© 1996 American Heart Association, Inc.
Articles |
Medial Artery Calcification
A Neglected Harbinger of Cardiovascular Complications in Non–Insulin-Dependent Diabetes Mellitus
the Departments of Medicine (S.L., L.N., M.L.) and Radiology (M.S.), Kuopio University Hospital, Kuopio; the Department of Medicine (T.R.), Turku University Hospital, Turku; and the Research and Development Centre (T.R.), Social Insurance Institution, Turku, Finland.
Correspondence to Markku Laakso, MD, Professor, Department of Medicine, University of Kuopio, SF-70210 Kuopio, Finland. E-mail Markku.Laakso@uku.fi.
Abstract
Medial artery calcification (MAC) is a nonobstructive condition leading to reduced arterial compliance that is commonly considered as a nonsignificant finding. The aim of our study was to investigate the predictive value of MAC in relation to 7-year cardiovascular mortality, coronary heart disease (CHD) events, stroke, and lower extremity amputation in 1059 patients (581 men and 478 women) with non–insulin-dependent diabetes mellitus (NIDDM). At baseline radiologically detectable MAC in femoral arteries was found in 439 patients (41.5%) and intimal-type calcification in 310 diabetic patients (29.3%). The mean fasting plasma glucose at baseline was somewhat higher in women and the duration of diabetes somewhat longer in patients with MAC than in those without, but otherwise the presence of MAC was unrelated to conventional cardiovascular risk factors. During the follow-up 305 diabetic patients died: 208 from cardiovascular disease, 158 from CHD, and 34 from stroke. Furthermore, 58 NIDDM patients underwent their first lower extremity amputation. MAC was a strong independent predictor of total (risk factor–adjusted odds ratio and 95% confidence interval: 1.6; 1.2, 2.2), cardiovascular (1.6; 1.1, 2.2), and CHD (1.5; 1.0, 2.2) mortality, and it was also a significant predictor of future CHD events (fatal or nonfatal myocardial infarction), stroke, and amputation. This relationship was observed regardless of glycemic control and known duration of NIDDM. MAC is a strong marker of future cardiovascular events in NIDDM unrelated to cardiovascular risk factors, supporting the hypothesis that reduced arterial elasticity could lead to clinical manifestations of diabetic macroangiopathy.
Key Words: medial artery calcification • non–insulin-dependent diabetes • mortality • cardiovascular disease
Mortality and morbidity from CVD are markedly increased in patients with NIDDM. The reasons for this excess mortality among diabetic patients have remained unknown and are only partly explained by the effects of diabetes on general risk factors.1 In addition to atherosclerotic changes, the vessels of NIDDM patients are characterized by increased amounts of connective tissue, such as fibronectin, collagen, and glycoproteins, as well as increased amounts of calcium in the medial layer of the arterial wall, a constellation named "diabetic macroangiopathy."2 These changes lead to a loss of elasticity of the arterial wall. Large arteries respond to changes in blood flow by adjusting their internal diameter to meet the demands of the organ supplied. This flow-dependent mechanism opposes neurogenic and myogenic vasoconstriction, increases conductance during exercise, and maintains shear stress within physiological values. The major mediator of this flow-dependent large-artery dilatation is nitric oxide.3 NIDDM,like obesity and essential hypertension, is characterized by disturbed insulin-mediated vasodilatation,4 5 6 7 and this mechanism can contribute to decreased insulin action in these clinical conditions. However, the functional consequences of this reduced arterial elasticity in terms of cardiovascular mortality and morbidity are unknown.
MAC, also known as Mönckeberg's arteriosclerosis, is a condition that leads to the stiffening of the elastic layer of the arterial wall, but in contrast to intimal artery calcification, it does not obstruct the arterial lumen.8 9 10 As intimal calcification represents an advanced state of atherosclerosis, MAC has been related to aging and diabetes, especially to long duration of diabetes and its complications.11 12 13 14 15 16 17 However, the pathogenesis and clinical significance of MAC have remained unsettled. We have shown18 in newly diagnosed patients with NIDDM that the presence of MAC is the most powerful predictive marker of future cardiovascular mortality even after adjustment for cardiovascular risk factors. To further explore this association with cardiovascular mortality and also with events in other arterial trees (coronary, cerebral, and peripheral), we assessed the predictive value of MAC in a large representative group of middle-aged patients with NIDDM.
