Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach

doi:10.1016/j.semcdb.2015.09.004

Seminars in Cell & Developmental Biology

Volume 46, October 2015, Pages 68-77

https://doi.org/10.1016/j.semcdb.2015.09.004 Get rights and content

Abstract

The presence of cardiovascular calcification significantly predicts patients’ morbidity and mortality. Calcific mineral deposition within the soft cardiovascular tissues disrupts the normal biomechanical function of these tissues, leading to complications such as heart failure, myocardial infarction, and stroke. The realization that calcification results from active cellular processes offers hope that therapeutic intervention may prevent or reverse the disease. To this point, however, no clinically viable therapies have emerged. This may be due to the lack of certainty that remains in the mechanisms by which mineral is deposited in cardiovascular tissues. Gaining new insight into this process requires a multidisciplinary approach. The pathological changes in cell phenotype that lead to the physicochemical deposition of mineral and the resultant effects on tissue biomechanics must all be considered when designing strategies to treat cardiovascular calcification. In this review, we overview the current cardiovascular calcification paradigm and discuss emerging techniques that are providing new insight into the mechanisms of ectopic calcification.

Introduction

Clinical evidence demonstrates that calcium burden significantly predicts and contributes to cardiovascular disease [1], [2], [3], the leading cause of death in the United States. However, no known therapeutic strategies exist to prevent or treat cardiovascular calcification. Previous studies have focused on the cellular and molecular changes that drive soft tissue calcification while the physicochemical processes by which mineral forms and grows remain unknown. Cardiovascular calcification lies at the interface of physical, chemical, and biological fields, requiring a multidisciplinary approach to connect the cellular and molecular changes to the remodeling that disrupts tissue function. Pathologic changes in cell phenotype (biological) create an environment favoring calcium phosphate mineralization (chemical), leading to loss in the biomechanical function of the soft tissue (physical). Understanding the integration of these processes requires a multidisciplinary approach with the common goal to develop new therapeutic strategies to control ectopic biomineralization. In this review, we provide a holistic discussion of cardiovascular calcification connecting the tissue alterations to the disease cellular underpinnings. Section 2 overviews the biomechanical changes that result in the clinical manifestation of calcification. Recent material and chemical analyses of cardiovascular calcification are reviewed in Section 3. In Section 4 we introduce the cellular populations and phenotypes responsible for mineral deposition. Finally, we discuss the commonly used methods exploring molecular mechanisms of calcification along with the emerging technologies offering novel mechanistic insight.

Section snippets

Conclusions

The relationship between cellular phenotypes responsible for fibrocalcific processes within cardiovascular tissues remains poorly understood. Numerous cell types contribute to ectopic calcification at different stages of the progression. In order to develop strategies to prevent calcification before the “state of no return” we need to understand the contribution of each cell type to the calcification process. Additionally, despite many overlapping risk factors it is now postulated that vascular

References (119)

L. Cardoso
Effect of tissue properties, shape and orientation of microcalcifications on vulnerable cap stability using different hyperelastic constitutive models
J. Biomech.
(2014)
N. Maldonado
The explosive growth of small voids in vulnerable cap rupture; cavitation and interfacial debonding
J. Biomech.
(2013)
G.A. Holzapfel
Computational approaches for analyzing the mechanics of atherosclerotic plaques: a review
J. Biomech.
(2014)
R. Virmani
Pathology of the vulnerable plaque
J. Am. Coll. Cardiol.
(2006)
P.D. Richardson et al.
Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques
Lancet
(1989)
K. Imoto
Longitudinal structural determinants of atherosclerotic plaque vulnerability: a computational analysis of stress distribution using vessel models and three-dimensional intravascular ultrasound imaging
J. Am. Coll. Cardiol.
(2005)
M.A. Gimbrone et al.
Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis
Cardiovasc. Pathol.
(2013)
W.G. Goodman
Vascular calcification in chronic kidney disease
Am. J. Kidney Dis.
(2004)
M.A. Guerraty
Relation of aortic valve calcium to chronic kidney disease (from the chronic renal insufficiency cohort study)
Am. J. Cardiol.
(2015)
H.C. Anderson
Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice
Am. J. Pathol.
(2004)

A. Cmoch

Matrix vesicles isolated from mineralization-competent Saos-2 cells are selectively enriched with annexins and S100 proteins

Biochem. Biophys. Res. Commun.

