As a major risk factor for cardiovascular (CV)

R e v i e w P a p e r Assessment of Global Risk: A Foundation for a New, Better Definition of Hypertension Thomas D. Giles, MD The prevalence of individuals with increased blood pressure (BP) is growing. A greater understanding of the various pathogenetic mechanisms of hypertension and associated BP increases would provide a better strategy for preventing and treating this condition. Hypertension is strongly associated with other cardiovascular risk factors. Additionally, there is no threshold of BP >115/70 mm Hg that identifies cardiovascular risk (i.e., risk is linear and doubles for each 20/10-mm Hg BP rise). These insights have led a group of hypertension experts to propose a new definition of hypertension as a progressive cardiovascular syndrome arising from complex and interrelated etiologies, which features early markers that are often present before blood pressure elevation is sustained. Early cardiovascular markers include widened pulse pressure, left ventricular hypertrophy, increased arterial stiffness, endothelial dysfunction, and microalbuminuria. Importantly, antihypertensive treatment for patients with prehypertension (systolic BP of 120 139 mm Hg or diastolic BP of 80 89 mm Hg) has recently been shown to prevent the development of frank hypertension. This revision of the definition of hypertension and the need to assess BP levels in the context of global cardiovascular risk should lead to earlier detection of at-risk patients. (J Clin Hypertens. 2006;8(8 suppl 2):5 14) 2006 Le Jacq From Tulane University School of Medicine, New Orleans, LA Address for correspondence: Thomas D. Giles, MD, 109 Holly Drive, Metairie, LA 70005 E-mail: tgiles4@cox.net www.lejacq.com ID: 5835 As a major risk factor for cardiovascular (CV) and renal morbidity and mortality, hypertension is one of the leading contributors to global disease burden. 1 Using the current definition of hypertension as being present when blood pressure (BP) is >140/90 mm Hg, the prevalence of hypertension may greatly increase worldwide over the next 20 years. 2,3 This projection is based primarily on the strong association of increasing age with an increase in BP, particularly systolic BP (SBP), along with the expected aging of the global population. 2 The links between aging and hypertension and its epidemiologic implications were clarified in a community-based prospective cohort study conducted from 1976 to 1998 in 1298 Framingham Heart Study (FHS) participants, 55 65 years of age, who had a BP <140/90 mm Hg. 3 The study found that the lifetime residual risk for developing an increase in BP in both men and women 55 years and older was 90%, and two thirds of those aged 65 years developed a further increase in BP within 10 years of follow-up (Figure 1). It is estimated that 25% of the world s adult population has a BP >140/90 mm Hg, a total of 972 million individuals, with the highest prevalence in the developed countries of North America and Europe. 2 The worldwide prevalence of hypertension is expected to increase by 9% in men and 13% in women, to 29% of the population, and the total number of hypertensive adults to increase by 60% to 1.56 billion by 2025. 2 The largest proportion of this upsurge is projected to occur in economically developing countries, with Asia and Africa accounting for 75% of such individuals in the future. 2 Hypertension may therefore present an even larger global health problem in 20 years than it does now. At the same time, concepts of the very SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006 THE JOURNAL OF CLINICAL HYPERTENSION 5

Risk of hypertension (%) 100 80 60 40 20 Men Women 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up (yr) Figure 1. The lifetime residual risk for developing hypertension in both men and women aged 55 years and older was 90% in 1298 Framingham Heart Study participants aged 55 to 65 years and normotensive at baseline who were followed for 22 years. Reproduced with permission from JAMA. 2002;287:1003 1010. 3 Table I. JNC 7 Cardiovascular Disease (CVD) Risk Factors and Markers RISK FACTORS MARKERS Age (>55 years for men, Estimated glomerular >65 years for women) filtration rate <60 ml/min Hypertension* Microalbuminuria Cigarette smoking Obesity (body mass index 30 kg/m 2 )* Physical inactivity Dyslipidemia* Diabetes mellitus* Family history of premature CVD (men <55 years, women <65 years) JNC=Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; *components of the metabolic syndrome nature of hypertension and how best to define and treat it have been evolving rapidly in recent years. Hypertension is increasingly being seen not only as a function of elevated BP, but also as part of a complex syndrome of pathologic changes in the vasculature and target organs, leading to CV and renal disease. 