In a compliant vasculature, energy is dissipated in the central circulation by viscous dampening of reflected waves.32
Loss of this protective mechanism with vascular stiffening exposes organs to high pulsatile pressure that leads to arterial remodeling and microcirculatory damage in the brain and kidney.53,62-65
Vascular stiffening is associated with cerebral small vessel changes, including small lacunar infarcts and white matter lesions that are common in individuals with cognitive impairment and dementia.66-68
Vascular stiffness is also associated with endothelial dysfunction that can lead to neuronal injury by compromising cerebral blood flow and the blood-brain barrier.53,62-66,69,70
Hence, it is plausible that chronic small vessel changes associated with vascular stiffness might predispose patients to impaired cerebral and renal blood flow and end-organ damage.
The heart also undergoes changes with age. Increased vascular stiffness causes increased afterload and leads to the development of myocardial hypertrophy, diastolic dysfunction, and heart failure. In addition, the myocardium undergoes age-related changes that are mechanistically related to those in the vasculature. Ultimately, increased vascular stiffness and the resultant increase in myocardial loading conditions lead to a coupled increase in both systolic and diastolic myocardial stiffness (). As arterial stiffness increases, LV systolic stiffness increases in parallel. That is, the changes in the vasculature and LV are coupled. Eventually, however, beyond moderate increases in arterial stiffness, the processes uncouple because the central vasculature loses its ability to accommodate the stroke volume; the result is less efficient LV ejection. In contrast to indices of stiffness, indices of contractility do not correlate with age, suggesting that arterial stiffness, and by inference structural elements in the myocardium, may be important factors in age-related changes. Moreover, it has been clearly demonstrated that indices of vascular stiffness (increased pulse pressure, decreased arterial elastance, increased pulse wave velocity) and myocardial systolic stiffness increase with age.71,72
However, SVR does not increase with age. Vascular-ventricular coupling of stiffer vessels with a stiffer heart has an overall deleterious effect on pressure and flow regulation (including coronary blood flow), resulting in decreased cardiovascular reserve and a lower threshold for the development of cardiovascular disease.71,72
Figure 4 A, Example pressure-volume loops with ventricular systolic (Ees) and effective arterial elastance (Ea) relations from a young and old patient. Ees defines chamber systolic stiffness, and the intersection point of the Ea and Ees lines is the ventricular-arterial (more ...)
There is a clear link between increased vascular stiffness and development of diastolic dysfunction. This pathological LV hypertrophy in aged myocardium is due not only to cardiac myocyte hypertrophy but also to the significant increase in connective tissue content that leads to pathological remodeling and heart fibrosis. The sclerotic changes in the heart cause LV stiffness, which leads to reduced LV compliance—a decreased ability of the LV to accommodate diastolic blood volume without high pressures. Decreased LV compliance manifests mainly during diastole; LV diastolic filling becomes impaired, and higher filling pressures are required to achieve the same LV diastolic volume. LV filling from the left atrium is impeded, leading to an increase in left atrial pressure. This high pressure is transmitted backwards to pulmonary veins and capillaries, and the resulting interstitial fluid accumulation is manifested as shortness of breath and even pulmonary edema.
The combination of LV diastolic dysfunction and vascular stiffness might have particular relevance for acute hemodynamic perturbations as may occur perioperatively or in critically ill patients. Arteriolar remodeling may necessitate higher arterial pressure for brain and kidney perfusion. At the same time, preload dependence associated with diastolic dysfunction may predispose patients to marked fluctuations in blood pressure that result from alterations in intravascular blood volume. As illustrated in , older patients operate on the steeper portion of the diastolic pressure-volume relationship compared with younger individuals. The clinical consequence is that small changes in the preload (defined as end-diastolic LV volume) will cause relatively large changes in systemic blood pressure. Other mechanisms may also contribute to end-organ (brain, kidney) damage in the setting of increased vascular stiffness. Autoregulation in the brain and kidney may become impaired or lower autoregulatory limits may develop in patients with increased vascular stiffness. Organ hypoperfusion may result when such individuals are exposed to what otherwise might be considered an “acceptable” blood pressure.73
Clinical Measurements of Vascular Stiffness
Increased arterial stiffness is a manifestation of vascular aging and is accompanied by increased central aortic pressure. However, peripheral blood pressure measurements do not fully reflect the central aortic pressure profile. Thus, the reliance on peripheral blood pressure measurements as markers of vascular alteration can underestimate vascular aging even in asymptomatic individuals. Several indices of vascular stiffness have been used in population-based studies, including brachial artery pulse pressure, central aorta augmentation index, pulse wave velocity, aortic distensibility, and the magnitude of reflected wave. These have been shown to be robust predictive indices of adverse cardiovascular outcomes in population-based studies and notably are independent of conventional risk factors, including age itself ().6,11,48,74
Pivotal studies linking vascular stiffness and adverse cardiovascular events in community-dwelling and cardiac surgical patients.