(2011)

J. Bujan

Modifications induced by atherogenic diet in the capacity of the arterial wall in rats to respond to surgical insult

Atherosclerosis

(1996)

D.A. Towler

Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice

J. Biol. Chem.

(1998)

M.A. Bowler et al.

In vitro models of aortic valve calcification: solidifying a system

Cardiovasc. Pathol.

(2015)

W.D. Merryman

Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast

Cardiovasc. Pathol.

(2007)

J.D. Hutcheson

Intracellular Ca(2+) accumulation is strain-dependent and correlates with apoptosis in aortic valve fibroblasts

J. Biomech.

(2012)

F. Della Rocca

Cell composition of the human pulmonary valve: a comparative study with the aortic valve – the VESALIO Project. Vitalitate Exornatum Succedaneum Aorticum labore Ingegnoso Obtinebitur

Ann. Thorac. Surg.

(2000)

R. Vliegenthart

Coronary calcification improves cardiovascular risk prediction in the elderly

Circulation

(2005)

A.S. Go

Heart disease and stroke statistics – 2014 update: a report from the American Heart Association

Circulation

(2014)

R.C. Johnson et al.

Vascular calcification: pathobiological mechanisms and clinical implications

Circ. Res.

(2006)

M.S. Sacks et al.

Heart valve function: a biomechanical perspective

Philos. Trans. R. Soc. Lond. B: Biol. Sci.

(2007)

M. Wu et al.

Vascular calcification: an update on mechanisms and challenges in treatment

Calcif. Tissue Int.

(2013)

E.J. Weinberg et al.

A computational model of aging and calcification in the aortic heart valve

PLoS ONE

(2009)

J.L. Ruiz et al.

Cardiovascular calcification: current controversies and novel concepts

Cardiovasc. Pathol.

(2015)

J.D. Miller et al.

Calcific aortic valve stenosis: methods, models, and mechanisms

Circ. Res.

(2011)

S. Ehara

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study

Circulation

(2004)

M.H. Criqui

Calcium density of coronary artery plaque and risk of incident cardiovascular events

JAMA

(2014)

A. Kelly-Arnold

Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries

Proc. Natl. Acad. Sci. U. S. A.

(2013)

N. Maldonado

A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture

Am. J. Physiol. Heart Circ. Physiol.

(2012)

M. Naghavi

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II

Circulation

(2003)

M. Naghavi

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I

Circulation

(2003)

P. Libby

Collagenases and cracks in the plaque

J. Clin. Invest.

(2013)

R. Virmani

Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque

J. Interv. Cardiol.

(2003)

R. Virmani

Vulnerable plaque: the pathology of unstable coronary lesions

J. Interv. Cardiol.

(2002)

G.C. Cheng

Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation

Circulation

(1993)

L. Cardoso et al.

Changing views of the biomechanics of vulnerable plaque rupture: a review

Ann. Biomed. Eng.

(2014)

Y. Vengrenyuk et al.

Micro-CT based analysis of a new paradigm for vulnerable plaque rupture: cellular microcalcifications in fibrous caps

Mol. Cell. Biomech.

(2008)

Y. Vengrenyuk

A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps

Proc. Natl. Acad. Sci. U. S. A.

(2006)

S.H. Rambhia

Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid–structure interaction study

Ann. Biomed. Eng.

(2012)

F. Otsuka

Has our understanding of calcification in human coronary atherosclerosis progressed?

Arterioscler. Thromb. Vasc. Biol.

(2014)

T.C. Lin

Mechanical response of a calcified plaque model to fluid shear force

Ann. Biomed. Eng.

(2006)

K.K. Wong

Effect of calcification on the mechanical stability of plaque based on a three-dimensional carotid bifurcation model

BMC Cardiovasc. Disord.

