Higher blood pressure as a risk factor for diseases other than stroke and ischemic heart disease
Hypertension and Cardiorenal Diseases
Atrial Fibrillation
Atrial fibrillation (AF) is one of the most common types of chronic arrhythmia and is a risk factor for ischemic stroke. 4 The Framingham Heart Study revealed that hypertension increases the risk of AF by factors of 1.5 for men and 1.4 for women. 5The Women’s Health Study and a cohort study of Norwegian men showed that high-normal blood pressure (BP) was associated with incident AF. 6, 7 All of these cohort studies were conducted in Westerners, and these associations were also confirmed in a recent Japanese cohort study. 8 In that investigation, compared with normal BP and normal weight, systolic prehypertension with overweight was shown to be associated with an increased risk of incident AF (P for interaction=0.04). Arterial stiffness, left ventricular hypertrophy, and increased left atrial size are important mediators of the relationship between BP and incident AF. 9 Higher systolic BP (SBP) and overweight may mutually exacerbate left ventricular hypertrophy and hypertension, and consequently, they may synergistically increase the risk of AF.
Chronic Kidney Disease and High BP
Chronic kidney disease (CKD) is characterized by a progressive decline in an individual’s glomerular filtration rate over several decades, resulting in permanent kidney dysfunction. Hypertension is consistently demonstrated to be an independent risk factor for declining glomerular filtration rate and the progression of CKD, 10 – 12 partly because of activation of the renin–angiotensin–aldosterone system and sympathetic nervous system activation. A systematic review and meta-analysis of prospective cohort studies showed that prehypertension is associated with incident end-stage renal disease. 3 Compared with a normal BP group, the prehypertensive group had a 1.59× increased risk of end-stage renal disease. Even normal BP increased the risk of end-stage renal disease; this association was accentuated by age, sex, and ethnicity and also varied depending on the study. In addition, a systematic meta-analysis showed that individual components of metabolic syndrome other than elevated BP (hazard ratio, 1.61; 95% confidence interval, 1.29–2.01) were also associated with the development of CKD. 13
The Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial showed that intensified BP control delayed the progression of renal disease in children with CKD who received a fixed high dose of an angiotensin-converting enzyme inhibitor. 14 In addition, strict BP control and antihypertensive medications were demonstrated to reduce proteinuria and prevent progression to end-stage renal disease. 15 A review revealed that irrespective of the antihypertension treatment adopted, the resulting short-term changes in proteinuria were strongly consistent with long-term outcomes (9 of 11 trials). The reduction of proteinuria was invariably associated with improved outcome (7 of 9 trials). 15
In individuals with both CKD and diabetes mellitus, glycemic control should be a part of a multifactorial intervention strategy addressing BP control and cardiovascular risk, promoting the use of angiotensin-converting enzyme inhibition or angiotensin receptor blockade, statins, and antiplatelet therapy where clinically indicated. Proven effects of lifestyle modification to lower BP and improve long-term cardiovascular and other outcomes in patients with CKD are shown in Table S1 in the online-only Data Supplement. These modifications are similar to those in guidelines for the prevention of hypertension per se. 16, 17
Comprehensive Linkages Among Brain, Heart, and Kidney
CKD is associated with an increased risk of cardiovascular disease. 18 – 21 More than one million people insured by an integrated healthcare system were followed up, and an independent, graded association was observed between lower levels of estimated glomerular filtration rate and the risks of death, cardiovascular events, and hospitalization was found. 18 A systematic review and meta-analysis of prospective studies confirmed this association and showed that a baseline e glomerular filtration rate <60 mL/min per 1.73 m2 was independently associated with incident stroke (relative risk, 1.43) across a variety of participants and study designs. 20
Impaired renal function is frequently observed in heart failure, and this is important because the presence of CKD is associated with worse outcomes. It is getting increasingly recognized that the kidney and heart interact with each other, as the widespread concept of the cardiorenal syndrome, which is further categorized into 5 subtypes (Table S2). 22 The mechanisms of renal dysfunction in heart failure seem to be a direct consequence of impaired renal blood flow in the setting of depressed left ventricular systolic function, and recent evidence has revealed important roles of neurohormonal elaboration, anemia, oxidative stress, and renal sympathetic activity as other potential contributors to these complex interactions. 23Nonhemodynamic factors, such as sympathetic overactivity, activated renin–angiotensin–aldosterone system, and inactivation of nitric oxide, are also known to be responsible for renal dysfunction in heart failure. 23 Recent experimental studies have shown that physiological active substances such as fibroblast growth factor 23 and epoxyeicosatrienoic acids not only regulate BP but also play an important role in regulation of cardiorenal syndrome. 24, 25
These results indicate that the brain, heart, and kidney interact with each other, and that the underlying mechanisms are also involved in the regulation of BP; these findings thus contribute to the notion that hypertension plays an important role in cardiorenal–brain interactions.
