Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Circ Heart Fail. 2012 Jan;5(1):36-46. doi: 10.1161/CIRCHEARTFAILURE.111.963702. Epub 2011 Dec 16.
Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation.
Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n=17), mutation negative HCM patients without an identified sarcomere mutation (HCM(mn); n=11), and nonfailing donors (n=12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33±5%, and similar in HCM(mn) compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCM(mn). Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCM(mn,) compared with donor (26.4±2.9, 28.0±3.7, and 37.2±2.3 kN/m(2), respectively), and higher myofilament Ca(2+)-sensitivity (EC(50)=2.5±0.2, 2.4±0.2, and 3.0±0.2 μmol/L, respectively). The sarcomere length-dependent increase in Ca(2+)-sensitivity was significantly smaller in both patient groups compared with donor (ΔEC(50): 0.46±0.04, 0.37±0.05, and 0.75±0.07 μmol/L, respectively). Protein kinase A treatment restored myofilament Ca(2+)-sensitivity and length-dependent activation in both patient groups to donor values.
Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression.
肥厚型心肌病（HCM）通常表现为左心室不对称性肥厚，常由肌节蛋白突变引起。我们研究了 HCM 中心肌肌节性质的变化是否取决于潜在的蛋白突变。
比较了携带 MYBPC3 突变的患者（MYBPC3(mut)；n=17）、未发现肌节突变的 HCM 患者（HCM(mn)；n=11）和非衰竭供体（n=12）的心脏样本。所有患者的收缩功能正常，但舒张功能受损。肌球蛋白结合蛋白 C（cMyBP-C）的蛋白表达在 MYBPC3(mut)中降低了 33±5%，与供体相似；而在 HCM(mn)中则降低了 33±5%。在 MYBPC3(mut)中，cMyBP-C 的磷酸化与供体相似，而在 HCM(mn)中则显著降低。与供体相比，两组患者的肌钙蛋白 I 磷酸化均降低。在单个通透的心肌细胞中进行的力测量表明，两组患者均存在类似的肌节功能障碍，其特征是与供体相比，MYBPC3(mut)和 HCM(mn)的最大肌力生成能力降低（分别为 26.4±2.9、28.0±3.7 和 37.2±2.3 kN/m2），肌球蛋白丝对 Ca2+的敏感性增加（EC50=2.5±0.2、2.4±0.2 和 3.0±0.2 μmol/L）。与供体相比，两组患者的肌节长度依赖性 Ca2+敏感性增加均显著降低（ΔEC50：分别为 0.46±0.04、0.37±0.05 和 0.75±0.07 μmol/L）。蛋白激酶 A 处理使两组患者的肌球蛋白丝 Ca2+敏感性和长度依赖性激活恢复至供体水平。
肌节功能的变化反映了 HCM 的临床表型，而不是特定的 MYBPC3 突变。收缩功能低下的肌节是人类 HCM 的一个常见缺陷，其左心室收缩功能正常，可能导致 HCM 疾病进展。