4 This broader, global view of CV disease risk is leading to changes in the approach to the prevention, detection, and treatment of hypertension. HYPERTENSION: A COMPONENT OF THE MULTIFACTORIAL CV DISEASE SYNDROME Hypertension seldom occurs in isolation from other CV risk factors. 5 In fact, these associated risk factors may be, in part, responsible for increases in systemic arterial BP. Data from the FHS indicate that >80% of patients with BPs >140/90 mm Hg have at least one of the following metabolically linked CV risk factors: elevated triglyceride and low-density lipoprotein cholesterol (LDL-C) levels; reduced high-density lipoprotein cholesterol (HDL- C); glucose intolerance; hyperinsulinemia; obesity; and left ventricular hypertrophy. 5 In hypertensive patients, about 30% of coronary events in men and 70% in women were attributable to the clustering of two or more CV risk factors in addition to hypertension, according to FHS data. 5 Obesity and weight gain were found in FHS participants to be the most important determinants of the rate of rise in BP and the tendency of other risk factors to cluster; weight loss was correlated with a decreased tendency for risk factor clustering. 5 Excess body fat, particularly abdominal obesity, is strongly related to insulin resistance because visceral adipocytes are relatively insulin-resistant; an increase in visceral adiposity promotes lypolysis and release of excess fatty acids, which contribute to insulin resistance in the liver and skeletal muscles. 6,7 The obesity/insulin resistance syndrome is associated with increased triglyceride levels, reduced HDL-C, and accumulation of small, dense low-density lipoprotein particles. 5 In addition, visceral adipocytes are the source of many adipokines that may contribute to CV pathological remodeling. 8 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) 9 suggests that the major risk factors for CV disease include age, hypertension (defined as a BP >140/90 mm Hg), cigarette smoking, obesity, and diabetes mellitus, while a reduced glomerular filtration rate (estimated <60 ml/min) and the presence of microalbuminuria represent the biochemical markers of increased CV risk (Table I). Included among these risk factors are components of the metabolic syndrome, a subgroup of CV risk factors that tend to cluster, with a prevalence of about 27% among US adults. 10 The metabolic syndrome is a significant, independent risk factor for type 2 diabetes, CV disease and stroke, based primarily on its hallmark characteristic of insulin resistance. 11,12 The metabolic syndrome is defined as the presence of three or more of the following risk factors: abdominal obesity (waist circumference of >40 inches in men and >35 inches in women); hypertriglyceridemia ( 150 mg/dl); HDL-C (<40 mg/dl in men and <50 mg/dl in women); elevated BP ( 130/85 mm Hg); and increased fasting glucose ( 110 mg/dl). 7 Other important risk factors or markers that may indicate the presence of incipient or active CV disease include reduced vascular compliance; absence of nocturnal dipping of BP; left ventricular 6 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006

hypertrophy; increased levels of high-sensitivity C- reactive protein (hs-crp); endothelial dysfunction; small, dense, oxidized LDL-C and increased apolipoprotein B particles; and increased fibrinogen and plasminogen activator inhibitor-1 levels. 13 Improving Prediction of CV Events The burgeoning list of CV risk factors and markers reflects the growing knowledge of mechanisms of CV disease. For example, CV events due to atherosclerosis are not merely a reflection of plaque formation, but are precipitated by inflammatory and oxidative stress factors. 14,15 To improve early detection of increased CV risk, a number of alternate markers of risk for future myocardial infarction (MI) have been proposed, including total plasma homocysteine, lipoprotein(a), hs-crp, fibrinogen, and tissue-type plasminogen activator antigen. 16 In apparently healthy middle-aged men in the Physicians Health Study (PHS), 16 the most powerful predictor of future MI was the combination of hs-crp plus the ratio of total cholesterol to HDL-C; hs-crp and the total cholesterol-to-hdl- C ratio were individually the next most powerful predictors (Figure 2). The PHS population, composed of predominantly middle-class American men, may not be Lipoprotein(a) Total homocysteine TC Fibrinogen tpa antigen TC:HDL-C hs-crp hs-crp + TC:HDL-C 0 1.0 2.0 4.0 6.0 Relative risk for future MI Figure 2. In apparently healthy, middle-aged men in the Physicians Health Study, the most powerful predictor of future myocardial infarction (MI) was high-sensitivity C-reactive protein (hs-crp) plus the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C). tpa=tissue-type plasminogen activator. Reproduced with permission from Ann Intern Med. 1999;130:933 937. 