Sala Valentina, Margaria Jean Piero, Murabito Alessandra, Morello Fulvio, Ghigo Alessandra, Hirsch Emilio
Department of Molecular Biotechnology, Molecular Biotechnology Center, University of Torino, Torino, Italy.
S.C. Medicina d'Urgenza, A.O.U. Città della Salute e della Scienza, Molinette Hospital, Torino, Italy.
Curr Heart Fail Rep. 2017 Jun;14(3):187-196. doi: 10.1007/s11897-017-0331-2.
Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms.
The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.
射血分数保留的心力衰竭（HFpEF）是一种普遍存在的疾病，给个人和社会带来了相当大的负担。HFpEF患者常患有多种病理状况，这些状况使管理变得复杂并对预后产生不利影响，包括肺动脉高压和慢性阻塞性肺疾病（COPD）。迄今为止，尚无治疗方法被证明能完全有效降低HFpEF的发病率和死亡率，这可能是由于对潜在分子机制的理解不完整。
新出现的观点认为，慢性全身性炎症导致内皮功能障碍和间质纤维化，是HFpEF的一个主要原因，而不仅仅是一种并存疾病。在过去十年中，制药公司致力于从药理学角度靶向在全身和肺部炎症中起关键作用的酶，如环核苷酸降解酶磷酸二酯酶（PDEs）和磷酸肌醇-3磷酸激酶（PI3Ks），尤其是为了限制COPD。在本综述中，我们将总结针对这些酶来解决HFpEF相关合并症中的炎症问题的主要成功之处和不足之处，主要关注已完成和正在进行的临床试验结果。最后，我们将讨论重新利用和/或开发新的PDE和PI3K抑制剂用于HFpEF治疗的潜力。