Methods
Subjects
All diabetic patients in Finland receive necessary antidiabetic drug therapy free of charge in compliance with the Sickness Insurance Act. The Social Insurance Institution maintains a central register of diabetic subjects receiving drug reimbursement. On the basis of this register, we identified all diabetic patients, aged 45 to 64 years, who were born and living in the Kuopio University Hospital district (east Finland) and the Turku University Central Hospital district (west Finland). The composition of the final patient population, which consisted of 510 diabetic subjects (253 men and 257 women) who participated in this study in east Finland (participation rate, 83%) and 549 diabetic subjects (328 men and 221 women) who participated in west Finland (participation rate, 79%) has been described.19 Insulin-dependent diabetes was excluded in all insulin-treated patients by C-peptide measurements. All NIDDM patients included in the final study population had a plasma C-peptide concentration of at least 0.20 nmol/L 6 minutes after glucagon 1 mg IV. A cutoff point of 0.20 nmol/L was chosen because postglucagon C-peptide values below this limit are associated with the occurrence of ketoacidosis in insulin-treated diabetic subjects.20 None of the patients classified as having NIDDM according to World Health Organization criteria21 and included in the final study population had a history of ketoacidosis. Of the 510 NIDDM patients from east Finland, 46 men and 38 women were treated with diet only, 183 men and 175 women with oral hypoglycemic drugs, and 24 men and 44 women with insulin. Of the 549 NIDDM patients from west Finland, 46 men and 17 women were treated with diet only, 227 men and 177 women with oral hypoglycemic drugs, and 55 men and 27 women with insulin. The age of diabetic men from east Finland was 56.8±0.3 years and from west Finland, 57.2±0.3 years, and the age of diabetic women from east Finland was 58.9±0.3 years and from west Finland, 58.7±0.3 years.
This study was approved by the Ethics Committee of Kuopio University Central Hospital.
Study Program and Methods at Baseline Examination, 1982 Through 1984
The study program was performed during one outpatient visit at the Clinical Research Unit of the University of Kuopio or the Rehabilitation Research Centre of the Social Insurance Institution in Turku. The study program and methods have been described.19 The visit included an interview on the history of chest pain symptoms suggestive of CHD, symptoms suggestive of stroke, smoking, alcohol intake, physical activity, and the use of drugs. All medical records of those subjects who reported during the interview that they had been admitted to the hospital on the basis of chest pain symptoms or symptoms suggestive of stroke or who had undergone lower extremity amputation were reviewed. Review of the medical records was performed by two of us (M.L. in Kuopio and T.R. in Turku) after a careful standardization of the methods between the reviewers. World Health Organization criteria for verified definite or possible MI based on chest pain symptoms, electrocardiographic changes, and enzyme determinations were used to diagnose previous MI.22
World Health Organization criteria for verified definite or possible stroke were used to diagnose previous stroke, which was defined as a clinical syndrome consisting of neurological symptoms persisting for >24 hours.23 Thromboembolic and hemorrhagic strokes but not subarachnoid hemorrhage were included in the diagnosis of stroke.
Blood pressure was measured with the subject in the sitting position after a 5-minute rest by using a mercury sphygmomanometer that was read to the nearest 2 mm Hg. Subjects were classified as having hypertension if they were receiving drug treatment for hypertension or if their systolic blood pressure was 
160 mm Hg or diastolic blood pressure 95 mm Hg.
Weight and height were measured in light clothing without shoes. Body mass index was calculated by weight (in kilograms)/height (in meters squared).
Biochemical Methods
All laboratory specimens were drawn after a 12-hour fast at 8 AM. Fasting plasma glucose levels were determined by the glucose oxidase method (Boehringer). Glycated hemoglobin A1 levels were determined by using affinity chromatography (Isolab). The plasma C-peptide response to glucagon was determined according to the method of Faber and Binder.24 Serum lipid and lipoprotein levels were determined from fresh serum samples drawn after a 12-hour overnight fast. Serum total cholesterol and triglyceride levels were assayed by using automated enzymatic methods (Boehringer). Serum HDL cholesterol was determined enzymatically after precipitation of LDL and VLDL with dextran sulfate–MgCl2.25
Radiological Methods
Soft-tissue native radiograms of the thigh were taken with the patient in a recumbent position. The radiological findings of the femoral artery were analyzed by a radiologist (M.S.) blinded to the clinical data. The degrees of lower-limb artery calcification were divided according to Lindbom10 into discrete plaque-like intimal-type (Fig 1
, left) and medial uniform linear railroad track–type (right) calcifications. The 
coefficients and the SE for (in parentheses) for intraobserver variation for the presence of intimal calcification were .87 (.24) and for the presence of medial calcification, .88 (.23).
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Research Design and Methods of Follow-up Study
In 1990 a postal questionnaire containing questions about hospitalization for acute chest pain, symptoms suggesting stroke, or lower limb amputation was sent to every surviving participant of the original study cohort. All medical records of those subjects who died between the baseline examination and December 31, 1989, or who reported in the questionnaire that they had been hospitalized for chest pain symptoms or symptoms suggesting stroke or who had undergone lower limb amputation between the baseline examination and December 31, 1989, were reviewed (S.L.). The criteria for MI and stroke were identical to those in the baseline study. Copies of death certificates of those patients who had died were obtained from the files of the Central Statistical Office of Finland. In the final classification of the causes of death, hospital records and autopsy records were used, if available. All deaths were ascertained from the register of the Social Insurance Institution, which has 100% coverage of the vital status of all diabetic subjects receiving drug reimbursement. Furthermore, the completeness of the information of CHD events, stroke, or lower extremity amputation was ascertained by a computerized hospital discharge register. By using these data files a list of hospital discharge diagnoses was produced for the subjects who participated in the baseline study. Hospital records of subjects found in this list and having CHD events, stroke, or lower extremity amputation were checked; it is therefore unlikely that we missed any of these cases.
