Calcification of Arteries is an Independent Cardiovascular Risk, Distinct from Atherosclerosis and Inflammation

The same underlying molecular and cellular damage of aging contributes to both calcification of blood vessel walls and the development of atherosclerosis, but researchers here argue that calcification can be considered on its own, an independent risk factor for cardiovascular dysfunction and mortality in later life. The presence of senescent cells is one of the common underlying factors that accelerates the progression of both atherosclerosis and calcification of blood vessels. This is due to the inflammatory signaling produced by these cells. That signaling distorts the behavior of macrophages trying to clear up deposits of cholesterol in blood vessel walls, but also makes other cells in the wall behave as though they are osteoblasts in bone, laying down mineral deposits.

Calcification, like the creation of cross-links or degradation of elastin in the extracellular matrix, is harmful because it reduces elasticity in blood vessels. That loss of elasticity breaks the feedback mechanisms that control blood pressure, and the result is the development of hypertension. Hypertension causes structural damage throughout the body: small blood vessels rupture at an accelerated rate in the delicate tissues of the brain, kidney, and other organs, killing tiny sections of tissue. Further, hypertension accelerates the progression of atherosclerosis, and increases the chance of a fatal breakage in blood vessels weakened by atherosclerotic lesions.

In 1903, scientists described typical concentric calcifications in the medial arterial wall as a distinct phenomenon from atherosclerotic plaques. These medial arterial calcifications (MAC) have long been considered as innocent normal aging. Current treatments for cardiovascular disease target luminal thrombosis and atherosclerosis in the intimal layer. Despite widespread preventative efforts, residual cardiovascular disease burden remains high. We hypothesize that arterial calcification, especially in the medial arterial layer, contributes to this residual cardiovascular risk.

Testing this hypothesis is relevant given the high prevalence of arterial calcifications in the population. Causal investigation, independent of inflammation, dyslipidaemia, and thrombosis is difficult and the diagnosis of MAC is challenging as intimal and medial calcification often co-occur. In the human body a complex network of calcification promoters and inhibitors is precisely tuned to inhibit MAC. Inorganic pyrophosphate (PPi) is one of the most potent calcification inhibitors in humans. It binds to hydroxyapatite crystals, thereby inhibiting further growth of the calcifications. The consequences of disrupted PPi homeostasis are shown in genetic disorders. These patients suffer from accelerated aging which results in severe visual impairment, peripheral arterial disease, gastric bleeding, ischemic stroke, and cerebral white matter lesions.

How relevant can this be for patients with diabetes, chronic kidney disease, and for aging in the general population? It is clear that the residual burden and health care costs for cardiovascular disease are huge. MAC contributes to arterial stiffening which results in hypertension and heart failure, but also to pulse pressure-related damage in susceptible high flow end-organs like the kidney and the brain. Indeed increased arterial stiffness is associated with worsening of chronic kidney disease and microvascular brain damage and might therefore contribute to the development and progression of cognitive decline.

In the general population, MAC is shown to be the predominant type of calcification in leg arteries and probably also in the intracranial carotid artery. In the femoral and crural arteries of leg amputees, 71% of the arteries contained MAC whereas in only 31% calcified atherosclerotic lesions were seen. These calcifications are the strongest predictor of major cardiovascular events such as stroke and leg amputation and also linked to dementia, heart failure, and kidney failure. Probably, these ectopic calcifications have evolved as a defence mechanism against resistant infections and, in a pre-antibiotic era with a much shorter life expectancy, have aided survival and population growth. In our era, preventing and removing MAC maybe essential for healthy vascular aging, prevention of chronic cardiovascular events and multi-organ failure and might contribute to further decrease of residual cardiovascular risk.



>Probably, these ectopic calcifications have evolved as a defence mechanism against resistant infections and, in a pre-antibiotic era with a much shorter life expectancy, have aided survival and population growth

That's an interesting hypothesis. But it would imply that chronic inflammation promotes or even causes calcificaiton

Posted by: cuberat at February 20th, 2019 9:46 AM

So this is now confirmed as primary rather than secondary damage? Is there any proposed method to remove this damage?

Posted by: jimofoz at February 20th, 2019 8:44 PM

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