(2012)

J.D. Hutcheson et al.

Potential drug targets for calcific aortic valve disease

Nat. Rev. Cardiol.

(2014)

M.J. Czarny et al.

Diagnosis and management of valvular aortic stenosis

Clin. Med. Insights Cardiol.

(2014)

E. Aikawa

Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo

Circulation

(2007)

D.S. Bach

Prevalence and characteristics of unoperated patients with severe aortic stenosis

J. Heart Valve Dis.

(2011)

E. Aikawa et al.

Look more closely at the valve: imaging calcific aortic valve disease

Circulation

(2012)

M. Rattazzi

Aortic valve calcification in chronic kidney disease

Nephrol. Dial. Transplant.

(2013)

M.J. Duer

Mineral surface in calcified plaque is like that of bone: further evidence for regulated mineralization

Arterioscler. Thromb. Vasc. Biol.

(2008)

S. Bertazzo

Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification

Nat. Mater.

(2013)

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Upregulation of NOR-1 in calcified human vascular tissues: impact on osteogenic differentiation and calcification
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Cardiovascular calcification is a significant public health issue whose pathophysiology is not fully understood. NOR-1 regulates critical processes in cardiovascular remodeling, but its contribution to ectopic calcification is unknown. NOR-1 was overexpressed in human calcific aortic valves and calcified atherosclerotic lesions colocalizing with RUNX2, a factor essential for osteochondrogenic differentiation and calcification. NOR-1 and osteogenic markers were upregulated in calcifying human valvular interstitial cells (VICs) and human vascular smooth muscle cells (VSMCs). Gain- and loss-of-function approaches demonstrated that NOR-1 negatively modulates the expression of osteogenic genes relevant for the osteogenic transdifferentiation (RUNX2, IL-6, BMP2, and ALPL) and calcification of VICs. VSMCs from transgenic mice overexpressing NOR-1 in these cells (TgNOR-1^VSMC) expressed lower basal levels of osteogenic genes (IL-6, BMP2, ALPL, OPN) than cells from WT littermates, and their upregulation by a high-phosphate osteogenic medium (OM) was completely prevented by NOR-1 transgenesis. Consistently, this was associated with a dramatic reduction in the calcification of both transgenic VSMCs and aortic rings from TgNOR-1^VSMC mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9^D374Y and a high-fat/high-cholesterol diet. Challenged-TgNOR-1^VSMC mice exhibited decreased vascular expression of osteogenic markers, and both less atherosclerotic burden (assessed in whole aorta and lesion size in aortic arch and brachiocephalic artery) and less vascular calcification (assessed either by near-infrared fluorescence imaging or histological analysis) than WT mice. Our data indicate that NOR-1 negatively modulates the expression of genes critically involved in the osteogenic differentiation of VICs and VSMCs, thereby restraining ectopic cardiovascular calcification.
Lysyl oxidase expression in smooth muscle cells determines the level of intima calcification in hypercholesterolemia-induced atherosclerosis
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La calcificación cardiovascular es un importante problema de salud pública para el que no se dispone de estrategias farmacológicas eficaces. Previamente habíamos demostrado que la actividad lisil oxidasa (LOX) influye de manera determinante en la calcificación de las células musculares lisas de la pared vascular (CMLV) y las células intersticiales valvulares (VIC) a través de su impacto en el remodelado de la matriz extracelular. Hemos profundizado en la participación de la LOX en la aterosclerosis y la calcificación asociada, así como en la mineralización de la válvula aórtica.
Se realizaron análisis inmunohistoquímicos y de expresión en lesiones ateroscleróticas humanas y de modelos experimentales, válvulas de pacientes con estenosis aórtica, VIC y estudios en un modelo de ratón modificado genéticamente que sobreexpresa LOX en CMLV (TgLOX^CMLV), en el que se indujo hiperlipemia y aterosclerosis mediante la administración de virus adenoasociados que codifican para una forma mutada de la PCSK9 (AAV-PCSK9^D374Y) y dieta aterogénica.
