Matrix-GLA-Protein and Vascular Calcification: Can Diet Influence the Consequences of Matrix GLA Protein Inactivation? A Review

In vascular calcification, as a physiological process, intimal arterial calcification (IAC) associated with increased cardiovascular risk is distinguished from medial arterial calcification (MAC) localized mainly in the lamina elatica interna, which are not only based on different pathophysiological mechanisms. They also lead to different cardiovascular diseases. While intimal arterial calcification involves inflammation and lipid accumulation, a calcification process similar to desmal ossification plays the main role in medial arterial calcification. In this context, the phenotype change of smooth muscle cells from muscular type to synthesizing form in the tunica media is considered to be of great importance, which puts the matrix GLA protein, mainly involved in bone metabolism, in the center of interest. The present review work elucidates the molecular biological basis of interaction of matrix GLA protein subunits in the pathogenesis of vascular calcifications and the influence of diet on the consequences of underactivation of matrix GLA protein.

Evaluating the Impact of Medial Arterial Calcification on Outcomes of Infrageniculate Endovascular Interventions for Treatment of Diabetic Foot Ulcers

Background: Medial arterial calcification (MAC) of the tibial and pedal arteries has been associated with an increased risk of amputation among people with diabetes. Endovascular interventions on infrageniculate vessels are frequently performed with the intent of treating peripheral artery disease (PAD) and decreasing the risk of amputation in those with diabetes. This study aimed to investigate how the extent of MAC impacts outcomes of endovascular procedures in people with diabetic foot ulcers (DFU). Methods: We identified all patients who had undergone infrageniculate angioplasty in the setting of DFU at our institution between 2009 and 2019. Subjects were assigned a MAC score based on the severity of MAC in each vessel visualized on plain radiographs of the ankle and foot. We evaluated the relationship between MAC and the primary outcome, major adverse limb event (MALE), using stratified Cox proportional modeling. Results: Among 99 subjects with DFU who had undergone infrageniculate angioplasty, MALE occurred in 50% (95% confidence interval [CI] 38%-61%) of patients within 1 year of intervention. On univariate Cox regression analysis, each 1 point increment in MAC score (hazard ratio [HR], 1.09; 95% CI 1.01-1.18), the third tertile of MAC score (HR, 2.27; 95% CI 1.01-5.11), age (HR 0.96; 95% CI 0.93-0.99), and wound grade (HR, 5.34; 95% CI 2.17-13.14), were significantly associated with increased risk of MALE. On adjusted analysis stratified by wound grade, MAC score was found to be associated with MALE only in patients with a low wound grade. Conclusion: Increased severity of MAC is associated with increased risk of MALE for subjects undergoing infrageniculate angioplasty with a low wound grade. Further research is needed to better understand the complex relationships of MAC, PAD, DFU, and interventions aimed at promoting healing of DFU.

Association of infrapopliteal medial arterial calcification with lower-limb amputations in high-risk patients: A systematic review and meta-analysis

Medial arterial calcification (MAC) is a known risk factor for cardiovascular morbidity. The association between vascular calcifications and poor outcome in several vascular districts suggest that infrapopliteal MAC could be a risk factor for lower-limb amputation (LLA). This study’s objective is to review the available literature focusing on the association between infrapopliteal MAC and LLA in high-risk patients. The PubMed and Embase databases were systematically searched. We selected original studies reporting the association between infrapopliteal MAC and LLAs in patients with diabetes and/or peripheral artery disease (PAD). Estimates were pooled using either a fixed-effects or a random-effects model meta-analysis. Heterogeneity was evaluated using the Q and I2 statistics. Publication bias was investigated with a funnel plot and Egger test. The trim-and-fill method was designed to estimate the possibly missing studies. Influence analysis was conducted to search studies influencing the final result. Test of moderators was used to compare estimates in good versus non-good-quality studies. Fifteen articles satisfied the selection criteria ( n = 6489; median follow-up: 36 months). MAC was significantly associated with LLAs (pooled adjusted risk ratio (RR): 2.27; 95% CI: 1.89–2.74; I2 = 25.3%, Q-test: p = 0.17). This association was kept in the subgroup of patients with diabetes (RR: 2.37; 95% CI: 1.76–3.20) and patients with PAD (RR: 2.48; 95% CI: 1.72–3.58). The association was maintained if considering as outcome only major amputations (RR: 2.11; 95% CI: 1.46–3.06). Our results show that infrapopliteal MAC is associated with LLAs, thus suggesting MAC as a possible new marker of the at-risk limb.

