Title: The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes
Abstract: HomeCirculationVol. 114, No. 25The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBThe Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient OutcomesPart I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Victor J. Dzau, MD, Elliott M. Antman, MD, Henry R. Black, MD, David L. Hayes, MD, JoAnn E. Manson, MD, DrPH, Jorge Plutzky, MD, Jeffrey J. Popma, MD and William Stevenson, MD Victor J. DzauVictor J. Dzau From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , Elliott M. AntmanElliott M. Antman From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , Henry R. BlackHenry R. Black From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , David L. HayesDavid L. Hayes From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , JoAnn E. MansonJoAnn E. Manson From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , Jorge PlutzkyJorge Plutzky From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author , Jeffrey J. PopmaJeffrey J. Popma From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author and William StevensonWilliam Stevenson From Duke University Medical Center and Health System DUMC (V.J.D.), Durham, NC; Harvard Medical School and Brigham and Women’s Hospital (E.M.A., J.E.M., J.P., J.J.P., W.S.), Boston, Mass; Rush University Medical Center, Chicago, Ill (H.R.B.); and the Mayo Clinic and Mayo Clinic Foundation, Mayo College of Medicine, Rochester, Minn (D.L.H.). Search for more papers by this author Originally published19 Dec 2006https://doi.org/10.1161/CIRCULATIONAHA.106.655688Circulation. 2006;114:2850–2870Fifteen years ago, a panel of experts representing the full spectrum of cardiovascular disease (CVD) research and practice assembled at a workshop to examine the state of knowledge about CVD. The leaders of the workshop generated a hypothesis that framed CVD as a chain of events, initiated by a myriad of related and unrelated risk factors and progressing through numerous physiological pathways and processes to the development of end-stage heart disease (Figure 1).1 They further hypothesized that intervention anywhere along the chain of events leading to CVD could disrupt the pathophysiological process and confer cardioprotection. The workshop participants endorsed this paradigm but also identified the unresolved issues relating to the concept of a CVD continuum. There was limited availability of clinical trial data and pathobiological evidence at that time, and the experts recognized that critical studies at both the mechanistic level and the clinical level were needed to validate the concept of a chain of events leading to end-stage CVD. Download figureDownload PowerPointFigure 1. The cardiovascular disease continuum. LVH indicates left ventricular hypertrophy; CHF, congestive heart failure. Adapted from Dzau et al1 with permission from Elsevier.In the intervening 15 years, new evidence for underlying pathophysiological mechanisms, the development of novel therapeutic agents, and the release of additional landmark clinical trial data have confirmed the concept of a CVD continuum and reinforced the notion that intervention at any point along this chain can modify CVD progression. In addition, the accumulated evidence indicates that the events leading to disease progression overlap and intertwine and do not always occur as a sequence of discrete, tandem incidents. Furthermore, although the original concept focused on risk factors for coronary artery disease (CAD) and its sequelae, the CVD continuum has expanded to include other areas such as cerebrovascular disease, peripheral vascular disease, and renal disease. Since its conception 15 years ago, the CVD continuum has become much in need of an update. Accordingly, this 2-part article will present a critical and comprehensive update of the current evidence for a CVD continuum based on the results of pathophysiological studies and the outcome of a broad range of clinical trials that have been performed in the past 15 years. It is not the intent of the article to include a comprehensive listing of all trials performed as part of the CVD continuum; instead, we have sought to include only those trials that have had the greatest impact. Part I briefly reviews the current understanding of the pathophysiology of CVD and discusses clinical trial data from risk factors for disease through stable CAD. Part II continues the review of clinical trial data beginning with acute coronary syndromes and continuing through extension of the CVD continuum to stroke and renal disease. The article concludes with a discussion of areas in which future research might further clarify our understanding of the CVD continuum.New Understanding of a Pathophysiological ContinuumOur understanding of the pathophysiology of CVD has expanded considerably since 1991. A pathophysiological continuum, which underlies the clinical CVD continuum, describes the progressive processes at molecular and cellular levels that manifest as clinical disease (Figure 2).2 In addition, cardiovascular risk factors, such as elevated cholesterol, hypertension, diabetes mellitus, and cigarette smoking, are now known to promote oxidative stress and to cause endothelial dysfunction, initiating a cascade of events, including alterations in vasoactive mediators, inflammatory responses, and vascular remodeling, that culminates in target-organ pathology (Figure 3).3 