16 reflective of the worldwide population where developing countries now bear 80% of the global incidence of CV disease. 17 The INTERHEART study 17 was conducted in 52 countries, representing every inhabited continent, including 12,461 cases and 14,637 controls, to investigate the associations of various common, established CV risk factors with the incidence of MI in various regions of the world. This study found that smoking, IHD mortality (floating absolute risk and 95% CI) 256 128 64 32 16 8 4 2 1 SBP 120 140 160 180 Usual SBP (mm Hg) Age at risk: 80 89 years 70 79 years 60 69 years 50 59 years 40 49 years 256 128 64 32 16 8 4 2 1 DBP 70 80 90 100 110 Usual DBP (mm Hg) Age at risk: 80 89 years 70 79 years 60 69 years 50 59 years 40 49 years Figure 3. A review of international data from 61 observational studies of blood pressure (BP) and mortality, involving 1 million adults with no previous cardiovascular disease at baseline and 12.7 million person-years, found that in adults aged 40 69 years, each difference of 20 mm Hg systolic BP (SBP) or 10 mm Hg diastolic BP (DBP), starting at a BP threshold of 115/75 mm Hg, was associated with a more than two-fold increase in stroke mortality and a twofold increased risk for death from ischemic heart disease (IHD) and other cardiovascular causes. While these proportional risks were about half as severe in patients aged 80 89 years, the absolute risks were greater in older patients. CI=confidence interval. Reproduced with permission from Lancet. 2002;360:1903 1913. 19 SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006 THE JOURNAL OF CLINICAL HYPERTENSION 7

diabetes, hypertension, and apolipoprotein B and apolipoprotein A-I had the strongest association to MI; however, all nine risk factors measured, which included waist-to-hip ratio, dietary patterns, physical activity, alcohol consumption, and psychosocial factors, were also significantly related to MI risk (p<0.0001 for all except alcohol consumption, p=0.003). Moreover, the clustering of risk factors greatly increased the risk of MI in a graded and multiplicative manner as to the number of risk factors. The four top risk factors cumulatively accounted for 76% of the population-attributed risk for MI; with the addition of obesity, the population-attributed risk increased to 80%. 17 Hypertension as a CV Risk Factor Chronic low-grade inflammation, linked to such factors as components of the metabolic syndrome, is associated with a progressive increase in BP, although the precise mechanisms of this relationship are unclear. 18 The predictive value of hs-crp, smoking, and abdominal obesity to the development of an increase in BP to >140/90 mm Hg was studied prospectively in a cohort of 379 middle-aged men who were normotensive at baseline. 18 After an 11- year follow-up, the 124 men who had developed an increased BP were 2.8 times more likely to have had an hs-crp 3 mg/l than those with hs-crp <1.0 mg/l, after adjustment for other risk factors. Cigarette smoking was also strongly and independently associated with the risk of increased BP. These data help confirm that hypertension is part of a syndrome of frequently clustered CV risk factors characterized by chronic inflammation. Recent data have also clarified the extent to which elevations in BP raise the risk for CV mortality. A review of data from 61 observational studies conducted in Europe, North America, Australia, Japan, and China involving 1 million adults with no previous CV disease at baseline and 12.7 million person-years, found that risks for mortality rose logarithmically per unit increase in BP level starting at a threshold of 115/75 mm Hg. 19 These data also suggest that age itself is by far the most predictive risk. Between the ages of 40 and 69 years, each difference of 20 mm Hg in SBP or of 10 mm Hg in diastolic BP (DBP) was associated with a more than two-fold increase in stroke mortality and a two-fold increase in deaths from ischemic heart disease and other CV causes (Figure 3). While these proportional risks were about half as severe in patients aged 80 89 years as in those aged 40 79 years, the absolute risks were greater in older patients. These data suggested that increases in BP could raise CV risks substantially, even at levels well below 140/90 mm Hg, which is widely accepted as the threshold for hypertension and among individuals who would normally be considered normotensive. 9,19 Based on results from studies of CV risk reductions with antihypertensive therapy, reductions of 10 mm Hg in SBP and 5 mm Hg in DBP could result in long-term risk reductions of 40% for stroke and 30% for ischemic heart disease or other CV disease, throughout middle age. 19,20 Proportionately, a 2-mm Hg reduction in SBP could reduce stroke mortality by 10% and deaths from ischemic heart disease or other CV causes by about 7% in middleaged patients. 