Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies
Hypertrophic cardiomyopathy (HCM) affects more than 1 in 500 people in the general population with an extensive burden of morbidity in the form of arrhythmia, heart failure, and sudden death. More than 25 years since the discovery of the genetic underpinnings of HCM, the field has unveiled significa...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.975076/full |
| _version_ | 1811201364434354176 |
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| author | Masataka Kawana Masataka Kawana James A. Spudich Kathleen M. Ruppel |
| author_facet | Masataka Kawana Masataka Kawana James A. Spudich Kathleen M. Ruppel |
| author_sort | Masataka Kawana |
| collection | DOAJ |
| description | Hypertrophic cardiomyopathy (HCM) affects more than 1 in 500 people in the general population with an extensive burden of morbidity in the form of arrhythmia, heart failure, and sudden death. More than 25 years since the discovery of the genetic underpinnings of HCM, the field has unveiled significant insights into the primary effects of these genetic mutations, especially for the myosin heavy chain gene, which is one of the most commonly mutated genes. Our group has studied the molecular effects of HCM mutations on human β-cardiac myosin heavy chain using state-of-the-art biochemical and biophysical tools for the past 10 years, combining insights from clinical genetics and structural analyses of cardiac myosin. The overarching hypothesis is that HCM-causing mutations in sarcomere proteins cause hypercontractility at the sarcomere level, and we have shown that an increase in the number of myosin molecules available for interaction with actin is a primary driver. Recently, two pharmaceutical companies have developed small molecule inhibitors of human cardiac myosin to counteract the molecular consequences of HCM pathogenesis. One of these inhibitors (mavacamten) has recently been approved by the FDA after completing a successful phase III trial in HCM patients, and the other (aficamten) is currently being evaluated in a phase III trial. Myosin inhibitors will be the first class of medication used to treat HCM that has both robust clinical trial evidence of efficacy and that targets the fundamental mechanism of HCM pathogenesis. The success of myosin inhibitors in HCM opens the door to finding other new drugs that target the sarcomere directly, as we learn more about the genetics and fundamental mechanisms of this disease. |
| first_indexed | 2024-04-12T02:20:39Z |
| format | Article |
| id | doaj.art-fce3ff08c1884e62bfca00d63a968e91 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-12T02:20:39Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-fce3ff08c1884e62bfca00d63a968e912022-12-22T03:52:08ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-09-011310.3389/fphys.2022.975076975076Hypertrophic cardiomyopathy: Mutations to mechanisms to therapiesMasataka Kawana0Masataka Kawana1James A. Spudich2Kathleen M. Ruppel3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, United StatesHypertrophic cardiomyopathy (HCM) affects more than 1 in 500 people in the general population with an extensive burden of morbidity in the form of arrhythmia, heart failure, and sudden death. More than 25 years since the discovery of the genetic underpinnings of HCM, the field has unveiled significant insights into the primary effects of these genetic mutations, especially for the myosin heavy chain gene, which is one of the most commonly mutated genes. Our group has studied the molecular effects of HCM mutations on human β-cardiac myosin heavy chain using state-of-the-art biochemical and biophysical tools for the past 10 years, combining insights from clinical genetics and structural analyses of cardiac myosin. The overarching hypothesis is that HCM-causing mutations in sarcomere proteins cause hypercontractility at the sarcomere level, and we have shown that an increase in the number of myosin molecules available for interaction with actin is a primary driver. Recently, two pharmaceutical companies have developed small molecule inhibitors of human cardiac myosin to counteract the molecular consequences of HCM pathogenesis. One of these inhibitors (mavacamten) has recently been approved by the FDA after completing a successful phase III trial in HCM patients, and the other (aficamten) is currently being evaluated in a phase III trial. Myosin inhibitors will be the first class of medication used to treat HCM that has both robust clinical trial evidence of efficacy and that targets the fundamental mechanism of HCM pathogenesis. The success of myosin inhibitors in HCM opens the door to finding other new drugs that target the sarcomere directly, as we learn more about the genetics and fundamental mechanisms of this disease.https://www.frontiersin.org/articles/10.3389/fphys.2022.975076/fullmyosinhypertrophic cardiomyopathysuper relaxed statemavacamtenomecamtiv mercarbil |
| spellingShingle | Masataka Kawana Masataka Kawana James A. Spudich Kathleen M. Ruppel Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies Frontiers in Physiology myosin hypertrophic cardiomyopathy super relaxed state mavacamten omecamtiv mercarbil |
| title | Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies |
| title_full | Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies |
| title_fullStr | Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies |
| title_full_unstemmed | Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies |
| title_short | Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies |
| title_sort | hypertrophic cardiomyopathy mutations to mechanisms to therapies |
| topic | myosin hypertrophic cardiomyopathy super relaxed state mavacamten omecamtiv mercarbil |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.975076/full |
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