Vascular calcification: Molecular mechanisms and therapeutic interventions.
MedComm
Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life-threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin-angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.
10.1002/mco2.200
Interactive and Multifactorial Mechanisms of Calcific Vascular and Valvular Disease.
Demer Linda L,Tintut Yin
Trends in endocrinology and metabolism: TEM
Calcific vascular and valvular disease (CVVD) is widespread and has major health consequences. Although coronary artery calcification has long been associated with hyperlipidemia and increased mortality, recent evidence suggests that its progression is increased in association with cholesterol-lowering HMG-CoA reductase inhibitors ('statins') and long-term, high-intensity exercise. A nationwide trial showed no cardiovascular benefit of vitamin D supplements. Controversy remains as to whether calcium deposits in plaque promote or prevent plaque rupture. CVVD appears to occur through mechanisms similar to those of intramembranous, endochondral, and osteophytic skeletal bone formation. New evidence implicates autotaxin, endothelial-mesenchymal transformation, and microRNA and long non-coding RNA (lncRNA) as novel regulatory factors. New therapeutic options are being developed.
10.1016/j.tem.2019.06.001
Potential mechanisms linking high-volume exercise with coronary artery calcification.
Heart (British Cardiac Society)
Recent studies have found an association between high volumes of physical activity and increased levels of coronary artery calcification (CAC) among older male endurance athletes, yet the underlying mechanisms have remained largely elusive. Potential mechanisms include greater exposure to inflammatory cytokines, reactive oxygen species and oxidised low-density lipoproteins, as acute strenuous physical activity has been found to enhance their systemic release. Other possibilities include post-exercise elevations in circulating parathyroid hormone, which can modify the amount and morphology of calcific plaque, and long-term exposure to non-laminar blood flow within the coronary arteries during vigorous physical activity, particularly in individuals with pre-existing atherosclerosis. Further, although the association has only been identified in men, the role of testosterone in this process remains unclear. This brief review discusses the association between high-volume endurance exercise and CAC in older men, elaborates on the potential mechanisms underlying the increased calcification, and provides clinical implications and recommendations for those at risk.
10.1136/heartjnl-2022-321986
Arterial calcification: A new perspective?
Nicoll R,Henein M
International journal of cardiology
Arterial calcification is commonly seen in atherosclerosis, chronic kidney disease (CKD) and diabetes and has long been considered a natural progression of atherosclerosis. Yet it is a systemic condition, occurring in a wide and diverse range of disease states and no medical treatment for cardiovascular disease has yet found a way to regress it; on the contrary, lipid-lowering therapy may worsen its progression. Although numerous studies have found associations between calcification and biomarkers, none has yet found a unifying mechanism that explains the calcification found in atherosclerosis, CKD or diabetes and many of the biomarkers are equally associated with atheroma development and cardiovascular events. Furthermore, both presence and absence of coronary artery calcification appear predictive of plaque rupture and cardiovascular events, indicating that the association is not causal. This suggests that we are no further forward in understanding the true nature of arterial calcification or its pathogenesis, other than noting that it is 'multifactorial'. This is because most researchers view arterial calcification as a progressive pathological condition which must be treated. Instead, we hypothesise that calcification develops as an immune response to endothelial injury, such as shear stress or oxidative stress in diabetics, and is consequently part of the body's natural defences. This would explain why it has been found to be protective of plaque rupture and why it is unresponsive to lipid-lowering agents. We propose that instead of attempting to treat arterial calcification, we should instead be attempting to prevent or treat all causes of endothelial injury.
10.1016/j.ijcard.2016.11.099
Coronary artery calcification: recent developments in our understanding of its pathologic and clinical significance.
Sakamoto Atsushi,Virmani Renu,Finn Aloke V
Current opinion in cardiology
PURPOSE OF REVIEW:Prior investigations have shown the close association between coronary artery calcification (CAC) and total atherosclerotic plaque burden as well as the risk of cardiovascular and all-cause mortality. However, recent pathologic and imaging-based studies suggested that massive dense calcifications are usually associated with stable plaque; whereas, micro calcifications, especially in the thin fibrous cap, are related to vulnerable characteristics. Further, the molecular mechanisms for initiation/progression of vascular calcification are highly complex and still need to be elucidated. In this manuscript, we discuss recent advancement in our understanding of CAC from the basic, pathologic, and clinical perspectives. RECENT FINDINGS:Research on the relationship between genetic polymorphisms and CAC has been growing and may potentially lead to future precision-based medicine. In basic research field, more attention has been focused on the relationship between inflammation and vascular calcification. Large-scale imaging based studies support the association between statin and calcification progression, maybe one of the ways by which statins prevent cardiovascular events. Nevertheless, the mechanism responsible for this effect is still not fully understood. Optical coherence tomography has improved resolution to detect CAC over traditional CT and may be especially promising for the detection of calcified nodules. SUMMARY:A better understanding of CAC in all of its forms will advance our understanding of its natural history of atherosclerosis. More work is needed to understand the basic molecular mechanisms responsible for the initiation/progression of CAC, which may eventually lead to the development of effective treatments for atherosclerosis.
10.1097/HCO.0000000000000558
Coronary arterial calcification: A review of mechanisms, promoters and imaging.
Andrews Jordan,Psaltis Peter J,Bartolo Belinda A Di,Nicholls Stephen J,Puri Rishi
Trends in cardiovascular medicine
Coronary artery calcification (CAC) was once thought to be a passive, degenerative, and quiescent development of disease. However, it has now been shown to be an active process associated with atherosclerosis that is stimulated by inflammatory pathways. Calcification forms within the intimal and medial layers of the vessel wall by way of mechanisms similar to bone development. A variety of imaging modalities have been used to identify and characterize CAC, from early microcalcifications to well-developed fibroatheromas that have calcified. There are sex and race differences in prevalence and development of CAC, and medical therapies such as statin and warfarin use exhibit pro-calcific effects on the vessel wall. Effective medical treatment of CAC has yet to be established; therefore a greater understanding of the factors that induce calcification is needed to develop appropriate therapeutic strategies.
10.1016/j.tcm.2018.04.007
Coronary Artery Calcification: From Mechanism to Molecular Imaging.
Nakahara Takehiro,Dweck Marc R,Narula Navneet,Pisapia David,Narula Jagat,Strauss H William
JACC. Cardiovascular imaging
Vascular calcification is a hallmark of atherosclerosis. The location, density, and confluence of calcification may change portions of the arterial conduit to a noncompliant structure. Calcifications may also seed the cap of a thin cap fibroatheroma, altering tensile forces on the cap and rendering the lesion prone to rupture. Many local and systemic factors participate in this process, including hyperlipidemia, ongoing inflammation, large necrotic cores, and diabetes. Vascular cells can undergo chondrogenic or osteogenic differentiation, causing mineralization of membranous bone and formation of endochondral bone. Calcifying vascular cells are derived from local smooth muscle cells and circulating hematopoietic stem cells (especially in intimal calcification). Matrix vesicles in the extracellular space of the necrotic core serve as a nidus for calcification. Although coronary calcification is a marker of coronary atheroma, dense calcification (>400 HU) is usually associated with stable plaques. Conversely, microcalcification (often also referred to as spotty calcification) is more commonly an accompaniment of vulnerable plaques. Recent studies have suggested that microcalcification in the fibrous cap may increase local tissue stress (depending on the proximity of one microcalcific locus to another, and the orientation of the microcalcification in reference to blood flow), resulting in plaque instability. It has been proposed that positron emission tomography imaging with sodium fluoride may identify early calcific deposits and hence high-risk plaques.
10.1016/j.jcmg.2017.03.005