Considerable evidence suggests that these processes begin earlier in life than previously recognized, indicating that CVD arises over decades. Beyond traditional risk factors, the role of biomarkers/biomediators and surrogate markers in CVD continues to be elucidated. In addition, it is now recognized that neurohormones contribute to disease at both the systemic and local level, exerting direct trophic and inflammatory effects on tissue. Download figureDownload PowerPointFigure 2. Cardiovascular and renal pathophysiological continuum. CHF indicates congestive heart failure; CV, cardiovascular; ESRD, end-stage renal disease; and MI, myocardial infarction.Download figureDownload PowerPointFigure 3. Integrated model of tissue angiotensin and vascular pathobiology. AII indicates angiotensin II; BP, blood pressure; ICAM, intracellular adhesion molecule; PAI-1, plasminogen activator inhibitor-1; and VCAM, vascular cell adhesion molecule. Adapted with permission from Dzau VJ.3Oxidative Stress and Endothelial DysfunctionAdvances in pathophysiological research suggest that the CVD continuum begins with risk factors that initiate the process that leads to tissue damage. The pathophysiological continuum includes oxidative stress, endothelial dysfunction, inflammatory processes, and vascular remodeling in the initiation and continuation of atherosclerotic disease. An understanding of these processes has enabled the development of therapeutic strategies targeting individual factors along the CVD continuum.Normal endothelial function appears to depend greatly on the homeostatic balance between nitric oxide (NO) and reactive oxygen species, such as superoxide anion and hydrogen peroxide.3 Oxidative stress results when an increase in reactive oxygen species generation leads to a reduction in NO activity and subsequent endothelial dysfunction. This imbalance is a known effect of established CVD risk factors such as cigarette smoking, diabetes mellitus, and obesity. In addition, oxidative stress induces the expression of proinflammatory mediators such as vascular cell adhesion molecule, intracellular adhesion molecule, and chemoattractant proteins that play a role in early atherogenesis.3Through receptor-mediated and non–receptor-mediated mechanisms, endothelial cells regulate vascular tone, inflammation, lipid metabolism, cell growth and migration, and interactions with the extracellular matrix.4 Any disruption of normal endothelial function can induce pathological vascular responses, such as smooth muscle cell proliferation, vasoconstriction, inflammation, and thrombosis. For example, endothelial dysfunction may shift relative concentrations of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 toward thrombosis. Plasminogen activator inhibitor-1 is the primary inhibitor of tissue-type plasminogen activator, and elevated levels of plasminogen activator inhibitor-1 relative to tissue-type plasminogen activator lead to inhibition of the fibrinolytic system.5 Endothelial dysfunction is also associated with changes in concentrations of important local inflammatory mediators, such as chemokines, adhesion molecules, and cytokines.Role of Risk Factors in Oxidative Stress and Endothelial DysfunctionOxidized low-density lipoprotein (LDL) inactivates NO, which results in increased oxidative stress and enhanced expression of cellular adhesion molecules.6 Higher oxidized LDL content in the lipid core of atherosclerotic plaques may also promote plaque instability.7 Small, dense LDL particles are highly atherogenic and are associated with increased triglyceride levels. The structure of small, dense LDL particles contributes to their atherogenicity, with increased susceptibility to oxidation, easier penetration into the arterial wall, and altered interactions with the LDL receptor.Elevated blood pressure promotes the development of atherosclerotic plaques and increases the risk of CVD complications.8 Endothelial dysfunction in chronic hypertension is associated with decreased endothelium-dependent relaxation. In hypertensive vessels, increased expression of matrix proteins, matrix proteinases, and growth factors leads to structural changes, such as decreased lumen diameter, increased extracellular matrix, and thickened media.4 In addition, hypertension is associated with increased production of free radicals and oxidative stress that may promote an inflammatory state and enhance the atherosclerotic process.8 Indeed, results from the Women’s Health Study9 and other epidemiological studies demonstrate that levels of C-reactive protein, a marker of systemic inflammation, correlate significantly with future risk of developing hypertension.The metabolic syndrome comprises a group of lipid and nonlipid risk factors, such as insulin resistance and its associated hyperinsulinemia, atherogenic dyslipidemia, central obesity, and hypertension.10 Metabolic syndrome is associated with increased CVD risk.10 Specifically, insulin resistance and subsequent hyperinsulinemia appear to contribute to endothelial dysfunction and impaired NO responses.11,12 Furthermore, the chronic exposure of vascular smooth muscle to hyperinsulinemia may promote intimal hyperplasia. In addition, the excess adipose tissue characteristic of the metabolic syndrome secretes prothrombotic factors and proinflammatory cytokines, which may contribute to vascular disease.12,13 Changes in the distribution of adipose tissue, namely, a