The Role of Exercise Training in the Treatment of Hypertension An Update

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1 REVIEW ARTICLE Sports Med 2000 Sep; 30 (3): /00/ /$20.00/0 Adis International Limited. All rights reserved. The Role of Exercise Training in the Treatment of Hypertension An Update James M. Hagberg, Jung-Jun Park and Michael D. Brown Department of Kinesiology, University of Maryland, College Park, Maryland, USA Contents Abstract Effect of Exercise Training on Blood Pressure (BP) in Patients With Hypertension Overall Effect on Systolic and Effect of Gender Effects of Age Effects of Exercise Training Intensity Effects of Exercise Training Length Effect of Weight Loss Effects of Ethnicity Role of Genetics in BP Reduction Resulting from Exercise Training Exercise Training and Other Cardiovascular Disease Risk Factors in Patients With Hypertension Plasma Lipoprotein-Lipid Levels Glucose and Insulin Metabolism Left Ventricular Hypertrophy Overall Effects of Exercise Training Conclusion Abstract Hypertension is a very prevalent cardiovascular (CV) disease risk factor in developed countries. All current treatment guidelines emphasise the role of nonpharmacological interventions, including physical activity, in the treatment of hypertension. Since our most recent review of the effects of exercise training on patients with hypertension, 15 studies have been published in the English literature. These results continue to indicate that exercise training decreases blood pressure (BP) in approximately 75% of individuals with hypertension, with systolic and diastolic BP reductions averaging approximately 11 and 8mm Hg, respectively. Women may reduce BP more with exercise training than men, and middle-aged people with hypertension may obtain greater benefits than young or older people. Low to moderate intensity training appears to be as, if not more, beneficial as higher intensity training for reducing BP in individuals with hypertension. BP reductions are rapidly evident although, at least for systolic BP, there is a tendency for greater reductions with more prolonged training. However, sustained BP reductions are evident during the 24 hours following a single bout of exercise in patients with hypertension.

2 194 Hagberg et al. Asian and Pacific Island patients with hypertension reduce BP, especially systolic BP, more and more consistently than Caucasian patients. The minimal data also indicate that African-American patients reduce BP with exercise training. Some evidence indicates that common genetic variations may identify individuals with hypertension likely to reduce BP with exercise training. Patients with hypertension also improve plasma lipoprotein-lipid profiles and improve insulin sensitivity to the same degree as normotensive individuals with exercise training. Some evidence also indicates that exercise training in hypertensive patients may result in regression of pathological left ventricular hypertrophy. These results continue to support the recommendation that exercise training is an important initial or adjunctive step that is highly efficacious in the treatment of individuals with mild to moderate elevations in BP. In 1995, we reviewed all available English literature articles that had assessed the role of exercise training in the treatment of hypertension. [1] Since then, 15 additional papers in the English literature have addressed this issue. [2-16] Furthermore, the US National Heart, Lung, and Blood Institute s Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) Report Number VI [17] continued to highlight the role that nonpharmacological interventions, including exercise training, play in the treatment of hypertension. Such nonpharmacological interventions are especially important in the 90% of hypertensive patients with mild to moderate blood pressure (BP) elevations (systolic BP 140 to 180mm Hg, diastolic BP 90 to 110mm Hg). The first goal of this review is to reassess the role of exercise training in the treatment of hypertension in light of the new evidence that has been published since our last review. The second goal is to summarise new information regarding the role that genetics may play in determining which patients with hypertension reduce their BP with exercise training. The third goal is to summarise the available literature on the effects of exercise training on other cardiovascular (CV) disease risk factors in patients with hypertension. This third goal is based on the fact that hypertension patients primarily die from CV disease, and elevated BP is only one of a number of CV disease risk factors often evident in these individuals. It is important to bear in mind that in the recently published studies, as in those published previously, there is a wide range in the age, gender and ethnicity of participants. In fact, the participants included in these 15 new publications [2-16] range from 40 to 75 years of age. Five of the study groups consisted of only female patients with hypertension, 8 consisted of only male patients, and 14 groups had populations that combined men and women. In addition, 12 study groups consisted of only Caucasian patients with hypertension, 10 had only Asian/Pacific Island patients, 1 included only African-American patients, 1 included only African patients, and 3 had mixed groups of Caucasian and African-American patients. There was also a wide range of exercise training programmes, with training length ranging from 8 to 78 weeks, training frequency ranging from2to6trainingsessionsperweek,andtraining intensity ranging from 50 to 80% of maximal oxygen uptake (V. O 2max ). This variability among the recent and previouslypublishedstudiescanbeviewedasanassetor as problematic when attempting to derive final conclusions about the effect of exercise training in patients with hypertension. The variability among studies is problematic because usually numerous participant or exercise training characteristics vary between studies. When comparing 2 studies, this generally makes it impossible to determine which specific study design differences might affect BP response differences. On the other hand, these dif-

