Abstract
The population in Asia has been rising since 2000 and is estimated to reach 932 million in 2050, making Asia the most populous elderly region in the world. The prevalence of hypertension is high even in Asia and it rises with age. In tandem with the aging population, Asia will have the largest population with hypertension in the world by the middle of this century.
While several of the mechanisms and pathophysiology responsible for the causation of hypertension are similar to younger adults, many differences also occur. The elderly have more arterial stiffness leading to a greater elevation of systolic blood pressure (BP) than the diastolic BP, resulting in a higher prevalence of isolated systolic hypertension which is more difficult to treat. The elderly is also more salt-sensitive and herein opportunities and evidence exist that lowering salt intake can lower BP. Evidence has also emerged that the white coat effect and masked hypertension are more common in the elderly and should be identified as they are associated with increased cardiovascular (CV) risk.
Hypertension in the elderly needs to be treated as reducing BP reduces CV mortality and morbidity. However, because the elderly is a more vulnerable group, usually having many other co-morbid conditions, including functional and cognitive impairments. Treatment may increase the occurrence of postural hypotension potentially leading to falls; thus, any treatment for the elderly has to be individualized. Target BP control for the elderly has to balance the benefits and adverse effects of anti-hypertensive therapy.
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Keywords
- Hypertension
- Aging
- Elderly
- Arterial stiffness
- Salt sensitivity
- Isolated systolic hypertension
- Postural hypotension
17.1 The Aging Population in Asia
The definitions of elderly vary somewhat in Asia where some countries use age ≥ 60 to define “elderly” while others adopt age ≥ 65 years as a cut-off point to define the elderly group. Notwithstanding these arbitrary age definitions of elderly, the number of people age ≥ 60 is increasing rapidly. It is estimated that between 2015 and 2050, the proportion of the world’s population over 60 years will nearly double from 12 to 22% [1]. In Asia, with falling fertility rates and increased life expectancy, the population age 65 and older has been rising since 2000 (Fig. 17.1). The proportion of the population age ≥ 65 years in Asia was 4.8% in 2019 and is predicted to rise to 17.8% in 2050, with an increase in absolute numbers from 400 million to 900 million [2]. Due to this rapid rise, several countries in Asia will have between 15% to as high as 34% of the total their population being elderly (Figs. 17.2 and 17.3). In India and China with the largest populations in the world, the proportion of the population aged ≥65 years in India was 3.8% in 1990 and is predicted to rise to 13.7% in 2050. In China, the proportion of the population aged ≥65 years was 5.6% in 1990 and is predicted to rise to 26% in 2050 [2]. Japan is a country with the longest life expectancy in the world, the proportion of the Japanese population aged ≥65 years was 11.8% in 1990 and was predicted to rise to 37.7% in 2050. Japan may represent the possible future age structure in many Asian countries. As a result of this rapid rise in the aging population, Asia is on track in the next few decades to become one of the oldest in the world [3] by the middle of this century.
Population aged 65 and older in Asia 1950–2050. (Source: Asia Development Bank. https://data.adb.org/dataset/population-and-aging-asia-and-pacific (accessed 9 Aug 2021))
The proportion of population aged 60 or over in 2015 and 2050. (Source: Global Age Watch https://www.helpage.org/global-agewatch/about/about-global-agewatch/(accessed 9 Aug 2021). Map: https://www.helpage.org/global-agewatch/population-ageing-data/population-ageing-map/ (accessed 9 August 2021))
Prevalence of hypertension by age group in Malaysia 2019. (Source: National health and Morbidity Survey 2019 Volume ll Report on Non-communicable Diseases http://iku.moh.gov.my/images/IKU/Document/REPORT/NHMS2019/Report_NHMS2019-NCD_v2.pdf)
17.2 Prevalence of Hypertension in Asia
Globally, the prevalence of hypertension is high where in 2015, 1 in 4 men and 1 in 5 women had hypertension resulting in an estimated 1.13 billion people worldwide suffering from hypertension. Most of these people live in Asia which is the world’s most populous continent and most (two-thirds) living in low- and middle-income countries [4].
