Goals and Objectives:
- Briefly define dilated cardiomyopathy (DCM) and explain the major presenting
symptoms
- Describe the genetics and various modes of transmission with DCM
- Describe the idiopathic and nonidiopathic causes of DCM
-Be able to clinically manage patients with DCM
Case Study:
You are a third year medical student asked to do a history and physical on
a 30 year-old patient presenting with 3-month history of palpitations and
shortness of breath. Family history is significant for sudden death in a
maternal uncle at a young age. Physical examination reveals a heart murmur.
An electrocardiogram and an echocardiogram are ordered; these tests reveal
that the patient likely has dilated cardiomyopathy.
Pretest Questions:
- What are the features of DCM?
- What type of murmur would you expect to hear?
- What are nonidiopathic causes of DCM?
- What are idiopathic causes of DCM?
- What are the different modes of transmission of familial DCM?
- What stages have been described in the Autosomal dominant form of this
disease?
- What are the diagnostic criteria for familial DCM?
- Is genetic testing needed for a patient found to have DCM? What more needs
to be done?
 What
is the clinical management of these patients?
Answers:
- What are the features of DCM?
Dilated cardiomyopathy, which is characterized by cardiac dilation and reduced
systolic function, represents an outcome of a heterogeneous group of inherited
and acquired disorders. The earliest sign of the
disease most often seen is arrhythmia and/or conduction defects. Symptoms of
pump failure usually are seen in adulthood, in the twenties or thirties. Patients
often present with fatigue, dyspnea on exertion, shortness of breath, orthopnea,
paroxysmal nocturnal dyspnea, and edema—symptoms of right heart failure.
On physical exam one would expect to see signs of heart failure and volume
overload—tachypnea, tachycardia, hypertension, jugular venous distension
(JVD), pulmonary edema (crackles and/or wheezes), S3 gallop, enlarged liver
or hepatojugular reflex, and peripheral edema.
- What type of murmur would you expect to hear?
One would expect to hear I/VI-VI/VI holosystolic murmur as a result of mitral
valve insufficiency secondary to the dilated ventricles.
- What are nonidiopathic causes of DCM?
Causes range from a wide variety of acute diseases, chronic diseases, and
toxins. Some include: alcohol, drugs (heavy metals, emetine, doxorubicin, cocaine,
methamphetamine, cobalt), infections (HIV, viral endocarditis, parasites, protozoa,
Chagas disease), high output states (anemia, thyrotoxicosis, pregnancy), collagen
vascular disease, glycogen storage disease, thiamine deficiency, zinc deficiency,
hypophosphatemia, amyloidosis, and neuromuscular disorders
- What are idiopathic causes of DCM?
Idiopathic DCM causes approximately one-half of all DCMs. Prevalence occurs
up to 36.5 per 100,000 and accounts for more than 10,000 deaths in the U.S.
annually. It is also the primary indication for cardiac transplantation. Among
cases of idiopathic DCM, familial occurrence accounts for 30%, according to
surveys. Gene studies have shown isolated DCM to have resulted from mutations
in the dystrophin gene. This familial DCM is characterized by an Autosomal
dominant pattern of inheritance with age-related penetrance. These patients
present with development of ventricular dilatation and systolic dysfunction
usually in the second or third decade of life.
- What are the different modes of transmission of familial DCM?
- Autosomal Dominant (AD)
Genes associated
with AD transmission include: those encoding actin, lamin A/C (CMD1A), and
desmin (all cytoskeletal proteins). Mutations are also observed in genes that
produce sarcomere protein, alpha-tropomyosin, cardiac troponin T, and cardiac
troponin C. These patients tend to develop early-onset ventricular dilation
and dysfunction. Additionally, multiple other loci, designated CMD1B-J, have
also been identified as causing DCM transmitted as an AD trait.
AD DCM can present with or without
an associated conduction system disease. DCM without conduction system disease has been associated
with mutations at loci on chromosomes 1q32, 9q13-22, 10q21-23, and 2q31 (CMD1G). These abnormalities
are associated with early-onset and rapidly progressive HF, but may fail to penetrate in some individuals
who are carriers. Multiple candidate genes have been identified at some of these loci, but neither
disease genes nor mutations have been defined in all cases. However, several genes have been identified:
mutation in the gene encoding for the giant-muscle filament titin (2q31 (CMD1G)), the delta-sarcoglycan
gene (a member of the dystrophin-associated protein complex), and the gene for phospholamban.
DCM with conduction system disease
is associated with mutations in the gene on chromosome 1p1-q21 that encodes for the nuclear-envelope
proteins lamin A and lamin C . Symptoms can range from HF and sudden death to cardiomyopathy with mild
skeletal abnormalities. Mutations in the lamin A/C gene can also cause Emery-Dreifuss muscular dystrophy,
a childhood-onset disease characterized by joint contractures and abnormalities of conduction in adults.
Other mutations associated with conduction disease include genes at chromosome 3p22-25 loci (cardiac
sodium channel gene (SCN5A)), chromosome 1p1-1q1 (gap junction protein connexin 40), an unidentified
gene on chromosome 19q13.2-13.3 (encodes myotonin protein kinase), and a gene on chromosome 6q23 (CMD1F).
- Autosomal Recessive (AR)
Genes associated
with AR transmission include mutations in the ALMS1 gene on chromosome 2p13.