Hypertension and Noncardiovascular Diseases
Dementia
Dementia is a decrease in cognitive abilities leading to functional decline and the inability to perform the usual activities for healthy individuals. 26 Vascular dementia (VaD) was initially described after dementia was observed to develop after stroke or in Binswanger disease, which is a severe white-matter disease associated with long-standing hypertension. These courses are commonly thought to be the primary cause of dementia in the elderly, as is arteriosclerosis. 27 Alzheimer disease is a progressive, degenerative disorder of neurons, resulting in losses of memory, and thinking and communication abilities, as well as behavioral changes. The relationship between dementia including Alzheimer disease and hypertension has been revealed many interesting findings as follows.
Dementia in Middle-Age
Hypertension causes arteriole walls to change and as a result can lead to arteriolar occlusive disease and ultimately to infarction. The effects of hypertension could also be related to changes in blood flow or blood–brain barrier integrity or to change in the brain in dementia. 28
Many longitudinal and prospective cohort studies have shown that hypertension in middle-age is a risk factor for dementia in old age. In addition, a meta-analysis of general large population-based prospective cohort studies in 10 areas in the United Kingdom showed that smoking increased the risk of dementia death by a factor of 1.75, whereas non-high-density lipoprotein cholesterol per 1.2 mmol/L, and obesity decreased that risk by factors of 0.82 and 0.73, respectively. 29 A meta-analysis of 6 longitudinal studies showed that hypertension increased the risk of incident VaD by 1.59. 30 An earlier study had found that a history of hypertension, particularly in the presence of heart disease, was significantly associated with VaD, but not with Alzheimer disease. 31
The Hisayama Study demonstrated that stage 1 and 2 hypertension increased the risk of incident VaD by 4.72× and 7.26× (P for trend=0.003), respectively, but were not associated with an increased risk of incident Alzheimer disease, compared with normal BP. 32 That study also showed the effects of changes in BP levels from midlife to late-life on the risk of incident dementia. Compared with normotensive subjects in both midlife and late-life, subjects with hypertension in midlife and normotension and hypertension in late-life had 5.32× and 4.72× increased risks of incident VaD, respectively. These data suggest that BP control in midlife is critical to avoid an increased risk of VaD in late-life.
Dementia in the Elderly
The relationship between dementia and BP in the elderly is controversial. Some studies of the elderly have found an association between dementia and hypertension, 26 whereas others connected dementia with hypotension, 33, 34abnormal circadian rhythm of BP, and postural hypotension. 35, 36
The Rotterdam study showed an inverse association between BP and dementia risk in elderly antihypertensive drug users. 37 In a double-blind randomized controlled trial conducted in the elderly (aged ≥80 years), BP lowering did not increase the risk of dementia although the target SBP/diastolic BP (DBP) was 150/80 mm Hg. A meta-analysis of this trial and 3 other similar trials 38 – 40 showed that the reduction in the risk of dementia associated with lowering BP might be clinically significant (relative risk, 0.87).
In a Japanese community-dwelling elderly population (mean age, 80 years), neurobehavioral function scores and daily-living activities were significantly lower in the postural dysregulation group, including both postural hypotension (6%) and hypertension (9%) groups, compared with the postural normotension group. 35 The postural dysregulation group exhibited significantly more advanced periventricular hyperintensities than the normotension group. In another study of elderly Japanese subjects, both the Mini-Mental State Examination and Barthel index values showed a significant positive correlation with daytime ambulatory BP but not with nighttime ambulatory BP. 36 A dip in nighttime BP was positively associated with the Barthel index, and activities of daily living had a greater influence on diurnal BP variation than did cognitive function. 36
For elderly people, therefore, BP lowering should be implemented with caution. It might be said that there is no strong evidence to date that indicates that elevated late-life BP is a risk factor for dementia.