While it is recognized that high-income countries like the United States of America (USA) has a high prevalence of 47.1% of adults age 20 and older in 2017–2018 having hypertension [5], this also occurs in high-income countries in Asia where 60% and 32.9% of adult men in Japan and Korea, respectively, are hypertensive [6]. Furthermore it is equally high in many low- and middle-income economies in Asia where prevalence of hypertension is 42.3% in adults age 30 years or older in Malaysia and 50.3% in Pakistan [6,7,8,9] and notably, hypertension is more prevalent in people of East and South Asian ancestry [10, 11].
The prevalence of hypertension increases with age. In the USA, among those aged 60 years and older, the prevalence is 74.5% compared to lower prevalence of 54.5% among the 40–59 age group [5]. This higher prevalence in older adults is also observed in the low- and middle-income countries in Asia where in countries like Malaysia, the prevalence of hypertension in older adults is much higher than in younger adults, reaching a prevalence of 75.4% in those age between 74 and 75 years [7] (Fig. 17.3). Many governments in Asia are generally poorly prepared for this change. There will be implications not only on the health care system but also social and economic consequences [12].
17.3 Pathophysiology of Hypertension in the Elderly
Multiple systems like the cardiac, renal, sympathetic nervous system, and other CV control mechanisms interact and can affect cardiac and vascular homeostasis resulting in changes in blood pressure (BP).
17.3.1 The Renin-Angiotensin-Aldosterone System in the Elderly
The kidneys are an important regulator role of blood pressure [13, 14]. Parenchymal damage to the kidneys or any impairment of renal function almost invariably leads to the development of hypertension [15]. The kidneys control blood pressure via natriuresis and the renin-angiotensin-aldosterone system (RAAS) [13, 14, 16]. BP and salt excretion is regulated by the RAAS system. The RAAS system is activated by a low salt intake stimulating renal sodium reabsorption and preserving intravascular volume to maintain BP. Conversely, a high salt intake dampens the RAAS, facilitating natriuresis, excreting more sodium to reduce intravascular volume and BP. Many therapeutic agents targeting the RAAS had been developed over the past few decades, starting with captopril, the first angiotensin converting enzyme (ACE) inhibitor in 1981, followed by losartan, the first AT-ll angiotensin receptor blocker (ARB) in 1990 and the direct renin inhibitor, aliskiren in 2005 [17, 18]. Spironolactone has been available since the 1970s and used as a potassium-sparing diuretic initially but is now used in resistant hypertension as demonstrated in recent clinical trials [19,20,21], particularly in hyperaldosteronism.
In the elderly, plasma renin activity declines with age and this has been attributed to the effect of age-associated nephrosclerosis [22, 23]. A study reported a reduced plasma renin activity in older adults age 65 years and older compared to younger individuals who were matched for mean arterial pressure, race, sex, height, and weight [24]. Nevertheless, a randomized control study comparing the efficacy of BP lowering of aliskiren to ramipril in the elderly found aliskiren lowered systolic and diastolic BP by 14 and 5.1 mmHg respectively, relative to baseline BP, while ramipril lowered systolic and diastolic BP by 11.76 and 3.6 mmHg respectively [25], indicating that aliskiren is able to lower BP in the elderly despite renin activity being reduced. However, to date no specific clinical outcome trials have been done on the efficacy and role of direct renin inhibitors in reducing cardiovascular mortality and morbidity in the hypertensive elderly.
Similarly, although plasma renin activity is decreased in the elderly, the fall in BP after ACE inhibitors is at least as great as in the younger age groups. One reason is due in part to a sustained ACE-inhibitor concentration as a consequence of slower clearance of the drug due to the poorer kidney function that is associated with aging.