3 Exercise Training and Hypertension 195 ferences in participant and exercise training characteristics among studies can be an asset because, with enough studies, we can assess the effects of each study design variable on the BP responses of hypertension patients to exercise training by pooling all of the study results, as we have done in the past [1,18] and as we will do in this review. 1. Effect of Exercise Training on Blood Pressure (BP) in Patients With Hypertension 1.1 Overall Effect on Systolic and In all previously published studies, there was a total of 74 groups of patients with hypertension, consisting of a total of 1284 individuals, who initially had systolic BP > 140mm Hg and who underwent endurance exercise training. A total of 56 of these groups, or 76%, decreased systolic BP significantly with exercise training. The initial systolic BP in these individuals, weighted for the sample size in each group, averaged 153mm Hg and the weighted systolic BP reduction with exercise training averaged 10.6mm Hg. Thus, while endurance exercise training resulted in a significant and substantial reduction in systolic BP in those with systolic hypertension, on average these individuals continued to be hypertensive after exercise training with a systolic BP that remained > 140mm Hg. In all studies, 73 groups of patients who initially had diastolic hypertension (diastolic BP > 90mm Hg) underwent endurance exercise training. These groups contained a total of 1261 individuals with diastolic hypertension. Of these 73 groups, 59, or 81%, reduced diastolic BP significantly with exercise training. These individuals initially had an average weighted diastolic BP of 97mm Hg and the average weighted reduction in diastolic BP with exercise training was 8.2mm Hg. Thus, with training the average individual in these studies reduced their initial diastolic BP from 97 to 89mm Hg, just below the conventional lower limit of diastolic hypertension of 90mm Hg. These results are very similar to those in our previousreviewbasedon47studiesandmorethan 900 patients with hypertension who underwent exercise training. [1] We previously concluded that 70% of groups with systolic hypertension reduced systolic BP significantly with exercise training and the average reduction was 10.5mm Hg, from 154 to 143mm Hg. For those with diastolic hypertension, 78% of groups reduced diastolic BP significantly andthereductionaveraged8.6mmhg,from98to 89mm Hg. 1.2 Effect of Gender Hypertension is equally prevalent in men and women. [19] However, because estrogen is known to modulate BP, it is possible that the effects of exercise training on BP will differ between men and women. Therefore, it is important to determine whether exercise training-induced reductions in BP differ between men and women with hypertension. Overall, the data generally support the conclusion that women with hypertension reduce their BP somewhat more and somewhat more consistently with exercise training than men. All of the studies inwomenwithhypertension(10of10groups)reported significant systolic BP reductions with exercise training and the average weighted reduction in systolic BP was 14.7mm Hg, whereas in men 72% of the studies reported significant reductions and the reductions averaged 8.7mm Hg. Studies that had combined populations of men and women had an average systolic BP reduction of 10.7mm Hg, a value intermediate between the individual averages for men and women, and 73% of these groups reduced systolic BP significantly with exercise training. The numbers of patients in these studies were 156, 330 and 794 for the women, men andcombinedgroups,respectively. The same general trend existed for exercise training-induced reductions in diastolic BP. Women with diastolic hypertension more consistently significantly reduced diastolic BP with exercise training (89%) and had a larger average diastolic BP reduction(10.5mmhg)thanmen(82%and7.8mm Hg, respectively). The number of women and men

4 196 Hagberg et al. in these studies were 132 and 404, respectively. Combined groups of men and women with diastolic hypertension, which amounted to a total of 721 individuals, had an average diastolic BP reduction of 8.0mm Hg with exercise training, and 81% of these groups reduced diastolic BP significantly with exercise training. 1.3 Effects of Age Since the prevalence of hypertension in the general population increases dramatically with age, [19] it is imperative to determine if the BP-lowering effects of exercise training are evident in hypertension patients of different ages (table I). In all of the studies published to date, it appears that middleaged patients with hypertension, those 41 to 60 years of age, reduced systolic BP somewhat more and somewhat more consistently with exercise training than younger or older patients. However, as we indicated in our previous review, this conclusion must be interpreted cautiously as the number of young and older patients were substantially less than in the middle-aged group. In all of the studies published previously, it appears that the reduction in diastolic BP resulting from exercise training is similar in individuals of all ages, although again minimal data are available in the young and older patients with hypertension. 1.4 Effects of Exercise Training Intensity Our previous reviews [1,18] and results of exercise training studies in animal models of hypertension [20] indicate that low to moderate intensity exercise training may be just as effective as higher intensity training for reducing BP in individuals with hypertension. The results of all studies published to date continue to support this conclusion. Those studies that used training intensities < 70% V. O 2max had approximately 50% greater systolic BP reductions than studies with training intensities 70% V. O 2max. reductions were only slightly larger in studies that used a training intensity less than as opposed to 70% V. O 2max (table II). The percentage of groups exhibiting significant BP reductions with exercise training was the same for both training intensities. Thus, these results continue to indicate that low to moderate intensity endurance exercise training is just as, if not more, efficacious as higher intensity training for reducing BP in hypertensive individuals. This result is especially important from the public health viewpoint because such low to moderate intensity exercise programmes are much easier for patients with hypertension to initiate and maintain, compared with higher intensity exercise programmes that result in more musculoskeletal injuries and CV events and require more medical supervision. Table I. Summary of the effects of age on systolic and diastolic blood pressure (BP) changes during exercise training in patients with hypertension Age of participants (years) Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c a The average weighted reduction is the average reduction in BP with exercise training weighting the average for the sample size of each study and assigning a value of zero to the change for studies with nonsignificant reductions. b The % groups reducing is the percentage of the total number of groups that reduced BP significantly with exercise training. c The total sample size is the sum of the number of hypertensive individuals (systolic BP > 140mm Hg; diastolic BP > 90mm Hg) that were in the studies (see section 1.3).

