Mechanisms and Clinical Consequences of Vascular Calcification

doi:10.3389/FENDO.2012.00095

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Mechanisms and Clinical Consequences of Vascular Calcification

Journal Article•DOI•

Mechanisms and Clinical Consequences of Vascular Calcification

Dongxing Zhu¹, Neil Mackenzie¹, Colin Farquharson¹, Vicky E MacRae¹•Institutions (1)

University of Edinburgh¹

06 Aug 2012-Frontiers in Endocrinology (Frontiers)-Vol. 3, pp 95-95

TL;DR: By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.

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Abstract: Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.

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Journal Article•DOI•

Effect of Calcium Supplements on Risk of Myocardial Infarction and Cardiovascular Events: Meta-analysis

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Mark J Bolland¹, Alison Avenell, John A. Baron, Andrew Grey¹, Graeme MacLennan, Greg D. Gamble¹, Ian R. Reid¹ - Show less +3 more•Institutions (1)

University of Auckland¹

01 Apr 2014

TL;DR: In this paper, the authors investigated whether calcium supplements increase the risk of cardiovascular events and found that calcium supplements without co-administered vitamin D are associated with an increased risk of myocardial infarction.

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Abstract: Objective To investigate whether calcium supplements increase the risk of cardiovascular events. Design Patient level and trial level meta-analyses. Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. Study selection Eligible studies were randomised, placebo controlled trials of calcium supplements (≥500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates. Results 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). Conclusions Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

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210 citations

Journal Article•DOI•

Extracellular vesicles are integral and functional components of the extracellular matrix.

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Kirsi Rilla¹, Anne-Mari Mustonen¹, Uma Thanigai Arasu¹, Kai Härkönen¹, Johanna Matilainen¹, Petteri Nieminen¹ - Show less +2 more•Institutions (1)

University of Eastern Finland¹

01 Oct 2017-Matrix Biology

TL;DR: This review addresses the relevance of EV as specific modulators of the ECM, such as during the assembly and disassembly of the molecular network, signaling through theECM and formation of niches suitable for tissue regeneration, inflammation and tumor progression to translational medicine.

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135 citations

Cites background from "Mechanisms and Clinical Consequence..."

...Vascular calcification Vascular calcification is a significant medical issue in several chronic inflammatory disorders, including chronic kidney disease, diabetes mellitus and atherosclerosis [125]....
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Journal Article•DOI•

Characterisation of matrix vesicles in skeletal and soft tissue mineralisation

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Lin Cui¹, Dean Houston¹, Colin Farquharson¹, Vicky E MacRae¹•Institutions (1)

University of Edinburgh¹

01 Jun 2016-Bone

TL;DR: The characteristics MVs possess that enable them to participate in mineral deposition are reviewed, the content of skeletal tissue- and soft tissue-derived MVs are outlined, and their key mineralisation mediators that could be targeted for future therapeutic use are discussed.

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125 citations

Cites background from "Mechanisms and Clinical Consequence..."

...Contents lists available at ScienceDirect Bone j ourna l homepage: www.e lsev ie r .com/ locate /bone Review Article Characterisation of matrix vesicles in skeletal and soft tissue mineralisation L. Cui ⁎, D.A. Houston, C. Farquharson, V.E. MacRae The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh Easter Bush Campus, Edinburgh, Midlothian, EH25 9RG, UK Abbreviations:AB, Apoptotic body; ADP, Adenosine di netic protein; CK, Choline kinase; CKD, Chronic kidney di terminal kinase; LPS, Lysophosphatidylserine; MEPE, Mat pyrophosphatase; nSMase2, Neutral sphingomyelinase 2; scription factor; PPi, Pyrophosphate; PS, Phosphatidylserin acid; Runx2, Runt-related transcription factor 2; SIBLING, nonspecific alkaline phosphatase; VDAC1, Voltage-depend ⁎ Corresponding author....
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...This is a condition commonly found in the elderly, diabetics, and patients who suffer from chronic kidney disease (CKD) [181]....
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...Recently, miRNA microarray analysis has identified for the first time a number of dysregulated miRNAs in MVs derived from CKD rats showing aortic mineralisation, including miRNA-667, −702, −3562, −3568 and −3584 [32]....
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...The latter study showed decreased TNAP activity, and reduced ability for MVs to calcify type I collagen in CKD rats following TGM2 inhibition....
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Journal Article•DOI•

Pyrophosphate: a key inhibitor of mineralisation.

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Isabel R. Orriss¹, Timothy R. Arnett², R. Graham G. Russell³•Institutions (3)

Royal Veterinary College¹, University College London², Nuffield Orthopaedic Centre³

01 Jun 2016-Current Opinion in Pharmacology

TL;DR: Evidence suggests pyrophosphate may also act as a signalling molecule to influence gene expression and regulate its own production and breakdown, and regulates bone mineralisation and prevents harmful soft tissue calcification.

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117 citations

Cites background from "Mechanisms and Clinical Consequence..."