shift from subcutaneous to visceral locations, may also be associated with a loss of antiinflammatory mediators such as adiponectin.NeurohormonesThe renin-angiotensin-aldosterone system (RAAS) is now understood to play a significant role in CVD pathophysiology.3 Interacting with the adrenergic system and various mediators, the RAAS mediates adaptive and maladaptive responses to tissue injury, such as may result from hypertension, ischemic heart disease, cardiomyopathy, other systemic or pulmonary diseases, or the effects of CVD risk factors.14 The important biologically active component of the RAAS is angiotensin II. Angiotensin II mediates hemodynamic and renal actions in addition to having direct cardiovascular tissue effects and has been implicated at every stage along the CVD continuum.The identified pathological effects of angiotensin II are myriad and include, but are not limited to, vasoconstriction, cardiac and vascular remodeling, inflammation, thrombosis, and plaque rupture.3 Although angiotensin II stimulates 2 major receptors, angiotensin II type 1 (AT1) and type 2 (AT2), the pathological effects of angiotensin II appear to be mediated through the AT1 receptor.15 Evidence suggests that stimulation of the AT2 receptor mediates more favorable actions, inducing NO and bradykinin release and promoting cGMP-mediated vasodilation.15 Furthermore, stimulation of AT2 receptors may promote cell differentiation and apoptosis and inhibit cell proliferation.Angiotensin II increases the tissue generation of reactive oxygen species, creating an environment of oxidative stress and decreased NO activity.3 These changes contribute to inflammatory responses, including the induction of monocytes and smooth muscle cells to release chemoattractant proteins such as monocyte chemotactic protein-1, as well as other cytokines and adhesion molecules. Angiotensin II promotes vascular remodeling by stimulating expression of growth factors in vascular smooth muscle cells, promoting smooth muscle cell proliferation, inducing the production and release of matrix metalloproteinases, and modulating vascular cell migration.3The RAAS, and specifically angiotensin II, also plays a role in fibrinolytic responses via the endothelium. ACE stimulates plasminogen activator inhibitor-1 production via angiotensin II and also degrades bradykinin. Bradykinin stimulates tissue-type plasminogen activator release from the endothelium.16,17 Accordingly, the interaction between bradykinin and angiotensin II at the endothelial surface modulates the prothrombotic/fibrinolytic state of the blood vessel.18,19An increase of tissue ACE in atherosclerotic lesions sets up a positive feedback mechanism for angiotensin II production.3 Increased ACE promotes an inflammatory response via angiotensin II, and inflammatory cells such as monocytes/macrophages, neutrophils, and mast cells release enzymes that generate angiotensin II. The increased level of angiotensin II creates an environment of oxidative stress and induces the release of cytokines, adhesion molecules, and growth factors, which leads to further inflammation and promotes atherogenesis. Tissue ACE and angiotensin II accumulate in the shoulder regions of vulnerable plaques and may contribute to the susceptibility of these plaques to rupture.Other neurohormones are involved in the pathophysiology of CVD. A-type natriuretic peptide (also called atrial natriuretic peptide) and B-type natriuretic peptide (also called brain natriuretic peptide) are smooth muscle relaxants that cause vasodilation and lower blood pressure. B- and A-type natriuretic peptide are released in response to myocyte stretch.20 A-type natriuretic peptide also inhibits the RAAS by blocking secretion of renin and aldosterone, and B-type natriuretic peptide appears to have direct relaxant effects on the myocardium. In addition, both A- and B-type natriuretic peptide inhibit sympathetic nervous system activity in the heart. Both B- and A-type natriuretic peptide generally act to oppose the actions of angiotensin II.21 Arginine vasopressin has been implicated in hyponatremia in heart failure patients.22 Arginine vasopressin acts on the V2 vasopressin receptor, which causes antidiuresis activity in the collecting duct of the kidney. In addition, arginine vasopressin binds to vasopressin V1 receptors on vascular smooth muscle, which may increase vascular resistance.Other hormones that may also be important include vasodilating prostaglandins and the vasoconstrictor endothelin. Prostacyclin and prostaglandin E generally act to counterbalance the vasoconstrictor actions of angiotensin II.22Inflammatory ProcessesAn inflammatory state has been associated with atherosclerosis. In the inflammatory response to endothelial injury, release of chemoattractant proteins (chemokines) promotes entry of monocytes into the vessel wall, where they can transform into macrophages. Macrophages then take up modified and oxidized LDL, becoming foam cells.3 Foam cells contribute to formation of fatty streaks, an early stage of atherosclerotic plaque.23 Repetitive cycles involving ongoing arterial injury, lipid uptake, and vascular remodeling can result in complicated plaques with large necrotic cores, thin fibrous caps, and accumulation of macrophages in the shoulder regions, where plaque rupture tends to occur. When activated by T cells, macrophages release proteolytic matrix metalloproteinases that