The mortality data included in the present article are mortality from CVD (International Classification of Diseases 9, codes 390 through 459) and mortality and morbidity from CHD (ICD-9, codes 410 through 414) as well as stroke (ICD-9, codes 430 through 438).26
Statistical Methods
Data analyses were conducted with the SPSSX and SPSS/PC+ programs (SPSS Inc). The results for continuous variables are given as mean±SEM or percentages. Differences between groups were assessed by using the 
2 test or, when appropriate, Student's two-tailed t test for independent samples. Multiple logistic regression analyses27 based on the maximum-likelihood method were used to investigate the association of cardiovascular risk factors with the incidence of CHD events, stroke, and amputation; the results are reported with 95% confidence intervals. The survival curves for MAC were obtained and compared by using the Cox regression model,28 including age and gender as covariates. Because of skewed distribution, triglyceride values were log-transformed for statistical analyses.
Results
Radiologically detectable MAC in femoral arteries was present at baseline in 439 patients (41.5%) and intimal-type calcification in 310 patients (29.3%). Table 1 summarizes baseline cardiovascular risk factors in relation to the presence of MAC by sex. Patients with MAC were older (P<.001) and the mean duration of diabetes was somewhat longer (P<.001) than in those without MAC. In women, plasma glucose (P<.001) and glycated hemoglobin A1 (P<.05) levels were higher in patients with MAC than in those without MAC. Otherwise, the presence of MAC was unrelated to conventional cardiovascular risk factors, and the risk factor profile was, if anything, more favorable in patients with MAC than in patients without MAC. We also analyzed baseline cardiovascular risk factors in relation to intimal artery calcification in the study population (data not shown). Diabetic patients with intimal artery calcification were older (P<.001), had lower HDL cholesterol (P<.05), and had a longer duration of diabetes (P<.001) than those without intimal calcification. Frequency of smokers among diabetic men with intimal artery calcification was significantly higher (P<.001) than among those without intimal artery calcification (data not shown).
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During the 7-year follow-up, 305 diabetic patients (28.8%) died: 158 (14.9%; 97 men and 61 women) from CHD and 34 (3.2%; 13 men and 21 women) from stroke. During the follow-up, altogether 256 diabetic patients had a fatal or nonfatal MI (24.2%; 156 men and 100 women), and 125 diabetic patients had fatal or nonfatal stroke. The incidence of first lower extremity amputation was 5.6% (58 of 1044 patients).
Diabetic men with MAC had higher total mortality (35.5% versus 24.4%; P<.01), CVD mortality (25.7% versus 15.5%; P<.01), CHD mortality (20.8% versus 13.3%; P<.05), and stroke mortality (3.0% versus 1.6%; P=NS) than men without MAC. Respective figures for women were total mortality (42.0% versus 20.1%; P<.001), CVD mortality (28.7% versus 13.5%; P<.001), CHD mortality (19.5% versus 8.9%; P<.001), and stroke mortality (6.9% versus 3.0%; P<.05). As the predictive value of MAC was similar between men and women, both sexes were combined in the following data analyses. Diabetic patients with MAC had a significantly higher total mortality (38.0% versus 22.3%; P<.001), CVD mortality (26.9% versus 14.5%; P<.001), CHD mortality (20.3% versus 11.1%; P<.001), and stroke mortality (4.6% versus 2.3%; P<.05) than patients without MAC (Fig 2). NIDDM patients with MAC also had a higher incidence of all CHD events (30.1% versus 20.0%; P<.001), all stroke events (14.6% versus 9.8%; P<.05), and lower extremity amputations (9.2% versus 3.1%; P<.001) than those without MAC (Fig 3).
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Fig 4 shows the age- and gender-adjusted survival curves regarding total and cardiovascular mortality in relation to the presence of MAC. NIDDM patients with MAC had significantly shortened survival with respect to total mortality (P<.001) and cardiovascular mortality (P=.002) than patients without MAC.
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Because MAC was associated in univariate analyses with cardiovascular events, we performed multiple logistic regression analysis to investigate the independent effect of MAC as a predictor for cardiovascular events. Interactions between variables were tested by including two variables in addition to their product into the same model. No significant interactions were present between the variables included in multivariate logistic regression models. The odds ratios and their 95% confidence intervals of MAC to predict mortality, adjusted for age, gender, area of residence, fasting plasma glucose, duration of diabetes, plasma lipids, the presence of intimal artery calcification, previous MI or stroke, and other cardiovascular risk factors are shown in Table 2. Even after adjustment for all these cardiovascular risk factors, MAC remained an independent predictor of death from all causes, CVD, and CHD. Furthermore, MAC was a nearly significant predictor of death from stroke in patients with NIDDM.