19 These assessments, based on the CV risks of elevated BP and supported by an earlier review of previously published observational studies and randomized trials from the FHS and the National Health and Nutrition Examination Survey (NHANES) II 21 populations, involving men and women aged 35 64 in the United States, estimated that a 2-mm Hg reduction in DBP in the mean of the population distribution would result in reductions of 6% in the risk of coronary heart disease (CHD) and 15% in the risk of stroke and transient ischemic attacks. The Importance of SBP In keeping with the increasing breadth and refinement of CV risk factor assessment, such as an evaluation of the entire lipid profile rather than only total cholesterol, specific BP components have also been increasingly studied. Among the major outcomes of this research is the increased emphasis on the importance of elevated SBP in CV disease risk and the corresponding importance of SBP reduction to lower those risks. 9 The JNC 7 report notes that in people older than 50 years, elevated SBP ( 140 mm Hg) is a much more important CV risk factor than DBP. 9 The report also states that reducing SBP should be the primary goal of hypertension treatment because most patients, especially those aged 50 years and older, will reach the diastolic goal once the SBP goal is reached. 9 A meta-regression analysis of 27 hypertension treatment studies, including 136,124 patients, showed that reduction of SBP lowered the risk of CV mortality by up to 50% in proportion to the degree of SBP reduction. 22 In the subset of older patients with isolated systolic hypertension, a decrease of 10 mm Hg in SBP achieved reductions of 30% and 23% in stroke and MI, respectively. 22 In addition, only modest reductions of 5 mm Hg in SBP accounted for much of the benefit in reduced risk of fatal and nonfatal outcomes combined in the entire analysis population. 22 8 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006

JNC VI (1997) BP (mm Hg) Optimal <120 and <80 Normal <130 and <85 High-Normal 130 139 or 85 89 JNC 7 (2003) BP (mm Hg) Normal <120 and <80 Prehypertension 120 139 or 80 89 Hypertension Stage 1 140 159 or 90 99 Stage 2 160 179 or 100 109 Stage 3 180 or 110 Stage 1 140 159 or 90 99 Stage 2 160 or 100 Figure 4. In comparison with the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI), JNC 7 simplified the nonhypertensive blood pressure (BP) categories to better reflect current views of normal and elevated BP levels and consolidated the previous stage 2 and 3 categories into one stage 2 group to emphasize that all individuals with markedly elevated BP levels should be treated equally, urgently, and aggressively. The relative importance of DBP, SBP, and pulse pressure as predictors of CHD is dependent on the age of the patient, which could have a bearing on treatment considerations. Researchers studied 6539 participants in the FHS (3060 men, 3479 women) between 20 and 79 years of age who were free of CHD and were not receiving antihypertensive drug therapy at baseline. 23 Over a 20-year follow-up period, the relationship of BP to CHD risk was assessed with the use of Cox proportional hazards model with adjustment for age, gender, and CV risk factors. After a mean follow-up of 17 years, 807 (12.3%) subjects had developed CHD. An analysis of single BP components showed that DBP was the strongest predictor of CHD risk in subjects younger than 50 years; all three BP components were comparable CHD predictors in patients between the ages of 50 and 59 years; and in those aged 60 years and older, DBP was inversely related to CHD risk while SBP was positively related, making pulse pressure (the difference of SBP and DBP) the strongest CHD risk predictor. 23 Elevated SBP, is therefore, the most important BP target for antihypertensive therapy in patients older than 60 years. Despite the wealth of evidence of the benefits of BP lowering, however, the optimal BP target for antihypertensive treatment has been a controversial subject. HYPERTENSION TREATMENT The JNC 7 committee convened to update the hypertension guidelines for four major reasons: 1) publication of many new hypertension trials since the previous report (JNC VI); 2) publication of an updated, concise, and useful guideline for clinicians; 3) simplification of the classification of BP; and 4) recognition that the JNC reports were clearly not being used to their maximum benefit. 9 SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006 THE JOURNAL OF CLINICAL HYPERTENSION 9

