Aortic stiffness predicts all-cause mortality in the general population and coronary heart disease and stroke in healthy individuals. It is typically estimated by measuring pulse wave velocity (PWV), which can be determined noninvasively by ultrasound or using one of several commercially available devices.1
The groundwork for widespread utilization of PWV in clinical decision-making has been laid by the Reference Values for Arterial Stiffness Collaboration, which established a normal range for PWV.2 Antihypertensive medications have different effects on aortic stiffness, and determining PWV may guide therapy. Also, increased PWV is recognized as a prognostic factor and utilized for cardiovascular risk stratification in the 2013 guidelines for the management of hypertension issued jointly by the European Society of Hypertension and the European Society of Cardiology.1
In previous commentaries, we have examined the role of mechanical fatigue of aortic elastin molecules in progressive aortic stiffening and aging. This month, we will discuss the role of aortic stiffness in atherosclerosis.
Root Causes of Atherosclerosis: Two Pathways
The Hemorheologic-Hemodynamic Theory of Atherogenesis holds that atherosclerosis is a disease of vulnerable low shear blood flow, which fosters the organization of mural thrombi into atherosclerotic plaques. As recognized by the pioneering 19th century pathologist, Rudolf Virchow, stasis of blood predisposes to thrombosis. Blood flow prevents thrombosis via influx of anticoagulant molecules and dispersal of activated clotting factors. Organization of thrombi entails ingrowth of capillaries and synthesis of collagen, which take time. Thus, to become organized, a thrombus must remain intact for days.
Larger areas of vulnerable low shear blood flow are created in the vascular tree by two mechanisms: increased blood viscosity and increased blood velocity. Flow is inversely proportional to viscosity, so increased viscosity will cause slower flow. Increased blood velocity creates larger areas of lower shear by creating areas of secondary flow, like eddy currents and pools. Alternatively, according to the Protective Adaptation Theory of Atherosclerosis3, elevated blood velocity increases high shear stress injury on the endothelium, which elicits a fibroproliferative response and atherosclerotic plaque formation.
In either pathway, normal aortic and arterial compliance function to moderate blood velocity, slowing and distributing blood flow over the cardiac cycle (the Windkessel effect). Aortic and arterial compliance attempt to normalize flow so that blood can pass between the Scylla of hemostasis and the Charybdis of disturbed turbulent flow.
Related Clinical Evidence
Two other publications on aortic stiffness have explored areas relevant to the Hemorheologic-Hemodynamic Theory. In “Increased Peak Blood Velocity in Association with Elevated Blood Pressure,4” Perret and Sloop reported that peak blood velocity in the common carotid was correlated with systolic blood pressure over the range of 135 to 160 mm Hg. We speculated this was due to increased aortic stiffness.
In “Aortic Compliance and Stiffness Among Severe Longstanding Hypertensive and Non-hypertensive[sic]5”, Kamberi and colleagues recently confirmed that hypertension is associated with aortic stiffening. They found that antihypertensive therapy improved, but did not normalize aortic stiffness in long-standing hypertensive patients, which is what would be expected if hypertension accelerates fatigue and fracture of elastin molecules in the aortic wall.
In a 1998 paper entitled “A Description of Two Morphologic Patterns of Aortic Fatty Streaks and a Hypothesis of Their Pathogenesis,6” Sloop et al. reported that retrograde or reverse blood flow in diastole began to disappear in the distal thoracic aorta by age 23 and was completely lost by age 37. Retrograde aortic flow in diastole is important because it limits the amount of time, called the residence or dwell time, that a thrombus can remain against an arterial wall. Areas of stasis created during antegrade or forward flow during systole are eliminated by diastolic retrograde flow, preventing organization.
The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, a 13-year nationwide NIH-funded study involving 15 different research centers, showed that the prevalence of atherosclerotic plaques in the abdominal aorta increases significantly over this age range.7 In white males aged 15 to 19, 0.9% of the abdominal aorta surface contained atherosclerotic plaque, while 7.8% of the surface was involved in white males aged 30 to 34.
