English
Abstract
Diastolic heart failure, also referred to as heart failure with preserved ejection fraction (HFpEF), is a complex cardiovascular clinical syndrome that is a growing health burden worldwide. Patients present with high abnormal left ventricular filling pressures but normal ejection fraction that can progress to diastolic heart failure and death. The causes of diastolic dysfunction are varied, and pharmacotherapies are limited to managing the symptoms of the disease. At the level of the myocyte, cytoskeletal disarray and mitochondrial dysfunction are common features associated with diastolic disease. Understanding the mechanisms of abnormal diastolic filling pressures is necessary to identify novel treatments, which remains an area of significant unmet need. In this article, we discuss the mechanisms of maladaptive feedback contributing to increased extracellular stiffness, cytoskeletal disarray, and mitochondrial dysfunction in diastolic heart failure. Since the mechanisms are complex, understanding the contributing factors provides opportunities for the development of novel drug targets. These will be discussed and examined in the context of current therapy.
Keywords:
cytoskeleton; diastolic heart disease; mitochondria; L-type calcium channel; PIEZO channels
1. Introduction and Background
Heart failure is a significant global public health issue, and the incidence and prevalence of heart failure are increasing worldwide. Approximately 50% of patients diagnosed with heart failure have a 5-year life expectancy, while those with severe heart failure and NYHA class IV typically die within one year [1]. Additionally, heart failure is the end stage of many disease processes, and the risk of developing heart failure increases with age [2]. Heart failure with reduced ejection fraction (<40%) or systolic failure (also known as HFrEF) is associated with pulmonary congestion, dyspnea, edema, fatigue, and impaired exercise tolerance. It is a progressive disease process, and progression is associated with decreased survival, regardless of underlying etiology.
Approximately half of all heart failure patients develop diastolic dysfunction with preserved ejection fraction (>50%). This is called HFpEF. Several factors conspire to cause HFpEF, in particular the presence of hypertension, renal disease, metabolic syndrome, diabetes, and aging. Additionally, patients with hypertrophic or diabetic cardiomyopathy can progress to HFpEF in advanced stages of disease, suggesting that HFpEF is an advanced form of diastolic heart disease. Despite the varying factors influencing the development of HFpEF, the cardiac phenotype remains relatively consistent, exhibiting concentric left ventricular hypertrophy and diastolic dysfunction (as a result of myocardial stiffening and fibrosis) coupled with systemic inflammation, microvascular endothelial dysfunction, and elevated natriuretic peptides.
It is argued that HFpEF consists of two main mechanisms—hypertensive ventricular hypertrophy and metabolic alterations involving increased oxidative stress coupled with decreased nitric oxide-soluble guanylate cyclase–protein kinase G (PKG) signaling. Hypertension increases mechanical stress through sheer force, activating pro-hypertrophic and pro-fibrotic signaling pathways in the heart, prompting the development of fibrosis and hypertrophy. Metabolic alterations in the heart increase passive stiffness through the phosphorylation of titin by the nitric oxide-soluble guanylate cyclase–PKG signaling pathway [3]. Excessive ROS production during oxidative stress also promotes pro-hypertrophic and pro-fibrotic signaling pathways in the heart. Clinically, HFpEF patients can exhibit either a hypertensive HFpEF phenotype, metabolic HFpEF phenotype, or a combination, suggesting that multiple mechanisms can contribute to HFpEF in some patients. The broad generalization of the HFpEF patient cohort despite varying HFpEF subtypes makes clinical treatment difficult.
Treatments for HFpEF have largely concentrated on managing hypertension and insulin resistance, as well as alleviating disease symptoms. Although the management of comorbidities may alleviate symptoms, there is limited clinical evidence suggesting that these therapeutic strategies improve diastolic function. Pharmacology targeting the sodium glucose transporter 2 (SGLT2) with SGLT2 inhibitors has demonstrated efficacy in reversing HFpEF and is effective in the absence of diabetes. However, SGLT2 inhibitors do not directly target the pathophysiological mechanisms that directly involve the heart. There remains an unmet need for therapeutic strategies that target cardiac-related mechanisms in HFpEF.
The complex mechanisms involved in HFpEF pathophysiology contribute significantly to the lack of translatability of therapeutics into the clinic. The progression of fibrosis, increased extracellular matrix (ECM) and myocardial stiffness, cytoskeletal disarray, altered cellular and nuclear signaling, and altered mitochondrial energetics are closely linked but are often targeted in isolation. Alterations in signaling, mitochondrial function, and the cytoskeleton also occur early before the development of hypertrophy or fibrosis. Furthermore, the recapitulation of HFpEF in murine models developed as a result of metabolic and hypertensive stress [4,5,6] or nitrosative stress [7] has progressed preclinical investigations into HFpEF but still lacks the mechanistic complexity seen in the human condition. To improve the efficacy of therapeutics for HFpEF, the mechanisms involved in HFpEF must be better understood. In this article, we examine the mechanisms for the contributing factors and discuss therapeutics that could target these sites to ameliorate the maladaptive feedback and prevent the development of HFpEF. We also discuss the translational considerations which must be taken into account when transitioning the preclinical mechanistic findings into therapeutics for the clinic. We have identified five sites as potential targets for therapy (Figure 1) and discuss how each site contributes to diastolic disease and propose therapies to prevent progression of disease.
The article is reprinted from MDPI, original link:https://www.mdpi.com/1422-0067/26/16/8055
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The FAI climbed 5.9 percent year-on-year in the first 11 months of 2018, quickening from the 5.7-percent growth in Jan-Oct, the National Bureau of Statistics (NBS) said Friday in an online statement.
The key indicator of investment, dubbed a major growth driver, hit the bottom in August and has since started to rebound steadily.
In the face of emerging economic challenges home and abroad, China has stepped up efforts to stabilize investment, in particular rolling out measures to motivate private investors and channel funds into infrastructure.
Friday's data showed private investment, accounting for more than 60 percent of the total FAI, expanded by a brisk 8.7 percent.
NBS spokesperson Mao Shengyong said funds into weak economic links registered rapid increases as investment in environmental protection and agriculture jumped 42 percent and 12.5 percent respectively, much faster than the average.
In breakdown, investment in high-tech and equipment manufacturing remained vigorous with 16.1-percent and 11.6-percent increases respectively in the first 11 months. Infrastructure investment gained 3.7 percent, staying flat. Investment in property development rose 9.7 percent, also unchanged.