Highlights
- •Cardiovascular calcification is increasing in prevalence and remains a contributor to morbidity and mortality.
- •Calcium deposition is associated with progression and severity of cardiovascular disease and linked to cardiovascular risk.
- •The lack of therapeutic or preventative strategies in cardiovascular calcification is an indicator of disease complexity.
- •Cardiovascular calcification is regulated through an integrated combination of innate and adaptive immune responses.
- •Immunomodulatory drugs possess the potential to target and treat calcification.
Abstract
Despite the focus placed on cardiovascular research, the prevalence of vascular and
valvular calcification is increasing and remains a leading contributor of cardiovascular
morbidity and mortality. Accumulating studies provide evidence that cardiovascular
calcification is an inflammatory disease in which innate immune signaling becomes
sustained and/or excessive, shaping a deleterious adaptive response. The triggering
immune factors and subsequent inflammatory events surrounding cardiovascular calcification
remain poorly understood, despite sustained significant research interest and support
in the field. Most studies on cardiovascular calcification focus on innate cells,
particularly macrophages’ ability to release pro-osteogenic cytokines and calcification-prone
extracellular vesicles and apoptotic bodies. Even though substantial evidence demonstrates
that macrophages are key components in triggering cardiovascular calcification, the
crosstalk between innate and adaptive immune cell components has not been adequately
addressed. The only therapeutic options currently used are invasive procedures by
surgery or transcatheter intervention. However, no approved drug has shown prophylactic
or therapeutic effectiveness. Conventional diagnostic imaging is currently the best
method for detecting, measuring, and assisting in the treatment of calcification.
However, these common imaging modalities are unable to detect early subclinical stages
of disease at the level of microcalcifications; therefore, the vast majority of patients
are diagnosed when macrocalcifications are already established. In this review, we
unravel the current knowledge of how innate and adaptive immunity regulate cardiovascular
calcification; and put forward differences and similarities between vascular and valvular
disease. Additionally, we highlight potential immunomodulatory drugs with the potential
to target calcification and propose avenues in need of further translational inquiry.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Heart disease and stroke statistics-2019 update: a report from the American heart association.Circulation. 2019; 139: e56-e528
- A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture.Am. J. Physiol. Heart Circ. Physiol. 2012; 303: H619-H628
- Cellular mechanisms of aortic valve calcification.Circ. Cardiovasc. Interv. 2012; 5: 605-614
- Value of progression of coronary artery calcification for risk prediction of coronary and cardiovascular events: result of the HNR study (heinz nixdorf recall).Circulation. 2018; 137: 665-679
- Giving calcification its due: recognition of a diverse disease: a first attempt to standardize the field.Circ. Res. 2017; 120: 270-273
- Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.Circ. Res. 2013; 113: 72-77
- Vascular smooth muscle cell calcification is mediated by regulated exosome secretion.Circ. Res. 2015; 116: 1312-1323
- Extracellular vesicles as mediators of cardiovascular calcification.Front. Cardiovasc. Med. 2017; 4: 78
- Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 11201-11206
- Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo.Circulation. 2007; 116: 2841-2850
- Look more closely at the valve: imaging calcific aortic valve disease.Circulation. 2012; 125: 9-11
- Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification.Circ. Res. 2011; 108: 1381-1391
- Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.Nat. Mater. 2016; 15: 335-343
- The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls.Circ. Res. 2011; 108: 1133-1145
- Innate and adaptive immunity in calcific aortic valve disease.J. Immunol. Res. 2015; 2015 (851945)
- Toll-like receptors, inflammation, and calcific aortic valve disease.Front. Physiol. 2018; 9: 201
- The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat. Immunol. 2010; 11: 373-384
- The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells.Immunol. Lett. 2014; 162: 103-112
- Macrophage transitions in heart valve development and myxomatous valve disease.Arterioscler. Thromb. Vasc. Biol. 2018; 38: 636-644
- Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent.J. Exp. Med. 2006; 203: 1273-1282
- Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease.Circulation. 2007; 115: 377-386
- Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation.Eur. Heart J. 2010; 31: 1975-1984
- RANK-independent osteoclast formation and bone erosion in inflammatory arthritis.Arthritis Rheum. 2016; 68: 2889-2900
- Interferon-gamma released by activated CD8(+) T lymphocytes impairs the calcium resorption potential of osteoclasts in calcified human aortic valves.Am. J. Pathol. 2017; 187: 1413-1425
- M1 macrophages promote aortic valve calcification mediated by microRNA-214/TWIST1 pathway in valvular interstitial cells.Am. J. Transl. Res. 2016; 8: 5773-5783
- M1/M2 macrophages and associated mechanisms in congenital bicuspid aortic valve stenosis.Exp. Ther. Med. 2014; 7: 935-940
- Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis.Cardiovasc. Pathol. 2005; 14: 80-87
- Parathyroid hormone induces differentiation of mesenchymal stromal/stem cells by enhancing bone morphogenetic protein signaling.J. Bone Miner. Res. 2012; 27: 2001-2014
- Bone morphogenetic protein 2: a potential new player in the pathogenesis of diabetic retinopathy.Exp. Eye Res. 2014; 125: 79-88
- Macrophage activation: classical versus alternative.Methods Mol. Biol. 2009; 531: 29-43
- Runx2-upregulated receptor activator of nuclear factor kappaB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 1387-1396
- Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans.J. Am. Coll. Cardiol. 2008; 52: 843-850
- Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis.J. Am. Coll. Cardiol. 2006; 47: 2229-2236
- ox-LDL induces PiT-1 expression in human aortic valve interstitial cells.J. Surg. Res. 2013; 184: 6-9
- Suppression of innate inflammation and immunity by interleukin-37.Eur. J. Immunol. 2016; 46: 1067-1081
- IL-37 suppresses MyD88-mediated inflammatory responses in human aortic valve interstitial cells.Mol. Med. 2017; 23: 83-91
- Augmented osteogenic responses in human aortic valve cells exposed to oxLDL and TLR4 agonist: a mechanistic role of Notch1 and NF-kappaB interaction.PloS One. 2014; 9e95400
- Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2711-2720
- Osteogenic responses in fibroblasts activated by elastin degradation products and transforming growth factor-beta1: role of myofibroblasts in vascular calcification.Am. J. Pathol. 2007; 171: 116-123
- Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis.Atherosclerosis. 2003; 170: 205-211
- Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease.Circulation. 2009; 119: 1785-1794
- Enrichment of calcifying extracellular vesicles using density-based ultracentrifugation protocol.J. Extracell. Vesicles. 2014; 3 (25129)
- Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL.Circulation. 2001; 104: 3103-3108
- Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction.Pharmacogenetics Genom. 2005; 15: 15-21
- Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction.Lancet. 1988; 2: 983-986
- Mechanisms of disease: toll-like receptors in cardiovascular disease.Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: 444-454
- Monocyte-Macrophages and T Cells in atherosclerosis.Immunity. 2017; 47: 621-634
- Coronary artery calcification and its progression: what does it really mean?.JACC Cardiovasc Imaging. 2018; 11: 127-142
- Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway.Circulation. 2000; 102: 2636-2642
- Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2589-2596
- Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure.Circulation. 2005; 111: 2364-2372
- Reducing vascular calcification by anti-IL-1beta monoclonal antibody in a mouse model of familial hypercholesterolemia.Angiology. 2016; 67: 157-167
- Rac2 modulates atherosclerotic calcification by regulating macrophage interleukin-1beta production.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 328-340
- Interleukin-1beta has atheroprotective effects in advanced atherosclerotic lesions of mice.Nat. Med. 2018; 24: 1418-1429
- Interleukin-6: designing specific therapeutics for a complex cytokine.Nat. Rev. Drug Discov. 2018; 17: 395-412
- TLR2 promotes vascular smooth muscle cell chondrogenic differentiation and consequent calcification via the concerted actions of osteoprotegerin suppression and IL-6-mediated RANKL induction.Arterioscler. Thromb. Vasc. Biol. 2019; 39: 432-445
- IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2.Bone. 2019; 124: 53-61
