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Hypertensive cardiac hypertrophy--is genetic variance the missing link?
D J Nunez1, C P Clifford, S al-Mahdawi
1Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Insights
Genetic factors significantly influence cardiac hypertrophy in hypertension. Investigating mutations in inherited cardiomyopathies may reveal how genes alter heart response to pressure overload, aiding risk prediction and treatment.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Hypertension Research
Background:
- Hypertensive cardiac hypertrophy predicts adverse cardiovascular events, with significant variability in human response.
- Genetic factors play a substantial role in regulating cardiac mass and variability.
- Some hypertensive patients display left ventricular hypertrophy (LVH) similar to inherited cardiomyopathies.
Purpose of the Study:
- Investigate if genetic factors from inherited hypertrophic cardiomyopathies alter the heart's hypertrophic response to pressure overload.
- Explore the role of mutations in familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) genes in hypertensive cardiac hypertrophy.
- Understand the mechanisms linking neuronal pathology in FA to cardiac manifestations.
Main Methods:
- Association analysis to compare allele frequencies in hypertensive patients with and without LVH.
- Characterization of cardiac manifestations in Friedreich's ataxia (FA).
- Creation of transgenic models to study gene-environment interactions in cardiac hypertrophy.
Main Results:
- Review of studies investigating genetic contributions to hypertensive cardiac hypertrophy.
- Analysis of allele frequencies and cardiac manifestations in specific genetic conditions.
- Development of models for studying genetic predisposition and hypertrophic stimuli.
Conclusions:
- Genetic factors are key regulators of cardiac mass in hypertension.
- Understanding these genes can improve risk stratification for LVH development.
- Research into cardiac-mass-modifying genes may offer new therapeutic targets for heart damage or hypoplasia.
Abstract:
1. Hypertensive cardiac hypertrophy is a major independent predictor of adverse cardiovascular events. In man the cardiac response to increased afterload is very variable, even when ambulatory blood pressure monitoring is used. Analysis of breeding experiments using normotensive and hypertensive rat strains, human twin studies and other data indicate that genetic factors play a significant role in regulating cardiac mass; in other words, a large component of total variability is accounted for by genetic variance. 2. The observation that some patients with only mild-to-moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload. Here we review briefly three lines of study: (i) association analysis to test whether the allele frequencies differ in hypertensive patients with or without left ventricular hypertrophy; (ii) characterization of the cardiac manifestations of FA to understand the mechanism by which the heart is affected in a disease associated with pathology in a subgroup of neurons, and (iii) creation of transgenic models to facilitate the investigation of the interaction between hypertrophic stimuli and underlying genetic predisposition. 3. Information on the nature of the cardiac-mass-modifying genes involved may be useful not only for selecting high risk patients in strategies aimed at preventing the development of LVH, but also in opening new avenues of research on the reprogramming of cardiac myocytes to encourage them to hypertrophy in situations where cardiac muscle has been damaged or is hypoplastic.