degrade the fibrous cap and interstitial collagen, which promotes rupture.23,24 One important signaling pathway between T lymphocytes and macrophages is the CD40:CD402 system. Macrophage accumulation appears to be associated with increased levels of inflammatory markers, such as fibrinogen and C-reactive protein.23,25 Thrombosis that results in a clinical event (eg, acute coronary syndrome) may also be caused by a superficial erosion, rather than intimal rupture, of the atherosclerotic plaque; in either case, the immediate site of plaque rupture or erosion is always marked by an inflammatory process.26C-reactive protein has emerged as a useful predictor of atherosclerotic CVD risk.27 Data suggest that C-reactive protein may also be a mediator and not just a marker of inflammation. C-reactive protein induces the expression of tissue factor and cell adhesion molecules, binds and activates complement, stimulates monocytes to enter the vessel wall, promotes the production of monocyte chemotactic protein-1, and mediates macrophage uptake of LDL.13 The role of C-reactive protein as a biomarker for CVD is discussed further in part II of this article.Coagulation CascadeWhen a plaque ruptures, the thrombogenic lipid core is exposed to circulating blood, which activates the coagulation cascade that initiates and sustains thrombus formation. During this process, platelets adhere to the site of trauma and contribute to the formation of thrombin, which converts fibrinogen into strands of fibrin. Fibrin strands trap additional platelets, blood cells, and plasma to form a clot that can partly or completely block an artery.Vascular RemodelingVascular remodeling occurs in response to chronic alterations in hemodynamic conditions that precipitate structural changes in the vessel wall, such as increased ratio of wall to lumen width, changes in luminal dimensions with minimal changes in wall thickness, neointima formation in response to injury, and rarefaction of the microcirculation.4 Inward remodeling typically occurs in response to reduced blood flow and results in decreased vessel size; conversely, outward remodeling usually is a reaction to increased flow and results in increased vessel size.28 Locally produced biologically active mediators, such as NO and matrix metalloproteinases, and growth factors, such as platelet-derived growth factor and transforming growth factor-β, in addition to hemodynamic stimuli, such as shear stress, interact to promote cell migration, cell growth, cell death, and the production and degradation of extracellular matrix, which results in these structural alterations.4,28 The pathophysiological changes in vascular structure that result from alterations in endothelial function have clinical implications.4Vascular remodeling in small resistance arteries may be the initial step in the progression from hypertension to target-organ damage.29 Small resistance arteries that have undergone hyperplastic/hypertrophic remodeling have an enhanced response to vasoconstrictor substances, further reducing vascular reserve. This reduction may contribute to tissue ischemia if surrounding arteries are stenotic. Small-artery remodeling is more common among persons with hypertension than those without, and patients with the highest blood pressures are also the most likely to develop left ventricular hypertrophy (LVH) and have the greatest incidence of small-artery changes.29Cardiac Remodeling and Target-Organ DamageCardiac remodeling is mediated by diverse endocrine, paracrine, and autocrine effects of a number of different hormones that result in hypertrophy.14 The hormones involved in changing the structure, function, and phenotype of the myocardium include angiotensin II, vasopressin, peptide growth factors, endothelin, natriuretic peptides, cytokines, and NO. Evidence indicates that insulin and insulin-like growth factor may be myocardial growth factors, which suggests that altered glucose and insulin metabolism, such as occurs in diabetes and the metabolic syndrome, further contributes to LVH and accelerated heart failure.30,31 Oxidative stress also plays an important role in the cardiac remodeling process; in animal studies, inhibition of antioxidant systems disrupts normal cell growth and apoptosis in cardiac myocytes.14 If uninterrupted, cardiac remodeling results in impaired systolic and diastolic functioning and progresses to heart failure.32Basic science investigations have rendered obsolete the concept that each disease event on the CVD continuum is mediated by a specific and single pathophysiological pathway; rather, common pathophysiological processes participate in multiple steps across the continuum. It is now apparent that common and overlapping mechanisms are involved in disease development across the entire spectrum of CVD. This understanding has therapeutic implications in that many interventions and drugs are effective in treating multiple disease events across the CVD continuum. Clinical trials supporting this conclusion will be discussed next.Clinical Trial Evidence for a Clinical ContinuumValidation of the concept of a clinical CVD continuum is based on clinical trial evidence that intervention disrupts the progression of disease. This review will examine interventional efforts at points along the CVD continuum to prevent or delay CVD and its consequences, with primary focus on major clinical trials published since the CVD continuum was