For many years, clinicians have used diastolic blood pressure as the main risk indicator in hypertensive patients. However, several developments have caused a paradigmatic shift in our thinking about hypertension as a risk factor. First of all, the recognition from epidemiological studies that systolic pressure is a much stronger predictor of future cardiovascular events than diastolic pressure. Secondly, many studies have shown that pulse pressure is independently associated with cardiovascular risk and an increased pulse pressure is mainly related to an elevated systolic pressure. Finally, with the aging of the world’s population more emphasis has been put on a more slowly evolving form of hypertension that is predominately systolic in nature and primarily affects middle-aged and older persons.
Currently, isolated systolic hypertension (ISH) is defined as a systolic blood pressure of 140 mm Hg or above together with a diastolic blood pressure below 90 mm Hg. It has become the most common and the most difficult form of hypertension to treat successfully, and hence a public health problem of major proportion. The purpose of this chapter is to provide a better understanding of ISH and how to treat it effectively.
Epidemiology of Isolated Systolic Hypertension
The longitudinal data from the Framingham Heart Study clearly indicate that systolic blood pressure (SBP) continues to rise with age whereas diastolic blood pressure (DBP) increases in young adulthood, but levels off at age 50 to 55 years only to decrease after age 60 to 65 years. As a corollary, pulse pressure (PP), defined as the difference between SBP and DBP, increases after age 50 to 55 years. Normotensives who reach the age of 65 years have a 90% lifetime risk of developing hypertension (and almost exclusively of the ISH subtype) if they live another 20 to 25 years.
Studies on the prevalence of ISH in untreated populations have yielded inconsistent results, which may, at least in part, be explained by differences in age, gender distribution, and in definition of ISH across the various surveys. Surely, when one takes a systolic pressure above 160 mm Hg as the criterion for ISH, then the condition is virtually nonexistent in younger people. However, with the currently accepted threshold of 140 mm Hg the situation may be different. In the Chicago Heart Association Detection Project in Industry Study, for instance, the prevalence of ISH in participants between 18 and 49 years of age was about 25% in men and 13% in women. These prevalence rates are higher than those found in several other studies and may well be related to comorbid conditions such as obesity.
In persons above age 60, ISH usually is found in a quarter to a third of the population. Of particular interest are the data from the National Health and Nutrition Examination Survey (NHANES) program. In the third survey (NHANES III, 1988 to 1994) it was found that ISH is the predominant form of hypertension above age 50 years, constituting 60% to 90% of all cases of uncontrolled hypertension. Recently, Liu and coworkers analyzed the data from six cycles of NHANES surveys from 1999 to 2010. Interestingly, they found that the overall prevalence of untreated ISH had decreased from 9.4% in 1999 to 2004 to 8.5% in 2005 to 2010, a highly significant difference ( p = 0.0025; Fig. 19.1 ). In participants aged 60 years and above there was an even more pronounced fall in the prevalence of ISH from 34% to 25% ( p < 0.0001). Consistent with previous reports the prevalence of ISH was greater in females than in males, most likely because blood pressure tends to rise more steeply with age in older women than in men. Nevertheless, also in women the prevalence of ISH has decreased over time. Finally, in non-Hispanic blacks, a group with a very high risk of developing ISH, there were also fewer cases during the last examination. This positive trend in the United States may be seen as a reflection of public health measures and better treatment of hypertensive patients. However, such a development is not seen globally. In Korea, for instance, a similar program as NHANES found that, although the proportion of untreated hypertensive patients had remained relatively constant from 1998 to 2012, ISH is becoming more prevalent attributed to the rapid aging of the population. Also in China, ISH has risen significantly over the last 20 years. Thus, the problem of ISH may be particularly relevant in the Asian-Pacific region.
A question that comes up frequently is whether in older people ISH develops de novo, that is, as a separate disease, or that it is a naturally occurring stage in the hypertensive process. In the Framingham study, the conversion from untreated or poorly controlled diastolic hypertension at a younger age to ISH later in life did occur in about 40% of patients but, as illustrated in Fig. 19.2 , the majority of people acquired ISH without going through a stage of elevated DBP.