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Because in univariate logistic regression analyses MAC was related to fasting plasma glucose and duration of diabetes, we analyzed the effect of MAC as a predictor of CVD mortality in relation to these variables. Median values of fasting plasma glucose (9.60 mmol/L) and known duration of diabetes (7.0 years) were used as cutoff points. The effect of MAC was seen also in those diabetic patients with lower glucose levels and shorter known duration of diabetes (Fig 5). The results were similar when analyzed with respect to total, CHD, or stroke mortality and the risk of amputation (data not shown).
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Discussion
This large population-based study demonstrates that MAC is a powerful and hitherto largely unrecognized marker for future total and cardiovascular mortality in patients with NIDDM. Furthermore, our study is the first to show that MAC is a also a powerful predictor of nonfatal events of all arterial branches.
We used native soft-tissue radiographs to visualize artery calcification. Distinguishing between the intimal and medial forms of calcification is in most instances easily done,10 14 but as an index of atherosclerosis, radiological assessment of intimal artery calcification is rather crude, and radiological examination is likely to underestimate the degree of atherosclerosis.29 In the same way, MAC may be insensitive as an index of reduced arterial elasticity. However, both are specific, and the method is relatively inexpensive and readily available. Although MAC can be visualized most easily from great lower limb arteries, it may affect arteries of all sizes.2 9 30 Because arterial lumen obstruction is not the main feature of MAC, it has been generally assumed that this type of calcification has no significant clinical implications with the exception that it may falsely elevate indirectly measured blood pressure levels. The stiffening of the arterial wall in diabetes not attributable to atherosclerosis has been described.31 32 33 34 Salomaa et al,35 in a large study comprising 4701 subjects, have demonstrated by noninvasive ultrasound technique that NIDDM patients and subjects with impaired glucose tolerance have increased arterial stiffness indexes compared with subjects with normal glucose tolerance. Therefore, it is reasonable to suggest that MAC represents the utmost and possibly the most severe form of this reduced arterial elasticity. Accordingly, the blood flow into the legs is lower in diabetic patients with MAC than in those without,14 and MAC has been shown to predict the development of intermittent claudication.36 In Pima Indians MAC has been shown to predict mortality, but the effect of general risk factors was not controlled.16 Our recent study18 and the present large study extend these concepts by demonstrating that the functional consequences of decreased arterial elasticity lead to markedly increased cardiovascular mortality and morbidity in patients with NIDDM; this excess burden of cardiovascular events associated with MAC becomes manifest from various arterial branches of the arterial tree (coronary and cerebral as well as lower leg arteries). Lower leg amputations may be due to diabetic neuropathy as well, but there is also a close connection between neuropathy and MAC.
The pathogenesis of MAC remains enigmatic. The risk factor profile associated with MAC at baseline showed an association only with age, glycemic control (in women), and known duration of diabetes. It is likely that the development of MAC is, at least partly, connected with hyperglycemia more than classic cardiovascular risk factors. A constellation of abnormalities that contributes to the occurrence of MAC occurs in diabetic vessels independently of the presence of atherosclerosis.2
The loss of autonomic innervation may lead to trophic disturbances in the smooth muscle cells of the tunica media. Since calcium is an important regulator of smooth muscle structure and function,37 subsequent calcification may ensue. Accordingly, lumbar sympathectomy is followed by the development of MAC.38 Our previous results indicate that autonomic neuropathy, as assessed by a decrease of beat-to-beat variation during deep breathing, is associated with the development of MAC in patients with NIDDM.36 The tendency to develop coronary and aortic calcification, including that of the medial layer, is strongly genetically determined in inbred and genetically engineered mice models.39 Whether there is a familial tendency to develop MAC in humans is not known, although a recent report described the familiar occurrence of linear-type aortic calcification that included that aortic valve.40
The mechanisms behind increased cardiovascular mortality and morbidity and MAC remain unknown. Recent studies strongly suggest that the mechanisms leading to excess mortality in patients with NIDDM may be related to hyperglycemia.41 42 MAC can be considered as a consequence of the age-related accumulation of advanced glycosylated proteins, which is exacerbated by diabetes, and therefore it may be a marker of an advanced state of the loss of arterial elasticity. The loss of arterial elasticity due to structural changes may lead to circulation derangement and further injury to the endothelium, thus increasing the risk of thrombosis. There is also a close relationship between MAC and autonomic neuropathy,35 38 and the latter may also contribute to increased cardiovascular mortality in NIDDM.
