REVIEW Circ J 2009; 73: 1381 – 1385

High-Normal and the Risk of Cardiovascular

Yoshihiro Kokubo, MD; Kei Kamide, MD*

The guidelines of the Joint National Committee 7 from the USA on have unified the normal and high-normal blood pressure categories into a single entity termed ‘prehypertension’. In contrast, The European Guidelines for the management of hypertension in 2007 considered ‘prehypertensive’ to be divided into normal and high-normal blood pressure. These patients with high-normal blood pressure or prehypertension might prog- ress to hypertension over time. Previous studies have shown that high-normal blood pressure is a risk factor for (CVD) in Western countries and Japan. The combination of high-normal blood pressure and other cardiovascular risk factors increases the risks of CVD. Recently, metabolic syndrome has also been shown to be a risk factor for CVD. In Japan, the association between metabolic syndrome and CVD was also found to be significant. The risks for CVD incidence were similar among participants who had the same number of components, regardless of the presence of abdominal obesity. In the Japanese guidelines for the management of hypertension published in 2009, patients are considered to be in a high-risk group if they have , chronic kidney disease, 3 or more risk factors, target organ damage or CVD, even if they have only high-normal blood pressure, and appropriate antihypertensive therapy should be initiated. (Circ J 2009; 73: 1381 – 1385) Key Words: Blood pressure category; Cardiovascular ; General population; Prospective studies; Risk factors

ypertension is a strong risk factor for cardiovascu- 1–3 High-Normal Blood Pressure lar disease (CVD) worldwide. Approximately, and Prehypertension H 50% in men and 30% in women with CVD inci- dence could be described as excessive incidence because In 2003, the JNC 7 on hypertension unified the normal and of higher blood pressure (≥120/80 mmHg).4 A decline in the high-normal blood pressure categories into a single entity annual incidence has been observed over a long period termed ‘prehypertension’.11 This change was based on in the , the Hisayama Study, and evidence from the Framingham Heart Study that the chance other cohorts1,2,5–7 in response to lowering blood pressure of developing hypertension is higher in these ‘prehyperten- and decreasing the smoking rate.8 sive’ patients than in those with optimal blood pressure Recently, slightly elevated blood pressure has been found (<120/80 mmHg) at all ages.12,13 It has been estimated that to be associated with the incidence of CVD.4,7,9 To prevent 31% of the general adult population in USA16 falls into the CVD, blood pressure should be kept as low as possible. prehypertensive category, as do 38% of men and 33% of The European Society of Hypertension and the European women in a general urban Japanese population.4 Society of (ESH-ESC) guidelines for the man- Previous studies have reported that individuals with agement of arterial hypertension consider prehypertensive high-normal blood pressure have a higher progression rate to be categorized into ‘normal blood pressure’ (systolic and risk of hypertension, compared with those with normal blood pressure (SBP) 120 to 129 mmHg or diastolic blood blood pressure.14,15 In 2007, the ESH-ESC Committee has pressure (DBP) 80 to 84 mmHg) and ‘high-normal blood decided not to use the term ‘prehypertension’ for the fol- pressure’ (SBP 130 to 139 mmHg or DBP 85 to 89 mmHg).10 lowing reasons: (1) even in the Framingham Heart study, In contrast, the guidelines of the Joint National Committee the risk of developing hypertension was definitely higher 7 from the USA (JNC 7) on hypertension have unified the in patients with high-normal blood pressure than in those normal and high-normal blood pressure categories into a with normal blood pressure;9,14 (2) because of the serious single entity termed ‘prehypertension’.11 In this article, high- meaning of the word hypertension for general populations, normal blood pressure is compared with prehypertension, the term ‘prehypertension’ might create anxiety and lead to and this category is reviewed as a risk factor for CVD. unnecessary consultations with a doctor; (3) this category is a highly differentiated one in practice, with the extremes (Received May 12, 2009; revised manuscript received May 20, 2009; consisting of patients in no need of any intervention as well accepted May 21, 2009; released online July 14, 2009) as of those with a very high-risk profile such as diabetes, Department of Preventive Cardiology, National Cardiovascular Cen- chronic kidney disease (CKD), or hyperlipidemia for whom ter, *Department of Geriatric Medicine, Osaka University Graduate drug treatment is required, although lifestyle changes School of Medicine, Suita, Japan recommended by the JNC 7 for all prehypertensive indi- Mailing address: Yoshihiro Kokubo, MD, Department of Preventive 11 Cardiology, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita viduals can be a valuable population strategy. 565-8565, Japan. E-mail: [email protected] All rights are reserved to the Japanese Circulation Society. For permis- sions, please e-mail: [email protected]

