RT Book, Section
A1 Seidman, Christine E.
A1 Seidman, J. G.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181476540
T1 Hypertrophic Cardiomyopathy
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181476540
RD 2024/04/19
AB Hypertrophic  cardiomyopathy  is  a  primary  disorder  of  ventricular  muscle  characterized  by  myocardial  and  myocyte  hypertrophy.  Disease  penetrance  and  clinical  manifestations  vary  considerably;  some  affected  individuals  lack  symptoms,  but  most  develop  angina,  dyspnea,  and  exercise  intolerance.  Sudden  death,  heart  failure,  and  thromboembolic  events  account  for  the  significant  morbidity  and  mortality  of  hypertrophic  cardiomyopathy.Clinical  diagnosis  is  based  on  family  history,  physical  exam,  electrocardiogram,  and  two-dimensional  echocardiography  demonstrating  unexplained  ventricular  hypertrophy  (wall  thickness  >13  to  15  mm  in  the  absence  of  confounding  factors  such  valvular  heart  disease  or  hypertension).Hypertrophic  cardiomyopathy  can  occur  as  isolated  (sporadic)  disease,  but  most  often  is  inherited  as  an  autosomal  dominant  trait  (termed  familial  hypertrophic  cardiomyopathy).Cardiac  pathology  demonstrates  increases  in  myocardial  mass,  predominantly  affecting  the  left  ventricle.  Although  a  variety  of  morphologic  forms  of  hypertrophy  are  recognized,  asymmetric  involvement  of  the  septum  is  most  common.  Histologic  findings  include  enlarged  disorganized  myocytes  (disarray)  interspersed  with  connective  tissue  and  fibrosis.The  pathophysiology  of  hypertrophic  cardiomyopathy  is  characterized  by  normal  or  hyperdynamic  systolic  function  and  impaired  diastolic  performance.  Subaortic  outflow  tract  gradients,  systolic  motion  of  the  anterior  mitral  valve  leaflet,  and  mitral  regurgitation  occur  in  a  subset  of  affected  individuals.Familial  or  sporadic  hypertrophic  cardiomyopathy  is  caused  by  mutations  in  one  of  eight  different  sarcomere  protein  genes:  cardiac  actin;  β-cardiac  myosin  heavy  chain;  α-tropomyosin;  cardiac  troponin  T;  cardiac  troponin  I;  essential  myosin  light  chain;  regulatory  myosin  light  chain;  and  cardiac  myosin-binding  protein  C.  At  least  one  other  disease  gene  (mapped  to  chromosome  7)  remains  unknown.Distinct  genetic  etiologies  of  hypertrophic  cardiomyopathy  account  for  some  of  the  variable  clinical  findings  of  disease,  including  age  of  onset  of  hypertrophy  and  survival.Hypertrophic  cardiomyopathy  mutations  rarely  produce  null  alleles,  but  rather  encode  mutant  polypeptides  that  are  likely  to  be  incorporated  into  sarcomeres.  The  predominant  mechanism  by  which  disease  alleles  perturb  cardiac  function  therefore  appears  to  be  through  dominant  negative  actions  by  mutant  polypeptides.Hypertrophic  cardiomyopathy  mutations  have  been  genetically  engineered  into  animals  to  produce  relevant  models  for  exploring  the  mechanisms  of  disease  and  consequences  of  protein  mutations  on  sarcomere  structure  and  function.