To conclude, MAC as visualized by plain soft-tissue radiograms is a powerful and easily recognizable risk marker for markedly increased cardiovascular events unrelated to conventional risk factors. These findings provide indirect support for the important role of reduced arterial compliance and disturbed blood flow in the pathogenesis of clinical manifestations of CVD in patients with NIDDM and strengthen the significance of diabetic macroangiopathy as a clinical entity. Thus, NIDDM patients with MAC could be an easily recognizable target for future intervention studies.
Selected Abbreviations and Acronyms
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Acknowledgments
This study was supported by grants from the Academy of Finland, the Aarne and Aili Turunen Foundation, and the Finnish Heart Research Foundation.
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R. J. Guzman, D. M. Brinkley, P. M. Schumacher, R. M.J. Donahue, H. Beavers, and X. Qin Tibial Artery Calcification as a Marker of Amputation Risk in Patients With Peripheral Arterial Disease J. Am. Coll. Cardiol., May 20, 2008; 51(20): 1967 - 1974. [Abstract] [Full Text] [PDF]
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 D. A. Towler Vascular Calcification: A Perspective On An Imminent Disease Epidemic IBMS BoneKEy, February 1, 2008; 5(2): 41 - 58. [Abstract] [Full Text] [PDF]
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S. M. Moe and N. X. Chen Mechanisms of Vascular Calcification in Chronic Kidney Disease J. Am. Soc. Nephrol., February 1, 2008; 19(2): 213 - 216. [Abstract] [Full Text] [PDF]
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 Z. Al-Aly, J.-S. Shao, C.-F. Lai, E. Huang, J. Cai, A. Behrmann, S.-L. Cheng, and D. A. Towler Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-{alpha} Dependent Signals in Diabetic Ldlr / Mice Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2589 - 2596. [Abstract] [Full Text] [PDF]
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 S. E. Heinonen, P. Leppanen, I. Kholova, H. Lumivuori, S.-K. Hakkinen, F. Bosch, M. Laakso, and S. Yla-Herttuala Increased Atherosclerotic Lesion Calcification in a Novel Mouse Model Combining Insulin Resistance, Hyperglycemia, and Hypercholesterolemia Circ. Res., November 9, 2007; 101(10): 1058 - 1067. [Abstract] [Full Text] [PDF]
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 M. E. Alnaeb, V. P. Crabtree, A. Boutin, D. P. Mikhailidis, A. M. Seifalian, and G. Hamilton Prospective Assessment of Lower-Extremity Peripheral Arterial Disease in Diabetic Patients Using a Novel Automated Optical Device Angiology, November 1, 2007; 58(5): 579 - 585. [Abstract] [PDF]
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 H. H.T. Saha, Y. K.J. Leskinen, J. P. Salenius, and J. T. Lahtela PERIPHERAL VASCULAR DISEASE IN DIABETIC PERITONEAL DIALYSIS PATIENTS Perit. Dial. Int., June 1, 2007; 27(Supplement_2): S210 - S214. [Abstract] [Full Text] [PDF]
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W. Post, L. F. Bielak, K. A. Ryan, Y.-C. Cheng, H. Shen, J. A. Rumberger, P. F. Sheedy II, A. R. Shuldiner, P. A. Peyser, and B. D. Mitchell Determinants of Coronary Artery and Aortic Calcification in the Old Order Amish Circulation, February 13, 2007; 115(6): 717 - 724. [Abstract] [Full Text] [PDF]
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 N. X. Chen, K. D. O'Neill, X. Chen, D. Duan, E. Wang, M. S. Sturek, J. M. Edwards, and S. M. Moe Fetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins Am J Physiol Renal Physiol, February 1, 2007; 292(2): F599 - F606. [Abstract] [Full Text] [PDF]
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 C. Bouvet, W. Peeters, S. Moreau, D. deBlois, and P. Moreau A new rat model of diabetic macrovascular complication Cardiovasc Res, February 1, 2007; 73(3): 504 - 511. [Abstract] [Full Text] [PDF]
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D. A. Towler Imaging Aortic Matrix Metabolism: Mirabile Visu! Circulation, January 23, 2007; 115(3): 297 - 299. [Full Text] [PDF]
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N. X. Chen, D. Duan, K. D. O'Neill, and S. M. Moe High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3435 - 3442. [Abstract] [Full Text] [PDF]
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A. L.M. de Francisco, C. Pinera, R. Palomar, and M. Arias Impact of Treatment with Calcimimetics on Hyperparathyroidism and Vascular Mineralization J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S281 - S285. [Abstract] [Full Text] [PDF]
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R. C. Johnson, J. A. Leopold, and J. Loscalzo Vascular Calcification: Pathobiological Mechanisms and Clinical Implications Circ. Res., November 10, 2006; 99(10): 1044 - 1059. [Abstract] [Full Text] [PDF]