Historically, the “gold standard” for arterial stiffness assessment is the measurement of pulse wave velocity (). Velocity is defined as change in distance over change in time. For pulse wave velocity, distance is measured at two separate points along the arterial tree, usually the carotid and femoral arteries or the carotid and radial arteries. The time interval is determined by measuring the time between the electrocardiogram R wave and the start or peak of the pulse wave at each of the arterial sites of measurement to derive the “time elapsed” as shown in . This measurement is obtained by timing the arrival of the pulse to peripheral sites (e.g., radial and femoral pulses) compared with more central pulses (e.g., the carotid pulse) in relation to a fixed time point, the electrocardiogram QRS complex. The pulse wave velocity in a young person is approximately 6 m/s; it increases to 10 m/s by the age of 65 years and continues to increase with advancing age.
Carotid-femoral pulse wave velocity constitutes a useful, safe, reproducible, and noninvasive method for assessing arterial stiffness.75
Increased carotid-femoral pulse wave velocity has been shown to be an independent predictor of cardiovascular events in the general population,6,11
in the elderly,48
and in patients with hypertension,44,64
and end-stage renal disease.77
Recent meta-analyses have confirmed that measures of arterial stiffness (e.g., pulse wave velocity) independently predict adverse cardiovascular outcomes and all-cause mortality.78,79
The pooled relative risk for cardiovascular events (myocardial infarction, stroke, revascularization) was 2.26 (95% confidence interval [CI]: 1.89 to 2.70; 14 studies) and the pooled relative risk for cardiovascular mortality was 2.02 (95% CI: 1.68 to 2.42; 10 studies) for subjects with high versus low aortic pulse wave velocity. As expected, the relative risk was higher in patients with coronary artery disease, renal disease, and hypertension compared with the general population. An increase in aortic pulse wave velocity by 1 m/s corresponded to an age-, sex-, and risk factor-adjusted risk increase of 15% for adverse events and mortality. An increase in aortic pulse wave velocity by 1 standard deviation was associated with a relative risk increase of 47% for these events.79
Vascular stiffness can be assessed noninvasively, and thus, can be incorporated into routine clinical assessements.80
Noninvasive assessment of arterial stiffness usually falls into one of three categories: measurement of pulse wave velocity, determination of arterial distensibility, or assessment of central arterial pressure augmentation (e.g., augmentation index) and pulse pressure. Pulse wave velocity measurements have been suggested as a means of assessing subclinical target organ damage.81
Indices of vascular stiffness all increase with advancing age; however, the age-related changes in augmentation index and aortic pulse wave velocity are nonlinear. Some investigators have suggested that augmentation index might be a more sensitive marker of arterial stiffening and cardiovascular risk in younger individuals because this measure increases at a younger age compared to other measurements. In contrast, aortic pulse wave velocity is thought to be a better measure of vascular risk in older individuals, because prominent changes in pulse wave velocity have been observed only in older individuals.82
Indeed, arterial pulse wave velocity, but not augmentation index, has been shown to be associated with the extent of coronary artery disease.83
The potential explanation for the lower predictive value of augmented pressure and augmentation index in predicting adverse cardiovascular events compared to pulse wave velocity may be that the former measurement depends on the timing of arrival of a reflected wave to the central circulation. Pulse wave velocity and magnitude of the reflected waves are time-independent measures of arterial stiffness that predict long-term cardiovascular mortality independent of conventional risk factors and other measures of arterial stiffness84
. The magnitude of the reflected wave is derived from pulse wave analysis via a mathematical algorithm.84
Recently, MRI has been suggested as another noninvasive modality for assessing central arterial compliance/stiffness.85
Aortic arch distensibility as assessed by MRI was found to be the most sensitive marker of arterial aging in individuals <50 years of age, whereas aortic arch MRI-derived pulse wave velocity was more sensitive in individuals >50 years of age. This study found a dramatic decrease in aortic arch distensibility by the third decade of life in individuals otherwise free of overt cardiovascular disease. Although the authors reported that the relationship between age and aortic stiffness was nonlinear, these results suggest that MRI might be useful for detecting early and subclinical vascular disease.
Several devices to measure arterial stiffness are commercially available (). Most derive their measurements from peripherally acquired waveforms by using tonometry. Central pressure waveforms are then extrapolated by mathematical modeling based on transfer function of waveforms. These methods have been validated against central aortic measurements.86
Measurements can be made easily with good inter- and intraoperator reproducibility.87
Commercial devices that measure central arterial stiffness
The predictive value of vascular stiffness in surgical patients has become increasingly appreciated.7-9
Pulse pressure was shown to be an independent predictor of renal,7
and cardiovascular events9
in patients undergoing cardiac surgery. Thus, there is emerging evidence that measurements of vascular stiffness provide unique prognostic information for future cardiovascular events in nonsurgical and surgical settings. These findings provide not only a means for improving current risk stratification models but also the potential for interventions to improve patient outcomes.