5 Exercise Training and Hypertension Effects of Exercise Training Length When advising patients of the benefits of starting a programme of increased physical activity, a critical issue that affects their enthusiasm and motivation is the length of time necessary before they begin to see benefits. In this case, the overall results of all previously published studies can be very useful in motivating patients, because the reductions in BP are observed very rapidly. For both systolic and diastolic BP, significant and substantial reductions were already evident after only 1 to 10 weeks of exercise training (table III). Thus, this response does not require many months or years of exercise training to elicit. In addition, systolic BP continues to decrease somewhat more when training continues for 11 to 20 weeks, or more than 20 weeks. On the other hand, diastolic BP does not appear to decrease further with more prolonged training. A number of years ago it was reported that BP in a single patient with hypertension was reduced for a number of hours after one acute endurance exercise session. [21] This initial report was followed by a number of studies investigating this response. The consensus is that systolic BP in hypertension patients is generally reduced for a number of hours following an acute bout of exercise. However, diastolic BP is decreased to a lesser extent, with many studies reporting nonsignificant reductions in diastolic BP following a single bout of exercise. [22,23] These early studies generally monitored patients during short recovery periods following exercise, up to several hours, and the recovery usually occurred in a confined laboratory setting. Brownley and colleagues [24] recently reported significant reductions in ambulatory BP for a number of hours following a single moderate intensity exercise session in middle-aged men and women with initial systolic/diastolic BP values that averaged 136/94mm Hg. They found that both systolic and diastolic BP were significantly lower, by 6 and 4mm Hg, respectively, for the first 5 hours following exercise. For hours 5 to 9 following exercise, nonsignificant trends towards reduced BP values werefoundontheexercisedaycomparedwiththe Table II. Summary of the effects of exercise training intensity on systolic and diastolic blood pressure (BP) in patients with hypertension Training intensity <70% V. O 2max >70% V. O 2max Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c a The average weighted reduction is the average reduction in BP with exercise training weighting the average for the sample size of each study and assigning a value of zero to the change for studies with nonsignificant reductions. b The % groups reducing is the percentage of the total number of groups that reduced BP significantly with exercise training. c The total sample size is the sum of the number of hypertensive individuals (systolic BP > 140mm Hg; diastolic BP > 90mm Hg) that were in the studies (see section 1.4). V. O 2max= maximal oxygen uptake. control day. BP values during sleep were not different on the exercise day compared with the control day. We recently compared 24-hour ambulatory BP in middle-aged and older sedentary men with hypertension after 45 minutes of endurance exercise versus an otherwise similar day without prior exercise. [25] In these men, systolic BP was reduced by 6 to 13mm Hg (p < 0.05) for the first 16 hours following exercise, and the 24-hour systolic BP reduction averaged 7.4mm Hg (p < 0.01). Diastolic BP was decreased by approximately 5mm Hg (p < 0.05) for 12 of the first 16 hours after exercise, and the diastolic BP reduction over the entire 24 hours averaged 3.6mm Hg (p < 0.01). However, while the BP responses of patients with hypertension following acute exercise are of interest in terms of BP regulatory mechanisms, no evidence to date indicates that the BP-lowering response following acute exercise is predictive of the BP-lowering response to prolonged exercise training. Eight of those men in our previous study of the effect of an acute bout of exercise on ambulatory

6 198 Hagberg et al. Table III. Summary of the effects of exercise training length on systolic and diastolic blood pressure (BP) in patients with hypertension Training length (weeks) Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c a The average weighted reduction is the average reduction in BP with exercise training weighting the average for the sample size of each study and assigning a value of zero to the change for studies with nonsignificant reductions. b The % groups reducing is the percentage of the total number of groups that reduced BP significantly with exercise training. c The total sample size is the sum of the number of hypertensive individuals (systolic BP > 140mm Hg; diastolic BP > 90mm Hg) that were in the studies (see section 1.5). BP following exercise [25] also had BP assessed after 9 months of exercise training. [7] In these men, the correlations between the BP change resulting from prolonged training did not correlate significantly with any of the ambulatory BP measures following acute exercise (total 24 hours, day, night) with the correlations ranging from 0.20 to 0.47 (p =0.23to0.89). Thus, it appears that the BP-lowering effect of exercise training is evident very early in an exercise training programme (1 to 10 weeks). Furthermore, most evidence indicates that in sedentary patients with hypertension, significant reductions in BP, especially systolic BP, are evident for a number of hours following a single session of submaximal endurance exercise. 