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 T. Yoshimura, E. Suzuki, K. Egawa, Y. Nishio, H. Maegawa, S. Morikawa, T. Inubushi, A. Hisatomi, K. Fujimoto, and A. Kashiwagi Low Blood Flow Estimates in Lower-Leg Arteries Predict Cardiovascular Events in Japanese Patients With Type 2 Diabetes With Normal Ankle-Brachial Indexes Diabetes Care, August 1, 2006; 29(8): 1884 - 1890. [Abstract] [Full Text] [PDF]
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S. M. Moe and G. M. Chertow The Case against Calcium-Based Phosphate Binders Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 697 - 703. [Abstract] [Full Text] [PDF]
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J.-S. Shao, J. Cai, and D. A. Towler Molecular Mechanisms of Vascular Calcification: Lessons Learned From The Aorta Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1423 - 1430. [Abstract] [Full Text] [PDF]
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 A. H. E. M. Maas, Y. T. van der Schouw, D. Beijerinck, J. J. M. Deurenberg, W. P. T. M. Mali, and Y. van der Graaf Arterial Calcifications Seen on Mammograms: Cardiovascular Risk Factors, Pregnancy, and Lactation Radiology, July 1, 2006; 240(1): 33 - 38. [Abstract] [Full Text] [PDF]
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D. V. Anand, A. Lahiri, E. Lim, D. Hopkins, and R. Corder The Relationship Between Plasma Osteoprotegerin Levels and Coronary Artery Calcification in Uncomplicated Type 2 Diabetic Subjects J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1850 - 1857. [Abstract] [Full Text] [PDF]
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 A. Silvestro, N. Diehm, H. Savolainen, D.-D. Do, J. Vogele, F. Mahler, S. Zwicky, and I. Baumgartner Falsely high ankle-brachial index predicts major amputation in critical limb ischemia Vascular Medicine, May 1, 2006; 11(2): 69 - 74. [Abstract] [PDF]
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H. M.H. Spronk Vitamin K Epoxide Reductase Complex and Vascular Calcification: Is This the Important Link Between Vitamin K and the Arterial Vessel Wall? Circulation, March 28, 2006; 113(12): 1550 - 1552. [Full Text] [PDF]
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L. M. Rasmussen, L. Tarnow, T. K. Hansen, H.-H. Parving, and A. Flyvbjerg Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients Eur. J. Endocrinol., January 1, 2006; 154(1): 75 - 81. [Abstract] [Full Text] [PDF]
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H. Taniwaki, E. Ishimura, T. Tabata, Y. Tsujimoto, A. Shioi, T. Shoji, M. Inaba, T. Inoue, and Y. Nishizawa Aortic calcification in haemodialysis patients with diabetes mellitus Nephrol. Dial. Transplant., November 1, 2005; 20(11): 2472 - 2478. [Abstract] [Full Text] [PDF]
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 A K Nightingale and J D Horowitz Aortic sclerosis: not an innocent murmur but a marker of increased cardiovascular risk Heart, November 1, 2005; 91(11): 1389 - 1393. [Abstract] [Full Text] [PDF]
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W. Y. Qunibi Reducing the Burden of Cardiovascular Calcification in Patients with Chronic Kidney Disease J. Am. Soc. Nephrol., November 1, 2005; 16(11_suppl_2): S95 - S102. [Abstract] [Full Text] [PDF]
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V. Aboyans, P. Lacroix, A. Postil, J. Guilloux, F. Rolle, E. Cornu, and M. Laskar Subclinical Peripheral Arterial Disease and Incompressible Ankle Arteries Are Both Long-Term Prognostic Factors in Patients Undergoing Coronary Artery Bypass Grafting J. Am. Coll. Cardiol., September 6, 2005; 46(5): 815 - 820. [Abstract] [Full Text] [PDF]
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L. J. Schurgers, K. J.F. Teunissen, M. H.J. Knapen, M. Kwaijtaal, R. van Diest, A. Appels, C. P. Reutelingsperger, J. P.M. Cleutjens, and C. Vermeer Novel Conformation-Specific Antibodies Against Matrix {gamma}-Carboxyglutamic Acid (Gla) Protein: Undercarboxylated Matrix Gla Protein as Marker for Vascular Calcification Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1629 - 1633. [Abstract] [Full Text] [PDF]
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 P. Raggi, B. Cooil, C. Ratti, T. Q. Callister, and M. Budoff Progression of Coronary Artery Calcium and Occurrence of Myocardial Infarction in Patients With and Without Diabetes Mellitus Hypertension, July 1, 2005; 46(1): 238 - 243. [Abstract] [Full Text] [PDF]
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H. H. Dao, R. Essalihi, C. Bouvet, and P. Moreau Evolution and modulation of age-related medial elastocalcinosis: Impact on large artery stiffness and isolated systolic hypertension Cardiovasc Res, May 1, 2005; 66(2): 307 - 317. [Abstract] [Full Text] [PDF]
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C. M. Giachelli, M. Y. Speer, X. Li, R. M. Rajachar, and H. Yang Regulation of Vascular Calcification: Roles of Phosphate and Osteopontin Circ. Res., April 15, 2005; 96(7): 717 - 722. [Abstract] [Full Text] [PDF]