Aging is also associated with a decline in renal function which may be amplified by intrinsic renal disease; for example, that caused by diabetes or other renovascular abnormalities. Hence, changes in tubular reabsorption of sodium will affect the ability and capacity of the kidney to adjust to fluctuations in normal sodium intake [26]. It has also been shown that compared to younger normal healthy individuals and normal older healthy individuals, the half-life for renal sodium excretion was prolonged. The elderly is less able to handle a high sodium load well, rendering them more salt-sensitive [27]. Herein suggests the role of diuretics for the treatment of hypertension in the elderly and is reflected in most guidelines for the management of hypertension.
17.3.2 Vascular Mechanism in the Elderly
Total peripheral resistance is one of the components determining BP. Structural and functional damage to the micro- or macrocirculation results in increased arterial stiffening [28] and total peripheral resistance causing a rise in BP. Microcirculatory damage could be a cause or a result of hypertension. Peripheral vascular resistance is controlled mainly at the arterioles and small arteries. Vascular tone is regulated by various factors including the sympathetic nervous system, humoral factors (the RAAS and endothelium), and auto-regulation. Endothelial damage and the resulting inflammation caused by low-density lipoprotein (LDL)-cholesterol, or hyperglycemia, stimulates the production of factors like the reactive oxygen species (ROS) and endothelin, leading to reduced nitric oxide and changes in the vasculature, and eventually raising BP.
Aging is associated with remodeling of large arteries leading to structural changes such as increased collagen deposition and rupture of elastin fibers [29] leading to a loss of elasticity, hypertrophy and sclerosis of muscular arteries and arterioles, and increasing arterial stiffness [30]. The loss of this elasticity with aging promotes the early return of reflected waves from the peripheral arterial circulation. Early wave reflection amplifies the systolic pressure wave generated with each heartbeat, leading to an increase in systolic pressure and a fall in diastolic pressure. These changes are responsible for the physiological changes in BP with aging, which is seen as a decline in diastolic BP and a rise in systolic BP, often presenting as isolated systolic hypertension (ISH), seen almost always in the elderly only. Abundant data has already confirmed that ISH is associated with at least twice the hazards ratio of increased CV mortality and morbidity compared to older individuals without ISH [31, 32]. Randomized clinical outcome trials have also demonstrated that treating ISH reduces CV mortality and morbidity [33, 34].
White coat hypertension (WCH) is a situation where in an untreated individual the BP measured in the clinic is ≥140/90 mmHg, while the day BP using ambulatory BP measurements or home BP measurements is <135/85 mmHg. WCH is common and is reported to be more common in the elderly [35, 36]. Although the term WCH was originally defined for individuals not on hypertensive medications, it is now being used to describe discrepancies between office and out-of-office BP in patients already on treatment for hypertension, with the term white coat uncontrolled hypertension (WUCH) or as white coat effect (WCE) [37]. WCE is reserved more for patients already on anti-hypertensive drugs, where similar to the WCH situation, the office BP is high but home is low [36, 38, 39]. These two terms are frequently used interchangeably.
Studies have found a correlation between WCE and arterial stiffness [36, 40, 41] and WCH/WCE is not uncommon. In a study involving many countries in Asia, WCE was as high as 40% in one country [42]. WCH WCE is more common in the elderly and was as high as 50% in the very old [35, 37, 38]. This has clinical implications especially in the elderly, as not identifying WCH/WCE may mean unnecessary anti-hypertensive therapy in an elderly who is often already burdened by many other co-morbidities or up-titrating hypertensive drugs giving rise to hypotension and/or postural hypotension leading to falls.
Masked hypertension (MH) is the reverse of WCH/WCE and is also referred to as isolated uncontrolled home hypertension. In this category, the clinic/office BP is normal, that is, <140/80 mmHg but the out-of-office home BP is ≥135/85 mmHg. MH is associated with increased risk of CV events and has been shown to be more common in the elderly [43,44,45,46,47]. In the Japanese J-HOME study, among a group of treated older hypertensive adults with mean age of 66 years, 23% had uncontrolled home hypertension [48]. As almost one in four treated older hypertensives adults have MH, it is important to identify such patients and modify management to reduce their cardiovascular risk.
