56 International Journal of Cardiovascular Sciences. 2016;29(1):56-64

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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 (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; ; 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 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 development of CAA was not established, nor the - Hypertension relationship of microalbuminuria with the development The optimal degree of reduction in blood pressure levels of CAA in diabetic patients. The role of the treatment of for the prevention of CAA, as well as the mechanism of hypertension and other risk factors in delaying CAA systemic arterial hypertension (SAH) in the genesis and progression in diabetic patients and the identification of progression of atherosclerosis and in the development the optimal pharmacotherapy for the treatment of of cardiac disease remained unknown1. hypertension in these patients was not well defined1.

The clinical meaning of metabolic abnormalities A new syndrome described by Reaven, the X syndrome associated with antihypertensive drugs, such as (1988) and, subsequently, metabolic syndrome (MS) was dyslipidemia, glucose and electrolytes was still uncertain, then recognized and considered associated with the whereas these changes could even increase the risk of development of atherosclerosis. In two decades, the role cardiovascular disease. This fact was questioned as a of MS was recognized as a clinical entity of high probable reason for the treatment of mild and moderate prevalence in adults and particularly associated with hypertension (130-159/85-104 mmHg)10. abdominal obesity, risk of infarction and stroke in the studies INTERHEART15 and INTERSTROKE16. The role of non-pharmacological therapy in the Abdominal obesity was been studied from the viewpoint management of hypertension remained undefined and of etiophysiology of atherosclerotic diseases of the untested. As well as the effects of other second-line adipose tissue, which was identified as an important antihypertensive drugs, such as diuretics and beta endocrine organ for the production of adipokines capable blockers on morbidity and mortality from SAH. Clinical of promoting cardiovascular inflammation17,18. studies demonstrating the potential benefits of antihypertensive treatment in CAA were not conclusive1. - Left ventricular hypertrophy (LVH) Specific factors that lead to LVH such as genetics, age, The treatment of moderate or severe hypertension intensity and duration of pressure load, the role of decreased the progression of hypertensive nephropathy, pathophysiology of hypertrophy, the differences in the but the level of reduction of SAH in patients with SAH type of hypertrophy and biochemical changes between and kidney disease was not well documented, as well as LVH induced by pressure overload and intense physical SAH and diabetes with or without renal failure1. activity were not known. The impact of regression of hypertrophy on mortality, on systolic and diastolic Since the 1989 workshop, three classes of antihypertensive functions, arrhythmia, peripheral vascular disease and drugs had scientific proof due to their efficacy and safety clinical symptoms was not clear1. in the management of SAH, and were incorporated as first-line: angiotensin-converting enzyme inhibitors LVH was recognized as an independent marker of (ACEI), angiotensin II receptor blockers (ARBs), and increased cardiovascular mortality and associated factor calcium channel blockers (CCB), which proved capable in the development of systolic (eccentric remodeling) of reducing cardiovascular morbidity and mortality in heart failure (HF). Medications that act on the renin- hypertensive patients11. angiotensin-aldosterone system (RAAS), such as ACEI, ARB, mineralocorticoid receptor inhibitors and plasma From a dietary point of view, salt restriction in foods has renin were proven to interfere with the development of become an important measure of SAH prevention among myocardial hypertrophy and effect on cardiovascular the population, as well as calorie restriction/combat to disease progression19,20. obesity, with greater emphasis on childhood obesity. Beside this, the dietary approaches to stop hypertension Beta-blockers promoted reverse remodeling on the left (the DASH diet), based on fresh fruits, vegetables, low-fat ventricle and reduction of morbidity and mortality in dairy, fiber, vitamins and minerals proven to be useful patients with heart failure with reduced ejection fraction in controlling hypertension12-14. (HFREF)21. 60 Mesquita et al. Int J Cardiovasc Sci. 2016;29(1):56-64 Cardiovascular Continuum 25 years Review Manuscript

