Several studies have shown that individuals with prehypertension are at a greater risk for progression to hypertension than those individuals who are normotensive. The rate of progression of prehypertension to hypertension can be relatively rapid, and particularly for those individuals whose BPs lie in the upper prehypertensive range and for the elderly individuals. In the Framingham Heart Study, a stepwise increase in the incidence of hypertension occurred across the three non-hypertensive BP categories; 5.3% of the participants with optimum BP, 17.6% with normal, and 37.3% with high normal BP aged below age 65 years progressed to hypertension over 4 years. Corresponding rates for patients 65 years and older were 16.0%, 25.5% and 49.5%, respectively. Obesity and weight gain also contributed to progression; a 5% weight gain on follow-up was associated with 20-30% increased odds for hypertension.12) The data obtained from two British Health and Lifestyle Surveys conducted 7 years apart were used a subsample of 2,048 normotensive men and women. The estimated RR for the normal BP group was 2.0 and that for the high-normals was 2.9. In this result, prehypertension appears to especially effect the younger high-normals, but these estimates are more conservative than the Framingham-based estimates.13) In the TRial Of Preventing HYpertension (TROPHY) study, 40% of the prehypertensive individuals receiving a placebo developed hypertension over 2 years of follow-up. Because of these rates of progression, annual or biannual monitoring of BP in prehypertensive persons would seem appropriate.14) A community-based integrated screening program in Keelung, Taiwan is the largest study of this type.11) That study showed that prehypertension progresses or regresses and the adjusted progression rate for hypertension is age-dependent and progression to stage 1 hypertension was positively related to the male gender, a higher waist circumference and having parents with hypertension. In our data, the 3-year progression rate to hypertension among the prehypertensive local residents aged 45 or over is 56.4% (56.9% for the men and 55.9% for the women).15)

The CVD risk factors are more commonly associated with prehypertensive individuals than with normotensive individuals. The 1999 to 2000 NHANES data suggested that 64% of prehypertensive subjects have more than one CVD risk factor (94% for the persons 60 years or over). The people with prehypertension were 1.65 times more likely to have at least 1 other adverse risk factor than were those with normotension (p<.001).7) The risk ratios for obesity, dyslipidemia, insulin resistance, metabolic syndrome and diabetes are all greater in the prehypertensive subjects than those in the normotensive subjects and they are intermediate between those risk ratios for the subjects with normotension and hypertension.16-19) Obesity is often associated with prehypertension.6)7)17)19)20) Both general and abdominal obesity could be responsible for the risk of prehypertension.16) In several studies, a higher body mass index (BMI) was the strongest predictor of prehypertension. 17)20)21) Prehypertensive individuals are more likely to have diabetes,19) impaired fasting glucose,20) metabolic syndrome,21) hypercholesterolemia,7)21) raised levels of low density lipoprotein cholesterol (LDL cholesterol) and triglycerides17)20) and reduced levels of high density lipoprotein cholesterol (HDL cholesterol)17)20) than normotensive individuals. Risk factors such as C-reactive protein (from Greece,22) and NHANES III 1988-199423)), serum tumor necrosis factor, interleukin 6, and tumor necrosis factor-[alpha],22)23) amyloid A and homocysteine,22) resistin and adiponectin24) and oxidative stress25) are also more common in people with prehypertension than in those people with normal BP.

People with prehypertension also have greater degrees of target-organ damage than do the normotensive individuals. In the population-based Rotterdam study,26) individuals with prehypertension had significantly smaller arteriolar and venular diameters and arteriolar-venular ratios and a greater intima-media thickness of the carotid artery than did those who had normal BP. Notably, these differences predicted the development of hypertension over a 6.6-year follow-up period. Furthermore, in a Korean study, microalbuminuria was significantly more common among subjects with prehypertension than among normotensive subjects (7.9% vs 4.0%, respectively), and the serum uric acid concentrations were higher in the prehypertensives than in the normotensive individuals with albuminuria.27)

