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Cardiovascular Continuum 25 Years – the Evolution of An 56 International Journal of Cardiovascular Sciences. 2016;29(1):56-64 REVIEW MANUSCRIPT Cardiovascular Continuum 25 years – The Evolution of an Etiopathophysiology Model Evandro Tinoco Mesquita, Amanda Vanessa Demarchi, Dezirrê dos Santos Bitencourt, Patricia Elaine de Azevedo Machado, Paula Meneguini Badran, Renata Gudergues Pereira de Almeida, Antonio José Lagoeiro Jorge Universidade Federal Fluminense – Hospital Universitário Antônio Pedro – Departamento de Medicina Clínica – Niterói, RJ – Brazil Abstract The concept of cardiovascular continuum was devised by Dzau and Braunwald and spread among cardiologists as an etiopathophysiology model that directs the development of interventionist measures in the prevention of cardiovascular diseases. After a workshop held in 1989, it was possible to gather resolved and unresolved issues about factors related to cardiovascular therapy and protection, resulting in the first publication by Dzau and Braunwald, in 1991. Progress in the studies of molecular and cellular biology allowed understanding the role of endothelial dysfunction in oxidative stress and nitric oxide in coronary artery atherosclerosis (CAA), awarding Nobel Prize to authors Ferid Murad, Robert Furchgott and Louis Ignarro. In 2006, a second publication, also led by Dzau, consolidated the classic model of cardiovascular continuum, in which risk factors for CAA are associated and trigger a progressive cascade of events leading to the final stages of cardiovascular disease. By observing the existence of ischemic myocardial diseases in populations with low incidence of coronary artery atherosclerosis, studies have shown that ischemic heart disease is not only associated with atherosclerosis, but also to vascular aging. This finding led to the publication of O’Rourke’s third manuscript in 2010, which presented an additional model: vascular aging continuum. The evolution of this model allowed focusing on preventive treatments for the risk factors of CAA and the search for therapies capable of preventing endothelial damage caused by vascular aging and modulating oxidative stress. This review aims to bring together the leading studies that support the evolution of the cardiovascular continuum model over 25 years. Keywords: Primary prevention; Secondary prevention; Coronary artery disease; Atherosclerosis Introduction (CAA), the leading cause of death in the United States, and sought to emphasize the importance of early In January 1989, the important workshop “Frontiers in identification of associated factors for the development Cardiovascular Therapy and Cardiac Protection — and progression of CAA. The proposal was a model that resolved and unresolved issues” was coordinated by associated a sequential chain of etiopathophysiology professors Victor Dzau and Eugene Braunwald1 events involving risk factors and the alterations caused (Figure 1), with the participation of major cardiovascular by these factors in the heart and coronary vasculature, researchers in the clinical, basic and epidemiological resulting in heart failure and progression to death fields. This group of scientists evaluated scientific (Figure 2), which in 2006 became known as cardiovascular evidence associated with coronary artery atherosclerosis continuum2,3. Corresponding author: Evandro Tinoco Mesquita Rua Marquês de Paraná, 303 – Centro – 24033-900 – Niterói, RJ – Brazil E-mail: [email protected] DOI: 10.5935/2359-4802.20160002 Manuscript received on July 8, 2015; approved on February 10, 2016; revised on February 15, 2016. Int J Cardiovasc Sci. 2016;29(1):56-64 Mesquita et al. 57 Review Manuscript Cardiovascular Continuum 25 years Scientific evidencehas shown from the use of non-invasive technologies and ABBREVIATIONS AND that this approach strategy cardiovascular images, thus expanding the knowledge ACRONYMS using pharmacological of the pathophysiological role of aging and • ACEI — angiotensin- measures for different stages hypertension on the flow dynamics in macro and converting enzyme of the continuum enabled the 6 inhibitors microcirculation . reduction of cardiovascular • AMI — acute myocardial damage and progression to infarction At the same time, myocardial ischemic disease has been the advanced forms of the • ARB — angiotensin II considered a distinct pathophysiological behavior, disease. Beside this, mortality receptor blocker particularly in the elderly in Asian countries. There has from cardiovascular disease in • CAA — coronary artery been significant growth in the prevalence of heart atherosclerosis the United States declined by 3 failure with normal ejection fraction (HFNEF). Both • CCB — calcium channel about 40% , which shows that blocker the continuum approach may conditions are associated with