Large-Artery Stiffness in Health and Disease: JACC State-of-the-Art Review

Abstract

A healthy aorta exerts a powerful cushioning function, which limits arterial pulsatility and protects the microvasculature from potentially harmful fluctuations in pressure and blood flow. Large-artery (aortic) stiffening, which occurs with aging and various pathologic states, impairs this cushioning function, and has important consequences on cardiovascular health, including isolated systolic hypertension, excessive penetration of pulsatile energy into the microvasculature of target organs that operate at low vascular resistance, and abnormal ventricular-arterial interactions that promote left ventricular remodeling, dysfunction, and failure. Large-artery stiffness independently predicts cardiovascular risk and represents a high-priority therapeutic target to ameliorate the global burden of cardiovascular disease. This paper provides an overview of key physiologic and biophysical principles related to arterial stiffness, the impact of aortic stiffening on target organs, noninvasive methods for the measurement of arterial stiffness, mechanisms leading to aortic stiffening, therapeutic approaches to reduce it, and clinical applications of arterial stiffness measurements.

Keywords: arterial stiffness; dementia; heart failure; liver disease; matrix gla protein; pre-eclampsia; renal disease; systolic hypertension; vascular calcification.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Central Illustration.

Role of large artery stiffness in health and disease. In young healthy adults, a compliant aorta (left): (a) effectively buffers excess pulsatilty due to the intermittent left ventricular ejection; (b) exhibits a slow pulse wave velocity (PWV), which allows pulse wave reflections to arrive to the heart during diastole, increasing diastolic coronary perfusion pressure but not systolic ventricular load. A number of factors (aging, lifestyle, etc.) increase aortic wall stiffness, which leads to several adverse hemodynamic consequences. Aortic stiffening leads to increased aortic root characteristic impedance (Zc) and forward wave amplitude on one hand, and premature arrival of wave reflections to the heart on the other. These hemodynamic changes result in adverse patterns of pulsatile load to the left ventricle in systole and a reduced coronary perfusion pressure in diastole, ultimately promoting myocardial remodeling, dysfunction, failure and a reduced perfusion reserve (even in the absence of epicardial coronary disease). This adverse hemodynamic pattern also results in excessive pulsatility in the aorta, which is transmitted preferentially to low-resistance vascular beds (such as the kidney, placenta and brain), because in these organs, microvascular pressure is more directly coupled with aortic artery pressure fluctuations. PWV=pulse wave velocity; Zc=characteristic impedance; BP=blood pressure.

Figure 1.. Compliance, distensibility and PWV.

A) Typical relationship between intra-arterial pressure and lumen area when varying the pressure over a sufficiently large range. The area compliance (red line) is the slope to the pressure-area relationship, which can be calculated at any pressure level. At low pressure, the load is mainly taken by elastin, and the artery has a high compliance. As pressure increases, the load is progressively shifted to stiffer collagen fibers, leading to a functionally lower compliance. Vascular smooth muscle tone also affects compliance, particularly in distal aortic segments and intermediate-sized arteries. Normalizing area compliance to the local radius yields the distensibility coefficient (see Table 1). B) For a homogenous tube, the distensibility coefficient (Dist coeff) is theoretically linked to the PWV via the Bramwell-Hill equation (where ρ is the density of the blood) in an inverse, non-linear fashion; an increase in PWV by a factor 2 (which is about the change observed in humans from the age of 20 to the age of 70) implies a decrease in distensibility by a factor 4. An alternative formulation is the Moens-Korteweg equation, linking PWV to the stiffness of the wall material (incremental elastic modulus, Einc), the wall thickness (h) and lumen diameter (D).

Figure 1.. Compliance, distensibility and PWV.

A) Typical relationship between intra-arterial pressure and lumen area when varying the pressure over a sufficiently large range. The area compliance (red line) is the slope to the pressure-area relationship, which can be calculated at any pressure level. At low pressure, the load is mainly taken by elastin, and the artery has a high compliance. As pressure increases, the load is progressively shifted to stiffer collagen fibers, leading to a functionally lower compliance. Vascular smooth muscle tone also affects compliance, particularly in distal aortic segments and intermediate-sized arteries. Normalizing area compliance to the local radius yields the distensibility coefficient (see Table 1). B) For a homogenous tube, the distensibility coefficient (Dist coeff) is theoretically linked to the PWV via the Bramwell-Hill equation (where ρ is the density of the blood) in an inverse, non-linear fashion; an increase in PWV by a factor 2 (which is about the change observed in humans from the age of 20 to the age of 70) implies a decrease in distensibility by a factor 4. An alternative formulation is the Moens-Korteweg equation, linking PWV to the stiffness of the wall material (incremental elastic modulus, Einc), the wall thickness (h) and lumen diameter (D).

Figure 2.. Consequences of increased aortic stiffness on the central pressure waveform.

The left side represents what occurs with a highly compliant aorta, as occurs in young healthy adults; the right side represents a very stiff aorta, as occurs in the elderly and/or in the presence of various disease states. A stiff aorta is associated with a high-ampitude forward wave and a faster PWV, determining a faster forward and backward (reflected) wave speeds. This determines an earlier arrival of wave reflections to the aorta, with progressive loss of diastolic pressure augmentation and increased late systolic augmentation. The figure illustrates 2 rather extreme situations, with most people falling “in between”. Moreover, it should be emphasized that the apparent distance to reflection sites is highly variable between individuals and may become a dominant determinant of the timing of wave reflections in populations that exhibit stiff aortas or in the setting of hypertension. The term “apparent” is used because reflection sites can modify the morphology of reflected waves making it appear “shifted” in time (i.e., a shift to the right appears as if a reflection site is further away from the heart, for any given PWV). FW=forward wave. BW=backward wave.

