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Mutation Type Is Not Clinically Useful in Predicting Prognosis in Hypertrophic Cardiomyopathy
Open accessAbstract
H ypertrophic cardiomyopathy (HCM), or clinically unex- plained hypertrophy of the heart, is a common genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity.As the genetic mutations underlying the pathogenesis of this disease have been identified, investigators have attempted to link mutations to clearly defined alterations in survival in hopes of identifying prognostically relevant biomarkers of disease.While initial studies labeling particular MYH7-encoded beta myosin heavy chain and TNNT2encoded cardiac troponin T mutations as "malignant" or "benign" raised hopes for mutation-specific risk stratification in HCM, a series of subsequent investigations identified mutations in families with contradictory disease phenotypes.Furthermore, subsequent proband-based cohort studies indicated that the clinical prognostic relevance of individual mutations labeled as "malignant" or "benign" in large referral centers is negligible.Herein, we seek to summarize the controversy and dispute the notion that mutation-specific risk stratification in HCM is possible at the present time.We provide evidence for clinicians and basic scientists alike to move beyond simple mutation descriptors to a more nuanced understanding of HCM mutations which fully captures the multi-factorial nature of HCM disease expression. Response by Ho on p 2450Over the last 2 decades, the genetic underpinnings of heritable cardiovascular disease have begun to be unveiled, starting with the discovery of rare pathogenic mutations that cause cardiomy-opathies and cardiac channelopathies.The simple paradigm of Mendelian inheritance, while helpful in certain monogenic disease processes, is fundamentally incapable of explaining the entirety of how complex diseases express in the context of complex human physiology under the influence of a myriad of intrinsic and extrinsic variables.Our understanding of the intricate interplay between 1 such intrinsic variable, the genome, and the manifestation of disease was advanced significantly in the decoding of a handful of human's genomes in February of 2001.1,2 Despite the decade of research these discoveries have initiated, clinicians and scientists alike are only beginning to appreciate the impact of this revolution on our understanding of health and disease.One disease, hypertrophic cardiomyopathy (HCM), typifies this struggle, as we seek to integrate the role of genetic alterations into the variation we see in this sudden-deathpredisposing disease.Defined by clinically unexplained hypertrophy of the ventricular walls and/or septum, HCM affects approximately 1 in 500 persons and is the most common inherited cardiovascular disease.3 HCM is the most common cause of sudden cardiac death (SCD) in young athletes and a significant cause of sudden death in the young in general.4,5 A heterogeneous disease, HCM demonstrates phenotypic variation in the degree of hypertrophy (none to extreme), fibrosis and myocyte disarray (none to extreme), left ventricular (LV) outflow tract obstruction (none to severe), morphological subtype (reverse curve, sigmoid, and apical-HCM, for example), associated symptoms (none to debilitating symptoms refrac-The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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“Although the genetic basis of HCM has been identified and continues to be studied, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited (3, 4, 11).”
From Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics (2020) · cites this paper as [3]
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“Moreover, genotype alone is not sufficient to predict clinical outcomes in HCM patients, given the multifactorial nature of the disease (3, 11, 42).”
From Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics (2020) · cites this paper as [3]
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Metadata
- Authors
- Landstrom, A. P., & Ackerman, M. J.
- Affiliations
- Mayo Clinic (US)
- Venue
- Circulation
- Published
- 2010-12-07
- Volume
- 122
- Issue
- 23
- Pages
- 2441-2450
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6309993
- OpenAlex
- W2089547093
- Cited by
- 146
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 7 · 2017: 14 · 2016: 6 · 2015: 13 · 2014: 21 · 2013: 14 · 2012: 15
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Mayo Clinic
- National Institutes of Health (5p01hl094291-05)
- National Heart, Lung, and Blood Institute (1P01HL094291, P01‑HL094291)
- National Institute of General Medical Sciences (T32GM072474)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- hypertrophic cardiomyopathy, mutation types, prognosis, risk stratification, MYH7, beta-myosin heavy chain, TNNT2, cardiac troponin T, sudden cardiac death, genotype-phenotype correlation, genetic heterogeneity, inherited cardiovascular disease, biomarkers, genotype-phenotype discordance, genotype-phenotype concordance
- MeSH terms
- Cardiomyopathy, Hypertrophic, Genotype, Humans, Mutation, Predictive Value of Tests, Prognosis
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