PhyMedExp, INSERM, CNRS.
Department of biochemistry and hormonology, Montpellier University, CHU Montpellier, Montpellier, France.
Am J Respir Cell Mol Biol. 2023 Aug;69(2):230-241. doi: 10.1165/rcmb.2022-0382OC.
Chronic obstructive pulmonary disease (COPD) is a clinical entity of increasing significance. COPD involves abnormalities of the airways and, in emphysema, parenchymal pulmonary destruction. Cardiovascular disease has emerged as a significant comorbidity to COPD. Heart failure with preserved ejection fraction (HFpEF) appears to be particularly associated with COPD-emphysema. Traditional treatments have shown limited efficacy in improving COPD-associated HFpEF. This lack of therapeutic efficacy highlights the need to identify potential mechanisms that link COPD-emphysema to HFpEF. Therefore, we aimed to study the delayed cardiac physiological impacts in a rat model with acute exacerbated emphysema. Emphysema was induced by four weekly 4 units elastase (ELA) intratracheal pulmonary instillations and exacerbation by one final additional lipolysaccharide (LPS) instillation in male Wistar rats. At 5 weeks after the ELA and LPS exposure, and pulmonary and cardiac measurements were performed. Experimental exacerbated emphysema resulted in decreased pulmonary function and exercise intolerance. Histological analysis revealed parenchymal pulmonary destruction without signs of inflammation or cardiac fibrosis. cardiac functional analysis revealed diastolic dysfunction and tachycardia. analysis revealed a cellular cardiomyopathy with decreased myofilament Ca sensitivity, cross-bridge cycling kinetics, and increased adrenergic PKA (protein kinase A)-dependent phosphorylation of troponin-I. Experimental exacerbated emphysema was associated with exercise intolerance that appeared to be secondary to increased β-adrenergic tone and subsequent cardiac myofilament dysfunction. A β-receptor antagonist treatment (bisoprolol) started 24 hours after ELA-LPS instillation prevented and diastolic dysfunction. These results suggest that novel treatment strategies targeted to the cardiac myofilament may be beneficial to combat exacerbated emphysema-associated HFpEF.
慢性阻塞性肺疾病（COPD）是一种日益重要的临床实体。COPD 涉及气道异常，在肺气肿中涉及肺实质破坏。心血管疾病已成为 COPD 的重要合并症。射血分数保留的心衰（HFpEF）似乎与 COPD-肺气肿特别相关。传统治疗在改善 COPD 相关 HFpEF 方面显示出有限的疗效。这种治疗效果的缺乏突出表明需要确定将 COPD-肺气肿与 HFpEF 联系起来的潜在机制。因此，我们旨在研究急性加重性肺气肿大鼠模型中的心脏延迟生理影响。肺气肿通过每周 4 次 4 个单位弹性蛋白酶（ELA）气管内肺滴注诱导，最后一次额外的脂多糖（LPS）滴注加重。在 ELA 和 LPS 暴露后 5 周，进行 和 肺和心脏测量。实验性加重性肺气肿导致肺功能下降和运动不耐受。组织学分析显示肺实质破坏，无炎症或心脏纤维化迹象。 心脏功能分析显示舒张功能障碍和心动过速。 分析显示细胞性心肌病，肌球蛋白钙敏感性降低，交联循环动力学改变，肾上腺素能 PKA（蛋白激酶 A）依赖性肌钙蛋白 I 磷酸化增加。实验性加重性肺气肿与运动不耐受有关，这似乎是由于 β-肾上腺素能张力增加和随后的心肌肌球蛋白功能障碍引起的。ELA-LPS 滴注后 24 小时开始的 β-受体拮抗剂治疗（比索洛尔）可预防 和 舒张功能障碍。这些结果表明，针对心肌肌球蛋白的新型治疗策略可能有益于对抗加重性肺气肿相关的 HFpEF。