80 Treatment Control 70 60 50 52% 52% 58% All hypertensives Hypertensive diabetics % 40 30 20 10 25% 23% 31% 29% 17% 25% 0 1988 1991 1991 1994 1999 2000 1988 1991 1991 1994 1999 2000 1988 1991 1991 1994 1999 2000 Figure 5. Trends in the treatment and blood pressure control of patients with hypertension in the United States, tracked by the National Health and Nutrition Examination Survey, have been fairly flat since 1988, with only modest improvement in the latest period for which there are data, 1999 2000. Reproduced with permission from JAMA. 2003;290:199 206. 24 Although JNC 7 did not lower the recommended BP goals, it simplified stage 2 and 3 categories into a single stage 2 and introduced the category of prehypertension (Figure 4). 9 The new prehypertension classification, which encompasses patients with SBP 120 139 mm Hg or DBP 80 89 mm Hg, was intended to facilitate identification of individuals at increased risk for increasing BP and, therefore, who might be considered for intervention with lifestyle modifications. The combining of the previous stage 2 and stage 3 hypertension categories into a combined stage 2, defined as a BP level of 160/100 mm Hg, helps to emphasize that all BPs over this level should be treated urgently and aggressively. Need for Improved Hypertension Treatment Although hypertension treatment guidelines have been revised to reflect important advances in research on hypertension as a CV risk factor, major challenges remain. Despite minor improvements in the rates of hypertension treatment and control in the United States, these rates are still grossly inadequate in light of the important role of hypertension in the enormous public health care burden of CV disease and the significant reductions in CV risks associated with BP lowering. NHANES, conducted by the National Center for Health Statistics, has been tracking trends in the awareness, treatment, and control of high BP among US adults since 1960. 24,25 Between 1960 and 1991, hypertension prevalence in the United States decreased, with the possible exception of rates in black men aged 50 years and older, and the entire distribution of SBP and DBP levels shifted downward. 25,26 Yet, NHANES data gathered since 1991 indicate that these improvement trends have slowed (Figure 5). 24 During the period of 1999 2000, the rate of BP control to the recommended level of <140/90 mm Hg was only 31% in all hypertensive patients, while only 25% of treated patients with both hypertension and diabetes mellitus were controlled to their goal of <130/85 mm Hg, according to NHANES data (Figure 5). 24 Clearly, the US health care community fell well short of the US Department of Health and Human Services goal of a 50% BP control rate in the hypertensive population by 2000, and it is highly likely if current trends continue to miss that same goal again in the new target year of 2010. 24 While the 31% BP control rate in hypertensive patients is derived in part from the approximately 40% of this population not receiving any treatment, the rate of BP control in treated patients is only 53%, indicating that the antihypertensive treatment being administered is inadequate almost half of the time. In general, a single antihypertensive drug will lower SBP by 10 mm Hg. 24 The results 10 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006

Table II. Hypertension Writing Group Definition and Classification of Hypertension CLASSIFICATION NORMAL STAGE 1 HYPERTENSION STAGE 2 HYPERTENSION STAGE 3 HYPERTENSION Descriptive category Normal BP or rare BP Occasional or intermittent Sustained BP elevations Marked and sustained elevations AND no identifiable CVD BP elevations OR early CVD OR progressive CVD BP elevations OR advanced CVD Cardiovascular risk factors None or few Several Multiple Multiple Early disease markers None Usually present Overtly present Overtly present with progression Target organ disease None None Early signs present Overtly present with or without CVD events BP=blood pressure; CVD=cardiovascular disease Table III. Early Markers of Cardiovascular Disease BLOOD PRESSURE CARDIAC VASCULAR RENAL RETINAL Loss of nocturnal dipping Exaggerated response to exercise Salt sensitivity Widened pulse pressure Left ventricular hypertrophy (mild) Increased atrial filling pressure Decreased diastolic relaxation Increased arterial stiffness Increased wave reflection and systolic pressure augmentation Increased carotid intima media thickness Coronary calcification Endothelial dysfunction Microalbuminuria Elevated creatinine Decreased estimated glomerular filtration rate Hypertensive retinal changes of major trials have shown that more than half of all hypertensive patients require two or more antihypertensive drugs to reach their BP goals. 27 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 28 the largest completed hypertension trial in the United States (N=33,357), 63% of patients required two or more drugs to reach their BP goal. In the Hypertension Optimal Treatment Trial (HOT), 29 68% of patients required more than one agent. In the United Kingdom Prospective Diabetes Study (UKPDS), 30 29% of patients needed three or more drugs to achieve a BP of <150/85 mm Hg at 9 years after randomization. A major reason for the need for multiple agents to lower elevated BP to goal level is that hypertension is a multifactorial disease. Effective combination therapy usually includes agents from different antihypertensive drug classes with different mechanisms of action that often potentiate each other. 