The Campania Salute Network study set out to determine which factors could predict the transition from systolic-diastolic hypertension toward ISH. In 7801 hypertensive patients who were free of cardiovascular or severe chronic kidney disease, ISH developed in 21% over an average period of 55 months. Independent predictors of incident ISH were older age, female gender, higher baseline SBP, lower DBP, longer duration of hypertension, higher cardiac mass, greater arterial stiffness, and higher intima-media thickness of the carotid artery. These predictors were independent of antihypertensive treatment, obesity, diabetes, and fasting glucose. This suggests that ISH is a sign of aggravation of the atherosclerotic disease already evident by the target organ damage.
The age-related changes in PP suggest an interaction between vascular aging and the development of systolic hypertension. Indeed, participants in the Framingham Heart Study who were followed from age 30 to 84 years in the absence of antihypertensive therapy and with a mean baseline blood pressure of 110/70 mm Hg at 30 years of age had no rise in PP from age 30 to 55 years of age. However, this group of subjects did show a significant rise in PP and fall in DBP after 60 years of age, presumably caused by an increase in large artery stiffness secondary to aging. In contrast, participants with a mean baseline blood pressure of 130/84 mm Hg at 30 years of age demonstrated a steeper rise in PP and a steeper fall in DBP after age 60 than was observed in the other group, again in the absence of antihypertensive therapy. This divergent, rather than parallel tracking pattern suggests a linkage between hypertension left untreated and subsequent acceleration of large artery stiffness and the development or worsening of ISH.
Pathophysiological Features of Isolated Systolic Hypertension
Some Considerations About Etiology
Normally, the conduit vessels (the aorta and the carotid, brachial, iliac, and femoral arteries) will substantially buffer the pressure rise, which results from the ejection of blood by the left ventricle (Windkessel function). They can do so by virtue of a high elastin content. During systole, the aortic wall is stretched so that it can accommodate the stroke volume and at the same time increase elastic tensile energy. At late-systole and during the diastolic phase this accumulated energy recoils the aorta and pushes, as it were, the amount of blood that has not yet been directed forward into the peripheral vasculature. This way, a continuous flow is ensured. The structural basis for this mechanism lies primarily in the medial and adventitial layers of the vessel wall. During normal aging, changes in the composition and the structure of the media lead to generalized arterial stiffening. This process needs to be distinguished from intimal changes, which may occur simultaneously and which form the basis of atherosclerotic lesions. Although our information about the age-related pathological changes in the arterial wall of humans, for obvious reasons, is limited, there is agreement that with time the elastin in the wall in the larger vessels nearby the heart decreases. In fact, elastin becomes thinner and fragmented and then is degraded and replaced by collagen, which is much stiffer. Why this happens, is not entirely clear. Some have suggested that it is a matter of fatigue failure as a result of repetitive cyclic loading. Indeed, by the time a person reaches age 55 years the heart has contracted about 2 billion times and the elastic protein in the central conduit vessels may well show signs of wear and tear at that time.
Another possibility is that calcification of the media plays a role in the stiffening of the larger arteries. The mechanisms of this mineralization process are very complex and involve an array of biochemical substances. Because most of the data on this process stem from animal and cellular studies and are not derived directly from human material these mechanisms will not be discussed in detail here. Nevertheless, it is likely that a combination of biochemical derangements and calcification contribute to a state of progressive arterial stiffening.
Despite an enormous body of evidence that links loss of elasticity and calcification via increased arterial stiffness to the development of de novo ISH, absolute proof that these are causally related to each other is still lacking. However, several clinical observations speak in favor of such a connection. For instance, elongation of the aorta or aortic unfolding as it is commonly called, is an age-related radiological change in the aorta, which is supposed to result from the loss of elastic material. With modern radiological techniques it has been possible to show that at least in normotensive people the ascending part of the thoracic aorta, the site of greatest pressure dampening, increases almost two-fold in length between 20 and 80 years of age. Interestingly, the aortic diameter does not change that much so that it seems longitudinal strain during the cardiac cycle is greater than circumferential strain. Of note, even in these normotensives the degree of lengthening correlated positively with measures of arterial stiffness as well as with the height of aortic systolic and pulse pressure. Thus, it is not unreasonable to assume that in susceptible individuals this will end in systolic hypertension.
A second line of evidence is provided by epidemiological observations, which indicate that people with diabetes (both type 1 and type 2) run a greater risk of developing ISH and sooner than those without diabetes. Conversely, the prevalence of type 2 diabetes is high in patients with ISH. It is also known that increased arterial stiffness is already apparent in the phase of impaired glucose tolerance. Most likely, this is related to the accumulation of advanced glycation endproducts, which stiffen the aorta. Thirdly, ISH becomes more prevalent in conditions that are associated with a tendency to increased calcification such as renal insufficiency and osteoporosis. Finally, aortic calcification, as measured by quantitative high-resolution computed tomography imaging at the ascending, descending, and abdominal aorta, correlates with aortic stiffness and with the severity of ISH in patients who are otherwise apparently healthy.