17.3.3 The Nervous System and Hypertension in the Elderly
Both short- and long-term control of BP are regulated by the sympathetic system. Studies have shown a significant decline in sympathetic and para-sympathetic response with aging [49, 50]. Postural hypotension occurs due to age-related impairment in baroreflex-mediated vasoconstriction, cardiac chronotropic responses, and deterioration of the diastolic filling of the heart [51, 52]. Postural hypotension increases with age where, in community dwelling individuals ≥65 years of age, its prevalence is approximately 20%; in those ≥75 years of age it is as high as 30% and in frail elderly individuals living in nursing homes, the prevalence is up to 50% [51, 53].
Patients with apparent and true resistant hypertension (RHT) often have increased sympathetic activity [54, 55]. Based on these findings, technology was developed to treat RHT by suppressing sympathetic activity with electrical stimulation of the carotid baroreflex and catheter-based renal denervation (RDN). Initial studies of renal nerve denervation (RDN) showed good decreases in BP with minimal adverse effects [56,57,58]. However, in sham-control trials, RDN was found to be not better at lowering BP compared with use of anti-hypertensive drugs alone [59]. One of the reasons for the failure of this study was that RDN was not standardized and many operators of RDN did not have any experience before the study.
17.3.4 Hypertension, Left Ventricular Hypertrophy, and Heart Failure in the Elderly
The prevalence of left ventricular hypertrophy (LVH) based on echocardiographic studies in hypertensive patients ranged from 36 to 41% [60]. In Asian hypertensive patients attending a primary care clinic with a mean age of 59.2 ± 7.7 years, 1 in 4 had echocardiography evidence of LVH [61]. The concentric LVH seen in hypertension makes the myocardium less compliant and results in diastolic dysfunction. This is more common in women, the elderly, and patents with diabetes [62, 63]. Also it is reported that isolated systolic hypertension, almost exclusively seen in the elderly, is associated more with concentric LVH [64, 65]. Hypertension with LVH and diastolic dysfunction when left untreated or not controlled well, leads to heart failure with preserved ejection fraction (HFpEF) [66].
Hypertensive heart failure (HF) is common in patients with hypertension in general and it is more common in the elderly than younger adults [67, 68]. The incidence of HF is strongly dependent on age, with an estimated incidence of 1% at age 65 that approximately doubles with each decade of age thereafter [69]. The prevalence of HF was about ten times higher in those aged ≥80 years (12.8% in men and 12% in women), compared to those aged 40–59 years (1.2% in men and 1.7% in women) [68]. Mortality and hospitalization rates due to HF is also higher in those aged ≥65 years than those aged <65 years [68, 69].
Several large HF registries showed that hypertension was the primary cause of HF in 11–23% of the patients [70, 71]. In an Asian HF registry, one-third of the patients with HF had hypertensive HF [72, 73]. A more recent study hypertensive HF accounted for 4% of HF, suggesting better control of hypertension [74]. The diagnosis and management of HF in the elderly is more challenging than for younger adults due to multi-comorbid diseases, polypharmacy, cognitive impairment, functional ability, and frailty. Studies have shown that 60% of elderly with HF usually have three or more other co-morbid conditions and 17% had cognitive impairment [75,76,77].
Many clinical trials on HF did not include patients over 75 years. HFpEF in the elderly remains without definitive treatment as most clinical trials were performed in HF patients with reduced ejection fraction (HFrEF). As hypertension is often the pre-disposing cause of HF in the elderly, control of hypertension is critical. Reduction in salt consumption is also important as the elderly are more salt-sensitive and even more so in elderly Asians with HF as Asians have been shown to not only have a higher salt intake but are also more salt-sensitive than their European counter-parts (see Sec. 17.4.3 on Salt Intake and Hypertension in the Elderly) (see Chap. 13 on HF for more details).
17.4 Atrial Fibrillation
The prevalence of atrial fibrillation (AF) increases with age, and is the most common arrhythmia in adults age 65 years and older [78]. The prevalence in individuals aged ≥75 years is 10% [79,80,81]. As high as 70% of individuals with AF were between 65 and 85 of age [78, 82]. AF often co-exists with hypertension and hypertension increases the risk of AF, with 60–80% of patients with AF also having hypertension [83, 84].
Although the epidemiological association between hypertension and AF is well established, the pathogenic mechanisms explaining the higher propensity of hypertensive patients to develop AF are still incompletely known. Experimental animal studies seem to suggest that it is due to a remodeling of the left atrium caused by hypertension. Although the entire mechanism is not well understood, it stands to reason that hypertension should be treated early and controlled well to prevent the progression to left atrium dilatation [84].
17.4.1 Genetic Factors and Hypertension in the Elderly
Hypertension develops because of an interaction between genetic and multiple environmental factors. Familial clustering of hypertension is well recognized and a family history of hypertension in an individual is a determinant of not only future hypertension but an earlier onset in the said individual. This implies that genetic factors are at play in the causation of hypertension.
Although gene analyses have identified many gene variants that predispose an individual to the development of hypertension, they are of modest effect. It has been estimated that the combination of different gene variants associated with the risk of hypertension contribute only around 3.5% of the trait variance [85]. Besides genetic predisposition to future risk of hypertension, there is the interaction between genes with epigenetics where environmental and life-style factors may influence the actual and potential onset of hypertension. This has been evaluated in a recent genome-wide association (GWAS) and replication study of BP phenotypes in 320,251 East and South Asian and European ancestry that suggested an interaction of genomic with epigenomic in the regulation of BP [86]. One of the suggested use of these GWAS studies is that it could generate a genetic risk score to predict future cardiovascular risk [87].
17.4.2 Environmental and Life-Style Factors and Hypertension in the Elderly
The prevalence of obesity is increasing rapidly worldwide [88]. Asia is not spared from this “epidemic” in spite of several countries being in the low-middle income group, with prevalence of obesity along with the metabolic syndrome, being just as high as in developed countries [89, 90]. Risk factors for CV disease like diabetes and even actual coronary heart disease occur at lower body mass index in Asians than in Europeans [11, 90, 91]. Obesity predisposes to an increased risk of diabetes mellitus and sleep apnea, which are both associated with higher prevalence of hypertension, and is independently associated with risk of CV and cerebrovascular events [92].
This increase in prevalence of obesity is also seen in the elderly, for example in the USA, to more than 30% in men and women aged 60 years and over [93, 94]. Similarly an Asian country also reports obesity rate of 30.2% in those aged 60 and above [95].
17.4.3 Salt Consumption and Hypertension in the Elderly
The daily average intake of salt globally is 9.8 g (equivalent to 3.95 g of sodium) [96]. This is much higher than the recommended daily intake of 5 g of salt by the World Health Organization (WHO) [97]. Asians consume more salt than populations in the USA and the United Kingdom [98] and studies have shown that higher salt consumption is associated with higher BP [99,100,101,102,103] and that different individuals have different salt sensitivity [100, 104,105,106].
Salt sensitivity is associated with reduced blood pressure dipping at night [107, 108], insulin resistance [109, 110], and increased sympathetic nerve activity [109, 111]. In the elderly, there is less nocturnal BP decline [112, 113] and this could be related to salt sensitivity and/or amount of salt intake. That salt sensitivity and/or high salt load in the elderly has been studied and when salt intake was reduced, there was a shift from non-dipping to a dipping state [114, 115]. Furthermore salt sensitivity is seen more commonly in hypertensives, blacks, women [116, 117], the elderly [116, 118], the obese [117, 119], and in Asians. Genetic studies done in Asia identified higher prevalence of salt sensitivity among the Chinese [120] and Japanese [104]. Due to the high intake of salt in Asia coupled with higher salt sensitivity in Asians and the elderly, and the evidence that salt reduction does indeed reduce BP, it would be beneficial to advise reduction in salt intake in elderly Asians.