La expresión de la LOX se incrementa en la neoíntima de lesiones ateroscleróticas de arterias coronarias humanas y en regiones ricas en CMLV de las placas de ateroma desarrolladas tanto en la arteria braquiocefálica de animales control (C57BL/6J) transducidos con PCSK9^D374Y como en la raíz aórtica de ratones ApoE^−/−. En ratones TgLOX^CMLV, la transducción con PCSK9^D374Y no alteró significativamente el incremento de la expresión aórtica de genes implicados en el remodelado de la matriz, la inflamación, el estrés oxidativo y la diferenciación osteoblástica. La transgénesis de LOX no afectó al tamaño ni al contenido lipídico de las lesiones ateroscleróticas del arco aórtico, la arteria braquiocefálica y la raíz aórtica, pero exacerbó la calcificación de la íntima de las lesiones. Entre las isoenzimas de la familia de lisil oxidasas, la LOX es el miembro más expresado en válvulas de pacientes muy calcificadas, detectándose en células VIC positivas para RUNX2. La menor deposición de calcio y la disminución de RUNX2 causadas por la sobreexpresión del receptor nuclear NOR-1 en VIC se asoció a una reducción de los niveles de proteína de LOX.
Nuestros resultados muestran que la expresión de LOX está aumentada en lesiones ateroscleróticas, y que la sobreexpresión de esta enzima en CMLV no afecta al tamaño ni al contenido lipídico de las lesiones pero sí a su grado de calcificación. Además, sugieren que la disminución de la calcificación inducida por NOR-1 en VIC estaría mediada por una reducción en nivel de LOX. Estas evidencias apoyan el interés de la LOX como diana terapéutica en la calcificación cardiovascular.
Cardiovascular calcification is an important public health issue with an unmeet therapeutic need. We had previously shown that lysyl oxidase (LOX) activity critically influences vascular wall smooth muscle cells (VSMCs) and valvular interstitial cells (VICs) calcification by affecting extracellular matrix remodeling. We have delved into the participation of LOX in atherosclerosis and vascular calcification, as well as in the mineralization of the aortic valve.
Immunohistochemical and expression studies were carried out in human atherosclerotic lesions and experimental models, valves from patients with aortic stenosis, VICs, and in a genetically modified mouse model that overexpresses LOX in CMLV (TgLOX^CMLV). Hyperlipemia and atherosclerosis was induced in mice through the administration of adeno-associated viruses encoding a PCSK9 mutated form (AAV-PCSK9^D374Y) combined with an atherogenic diet.
LOX expression is increased in the neointimal layer of atherosclerotic lesions from human coronary arteries and in VSMC-rich regions of atheromas developed both in the brachiocephalic artery of control (C57BL/6J) animals transduced with PCSK9^D374Y and in the aortic root of ApoE^−/− mice. In TgLOX^CMLV mice, PCSK9^D374Y transduction did not significantly alter the enhanced aortic expression of genes involved in matrix remodeling, inflammation, oxidative stress and osteoblastic differentiation. Likewise, LOX transgenesis did not alter the size or lipid content of atherosclerotic lesions in the aortic arch, brachiocephalic artery and aortic root, but exacerbated calcification. Among lysyl oxidase isoenzymes, LOX is the most expressed member of this family in highly calcified human valves, colocalizing with RUNX2 in VICs. The lower calcium deposition and decreased RUNX2 levels triggered by the overexpression of the nuclear receptor NOR-1 in VICs was associated with a reduction in LOX.
Our results show that LOX expression is increased in atherosclerotic lesions, and that overexpression of this enzyme in VSMC does not affect the size of the atheroma or its lipid content, but it does affect its degree of calcification. Further, these data suggest that the decrease in calcification driven by NOR-1 in VICs would involve a reduction in LOX. These evidences support the interest of LOX as a therapeutic target in cardiovascular calcification.
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Pseudomonas aeruginosa β-carbonic anhydrase, psCA1, is required for calcium deposition and contributes to virulence
2019, Cell Calcium
Citation Excerpt :
However, the origins and the contributing factors of calcification are poorly understood. Initiation of calcification is commonly associated with misbalance of calcium ion (Ca2+) and activity of human alkaline phosphatases and carbonic anhydrases (CAs) [1,2]. Several diseases lead to elevated levels of Ca2+ in different liquids of the human body.