Myocardial ischemia, plaque rupture and Heart failure atherothrombosis HF is the ultimate expression of the chain of CAA events, The prevalence of myocardial ischemia in the population consisting of a multisystem syndrome fundamentally was not known because there was asymptomatic associated with cardiac dysfunction, and involves both myocardial ischemia, among other reasons. The reference the heart and the peripheral circulation1. values on test results to classify patients as CAA patients at high risk and the interrelationship between CAA and Neurohumoral activation is a physiological response to sudden death were not yet defined1. contractile dysfunction. It was believed that this The mechanisms leading to plaque stabilization, the activation also contributed to the pathophysiology of HF, ultrastructure that constitutes it and its instability factors, perhaps influencing renal perfusion, sodium excretion, besides the different types of atheroma, were not yet well exercise tolerance, ventricular contractility and established. Many issues regarding the thrombotic and development of arrhythmias, but the role of stimulation non-thrombotic mechanisms on the progression of as an independent risk factor was not well understood coronary obstruction, the vasoconstriction mechanism either. An important issue was whether the beta- associated with thrombus, the formation of mobile adrenergic receptors should be stimulated or blocked thrombus in response to plaque fissure and thrombus in in HF1. response to ulceration were not clear and there was no specific therapy for prevention1. In recent decades, it has been demonstrated, through robust scientific evidence, that beta-blockers, ACEI or The use of thrombolytic agents had been introduced in ARBs and mineralocorticoid receptor inhibitors reduce cases of acute (AMI), but the risk- benefit ratio between the period of 6-24 hours post-AMI, morbidity and mortality in HFREF and were then 25 its role in cardiogenic shock, and the combined use with incorporated into the HF treatment guidelines . antiplatelet agents and anticoagulants were not well established. Besides this, there was no scientific basis for Establishment of cardiovascular continuum and the the use of myocardial revascularization in acute new era of molecular biology myocardial infarction, which later became the gold standard method1. Important findings about the functions of nitric oxide (NO) in the cardiocirculatory system in the 1980s Myocardial remodeling and the importance of artery promoted a change in the scientific community patency related to AMI as a determinant in left ventricular mindset1. dilation was uncertain. In addition, the use of medications such as ACEI in post-AMI and their effectiveness in In 1992, NO was considered the molecule of the 1 remodeling were not well defined yet . year by Science magazine26. In 1998, Ferid Murad, Robert Furchgott and Louis Ignarro (Figure 3) were Nowadays, the use of ACEI, beta-blockers, awarded the Nobel Prize of Physiology and Medicine mineralocorticoid inhibitors in patients with ventricular for discovering the signaling properties of NO. dysfunction or HF following AMI reduces mortality. Myocardial reperfusion associated with dual-antiplatelet therapy represents the standard therapy currently Endothelial dysfunction and oxidative stress became recommended by the guidelines of Brazilian and the basis of CAA understanding. These concepts have international medical societies22-24. influenced this second major publication on cardiovascular continuum, led by Dzau. Studies Secondary prevention conducted by the brilliant pathologist Russell Ross The role of reducing cholesterol levels in secondary et al. have incorporated these sets of information prevention demanded further investigation. Strategies from basic science, supported by the emerging using antiplatelet agents, beta-blockers, RAAS inhibitors molecular and cellular biology techniques, promoting and statins have progressively become standard changes to the clinical practice of etiopathophysiology medications in secondary prevention1. understanding5. Int J Cardiovasc Sci. 2016;29(1):56-64 Mesquita et al. 61 Review Manuscript Cardiovascular Continuum 25 years

Figure 3 Scientists Ferid Murad, Robert Furchgott and Louis Ignarro.

Endothelial dysfunction promoted by risk factors such as hypertension, diabetes, smoking and dyslipidemia would lead to functional abnormalities following monocyte infiltration and LDL-cholesterol deposition. This process results in the development of anatomic abnormalities that progressively evolve, forming atherosclerotic plaque (Figure 4). Then, the lymphocyte- modulated immunological phenomena would play a supporting role in the formation and rupture of fibrous plaque, leading to instability and acute events, known as atherotrombosis5.

