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Last updated: 7/18/2024
Years published: 2024
NORD gratefully acknowledges Milind Desai, MD MBA FACC FAHA FESC, Haslam Family Endowed Chair in CV Medicine, Professor of Medicine, CCLCM, Vice Chair, Education, Heart Vascular Thoracic Institute, Co-Director, CV Imaging Laboratories (CT and CMR), Director, HCM Center, Medical Director, Aorta Center Director, Clinical Operations, Department of Cardiovascular Medicine Cleveland Clinic, for assistance in the preparation of this report.
Summary
Hypertrophic cardiomyopathy (HCM) is a progressive, genetic disease that results in excessive thickening of the heart muscle, not explained by other causes, affecting the size and function of the heart. Approximately 70% of HCM patients have obstruction of the flow of blood outside the heart and this is called obstructive HCM (oHCM), while the rest do not have obstruction, and this is called nonobstructive HCM (nHCM). In addition, the heart becomes stiff and less flexible. This causes the heart to beat harder than usual without relaxing in between beats. The symptoms of oCHM can be different from person to person, and many people with oHCM have no symptoms. When symptoms are present, the most common include breathlessness, heart palpitations, chest pain, tiredness and dizziness. Often, such symptoms become worse due to dehydration or after heavy meals. Over time, some patients with oHCM may develop congestive heart failure. Sudden death due to an irregular heartbeat is a rare complication of oHCM.
Both oHCM and nHCM can be caused by changes (disease-causing variants) in certain genes. There are currently 11 genes known to be involved in the development of the heart muscle that affect how the heart contracts. Variants in two of these genes, MYBPC3 and MYH7, account for about 80% of HCM. HCM follows an autosomal dominant pattern in families. Diagnosis is based on symptoms, imaging studies of the heart and genetic testing. Treatment for oHCM is focused on managing the symptoms and includes medications and invasive procedures (surgical myectomy or alcohol septal ablation). For symptomatic individuals with oHCM, the U.S. Food and Drug Administration (FDA) has approved the drug mavacamten (Camzyos) that acts directly on the defect in cardiac muscle cells, allowing the heart to beat more normally. In clinical trials, it has been shown to help oHCM patients improve their symptoms and exercise capacity. In oHCM patients with advanced symptoms, it has also been shown to reduce the need for surgery or to delay or avoid invasive procedures.
Introduction
Hypertrophic cardiomyopathy was first described in the early 1960s. HCM is part of a group of conditions known as cardiomyopathies which are disorders of the heart muscle. HCM is the most common inherited form of cardiomyopathy.
Heart structure and function
The job of the heart is to act as a pump moving blood with oxygen and nutrients throughout the body. The normal heart has four chambers: a left and right atrium which are located on top of the heart, and a left and right ventricle which are located below the atria. The ventricles act as the main pump of the heart. In the normal heart, the atria are separated from the ventricles by valves that allow blood to flow in only one direction. The heartbeat and rhythm are controlled by an electrical system that keeps the rhythm even and signals the heart to speed up or slow down in response to the bodyโs needs. Blood flows through the body in a circular path moving through the lungs and heart. The steps are as follows:
The type and severity of symptoms of oHCM may be very different from person to person, even within the same family. Many people with oHCM have few or no symptoms. The first symptoms of oHCM can appear at any age, but most often start in early adulthood. Symptoms are often mild but may get worse over time. Sometimes symptoms get worse very quickly, while in others, symptoms progress slowly or not at all. The age at which symptoms start to get worse can also vary from person to person.
For most people, the first symptoms of oHCM start in late adolescence or early adulthood and may include:
Less common symptoms include:
About 5-10% of people with hypertrophic cardiomyopathy will have complications that get worse over time. Complications may include:
Females are at higher risk for complications of hypertrophic cardiomyopathy than males and tend to get diagnosed at a later age. oHCM was once thought to be a significant cause of sudden death, but due to advancements in treatment, people with this condition can live a normal lifespan. In rare cases, the first symptom of oHCM is a serious cardiac event that leads to sudden death.
The signs and symptoms of oHCM occur because of changes to heart structure and function. In oHCM, the heart muscle is typically excessively thickened. The thickening of the septum (muscular wall between the 2 ventricles) can result in obstruction to the flow of blood outside the heart leading to less oxygenated blood to the whole body. In addition, there is a phenomenon called systolic anterior motion of the mitral valve (SAM) that occurs at the same time. SAM further compounds the problem by adding to the obstruction of blood flow and leaking of the mitral valve (mitral regurgitation). In addition, there is also evidence of progressive scarring of the thickened muscle, along with increased stiffness and inability to relax. As a result, the ventricles donโt fill up with blood properly and blood backs up in the other organs. The left atrium may also increase in size to compensate for increased stiffness in the left ventricle. In addition, there is progressive scarring of the heart muscle which increases the risk of abnormal heart rhythm predisposing patients to increased risk of sudden death.
Based on current knowledge, oHCM can be caused by changes (pathogenic variants) in 11 different genes. Variants in any one of these genes disrupt the formation of the cells of the heart wall, impacting the way the heart muscle contracts. This leads to thickening of the wall between the two ventricles, eventually blocking blood flow out of the heart. About 80% of people with HCM have a disease-causing variant in the MYBPC3 or MYH7 gene.
oHCM follows autosomal dominant inheritance in families. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Dominant disorders can vary in severity from person to person. Sometimes, someone who inherits a disease-causing gene variant for a dominant condition will not have any symptoms of the condition but can still pass it on to a child who may have symptoms. Currently, gene variants can be identified in 35-40% HCM patients, and the rest have no identifiable variant or have a variant that may or may not be associated with HCM (variant of uncertain significance).
Hypertrophic cardiomyopathy (HCM) affects between 1/200 to 1/500 people. It has been diagnosed equally in males and females and in all ethnic and racial groups. It has been estimated that there are at least 750,000 people in the United States with HCM and about 15-20 million people with HCM worldwide. Because people with HCM often do not have obvious symptoms, it is thought that only 10% of people with HCM get diagnosed. In a large study using a national database of private insurance claims, the authors found that the prevalence of oHCM was 1.65 per 10,000 individuals in 2016 and remained fairly stable over the 3-year time period.
oHCM is diagnosed based on the symptoms, clinical examination, a detailed family history, laboratory testing and imaging of the heart. Because the symptoms of hypertrophic cardiomyopathy look the same as the symptoms of other more common conditions such as high blood pressure, anxiety or asthma, these more common conditions need to be excluded before a diagnosis of hypertrophic cardiomyopathy can be made. The most useful tests for diagnosing oHCM are a special ultrasound of the heart known as an echocardiogram and a special type of MRI called cardiac magnetic resonance (CMR). Both echocardiogram and CMR look at the heart structure and function.
An echocardiogram is used to evaluate the function of the heart, along with wall thickness and mass of the heart. It is also used to evaluate the presence of obstruction to the flow of blood outside the heart, both at rest and with special maneuvers that mimic exertion. These include a Valsalva maneuver (bearing down against a closed breathing pipe) or by using a short acting drug like amyl nitrite. In some patients, a stress test is performed along with an echocardiogram to measure exercise capacity and obstruction to flow of blood. In addition, the mitral valve is evaluated for presence of a leak. Some advanced techniques like strain assessment and assessment of heart muscle stiffness are also typically performed. A CMR can be done to get a more precise measurement of wall thickness and cardiac mass, and to precisely measure scarring (fibrosis).
Genetic testing can also be helpful for making a diagnosis. A disease-causing gene variant is found in about 50-60% of patients with a family history of HCM and about 20-30% of patients without a family history. Testing often involves using a gene panel which allows the lab to look for variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations. In families with HCM, genetic testing can be especially important for identifying people who have HCM but do not have any symptoms.
There is currently no cure for oHCM. The treatment is based on managing the symptoms. For mild symptoms, initial treatment may include medications that slow down and reduce the force of heart contractions. Other medications can be used to reduce blood pressure and regulate the heartbeat. However, these medications have not been adequately proven in clinical trials designed specifically for oHCM patients. Lifestyle and diet changes may also be part of the treatment. Avoiding intense isometric exertion, dehydration and excessive alcohol intake is recommended. Based on current knowledge, aerobic exercise is not restricted, but in fact recommended. Maintaining an ideal body weight is helpful. Many patients also have sleep apnea and testing for and treating that condition is important.
Because of the risk of sudden cardiac death due to ventricular fibrillation, people diagnosed with HCM are often offered a subcutaneous or transvenous implantable cardioverter-defibrillator (ICD). This device is surgically implanted under the skin and monitors the heart rate. It delivers a shock when it detects an irregular heart rhythm (ventricular tachycardia or fibrillation), causing the heart to beat normally again. ICDs have greatly reduced the risk of sudden death in people with HCM.
Surgery is also an option for people with oHCM who have more serious symptoms. Options include a myectomy and alcohol septal ablation (ASA). Myectomy is a type of open-heart surgery that removes the thickened part of the muscle (the septum) between the left and right side of the heart. ASA is done by injecting alcohol into the blood vessel that supplies blood to the septum. This cuts off blood supply to a small part of the septum and reduces its ability to contract. Both procedures treat breathing problems and chest pain. ASA is less invasive and used more often in patients at a higher surgical risk. While these procedures are highly effective in relieving symptoms, they require significant expertise which is not uniformly available. As a result, there is an unmet need for better medical alternatives.
In 2022, mavacamten (Camzyos) was approved by the FDA to treat oHCM. This medication targets the underlying cause of oCHM and acts by allowing the heart muscle to relax and use energy more efficiently. In studies, it has been shown to reduce symptoms, improve exercise capacity and significantly reduce the need for invasive procedures. Data also suggests that it might positively impact the underlying structure of the heart by reducing mass and wall thickness. However, it can also result in abnormal reduction in cardiac function (left ventricular ejection fraction). As a result, currently it can only be prescribed under an FDA mandated Risk Evaluation and Mitigation Strategy (REMS) program. Treatment involves a daily pill and regular echocardiograms to check the heart function.
People with oHCM may need to see a variety of specialists including a cardiologist and a heart surgeon.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Bishev D, Fabara S, Loseke I, Alok A, Al-Ani H, Bazikian Y. Efficacy and safety of mavacamten in the treatment of hypertrophic cardiomyopathy: a systematic review. Heart Lung Circ. 2023;32(9):1049-1056. doi:10.1016/j.hlc.2023.05.019
Liu G, Su L, Lang M. A systematic review and meta-analysis of sex differences in clinical outcomes of hypertrophic cardiomyopathy. Front Cardiovasc Med. 2023;10:1252266. Published 2023 Dec 5. doi:10.3389/fcvm.2023.1252266
Mehra N, Ali AH, Desai MY. Obstructive hypertrophic cardiomyopathy: a review of new therapies. Future Cardiol. 2023;19(13):661-670. doi:10.2217/fca-2023-0056
Yokoyama Y, Shimoda T, Shimada YJ, et al. Alcohol septal ablation versus surgical septal myectomy of obstructive hypertrophic cardiomyopathy: systematic review and meta-analysis. Eur J Cardiothorac Surg. 2023;63(3):ezad043. doi:10.1093/ejcts/ezad043
Butzner M, Leslie DL, Cuffee Y, Hollenbeak CS, Sciamanna C, Abraham T. Stable rates of obstructive hypertrophic cardiomyopathy in a contemporary era. Front Cardiovasc Med. 2022;8:765876. Published 2022 Jan 6. doi:10.3389/fcvm.2021.765876
Lioncino M, Monda E, Verrillo F, et al. Hypertrophic cardiomyopathy in RASopathies: diagnosis, clinical characteristics, prognostic implications, and management. Heart Fail Clin. 2022;18(1):19-29. doi:10.1016/j.hfc.2021.07.004
Maron BJ, Desai MY, Nishimura RA, et al. Diagnosis and evaluation of hypertrophic cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):372-389. doi:10.1016/j.jacc.2021.12.002
Maron BJ, Desai MY, Nishimura RA, et al. Management of hypertrophic cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):390-414. doi:10.1016/j.jacc.2021.11.021
Maron BJ, Rowin EJ, Maron MS. Hypertrophic cardiomyopathy: new concepts and therapies. Annu Rev Med. 2022;73:363-375. doi:10.1146/annurev-med-042220-021539
Ciarambino T, Menna G, Sansone G, Giordano M. Cardiomyopathies: an overview. Int J Mol Sci. 2021;22(14):7722. Published 2021 Jul 19. doi:10.3390/ijms22147722
Antunes MO, Scudeler TL. Hypertrophic cardiomyopathy [published correction appears in Int J Cardiol Heart Vasc. 2020 Nov 18;31:100676]. Int J Cardiol Heart Vasc. 2020;27:100503. Published 2020 Mar 25. doi:10.1016/j.ijcha.2020.100503
Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25):e533-e557. doi:10.1161/CIR.0000000000000938
Teekakirikul P, Zhu W, Huang HC, Fung E. Hypertrophic cardiomyopathy: an overview of Genetics and Management. Biomolecules. 2019;9(12):878. Published 2019 Dec 16. doi:10.3390/biom9120878
INTERNET
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Hypertrophic cardiomyopathy. MedGen. National Library of Medicine, National Center for Biotechnology Information. Available from https://www.ncbi.nlm.nih.gov/medgen/2881 Accessed April 22, 2024.
Raj MA, Ranka S, Goyal A. Hypertrophic Obstructive Cardiomyopathy. [Updated 2022 Oct 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430820/ Accessed April 22, 2024.
Hypertrophic cardiomyopathy. MedlinePlus. 5/8/2022. Available from: https://medlineplus.gov/ency/article/000192.htm Accessed April 22, 2024.
Hypertrophic Cardiomyopathy (HCM) and Family Health History of Sudden Death. Centers for Disease Control, Genomics & Precision Health.12/6/2022. Available from https://www.cdc.gov/genomics/disease/hcm.htm Accessed April 22, 2024.
Hypertrophic cardiomyopathy. Mayo Clinic: Diseases and Conditions.2/23/2024. Available from: https://www.mayoclinic.org/diseases-conditions/hypertrophic-cardiomyopathy/symptoms-causes/syc-20350198 Accessed April 22, 2024.
Hypertrophic Cardiomyopathy. American Heart Association. 5/13/2022.Available from: https://www.heart.org/en/health-topics/cardiomyopathy/what-is-cardiomyopathy-in-adults/hypertrophic-cardiomyopathy Accessed April 22, 2024.
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