1.6 Effect of Weight Loss Another nonpharmacological intervention commonly recommended for individuals with mild to moderate BP elevations is weight loss. [17] An important mechanistic issue is whether the exercise training-induced BP reductions are related to, and potentially the result of, the varying amount of weight loss that occurs with exercise training. In the 61 previous studies that reported bodyweight changes in hypertensive patients with exercise training, the correlation between reduction in systolic BP and the reduction in bodyweight was 0.11 [p = not significant (NS)]. The relationship was even weaker between the reduction in bodyweight and the reduction in diastolic BP (r = 0.07, p = NS). Thus, the exercise training-induced reductions in systolic and diastolic BP do not appear to be the result of the small and highly variable changes in bodyweight that occur with endurance exercise training. Another important practical question is whether combining a weight loss programme with endurance exercise training results in greater BP reductions than either intervention independently. Two recent studies have directly compared the BP-lowering effects of these different interventions. The first of these studies compared the effects of 12 weeks of exercise with and without weight loss, and weight loss by dietary means. [15] Dietary sodium intake was restricted to < 2.3 g/day during the study in only the 2 dietary intervention groups. All 3 interventions had the desired overall effects as the exercise training group increased V. O 2max by 10%, the diet group decreased bodyweight by approximately 6kg, and the combined intervention group increased V. O 2max by 9% and decreased bodyweight by approximately 7kg. Although there was a tendency for the combined intervention group to reduce both systolic and diastolic BP somewhat more ( 12.5/ 7.9mm Hg), the differences were not sig-

7 Exercise Training and Hypertension 199 nificant compared with exercise training ( 9.9/ 5.9 mm Hg) or diet ( 11.3/ 7.5mm Hg) used independently. We recently reported similar results in middleaged and older overweight men with hypertension with much longer interventions (9 months). [7] In these men, weight loss by dietary restriction resultedinanapproximate9kgweightlossbutno change in V. O 2max, endurance exercise training resulted in an approximate 1kg weight loss and an 18% increase in V. O 2max, and dietary restriction combined with exercise training resulted in an approximate 9kg weight loss and a 16% increase in V. O 2max. However, the BP reductions in these groups were similar, with the reductions averaging 12, 9 and 11mm Hg for systolic BP, and 8, 7 and 9mm Hg for diastolic BP in the weight loss, exercise training and exercise training/weight loss groups, respectively. It is important to note that sodium intake was also controlled in this study, so that all volunteers were ingesting approximately 3g sodium/day, Table IV. Summary of the effects of ethnicity on systolic and diastolic blood pressure (BP) changes with exercise training in patients with hypertension Ethnic group Caucasians Asian/Pacific Islanders Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c Average weighted reduction (mm Hg) a % Groups reducing b Total sample size c a The average weighted reduction is the average reduction in BP with exercise training weighting the average for the sample size of each study and assigning a value of zero to the change for studies with nonsignificant reductions. b The % groups reducing is the percentage of the total number of groups that reduced BP significantly with exercise training. c The total sample size is the sum of the number of hypertensive individuals (systolic BP > 140mm Hg; diastolic BP > 90mm Hg) that were in the studies (see section 1.7). whether they were in a caloric restriction group or an exercise training group. Thus, it appears that the effects of exercise training on BP in patients with hypertension are not dependent on substantial reductions in bodyweight with exercise training. Furthermore, the evidence indicates that the BP-lowering effects of exercise training and dietary-induced weight loss are not additive. 1.7 Effects of Ethnicity In our most recent review, [1] we assessed the impact of ethnicity on the BP responses of individuals with hypertension to exercise training and concluded that Asian/Pacific Island patients with hypertension reduced their systolic BP more consistently and to a greater extent than Caucasian patients. On the other hand, both of these ethnic groups appeared to reduce diastolic BP to the same extent and with the same consistency (table IV). The same general trends for different BP-lowering responses to exercise training in patients with hypertension with different ethnic backgrounds were also evident after considering the studies published since our previous review. Asian and Pacific Island patients with hypertension appeared to reduce systolic BP more with exercise training and more consistently than Caucasian patients. As we found previously, diastolic BP reductions with exercise training appeared to be similar in Asian/Pacific Island and Caucasian patients. Unfortunately, only minimal information is available in African-American patients with hypertension, in whom the prevalence of hypertension is among the highest in the world and the effects are devastating. However, in 1995 Kokkinos and coworkers [10] published an important paper on the effects of exercise training on African-American men with severe hypertension. Men in this study had systolic BP > 180mm Hg or diastolic BP > 110mm Hg, and in the first phase of the study BP was controlled with a standard medication regimen. In spite of this treatment with medications, after 16 weeks of exercise training systolic BP showed a tendency towards a further reduction ( 7mm Hg; p = 0.13),