9 The increasing recognition of the multifactorial nature of hypertension, its strong association with various other CV risk factors and comorbidities, and the need for hypertension treatment to address these factors contributed to the attempt to establish a new definition of hypertension that could help improve prevention and treatment of this disease. A NEW DEFINITION OF HYPERTENSION The Hypertension Writing Group, which presented the new definition of hypertension at the 2005 meeting of the American Society of Hypertension, expanded the JNC 7 definition and classification of hypertension by incorporating the presence or absence of risk factors, early disease markers, and target organ damage in addition to BP levels. This redefinition was intended to assist practitioners in identifying individuals at risk for CV disease at an earlier point in the disease process. 4 The Writing Group proposed a new definition of hypertension as follows: Hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before blood pressure elevation is sustained; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds. Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature and other organs and lead to premature morbidity and death. 4 The Writing Group further explained the need for a redefinition of hypertension by noting that any one CV risk factor taken in isolation, such as BP level, has limited prognostic value; since sporadic BP elevations may occur in individuals with no evidence of early CV disease, a diagnosis of hypertension based on such an isolated factor may be inaccurate. 4 Conversely, patients with a BP below the threshold value of 140/90 mm Hg may still have hypertension based on other risk factors or the presence of functional or structural cardiac and vascular abnormalities. 4 Based on these concepts, SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006 THE JOURNAL OF CLINICAL HYPERTENSION 11

the Hypertension Writing Group proposed to convert classification of hypertension from the four categories of JNC 7 normal, prehypertension, stage 1, and stage 2 to normal and hypertension stages 1, 2, and 3 as defined by the patient s overall CV risk profile (Table II). The three stages of hypertension in the new Hypertension Writing Group definition correspond not only to BP level but also to the presence of other CV risk factors, disease markers, or target organ disease (Table II). Early markers of CV disease include BP, cardiac, vascular, renal, and retinal abnormalities (Table III). They may provide key indications of vascular abnormalities or disease, even in the absence of elevated resting BP. For example, an exaggerated BP response to exercise a rise of perhaps 190 to 200 mm Hg is likely a sign of a rigid and sclerosed arterial system. Research in Early CV Disease The hypotheses that hypertensive CV disease begins to develop in many patients even before BP levels are elevated to 140/90 mm Hg and that antihypertensive therapy may significantly reduce CV risks in such patients are supported by data from several large, long-term trials. In the 4-year Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 31 (N=6105), antihypertensive drug therapy with the angiotensin-converting enzyme inhibitor perindopril, with the addition of the diuretic indapamide at the discretion of treating physicians, produced significant and similar relative risk reductions (RRRs) for stroke, compared with placebo, in both normotensive (RRR, 27%) and hypertensive (RRR, 32%) patients with a history of stroke or transient ischemic attack (p<0.01 for both subgroups). Combination therapy seemed to confer advantages over single-drug therapy. The RRRs for stroke with combination therapy were 44% in hypertensive patients and 42% in the nonhypertensive population. Active therapy also produced similar RRRs of 29% in the hypertensive patients and 24% in the nonhypertensive group for total major vascular events (RRR, 26% overall). While patients were considered to be hypertensive in PROGRESS if they had an SBP of 160 mm Hg (well above the current SBP threshold of 140 mm Hg) or a DBP of 90 mm Hg, the mean BP at baseline of those designated nonhypertensive was 136/79 mm Hg, compared with 159/94 mm Hg in the hypertensive group, and the mean baseline BP in the total population was 147/86 mm Hg. Similarly, the 2-year Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study 32 (N=1991) investigated the effects of antihypertensive treatment with the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril on CV disease events in patients with normal BP (DBP <100 mm Hg; mean BP of 129/77.5 mm Hg at baseline) and angiographically documented CHD. This study found that, compared with placebo, an amlodipine- but not enalapril-based treatment program significantly reduced CV disease morbidity and mortality (RRR, 31%; p=0.003 with amlodipine), although the difference in the primary end point between amlodipine and enalapril was not significant. In addition, the Trial of Preventing Hypertension (TROPHY) 33 investigated whether pharmacologic treatment would prevent or postpone the development of stage 1 hypertension among individuals with prehypertension. This 4-year randomized trial was conducted in 809 patients with high-normal SBP/DBP levels of 130 139 mm Hg or 85 89 mm Hg, respectively, which would include patients in the JNC 7 prehypertension category. 