Figure 3.. Arterial blood flow per unit of tissue mass in various organs.

The kidney, placenta-fetal unit, heart, brain, liver and testicle are shown. Although liver blood flow is much higher than shown, most of it is from the portal vein (not accounted for in the graph, which represents only arterial flow).

Figure 4.. Potential consequences of LAS on target organs.

LAS can impact the heart through effects on afterload (particularly, modulation of the timing of wave reflections) and may damage low-resistance organs via excess arterial pulsatility. Importantly, not all these potential consequences are similarly well-established. In general, there is a large body of evidence supporting deleterious effects on the kidney and heart, moderate evidence for the brain and the placenta, and early/limited evidence for the liver and testicles (see text for details). ASH=Non-alcoholic steatohepatitis.

Figure 5.. Cardiac Consequences of Arterial Stiffening.

Earlier arrival of wave reflections favor a loss of coronary perfusion pressure on one hand, and increased mid-to-late systolic load on the other, due to a shift of wave reflection arrival from diastole to systole. In populations with stiff aortas, muscular artery function may become a key determinant of the apparent distance to reflection sites and thus the effects of wave reflections on the central aorta, for any given PWV. PWV=pulse wave velocity. FW=forward wave. BW=backward wave.

Figure 6.. Impact of LAS on the kidney.

The kidney and the arterial wall exert important influences on each other and this interaction may lead to a vicious circle of arterial stiffening and the appearance/progression of chronic kidney disease and its complications. RAAS=renin-angiotensin-aldosterone system.

Figure 7.. Arterial stiffness and age-related changes in the brain commonly seen in Alzheimer’s disease and related dementias.

These changes include declines in cerebral perfusion to the gray matter, evidence of multiple forms of cerebral small vessel disease [lacunar infarcts (white circles), white matter hyperintensities (white streaks), cerebral microbleed (red triangles), enlarged perivascular (Virchow-Robin) spaces], loss of brain volume, and ß-amyloid deposition in the brain (brown plaques). Such changes are suspected to affect the integrity of the white matter and neurovascular unit.

Figure 8.. General Mechanisms of Arterial Stiffness.

Various mechanisms can increase the stiffness of the intima, media and adventitia. The media is however, the most important layer in large arteries. See text for details. NO=nitric oxide. AGE=advanced glycation end-products. RAAS=renin-angiotensin-aldosterone system. ERP=elastin-related peptides.

Figure 9.. Vitamin K-dependent Matrix Gla protein (MGP) maturation.

MGP maturation requires vitamin K, and leads to the formation of pc-MGP (phosphorylated, carboxylated MGP), which is a strong inhibitor of vascular calcification via inhibition of Bone morphogenetic protein 2 (BMP-2) signaling and VSMC osteogenic-differentiation. Vitamin K deficiency in the vascular wall leads to the formation of uncarboxylated (uc-)MGP (which accumulates in the vessel wall) and dephosphorylated, uncarboxylated (dpuc-)MGP which can be measured in serum.

Figure 10.. Methods of measurement of carotid-femoral PWV (A–C), CAVI (D) and ba-PWV (E) by various devices.

Sensors and examples of recorded signals are shown. C=carotid signal; F=femoral signal; P=phonocardiographic signal; B=brachial signal; A=ankle signal. 1: FDA-approved; 2: the vicorder uses a neck cuff, rather than a tonometry sensor.

Figure 11.. Echocardiographic Assessment of Thoracic Aortic transit time.

ECG signals and digital flow traces are extracted from DICOM images of pulsed-wave Doppler interrogations from the left ventricular outflow tract (LVOT, 1), descending aorta (DA, 2) and proximal abdominal aorta (AA, 3). Beats at each location relate consistently to the QRS complex, which can be used as a time-reference. The top left panel shows the signal averaged pulses at the 3 locations, clearly demonstrating the transit time. The development of methods to estimate aortic path length (distance) between 2 points using anthropometric and echocardiographic imaging data is under development, and could facilitate a broad application of PWV measurements in clinical practice.

Figure 12.. Assessment of Thoracic Aortic PWV by through-plane phase-contrast MRI.

Magnitude and phase (top right panels) images of an aortic cross section are used to extract time-resolved flow curves. The path length can be directly measured from aortic images.

Figure 13.. Carotid-femoral PWV as a predictor of cardiovascular events in a recent meta-analysis of prospective studies.

Carotid-femoral-PWV was an independent predictor of risk across multiple subpopulations although the effect was more pronounced among participants aged 60 or younger. Reproduced from (5)

Figure 14.. Normal values of carotid-femoral PWV by age and blood pressure status established by the European Arterial Stiffness Collaboration (A) and concept of life-course of vascular aging.

PWV increases with age and BP category (A, reproduced with permission from (87)); note that blood pressure categories correspond to European guidelines, rather than to recent AHA/ACC categories. Panel B demonstrates the concept of life-course of vascular aging and preventable thresholds for cardiovascular disease across the health-disease continuum (Partially reproduced from (95)). QOL=quality of life.