8 200 Hagberg et al. while diastolic BP was reduced significantly ( 5mm Hg; p = 0.002) with exercise training. The same general BP trends were evident after 32 weeks of exercise training, despite the fact that antihypertensivemedicationswerereducedby24to38%in10 of the 14 patients in the exercise group. Thus, it appears that exercise training has a substantial and significant effect on the BP of African Americans with hypertension and may substantially reduce their need for antihypertensive medications. However, many more studies are necessary in African-American patients before this somewhat preliminary conclusion can be substantiated. 2. Role of Genetics in BP Reduction Resulting from Exercise Training Since ethnicity appears to play a substantial role in determining BP responses to exercise training in patients with hypertension, we began to explore potential genetic bases for this differential response, as genetic background can differ widely among ethnic groups. BP clearly has a genetic basis, with heritability estimates ranging from 25 to 65%. [19] In recent years, numerous candidate genes have been investigated to assess their role in predisposing individuals to hypertension. One demonstration of this interest is the fact that in only the past 2 years, 37 individual papers assessing the relationship between common polymorphic gene variations and a person s risk of having or developing hypertension have been published in the American Heart Association journal Hypertension, which is only one of many journals that would be an appropriate forum for such findings. The list of genes with common polymorphic variations that have been assessed relative to their risk of hypertension in the journal Hypertension in the last 2 years includes angiotensinogen, angiotensin converting enzyme, α-adducin, epithelial sodium channels, glucagon receptor, transforming growth factor β-1, tyrosine hydroxylase, β 2 -andβ 3 -adrenergic receptors, apolipoprotein B, renin, G protein β 3 subunit, aldosterone synthase, enos, inos, endothelin-1, kallikrein, angiotensin II Type 1 receptor, and glucocorticoid receptor loci. Initial interest in this area was focused on common polymorphic variations that occur at the angiotensin converting enzyme (ACE) and angiotensinogen (AGT) gene loci, as such genes could easily be proposed to be putative hypertension genes because of their involvement in the renin-angiotensin system. Initial reports found that the ACE genotype was associated with increased prevalence or risk of developing hypertension. [26] This is not generally believed to be the case at the present time because further studies have not replicated this finding. However, 2 recent studies indicated that the ACE genotype may affect BP via its interactions with gender, age and body size. [27,28] The common M235T variant at the AGT locus also was initially believed to provide substantial information concerning a person s risk of developing or having hypertension. [29] Two recent reviews indicated that AGT genotype is related to risk of hypertension, but the effects are smaller than initially indicated. [30,31] A meta-analysis of 69 published reports relating AGT genotype to BP/hypertension indicated that the AGT TT genotype is associated with a 31% increased risk and the MT genotype an 11% increased risk of developing hypertension compared with otherwise similar individuals with the MM genotype. [31] We recently reported [32] that genotypes at putative CV system-related gene loci may identify hypertensive individuals who reduce their BP the most with endurance exercise training. With 9 months of endurance exercise training, older overweight hypertensive men with the ACE II or ID genotype decreased both their systolic and diastolic BP significantly more than otherwise similar hypertensive men having the ACE DD genotype (fig. 1). In these same men, APO E3 and E4 genotype individuals reduced their systolic BP significantly more and tended to reduce their diastolic BP more than APO E2 men with hypertension (fig. 2). Similarly, men with the lipoprotein lipase (LPL) HindIII +/+ or +/ genotype decreased both systolic and diastolic BP more than men with the LPL HindIII / genotype (fig. 3). Finally, hypertensive men with the LPL PvuII +/+ genotype decreased both systolic and diastolic BP significantly more with ex-

9 Exercise Training and Hypertension 201 BP changes (mm Hg) * ercise training than hypertensive men with the LPL PvuII / or +/ genotypes (fig. 4). In general, these genotype groups were similar prior to exercise training in terms of age, bodyweight, body composition and V. O 2max.Inafewof these cases, the more responsive genotype group had somewhat higher BP prior to exercise training. In virtually all cases, the changes in bodyweight, body composition and V. O 2max with exercise training were the same in all genotype groups. These men all underwent a highly standardised exercise training intervention and were all on a standardised low fat, low salt diet for 2 months prior to initiating exercise training. Because of the relatively small number of men in this study, we were not able to assess which of these markers played the greatest independent role in determining BP reductions with exercise training. Thus, these results provide strong preliminary evidence that the degree to which hypertensive individuals decrease BP with exercise training may be affected by common genetic polymorphisms at critical gene loci related to the CV system. In a previous study we determined the effect of 7 consecutive days of moderate intensity exercise on insulin sensitivity and ambulatory BP in middle-aged to older hypertensive African-American ** II+ID DD II+ID DD ACE genotype Fig. 1. Changes in systolic and diastolic blood pressure (BP) in men with hypertension during endurance exercise training as a function of ACE genotype. * indicates change with exercise training different between genotype groups at p = 0.16; ** indicates change at p < women. [33] Ambulatory BP in the entire group of women did not change significantly following the 7 days of exercise. However, ACE II women tended to reduce 24-hour diastolic and mean BP, day systolic BP, and night systolic, diastolic and mean BP, whereas otherwise similar women with the ACE ID genotype experienced no changes whatsoever in ambulatory BP. We also obtained genotypes at a