34 Baseline profile data for the TROPHY participants revealed a strikingly common prevalence of CV risk factors other than elevated BP. Among the TROPHY patients, 96% had at least one additional CV risk factor, including various measures of dyslipidemia, insulin resistance, and obesity, as well as elevated hematocrit and heart rate values; 81% had two or more additional risk factors; and 33% had four or more additional risk factors. 34 The most prevalent risk factor in the cohort was being overweight, which might have been linked to insulin resistance and the clustering of metabolic risk factors. In their report, the TROPHY investigators clearly suggest that the risk of CV disease begins to rise before the diagnosis of hypertension is evident and most likely is caused by other concurring risks in addition to a rising BP. Although lifestyle modifications such as weight loss, dietary salt restriction, and exercise are the recommended treatment for prehypertension, the investigators revealed that such therapies have not yet demonstrated significant long-term efficacy in preventing hypertension in the United States. A total of 409 patients were randomized to the angiotensin II receptor blocker candesartan and 400 to placebo for 2 years, after which all patients were given placebo for an additional 2 years; data on 772 patients were ultimately available for analysis. After 2 years, hypertension had developed in 154 patients in the placebo group and 53 patients in the candesartan group, representing a significant 63% RRR with pharmacotherapy (p<0.001); after 4 years, 240 12 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006

Cumulative incidence (%) 100 90 80 70 60 50 40 30 20 10 0 No. of patients without hypertension: Candesartan group Placebo group 0 391 381 Placebo 1 2 3 4 Study year 356 269 309 184 191 118 Candesartan 127 85 Figure 6. In the Trial of Preventing Hypertension (TROPHY), patients with high-normal blood pressure (BP) of 130 139 mm Hg systolic BP or 85 89 mm Hg diastolic BP were randomized to treatment with candesartan or placebo for 2 years and then placebo for all patients for an additional 2 years. Study data were available for 772 patients. Kaplan-Meier analysis shows that after 2 years, new-onset hypertension had developed in 154 (40%) patients in the placebo group and 53 (14%) patients in the candesartan group, representing a significant relative risk reduction of 63% with pharmacotherapy (p<0.001); after 4 years, 240 (63%) patients in the placebo group vs. 208 (52%) in the candesartan group had become hypertensive, a significant 15.6% relative risk reduction (p<0.007). Reproduced with permission from N Engl J Med. 2006;354:1685 1697. 33 patients in the placebo group vs. 208 in the candesartan group had become hypertensive, a significant 15.6% RRR (p<0.007) (Figure 6). The TROPHY data thus illustrate that antihypertensive therapy may help prevent the development of elevated BP levels among individuals with BP <140/90 mm Hg who are at high risk for frank hypertension. Despite the advances made over the past 40 years in hypertension treatment, further improvement could have a huge impact on the US public health burden. The failure to control BP in hypertensive Americans results in an estimated 12,000 to 32,000 avoidable deaths each year, at an annual cost of $382 million to $1 billion, according to a report of the National Committee for Quality Assurance. 35 CONCLUSIONS Despite major advances in the understanding and treatment of hypertension, progress in alleviating the burden of this disease is slowing in developed nations; simultaneously, the incidence of hypertension is increasing rapidly worldwide, particularly in underdeveloped nations. Mounting evidence has shown that hypertension rarely occurs alone but is usually associated with one or more additional CV risk factors, such as smoking, obesity, dyslipidemia, and hyperglycemia, which tend to cluster. Because of the interdependent and interactive nature of CV risk factors, some researchers have begun to doubt the clinical efficacy of defining hypertension solely as a threshold level of BP, currently 140/90 mm Hg. Data