Pharmacologic Modification of Vascular Stiffness
Data from studies in nonsurgical patients suggest that therapy to reduce central arterial stiffness may improve patient outcomes independent of blood pressure reduction. In the REASON study, angiotensin blockade was shown to reduce arterial stiffness, wave reflections, and central pulse pressure independent of mean arterial blood pressure reduction after 1 year of treatment. In addition to decreasing SVR, blockade of angiotensin II restores the remodeling of large arteries and decreases the thickness of resistance arteries; the resulting changes in arterial morphology, in turn, lead to a reduction in pressure wave reflections and augmentation index 43
The Conduit Artery Function Evaluation (CAFE) Study88
demonstrated that an antihypertensive regimen consisting of an angiotensin converting enzyme inhibitor and a calcium antagonist preferentially reduced central vascular pressures (and presumably central vascular stiffness) and decreased the long-term cardiovascular event rates compared with a regimen of β-blockers and diuretics, even though both regimens had similar effects on peripheral blood pressure (). The CAFE study suggested that β-blockers may have been less beneficial because they are less effective at decreasing central aortic pressure. Subsequent analysis of the CAFE study’s heart rate data showed that heart rate reduction was the main reason that β-blocker–based therapies were less effective than the others at reducing central pressure.89
In addition, it has been shown that augmentation index is inversely related to heart rate, such that slow heart rate leads to increased augmentation index and high central aortic pressures, but only minimal increases in peripheral systolic blood pressure.90,91
The authors of the CAFE heart rate study found that the main impact of heart rate reduction was on the augmentation of the reflected wave, which increased by 3 mm Hg per 10 beats/min reduction in heart rate, with minimal effect on the incident outgoing pressure waves. Similarly, after adjustment for the brachial blood pressure, heart rate was the major determinant of central systolic and pulse pressure, pressure wave reflections, and pulse pressure amplification. Even more importantly, after the authors adjusted for heart rate, the differences in central systolic and pulse pressures between treatment arms were no longer significant, and the differences in indices of central blood pressure augmentation were minimal. The authors suggested that reduction in heart rate was the major reason that β-blocker–based therapy has been less effective at reducing cardiovascular events, especially stroke, when compared with other treatments. In addition, the decrease in pulse pressure observed with nitrates, calcium channel blocking drugs, and angiotensin converting enzyme inhibitors has a marked benefit on microvascular function and may explain their ability to protect brain and kidney function.92
Figure 5 Top: Changes in brachial (solid symbols) and derived central aortic (open symbols) pulse pressure (PP) over time (mean, 95% CI) for patients randomized to receive atenolol±thiazide- or amlodipine±perinodopril-based therapy. Bottom, Changes (more ...)
The suggestive protective effect of calcium channel blockers was illustrated in a study by Aronson et al.93
that assessed the efficacy and safety of the novel, ultra-short-acting dihydropyridine calcium channel blocker clevidipine. The efficacy of treating acute hypertension with clevidipine, nicardipine, nitroglycerin, and sodium nitroprusside was assessed by analyzing the duration and extent of blood pressure excursions beyond predetermined upper and lower limits. Notably, sodium nitroprusside and nitroglycerine were associated with longer time periods outside the predefined blood pressure limits, and this was associated with a tendency toward increased mortality, stroke, and renal dysfunction. However the authors measured only peripheral blood pressure; no data regarding central aortic pressure were reported. Given the known cardioprotective role of statin therapy (e.g., ASCOT trial), the CAFE-LLA study was designed to investigate whether the beneficial effects of atorvastatin were at least partially due to a decrease in central aortic pressures. CAFE-LLA demonstrated no effects of atorvastatin on either central aortic pressures or hemodynamic indices.94
All conventional strategies with well-established benefits in the prevention of cardiovascular events improve endothelial function. Such strategies include physical exercise training, avoidance of stress, and smoking cessation. The decreased cardiovascular risk is associated with a reduction in vascular stiffness. Specifically, regular physical exercise has been reported to slow the increases in arterial stiffness with age and improve arterial compliance in healthy subjects and in patients with chronic inflammatory diseases.95-97
Finally, it is important to emphasize that two different patients with the same peripheral blood pressure-decreasing effect from antihypertensive therapy may have completely different central aortic pressure responses, depending on vascular stiffness. Thus, indices of vascular stiffness may not only improve the precision of risk stratification models for patients undergoing surgery, but may also allow select patients to benefit from treatment paradigms targeting patient-specific hemodynamic end points.
Despite the importance of, growing interest in, and number of studies focusing on indices of vascular stiffness and central aortic pressure in the medical literature, only a few studies have been performed in a surgical population. Given the importance of pulsatile phenomena for the cardiovascular system and its dependence on vascular age, we strongly believe that measurements of vascular stiffness and central aortic pressure should be used in the perioperative period as predictors of adverse outcomes and to set goals for hemodynamic management. Future studies will explore the perioperative implications of vascular aging and provide evidence-based guidance.