number of putative CV gene loci in men in our previous study on the effect of an acute exercise bout on 24-hour ambulatory BP. [25] Although the sample sizes were small, a number of genotypes appeared to identify individuals more likely to reduce ambulatory BP following a single acute session of endurance exercise. AGT TT genotype men reduced 24-hour systolic,diastolicandmeanbpby7to11mmhgmore (all p < 0.04) than otherwise similar men with the AGT MT genotype. Furthermore, hypertensive men with the LPL HindIII +/ genotype, the LPL PvuII / or +/ genotype, or the ACE II or DD genotype generally tended to reduce 24-hour systolic, diastolic and mean BP more (p = 0.07 to 0.19) than otherwise similar men with other genotypes at these loci. Thus, these results provide preliminary evidence that the BP-lowering effect of a single exercise session in patients with hypertension may be affected by a person s genotype at these putative CV system gene loci. 3. Exercise Training and Other Cardiovascular Disease Risk Factors in Patients With Hypertension From the evidence summarised in the first section of this review, it is clear that exercise training has a beneficial impact on the BP of the large majority of individuals with hypertension. However, it is important to bear in mind that JNC V and VI [17,34] both indicate that treatment of patients with hypertension should be based on the outcome of the treatment relative to overall CV disease risk, because hypertension is only one risk factor for CV disease and mortality in patients with hypertension is the result of CV disease, not hypertension. It is also important to bear in mind that the different compo-

10 202 Hagberg et al. BP changes (mm Hg) nents of the insulin resistance syndrome, including hypertension, insulin resistance, hyperinsulinaemia, abnormal plasma lipoprotein-lipid levels, obesity and accelerated atherosclerosis, tend to cluster in patients with hypertension. This further emphasises the need to treat this entire constellation of CV disease risk factors, as opposed to only reducing the BP of patients with hypertension. In our most recent review, the potential benefits of exercise training for patients with hypertension in terms of other major CV disease risk factors had to be extrapolated from results in normotensive individuals, because the effects of exercise training on other major CV disease risk factors had not been assessed in patients with hypertension. [1] However, a number of recent studies have quantified the effects of exercise training on other major CV disease risk factors in patients with hypertension. 3.1 Plasma Lipoprotein-Lipid Levels * E2 E3+E4 E2 E3+E4 APO E genotype Fig. 2. Changes in systolic and diastolic blood pressure (BP) in men with hypertension during endurance exercise training as a function of APO E genotype. * indicates change with exercise training different between genotype groups at p < Endurance exercise training is generally believed to beneficially affect the different components of the plasma lipoprotein-lipid profile. [35] At present 7 studies have assessed the impact of endurance exercise training on plasma lipoprotein-lipid levels in patients with hypertension. [2,8,36-40] In terms of total plasma cholesterol levels, 2 of the 7 studies found significant reductions with exercise training, with 2 other studies exhibiting nonsignificant reductions in plasma total cholesterol levels with exercise training. The initial plasma total cholesterol levels averaged 206 mg/dl and the reductions averaged 7 mg/dl. Three of 5 studies found significant reductions in plasma low density lipoprotein cholesterol (LDL-C) levels in hypertensive patients with exercise training, with the initial levels averaging 127 mg/dl and the reductions averaging 9 mg/dl. Three of 6 studies reported significant increases in plasma high density lipoprotein cholesterol (HDL-C) levels in hypertensive patients with exercise training, with initial values averaging 42 mg/dl and the increases averaging 3 mg/dl. One study assessed HDL 2 -C level changes with exercise training in patients with hypertension and reported a doubling of the levels (1.9 to 3.9 mg/dl) with 9 months of exercise training, [2] while a second study reported that plasma HDL 2 -C levels increased by approximately 35% with 10 weeks of exercise training. [39] Forplasmatriglyceride(TG)levels,2ofthe7 studies reported significant reductions in patients with hypertension with exercise training, with initial values averaging 159 mg/dl and the reductions averaging 15 mg/dl. Those participants in the studies that reported significant reductions in plasma TG levels with exercise training had the highest initial plasma TG levels. [2,37] A previous review concluded that in the general population, exercise training reduced plasma total and LDL-C levels by approximately 10 mg/dl, but these reductions were generally not statistically significant. [35] Exercise training longer than 12 weeks resulted in an average HDL-C level increase of 5 mg/dl, while TG levels only decreased with exercise training in those with initially elevated levels. [35] Thus, the changes in plasma lipoprotein-lipid levels in patients with hypertension undergoing exercise training are very similar to those reported with exercise training in the general population. [35] Therefore, in addition to beneficially affecting BP in the large majority of hypertensive patients, endurance exercise training also reduces CV disease

11 Exercise Training and Hypertension 203 risk by improving the components of the plasma lipoprotein-lipid profile (total cholesterol, LDL-C, HDL-C, HDL 2 -C and TG levels) associated with altered CV disease risk. 3.2 Glucose and Insulin Metabolism The evidence now also clearly indicates that, as in the general population, insulin sensitivity is increased with endurance exercise training in those with hypertension. This is especially important because patients with hypertension have consistently been found to be insulin resistant compared with their normotensive peers. [41,42] At least 3 studies have reported reductions in fasting insulin levels in hypertensive patients with exercise training. [40,43,44] During oral glucose tolerance tests, 4 studies have also reported significant reductions in integrated glucose and insulin response areas after exercise training compared with before such training; [2,4,7,44] results consistent with improved insulin sensitivity resulting from exercise training. Recently, definitive results documenting enhanced insulin sensitivity in hypertensive patients with exercise training have been published. [2] This study used hyperinsulinaemic euglycaemic clamps and found that glucose disposal rate increased by approximately 40% at 2 submaximal plasma insulin levels, while maximal responsiveness did not change significantly. We have also reported that 7 consecutive days of 50 minutes of exercise per day at 65% V. O 2max increased the insulin sensitivity index (determined using an intravenous glucose tolerance test), by 58% in middle-aged African-American female patients with hypertension. [33] Initially, 11 of these 12 women were insulin resistant (Bergman Minimal Model S I < 3.0), but after 7 days of exercise only 6 were still insulin resistant, despite the fact that they experienced no changes in bodyweight or composition. Thus, these data all clearly demonstrate that the increase in insulin sensitivity that occurs with exercise training in the general population also occurs in patients with hypertension undergoing exercise training. 3.3 Left Ventricular Hypertrophy Another CV disease risk factor that is especially critical for individuals with hypertension is left ventricular hypertrophy (LVH). [19] Three of the 4 studies that have assessed LVH in patients with hypertension undergoing exercise training have reported significant reductions in LV mass index. [10,13,45] The reductions in LV mass index in these 3 studies averaged 12% from an average initial value of 137 g/m 2. This degree of reduction in LV mass index would indicate that, on average, with exercise training these individuals changed their status from one of LVH to either a normal LV or one undergoing concentric remodelling. [46] All 3 studies that reported LV mass index reductions with exercise training also reported decreased posterior wall and intraventricular septal thicknesses, although in some cases the changes were not significant, without changes in LV end-diastolic dimensions. This would indicate that they had converted or were in the process of converting from concentric to eccentric LVH, or from concentric LV remodelling to a normal LV. Both of these changes would result in substantial mortality reductions in these patients with hypertension. [47] BP changes (mm Hg) * +/+ and +/ / +/+ and +/ LPL Hind III genotype Fig. 3. Changes in systolic and diastolic blood pressure (BP) in men with hypertension during endurance exercise training as a function of LPL HindIII genotype. * indicates change with exercise training different between genotype groups at p < * /

12 204 Hagberg et al. BP changes (mm Hg) * / and +/ +/+ / and +/ LPL Pvu II genotype Fig. 4. Changes in systolic and diastolic blood pressure (BP) in men with hypertension during endurance exercise training as a function oflplpvuiigenotype. * indicates change with exercise training different between genotype groups at p = TheonestudythatreportedanincreaseinLV mass index with training was the only training programme that included some amount of resistance training. [38] However, the LVH observed in this study was of the eccentric type, as posterior wall and intraventricular septal wall thicknesses did not change with exercise training. Thus, exercise training appears to have substantial benefits for hypertensive patients in terms of regression of their pathological LVH. If these improvements are replicated in future studies, this regression of LVH resulting from exercise training could result in dramatic reductions in mortality in patients with hypertension. [47] 3.4 Overall Effects of Exercise Training * +/+ Thus, it is clear that exercise training has substantial benefits for individuals with hypertension, not only in terms of reducing BP but also by improving a number of other risk factors that dramatically increase their risk of developing CV disease. CV disease risk equations based on the Framingham Study [48] estimate that approximately 10% of 50- year-old men and women with systolic/diastolic BP of 153/97mm Hg, cholesterol of 206 mg/dl and HDL- C of 42 mg/dl who are nonsmokers without type 2 diabetes mellitus and LVH would develop CV disease within 10 years (fig. 5, case A). These baseline values are the average for all values summarised earlier in this review. This risk is reduced substantially (by approximately 25%), with the average CV disease risk factor changes elicited with exercise training ( systolic/diastolic BP = 11/ 8mm Hg, cholesterol = 7 mg/dl, HDL-C = +3 mg/dl). The same individuals who also have type 2 diabetes mellitus have an approximately 16% risk of developing CV disease in the next 10 years (fig. 5, case B). If exercise training elicits the usual changes in CV disease risk factors in these individuals and eliminates their type 2 diabetes mellitus, which is quite possible based on numerous previous studies and those summarised above, [2,33,48,49] their risk would be reduced by approximately 50%. If these same individuals have both type 2 diabetes mellitus and LVH, their risk of developing CV disease in the next 10 years increases to 35% (fig. 5, case C). If these individuals elicit the expected improvements in CV disease risk factors with exercise training, and they eliminate type 2 diabetes mellitus and LVH with exercise training, their risk of developing CV disease in the next 10 years is reduced by approximately 80%. These