Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality

Roberts, Robert

doi:10.1161/01.cir.0000021163.86906.b2

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…To contend with this incomplete age-related penetrance and to increase ascertainment in the "at-risk" population using clinical tools, either echocardiographic screening would need to continue indefinitely (at great financial and emotional cost), or a more sensitive form of echocardiography (e.g., tissue Doppler imaging) would have to be validated that would identify patients with HCM but no overt LVH (31). It is also apparent that with respect to phenocopies, even these advanced techniques may be inadequate to diagnose or exclude HCM.…”

Section: Is Genetic Screening For Diagnosis and Prognosis Feasible?mentioning

confidence: 99%

Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications

Ashrafian¹,

Watkins²

2007

Journal of the American College of Cardiology

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The enduring subdivision of cardiomyopathies into hypertrophic (HCM), dilated (DCM), and restrictive (RCM) categories reflects the emphasis of traditional classifications on morphology. Rapid advances in the genetic interrogation of these disorders have redefined their taxonomy and revealed potential conflicts between the old and new classifications. Hypertrophic cardiomyopathy has been redefined as a disease of perturbed sarcomere function. Dilated cardiomyopathy is a disease that results from more varied perturbations, including, but not limited to, defects of the cytoskeleton. Positional cloning and candidate gene approaches have been successful in identifying >40 disease loci, many of which have led to disease genes in HCM, DCM, RCM, and arrhythmogenic right ventricular cardiomyopathy. These findings provide mechanistic insights, permit genetic screening, and to a limited extent, facilitate prognostication. Although single gene analyses rapidly focus down to the underlying mechanistic pathways, they do not take account of all relevant variation in the human genome. Correspondingly, advances in genomics, through microarrays, have facilitated characterization of these broader downstream elements. As well as refining the taxonomic reclassification of cardiomyopathies, these genomic approaches, coupled with functional studies, have identified novel potential therapeutic targets, such as cardiac energetics, calcium handling, and apoptosis. We review the successes and pitfalls of genetic and genomic approaches to cardiomyopathy and their impact on current and future clinical care.

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Section: Is Genetic Screening For Diagnosis and Prognosis Feasible?mentioning

confidence: 99%

Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications

Ashrafian¹,

Watkins²

2007

Journal of the American College of Cardiology

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“…Reduced myocardial Doppler velocity was observed similar to the observation in transgenic rabbits with the mutation but without the phenotype. Results of other studies 33,34 performed in humans confirm that reduced tissue Doppler velocities are an early feature of the disease and precede the conventional clinical manifestations of the disease such as hypertrophy. These studies have obvious implications for screening individuals and also for therapeutic prevention.…”

Section: Animal Models Provide For Improved Early Diagnosismentioning

confidence: 52%

Genetic Basis for Hypertrophic Cardiomyopathy: Implications for Diagnosis and Treatment

Roberts

Sidhu

2003

Amer Heart Hosp J

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Familial hypertrophic cardiomyopathy is a genetic disease defined by cardiac hypertrophy in the absence of an increased external load. It is the most common inherited cardiac disorder occurring in 1 in 500 individuals. Ten genes exhibiting over 200 mutations have been identified. However, about 75% are due to mutations in just three genes: e-myosin heavy chain, cardiac troponin T, and myosin binding protein-C. Certain phenotypes are more common with certain genes, such as the myosin binding protein-C gene, which induces the disease predominantly in the fifth or sixth decade of life. Genetic animal models in the mouse and rabbit have helped to elucidate the pathophysiology. The primary defect imparted by the specific mutation alters contractile function, which stimulates release of various growth factors that induce secondary cardiac hypertrophy and fibrosis. Placebo single-blinded studies in the mouse indicate that losartan reverses the phenotype; in the rabbit, simvastatin essentially reversed the phenotype after 12 weeks of therapy. Clinical trials are ongoing in human familial hypertrophic cardiomyopathy.

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“…Investigation of these deaths places particular pressure on the medical examiner and his team. 16 HCM mutations have been identified in 14 different genes. Most are single nucleotide substitutions found within coding exons, intron-exon junctions, or promoter regions of the genes for b-myosin heavy chain, cardiac troponin T, or myosin binding protein-C. Clusters of mutations have been described in the b-myosin heavy chain gene (MYH7) that are generally associated with marked hypertrophy and poor prognosis.…”

Section: The Microarray and The Genetic Revolutionmentioning

confidence: 99%

Changing times: DNA resequencing and the “nearly normal autopsy”

Karch

2007

Journal of Forensic and Legal Medicine

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Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality

Cited by 5 publications

References 14 publications

Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications

Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications

Genetic Basis for Hypertrophic Cardiomyopathy: Implications for Diagnosis and Treatment

Changing times: DNA resequencing and the “nearly normal autopsy”

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