The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Narrative Review: Harnessing Molecular Genetics for the Diagnosis and Management of Hypertrophic Cardiomyopathy

Libin Wang, MD, PhD; Jonathan G. Seidman, PhD; and Christine E. Seidman, MD
[+] Article, Author, and Disclosure Information

From Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts.

Grant Support: In part by grants from the Howard Hughes Medical Institute (Dr. C.E. Seidman) and the National Institutes of Health (Drs. J.G. and C.E. Seidman).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1230.

Requests for Single Reprints: Christine E. Seidman, MD, Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Louis Pasteur Avenue, Boston, MA 02115; e-mail, cseidman@genetics.med.harvard.edu.

Current Author Addresses: Dr. Wang: Department of Internal Medicine, Jackson Memorial Hospital, University of Miami, 1400 Northwest 12th Avenue, Miami, FL 33130.

Drs. J.G. Seidman and C.E. Seidman: Department of Genetics, Harvard Medical School, Room 256 NRB, 77 Louis Pasteur Avenue, Boston, MA 02115.

Author Contributions: Analysis and interpretation of the data: L. Wang, J.G. Seidman, C.E. Seidman.

Drafting of the article: L. Wang, J.G. Seidman, C.E. Seidman.

Critical revision of the article for important intellectual content: L. Wang, C.E. Seidman.

Final approval of the article: C.E. Seidman.

Statistical expertise: J.G. Seidman.

Obtaining of funding: C.E. Seidman, J.G. Seidman.

Administrative, technical, or logistic support: C.E. Seidman.

Collection and assembly of data: L. Wang, C.E. Seidman.

Ann Intern Med. 2010;152(8):513-520. doi:10.7326/0003-4819-152-8-201004200-00008
Text Size: A A A

Unexplained cardiac hypertrophy, the diagnostic criterion for hypertrophic cardiomyopathy (HCM), occurs in 1 in 500 adults. Insights into the genetic cause and molecular pathophysiology of HCM are reshaping clinical paradigms for diagnosis and treatment of this common myocardial disorder. Human genetic studies have established that dominant mutations in the proteins that make up the contractile apparatus (the sarcomere) cause HCM. With the current availability of clinical gene-based diagnostics, pathogenic mutations in affected patients can be defined, which can suggest a clinical course and allow definitive preclinical identification of family members at risk for HCM. Genetic discoveries have also fos-tered mechanistic investigations in model organisms that are engineered to carry human HCM mutations. Novel therapeutic targets have emerged from these fundamental studies and are currently under clinical assessment in humans. The combination of contemporary gene-based diagnosis with new strategies to attenuate disease development and progression is changing the natural history of lifelong cardiac symptoms, arrhythmias, and heart failure from HCM.


Grahic Jump Location
Figure 1.
Remodeling in HCM.

The mass of the normal myocardium (A) is increased in HCM because of ventricular hypertrophy, which can be asymmetrical (B), concentric (C), or focal (not shown). Diastolic dysfunction in HCM leads to atrial enlargement and increases risk for atrial clots (C), an important cause of thromboembolic events in HCM. The normal myocyte histology (D) is perturbed in HCM, with marked enlargement and disarray of myocytes (E) (hematoxylin–eosin staining). Masson trichrome staining (F) reveals increased amounts of interstitial fibrosis (blue). HCM = hypertrophic cardiomyopathy.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Pedigree analysis of a family with HCM reveals autosomal dominant inheritance and age-related penetrance.

Symbols denote sex (square, male; circle, female) and clinical status (solid, HCM; open, unaffected; slashed, deceased; green, status unknown). Analyses of the DNA of sarcomere genes (Table) identified a causal mutation in the β-myosin heavy-chain gene in the proband (arrow), which allowed gene-based diagnosis of all family members. The same mutation was found in adults with clinical evidence of HCM (+) but was absent in unaffected adults (−). Note that 5 children have preclinical HCM: They carry the β-myosin heavy-chain mutation but have no evidence of disease. HCM = hypertrophic cardiomyopathy.

Grahic Jump Location
Grahic Jump Location
Figure 3.
HCM remodeling pathways.

Ca2+ enters the myocyte through the voltage-gated L-type Ca2+ channel and triggers CICR. Ca2+ is released from the SR through the RyR2 complexes comprising cardiac ryanodine receptor, calsequestrin, junctin, triadin, and sorcin. When one contractile protein in the sarcomere carries an HCM mutation (red stars), sarcomere contractility increases and relaxation diminishes. This results in abnormal Ca2+ cycling with slower Ca2+ reuptake of the SR by the SERCA pump and reduced Ca2+ content in the SR (blue arrows). Abnormal Ca2+ cytosolic concentration and mechanical dynamics of the mutant sarcomere stimulate signaling pathways in the nucleus that promote myocyte growth, premature myocyte death, and increased myocardial fibrosis. In model organisms that carry a human HCM mutation, early normalization of Ca2+ handling during the preclinical phase of disease attenuated the subsequent development of hypertrophy and fibrosis. CICR = Ca2+-induced Ca2+ release; HCM = hypertrophic cardiomyopathy; RyR2 = cardiac ryanodine receptor; SERCA = sarco/endoplasmic reticulum Ca2+–adenosine triphosphatase; SR = sarcoplasmic reticulum.

Grahic Jump Location




CME Activities are only available to ACP members and Individual Annals subscribers. If you are a member or a subscriber please sign in. Otherwise please become a member or subscribe to Annals.
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Journal Club
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.