Medial vascular calcification revisited: review and perspectives

Abstract

Vascular calcifications (VCs) are actively regulated biological processes associated with crystallization of hydroxyapatite in the extracellular matrix and in cells of the media (VCm) or intima (VCi) of the arterial wall. Both patterns of VC often coincide and occur in patients with type II diabetes, chronic kidney disease, and other less frequent disorders; VCs are also typical in senile degeneration. In this article, we review the current state of knowledge about the pathology, molecular biology, and nosology of VCm, expand on potential mechanisms responsible for poor prognosis, and expose some of the directions for future research in this area.

Keywords: Mönckeberg's media sclerosis; Vascular calcifications; Vascular function; Vascular molecular biology and genetics.

Figure 1

Simplified nomenclature of biological calcifications. Medial vascular calcifications comprise in humans a number of diseases; in the absence of knowledge of molecular pathogenesis of different types of medial vascular calcifications, the proposed nomenclature is based on the presence or absence of known risk factors. Mönckeberg's media sclerosis represents the most common variety of medial calcifications; it is frequently associated with type II diabetes and chronic kidney disease, yet, in some cases none of these diseases and no other known risk factors for vascular calcifications are present. In the latter case genetic or other as yet not known risk factors are likely.

Figure 2

Microscopical images of medial calcifications. Small calcifications (arrow) alongside the internal elastic membrane (asterisk) characteristic of Mönckeberg medial sclerosis stage 1 are shown (femoral artery, fluorescence microscopy, 400×) (A). Larger amounts of medial calcifications (arrow) in vicinity of vascular smooth muscle cells (asterisk) in Mönckeberg medial sclerosis stage 1 lesion are demonstrated (femoral artery, haematoxylin–eosin stain, 200×) (B). Calcifications becoming confluent and forming solid plates (arrows) and subendothelial hyperplasia (asterisks) in the intima are seen; the findings correspond to Mönckeberg medial sclerosis stage 2 (femoral artery, haematoxylin–eosin stain, 40×) (C). Mönckeberg medial sclerosis stage 3 is characterized by calcifications distorting the media spanning the entire circumference (arrows) (tibial anterior artery, haematoxylin–eosin stain, 40×) (D).

Figure 3

Suggested pathogenesis of medial calcifications. Shown are simplified molecular pathways potentially associated with initiation and propagation of medial calcifications. Nanocrystals of calcium phosphates could be nucleated and either deposited on elastine fibres and extracellular vesicles or endocysted and directed to lysosomes where they are then dissolved at low pH and Ca²⁺ are released to the cytosol. Cell death or osteochodrotic transdifferentiation could follow the transient increase in calcium concentration.

Figure 4

X-ray images of left femoral bifurcation. Shown are native X-ray image (A) and selective needle angiogram (B) of the femoral bifurcation of a 56-year-old male patient. The typical ‘railroad trucks’ pattern (arrows) of medial calcification (A) and smooth endothelial interface (arrows) (B) of the femoral superficial and profunda arteries typical for Mönckeberg's type of medial calcification can be appreciated.

Figure 5

Native X-ray images of a left thigh. Shown are native X-ray images of the left thigh of a male patient acquired at baseline at the age of 46 years (A) and on 16-year follow-up at the age of 62 years (B). The typical ‘railroad trucks’ pattern of medial calcification of the superficial femoral artery is seen on both images (arrows), however, on the image at baseline the pattern appears finely granulated while on the follow-up image the pattern appears coarse and more prominent signifying the progression of the disease.

Figure 6

Ultrasound images of medial vascular calcifications. Shown are typical B-mode (A) and colour-mode (B) ultrasound images of a superficial femoral artery. B-mode images show the typical ‘string-of-beads’ pattern of media calcifications (arrows) with intact endothelial interface in both longitudinal sector and cross section (insert) images (courtesy C Garn). On colour-mode ultrasound image, the dense pattern of media calcifications (arrows), smooth endothelial interface, and homogeneous blood flow pattern (red colour) is shown.

Figure 7

Typical images of medial vascular calcifications type Mönckeberg acquired by invasive imaging techniques. Intravascular ultrasound (A) and optical coherence tomography (B) cross-sectional images of a proximal superficial femoral artery are shown. On the intravascular ultrasound image dense tunica media calcification (arrows), the absence of acoustic shadowing and freedom from intimal atherosclerotic disease is demonstrated (Eagle Eye catheter, Volcano, 20 MHz, lateral resolution 200–250 µ, axial resolution 80–100 µ). On the optical coherence tomography image, the circumferential layer of medial calcifications (arrows) is documented. The intraluminal prolapsing fibrotic plaque is also seen (yellow arrows); ^§OCT catheter, *0.0.14 inch guidewire (Akquise, St Jude Medical, C7 Dragonfly catheter, lateral resolution 20 µ, axial resolution 10 µ).