Department of Physiology, Cardiology, Pathology, and Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Circulation. 2012 Aug 14;126(7):830-9. doi: 10.1161/CIRCULATIONAHA.111.076075. Epub 2012 Jul 17.
Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F(passive)) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F(passive) and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF).
Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(passive) was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(passive) in HFPEF was corrected by in vitro PKG administration.
Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F(passive) and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.
射血分数保留的心力衰竭（HFPEF）中心肌重构的显著特征是心肌细胞静息张力（F(passive)）高和心肌细胞肥大。在实验模型中，两者对升高的蛋白激酶 G（PKG）活性均有良好反应。本研究评估了心肌 PKG 活性、其对心肌细胞 F(passive)和心肌细胞直径的下游作用，以及环鸟苷酸单磷酸（cGMP）、硝化/氧化应激和脑钠肽（BNP）对其上游的控制。为了辨别 PKG 对心肌重构控制的改变，将 HFPEF 与主动脉瓣狭窄和射血分数降低的心力衰竭（HFREF）进行了比较。
HFPEF 患者（n=36）、AS 患者（n=67）和 HFREF 患者（n=43）均无冠状动脉疾病。更多的 HFPEF 患者肥胖（P<0.05）或患有糖尿病（P<0.05）。HFPEF 和 HFREF 经血管内获取左心室心肌活检，主动脉瓣狭窄手术时获取心肌匀浆。PKG 给药前后测量心肌细胞的 F(passive)。使用心肌匀浆评估 PKG 活性、cGMP 浓度、前脑啡肽 108 表达和硝基酪氨酸表达，以评估硝化/氧化应激。还进行了 PKG 活性和硝基酪氨酸表达的额外定量免疫组织化学分析。与主动脉瓣狭窄（P<0.01）或 HFREF（P<0.001）相比，HFPEF 中的 PKG 活性较低（P<0.01），与较高的心肌细胞 F(passive)（P<0.001）相关，与较低的 cGMP 浓度（P<0.001）和较高的硝化/氧化应激（P<0.05）相关。HFPEF 中较高的 F(passive)通过体外 PKG 给药得到纠正。
HFPEF 中心肌 PKG 活性降低与心肌细胞 F(passive)升高有关，与心肌硝化/氧化应激增加有关。后者可能是 HFPEF 中代谢合并症高发所引起的。纠正心肌 PKG 活性可能是针对 HFPEF 特定治疗的靶点。