estimated reductions in CV disease risk with exercise training are clearly dramatic and substantial for patients with hypertension. Importantly, the risk reductions are also greatest in those hypertensive patients with the highest risk. These reductions in CV disease risk with exercise training are also substantially larger than the CV disease morbidity and mortality reductions evident in large antihypertensive medication trials. [19] 4. Conclusion The overall results encompassing all studies published in the English literature continue to support the conclusion that exercise training decreases BP in the large majority of patients with hypertension, with systolic and diastolic BP reductions averaging approximately 11 and 8mm Hg, respectively. Some evidence indicates that women (compared with men) and the middle-aged (compared with young and older patients with hypertension) may obtain greater

13 Exercise Training and Hypertension 205 benefits with exercise training. The overall results indicate that low to moderate intensity training reduces BP the same as, or even more than, higher intensity training. BP reductions are evident early in a training programme, although for at least systolic BP, there is a tendency for greater reductions with more prolonged training. Prolonged BP reductions are also evident during the 24 hours following a single bout of exercise in sedentary patients with hypertension. Ethnicity also affects the BP-lowering effect of exercise training, with Asian/Pacific Island patients with hypertension reducing BP, especially systolic BP, more and more consistently than Caucasian Risk and % risk reduction Risk % Reduction Risk % Reduction Risk % Reduction Case A Case B Case C Fig. 5. Risk of developing cardiovascular (CV) disease for hypertensive individuals with different combinations of CV disease risk factors and the reductions in risk expected with exercise training. Case A: Average 10-year risk for a 50-year-old man and woman with systolic/diastolic blood pressure (BP) = 153/97mm Hg, cholesterol = 206 mg/dl, high density lipoprotein cholesterol (HDL-C) = 42 mg/dl, nonsmoker, and not having diabetes mellitus or left ventricular hypertrophy (LVH). Percentage risk reduction in these individuals is that resulting from usual CV disease risk factor changes with exercise training in patients with hypertension ( BP = 11/ 8mm Hg, cholesterol = 7 mg/dl, HDL-C = +3 mg/dl). Case B: same man and woman as in case A except that both have type 2 diabetes mellitus [noninsulin-dependent diabetes mellitus (NIDDM)]. The type 2 diabetesmellitusiseliminatedwithexercisetraininginboththe man and woman, and all other expected changes as in case A occur with exercise training. Case C: same man and woman as in case A except that both have type 2 diabetes mellitus and LVH. Type 2 diabetes mellitus and LVH are eliminated with exercise training in both the man and the woman, and all other expected changes as in case A occur with exercise training. All risks are calculated using the equations of Anderson et al. [48] based on the Framingham Study. patients. The minimal data available indicate that African-American patients also reduce BP with exercise training. Some preliminary evidence indicates that common genetic variations may identify those hypertensive patients likely to reduce BP the most with exercise training. Individuals with hypertension also improve plasma lipoprotein-lipid profiles and insulin sensitivity to the same degree with exercise training as normotensive individuals. Preliminary evidence also indicates that exercise training in patients with hypertension may result in regression of pathological LVH. These results continue to support and emphasise the recommendation that exercise training is an important initial or adjunctive step in the treatment of individuals with mild to moderate elevations in BP. References 1. Brown M, Hagberg J. Does exercise training play a role in the treatment of essential hypertension? J Cardiovasc Risk 1995; 2: Dengel DR, Hagberg JM, Pratley RE, et al. Improvements in blood pressure, glucose metabolism, and lipoprotein lipids after aerobic exercise plus weight loss in obese, hypertensive middle-aged men. Metabolism 1998; 47: Motoyama M, Sunami Y, Kinoshita F, et al. Blood pressure lowering effect of low intensity aerobic training in elderly hypertensive patients. Med Sci Sports Exerc 1998; 30: Kohno K, Matsuoka H, Takenaka K, et al. Renal depressor mechanisms of physical training in patients with essential hypertension. Am J Hypertens 1997; 10: Tanaka H, Bassett Jr DR, Howley ET, et al. Swimming training lowers the resting blood pressure in individuals with hypertension. J Hypertens 1997; 15: Ishikawa K, Ohta T, Zhang J, et al. Influence of age and gender on exercise training-induced blood pressure reduction in systemic hypertension. Am J Cardiol 1999; 84: Dengel DR, Galecki AT, Hagberg JM, et al. The independent and combined effects of weight loss and aerobic exercise on blood pressure and oral glucose tolerance in older men. Am J Hypertens 1998; 11: Higashi Y, Sasaki N, Nakagawa K, et al. Daily aerobic exercise improves reactive hyperemia in patients with essential hypertension. Hypertension 1999; 33: Moreira WD, Fuchs FD, Ribeiro JP, et al. The effects of two aerobic training intensities on ambulatory blood pressure in hypertensive patients: results of a randomized trial. J Clin Epidemiol 1999; 52: Kokkinos P, Narayan P, Colleran J, et al. Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. N Engl J Med 1995; 333: Ketelhut RG, Franz IW, Scholze J. Efficacy and position of endurance training as a non-drug therapy in the treatment of arterial hypertension. J Hum Hypertens 1997; 11: 651-5

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Acta Med Scand 1986; 711: Correspondence and offprints: Dr James M. Hagberg, Department of Kinesiology, University of Maryland, College Park, MD , USA. jh103@umail.umd.edu