A Surgeon’s View on the Pathogenesis of Atherosclerosis

August 19, 2016, my coronary artery bypass grafting procedure #3431. A 67-year-old woman presents with calcified triple-vessel coronary artery disease, hypercholesterolemia, 42 pack-years of smoking, and arterial hypertension. Her left carotid artery is totally occluded, there is stenosis of the right subclavian artery, and she has had previous femoral artery reconstruction. Hours after completion of triple-bypass surgery, I am reflecting about the fact that atherosclerosis does not uniformly involve all large- and medium-sized human arteries, an observation I have made hundreds of times before. We had started the procedure by harvesting the left radial artery, which showed no evidence of atherosclerosis, but increased wall thickness with no visible vasa vasorum (VV) on its adventitial surface. After sternotomy, the left internal mammary artery was dissected, with no atherosclerosis, a thin wall, and again, no visible VV. Both grafts appeared unscathed from atherosclerosis despite the risk factors mentioned. Against the background of her coronary disease and the status of her supra-aortic and femoral vessels, it is remarkable that certain segments of the arterial tree remained free from disease.

Later, her ascending aorta appeared heavily calcified, as did the proximal segments of all epicardial coronary arteries. Distally, the left anterior descending and right coronary arteries exhibited localized calcified plaques, and highly vascularized areas with an inflamed adventitial layer, as well. Suitable sites for bypass insertion could be identified. The only branch of the circumflex artery large enough for a bypass anastomosis, however, displayed maximum sclerosis in its peripheral segments. One short stretch was diving into the myocardium of the lateral wall of the left ventricle. After dissecting the flat myocardial bridge, a thin-walled, plaque-free artery was visualized without any adventitial VV.

This picture has been described repeatedly, with many surgeons taking advantage of these well-known disease-free sites in coronary artery bypass grafting procedures. My second assistant, however, a sixth-year medical student, started asking questions. Rightfully so! How can an artery showing severe proximal and distal sclerosis have, at its midpoint, a segment entirely free from disease with an infant-like wall structure? Why do the patient’s risk factors not affect the intramyocardial segment of her circumflex artery? How should the external muscle bridge prevent damage of the intima, the location thought to be where disease is initiated? As a long-term skeptic of intimal damage being the primary initiator of atherosclerosis, I brought to his attention the fact that areas predictably spared from atherosclerosis often lack VV. Alas, I could not impart to the student the underlying pathogenesis of the disease.

With our observations and my sparse comments to the student still on my mind, I tried to develop a unifying theory. If a single mechanism like muscular coverage can protect a blood vessel wall against a plethora of atherosclerosis risk factors, perhaps there is an additional unrecognized pathophysiological mechanism that could account for the initiation of the disease process. This factor would need to involve the adventitia rather than the intima, because growing evidence supports an outside-in progression of disease development whereby vascular inflammation is initiated in the adventitia and is propagated inward toward the intima. The mechanism should also be able to precipitate the 2 major phenotypes of atherosclerosis, namely obstruction by plaques and aneurysmal dilatation.

As with the phenomenon of healthy arteries in multifocal disease, cardiac surgeons know the reverse pattern: vascular structures in terminal stages of degeneration in individuals free from multifocal atherosclerosis. Such focal processes may occur under conditions of accelerated disease development, examples of which include:

These examples would suggest that blood vessel wall ischemia participates in the early stages of the process of atherosclerosis. Indeed, in experimental animals, physical constriction of VV precipitates fatty streak development in the underlying arterial segment,³ and obstruction of VV in the abdominal aorta results in aneurysm formation.⁴

VV are responsible for vessel wall nutrition via the adventitial layer in large- and medium-sized arteries. When operating on arteries in infants, no VV are detectable, not even in the ascending aorta. With growth, wall thickness in our arterial system, especially in the intimal layer,⁵ increases because of a rise in wall tension, and VV are needed because nutrition via diffusion is limited. Because they are functional end arteries, VV obstruction results in ischemic necrosis of cells in subintimal layers, corresponding to their individual supply area. In all the examples listed above, vessel wall ischemia from disrupted or occluded VV would represent a uniform pathophysiological mechanism early in the process of atherosclerosis. Accordingly, we propose that atherosclerosis represents a microvascular disease rather than a large-vessel disease. Larger arteries are involved secondarily after microvascular disease of their vessel wall. Areas predictably spared from atherosclerosis (eg, intramyocardial bridges, mammary arteries) carry few if any VV and thus cannot suffer from vessel wall ischemia from disturbed microcirculation.

Two major theories on the initiating factors of atherosclerosis have been proposed by others: response to injury and response to inflammation. In both, the endothelium would be the prime target. Endothelium dysfunction, however, would cause much more damage from thrombotic events in microvessels than in larger arteries. Obstruction of VV then translates into functional impairment followed by structural damage in the mother vessel.

When one considers atherosclerosis as an adventitial microvessel disease, many risk factors like hypertension, stress, smoking, and perivascular adipose tissue (increased in obesity), start to make sense. Therefore, much of what pediatric and adult cardiologists recommend today for prevention and treatment of atherosclerosis is already directed toward protection of the microvascular system. Future research focusing on microvessel disease could build on many proven concepts already being investigated. As surgeons, we cannot protect all larger arteries in the human body from VV dysfunction. Blood vessel walls of our species require external blood supply, with more VV probably being better than less. Their augmentation could be a field of future research in regenerative medicine, if my assisting medical student’s generation keeps on asking questions.