Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF ...is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins. Furthermore, in addition to an excess of collagen, qualitative changes in collagen fibers also contribute to the detrimental impact of MIF. In this part 3 of a 4-part JACC Focus Seminar, we review the evidence on the complex mechanisms leading to MIF, as well as its contribution to systolic and diastolic cardiac dysfunction and impaired clinical outcomes in patients with nonischemic heart disease.
The endothelium is one of the largest organ systems in the body, and data continue to emerge regarding the importance of endothelial cell (EC) dysfunction in vascular aging and a range of ...cardiovascular diseases (CVDs). Over the last two decades and as a process intimately related to EC dysfunction, an increasing number of studies have also implicated endothelial to mesenchymal transition (EndMT) as a potentially disease-causal pathobiologic process that is involved in a multitude of differing CVDs. However, EndMT is also involved in physiologic processes (e.g., cardiac development), and transient EndMT may contribute to vascular regeneration in certain contexts. Given that EndMT involves a major alteration in the EC-specific molecular program, and that it potentially contributes to CVD pathobiology, the clinical translation opportunities are significant, but further molecular and translational research is needed to see these opportunities realized.
Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., ...myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a "bystander-phenomenon"), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels.
Vascular disease and heart failure impart an enormous burden in terms of global morbidity and mortality. Although there are many different causes of cardiac and vascular disease, most causes share an ...important pathological mechanism: oxidative stress. In the failing heart, oxidative stress occurs in the myocardium and correlates with left ventricular dysfunction. Reactive oxygen species (ROS) negatively affect myocardial calcium handling, cause arrhythmia, and contribute to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis. Similarly, oxidative balance in the vasculature is tightly regulated by a wealth of pro- and antioxidant systems that orchestrate region-specific ROS production and removal. Reactive oxygen species also regulate multiple vascular cell functions, including endothelial and smooth muscle cell growth, proliferation, and migration; angiogenesis; apoptosis; vascular tone; host defenses; and genomic stability. However, excessive levels of ROS promote vascular disease through direct and irreversible oxidative damage to macromolecules, as well as disruption of redox-dependent vascular wall signaling processes.
Coronary Artery Manifestations of Fibromuscular Dysplasia Michelis, Katherine C., MD; Olin, Jeffrey W., DO; Kadian-Dodov, Daniella, MD ...
Journal of the American College of Cardiology,
09/2014, Letnik:
64, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Abstract Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially ...sudden cardiac death. Although the classic angiographic “string of beads” that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.
Air pollution is a major global challenge for a multitude of reasons. As a specific concern, there is now compelling evidence demonstrating a causal relationship between exposure to airborne ...pollutants and the onset of cardiovascular disease (CVD). As such, reducing air pollution as a means to decrease cardiovascular morbidity and mortality should be a global health priority. This review provides an overview of the cardiovascular effects of air pollution and uses two major events of 2020—the Australian bushfires and COVID‐19 pandemic lockdown—to illustrate the relationship between air pollution and CVD. The bushfires highlight the substantial human and economic costs associated with elevations in air pollution. Conversely, the COVID‐19‐related lockdowns demonstrated that stringent measures are effective at reducing airborne pollutants, which in turn resulted in a potential reduction in cardiovascular events. Perhaps one positive to come out of 2020 will be the recognition that tough measures are effective at reducing air pollution and that these measures have the potential to stop thousands of deaths from CVD.
The 2019–2020 Australian bushfires, and the COVID‐19‐related lockdowns, highlight the intimate relationship between air pollution and cardiovascular disease. While the bushfires illustrate the dire effects of air pollution, the COVID‐19‐related lockdowns showed that stringent measures can reduce airborne pollutants, which in turn may reduce cardiovascular events.
Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk ...factors in promoting oxidative stress: diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting. Here, we explore the role of different ROS sources arising in obesity and diabetes, and the effect of excessive ROS production on the development of cardiac lipotoxicity. In parallel, contaminants in the air that we breathe pose a significant threat to human health. This paper provides an overview of cigarette smoke and urban air pollution, considering how their composition and biological effects have detrimental effects on cardiovascular health.
Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including ...fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.
Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition. We attempted to induce this process in mouse fibroblasts by screening a panel of factors for ...hemogenic activity. We identified a combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6, that efficiently induces endothelial-like precursor cells, with the subsequent appearance of hematopoietic cells. The precursor cells express a human CD34 reporter, Sca1, and Prominin1 within a global endothelial transcription program. Emergent hematopoietic cells possess nascent hematopoietic stem cell gene-expression profiles and cell-surface phenotypes. After transgene silencing and reaggregation culture, the specified cells generate hematopoietic colonies in vitro. Thus, we show that a simple combination of transcription factors is sufficient to induce a complex, dynamic, and multistep developmental program in vitro. These findings provide insights into the specification of definitive hemogenesis and a platform for future development of patient-specific stem and progenitor cells, as well as more-differentiated blood products.
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•Gata2, Gfi1b, cFos, and Etv6 induce a hemogenic program in fibroblasts•Initial production of Sca1+Prom1+ endothelial-like precursors•Progression to emergence of hematopoietic cells with HSC features•Emergent cells generate colonies in vitro after reaggregation culture
A cocktail of four transcription factors, Gata2, cFos, Gfi1b, and Etv6, can induce a hemogenic program in mouse fibroblasts, leading to formation of an endothelium that gives rise to hematopoietic cells.
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