Circulation Journal Vol.73, August 2009 1382 KOKUBO Y et al.

High-Normal Blood Pressure Progression years. High-normal blood pressure has also been associated with increased risk of carotid atherosclerosis,33 altered to Hypertension cardiac morphological features,27 and diastolic ventricular Optimal, normal, and high-normal blood pressure might dysfunction,26 all of which might be precursors of CVD. progress to hypertension over time. In the Framingham Heart Study, the progression rates to hypertension over a High-Normal Blood Pressure 4-year period were 5%, 18%, and 37% for the younger age (aged 35 to 64 years) groups with optimal, normal, and and CVD in Japan high-normal blood pressure, and were 16%, 26%, and 50% Of the prospective studies examining the incidence of for the older (aged 65 to 94 years) age groups with optimal, CVD in Japanese populations, the Suita study showed that normal, and high-normal blood pressure, respectively.14 the risks of and stroke for high-normal Clinical trial data from patients with high-normal blood blood pressure and hypertension (Stage ≥1 group) were pressure showed that 40% over 2 years and 63% over 4 observed in men (hazard ratio =2.3, 95% confidence inter- years developed hypertension,17 which is consistent with vals: 1.0–5.3 and hazard ratio =3.4, 95% confidence inter- the Framingham Heart study.14 There are several potential vals: 1.6–6.8 for myocardial infarction; hazard ratios =2.0, reasons for progression to hypertension in individuals with 95% confidence intervals: 1.0–4.2 and hazard ratios =3.3, high-normal blood pressure relative to optimal and normal 95% confidence intervals: 1.8–6.2 for stroke, respectively). blood pressure groups. First, individuals with high-normal The multivariable hazard ratio of CVD incidence in women blood pressure require a smaller increment of blood pres- was 2.1 (95% confidence intervals: 1.3–3.6) for the hyper- sure on follow-up to progress to hypertension than the other tension (Stage ≥1 groups).4 groups.14 Second, risk factors for hypertension are more The Ohasama study showed that high-normal blood pres- common in the high-normal blood pressure group.18 sure is a risk factor for stroke by using home blood pressure rather than causal blood pressure.34 The Hisayama study, High-Normal Blood Pressure which observed the natural course of untreated hyperten- sion in a general Japanese elderly population over a 32-year and Precursors of CVD period, indicated that high-normal blood pressure is not a Elevated concentrations of C-reactive protein,19,20 tumor risk factor for cerebral infarction.35 This cohort was approx- necrosis factor-α,20 homocysteine,21,22 oxidized low-density imately half the size of the participants of the Suita study, lipoprotein,23 gamma-glutamyltransferase,24 microalbumin- and the patients were older and observed for longer periods. uria,25 and other inflammatory markers20,23 are associated Hypertensive risk for CVD decreased with advancing age.36 with higher blood pressure. High-normal blood pressure has Over very long periods, confounding factors, including been associated with increased carotid intima and media advancing age, menopause, lifestyle modifications, and thickness,26 altered cardiac morphological features,26 and medication, might affect the blood pressure classification. diastolic ventricular dysfunction,27 which might be precur- The Tanno-Sobetu Study determined that high-normal blood sors of cardiovascular events. The additive effect of more pressure, determined according to the 1999 World Health than 1 risk factor on the risk of CVD has been well estab- Organization/International Society of Hypertension (WHO/ lished.28,29 Thus, high-normal blood pressure is considered ISH) criteria, is not a risk factor for CVD in comparison to to be associated with an increased risk of ischemic heart optimal and normal blood pressures, because of the small disease and stroke compared with optimal blood pres- sample size.37 sure.9,13,30 Some prospective studies have looked at mortality from CVD in Japanese populations. Murakami et al have sum- High-Normal Blood Pressure marized a relationship between prehypertension and overall mortality by performing a meta-analysis of data from and CVD in Caucasians 13 population-based cohort studies conducted in Japan The Framingham Heart study has indicated that men and (176,389 participants).38 In this study, the interactions women with high-normal blood pressure have a more than between age and SBP for all causes of mortality were 2-fold increase in relative risk for CVD compared with statistically significant (P for interaction =0.01 for men and those who have optimal blood pressure.9 This finding was 0.02 for women). The primary prevention of high blood further confirmed by tests for trend (P for trend =0.01 for pressure for all-cause of mortality reduction has a greater men and <0.001 for women). In analyses accounting for the benefit for younger than for older groups, although the blood pressure category during follow-up, the association of absolute levels of all causes of mortality are lower for those high-normal blood pressure with an increased risk of car- who are younger. Sairenchi et al have showed that high- diovascular events persisted in men (hazard ratio =1.6, 95% normal blood pressure is associated with an increased risk confidence intervals: 1.1–2.3) but was attenuated in women of CVD mortality in Japanese men.39 The NIPPON DATA (hazard ratio =1.8, 95% confidence intervals: 1.0–3.1). 80 also indicate that high blood pressure is a risk factor for Compared with optimal blood pressure, the hazard ratio mortality from all-causes as well as death from CVD among of CVD is 2.3 (95% confidence intervals: 1.9–2.9) for high- Japanese.40 All of these studies have used endpoints of normal blood pressure, and is 1.8 (95% confidence intervals: mortality. The risk of CVD incidence, as used in this study, 1.5–2.2) for normal blood pressure among blacks.31 A posi- is a more direct measure of CVD risk than is the risk of tive association of normal blood pressure and stage I hyper- CVD mortality, which is heavily influenced by treatment. tension with coronary heart disease were observed in men, Recently, 2 larger cohort studies have been investigated compared with optimal blood pressure.32 The Framingham in Japan. The Ohsaki study showed that hazard ratios (95% Heart study showed that 17.6% and 37.3% of individuals confidence interval) for CVD mortality for prehypertension with baseline normal and high-normal blood pressure, and hypertension were 1.3 (0.6–2.9) and 3.0 (1.4–6.4) in the respectively, were diagnosed with hypertension within 4 middle-aged group, and 1.0 (0.6–1.7) and 1.7 (1.0–2.6) in

