Knowing the Risks of the Vessels From the Vessels

During the long voyage of life, atherosclerotic cardiovascular disease (CVD) is among the most frequent causes of death. Knowing the risks of the blood vessels is a key to a community with healthy longevity, by the prevention, early detection, and better management of life-threatening cardiovascular events. Most risk prediction models are derived from large cohort studies in general populations without apparent CVD. Among these, the most well-recognized Framingham Heart Study published the “classical” risk factors of coronary heart disease in 1961, including age, sex, hypertension, dyslipidemia, and diabetes, which led to the later development of the Framingham risk scores.^1,2 After the introduction of these risk scores, several medical communities tested their predictive value.² The Hisayama Study, initiated in 1961 in Japan also confirmed the prognostic value of the clinical risk factors in the Japanese population.³ Even accepting the prognostic value of the classical risk factors, critiques have always aroused debate over for the use of these clinical risk factors in high-risk populations. Several measures such as genomics, biomarkers and physiological tests have been developed to identify high-risk individuals non-invasively.

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In this issue of the Journal, Kusunose et al⁴ evaluate the predictive value of several vascular function tests, namely flow-mediated vasodilatation (FMD), brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) and ankle-brachial blood pressure index (ABI), among subjects with multiple clinical risk factors. The primary outcome was major adverse cardiac events (MACE), a composite of cardiac death, nonfatal myocardial infarction/coronary revascularization, acute pulmonary edema or stroke. Over a period of 51 months, 35 (31%) patients had a MACE, 89% of which were cardiac events most likely driven by coronary artery disease. Kusunose et al found that among the 4 modalities of vascular function test, ABI was the best for identifying subjects at high risk of MACE. Low ABI (<1.04) had an independent prognostic value over the Framingham risk score and laboratory data.

The Figure illustrates typical pathologic changes in an artery during progression of atherosclerosis, causing abnormal findings on vascular function testing. Clinical risk factors, and resulting pathophysiology including inflammation, oxidative stress, and activation of the renin-angiotensin system affect all steps in the progression (ie, endothelial dysfunction, arterial stiffness caused by a thickening of the intima and media, obstructive stenosis caused by the development of plaques, and thrombotic occlusion of the artery, the last of which leads to acute coronary syndrome as MACE). Vascular function tests are performed non-invasively in the peripheral blood vessels, in order to estimate the pathologic status of the coronary vessels, and ultimately the risks of coronary artery occlusion.

Figure.

Typical pathological changes in an artery during progression of atherosclerosis. Arteries exposed to clinical risk factors and secondary activation of inflammation, oxidative stress, and renin-angiotensin system undergo serial pathological changes: (1) endothelial dysfunction, (2) arterial stiffness caused by intima-media thickening, (3) plaque formation causing obstructive stenosis, and (4) thrombotic occlusion causing MACE. Vascular function tests detect corresponding pathologic changes; diagnostic value of each vascular function test is presented as C statistic value* for predicting MACE. *Data provided by Kusunose K, et al.⁴ MACE, major adverse cardiac events.

Endothelial Dysfunction

Vascular endothelium covers the intimal surface of blood vessels, and maintains vascular homeostasis via the production of endothelium-derived vasoactive factors including nitric oxide and endothelium-derived hyperpolarizing factors, regulating vascular tone and mural thrombosis.⁵ Endothelial dysfunction, caused by clinical risk factors and resulting inflammation and oxidative stress, is the earliest hallmark of progression of atherosclerosis.⁶ FMD determines hyperemic endothelium-dependent vasodilatation in the brachial artery, and a lower FMD value is associated with the presence of clinical risk factors and predicts future coronary events.⁷ Low C statistic value (0.51) in the study by Kusunose et al, however, limited the effect of FMD for prediction of MACE in a cohort already exposed to multiple clinical risk factors and medications that may affect endothelial function.⁴

Arterial Stiffness

Currently, 2 methods are widely used to measure arterial stiffness (ie, baPWV and CAVI), both of which utilize the arterial pulse at different arterial sites. Arterial stiffness is caused by thickening of the media and intima, with an increase in collagen expression, and is typically a consequence of hypertension and aging. Although arterial stiffness does not necessarily imply early atherosclerotic changes with plaque formation, it shares risk factors with atherosclerosis, and arterial stiffness also accelerates the susceptibility of arterial walls to atherogenic risk factors such as hyperlipidemia.⁸ Indeed, the Rotterdam study⁹ showed that carotid-femoral PWV correlated with carotid intima-media thickening and also with the severity of the plaque burden. The study by Kusunose et al⁴ showed that higher baPWV (>1,703 cm/s) predicted MACE in subjects with multiple clinical risk factors, which suggests, at least in part, the role of arterial stiffening in the pathogenesis of atherosclerosis in this cohort (Figure).

Obstructive Arterial Stenosis

ABI is a simple metric calculated from the ratio of the systolic blood pressures in the upper and lower limbs and is a standard diagnostic test for peripheral artery disease (PAD). The current guideline for PAD⁹ defines a normal ABI range of 1.00–1.40, and abnormal values are defined as ≤0.90; ABI values of 0.91–0.99 are considered “borderline” and values >1.40 indicate non-compressible arteries. Kusunose et al⁴ showed that ABI values <1.04 predicted MACE with highest C statistic value (0.74) among the 4 vascular function tests. Superiority of the prognostic value of ABI over other vascular function tests is understandable based on the concept that atherosclerosis is an integral of serial pathologic changes in the vessel walls (Figure). Kajikawa et al recently showed that borderline ABI values of 0.91–0.99 are associated with lower FMD in healthy subjects,¹⁰ agreeing with this notion. Applying ABI to clinically high-risk populations, therefore, may identify individuals with advanced atherosclerosis at even higher risk of MACE, more specifically than other vascular function tests.

Notably, MACE as the primary outcome includes not only coronary events, but stroke and heart failure.⁴ Recently, it was reported that lower ABI was associated with higher cardiac mortality in patients with heart failure.¹¹ The presence of obstructive stenosis in the lower limb may correlate with advanced atherosclerosis in the coronary arteries that worsens ischemic heart failure; an alternative explanation is that systemic atherosclerotic burden may exacerbate heart failure through secondary activation of inflammation, oxidative stress, and the renin-angiotensin system, etc.¹¹ By contrast, different outcomes such as stroke and chronic kidney disease have different pathogenesis from coronary artery disease, thereby different markers for risk evaluation. Indeed, baPWV, but not ABI, predicted a decline in kidney function in the analysis by Kusunose et al,⁴ suggesting a different pathogenesis between coronary artery disease and chronic kidney disease. Applying appropriate vascular function tests based on sensible understanding of the pathogenesis of blood vessels will provide us with a compass for the voyage of lives facing the risks of CVD.

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