- Endogenous bone morphogenetic protein 2 plays a role in vascular smooth muscle cell calcification induced by interleukin 6 in vitro.Int. J. Immunopathol. Pharmacol. 2017; 30: 227-237
- Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis.Arthritis Rheum. 2009; 61: 1580-1585
- IL 6 but not TNF is linked to coronary artery calcification in patients with chronic kidney disease.Cytokine. 2019; 120: 9-14
- Interleukin-18 enhances vascular calcification and osteogenic differentiation of vascular smooth muscle cells through TRPM7 activation.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1933-1943
- Interleukin 18 promotes myofibroblast activation of valvular interstitial cells.Int. J. Cardiol. 2016; 221: 998-1003
- Matrix metalloproteinase-10 deficiency delays atherosclerosis progression and plaque calcification.Atherosclerosis. 2018; 278: 124-134
- Sequential activation of matrix metalloproteinase 9 and transforming growth factor beta in arterial elastocalcinosis.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 856-862
- Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1852-1861
- Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-beta signaling.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 525-533
- Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCalpha signalling and cross-talk with TGFbeta.Cardiovasc. Res. 2017; 113: 1639-1652
- Cardiovascular calcification: artificial intelligence and big data accelerate mechanistic discovery.Nat. Rev. Cardiol. 2019; 16: 261-274
- Macrophage heterogeneity complicates reversal of calcification in cardiovascular tissues.Circ. Res. 2017; 121: 5-7
- Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques.Atherosclerosis. 2004; 176: 101-110
- Dendritic cells in atherosclerosis: evidence in mice and humans.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 763-770
- Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves.J. Exp. Med. 2009; 206: 497-505
- DC isoketal-modified proteins activate T cells and promote hypertension.J. Clin. Invest. 2014; 124: 4642-4656
- The human mast cell: an overview.Methods Mol. Biol. 2006; 315: 13-34
- Mast cells in calcific aortic stenosis.Pathol. Res. Pract. 2018; 214: 163-168
- Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-perpetuating angiogenic pathway in aortic valve stenosis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1220-1227
- Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice.Atherosclerosis. 2013; 226: 82-87
- Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries.J. Pathol. 1997; 182: 115-122
- Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness.Cardiovasc. Res. 2018; 114: 590-600
- Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1707-1715
- Hemodynamic force triggers rapid NETosis within sterile thrombotic occlusions.J. Thromb. Haemostasis. 2018; 16: 316-329
- Inflammation and coagulation.Crit. Care Med. 2010; 38: S26-S34
- Activated platelets promote an osteogenic programme and the progression of calcific aortic valve stenosis.Eur. Heart J. 2019; 40: 1362-1373
- Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis.Front. Immunol. 2017; 8: 928
- Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis.Science. 2015; 349: 316-320
- The immune system in atherosclerosis.Nat. Immunol. 2011; 12: 204-212
- NETosis is associated with the severity of aortic stenosis: links with inflammation.Int. J. Cardiol. 2019; 286: 121-126
- Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure.Am. J. Cardiol. 2011; 107: 433-438
- The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis.Atherosclerosis. 2019; 288: 9-16
- Cathepsin G activity lowers plasma LDL and reduces atherosclerosis.Biochim. Biophys. Acta. 2014; 1842: 2174-2183
- Defensins and cathelicidins: neutrophil peptides with roles in inflammation, hyperlipidemia and atherosclerosis.J. Cell Mol. Med. 2005; 9: 3-10
- Inactivation of platelet-derived TGF-beta1 attenuates aortic stenosis progression in a robust murine model.Blood Adv. 2019; 3: 777-788
- Platelets express and release osteocalcin and co-localize in human calcified atherosclerotic plaques.J. Thromb. Haemostasis. 2013; 11: 357-365
- Genetic depletion or hyperresponsiveness of natural killer cells do not affect atherosclerosis development.Circ. Res. 2018; 122: 47-57
- Identification of natural killer cells in human atherosclerotic plaque.Atherosclerosis. 2005; 180: 423-427
- Revisiting the functional impact of NK cells.Trends Immunol. 2018; 39: 460-472
- Coronary artery calcification: from mechanism to molecular imaging.JACC Cardiovasc Imaging. 2017; 10: 582-593
- Role and function of extracellular vesicles in calcific aortic valve disease.Eur. Heart J. 2017; 38: 2714-2716