Taken together, these observations are consistent with the view that loss of elastin and/or calcification in the proximal aorta cause or contribute to arterial stiffness and the development of ISH.
Hemodynamics
When discussing hemodynamics in ISH it is essential to make a distinction between central hemodynamics and arterial stiffness. Central (or systemic) hemodynamics comprises intravascular pressure, cardiac output (CO), and total peripheral resistance (TPR). Although cross-sectional studies in normotensives suggest that an age-related rise in blood pressure is as a result of an increase in TPR, longitudinal investigations hardly show any changes in either pressure or CO or TPR over time. In patients with hypertension hemodynamic changes with age are more pronounced. Cardiac output falls by about 15% over a period of 10 to 20 years caused by a reduction in stroke volume without significant changes in heart rate. The almost parallel rise in SBP, DBP, and mean arterial pressure (MAP) up to age 50 to 55 years can best be explained by the increase in peripheral vascular resistance.
The consequence of diminished elasticity of the aorta and the larger vessels is loss of the Windkessel function and, hence, less dampening of the pulsatility. This will result in a greater rise in systolic pressure and in pulse pressure. Another sequela is that the pressure wave now travels much faster along the stiffened arterial system than it used to do when the system was still more elastic. Because of the high resistance in the microcirculation the forward moving pressure wave is reflected, thus causing a retrograde pressure wave, which amplifies the former. Although this sequence of events fairly well explains the rise in SBP and the widening of PP with advancing age, it is less easy to understand why DBP falls. A commonly held view is that with age-related stiffening of the aorta, there is a greater peripheral runoff of stroke volume during systole. With less blood remaining in the aorta at the beginning of diastole, and with diminished elastic recoil, DBP decreases and the diastolic decay curve becomes steeper. Although this may be true for the ones who develop ISH de novo, it remains enigmatic why those patients who initially exhibited elevated diastolic pressures and a high TPR would lower their DBP.
Whatever the precise mechanisms, the blood pressure pattern of ISH with wide PP, from age 50 to 55 onward, is best explained by a predominance of large artery stiffness. The rise in PP is both a marker for large artery stiffness and a measure of vascular aging. In fact, untreated hypertension can accelerate the rate of vascular aging by as many as 15 to 20 years as illustrated in Fig. 19.3 . Thus, although increased PVR probably initiates essential hypertension, acceleration of large artery stiffness is the driving force leading to the development of ISH with a steeper rise of SBP after 50 years of age and a fall in DBP as compared with normotensive people. Beyond 60 years of age, increased central arterial stiffness and forward wave amplitude (rather than increased TPR, MAP, and early wave augmentation) become the dominant hemodynamic factors in both normotensive and hypertensive individuals. At that point, cardiac workload and myocardial oxygen demand during ventricular ejection will progressively increase and cardiac output may decline further. Ultimately, with no or inadequate treatment left ventricular failure may ensue.
Arterial Wave Reflection, Central Blood Pressure, Pressure Amplification, and Pulse Wave Velocity
The morphology of any pulse wave results from the summation of incident (forward-traveling) and reflected (backward-traveling) pressure waves ( Fig. 19.4 ). Timing depends on both pulse wave velocity (PWV) and distance to the predominant or “effective” reflecting site. As has been known for a long time, the summation of the incident pressure wave with the reflected wave produces in young healthy adults a normal phenomenon of pressure amplification from the aorta to the brachial artery, resulting in a higher SBP and PP at the distal brachial artery as compared with the proximal ascending aortic site. The degree to which amplification occurs can be quantified as the augmentation index (Aix). A marked increase in stiffness or impedance at the reflecting site generates a larger reflected wave and can add to a greater augmentation index.