Prehypertension is associated with an increased incidence of CVD, and particularly in those individuals with upper range prehypertensive BP levels and those individuals with diabetes or glucose intolerance.19)28)29) The Framingham Heart Study30) investigated the association between the blood-pressure category at baseline and the incidence of CVD on follow-up among 6859 participants who were initially free of hypertension and CVD. The 10-year cumulative incidence of CVD in the subjects with high-normal BP was 4% for women and 8% for men who were 35 to 64 years old, respectively; for the older subjects (65 to 90 years old), the incidence was 18% for women and 25% for men. As compared with optimal BP, high-normal BP was associated with a risk-factor-adjusted hazard ratio for CVD of 2.5 for women and 1.6 for men. The same conclusion was reached in a meta-analysis of 61 prospective observational studies.5) In the Atherosclerosis Risk in Communities (ARIC) study29) that analyzed 8960 middle-aged adults, the outcome was the incidence of CVD, which was defined as fatal/nonfatal coronary heart disease, cardiac procedure, silent myocardial infarction or ischemic stroke. Compared with optimal BP, the relative risk (RR) of CVD for high-normal blood pressure was 2.33 and the RR for normal BP was 1.81. The prehypertensives have an increased risk of developing CVD relative to those with optimal BP levels. The association is pronounced among blacks, diabetics and among those with high BMI and chronic kidney disease. The more recent data from a Swiss study of 22,927 men also showed higher all-cause and cardiovascular-related mortality in prehypertensives than in normotensives.31) Several analyses of the Framingham Heart Study data have been carried out to identify the types of cardiovascular events that are associated with prehypertension. The original Framingham cohort32) was also associated with an elevated risk of myocardial infarction (hazard ratio or HR: 3.5), coronary artery disease events (HR: 1.7), atherothrombotic brain infarction (HR: 2.2), and all stroke types (HR: 2.3) in the prehypertensives. The NHANES I Epidemiologic Follow-Up Study (NHEFS) and the NHANES II Mortality Study (1992) have also concluded that prehypertension significantly increases the risk for cardiovascular events. In the Strong Heart Study19) there was a synergistic effect of prehypertension and diabetes on the occurrence of CVD events; the hazard ratios for CVD were 3.70 for those individuals with both prehypertension and diabetes, 1.80 for those individuals with prehypertension alone and 2.90 for those individuals with diabetes alone. Impaired glucose tolerance or impaired fasting glucose also greatly increased the CVD risk in prehypertensive people. Currently, the Women's Health Initiative33) is the largest cohort that's reported an elevated risk of cardiovascular events among prehypertensives. Prehypertension is commonly associated with an increased risk of myocardial infarction, stroke, heart failure and cardiovascular death in white and nonwhite postmenopausal women. The Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study34) enrolled a population-based 2,347 Danish nationals between 1982 and 1984, and the study determined the progression rate to hypertension until 1993-1994, and it followed the prognostic significance of progression until 2003. During 9.4 years, 218 first cardiovascular end points (cardiovascular death, nonfatal stroke and nonfatal coronary heart disease) occurred. The hazard ratios were 1.57 for progression to high-normal BP, 1.64 for progression to hypertension and 1.78 for sustained high-normal BP or hypertension. The absolute 10-year cardiovascular risks were 5.1% for optimal or normal BP without progression, 11.1% and 13.9% for progression to high-normal BP or hypertension, respectively, and 18.7% for sustained high-normal BP or hypertension.