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D. A. Towler Inorganic Pyrophosphate: A Paracrine Regulator of Vascular Calcification and Smooth Muscle Phenotype Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 651 - 654. [Full Text] [PDF]
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 I del Rincon, R W Haas, S Pogosian, and A Escalante Lower limb arterial incompressibility and obstruction in rheumatoid arthritis Ann Rheum Dis, March 1, 2005; 64(3): 425 - 432. [Abstract] [Full Text] [PDF]
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P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]
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C. M. Giachelli Vascular Calcification Mechanisms J. Am. Soc. Nephrol., December 1, 2004; 15(12): 2959 - 2964. [Abstract] [Full Text] [PDF]
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J. W. Fischer, S. A. Steitz, P. Y. Johnson, A. Burke, F. Kolodgie, R. Virmani, C. Giachelli, and T. N. Wight Decorin Promotes Aortic Smooth Muscle Cell Calcification and Colocalizes to Calcified Regions in Human Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2391 - 2396. [Abstract] [Full Text] [PDF]
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M. Tsuchiya, E. Suzuki, K. Egawa, Y. Nishio, H. Maegawa, S. Inoue, K. Mitsunami, S. Morikawa, T. Inubushi, and A. Kashiwagi Stiffness and Impaired Blood Flow in Lower-Leg Arteries Are Associated With Severity of Coronary Artery Calcification Among Asymptomatic Type 2 Diabetic Patients Diabetes Care, October 1, 2004; 27(10): 2409 - 2415. [Abstract] [Full Text] [PDF]
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 T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]
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 M. Schoppet, N. Al-Fakhri, F. E. Franke, N. Katz, P. J. Barth, B. Maisch, K. T. Preissner, and L. C. Hofbauer Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-{kappa}B Ligand in Monckeberg's Sclerosis and Atherosclerosis J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4104 - 4112. [Abstract] [Full Text] [PDF]
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M. Abedin, Y. Tintut, and L. L. Demer Vascular Calcification: Mechanisms and Clinical Ramifications Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1161 - 1170. [Abstract] [Full Text] [PDF]
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T. Adragao, A. Pires, C. Lucas, R. Birne, L. Magalhaes, M. Goncalves, and A. P. Negrao A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1480 - 1488. [Abstract] [Full Text] [PDF]
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P. Raggi, L. J. Shaw, D. S. Berman, and T. Q. Callister Prognostic value of coronary artery calcium screening in subjects with and without diabetes J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1663 - 1669. [Abstract] [Full Text] [PDF]
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 R. Vattikuti and D. A. Towler Osteogenic regulation of vascular calcification: an early perspective Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E686 - E696. [Abstract] [Full Text] [PDF]
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 Z. Aherrahrou, S. B. Axtner, P. M. Kaczmarek, A. Jurat, S. Korff, L. C. Doehring, D. Weichenhan, H. A. Katus, and B. T. Ivandic A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice Am. J. Pathol., April 1, 2004; 164(4): 1379 - 1387. [Abstract] [Full Text] [PDF]
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 T. M. Doherty, L. A. Fitzpatrick, A. Shaheen, T. B. Rajavashisth, and R. C. Detrano Genetic Determinants of Arterial Calcification Associated With Atherosclerosis Mayo Clin. Proc., February 1, 2004; 79(2): 197 - 210. [Abstract] [PDF]
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 J.-S. Shao, S.-L. Cheng, N. Charlton-Kachigian, A. P. Loewy, and D. A. Towler Teriparatide (Human Parathyroid Hormone (1-34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., December 12, 2003; 278(50): 50195 - 50202. [Abstract] [Full Text] [PDF]
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S.-L. Cheng, J.-S. Shao, N. Charlton-Kachigian, A. P. Loewy, and D. A. Towler Msx2 Promotes Osteogenesis and Suppresses Adipogenic Differentiation of Multipotent Mesenchymal Progenitors J. Biol. Chem., November 14, 2003; 278(46): 45969 - 45977. [Abstract] [Full Text] [PDF]
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G. M. London, A. P. Guerin, S. J. Marchais, F. Metivier, B. Pannier, and H. Adda Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality Nephrol. Dial. Transplant., September 1, 2003; 18(9): 1731 - 1740. [Abstract] [Full Text] [PDF]
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C. M. Giachelli Vascular Calcification: In Vitro Evidence for the Role of Inorganic Phosphate J. Am. Soc. Nephrol., September 1, 2003; 14(90004): S300 - 304. [Abstract] [Full Text]
