The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure withpreserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used toimprove the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms ofdevelopment of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory statecauses a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with someevidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

Ferroptosis: The Potential Target in Heart Failure with Preserved Ejection Fraction

“…M1 macrophages secrete pro-inflammatory cytokines TNF and IL-1β, which maintain the inflammatory response and myocardial injury; M2 macrophages are involved in fibrosis and diastolic dysfunction by producing pro-fibrotic cytokines TGF-β, IL-10, galectin-3, and osteopontin [ 29 ]. The two macrophage phenotypes are often present together during chronic coronary microvascular inflammation [ 6 ]. The synergy of M1 (pro-inflammatory phenotype) and M2 (pro-remodeling/anti-inflammatory phenotype) aggravates the feedforward loop of myocardial inflammation and fibrosis.…”

“…Increased levels of ROS frequently attack the cellular genome, proteins, and lipids, leading to a rise in lipid peroxidation (LPO) products, disruption of endogenous antioxidant mechanisms, and a decrease in glutathione (GSH) levels [ 5 ]. Furthermore, this systemic pro-inflammatory state can affect coronary microvascular function and compromise cardiomyocyte structure and cardiac function [ 6 ], implying a connection between inflammation, oxidative stress of ferroptosis, and HFpEF. In addition, studies have shown that left ventricular (LV) diastolic function may be a more sensitive early marker of myocardial iron overload than systolic function [ 7 , 8 ].…”

Potential of valsartan+sacubitril therapy in hypertensive heart disease

“…Об этом же говорят и результаты нашего ретроспективного когортного исследования, в котором при длительном наблюдении за 223 пациентами с бессимптомным ГС (медиана наблюдения составила 8,1 года) систолическая дисфункция ЛЖ по "внутреннему" механизму возникла лишь у 7% пациентов, причём во всех случаях была незначительной [22]. нического воспаления коронарных микрососудов [27]. В экспериментальных моделях с перегрузкой давлением в гипертрофированном миокарде помимо фиброза всегда обнаруживаются и признаки воспаления, при этом области фиброза и воспаления полностью совпадают, воспаление случается раньше фиброза, и если удаётся подавить воспаление, то не будет и фиброза [28].…”

“…Откуда в гипертрофированном миокарде берётся воспаление? Большинство больных с ГЛЖ и СНсФВ имеют сопутствующие заболевания, такие как ожирение, сахарный диабет типа 2, хроническую болезнь почек, хроническую обструктивную болезнь лёгких, анемию [27]. Эти заболевания поддерживают в организме хронический провоспалительный статус, который проявляется высоким уровнем циркулирующих провоспалительных цитокинов.…”

Biomarkers of HFpEF: Natriuretic Peptides, High-Sensitivity Troponins and Beyond

“…Myocardial microvascular inflammation, mediated by pro-inflammatory cytokines, leads to activation of endothelial cells, which highly express adhesion molecules that trigger monocyte migration from the bloodstream into the myocardium and their differentiation into macrophages. This vicious circle leads to a state called “endothelial dysfunction”, which contributes to fibrosis and progressive diastolic dysfunction [ 7 , 8 ]. Conversely, HF with reduced ejection fraction (HFrEF; LVEF ≤ 40%) is mainly characterized by systolic dysfunction as a consequence of a direct heart damage, such as an acute coronary syndrome, a cardiomyopathy or a valve disease.…”