hypertension and aging. These new findings have led Dzau et al. to propose • DM — diabetes mellitus have helped reducing mortality 4 an additional model to cardiovascular continuum — • HF — heart failure from CAA . vascular aging continuum, emphasizing the • HFNEF — heart failure with normal ejection Advances in molecular and pathobiological processes that lead to aging/hardening fraction cellular biology techniques, of the great arteries and abnormalities of • HFREF — heart failure with discovery of nitric oxide and the microcirculation7. reduced ejection fraction study of histopathology of • LV — left ventricle atherosclerotic plaque in human The purpose of this review is to present the important • LVH — left ventricular and animal models gradually landmarks of the evolution, over the last 25 years, of the hypertrophy helped consolidating a view of concept of cardiovascular continuum paradigm. • MS — metabolic syndrome coronary atherosclerosis as a • RAAS — renin-angiotensin- degenerative immunoinflammatory aldosterone system process, rather than as an Cardiovascular continuum — Starting point • SAH — systemic arterial inexorable sclerodegenerative hypertension process associated with aging The workshop “Frontiers in Cardiovascular Therapy of individuals5. and Cardiac Protection: Resolved and Unresolved Issues,” held from January 8 to 10, 1989 in Boston, was led by the physicians Eugene Braunwald and Victor Dzau, involving 37 other North-American participants1. That meeting resulted in the publication of an important document entitled “Resolved and unresolved issues in the prevention and treatment of arterial disease: a workshop consensus statement,” in 1991. The paper was published to summarize and establish what was known and what was still unknown or unresolved on each etiopathophysiology process involved in the final stage of cardiac disease1. Figure 1 Primarily focusing on the risk factors for cardiovascular Cardiologists Eugene Braunwald and Victor Dzau. disease, such as dyslipidemia, hypertension, diabetes, smoking and left ventricular hypertrophy, In the past two decades, there have been important issues hitherto unresolved for each factor have been advances in the knowledge of vascular physiology clarified. 58 Mesquita et al. Int J Cardiovasc Sci. 2016;29(1):56-64 Cardiovascular Continuum 25 years Review Manuscript Figure 2 Chain of events involved in CAA. Source: adapted from Dzau and Braunwald1. CAA – coronary artery atherosclerosis Risk factors Medications available to control dyslipidemia represented an addition to intervention diet in patients with high - Dyslipidemia levels, but further information was needed on their long- The National Cholesterol Education Program (NCEP) term effects as well as the effects of combination therapy, defined serum levels of LDL-cholesterol (low density such as resins and inhibitors of coenzyme A-hydroxy-3- lipoprotein cholesterol) > 159 mg/dL as a high risk factor methyl-glutaryl reductase (HMG CoA reductase) or for the development of cardiovascular disease and niacin. These medications were introduced as cholesterol patients with coronary artery disease or two or more risk reducers, but although the long-term risk-benefit ratios factors for CAA should reach ≤130 mg/dL levels through of reducing cholesterol were unknown, an association lifestyle changes and therapy. At the time, there was no was found between families with low levels of LDL and consensus about what would be the best treatment for total cholesterol and high longevity1. high levels of triglycerides1. Over the past 25 years, there has been a great revolution in the understanding of the role of dyslipidemia in the Another issue was the finding that lipoproteins oxidized progression of CAA and treatment of this condition. on the arterial walls were more atherogenic than native Statins, approved in 1987 by the Food and Drug LDL-cholesterol, but further methods required to prove Administration (FDA), have become the standard that finding. Beside this, they found that HDL-cholesterol therapy in the treatment of hypercholesterolemia and (high-density lipoprotein cholesterol) had a protective has had its role demonstrated in the regression of effect on the development of atherosclerosis1. atherosclerosis. This effect and the change in composition Int J Cardiovasc Sci. 2016;29(1):56-64 Mesquita et al. 59 Review Manuscript Cardiovascular Continuum 25 years of the plaque be supported by various methods, such as - Diabetes mellitus angiographic techniques, magnetic resonance imaging Diabetes mellitus (DM) has been identified as a risk factor and vascular ultrasound, using statins and synthetic for the development of CAA and its presence enhanced molecules of HDL (HDL milano)8,9. other risk factors. The mechanism by which it accelerated the
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