Circulation Journal Vol.73, August 2009 High-Normal Blood Pressure and CVD 1383

Table 1. Previous Criteria Proposed for the Definition of Metabolic Syndrome Components WHO, 1998 NCEP-ATPIII, 2001 IDF, 2005 Japanese, 2005 Insulin resistance IGT, IFG, Type 2 DM, or Any 3 of the following None None lowered insulin sensitivity. 5 components Plus any 2 of the following Obesity WHR >0.9 for men and WC ≥102 cm in men Increased WC, population-specific. WC ≥85 cm in men >0.85 and/or BMI >30 kg/m2 or ≥88 cm in women Plus any 2 of the following or ≥90 cm in women. Plus any 2 of the following Lipids TG ≥150 mg/dl and/or TG ≥150 mg/dl and/or TG ≥150 mg/dl TG ≥150 mg/dl and/or HDL <35 mg/dl in men HDL <40 mg/dl in men HDL <40 mg/dl in men HDL <40 mg/dl or <39 mg/dl in women or <50 mg/dl in women or <50 mg/dl in women Blood pressure ≥140 / 90 mmHg ≥130 / 85 mmHg ≥130 / 85 mmHg ≥130 / 85 mmHg Glucose IGT, IFG, ≥110 mg/dl* ≥100 mg/dl ≥110 mg/dl or type 2 DM including diabetes including diabetes including diabetes Other Microalbuminuria

