The end stage of atherosclerosis involves blood vessels with walls that are distorted and weakened by inflamed fatty deposits, and the vessel itself narrowed. Sooner or later something important ruptures catastrophically, causing death or serious injury. This is the outcome of a number of different, entirely ordinary biochemical processes operating over the years. These processes are also at work in the heart itself, however. When we consider efforts to clean up the root causes of atherosclerosis, such as those pioneered in the SENS research programs and elsewhere, we might also look at how that would play out in heart tissue.
What lies at the root of atherosclerosis? Firstly persistent cross-links form in the extracellular matrix of all tissues over the years, altering their structural properties. In the case of blood vessels this reduces their elasticity. Secondly, blood vessel tissues calcify with age. The causes of this are less well understood, but there are strong indications that inflammation and the growing numbers of senescent cells resident in older tissues are at fault. Like cross-linking, calcification serves to reduce elasticity. Reduced blood vessel elasticity distorts the feedback mechanisms that determine blood pressure, and the outcome is age-related hypertension. Increased blood pressure is an important component in the lethality of atherosclerosis, as it determines how readily weakened blood vessels will rupture.
Secondly, our metabolism produces an output of damaged lipids, such as those created as a consequence of cells suffering mitochondrial dysfunction. Aging and a larger number of such malfunctioning cells brings a larger flow of these damaged lipids. Ever more of them find their way into the bloodstream, where they can irritate blood vessel walls. In some cases nearby cells will overreact, or immune system cells will be damaged and overwhelmed by the lipids. There, a growing and inflammatory lesion of dead cells will start to form, sustained by a continual supply of cells turning up to try to clean up the damage - and failing, adding their remains to the problem. This is how atherosclerotic plaques start, ultimately growing so large that they harm blood flow and blood vessel structure.
Although aortic valvular sclerosis and aortic stenosis (AS) have long been thought of as two independent entities, they are now considered to be different stages of the same process. This disease manifests initially as valve thickening caused by lipocalcified deposits, leading to progressive reduction of the valve orifice which, over time, causes hemodynamically significant stenosis. Its incidence increases exponentially with age and hence was long considered a simple passive age-related degenerative process with calcium buildup. However, several studies have shown that, in addition to age, calcific aortic valve disease (CAVD) is related to the presence of cardiovascular risk factors such as male sex, arterial hypertension, diabetes mellitus, dyslipidemia, and smoking, sharing many similarities with the process that regulates atherosclerosis.
There is therefore a direct relationship between the presence of valvular calcium deposits and the development of coronary disease and cardiovascular events, to the point that some authors even consider aortic calcification a possible marker of atherosclerosis and subclinical coronary artery disease. In 1986, it was suggested that the presence of aortic alcification was a form of atherosclerosis and numerous authors have since demonstrated this fact. In the Cardiovascular Health Study, the presence of aortic sclerosis in patients without previous coronary disease increased the risk of myocardial infarction and cardiovascular mortality 1.4 and 1.5 times, respectively.
In the initial stage of the disease, there is a thickening of the valves with formation of calcium nodules that begins on the aortic valve side. These valves remain flexible for a long time, so that their opening mechanism is not affected. With the passage of time, the areas of thickening converge in large calcified masses that end up protruding into the exit tract of the aortic valve, conferring greater stiffness to the valves and significantly decreasing the valvular area, thus interfering with its normal functioning. From the microscopic point of view, there are many similarities with the lesions observed in the earliest stages of atherosclerosis. These lesions, initially interspersed with areas of normal tissue, will eventually coalesce and are characterized by disruption of the basement membrane, with areas of inflammation and cellular infiltration, deposit of atherogenic lipoproteins, and participation of the active mediators of calcification.
Lipid deposit plays an important initiator role in the cascade of cellular signaling leading to valvular calcification. The lipoproteins involved in the process include low-density lipoproteins (LDLs) and lipoprotein A. These are atherosclerosis molecules that undergo oxidation with the release of free radicals which are highly cytotoxic and also capable of stimulating inflammatory activity and mineralization. LDLs are phagocytized by macrophages, converting them into foam cells, the fundamental substrate of the atherosclerotic plaque. With progressive lipid uptake, these macrophages begin an irreversible transformation process that ends with apoptosis. Apoptosis also causes the release of factors that promote atherogenesis and progression to the complicated plaque stage, characterized by the presence of necrotic areas.
Unlike atherosclerotic plaque where the nucleus is composed of lipids associated with foam cells and areas of necrosis, in calcified valves the lipids are deposited mainly in the subendothelial zone and to a lesser extent in the deeper areas. Lipid-laden macrophages are evenly distributed in areas where there are high lipid concentrations and no areas of necrosis. In atherosclerotic plaques, the toxic accumulation of oxidized LDL causes cell death leading to plaque fracture. This is the major event that precipitates the appearance of clinically relevant symptoms. However, this mechanism has not been demonstrated in the case of CAVD, where the onset of symptoms is conditioned by the progression of calcification and increased valve rigidity.
In the more advanced phases of the disease there is remodeling of the extracellular matrix and calcification. Alteration of the matrix is promoted by the release of inflammatory cytokines. Aortic calcification is a very complex active process involving the production of proteins that promote tissue calcification. In fact, extracellular matrix proteins normally found in bone, such as osteocalcin, osteopontin, and osteonectin, can also be found in calcified valves. This presence reveals pathological calcification and bone formation at the valve level. In short, this process involves different mechanisms of bone mineralization and resorption.
In conclusion, CAVD is highly prevalent. Long understood as a passive process, it is now known to be complex and one which involves pathophysiological mechanisms similar to those of atherosclerosis. Understanding these mechanisms could help to establish new therapeutic targets that might allow us to halt or at least slow down the progression of the disease.