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M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. C. Hofbauer Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1024 - 1028. [Abstract] [Full Text] [PDF]
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S. A. Steitz, M. Y. Speer, M. D. McKee, L. Liaw, M. Almeida, H. Yang, and C. M. Giachelli Osteopontin Inhibits Mineral Deposition and Promotes Regression of Ectopic Calcification Am. J. Pathol., December 1, 2002; 161(6): 2035 - 2046. [Abstract] [Full Text] [PDF]
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M. Bidder, J.-S. Shao, N. Charlton-Kachigian, A. P. Loewy, C. F. Semenkovich, and D. A. Towler Osteopontin Transcription in Aortic Vascular Smooth Muscle Cells Is Controlled by Glucose-regulated Upstream Stimulatory Factor and Activator Protein-1 Activities J. Biol. Chem., November 8, 2002; 277(46): 44485 - 44496. [Abstract] [Full Text] [PDF]
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 M. Y. Speer, M. D. McKee, R. E. Guldberg, L. Liaw, H.-Y. Yang, E. Tung, G. Karsenty, and C. M. Giachelli Inactivation of the Osteopontin Gene Enhances Vascular Calcification of Matrix Gla Protein-deficient Mice: Evidence for Osteopontin as an Inducible Inhibitor of Vascular Calcification In Vivo J. Exp. Med., October 21, 2002; 196(8): 1047 - 1055. [Abstract] [Full Text] [PDF]
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J. B. Meigs, M. G. Larson, R. B. D'Agostino, D. Levy, M. E. Clouse, D. M. Nathan, P. W. F. Wilson, and C. J. O'Donnell Coronary Artery Calcification in Type 2 Diabetes and Insulin Resistance: The Framingham Offspring Study Diabetes Care, August 1, 2002; 25(8): 1313 - 1319. [Abstract] [Full Text] [PDF]
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C. Top, Z. Cankir, E. Silit, S. Yildirim, and M. Danaci Monckeberg's Sclerosis: An Unusual Presentation: A Case Report Angiology, July 1, 2002; 53(4): 483 - 486. [Abstract] [PDF]
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R. F. Redberg, P. Greenland, V. Fuster, K. Pyorala, S. N. Blair, A. R. Folsom, A. B. Newman, D. H. O'Leary, T. J. Orchard, B. Psaty, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group III: Risk Assessment in Persons With Diabetes Circulation, May 7, 2002; 105 (18): e144 - e152. [Full Text] [PDF]
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M. Hosoi, T. Sato, K. Yamagami, T. Hasegawa, T. Yamakita, M. Miyamoto, K. Yoshioka, T. Yamamoto, T. Ishii, S. Tanaka, et al. Impact of Diabetes on Coronary Stenosis and Coronary Artery Calcification Detected by Electron-Beam Computed Tomography in Symptomatic Patients Diabetes Care, April 1, 2002; 25(4): 696 - 701. [Abstract] [Full Text] [PDF]
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W. S. Browner, L.-Y. Lui, and S. R. Cummings Associations of Serum Osteoprotegerin Levels with Diabetes, Stroke, Bone Density, Fractures, and Mortality in Elderly Women J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 631 - 637. [Abstract] [Full Text]
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A Farzaneh-Far, D Proudfoot, C Shanahan, and P L Weissberg Vascular and valvar calcification: recent advances Heart, January 1, 2001; 85(1): 13 - 17. [Full Text]
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S.-M. Herrmann, C. Whatling, E. Brand, V. Nicaud, J. Gariepy, A. Simon, A. Evans, J.-B. Ruidavets, D. Arveiler, G. Luc, et al. Polymorphisms of the Human Matrix Gla Protein (MGP) Gene, Vascular Calcification, and Myocardial Infarction Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2386 - 2393. [Abstract] [Full Text] [PDF]
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C. M. Shanahan, N. R. B. Cary, J. R. Salisbury, D. Proudfoot, P. L. Weissberg, and M. E. Edmonds Medial Localization of Mineralization-Regulating Proteins in Association With Monckeberg’s Sclerosis : Evidence for Smooth Muscle Cell-Mediated Vascular Calcification Circulation, November 23, 1999; 100(21): 2168 - 2176. [Abstract] [Full Text] [PDF]
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S. D. Kanters, J.-D. Banga, R. P Stolk, and A. Algra Incidence and determinants of mortality and cardiovascular events in diabetes mellitus: a meta-analysis Vascular Medicine, May 1, 1999; 4(2): 67 - 75. [Abstract] [PDF]
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C. M. Giachelli Ectopic Calcification : Gathering Hard Facts about Soft Tissue Mineralization Am. J. Pathol., March 1, 1999; 154(3): 671 - 675. [Full Text] [PDF]
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D. A. Towler, M. Bidder, T. Latifi, T. Coleman, and C. F. Semenkovich Diet-induced Diabetes Activates an Osteogenic Gene Regulatory Program in the Aortas of Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., November 13, 1998; 273(46): 30427 - 30434. [Abstract] [Full Text] [PDF]
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