suggest that patients with BP levels below this threshold may have early or overt CV disease, whereas many patients with elevated BP may have no other signs of CV disease. Therefore, a new definition of hypertension has been proposed that describes hypertension as a complex and progressive CV syndrome that cannot be identified by a discrete BP level alone but, rather, should be diagnosed on the basis of the entire CV risk profile, with a particular focus on vascular abnormalities. Recent trial evidence in patients with prehypertension supports this approach by showing that many patients with BP levels below the hypertension threshold, but above optimal levels, are at significantly increased risk of hypertension and CV disease. REFERENCES 1 Ezzati M, Lopez AD, Rodgers A, et al., and the Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet. SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006 THE JOURNAL OF CLINICAL HYPERTENSION 13

2002;360:1347 1360. 2 Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217 223. 3 Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA. 2002;287:1003 1010. 4 Giles TD, Berk BC, Black HR, et al., on behalf of the Hypertension Writing Group. Expanding the definition and classification of hypertension. J Clin Hypertens (Greenwich). 2005;7:505 512. 5 Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens. 2000;13(suppl 1):3S 10S. 6 Sowers JR. Recommendations for special populations: diabetes mellitus and the metabolic syndrome. Am J Hypertens. 2003;16(11 pt 2):41S 45S. 7 Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486 2497. 8 Wang P, Mariman E, Keijer J, et al. Profiling of the secreted proteins during 3T3 L1 adipocyte differentiation leads to the identification of novel adipokines. Cell Mol Life Sci. 2004;61:2405 2417. 9 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560 2572. 10 Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27:2444 2449. 11 Scuteri A, Najjar SS, Morrell CH, et al. The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care. 2005;28:882 887. 12 Zavaroni I, Bonini L, Gasparini P, et al. Hyperinsulinemia in a normal population as a predictor of non-insulindependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited. Metabolism. 1999;48:989 994. 13 McFarlane SI, Kumar A, Sowers JR. Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol. 2003;91(suppl 1):30H 37H. 14 Ross R. Atherosclerosis an inflammatory disease. N Engl J Med. 1999;340:115 126. 15 Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973 979. 16 Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med. 1999;130:933 937. 17 Yusuf S, Hawken S, Ounpuu S, et al., on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937 952. 18 Niskanen L, Laaksonen DE, Nyyssonen K, et al. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension. 2004;44:859 865. 19 Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903 1913. 20 Blood Pressure Lowering Treatment Trialists Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356:1955 1964. 21 Cook NR, Cohen J, Hebert PR, et al. Implications of small reductions in diastolic blood pressure for primary prevention. Arch Intern Med. 1995;155:701 709. 22 Staessen JA, Wang J-G, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;358:1305 1315. 23 Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001;103:1245 1249. 24 Hajjar I, Kotchen T. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988 2000. JAMA. 2003;290:199 206. 25 Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension. 1995;26:60 69. 26 Goff DC, Howard G, Russell GB, et al. Birth cohort evidence of population influences on blood pressure in the United States, 1887 1994. Ann Epidemiol. 2001;11:271 279. 27 Bakris GL, Williams M, Dworkin L, et al., for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646 661. 28 Cushman WC, Ford CE, Cutler JA, et al., for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393 404. 29 Hansson L, Zanchetti A, Carruthers SG, et al., for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755 1762. 30 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703 713. 31 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033 1041. 32 Nissen SE, Tuzcu EM, Libby P, et al., for the CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:2217 2226. 33 Julius S, Nesbitt SD, Egan BM, et al., for the Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensinreceptor blocker. N Engl J Med. 2006;354:1685 1697. 34 Nesbitt SD, Julius S, Leonard D, et al., and the TROPHY Study Investigators. Is low-risk hypertension fact or fiction? Cardiovascular risk profile in the TROPHY study. Am J Hypertens. 2005;18:980 985. 35 National Committee for Quality Assurance. The State of Health Care Quality: 2005. Available at: http://www.ncqa. org/communications/news/sohc_2005.htm. Accessed May 10, 2006. 14 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 8 NO. 8 AUGUST 2006