...It shares some outward similarities with bone mineralisation and is associated with a phenotypic transdifferentiation of vascular smooth muscle cells (VSMCs) towards a more osteoblast-like phenotype [80]....
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Journal Article•DOI•

The effect of particle agglomeration on the formation of a surface-connected compartment induced by hydroxyapatite nanoparticles in human monocyte-derived macrophages.

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Karin H. Müller¹, Michael Motskin¹, Alistair J. Philpott¹, Alexander F. Routh, Catherine M. Shanahan², Melinda J. Duer¹, Jeremy N. Skepper¹ - Show less +3 more•Institutions (2)

University of Cambridge¹, King's College London²

01 Jan 2014-Biomaterials

TL;DR: It is shown that hydroxyapatite nanoparticles formed large agglomerates in biological medium resulting in extensive particle uptake and dose-dependent cytotoxicity in human macrophages, and Agglomerate dispersion prevented the SCC from forming, but did not completely inhibit nanoparticle uptake by other mechanisms.

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112 citations

Cites background from "Mechanisms and Clinical Consequence..."

...Dysregulation of HA metabolism can lead to pathological calcification with serious clinical consequences, as seen in arterial calcification, chronic kidney disease and osteoporosis [2,3]....
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Journal Article•DOI•

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

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H. C. Stary¹, A. B. Chandler¹, R. E. Dinsmore¹, Valentin Fuster¹, S. Glagov¹, William Insull, M. E. Rosenfeld¹, C. J. Schwartz¹, W. D. Wagner¹, R. W. Wissler¹ - Show less +6 more•Institutions (1)

American Heart Association¹

01 Sep 1995-Circulation

TL;DR: The histological classification of human atherosclerotic lesions found in the second part of this report led to the earlier definitions of precursor lesions, and the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes was attempted.

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Abstract: This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

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3,698 citations

Journal Article•DOI•

Burden of valvular heart diseases: a population-based study.

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Vuyisile T. Nkomo¹, Julius M. Gardin, Thomas N. Skelton², John S. Gottdiener³, Christopher G. Scott¹, Maurice Enriquez-Sarano¹ - Show less +2 more•Institutions (3)

Mayo Clinic¹, University of Mississippi Medical Center², University of Maryland, Baltimore³

16 Sep 2006-The Lancet

TL;DR: In this paper, the authors assess the prevalence and effect of valve disease on overall survival in the general population and find that moderate or severe valve disease is common in this population and increase with age.

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3,468 citations

Journal Article•

Burden of valvular heart diseases : a population-based study. Commentary

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Bernard Iung, Alec Vahanian, Vuyisile T. Nkomo, Julius M. Gardin, Thomas N. Skelton, John S. Gottdiener, Christopher G. Scott, Maurice Enriquez-Sarano - Show less +4 more

01 Jan 2006-The Lancet

TL;DR: Moderate or severe valvular heart diseases are notably common in this population and increase with age and in the community, women are less often diagnosed than are men, which could indicate an important imbalance in view of the associated lower survival.

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3,210 citations

"Mechanisms and Clinical Consequence..." refers background in this paper

...CAVS is also correlated with a high risk of cardiovascular dysfunction, and is the third leading cause of cardiovascular disease (Ribeiro et al., 1998; Nkomo et al., 2006)....
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Journal Article•DOI•

Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis

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Geoffrey A. Block, Preston S. Klassen, J. Michael Lazarus, Norma J. Ofsthun, Edmund G. Lowrie, Glenn M. Chertow - Show less +2 more

01 Aug 2004-Journal of The American Society of Nephrology

TL;DR: Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization, and the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperph phosphatemia.

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Abstract: Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

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2,475 citations

"Mechanisms and Clinical Consequence..." refers background in this paper

...5 mg/dL are strongly correlated with mortality in ESRD patients (Block et al., 2004; Tentori et al., 2008)....
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...Serum phosphate levels greater than 5.5 mg/dL are strongly correlated with mortality in ESRD patients (Block et al., 2004; Tentori et al., 2008)....
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Journal Article•DOI•

osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification

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N. Bucay¹, Ildiko Sarosi, Colin R. Dunstan, Sean Morony, John E. Tarpley, C. Capparelli, S. Scully, Hong Lin Tan, Weilong Xu, David L. Lacey, William J. Boyle, William S. Simonet - Show less +8 more•Institutions (1)

Amgen¹

01 May 1998-Genes & Development

TL;DR: It is demonstrated that OPG is a critical regulator of postnatal bone mass and regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

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Abstract: Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. In this study the physiological role of OPG is investigated by generating OPG-deficient mice. Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures. These findings demonstrate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

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2,444 citations

"Mechanisms and Clinical Consequence..." refers background in this paper

...In genetically altered animals with deletions of OPG and klotho, a combined osteoporosis-arterial calcification phenotype has been observed (Bucay et al., 1998; Nabeshima, 2002)....
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...OPG, the endogenous inhibitor MGP and the circulating inhibitor fetuin-A have also been shown to block VSMC calcification (Bucay et al., 1998; Canfield et al., 2002; Speer et al., 2002; Bennett et al., 2006; Matsui et al., 2009)....
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