Calcification of soft tissue leads to serious diseases and has been associated with bacterial chronic infections. However, the origin and the molecular mechanisms of calcification remain unclear. Here we hypothesized that a human pathogen Pseudomonas aeruginosa deposits extracellular calcium, a process requiring carbonic anhydrases (CAs). Transmission electron microscopy confirmed the formation of 0.1-0.2 μm deposits by P. aeruginosa PAO1 growing at 5 mM CaCl₂, and X-ray elemental analysis confirmed they contain calcium. Quantitative analysis of deposited calcium showed that PAO1 deposits 0.35 and 0.75 mM calcium/mg protein when grown at 5 mM and 10 mM CaCl₂, correspondingly. Fluorescent microscopy indicated that deposition initiates at the cell surface. We have previously characterized three PAO1 β-class CAs: psCA1, psCA2, and psCA3 that hydrate CO₂ to HCO₃⁻, among which psCA1 showed the highest catalytic activity (Lotlikar et. al. 2013). According to immunoblot and RT-qPCR, growth at elevated calcium levels increases the expression of psCA1. Analyses of the deletion mutants lacking one, two or all three psCA genes, determined that psCA1 plays a major role in calcium deposition and contributes to the pathogen’s virulence. In-silico modeling of the PAO1 β-class CAs identified four amino acids that differ in psCA1 compared to psCA2, and psCA3 (T59, A61A, A101, and A108), and these differences may play a role in catalytic rate and thus calcium deposition. A series of inhibitors were tested against the recombinant psCA1, among which aminobenzene sulfonamide (ABS) and acetazolamide (AAZ), which inhibited psCA1 catalytic activity with K_Is of 19 nM and 37 nM, correspondingly. The addition of ABS and AAZ to growing PAO1 reduced calcium deposition by 41 and 78, respectively. Hence, for the first time, we showed that the β-CA psCA1 in P. aeruginosa contributes to virulence likely by enabling calcium salt deposition, which can be partially controlled by inhibiting its catalytic activity.
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2019, Clinica Chimica Acta
Citation Excerpt :
The X-box binding protein 1 (XBP1) mediates functions of ECs and SMCs, and XBP1 splicing in SMCs controls migration of ECs via EV-mediated miR-150 transfer, maintaining vessel wall homeostasis [66]. In a hyperphosphatemic environment or inflammation-driven AS, EVs released by VSMCs promote extracellular mineralization [67,68]. Endothelial autophagy disorder is an important pathogenic factor in cardiovascular dysfunction and AS, and human aortic smooth muscle cell (HAoSMC)-derived miR-221/222 inhibits autophagy of HUVECs via the PTEN/Akt signalling pathway [69].
Extracellular vesicles (EVs), which exist in human blood, are increased in some inflammation-related cardiovascular diseases. EVs are involved in inflammation, immunity, signal transduction, cell survival and apoptosis, angiogenesis, thrombosis, and autophagy, all of which are highly significant for maintaining homeostasis and disease progression. Therefore, EVs are also associated with key steps in atherosclerosis, including cellular lipid metabolism, endothelial dysfunction and vascular wall inflammation, ultimately resulting in vascular remodelling. In this review, we summarize recent studies on EV contents and biological function, focusing on their potential effect in atherosclerosis, including cholesterol metabolism, vascular inflammation, angiogenesis, coagulation and the development of atherosclerotic lesions. EVs may represent potential biomarkers and pharmacological targets for atherosclerotic diseases.
Human aortic endothelial cells have osteogenic Notch-dependent properties in co-culture with aortic smooth muscle cells
2019, Biochemical and Biophysical Research Communications
Cardiovascular calcification is one of the leading reasons of morbidity and mortality in Western countries and has many similarities to osteogenesis. The role of smooth muscle calcific transformation is well established for atherogenic lesions, but mechanisms driving initial stages of proosteogenic cell fate commitment in big vessels remain poorly understood. The role of endothelial and underlying interstitial cell interaction in driving cellular decisions is emerging from recent studies. The aim of this study was to analyze co-culture of endothelial and smooth muscle cells in vitro in acquiring proosteogenic phenotype. We co-cultured human aortic endothelial cells (EC) and human aortic smooth muscle cells (SMC) and analyzed osteogenic phenotype by ALP staining and proosteogenic gene expression by qPCR in co-cultures and in separate cellular types after magnetic CD31-sorting. In EC and SMC co-cultures osteogenic phenotype was induced as well as activated expression of RUNX2, POSTIN, BMP2/4, SOX5, COL1A SMC; co-culture of EC with SMC induced NOTCH1, NOTCH3, NOTCH4 and HEY1 expression; Notch activation by lentiviral activated Notch intracellular domain induced expression of RUNX2, OPN, POSTIN in SMC; NOTCH1 and NOTCH3 and HEY1 were selectively induced in EC during co-culture. We conclude that endothelial cells are capable of driving smooth muscle calcification via cell-cell contact and activation of Notch signaling.