Hypertensive Treatment as a Preventive Therapy for Dementia
Evidence on the dementia-preventive effect of BP lowering is limited and controversial. 41 – 45 Two studies indicated a dementia-preventive effect of brain-transferable angiotensin-converting enzyme inhibitors. 46, 47 However, one trial as a substudy of the Hypertension in the Very Elderly Trial (HYVET) in hypertensive octogenarians showed that antihypertensive medication did not significantly reduce incident dementia (possibly because of the short follow-up or the early termination of the trial), and it showed only a modest effect of treatment; an accompanying meta-analysis showed a limited benefit. 41
In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) studies, meta-regression analyses did not show any benefits of BP lowering on cognition over several years of treatment although patients with the lowest SBP had the greatest preservation of cognitive function. 45 A substudy of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) and a prospective observational study suggested that BP lowering prevented white-matter lesions. 48, 49 A recent systematic review of observational studies revealed a beneficial effect of antihypertensive medication on the incidence of dementia in longitudinal studies. 50Further randomized controlled trial s with longer periods of follow-up should be performed.
Certainly, the available information as to whether antihypertensive treatment can modify the evolution of cognitive decline and dementia is mixed; nonetheless, cognitive evaluation tests will continue to be useful in the clinical assessment of elderly hypertensive patients. 51, 52 To date, suggested diets for preventing dementia include the consumption of plenty of vegetables, dairy products, 53, 54fruits, cereals, legumes, preferably whole grains, a limited salt intake, saturated fat, moderate total fat intake, lean meat, fish, and poultry, drinking plenty of water, 53the consumption of algae, and a low intake of rice. 54 However, it is also necessary to emphasize that clinical trials have not fully established that these suggested lifestyle modifications will help prevent the development of dementia. On the basis of these results, we conclude that hypertensive treatment is recommended for middle-aged individuals and is becoming established as another means to combat the development of dementia. 26, 55 For the elderly, in contrast, the evidence is inconsistent. 17, 33
Cancer
A prospective study of 363 000 Swedish men showed that the risk of renal-cell cancer was >1.6× to 1.7× and 2.1× to 2.3× increased in men with SBP≥150 mm Hg and DBP≥90 mm Hg, compared with those with SBP<120 mm Hg and DBP<70 mm Hg, respectively. 56 At the 6-year follow-up, the risk rose further with increasing DBP and decreased with decreasing DBP. A reduction in BP clearly lowers the risk of renal-cell cancer in men.
A meta-analysis based on 10 longitudinal studies (n=47 119) showed that hypertension was related to a 1.23× increased risk of cancer mortality, 57 and a study of 17 498 middle-aged London government employees found that BP was inversely associated with mortality from leukemia (29% decreased risk per 10 mm Hg of DBP), whereas it was positively associated with mortality from liver cancer (19% and 38% increased risks per 10 mm Hg of SBP and DBP, respectively). 58
On the basis of 7 European cohorts, we found that the risks of incident all-cancer per 10-mm Hg increment of SBP and DBP were increased by 5% and 8% in men, whereas the risks of cancer mortalities were increased by 9% and 12% in men and 4% and 10% in women, respectively. 59 Among the subtypes of incident cancers in that study, high BP was significantly associated with the incidence of esophageal cancer in both men and women, and with the incidence of lip, oral cavity, pharynx, colon, lung, kidney and bladder cancers, and melanoma in men and with the incidence of pancreatic cancer in women (P<0.01). The sex differences in these results may be related to the interplay between sex hormones and BP in relation to cancer.
Potential roles for high BP in tumor initiation and progression might interact with other metabolic and carcinogenic factors in these associated risks of cancer. Additional studies are needed to elucidate the mechanisms of hypertension as a risk factor for cancer. Healthy lifestyle modification is an established way to reduce the risks of both high BP and cancer, namely, regular exercise, quitting smoking, moderation of alcohol consumption, and eating a healthy diet that conforms to the hypertension guidelines.