first proposed in 1991. Potential trials to include were identified by performing a search of the MEDLINE literature from 1991 to 2005. Search terms used included the well-established risk factors for CVD and major points along the clinical CVD continuum. The resulting trial lists, organized by therapeutic category, were supplemented by a review of major clinical guidelines. Finally, the trial lists were sent to a panel of expert validators, who determined which trials were the most important to be discussed and who suggested additional trials to be included.Risk Factors for CVDWell-known risk factors for CVD include hypertension, dyslipidemia, diabetes mellitus, cigarette smoking, obesity, and physical inactivity.33 Prevention or control of these risk factors through lifestyle modification (eg, diet, exercise, and smoking cessation) is a key element of preventive cardiology. Many studies investigating lifestyle changes were not designed to quantify benefit on hard clinical end points but instead relied on surrogate end points such as reduced blood pressure and lipid changes and their epidemiological link to decreased CVD risk. Although the present review focuses on specific interventions that have yielded direct benefit on morbidity and mortality, the authors strongly endorse lifestyle modification as a component of optimizing health and effectively managing CVD.Nonpharmacological InterventionsThere exists broad consensus based on evidence from a number of clinical trials that lifestyle modifications can lower the risk of developing CVD and can delay the progression of CVD (secondary prevention).34–42 Trials evaluating the effects of lifestyle modification are summarized in Table I of the online data supplement. For example, reduction or modification of dietary fat intake may be sufficient to reduce cardiovascular events in certain patients.38,43,44 The often-cited Lyon Diet Heart Study38 found that post–myocardial infarction (MI) patients who followed a Mediterranean diet rich in polyunsaturated fat and fiber had a lower risk of cardiac death or recurrent MI than those who followed a typical Western diet high in saturated fats and low in fiber. Among seemingly healthy elderly men and women in Healthy Ageing: a Longitudinal study in Europe (HALE),42 adherence to a Mediterranean diet and healthful lifestyle was associated with a lower rate of all-cause and cause-specific mortality, including death due to coronary heart disease (CHD) and CVD.Some of the benefit derived from the Mediterranean diet in these studies may have been due to increased consumption of fish. One study that specifically examined the impact of dietary supplementation with fish oil was the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI)-Prevenzione trial,39 in which patients with recent (≤3 months) MI were randomized to receive omega (n)-3 polyunsaturated fatty acids, vitamin E, their combination, or no dietary supplementation. After 3.5 years of follow-up, n-3 fatty acids led to a clinically important and statistically significant (P=0.023) benefit on the combined end point of death, nonfatal MI, and stroke. Vitamin E showed no significant benefit.39 In fact, despite the abundant evidence for a role of oxidative stress in the pathophysiology of atherosclerosis, clinical trials of antioxidants such as vitamin E and beta-carotene have consistently yielded disappointing results.45,46More intense regimens that combine strict lifestyle modifications and pharmacological therapy to aggressively lower LDL cholesterol and triglycerides and increase HDL cholesterol levels may be more effective in reducing events in CAD patients than either dietary changes or lipid-lowering therapy alone.35,40 Similarly, evidence from the Steno-2 study indicates that a combination of lifestyle and pharmacological interventions targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria also significantly reduces the risk of CVD events in patients with diabetes and other CHD risk factors.41 Even modest physical activity significantly decreases the risk of developing diabetes. Interestingly, exercise can also lower C-reactive protein levels.Smoking cessation substantially decreases the risk of clinical cardiovascular events. In fact, 1 year after a person quits smoking, the risk of CHD decreases by ≈50%.47 A review48 of 20 studies of smoking cessation found that persons who quit smoking had a 36% reduction in crude relative risk (RR) for all-cause mortality (95% CI 29% to 42%) compared with those who continued to smoke. The crude RR for nonfatal MI was reduced by 32% (95% CI 18% to 43%) in former smokers versus continued smokers. However, the review was not able to assess how quickly these benefits occurred.48Pharmacological InterventionsClinical trials of pharmacological therapy have shown unequivocally that risk factor reduction decreases the risk of morbidity and mortality. Evidence accumulated over the past several decades indicates that antihypertensive treatment with several classes of agents, including diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, and calcium channel blockers, effectively lowers blood pressure in a broad range of patients, while also reducing CVD morbidity and mortality.49,50 In clinical trials, antihypertensive treatment has been associated with reductions averaging 35% to 40% in stroke, 20% to 25% in MI, and >50% in heart failure.33 A meta-analysis51 of 58 randomized trials