IGT, impaired glucose intolerance; IFG, impaired fasting glucose; WC, waist circumference; BMI, body mass index; TG, triglycerides. Subjects taking medication for hypertension, hyperlipidemia, or diabetes were included as having that component. *The 2001 definition identified fasting plasma glucose of ≥110 mg/dl. This was modified in 2004 to be ≥100 mg/dl, inaccordance with the American Diabetes Association’s updated definition of IFG.

Table 2. Stratification of Cardiovascular Risk in 4 Categories on the Basis of Blood Pressure Classification and Risk Strata High-normal Grade I Grade II Grade II Risk strata (risk factors other than blood pressure) blood pressure hypertension hypertension hypertension No other risk factors No additive risk Low risk Moderate risk High risk 1 to 2 risk factors (other than diabetes) Moderate risk Moderate risk High risk High risk or metabolic syndrome 3 or more risk factors, diabetes, chronic kidney disease, High risk High risk High risk High risk target organ damage/cardiovascular disease) the elderly, respectively.41 The Japan Public Health Center- and Japanese definitions, the presence of abdominal obesity based Prospective Study (JPHC Study) showed that the is the essential component for a diagnosis of metabolic contributions of normal blood pressure, high-normal blood syndrome. Among the several definitions of metabolic pressure, and mild hypertension to the occurrence of stroke syndrome, the definitions of higher blood pressure was events are greater than those made by moderate and severe 140/90 mmHg based on the World Health Organization hypertension, highlighting the importance of primary pre- criteria and 130/85 mmHg (high-normal blood pressure) vention and of treatment for low-to-moderate degrees of based on the NCEP-ATPIII, IDF, and the Japanese criteria. hypertension.42 In a general urban Japanese population, the association between metabolic syndrome and CVD was found to be Combination of Higher Blood Pressure significant when the NCEP-ATPIII definition is applied. Metabolic syndrome based on the Japanese criteria was and Cardiovascular Risk factors associated with CVD incidence in women, whereas in men, The combination of higher blood pressure and cardiovas- the association was found only in those under 60 years of cular risk factors leads to an increased risk of CVD. age. In addition, the risks for CVD incidence were similar Recently, metabolic syndrome, which involves a clustering among participants who had the same number of compo- of impaired glucose metabolism, abdominal fat accumula- nents regardless of the presence of abdominal obesity. We tion, dyslipidemia (hypertriglyceridemia and hypo high- have shown that the components of metabolic syndrome density lipoprotein cholesterol), and elevated blood pres- synergistically increase CVD risk. Abdominal obesity does sure, has also been shown to be a risk factor for CVD.43 not affect the association between the number of metabolic Metabolic syndrome has been defined in several ways by syndrome components and the risk for CVD incidence. The several groups (Table 1), including WHO,44 the European combination of risk factors per se is therefore more impor- Group for the Study of Insulin Resistance,45 the American tant than abdominal obesity for conferring risk. Association of Clinical Endocrinologists, and the National The Japanese Society of Hypertension Committee for Cholesterol Education Program Adult Treatment Panel III Guidelines for the Management of Hypertension published (NCEP-ATPIII).46 However, these definitions are aimed their guidelines in 2009.50 In these guidelines, patients are primarily at Western countries. The International Diabetes considered to belong to a high-risk group if they have Foundation (IDF)47 and the American Heart Association48 diabetes mellitus, CKD, 3 or more risk factors, target organ have recently introduced alternative definitions that can damage or CVD, even those with high-normal blood pres- be applied worldwide.46 The Japanese Committee on the sure, and appropriate antihypertensive therapy must be Criteria for metabolic syndrome has recently proposed a initiated (Table 2). definition for metabolic syndrome.49 Under both the IDF In the Suita study, compared with the optimal blood pres-

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