In a paper published in the September 2013 issue of Hypertension, “Aortic Stiffness Determines Diastolic Blood Flow Reversal in the Descending Thoracic Aorta,8” Hashimoto and Ito determined that diastolic retrograde flow in the proximal thoracic aorta is modulated by aortic stiffness. In their study, retrograde flow during diastole became more prominent with advancing age and progressive aortic stiffening, being present in all of the subjects in their study, who had an average age of 54. The different prevalence of retrograde diastolic flow in the two studies is probably due to the different sites which were studied, distal thoracic versus proximal thoracic aorta (personal communication with J. Hashimoto).
These data provide an explanation for the decreased extent of atherosclerotic plaques in the thoracic aorta compared to the abdominal aorta.7 In 30 to 34 year-old white males in the PDAY study, 7.8% of the surface of the abdominal aorta contained atherosclerotic plaque, while only 0.8% of the surface of the thoracic aorta contained plaque. Constant blood flow throughout the cardiac cycle limits the residence time for mural thrombi, preventing their organization into atherosclerotic plaques.
However, pathologic aortic stiffness and augmented retrograde flow in the proximal thoracic aorta cannot be entirely beneficial. Increased diastolic retrograde flow in the proximal thoracic aorta will affect the two most important circulations: the carotid and coronary, both of which originate from the proximal aorta.
Brief Examination of Blood Flow Regimes
The carotid waveform is biphasic with rapid antegrade flow in systole and slower antegrade flow in diastole. Any thrombi generated in areas of secondary flow created in systole will be dispersed by the slower laminar flow during diastole, limiting residence time to less than one cardiac cycle. Augmented retrograde diastolic aortic flow increases the velocity of the antegrade diastolic carotid flow, allowing areas of secondary flow to persist throughout the cardiac cycle. Thus, the residence time of thrombi will be indefinite, long enough for organization to occur. Because of its slight fusiform dilatation, the carotid sinus is a hemodynamically adverse environment, prone to stasis and atherosclerosis.9
Augmented retrograde aortic flow will increase the peak velocity of antegrade coronary diastolic flow, just as in the carotid circulation. The potential to develop mural thrombi in the coronary circulation is increased because there is only minimal flow during systole because of myocardial contraction. Thus, there is no opportunity for protective laminar flow to occur. The convex surface of the heart and numerous branches make the coronary circulation hemodynamically adverse in comparison to long straight arteries with no branches.
In both circulatory regimes, the pathologic consequence of increased blood viscosity creates larger areas of vulnerable low shear blood flow in the areas of secondary flow. LDL particles increase erythrocyte aggregation, increasing blood viscosity at low shear rates. In blood with enhanced thixotropic properties (i.e., the exaggerated increases in viscosity observed at lower shears) as due to elevated LDL levels, a vicious pathophysiologic cycle occurs where erythrocyte aggregation increases viscosity, which decreases flow, allowing further erythrocyte aggregation, higher viscosity, increasingly aggravating with vulnerable low shear stress. This unrestricted pathologic feedback mechanism results ultimately in thrombosis. Not surprisingly, hypercholesterolemia is a risk factor for deep venous thrombosis.10
The measurement of blood viscosity and pulse wave velocity has the capacity to enhance the many biomarkers currently in use for cardiovascular disease risk stratification, such as lipid profiles, apolipoprotein quantitation, high sensitivity C-reactive protein, and homocysteine, among others.
1. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2013 EWSH/ESC Guidelines for the management of arterial hypertension. European Heart Journal doi: 10.1093/eurheartj/eht151.
2. The Reference Values for Arterial Stiffness Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J 2010;31: 2338-2350.
7. Prevalence and extent of atherosclerosis in adolescents and young adults. Implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. Strong JP, et al. JAMA 1999; 281(8): 727-735.
8. Aortic stiffness determines diastolic blood flow reversal in the descending thoracic aorta. Potential implication for retrograde embolic stroke in hypertension. Hashimoto J, Ito S. Hypertension 2013; 62(3): 542-549.
Last Updated: 2014-12-30