- Innate and adaptive immunity in the pathogenesis of atherosclerosis.Circ. Res. 2002; 91: 281-291
- Impact of B-Cell-Targeted Therapies on cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2019; 39: 1705-1714
- Adaptive immune cells in calcific aortic valve disease.Am. J. Physiol. Heart Circ. Physiol. 2019; 317: H141-H155
- Lymphocyte and monocyte subpopulations in severe aortic stenosis at the time of surgical intervention.Cardiovasc. Pathol. 2018; 35: 1-7
- T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves.Heart. 2002; 88: 348-351
- RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing.Physiol. Genom. 2016; 48: 749-761
- The lymphocytic infiltration in calcific aortic stenosis predominantly consists of clonally expanded T cells.J. Immunol. 2007; 178: 5329-5339
- Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis.J. Immunol. 2011; 187: 1006-1014
- Decreased naive and increased memory CD4(+) T cells are associated with subclinical atherosclerosis: the multi-ethnic study of atherosclerosis.PloS One. 2013; 8e71498
- T-helper 2 immunity is associated with reduced risk of myocardial infarction and stroke.Arterioscler. Thromb. Vasc. Biol. 2013; 33: 637-644
- Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells.Thromb. Haemostasis. 2006; 95: 708-714
- Regulatory T cells in cardiovascular diseases.Nat. Rev. Cardiol. 2016; 13: 167-179
- Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events.Ann. Thorac. Surg. 2007; 83: 946-953
- TGF-beta prevents phosphate-induced osteogenesis through inhibition of BMP and Wnt/beta-catenin pathways.PloS One. 2014; 9e89179
- Circulating regulatory T cells in patients with aortic valve stenosis: association with disease progression and aortic valve intervention.Int. J. Cardiol. 2016; 218: 181-187
- Natural killer T cells in atherosclerosis.Nat. Rev. Cardiol. 2017; 14: 304-314
- Perforin and granzymes: function, dysfunction and human pathology.Nat. Rev. Immunol. 2015; 15: 388-400
- Immunity and inflammation in atherosclerosis.Circ. Res. 2019; 124: 315-327
- Association of anti-citrullinated peptide antibodies with coronary artery calcification in rheumatoid arthritis.Arthritis Care Res. 2017; 69: 1276-1281
- Association of serum antibodies to heat-shock protein 65 with coronary calcification levels: suggestion of pathogen-triggered autoimmunity in early atherosclerosis.Circulation. 2004; 109: 36-41
- Systemic lupus erythematosus risk factors for coronary artery calcifications.Rheumatology. 2012; 51: 110-119
- Spatiotemporal multi-omics mapping generates a molecular atlas of the aortic valve and reveals networks driving disease.Circulation. 2018; 138: 377-393
- Presence of B cells within aortic valves in patients with aortic stenosis: relation to severity of the disease.J. Cardiol. 2016; 67: 80-85
- The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy.NPJ Aging Mech. Dis. 2018; 4: 7
- Statin medication enhances progression of coronary artery calcification: the heinz nixdorf recall study.J. Am. Coll. Cardiol. 2016; 68: 2123-2125
- PCSK9 R46L loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis.J. Clin. Endocrinol. Metab. 2016; 101: 3281-3287
- PCSK9 involvement in aortic valve calcification.J. Am. Coll. Cardiol. 2018; 72: 3225-3227
- PCSK9: a novel inflammation modulator in atherosclerosis?.J. Cell. Physiol. 2019; 234: 2345-2355
- PCSK9 and inflammation: a review of experimental and clinical evidence.Eur. Heart J. Cardiovasc. Pharmacother. 2019; 5: 237-245https://doi.org/10.1093/ehjcvp/pvz022
- PCSK9 is a critical regulator of the innate immune response and septic shock outcome.Sci. Transl. Med. 2014; 6 (258ra143)
- Antiinflammatory therapy with canakinumab for atherosclerotic disease.N. Engl. J. Med. 2017; 377: 1119-1131
- Inhibition of interleukin-1beta by canakinumab and cardiovascular outcomes in patients with chronic kidney disease.J. Am. Coll. Cardiol. 2018; 71: 2405-2414
- Immune checkpoint inhibitors and cardiovascular toxicity.Lancet Oncol. 2018; 19: e447-e458
- Cardiac complications in immune checkpoint inhibition therapy.Front. Cardiovasc. Med. 2019; 6: 3
- Imaging cardiovascular calcification.J. Am. Heart Assoc. 2018; 7
- 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis.Circ. Cardiovasc. Imag. 2014; 7: 371-378
- Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.Circulation. 2012; 125: 76-86
Article Info
Publication History
Published online: February 28, 2020
Accepted:
February 20,
2020
Received in revised form:
January 10,
2020
Received:
October 25,
2019
Identification
Copyright
© 2020 Elsevier B.V. All rights reserved.