Dzau’s second manuscript — The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes — published in the journal Circulation in 2006, presents a body of scientific evidence that has been progressively marked in pharmacological interventions at different stages of the cardiovascular continuum, capable of reducing morbidity and 2,3 mortality . Figure 4 Endothelial dysfunction in atherosclerosis. 5 The role of statins, not only as drugs capable of reducing Source: adapted from Ross cholesterol, but also capable of interfering with inflammation has been studied, as well as new agents CAA has a strong inflammatory component. An capable of improving endothelial function and reducing association between levels of C-reactive ultrasensitive cardiovascular inflammation, such as exercise, protein (CRP), an inflammatory marker, and CAA risk antioxidants and vitamins2,3,5. has been demonstrated. The use of statins reduces CRP 62 Mesquita et al. Int J Cardiovasc Sci. 2016;29(1):56-64 Cardiovascular Continuum 25 years Review Manuscript

levels indicating an anti-inflammatory effect of the drug aging process, culminating not only in the final stages of on disease progression. Today, new medications with an CAA, but also in microvascular diseases, mainly affecting anti-inflammatory action on CAA have been tested in richly perfused organs such as the brain and kidneys. many clinical trials27. This new view is based on the progressive degeneration of the proximal aorta, causing its stiffening and swelling with consequently harmful effects on the heart, brain and Vascular aging continuum kidneys, thus ruling out the idea that CAA would The classical model of the cardiovascular continuum, necessarily linked to atherosclerosis7. due to epidemiological changes, advances in etiopathophysiology knowledge and studies on vascular The vascular aging continuum can be divided into four 7 aging, led Dzau to incorporate vascular aging continuum stages : in this model7 (Figure 5). • Stage one Over time, blood flow in the aorta and in the large aged vessels cause micro-lesions of the elastic layer The emerging epidemic of HFNEF, a condition leading to swelling and stiffening of the arterial wall. associated with hypertension and aging, as well as the • Stage two emergence of ischemic heart disease in eastern elderly It includes the harmful effects of arterial stiffening, individuals in the absence of obstructive coronary increasing left ventricular (LV) workload in atherosclerosis, point to the need for clinicians and combination with reduced coronary perfusion in a researchers to expand the traditional paradigm of way that proximal aorta stiffness would lead to an cardiovascular continuum and integrate it to the vascular increased afterload, resulting in increased cardiac aging continuum7. work and LHV, generating isolated systolic hypertension. In addition, this increase in LV mass This new model described by O’Rourke et al. in 2010 causes perfusion deficit and consequent myocardial brings an additional insight, emphasizing the vascular ischemia.

Figure 5 Cardiovascular continuum (left), aging continuum (right) and their interactions. Source: adapted from O’Rourke et al.7 HFREF – heart failure with reduced ejection fraction; HFNEF – heart failure with normal ejection fraction Int J Cardiovasc Sci. 2016;29(1):56-64 Mesquita et al. 63 Review Manuscript Cardiovascular Continuum 25 years