Importantly, central SBP and PP, augmentation index, and pressure amplification are all influenced by arterial stiffness without necessarily being an accurate measurement of arterial stiffness itself. Indeed, all these variables are determined primarily by the speed of wave travel, the sites of reflectance, the amplitude of the reflected wave, and left ventricular ejection and contractility. On the other hand, aortic PWV is a well-defined surrogate for arterial stiffness that can be determined from pulse transit time and the distance traveled by the pulse between the common carotid and femoral arteries (CF-PWV). Aortic PWV increases with aging and the development of ISH, and therefore is a sensitive indicator of physiologic stiffness after the age of 50 to 60 years. By that time, the fall in DBP and the rapid widening of PP become surrogate indicators of central arterial stiffening. At that age, however, aortic stiffness (measured by CF-PWV) reaches and then exceeds peripheral arterial stiffness, measured by carotid-to-brachial PWV. As a result, reflection at this interface is reduced with reflecting sites shifting distally. This impedance matching at the proximal reflecting sites leads to reduced reflectance and therefore increased transmission of pulsatility distally, with a resultant increase in brachial artery PP and the development of ISH.
Target Organ Damage in Isolated Systolic Hypertension
Should increased arterial stiffness be considered as a cause or a consequence of the elevated pulse pressure? Data from the Baltimore Longitudinal Study of Aging (BLSA) demonstrate a greater arterial stiffness at baseline predicted a larger increase in systolic blood pressure with aging as well as the incidence of hypertension, whereas a higher SBP at baseline was associated with a greater increase in stiffness over time. Thus, it is a vicious cycle and any attempt to detect a starting point is bound to fail.
The organ that is closest to the site of the stiffened aorta is of course the heart and it is not surprising, therefore, that this organ gets most of the complications of ISH. In fact, the increased PP may even be a surrogate marker for several possible cardiac abnormalities, which all originate from the underlying increased central arterial stiffness and wave reflection. Increased aortic pulsatile afterload is a major factor in the development of left ventricular hypertrophy (LVH) with increased coronary blood flow requirements. In addition, increased turbulent flow leads to endothelial dysfunction with a greater propensity for coronary atherosclerosis and for rupture of unstable atherosclerotic plaques.
The rise in SBP and the fall in DBP in elderly persons with ISH could result in a coronary supply/demand imbalance and myocardial ischemia. The decline in DBP, however, rarely falls to the critical level (<60 mm Hg) required to disturb coronary flow autoregulation. Thus, it is unlikely that the reduction in DBP that occurs in most individuals with ISH compromises coronary perfusion. Nonetheless, there is a potential imbalance between systolic demand and coronary supply. Furthermore, cardiac ejection into the stiff arterial system results in more coronary perfusion during the systolic period, making the heart more vulnerable to changes in SBP and systolic heart function. In addition to arterial stiffening, the left ventricle itself develops systolic stiffness, perhaps as an adaptive change to facilitate cardiac ejection and to maintain matched coupling of heart to arteries. The combination of an elevated cardiac afterload and a compromised left ventricle will ultimately lead to heart failure.
Importantly, the increase in forward wave amplitude that leads to the development of ISH also increases transmission of pulsatility to the microcirculation of the brain and kidneys. This can stimulate local hypertrophy, remodeling, and rarefaction. This, in turn, will lead to a further rise in TPR and blood pressure and enhanced burden on the heart. In addition, endothelial function in stiffened vessels is impaired and this may accelerate the development of atherosclerotic lesions. All these abnormalities markedly increase the cardiovascular risk profile of patients with ISH.
Cardiovascular Risk in Persons with Isolated Systolic Hypertension
Risk of Coronary Heart Disease
Numerous population-based investigations confirm that ISH is a significant risk factor for cardiovascular complications. In Framingham, a cohort consisting of 1924 men and women between 50 and 79 years of age at baseline was followed up for 20 years. When Framingham was started none of the participants had any clinical evidence of coronary heart disease (CHD) or were receiving any antihypertensive drugs. In this population, CHD risk was inversely correlated with DBP at any level of SBP greater than 120 mm Hg, suggesting that pulse pressure is an important component of CHD risk in persons with ISH ( Fig. 19.5 ). There was a greater increase in CHD risk with increments in PP for a given SBP than with increments in SBP with a constant PP. These observations are consistent with the premise that in people above age 50 years the risk of CHD events is more closely related to the pulsatile stress of elastic artery stiffness during systole (as reflected by a rise in PP) than to the steady-state stress of resistance during diastole (as reflected by a parallel rise in SBP and DBP).
The increased risk is not only apparent in people over age 65 years but also in younger people. The Chicago Heart Association Detection Project in Industry Study followed 27,000 people who originally were 18 to 49 years over an average period of 31 years. In this population CHD mortality was significantly increased in those who had ISH at baseline.
