A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening

Abstract

Objective: Medial vascular fibrosis contributes to arterial stiffening and reduced compliance, increasing the risk of cardiovascular events. We undertook the first comprehensive histopathologic study of medium-to-large caliber blood vessels (carotid, coronary, dorsalis pedis, internal mammary, iliac, mesenteric, pulmonary, and renal arteries) in 100 autopsy subjects to characterize medial fibrosis in relation to cardiovascular risk factors.

Methods and results: Masson Trichrome staining of vascular tissue microarrays (TMAs) was digitally analyzed to determine the percent fibrosis (% collagen) of over 700 vascular segments. The percent fibrosis of the tunica media was strongly correlated within subjects across all systemic blood vessels (average r=0.53), suggesting that fibrosis is a global process independent of the predilection of the vessel towards the development of atherosclerosis. Hypertension, diabetes, age and poor renal function were significantly associated with increased systemic vascular fibrosis (p< or =0.03). By multivariable analysis, only poor renal function (p=0.003) was an independent predictor of higher levels of fibrosis. Finally, in a subset of 13 individuals we observed a significant correlation between pre-mortem pulse pressure and systemic vascular fibrosis (p<0.001).

Conclusions: This study demonstrates that vascular fibrosis is a global process associated with diseases of aging and elevated pulse pressures.

Fig. 1

Determination of vascular fibrosis by digital analysis of TMA core images. The left panels (A, C, E) show 3 examples of blood vessels stained with Masson Trichrome. The right panels (B, D, F) show these images segmented into four areas: medial fibrosis (blue), medial non-fibrosis (red), intimal fibrosis (green), and intimal non-fibrosis (yellow). (A, B) Internal mammary artery from a 65 year old diabetic, hypertensive male. (C, D) Dorsalis pedis from a 43 year old non-hypertensive, non-diabetic male. (E, F) Coronary artery from a 59 year old non-hypertensive, non-diabetic male.

Fig. 2

Scatter plots for percent medial fibrosis from each blood vessel and patient age. *p≤0.05. X axes are age (years). Open circle (○) is a 27 year old poorly controlled type 1 diabetic male and the open triangle (Δ) is a 101 year old female without hypertension or diabetes. (Note that data points for the subject Δ are missing for 2 blood vessels.)