Course:MEDG550/Student Activities/HCM

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A normal (top) and hypertrophied (bottom) heart. In HCM, the heart muscle in the lower left chamber of the heart becomes thickened, affecting the heart's ability to pump properly[1].

Hypertrophic cardiomyopathy (HCM) is a heart condition where a part of the heart muscle (myocardium) becomes thickened (hypertrophied), which can sometimes cause dangerous heart rhythms (also known as arrhythmias)[1]. Thickening most commonly occurs in the left ventricle (the lower chamber on the left side of the heart)[1]. This thickening can then affect the heart's ability to pump effectively, causing abnormal heart rhythms that can result in heart failure and sudden cardiac death[1].

Clinical Features

The presentation of HCM is highly variable, even within families. Many people with HCM may never develop signs or symptoms of the condition. The severity of symptoms ranges from absent or mild to severe (such as in cases of heart failure or sudden cardiac death), and is usually delayed into adulthood.

Common symptoms of HCM include:

  • Shortness of breath
  • Chest pain
  • Lightheadedness
  • Exercise intolerance
  • Skipping or fluttering sensations in the chest (palpitations)
  • Sudden loss of consciousness or fainting (syncope)

With progressively worse thickening of the heart muscle, the severity of symptoms increases and begins earlier in life[1][2]. In rare cases, sudden cardiac arrest or sudden cardiac death can be the first presentation of the condition[1][2].

Diagnosis and Classification

HCM is diagnosed based on otherwise unexplained thickening of the lower left chamber of the heart, identified by cardiac imaging techniques, such as echocardiogram or cardiac MRI (see below)[2]. A thickness of 15 mm or more, or of 13 mm or more with a family history, is diagnostic of HCM[2][3].

  • Echocardiogram – An ultrasound of the heart to identify the thickness of the heart muscle and the area of the heart where the thickening occurs.
  • Cardiac magnetic resonance imaging (CMR) – An MRI of the heart to assess the function and structure fo the heart with a better resolution than an echocardiogram. Individuals with electronic heart devices like pacemakers and defibrillators may not be eligible for CMRs due to safety concerns.
  • Autopsy – Unfortunately, sometimes HCM is only diagnosed after an individual has suffered a sudden cardiac death. Autopsy results may show thickening of the heart muscle.

HCM can be classified as obstructive or non-obstructive using the above cardiac imaging techniques[3]:

  • Hypertrophic obstructive cardiomyopathy (HOCM) – Thickening of the heart muscle causes obstruction of the outflow of blood from the lower left chamber of the heart.
  • Non-obstructive HCM (also known as Apical HCM) – Thickening of the heart muscle occurs at the lower tip of the left chamber and does not cause obstruction of the outflow of blood.

The differential diagnoses of HCM includes acquired or secondary left ventricular hypertrophy (LVH) and syndromic HCM[3]:

Management

There is currently no cure for HCM but there are medical management options for at-risk individuals and those who have signs and symptoms of HCM.

  • Surveillance and screening – Asymptomatic individuals with a family history of HCM are recommended to have cardiac screening every 12-18 months (from ages 12-18) or at least every five years (after the age of 18)[2][3]. Cardiac screening involves an echocardiogram to assess the thickness of the heart muscle and an electrocardiogram (ECG) that records the electrical activity of the heart. Because HCM can cause abnormal heart rhythms, ECGs are used to monitor possible arrhythmias that may develop. Individuals in competitive athletics should be monitored more often and screened for risk factors of sudden cardiac death[2].
  • Medications – Primarily aims to relieve symptoms of HCM and control abnormal heart rhythms. Beta-blockers are commonly prescribed to lower the heart rate (by reducing the effect of adrenaline on the heart) and decrease the chance of developing abnormal heart rhythms[2].
  • Surgical septal myectomy – An operation that is done to reduce symptoms in severely affected people with obstructive HCM[2]. It involves the surgical removal of the thickened heart muscle to decrease obstruction and improve blood flow.
  • Alcohol septal ablation – A non-surgical technique that uses a catheter to deliver an injection of alcohol into the heart muscle to destroy some of the thickened muscle and replace it with thinner scar tissue[2]. This technique is used to relieve symptoms in individuals with obstructive HCM and improve blood flow.
  • Implantable cardioverter-defibrillator (ICD) – A device that is implanted in the body to monitor the heart rhythm and deliver shocks in the event of a dangerous heart rhythm to reset the heart's pacing[2]. ICDs are more commonly implanted in individuals at risk for sudden cardiac death.
  • Heart transplantation – An option for individuals that have exhausted all other forms of treatment or those who have progressed to end-stage heart failure[2].

