Abstract】The basic mechanism for the development of heart failure is cardiac remodeling. This paper reviews the new therapeutic targets for heart failure in recent years, the progress of drugs and other therapeutic methods, and discusses the role of extracellular matrix and its clinical application prospects in heart failure and myocardial fibrosis as a therapeutic target, as well as summarizes the clinical progress in the assessment of interstitial heart disease by extracellular volume fraction. Liu Wei, Department of Cardiology, The First Hospital of Harbin Medical University
[Keywords] Extracellular matrix; heart failure; therapeutic target; extracellular volume fraction
The relationship between interstitial cardiac disease and heart failure
(Department of Critical Care Medicine, The First Clinical College, Harbin Medical University, Harbin 150001, China)
[Abstract Key Words】extracellular matrix；heart failure；therapeutic targets；extracellular volume fraction The main pathological feature of “interstitial heart disease” is myocardial extracellular matrix (ECM) remodeling, which is closely related to mechanical, electrical and vasodilatory dysfunction and poor clinical prognosis. Current advances in cardiovascular magnetic resonance allow clinicians and researchers to use extracellular volume fraction (ECV) to assess the intercellular matrix and quantify the extent of ECM remodeling and other cardiovascular structural disorders. The above advances have deepened our understanding of the role of ECM and facilitated the development of novel therapies that may be a new direction for future research to improve the prognosis of patients with heart failure (HF) through targeted therapy of the myocardial interstitium. Twenty years ago, Weber et al. introduced the concept of “interstitial heart disease” characterized by myocardial ECM remodeling due to excess collagen [1]. They found that the heart is composed of independently regulated cardiomyocytes and myocardial interstitium (mainly cardiac fibroblasts). Fibroblast activation leads to ECM remodeling, resulting in altered cardiac structure and function. Fibroblast activation and ECM remodeling play a central role in the pathophysiology of HF and pathological LV remodeling [2]. The increase in myocardial collagen content leads to a series of adverse consequences such as mechanical, electrical and vasodilatory dysfunction, and reduces myocardial tolerance to ischemia. In patients with sudden cardiac death, there is an “interstitial myocardial abnormality” [3], and the pattern of myocardial fibrosis on magnetic resonance images is similar to that of liver fibrosis in cirrhosis. 1 The role of ECM in heart failure 1.1 ECM affects cardiac myocyte function The ECM plays an important role in maintaining the structural and functional integrity of the myocardial cells, and disruption of the ECM is associated with myocardial fibroblast activation, excessive collagen deposition and myocardial fibrosis, a series of interstitial abnormalities that will exacerbate myocardial remodeling and lead to the HF phenotype [4]. In addition, abnormal material deposition in the myocardial interstitium can also lead to HF, e.g., cardiac amyloid deposition leads to restrictive cardiomyopathy, which can result in decreased myocardial compliance, myocardial ECM remodeling, diastolic dysfunction or failure, and ultimately systolic dysfunction, even in the absence of primary lesions in cardiac myocytes and fibroblasts. (BNP) is significantly elevated, with deterioration of clinical condition and early death in patients [5]. 1.2 Interactions between fibroblasts and cardiomyocytes in ECM remodeling The factors of fibroblast proliferation and myocardial cell injury have not been clearly reported to play a major role in ECM remodeling. The interactions between cardiac fibroblasts and cardiomyocytes have not been elucidated. Fibroblasts are essentially inflammatory cells that secrete inflammatory mediators such as cytokines and matrix metalloproteinases, which act paracrine on cardiomyocytes, leading to cardiomyocyte hypertrophy, apoptosis, and necrosis. Recent studies have shown that cardiac fibroblasts can undergo reprogramming and transdifferentiation into cardiomyocytes in response to transcription factors such as KLF4 and Sox2 [6]. Therefore, it may be a potential target for myocardial repair. 2 Interstitial heart disease 2.1 Pathogenesis of interstitial heart disease The ECM has an important role in cardiomyocyte proliferation and signal transduction and consists mainly of the more tense type I collagen fibers, and one of the major changes in cardiac ECM remodeling is myocardial fibrosis [7]. Fibroblasts are the most abundant cells in the heart and are essential for the dynamic balance of collagen and ECM. fibroblasts secrete extracellular procollagen chains, which are assembled into protofibrils by lysyl oxidase and cross-linked. Collagen cross-linking is an important post-translational modification that increases myocardial tensile strength and is strongly associated with diastolic dysfunction; it can also prevent ventricular dilation by matrix metalloproteinase resistance to degradation and increasing the integrity of the cardiac matrix [7]. Myocardial fibrosis and extracellular matrix remodeling occur when the dynamic balance of collagen is imbalanced and activated fibroblasts secrete excess collagen that accumulates in the interstitium. The transformation of fibroblasts into myofibroblasts involves the characteristic expression of α-smooth muscle actin in myocytes and the presence of an effective endoplasmic reticulum. Myocardial fibroblasts are sensitive to various inflammatory factors and can generate a proliferative response after pathological stimuli that have not been elucidated. The key mediators of ECM remodeling include the renin-angiotensin-aldosterone system (RAAS), transforming growth factor-β (TGF-β), reactive oxygen species, tumor necrosis factor-α (TNF-α), and various cytokines.
