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Entry
map05410                    Pathway                                

Name
Hypertrophic cardiomyopathy (HCM)
Description
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myfibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myfilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction.
Class
Human Diseases; Cardiovascular diseases
BRITE hierarchy
Pathway map
map05410  Hypertrophic cardiomyopathy (HCM)
map05410

Ortholog table
Disease
H00292  Hypertrophic cardiomyopathy
H00728  Brugada syndrome
H01154  Wolff-Parkinson-White (WPW) syndrome
Reference
  Authors
Fatkin D, Graham RM
  Title
Molecular mechanisms of inherited cardiomyopathies.
  Journal
Physiol Rev 82:945-80 (2002)
DOI:10.1152/physrev.00012.2002
Reference
  Authors
Moolman-Smook JC, Mayosi BM, Brink PA, Corfield VA
  Title
Molecular genetics of cardiomyopathy: changing times, shifting paradigms.
  Journal
Cardiovasc J S Afr 14:145-55 (2003)
Reference
  Authors
Taylor MR, Carniel E, Mestroni L
  Title
Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing.
  Journal
Expert Rev Mol Diagn 4:99-113 (2004)
DOI:10.1586/14737159.4.1.99
Reference
  Authors
Marian AJ
  Title
Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy.
  Journal
Lancet 355:58-60 (2000)
DOI:10.1016/S0140-6736(99)06187-5
Reference
  Authors
Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H
  Title
Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.
  Journal
Hum Mol Genet 10:1215-20 (2001)
DOI:10.1093/hmg/10.11.1215
Reference
  Authors
Franz WM, Muller OJ, Katus HA
  Title
Cardiomyopathies: from genetics to the prospect of treatment.
  Journal
Lancet 358:1627-37 (2001)
DOI:10.1016/S0140-6736(01)06657-0
Reference
  Authors
Morimoto S
  Title
Sarcomeric proteins and inherited cardiomyopathies.
  Journal
Cardiovasc Res 77:659-66 (2008)
DOI:10.1093/cvr/cvm084
Reference
  Authors
Cambronero F, Marin F, Roldan V, Hernandez-Romero D, Valdes M, Lip GY
  Title
Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis.
  Journal
Eur Heart J 30:139-51 (2009)
DOI:10.1093/eurheartj/ehn538
Reference
  Authors
Towbin JA, Bowles NE
  Title
The failing heart.
  Journal
Nature 415:227-33 (2002)
DOI:10.1038/415227a
Reference
  Authors
Sorajja P, Elliott PM, McKenna WJ
  Title
The molecular genetics of hypertrophic cardiomyopathy: prognostic implications.
  Journal
Europace 2:4-14 (2000)
DOI:10.1053/eupc.1999.0067
Reference
  Authors
Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ
  Title
Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.
  Journal
J Mol Cell Cardiol 45:281-8 (2008)
DOI:10.1016/j.yjmcc.2008.05.003
KO pathway
ko05410   

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