Lifestyle modifications are currently recommended to lower BP in those individuals with hypertension or those individuals who are at risk for hypertension.1)2)36-38) Major lifestyle modifications include weight reduction in those individuals who are overweight or obese,21) adoption of the Dietary Approaches to Stop Hypertension eating plan,39) dietary sodium reduction,39-41) physical activity18)42) and moderation of alcohol consumption.43) Nonpharmacological therapies have not prevented cardiovascular events in long-term clinical trials, but lifestyle modifications are necessary for the treatment and prevention of diabetes, dyslipidemia, obesity and other CVDs associated with prehypertension. Weight loss is likely to be the most effective lifestyle modification because of the high prevalence of being overweight and obese (34% and 31%, respectively, in the untreated prehypertensive subjects in the NHANES 1999-2000). In the Framingham study, the participants who successfully reduced their weight by 6.8 kg or more over a 4-year period decreased their risk of developing hypertension by 21-29%. In the Keelung study, the strongest age-independent predictor of regression from prehypertension to normotension was reduction of the BMI. The Dietary Approaches to Stop Hypertension (DASH) eating plan induced a significant lowering of BP, which was reduced even further when dietary sodium was restricted. The PREMIER trial studied the combined effects of lifestyle modification (diet, physical activity and weight reduction) and counseling intervention over an 18-month period.21) All the groups demonstrated significant reductions in BP in both the prehypertensive and hypertensive subjects, and even in the group that was given relatively minimal counseling. Although long-term maintenance of lifestyle modifications is admittedly difficult, many individuals modify their lifestyles successfully for long periods of time and the beneficial effects on BP seem to persist. In the Trial of Nonpharmacologic Intervention in the Elderly (TONE), BP reduction was maintained over 30 months without medication and without the occurrence of cardiovascular events in 44% of the 147 people randomized to both weight loss and sodium-intake restriction.44) Therefore, now is the time to plan improving patients' lifestyle and we should develop better ways to modify lifestyle and maintain the beneficial effects.

All the hypertension guidelines now recommend drug therapy for the patients with diabetes and chronic kidney disease and who are in the prehypertensive range.1)2)36-38) Others advocate a lower-than-usual BP goal for people with established cardiovascular disease or those at high risk (e.g. African Americans). How about antihypertensive drug treatment for prehypertensive subjects in the absence of diabetes or chronic kidney disease? The TROPHY study is the first randomized, placebo controlled, double-blinded clinical trial of pharmacologic intervention for treating prehypertension.14) It was designed to study whether 2 years of treatment with the angiotensin receptor blocker (ARB) candesartan cilexetil at 16 mg daily prevents or delays the development of hypertension during treatment and for up to 2 years after discontinuing treatment in those subjects who are in the upper half of the JNC-7 stage of prehypertension (systolic blood pressure 130-139 mmHg or diastolic blood pressure 85-89 mmHg). 809 study participants were middle-aged (mean age: 49 years old), primarily Caucasian (80% white, 10% African American, 4% Asian and 3% other) and overweight (mean BMI of 29 kg/m²), and approximately 60% of the subjects were male. Their mean BP was 134±4/85±4 mmHg. They had excess additional cardiovascular risk factors. 95% of them had at least one additional risk factor, 80% had two or more and 31% had four or more risk factors. The primary outcome of the trial was the development of hypertension or the development of target organ damage or diabetes. The results demonstrated that pharmacologic treatment can prevent or postpone the development of hypertension with a 66.3% reduction in the incidence of hypertension relative to placebo over the first 2 years (26.8% absolute reduction). Over all four years, including drug withdrawal of 2 years, there was a 15.6% reduction in the incidence of hypertension relative to placebo (9.8% absolute reduction). There was a net difference of 1.1 years of hypertension free time between the placebo (2.2 years, 95% CI 2.0-2.5) and candesartan groups (3.3 years, 95% CI 3.0-3.8). In addition, treatment with 16 mg of candesartan cilexetil was not only safe but also well tolerated with a low report of side-effects which was not significantly different from the placebo group. Yet to translate the results of the TROPHY study into daily practice is another challenge because of the current high cost of the required medication, and candesartan did not significantly reduce cardiovascular disease events. Other drug therapy trials like the Program to Improve Life and Longevity (PILL) and the Aliskiren in Visceral Obesity at Risk Patients Out-comes Research (AVIATOR) are now ongoing. On-going research will probably identify which individuals with blood pressure in the prehypertensive range would benefit from drug treatment.