Ischemic heart disease (IHD) is commonly recognized as the consequence of coronary atherosclerosis and obstructive coronary artery disease (CAD). However, a significant number of patients may present ...angina or myocardial infarction even in the absence of any significant coronary artery stenosis and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. The term “coronary microvascular dysfunction” (CMD) encompasses several pathogenic mechanisms resulting in functional and/or structural changes in the coronary microcirculation and determining angina and myocardial ischemia in patients with angina without obstructive CAD (“primary” microvascular angina), as well as in several other conditions, including obstructive CAD, cardiomyopathies, Takotsubo syndrome and heart failure, especially the phenotype with preserved ejection fraction. The pathogenesis of CMD is complex and involves the combination of functional and structural alterations leading to impaired coronary blood flow and resulting in myocardial ischemia. In the absence of therapies specifically targeting CMD, attention has been focused on the role of modifiable risk factors. Here, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD, with a particular focus on the role of cardiovascular risk factors and comorbidities. Moreover, we discuss the specific pathogenic mechanisms of CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.
Pathophysiology of Takotsubo Syndrome Pelliccia, Francesco; Kaski, Juan Carlos; Crea, Filippo ...
Circulation (New York, N.Y.),
2017-Jun-13, Letnik:
135, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, ...however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.
The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in ...the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.
Pathogenesis of Acute Coronary Syndromes Crea, Filippo, MD; Liuzzo, Giovanna, MD, PhD
Journal of the American College of Cardiology,
01/2013, Letnik:
61, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Experimental models of atherogenesis have provided a growing body of information about molecular mechanisms of plaque growth; however, transition from coronary stability to instability is less well ...understood due to the lack of animal models reflective of human disease. The abrupt clinical presentation of acute coronary syndromes gives a strong signal of discontinuity in the natural history of atherothrombosis. The causes of such discontinuity are complex, probably multiple, and still largely unknown. A better knowledge of the causes of coronary instability might allow identification of new therapeutic targets aimed at the preservation of plaque stability in those subjects in whom primary prevention fails to prevent plaque growth. The goal of this review was to propose a pathogenetic classification of acute coronary syndromes that might help in the search of new diagnostic algorithms and therapeutic targets.
The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first ...symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field.
Standardization of diagnostic criteria for ischemic symptoms due to coronary microvascular dysfunction (CMD) is needed for further investigation of patients presenting with anginal chest pain ...consistent with “microvascular angina” (MVA). At the annual Coronary Vasomotion Disorders International Study Group (COVADIS) Summits held in August 2014 and 2015, the following criteria were agreed upon for the investigative diagnosis of microvascular angina: (1) presence of symptoms suggestive of myocardial ischemia; (2) objective documentation of myocardial ischemia, as assessed by currently available techniques; (3) absence of obstructive CAD (<50% coronary diameter reduction and/or fractional flow reserve (FFR) >0.80) (4) confirmation of a reduced coronary blood flow reserve and/or inducible microvascular spasm. These standardized criteria provide an investigative structure for mechanistic, diagnostic, prognostic and clinical trial studies aimed at developing an evidence base needed for guidelines in this growing patient population. Standardized criteria will facilitate microvascular angina registries and recruitment of suitable patients into clinical trials. Mechanistic research will also benefit from the implementation of standardized diagnostic criteria for MVA.
Abstract
The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of ...COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels, fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm interleukin (IL)-6, IL-7, IL-22, IL-17, etc. during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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