Oral Health Disorders
OHDs, such as cavities, periodontal disease, and gingival bleeding, are a common. Several epidemiological surveys have suggested the existence of a positive relationship between hypertension and OHD such as periodontal disease, gingival bleeding, and tooth loss. 60 – 66 These 2 conditions (OHD and hypertension) share multiple common risk factors that should be controlled for when assessing their possible association. The systemic inflammatory response that may accompany these conditions has been implicated as a mechanism in the development of hypertension. 67 Inflammation, in turn, causes endothelial dysfunction and arteriolar bleeding, which could lead to the development of hypertension. If left untreated, this leads to deterioration of the supportive tissue of the teeth and eventually to tooth loss. 68
Periodontal disease and subsequent tooth loss may lead to poor dietary habits, or vice versa, and patients with these conditions may be likely to favor soft carbohydrate foods 69 and to restrict their fruit intake, 70 which influences BP. 71 The modification of diet that occurs with these conditions has been speculated to be another possible mechanism in the development of hypertension. 67, 72 In the Suita study, the relationships between hypertension and various oral health markers including periodontitis, gingival bleeding, tooth number, and occlusal status were investigated, and an additive relationship was found between OHD and risk of hypertension. 73 After adjustment for confounding variables including eating habits, the odds ratio for hypertension was 1.82 (95% confidence interval, 1.23–2.72) in the subjects with ≥3 of the oral health markers compare with those with none of the markers. These findings suggest a direct relationship between OHD and hypertension, but the relevant studies are mostly cross-sectional, often subanalyses of larger cohorts, and they do not establish a cause and effect relationship.
Whether periodontal disease leads to hypertension was examined in the Health Professionals’ Follow-Up study, which included middle-aged men with no previous history of hypertension; a negative association between periodontal disease and incident hypertension was reported. 74
Bone Metabolism
In general, the prevalence of hypertension or osteoporosis increases with advancing age. Calcium, vitamin D metabolites, parathyroid hormone, physical activity, and proper nutrition are crucial determinants of bone mass. Disturbances of calcium metabolism, including increased urinary calcium excretion, often accompany hypertension and osteoporosis, 75, 76 and accumulating evidence suggests that an inadequate vitamin D status seems to predispose to hypertension via elevation of parathyroid hormone level and disturbed calcium homeostasis. 77 – 79 Vitamin D may have a role in regulating vascular tone by influencing the concentration of calcium in vascular smooth muscle cells. In addition, low vitamin D levels have been linked to insulin resistance, systemic inflammation, and dysregulation of the renin–angiotensin–aldosterone system. 80 – 82
Indeed, hypertension is closely related to nutritional habits including high-sodium and low-calcium intake, and both hypertension and osteoporosis are among the main health problems of the elderly. More than 30 cross-sectional analyses have been published (mainly of whites), many of which found a close relationship between vitamin D status or bone mass and BP or hypertension; however, the results obtained are not consistent across all studies. 83 At present, the causal relationship between hypertension and abnormal bone metabolism remains unclear; however, hypertensive treatment (especially thiazide-type diuretics therapy) is an important and effective means to maintain bone density. Thiazide-type diuretic therapy, similar to salt reduction, is recommended as the initial hypertensive treatment in most guidelines, 16, 84, 85 and is well-established as effective at decreasing BP and the excretions of urinary albumin and urine calcium, which are in turn associated with greater bone density and fewer fractures.
Clinical Implications
Accumulating evidence suggests the importance of treating hypertension not only toward preventing cardiovascular disease but also in the management of other diseases. This evidence highlights a central role of hypertension in the development of cerebrocardiovascular disease, and in other words, also has an important role in brain–cardiorenal cross talk. As noted above, recent findings revealed that hypertension could also be linked to noncardiovascular diseases including dementia, cancer, oral health disorders, and osteoporosis although conflicting results have been reported. Of the above-mentioned diseases, the importance of hypertensive treatment is becoming well established in cardiorenal diseases and dementia in the middle-aged, whereas in other diseases, further evidence is needed before recommending hypertension treatment.
Sources of Funding
This work was supported by the Intramural Research Fund of the National Cerebral and Cardiovascular Center (22-4-5), and by Grant-in-Aid for Scientific Research (A, No. 25253048; B, No. 25293147) and Challenging Exploratory Research (No. 26670320) in Japan.
Disclosures
None.
Footnotes
- The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.03480/-/DC1.
- Received March 14, 2015.
- Revision received March 21, 2015.
- Accepted May 25, 2015.
- © 2015 American Heart Association, Inc.
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