39 sarcomere 4 . About two-thirds of HCM patients harbor heterozygous mutations in one of two sarcomere 40 genes: b-myosin heavy chain (MHC-b is encoded by MYH7) or myosin-binding protein C (MYBPC3) 4 . 41 Along with titin, MHC-b and MYBPC3 are located in the thick filament where ATP hydrolysis by MHC-42b is coupled to force generation through interactions with the actin-rich thin filament ( fig.1A). A 43 prevailing model suggests that HCM mutations alter cardiac force generation through dysregulation of 44 calcium handling 5, 6 . Whether MYBPC3 and MYH7 mutations result in HCM by shared or heterogeneous 45 mechanisms also remains unclear. 46 Recent functional studies of thick filament HCM mutations in reconstituted sarcomere and 47 motility assays 7, 8 . Equally puzzling, contractile studies of single cardiomyocytes from MYH6-R403Q +/-1 mouse models, which recapitulate LVH and fibrosis in vivo 9 , have produced similarly conflicting results 2 for the identical mouse model and strain 10, 11 . Human patient-specific induced pluripotent stem cell (iPSc) 3 HCM models of MYH7-R663H (arginine 663 substituted with histidine) have recapitulated some features 4 of HCM including cellular enlargement and altered calcium handling 6 , but mechanical phenotypes of 5 1 expertise in confocal microscopy. We also thank Bo Reese for RNA sequencing technical expertise. We 2 thank Samantha Harris for her generous contribution of MYBPC3 antibody.3 4 Sources of Funding:5

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Section: Resultssupporting

confidence: 79%

A contraction stress model of hypertrophic cardiomyopathy due to thick filament sarcomere mutations

Cohn

Thakar

Lowe

et al. 2018

Preprint

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“…Diastolic function parameters were normal in 97% of G+/LVH and 95% of unaffected relatives, and no significant difference was detected in any parameter of LV relaxation and estimation of LV filling pressures. However, while NT-proBNP levels did not discriminate preclinical (G+/LVH−) subjects from controls in prior studies,12 13 20 23 24 levels were higher in our G+/LVH− compared with unaffected relatives, although still within the normal range. ECG abnormalities, predominantly Q waves and repolarisation changes, were more prevalent among G+/LVH− individuals than among unaffected relatives (27% vs 15%; p=0.028) and may reflect early manifestations of HCM,11 although with low positive predictive value.…”

Section: Discussioncontrasting

confidence: 98%

“…Early morphological and electrophysiological phenotypes reported among sarcomere mutation carriers with normal LVWT include subtle changes in LV cavity size and geometry, impaired LV relaxation19–22 and ECG abnormalities 11. As most of these studies analysed small and/or heterogeneous cohorts, interpretation of these findings has been difficult 20 23.…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers

et al. 2020

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ObjectiveThe myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation.MethodsWe studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped.ResultsGenetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH−) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH− subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives.ConclusionsPhenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH− individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.

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“…Detailed examination of the mutation carriers might detect clinical and laboratory abnormalities, such as reduced tissue Doppler velocities, and elevated serum biomarkers. 191, 225, 226 Given the age-related penetrance of the mutation, a number of mutation carriers/phenotype negative relatives, especially those below the age of 25–30 years will eventually express the phenotype. However, as such individuals age, the likelihood of their conversion to phenotype positivity diminishes progressively, and longer intervals between follow-up examinations (e.g.…”

Section: Genetic Testingmentioning

confidence: 99%

Hypertrophic Cardiomyopathy

Marian

Braunwald

2017

Circulation Research

905

533

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Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetric with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients, and can be provoked in another third. The histologic features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common genes involved, together accounting for about 50% of the HCM families. In approximately 40% of HCM patients the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

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The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers

Cited by 56 publications

References 29 publications

A contraction stress model of hypertrophic cardiomyopathy due to thick filament sarcomere mutations

A contraction stress model of hypertrophic cardiomyopathy due to thick filament sarcomere mutations

Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers

Hypertrophic Cardiomyopathy

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