17.4.4 Clinical Significance of the Pathophysiological Differences of Hypertension in the Elderly in Asia
The elderly is a vulnerable group with a high burden of diseases [75, 76, 121, 122] necessitating multiple drugs. Hence, it is not uncommon to see polypharmacy in the elderly. In Korea, 86.4% of elderly age 65 years and older were on multiple drugs, and similarly, in Japan the number of drugs ranged from 4.8 to 5.6 [123,124,125]. Because of multi-morbidity and differences in the pathophysiology of hypertension in the elderly, management of hypertension has to be adjusted accordingly when compared to younger individuals.
The differences between younger and older hypertensive patients can be summarized:
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Isolated systolic hypertension is more common in the elderly and in the very old adults aged 75 years and older [31, 32].
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Heart failure, HFpEF, is more common in the elderly [66, 69, 72, 73].
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Elderly patients have more atrial fibrillation [79,80,81, 83, 84].
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Renin concentrations are lower in the elderly [24].
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White coat effect (isolated office hypertension) is more common in the elderly [35,36,37,38].
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Masked hypertension is more common in the elderly [43, 47, 48].
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Postural hypotension is more common in the elderly [45, 51,52,53].
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Nocturnal dipping is commonly absent in elderly patients [112, 113].
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Multi-comorbidities, more functional and cognitive impairments occur in the elderly [75, 76, 121, 122].
The clinical diagnosis of hypertension in the elderly is universally the same as for younger adults, ie a BP ≥140/90 mmHg [126,127,128] except for the recommendations by the USA where in 2017, their cut-off point for diagnosis was lowered by 10 mmHg to 130/80 irrespective of age [129]. Similarly, the diagnosis of isolated systolic hypertension is based on a systolic BP of ≥140 and diastolic BP of <90 mmHg while the USA uses systolic BP ≥130 and diastolic BP <80 mmHg.
Hypertension guidelines recommend assessing total CV risk rather than relying on the BP alone to decide on treatment. This is useful as often several mildly raised CV risk factors in someone with BP in the range of SBP of 140–150 mmHg may appear to be at low risk and hence dismissed as not needing treatment when in fact a formal calculation shows the patient actually to be at medium to high risk, thus necessitating treatment [130]. Most assessments in older patients for total/global CV risk invariably will be of medium or high risk, and a formal calculation is usually not needed. However, it is useful to do a global CV risk as it helps to decide how far to treat and the target BP. It is also helpful when there is uncertainty as to whether one really need to put a patient on anti-hypertensive therapy especially if patient is frail, has many other co-morbid conditions and a limited life span.
The elderly with hypertension of various forms will benefit from treatment [33, 34], and even the very elderly aged 80 and older also benefit [131, 132]. Several of the Asian guidelines do not differentiate between the “old” (≥65–74 years) and the “very old” (≥75 years) elderly. Most of the Asian guidelines for the management of hypertension in the elderly recommend a target that is similar to younger adults, <140/90 mmHg but not going below systolic BP of 130 mmHg for the old, and a target of <150/90 mmHg for the very old [127] (Table 17.1).
The recommended drug of choice for treatment of hypertension in the elderly is based on the mechanistic and pathophysiologic differences between younger and older adults and on clinical outcome trials. In Asia, all the guidelines recommend diuretics and calcium blockers for the elderly while a few countries included the RAS blockers [127, 133,134,135,136,137,138].
Many commonly used classes of anti-hypertensive drugs are generic, and more affordable to treat hypertension, even in the low middle-income countries in Asia. Despite this, BP control rates in Asia are all <50%, except for countries like Korea, Taiwan, and Singapore [6, 9].
In summary, hypertension in the elderly should be treated. However, the management of hypertension in the elderly needs to be individualized, where in healthier, ambulant elderly who are community dwelling, greater efforts could be made to achieve target BP. Rather than base treatment on chronological age, we should be using biological age as our guide on the management of hypertension in the elderly.
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Chia, YC. (2022). Hypertension in the Elderly: Pathophysiology and Clinical Significance. In: Ram, C.V.S., Teo, B.W.J., Wander, G.S. (eds) Hypertension and Cardiovascular Disease in Asia. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-030-95734-6_17
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