It should be emphasized that ISH is not always a significant predictor of coronary events. A meta-analysis of eight treatment trials involving ISH patients failed to show an association with coronary events although other outcome measures were associated. The lack of an association with coronary complications in this analysis may be attributed to the threshold for diagnosis of ISH that was set at a systolic pressure of 160 mm Hg. If there were also more coronary events in the 140 to 160 mm Hg range, this could have diluted any difference between those with and without ISH.
A recent survey in a Mongolian cohort of almost 2600 adults in China also could not convincingly show an increased risk of cardiovascular disease in individuals with ISH either. Although the hazard ratio, adjusted for age and gender as well as other cardiovascular risk factors was 2.00, this failed to reach statistical significance. In all likelihood, methodological differences and perhaps ethnic characteristics underlie this discrepancy with other studies.
Risk of Cerebrovascular Disease
As early as 1980, information was available from the Framingham study that ISH could increase the risk of cerebrovascular complications by a factor of two to four relative to normotensive people. This was corroborated in a follow-up study among 2636 Californian adults aged 60 years or older, of whom 6.3% had isolated systolic hypertension at baseline. At that time ISH was still defined as a systolic blood pressure 160 or higher mm Hg and a diastolic blood pressure less than 90 mm Hg. After a 6.4-year follow-up of this cohort, males (but not females) with isolated systolic hypertension had an excess risk of death from stroke, even after adjustment for age and other covariates. At the same time, reports from Europe started to appear that highlighted the unfavorable prognosis of ISH. Since then various clinical studies have confirmed that ISH predisposes to cerebrovascular disease and stroke.
The data from the Framingham study on stroke incidence in relation to blood pressure suggest that the risk associated with isolated systolic hypertension is independent of the height of diastolic pressure. Although diastolic pressure is related to stroke incidence as well, the diastolic component adds little to risk assessment and even appears unrelated to stroke incidence in men with ISH.
Except for stroke, cognitive impairment may be aggravated by ISH. Indeed, the Baltimore Longitudinal Study on Aging showed that elevated PP and PWV were related to cognitive impairment, based on decline in verbal and nonverbal memory test scores in nondemented middle-aged individuals. Although cognitive impairment has not been specifically linked to ISH, the data from Baltimore at least suggest that such a relationship may exist.
Vascular Complications
Subclinical abnormalities such as diastolic dysfunction or an increased intima-media thickness (IMT) of the carotid artery also occur in conjunction with ISH. A recent study from Greece evaluated IMT in patients with so-called masked ISH. This condition was defined as an office pressure below 140 mm Hg systolic and 90 mm Hg diastolic with an average SBP 135 or higher mm Hg and DBP less than 85 mm Hg on 24-hour ambulatory monitoring. In these patients the IMT was significantly higher than in other forms of masked hypertension. An increased carotid IMT is a biomarker for atherosclerotic disease, not only in the cerebral vasculature but also elsewhere in the body. Indeed, compared with a normotensive group, patients with ISH also have more evidence of carotid stenosis, especially when diastolic BP is below 75 mm Hg. In the Rotterdam Study, an increased IMT was even associated with future cerebrovascular and cardiovascular events.
Peripheral vascular complications are frequently seen in patients with ISH as well, although these could easily be considered as manifestations of underlying atherosclerosis. In the prospective Women’s Health Study the incidence of peripheral arterial disease was three-fold to four-fold higher in those with ISH (SBP ≥ 140 mm Hg, DBP < 90 mm Hg) than in normotensive women. Obviously, this study had several limitations, yet it fits with other observations. Taken together, both carotid and lower extremity arterial disease seem to be prevalent abnormalities in patients with ISH, but the cause-and-effect relationship remains to be determined.
A similar problem concerns the role of the kidney. There is no doubt that impaired renal function increases arterial stiffness and that the prevalence of ISH increases stepwise with the stages of chronic kidney disease. Whether the opposite is also true, is less easy to define. In one cross-sectional study, renal hemodynamics (renal plasma flow, glomerular filtration rate) were inversely related to pulse pressure in patients with ISH but, after correction for age, the relationship persisted only in persons above 60 years of age ( Fig. 19.6 ). Although this suggests that ISH is detrimental for the kidney in elderly patients, it does not rule out the alternative possibility that a subtle decline in kidney function initiated or aggravated loss of arterial elasticity, which in turn accounted for the development of ISH.