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¹: These authors contributed equally to the preparation of this manuscript.

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ReviewRevisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach

Abstract

Introduction

Section snippets

Conclusions

J. Biomech.

J. Biomech.

J. Biomech.

J. Am. Coll. Cardiol.

Lancet

J. Am. Coll. Cardiol.

Cardiovasc. Pathol.

Am. J. Kidney Dis.

Am. J. Cardiol.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

Atherosclerosis

J. Biol. Chem.

Cardiovasc. Pathol.

Cardiovasc. Pathol.

J. Biomech.

Ann. Thorac. Surg.

Coronary calcification improves cardiovascular risk prediction in the elderly

Circulation

Heart disease and stroke statistics – 2014 update: a report from the American Heart Association

Circulation

Vascular calcification: pathobiological mechanisms and clinical implications

Circ. Res.

Heart valve function: a biomechanical perspective

Philos. Trans. R. Soc. Lond. B: Biol. Sci.

Vascular calcification: an update on mechanisms and challenges in treatment

Calcif. Tissue Int.

A computational model of aging and calcification in the aortic heart valve

PLoS ONE

Cardiovascular calcification: current controversies and novel concepts

Cardiovasc. Pathol.

Calcific aortic valve stenosis: methods, models, and mechanisms

Circ. Res.

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study

Circulation

Calcium density of coronary artery plaque and risk of incident cardiovascular events

JAMA

Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries

Proc. Natl. Acad. Sci. U. S. A.

A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture

Am. J. Physiol. Heart Circ. Physiol.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II

Circulation

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I

Circulation

Collagenases and cracks in the plaque

J. Clin. Invest.

Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque

J. Interv. Cardiol.

Vulnerable plaque: the pathology of unstable coronary lesions

J. Interv. Cardiol.

Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation

Circulation

Changing views of the biomechanics of vulnerable plaque rupture: a review

Ann. Biomed. Eng.

Micro-CT based analysis of a new paradigm for vulnerable plaque rupture: cellular microcalcifications in fibrous caps

Mol. Cell. Biomech.

A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps

Proc. Natl. Acad. Sci. U. S. A.

Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid–structure interaction study

Ann. Biomed. Eng.

Has our understanding of calcification in human coronary atherosclerosis progressed?

Arterioscler. Thromb. Vasc. Biol.

Mechanical response of a calcified plaque model to fluid shear force

Ann. Biomed. Eng.

Effect of calcification on the mechanical stability of plaque based on a three-dimensional carotid bifurcation model

BMC Cardiovasc. Disord.

Potential drug targets for calcific aortic valve disease

Nat. Rev. Cardiol.

Diagnosis and management of valvular aortic stenosis

Clin. Med. Insights Cardiol.

Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo

Circulation

Prevalence and characteristics of unoperated patients with severe aortic stenosis

J. Heart Valve Dis.

Review
Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach