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Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy
Anita C Hoskins1, Adam Jacques, Sonya C Bardswell
1Cardiovascular Division, King's College London British Heart Foundation Centre, London, UK.
Insights
Hypertrophic cardiomyopathy (HCM) involves impaired heart muscle function. This study found that reduced maximal force and increased calcium sensitivity in heart myofibrils, not passive stiffness, contribute to HCM dysfunction.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Cardiac Pathophysiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy, increased stiffness, and diastolic dysfunction.
- Understanding the underlying myocardial functional defects is crucial for explaining HCM pathophysiology.
- Previous research has focused on genetic mutations, but the direct impact on myofibril mechanics requires further investigation.
Purpose of the Study:
- To determine if alterations in passive and active properties of human cardiac myofibrils explain myocardial functional defects in hypertrophic cardiomyopathy (HCM).
- To compare myofibrillar mechanics between HCM patients and healthy donors.
- To investigate the role of protein phosphorylation in altered myofibrillar function.
Main Methods:
- Skinned ventricular myocytes were isolated from six obstructive HCM patients and four healthy donors.
- Measurements included passive stiffness, viscous properties, titin isoform expression, maximal Ca(2+)-activated force, cross-bridge kinetics, and Ca(2+) sensitivity.
- Western blotting was used to assess phosphorylation of troponin-I and MyBP-C.
Main Results:
- Passive stiffness and viscous properties were similar between HCM and donor myocytes.
- Maximal Ca(2+)-activated force was significantly lower in HCM myocytes (14 ± 1 kN/m(2)) compared to donor myocytes (23 ± 3 kN/m(2)).
- HCM myocytes exhibited higher myofibrillar Ca(2+) sensitivity (pCa(50)=6.40) and reduced troponin-I and MyBP-C phosphorylation.
Conclusions:
- Passive viscoelastic properties of myocytes do not account for increased ventricular stiffness in HCM.
- Reduced maximal force and increased Ca(2+) sensitivity of myofilaments are key contributors to systolic and diastolic dysfunction in HCM.
- Altered phosphorylation of regulatory proteins likely underlies these functional changes in HCM myofibrils.
Abstract:
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca(2+)-activated force was much lower in HCM myocytes (14 ± 1 kN/m(2)) than in donor myocytes (23 ± 3 kN/m(2); P<0.01), though cross-bridge kinetics (k(tr)) during maximal Ca(2)(+) activation were 10% faster in HCM myocytes. Myofibrillar Ca(2)(+) sensitivity in HCM myocytes (pCa(50)=6.40 ± 0.05) was higher than for donor myocytes (pCa(50)=6.09 ± 0.02; P<0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca(2+) concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca(2+)-activated force and high Ca(2+) sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients.
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