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.