The Process of Plaque Rupture: The Role of Vasa Vasorum and Medial Smooth Muscle Contraction Monitored by the Cardio-Ankle Vascular Index

Abstract

A warning sign for impending cardiovascular events is not fully established. In the process of plaque rupture, the formation of vulnerable plaque is important, and oxidized cholesterols play an important role in its progression. Furthermore, the significance of vasa vasorum penetrating the medial smooth muscle layer and being rich in atheromatous lesions should be noted. The cardio-ankle vascular index (CAVI) is a new arterial stiffness index of the arterial tree from the origin of the aorta to the ankle. The CAVI reflects functional stiffness, in addition to structural stiffness. The rapid rise in the CAVI means medial smooth muscle cell contraction and strangling vasa vasorum. A rapid rise in the CAVI in people after a big earthquake, following a high frequency of cardiovascular events has been reported. There are several cases that showed a rapid rise in the CAVI a few weeks or months before suffering cardiovascular events. To explain these sequences of events, we proposed a hypothesis: a rapid rise in the CAVI means medial smooth muscle contraction, strangling vasa vasorum, leading to ischemia and the necrosis of vulnerable plaque, and then the plaque ruptures. In individuals having a high CAVI, further rapid rise in the CAVI might be a warning sign for impending cardiovascular events. In such cases, treatments to decrease the CAVI better be taken soon.

Keywords: atheromatous lesion; cardio-ankle vascular index; cholesterol oxidative products; plaque rupture; vasa vasorum.

Figure 1

Formation of an arteriosclerotic lesion: Stage Ⅰ. Cholesterol-rich lipoproteins such as LDL, IDL, and small dense LDL are carried by vasa vasorum and enter the deep intimal area. There, cholesterols are oxidized, and several oxidative products are produced. Oxysterols are toxic and damage the surrounding tissues. For example, 7-ketocholeterol induces apoptosis of smooth muscle cells and expands the lipid pool. Then, oxysterols induced an inflammatory reaction, and macrophages infiltrated. Smooth muscle cells migrate from the media to the intima and proliferate to make intimal thickening. During this process, vasa vasorum develop from adventitia into an intimal lesion through the medial smooth muscle layer (neovascularization). The CAVI increases as arteriosclerosis develops. CAVI: cardio-ankle vascular index; IDL: intermediate-density lipoprotein; LDL: low-density lipoprotein.

Figure 2

Oxysterol-induced apoptosis of smooth muscle cells. (A) Oxysterol-rich fraction-induced apoptosis of cultured smooth muscle cells. (B) Smooth muscle cells are observed to fall into apoptosis in human arteriosclerotic lesions.

Figure 3

(A) The surface of the medial layer peeled off the intimal atheromatous layer. At endarterectomy of the carotid artery, the intimal atheromatous layer could be peeled away from the medial smooth muscle cell layer. The denuded surface of the medial smooth muscle layer was promptly covered with blood, indicating that the intimal arteriosclerotic lesion was supplied by blood with vasa vasorum, which penetrated through the medial smooth muscle layer from the adventitia. (B) Bleeding at the surface of the peeled medial layer of the arteriosclerotic artery at endarterectomy. When the surface of the smooth muscle cell layers was covered with a sheet of gauze dipped with norepinephrine, the blood exuding from the medial smooth muscle layer was stopped, indicating that contraction of the medial smooth muscle stopped blood supply from the adventitia and caused ischemia of the intimal lesion. The medial smooth muscle contraction would bring a rapid increase in the CAVI.

Figure 4

Equation of the cardio-ankle vascular index and measuring methods (adapted from Ref. [14]). Ps: systolic blood pressure, Pd: diastolic pressure, In: natural logarithm, ΔP: Ps-Pd, ρ: blood viscosity, a,b: coefficiency, PWV: pulse wave velocity, L: length from the origin of the aorta to the ankle, T: time taken for the pulse wave to propagate from the aortic valve to the ankle, tba: time between the rise of brachial pulse wave and the rise of ankle pulse wave, tb: time between aortic valve closing sound and the notch of brachial pulse wave, t’b: time between aortic valve opening sound and the rise of brachial pulse wave.

Figure 5

Various stages of atherosclerosis of the aortae and the CAVI. (A) Aorta of a 50-year-old woman. The CAVI was 7.3, which is a nearly normal level (−0.5SD). (B) Aorta of a 74-year-old man. The CAVI was 11.0, which is high for his age (+2SD). (C) Aorta of a 76-year-old man. The CAVI was 11.0, which is high for his age (+2SD). A high CAVI value over +2SD from the average value for ages might indicate the presence of arteriosclerosis with vulnerable plaque. CAVI: cardio-ankle vascular index.

Figure 6

The process of plaque rupture of vulnerable plaque triggered by medial smooth muscle contraction monitored with a rapid rise in the CAVI: Stage II. When a rapid rise in the CAVI was observed, medial smooth muscle contraction occurred. Then, the vasa vasorum are strangled, and blood supply to the intimal lesion is stopped, which causes ischemia and necrosis of vulnerable plaque, following plaque rupture. Cardiovascular events such as cerebral bleeding, myocardial infarction, and dissecting aneurysms in the aorta might happen in the near future (Quoted from Ref. [20]).