Genetics

In most cases, HCM is caused by changes in genes (also called variants) that are important for regulating the structure and function of the heart. Genes are segments of genetic information (or DNA) that provide instructions for how cells in the body should function. There are at least 9 genes that are associated with HCM and more than 1400 changes in these genes have been identified[4]. Changes in these genes are found in 50-60% of individuals with a family history of HCM and 20-30% of individuals without a family history of HCM[3].

Gene Name (Symbol) Prevalence[4][3]
Myosin Binding Protein C, Cardiac (MYBPC3) 50%
Myosin Heavy Chain 7 (MYH7) 33%
Troponin I3 (TNNI3) 5%
Troponin T2, Cardiac Type (TNNT2) 4%
Actin Alpha Cardiac Muscle 1 (ACTC1) <3%
Myosin Light Chain 2 (MYL2) <3%
Myosin Light Chain 3 (MYL3) <3%
Tropomyosin 1 (TPM1) <3%
Phospholamban (PLN) <3%

Prevalence

HCM affects an estimated 1 in 500 people worldwide in the general population[5]. HCM affects both men and women equally and people of all ages[5].

Inheritance

Autosomal dominant inheritance. An affected parent has a 50% chance of passing on the gene change to each of child, assuming the other parent is unaffected.

Autosomal Dominant

Humans have two copies of every gene, one inherited from each parent. HCM is typically inherited in an autosomal dominant manner, which means that an individual only needs a change in one copy of the gene to be at increased risk of developing HCM. This gene change could have been inherited from either parent or could have occurred randomly for the first time during fertilization. This individual then has a 50% of passing on that same gene change to all of their children.

First-degree relatives (parents, children, and siblings) of an affected individual with an identified gene change are also at 50% risk of carrying the same gene change and are recommended to receive cardiac screening. First-degree relatives are also eligible for genetic testing (see below) for the specific gene change identified in the affected individual.

Genetic Counselling

HCM is a condition with a genetic basis and genetic counselling can help individuals and families affected by or are at-risk of developing HCM learn about their genetic testing options and what HCM looks like in the context of their family. Genetic counsellors and cardiologists work together to collect and assess the individual's family and medical history and help facilitate decision making regarding appropriate genetic testing and treatment options.

Genetic Testing

Because HCM is diagnosed using cardiac imaging techniques, genetic testing is primarily used as a clinical tool for identifying at-risk first-degree relatives of an affected individual[6]. First-degree relatives who test negative for the familial gene change are not at increased risk of developing HCM and can be discharged from cardiac monitoring[6]. Genetic testing results do not affect the medical management of the affected individual and is not recommended for the purpose of risk stratification and treatment decisions[6]. Genetic testing is also not recommended for the purpose of confirming the diagnosis if there are no other at-risk first-degree relatives.[6]

Genetic testing involves providing a blood or a saliva sample which is analyzed for changes in the genes associated with HCM. When possible, testing is initiated in the most affected family member. Genetic testing can involve a panel that looks at many HCM-associated genes and there are three possible results from this type of genetic test:

  • A positive result means a disease-causing or likely disease-causing change was found in one of the HCM-associated genes. Approximately 50-60% of HCM patients with a family history will test positive. Targeted genetic testing can then be offered to first-degree relatives to look specifically for the gene change found in the affected individual. The results of targeted genetic testing will either be positive or negative for the specific gene change in the family.
  • A negative result means no disease-causing or likely disease-causing change was found in any of the HCM-associated genes. A negative result does not rule out the diagnosis for the affected individual and does not change their medical management. An affected individual could test negative and still have an inherited form of HCM because the available genetic tests are not exhaustive of all genes that could contribute to HCM. A negative result means that genetic testing is not available for first-degree relatives but they should undergo cardiac screening.
  • A variant of uncertain significance (VUS) means that a change was found in an HCM-associated gene, but it is unknown at this time whether or not this gene change is disease-causing. Individuals with a VUS and their first-degree relatives are recommended to be followed by a cardiologist and undergo cardiac screening. In most circumstances, genetic testing is not available for first-degree relatives of individuals with a VUS, unless there is sufficient evidence that the VUS is likely to be explanatory for the individual's HCM in the context of their family and medical history.

Living with HCM

Genetic counsellors can also provide resources and education for individuals affected with HCM. Common topics that are addressed are genetic discrimination, family communication of medical or genetic information, lifestyle changes, and family planning[7][8]. In families where disease-causing mutations have been identified, there is a possibility of prenatal diagnosis of HCM, though it is very rarely indicated because of the variability in expression and delayed onset of symptoms[8]. A genetic counsellor is a genetics expert that can facilitate these discussions as they pertain to the individual's specific circumstances.

Patient Resources

For more information about HCM, visit:

For patient support groups, visit:

To find a genetics specialist, please visit www.cagc-accg.ca (Canada) or www.nsgc.org (United States).

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Maron, B. J., & Maron, M. S. (2013). Hypertrophic Cardiomyopathy. The Lancet, 381, 242-255. doi: 10.1016/S0140-6736(12)60397-3.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Gersh, B. J., Maron, B. J., Bonow, R. O., Dearani, J. A., Fifer, M. A., Link, M. S., ... Yancy, C. W. (2011). 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 124, 2761-2796. doi: 10.1161/CIR.0b013e318223e230.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Cirino, A. L., & Ho, C. (2008). Hypertrophic Cardiomyopathy Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1768/.
  4. ↑ 4.0 4.1 Alfares, A. A., Kelly, M. A., McDermott, G., Funke, B. H., Lebo, M. S., Baxter B. S., ... Rehm, H. L. (2015). Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genetics in Medicine, 17, 880-888. doi: 10.1038/gim.2014.205.
  5. ↑ 5.0 5.1 Maron, B. J., Gardin, J. M., Flack, J. M., Gidding, S. S., Kurosaki, T. T., & Bild, D. E. (1995). Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation, 92, 785-789. doi: 10.1161/01.cir.92.4.785.
  6. ↑ 6.0 6.1 6.2 6.3 Gollob, M. H., Blier, L., Brugada, R., Champagne, J., Chauhan, V., Connors, S., ... Woo, A. (2011). Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated with Sudden Cardiac Death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Paper. Canadian Journal of Cardiology, 27, 232-245. doi: 10.1016/j.cjca.2010.12.078.
  7. ↑ Michels, M., Hoedemaekers, Y. M., Kofflard, M. J., Frohn-Mulder, I., Dooijes, D., Majoor-Krakauer, D., & Ten Cate, F. J. (2007). Familial screening and genetic counselling in hypertrophic cardiomyopathy: the Rotterdam experience. Netherlands Heart Journal, 15, 184-190. doi: 10.1007/bf03085978.
  8. ↑ 8.0 8.1 Voseberg, H. P. (2000). Genetic counselling for hypertrophic cardiomyopathy: are we ready for it? Current Control Trials in Cardiovascular Medicine, 1, 41-44. doi: 10.1186/cvm-1-1-041.
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