• Third stage physiology in hypertensive individuals and in the elderly Arterial stiffening culminates in damping deficit of in order to demonstrate that this new concept may the arterial pulse wave, transmitted to microcirculation, interfere with morbidity and mortality in target organs hence damaging the brain and kidneys. In the brain, such as chronic kidney disease, vascular dementia and these damages are called pulse wave encephalopathy. HF7. This aggression harms vascular endothelium by increasing the levels of endothelial cell fragments and C-reactive protein in the circulation, predisposing to Conclusion thrombosis and infarctions due to inflammation with consequent vascular repair. Cardiovascular continuum exerts strong influence on the • Stage four CAA approach by cardiologists and general practitioners It occurs concurrently with stage three and consists from renewed insights on etiopathophysiology through in later damage to the heart, which can be explained a cascade of pathophysiological events, which allowed by coronary perfusion deficit caused by increased the development of evidence-based strategies capable of muscle mass (LVH) leading to greater need for blood delaying the progress or improving disease symptoms. supply that turns out to be insufficient, combined Beside this, the concept of cardiovascular inflammation with reduced diastolic period and systolic increase. in the context of endothelial dysfunction and Both conditions affect the perfusion of coronary ostia, atherosclerosis has been gradually established, explaining increasing the risk of myocardial ischemia and the effects of risk factors in CAA. A new concept capable infarction, even in the absence of significant coronary of expanding the initial view has been recently proposed obstruction. by Dzau, associating vascular aging with hypertension Both continuum models result in the final stages of in macro and microcirculation, causing myocardial CAA. However, as classic risk factors are not directly infarction even in the absence of significant vascular involved in arterial aging, individuals who do not have obstruction. significant atherosclerosis can develop myocardial ischemia7. Potential Conflicts of Interest The importance of this additional insight on vascular This study has no relevant conflicts of interest. aging continuum lies in the use of medications that reduce blood pressure, especially central pressure, Sources of Funding thereby reducing vascular damage7. This study had no external funding sources. Academic Association Studies using hypertension management drugs should This study is associated with the Graduate Program in also assess the impact of medications the vascular Cardiovascular Sciences of Universidade Federal Fluminense.

References

1. Dzau V, Braunwald E. Resolved and unresolved issues in the 4. Braunwald E. Heart failure. JACC Heart Fail. 2013;1(1):1-20. prevention and treatment of coronary artery disease: a workshop 5. Ross R. Atherosclerosis – an inflammatory disease. N Engl J consensus statement. Am Heart J. 1991;121(4 Pt 1):1244-63. Med. 1999;340(2):115-26. 2. Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, 6. Nürnberger J, Michalski R, Opazo-Saez A, Kribben A. Plutzky J, et al. The cardiovascular disease continuum validated: Evaluation of pulse wave velocity and augmentation index in clinical evidence of improved patient outcomes: part I: supine and sitting position. Artery Res. 2009;3(4):167. Pathophysiology and clinical trial evidence (risk factors through 7. O’Rourke MF, Safar ME, Dzau V. The cardiovascular continuum stable coronary artery disease). Circulation. 2006;114(25):2850–70. extended: aging effects on the aorta and microvasculature. Vasc 3. Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Med. 2010;15(6):461-8. Plutzky J, et al. The cardiovascular disease continuum validated: 8. Berry C, L’Allier PL, Grégoire J, Lespérance J, Levesque S, Ibrahim clinical evidence of improved patient outcomes: part II: Clinical R, et al. Comparison of intravascular ultrasound and quantitative trial evidence (acute coronary syndromes through renal disease) coronary angiography for the assessment of coronary artery and future directions. Circulation. 2006;114(25):2871–91. disease progression. Circulation. 2007;115(14):1851-7. 64 Mesquita et al. Int J Cardiovasc Sci. 2016;29(1):56-64 Cardiovascular Continuum 25 years Review Manuscript

9. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu Survival Study (CONSENSUS). The CONSENSUS Trial Study T, et al. Statins, high-density lipoprotein cholesterol, and Group. N Engl J Med.1987:316(23):1429-35. regression of coronary atherosclerosis. JAMA. 2007;297(5):499-508. 20. Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, 10. Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic Ohlin G, et al. Candesartan in heart failure--assessment of and diastolic) and risk of fatal coronary heart disease. reduction in mortality and morbidity (CHARM): rationale and Hypertension. 1989;13(5 Suppl):I2-12. design. CHARM-Programme Investigators. J Card Fail. 11. The fifth report of the Joint National Committee on Detection, 1999;5(3):276-82. Evaluation, and Treatment of High Blood Pressure (JNC V). 21. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Arch Intern Med. 1993;153(2):154-83. Krum H, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on 12. James PA, Oparil S, Carter BL, Cushman WC, Dennison- the morbidity of patients with severe chronic heart failure: results Himmelfarb C, Handler J, et al. 2014 Evidence-based guideline of the Carvedilol Prospective Randomized Cumulative Survival for the management of high blood pressure in adults: report (COPERNICUS) study. Circulation. 2002;106(17):2194-9. from the panel members appointed to the Eighth Joint National 22. Task Force on the management os ST-segment elevation acute Committee (JNC 8). JAMA. 2014;311(5):507-20. Erratum in: myocardial infarction of the European Society of JAMA. 2014;311(17):1809. (ESC), Steg G, James SK, Atar D, Badano LP, Blömstrom- 13. Sociedade Brasileira de Cardiologia; Sociedade Brasileira de Lundqvist C, Borger MA, et al. ESC Guidelines for the Hipertensão; Sociedade Brasileira de Nefrologia. VI Diretrizes management of acute myocardial infarction in patients Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl. presenting with ST-segment elevation. Eur Heart J. 1):1-51. Erratum in: Arq Bras Cardiol. 2010;95(4):553. 2012;33(20):2569-619. 14. Sachs FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, 23. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Harsha D, et al; DASH-Sodium Collaborative Research Group. Hand M, et al; American College of Cardiology/American Effects on blood pressure of reduced dietary sodium and the Dietary Heart Association Task Force on Practice Guidelines (Writing Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Committee to Revise the 1999 Guidelines for the Management Collaborative Research Group. N Engl J Med. 2001;344(1):3-10. of Patients With Acute Myocardial Infarction). ACC/AHA 15. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, guidelines for the management of patients with ST-elevation et al; INTERHEART Study Investigators. Effect of potentially myocardial infarction—executive summary : a report of the modifiable risk factors associated with myocardial infarction American College of Cardiology/American Heart Association in 52 countries (the INTERHEART study): case-control study. Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute Lancet. 2004;364(9438):937-52. myocardial infarction). Circulation. 2004;110(5):588-636. 16. O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini Erratum in: Circulation. 2005;111(15):2013. P, et al; INTERSTROKE Investigators. Risk factors for ischaemic 24. Piegas LS, Feitosa G, Mattos LA, Nicolau JC, Rossi Neto JM, and intracerebral haemorrhagic stroke in 22 countries (the Timerman A, et al. Sociedade Brasileira de Cardiologia. IV INTERSTROKE study): a case-control study. Lancet. Diretriz da Sociedade Brasileira de Cardiologia sobre tratamento 2010;376(9735):112-23. do infarto agudo do miocárdio com supradesnível do segmento 17. Sjöstrom L, Lindroos AK, Peltonen M, Torgerson J, ST. Arq Bras Cardiol. 2009;93(6 supl. 2):e179-264. Bouchard C, Carlsson B, et al; Swedish Obese Subjects Study 25. Bocchi EA, Braga FG, Ferreira SM, Rohde LE, Oliveira WA, Scientific Group. Lifestyle, diabetes, and cardiovascular risk Almeida DR, et al; Sociedade Brasileira de Cardiologia. III factors 10 years after bariatric surgery. N Engl J Med. Diretriz brasileira de insuficiência cardíaca crônica. Arq Bras 2004;351(26):2683-93. Cardiol. 2009;93(1 supl. 1):3-70. 18. Vest AR, Heneghan HM, Agarwal S, Schauer PR, Young JB. 26. Koshland DE Jr. The molecule of year. Science. Bariatric surgery and cardiovascular outcomes: a systematic 1992;258(5090):1861. review. Heart. 2012;98(24):1763-77. 27. Jamkhande PG, Chandak PG, Dhawale SC, Barde SR, Tidke PS, 19. Effects of enalapril on mortality in severe congestive heart Sakhare RS. Therapeutic approaches to drug targets in failure. Results of the Cooperative North Scandinavian Enalapril atherosclerosis. Saudi Pharm J. 2014;22(3):179-90.