Qualitative evaluation of coronary atherosclerosis in a large cohort of young and middle-aged Dutch tissue donors implies that coronary thrombo-embolic manifestations are stochastic

Abstract

Background and aims: With the intention to gain support for the hypothesis that incident ischemic complications of atherosclerotic disease involve a stochastic aspect, we performed a histological, qualitative evaluation of the epidemiology of coronary atherosclerotic disease in a cohort of aortic valve donors.

Patients and methods: Donors (n = 695, median age 54, range 11-65 years) were dichotomized into a non-cardiovascular (non-CVD) and a cardiovascular disease death (CVD) group. Consecutive 5 mm proximal left coronary artery segments were Movat stained, and the atherosclerotic burden for each segment was graded (revised AHA-classification).

Results: Non-CVD and CVD groups showed steep increase of atherosclerosis severity beyond the age of 40, resulting in an endemic presence of advanced atherosclerosis in men over 40 and women over 50 years. In fact, only 19% of the non-CVD and 6% of the CVD donors over 40 years were classified with a normal LCA or a so called non-progressive lesion type. Fibrous calcified plaques (FCP), the consolidated remnants of earlier ruptured lesions, dominated in both non-CVD and CVD donors. Estimates of the atherosclerosis burden (i.e. average lesion grade, proportion of FCPs, and average number of FCPs per cross-section) were all higher in the CVD group (p<1.10-16, p<0.0001, and p<0.05, respectively).

Conclusions: Dominance of consolidated FCP lesions in males over 40 and females over 50 years, show that plaque ruptures in the left coronary artery are common. However, the majority of these ruptures remain asymptomatic. This implies that the atherosclerotic process is repetitive. A relative difference in disease burden between CVD and non-CVD donors supports the concept that complications of atherosclerotic disease involve a stochastic element.

Fig 1. Movat staining of a coronary artery cross section illustrating the foot prints of consolidated calcified lesions (purple-brown demarcations indicated by the arrow in the enlarged insert), and the presence of multiple lesions within a single cross section.

I: late fibro-atheroma (LFA) lesion (necrotic core covered by a fibrous cap). II-V: indicating consolidated former lesions (fibrotic calcified plaque (FCP)) [15].

Fig 2. Adapted AHA (Virmani) classification of coronary atherosclerotic lesions [15] (Movat stained coronary artery segments).

(2-A) Normal and non-progressive (reversible) lesions [15] Adaptive intimal thickening (AIT) is characterized by hyperplasia of the tunica intima (blue); intimal infiltration of macrophages (black arrows) and presence of foam cells characterize intimal xanthoma (IX). (2-B) Progressive atherosclerotic lesions.[15] Pathological intimal thickening (PIT) is hallmarked by a pre-necrotic lipid core, with or without surrounding infiltrated foam cells (black arrows). Early and late fibro-atheroma (EFA and LFA) are characterized by a necrotic lipid core, cholesterol crystals, and an overlying thick collagen-rich (yellow/green) fibrous cap. Thin cap fibro-atheroma (TCFA) is characterized by a thin fibrous cap, which precedes rupture (plaque rupture (PR)). Rupture is followed by a healing process with formation of a new proteoglycan/cell rich cap (healed rupture (HR)). (2-C) Stabilized atherosclerotic lesions and acute total occlusion.[15,16] The healed rupture ultimately transforms into a scar, the fibrotic calcified plaque (FCP) contains calcified remnants of the necrotic core. New lesions can develop on top of FCPs (neo-intima, blue), which can ultimately result in stacked lesions. This may eventually cause accumulation of multiple lesions within one cross section (red arrows) and formation of a neo-intima overlying the consolidated earlier lesions. Acute occlusion represents an example of a (fatal) thrombo-embolic acute full occlusion of the LCA.

Fig 3. Age distribution for the most advanced lesion type present in the proximal left coronary artery .segment studied.

Fig 3A: non-cardiovascular death donors. Fig 3B: cardiovascular death donors. ‘+’ represent females and ‘o’ represent males. Data points have been jittered [17] in order to avoid overlap.