However, these factors lead to a series of molecular drivers of ECM remodeling and other links are not fully known [7]. Many innate and adaptive immune response molecules are involved in the activation and differentiation of fibroblasts [8] and are the basis of interstitial heart disease. There are significant individual differences in tolerance to myocardial injury, susceptibility to fibroblast activation and the occurrence of interstitial heart disease in different individuals. 2.2 Determinants of interstitial heart disease Not all factors leading to interstitial heart disease have been elucidated to date, especially regarding the modifiable and non-modifiable risk factors for myocardial fibrosis. At the molecular level, angiogenic factors, various growth factors, protein hydrolases and fibrogenic cytokines are important elements that lead to ECM remodeling and are involved in fibroblast regulation [9]. tGF-β, endothelin-1, angiotensin II, platelet-derived growth factor and connective tissue growth factor are key proteins that regulate fibroblast differentiation into α-rich -MicroRNAs also play a very important role in the development of fibrosis, such as miR-30, miR-133 and miR-21 [9]. MicroRNA therapies targeting fibroblasts and the ECM are actively being explored. The role of myocardial cell necrosis in ECM remodeling is not absolute, and the mechanisms by which fibrosis occurs in noninfarcted myocardium in coronary artery disease are unclear (e.g., increased ventricular wall stress, neurohormonal activation, etc.). Once myocardial fibrosis has occurred, it remains unknown whether “this fibrosis causes the other fibrosis”. 3 Extracellular volume fraction Quantifying myocardial ECM will help to elucidate the mechanisms of HF response, assess the risk of death in HF patients [10], and may optimize clinicians’ diagnostic and therapeutic strategies. However, ECM remodeling was previously difficult to image and quantify with any kind of technology, thus making the study of ECM impossible, but now advances in cardiovascular magnetic resonance (CMR) technology have made it possible [10]. Quantification of ECM remodeling has been achieved by measuring ECV. changes in the CMR technique T1 signal, before and after contrast response to gadolinium (Gd) concentration, myocardial uptake ratio for Gd, and other indicators quantify myocardial ECV. separate contrast myocardial T1 measurements correlate with collagen volume fraction, which is less influenced by other clinical factors and exhibits a correlation with collagen volume fraction are more highly correlated [11]. 3.1 Quantification of ECV Myocardial ECV is an indicator of ECM remodeling quantified by CMR and highly correlated (R2=0.7-0.9) with the collagen volume fraction of human myocardium [11]. At the cellular level, Gd tracks thin collagen with high fidelity and ECV quantification is reproducible with CMR scans at different times [12]. Limited spatial resolution limits partial volume effects and partial volume effects limit ECV, thus requiring larger pixels across tissue boundaries; ECV sampling is currently unsuitable due to thin right ventricular and left atrial walls [13].ECV for monitoring the response of left ventricular ECM to therapy holds greater promise for clinical applications [13]. 4 Novel therapeutic perspectives 4.1 ECM as a therapeutic target for HF Numerous studies have demonstrated that prevention and improvement of ECM remodeling are key to the success of HF treatment [14]. The ECM remodeling caused by excess collagen and its adverse effects are reversible. treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists can lead to reversal of ECM remodeling and improvement in cardiac functional parameters and coronary flow reserve. RAAS is known to be involved in the regulation of cardiovascular activity, and RAAS modulators antagonize fibroblast activation and myocardial ECM remodeling [15], contributing to the treatment of HF, which may improve survival and reduce the risk of rehospitalization in patients with subclinical HF [16]. myocardial fibrosis in HF, would benefit most from RAAS modulators. The novel drug, recombinant human relaxin 2, produced promising results in hospitalized HF patients [17], reversing myocardial ECM remodeling and myocardial fibrosis. The direct renin receptor blocker aliskiren has also been shown to lower blood pressure and improve left ventricular diastolic function [18]. 4.2 Novel drugs to improve ECM remodeling Since reversal of ECM remodeling helps to improve the prognosis of HF patients, myocardial interstitium has become a new target for drug treatment of HF. Certain new agents, e.g., potent selective nonsteroids, offer new therapeutic approaches for ECM remodeling due to myocardial fibrosis. Although the development of some drugs targeting myocardial fibrosis has failed, and previous drugs targeting interstitial and other disorders (e.g., omapatrilat, nesiritide) have not been successful, this only shows that the challenges we face in drug development are enormous and that lessons need to be learned from the failures to develop novel drugs that improve ECM remodeling [20]. 5 Conclusion HF is the end stage in the development of various cardiovascular diseases, which seriously affects the physical and mental health and quality of life of many patients, so the search for new therapies to reduce the number of HF patients and improve the prognosis of HF patients has become an urgent problem in the field of cardiovascular medicine. There is a need to develop new therapeutic approaches and the future focus should be on intrinsic ventricular modification pathways without disrupting collagen metabolism in other organs. Myocardial ECM remodeling is the main pathophysiological abnormality causing HF, and inhibition or improvement of ECM remodeling will become a hot topic in the treatment of HF. It has been difficult to image and quantify ECM remodeling, and the use of CMR to quantify ECM remodeling, myocardial fibrosis, and cardiovascular structural disorders can provide a reference for clinical drug development in order to further explore new approaches for targeted treatment of ECM remodeling. [Ref. [1] Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen
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