This mutation is also associated with Alstrom syndrome, which causes a dilated
cardiomyopathy and hearing impairment in association with cone-rod ocular dystrophy,
obesity, and type 2 diabetes. A family with Autosomal recessive dilated cardiomyopathy
has been reported to have a mutation in the gene for cardiac troponin I.
- X-linked
Dystrophin
gene mutations — Familial dilated cardiomyopathy
that is transmitted as an X-linked trait most often results from mutations
in the dystrophin gene (Xp21), especially in the 5’ muscle promoter,
which can cause a predominant cardiac phenotype. Most dystrophin mutations
produce either Duchenne or Becker muscular dystrophy, both of which are associated
with cardiac involvement. Skeletal muscle biopsies of individuals with X-linked
dilated cardiomyopathy due to dystrophin deletions demonstrate the classic
pathologic changes of Duchenne or Becker dystrophies, but the muscle manifestations
may be subclinical. Absence of, versus reduction in, dystrophin has been
hypothesized to account for the variable dysfunction observed in cardiac
compared with skeletal muscle. One study of a family with X-linked cardiomyopathy,
without skeletal muscle abnormalities, found that all affected family members
had a translation-termination mutation (C4148T) in exon 29 of the dystrophin
gene. This mutation was associated with a reduction of beta-sarcoglycan and
delta-sarcoglycan in the sarcolemma of cardiac, but not skeletal, muscle.
- What stages have been described in the Autosomal dominant form
of this disease?
Stage I occurs in the second and third decades and is characterized by absence
of symptoms, normal heart size, sinus bradycardia, and premature atrial contractions.
Stage II is marked by first-degree AV block in the third and fourth decades.
Stage III occurs in the fourth and fifth decades and is accompanied by chest
pain, fatigue, lightheadedness, and advanced AV block, followed by the development
of atrial fibrillation or flutter. Stage IV occurs in the fifth and sixth decades
of life, and is characterized by congestive heart failure and recurrent ventricular
arrhythmias.
- What is the diagnostic criteria for familial DCM?
One individual diagnosed with idiopathic DCM in a family, with at least:
=>One relative also diagnosed with idiopathic DCM
-Or-
=>One first-degree relative with an unexplained sudden death under the age
of 35 years.
8. Is genetic testing needed for a patient found
to have DCM? What more needs to be done?
Family history should be reviewed in all patients with DCM, especially in those
patients who present before the age of 60. Further investigation of relatives
should be performed if there are cases of unexplained heart disease, sudden
unexpected death, or syncopal episodes. Investigation can be as simple and
noninvasive as echocardiography. Early diagnosis is indicated for 2 reasons:
treatment of significant arrhythmias may prevent sudden unexpected death, and
genetic counseling can be provided. Studies have shown that the familial form
of dilated cardiomyopathy is more malignant, occurring at an earlier age, and
progressing more rapidly. Thus it is imperative that all patients with this
disease have their family members be tested and followed--The 2005 American
College of Cardiology/American Heart Association heart failure guidelines concluded
that the weight of evidence supported the efficacy (class IIa) of screening
asymptomatic first-degree relatives with an electrocardiogram and echocardiography
and that families with a highly positive family history should be referred
to a cardiovascular genetics center [19].
9. What is the clinical management of these patients?
Management for these patients is based on symptoms and what is found during
testing. For those with progressive conduction block and sinus block,
pacemaker implantation is indicated. However, studies have shown that patients
with dilated cardiomyopathy associated with the lamin A/C mutation are better
treated with implantable cardioverter-defibrillators (ICD) compared to the
standard pacemaker to prevent lethal tachyarrhythmias.
Resources for patients:
American Heart Association
National Center
7272 Greenville Avenue
Dallas, TX 75231
Phone: 1-800-AHA-USA-1
http://www.americanheart.org/presenter.jhtml?identifier=4468
Texas Heart Institute
St. Luke's Episcopal Hospital
6720 Bertner Ave.
Houston, TX 77030
Phone: 832-355-4011
http://www.texasheart.org/HIC/Topics/Cond/dilated.cfm
Cardiomyopathy Association
40 The Metro Centre
Tolpits Lane
Watford Herts WD18 9SB
United Kingdom
Phone: (+44) 1923 249 977
Fax: (+ 44) 1923 249 987
Email: info@cardiomyopathy.org
www.cardiomyopathy.org
Citations:
OMIM
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=115200
Hunt, SA, Abraham, WT, Chin, MH, et al. ACC/AHA 2005 Guideline Update for
the Diagnosis and Management of Chronic Heart Failure in the Adult: a report
of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for
the Evaluation and Management of Heart Failure): developed in collaboration
with the American College of Chest Physicians and the International Society
for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation
2005; 112:e154.
McKenna W. Genetics of dilated cardiomyopathy. Retrieved
August 21, 2006 at http://www.utdol.com/utd/content/topic.do?topicKey=myoperic/10134&type=A&selectedTitle=1~5
Mestroni L, Maisch B, McKenna WJ, et al. Guidelines for the study of familial
dilated cardiomyopathies. Eur Heart J. 1999; 20: 93–102.
Ku L, Feiger J, Taylor M, Mestroni L. Familial dilated cardiomyopathy. American
Heart Association. Retrieved August 21, 2006 at http://circ.ahajournals.org/cgi/content/full/108/17/e118#FIG1
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