Assessment of Diabetic Foot through the Developmental Stages of Lower Limb Abnormalities Using Ultrasound

A diabetic foot is one of the most serious complications of diabetes mellitus. This causes large number of lower leg amputations worldwide. Usually this disease is getting diagnosed in a very later stage. Ankle-arm index, diastolic blood pressure, fasting plasma glucose, hemoglobin A1C, high blood pressure, medial arterial calcification, nerve conduction velocity, peripheral vascular disease, systolic blood pressure, transcutaneous oxygen tension, etc. are some of the major indicators of a diabetic foot. Among these peripheral arterial abnormalities and neuropathy are the most dominant visible factors. Detection and monitoring of diabetic foot help to demonstrate the feet at risk of ulceration positively. This study reveals the various assessment methodologies of lower limb abnormalities leading to diabetic foot using ultrasound. Ultrasound is being used in various cases related to diabetic foot, from the identification of systolic pressure for the ankle brachial pressure index to the velocity analysis of hemodynamic studies. The study analyses the lower limb abnormalities and extracts the features of diabetic foot from the velocity spectrum of ultrasound Doppler scan.

Abstract 13571: Association Between Pre-kidney Transplantation Medial Arterial Calcification Andpost-transplant Visit-to-visit Blood Pressure Variability: A Propensity Score Matching Analysis

Introduction: Arterial calcification is associated with vascular stiffness, which manifests with visit-to-visit blood pressure variability (VVBPV). Although media arterial calcification (MAC) is significantly associated with poor cardiovascular outcomes in kidney patients, the association in kidney transplant (KT) patients is unknown. Hypothesis: We hypothesize that MAC is associated with VVBPV in long-tern post-KT. Methods: Since MAC, which is detected from mammogram (MG) and determined by linear calcified breast arteries, is exclusively medial, female KT patients with ≥1 MG during pre-KT period were included in this study. VVBPV was examined by average successive variability (ASV), which is the average absolute difference between successive BP measured at 4, 12, 24, 36, and 48 weeks post-KT. After balancing patients with and without MAC by using propensity score matching based on age, diabetes, and obesity status, the association between MAC and systolic and diastolic VVBPV (VVSBPV and VVDBPV) at 48 weeks post-KT was tested by multiple linear regression (Figure1A&1B). Results: Of 51 patients, mean age±SD is 54±12 years, 21 had diabetes, and 21 were obese. Mean duration of follow-up was 47±9 years. Among 20 patients with MAC, mean VVSBPV was 20±14 mmHg; whereas, VVSBPV in non-MG group was 14±8 mmHg (mean difference -6± 3.0, p 0.06, 95%CI -12.03, 0.15). Mean VVDBPV in MG and non-MG groups were 12±5 and 11±5.6 mmHg, respectively (mean difference -1±1.6, p 0.41, 95%CI -4.44, 1.86). Laboratory-related bone and mineral metabolism were not different between both groups. On average, MG group had 8 mmHg higher VVSBPV compared to non-MG group (Coef. 3.62, p 0.02, 95%CI 1.16, 15.34). The MG group remained having higher VVDBPV but the magnitude of the association decreased and no statistical significance (Coef. 0.58, p 0.83, 95%CI -4.58, 5.73). Conclusions: Similar to non-transplant patients, KT recipients with pre-KT MAC had significant higher VVSBPV at the late post-KT.

A Novel Scoring System for Small Artery Disease and Medial Arterial Calcification Is Strongly Associated With Major Adverse Limb Events in Patients With Chronic Limb-Threatening Ischemia

Purpose: To evaluate the roles of small artery disease (SAD) and medial arterial calcification (MAC) in patients with chronic limb-threatening ischemia (CLTI) and to identify any correlation between these factors and peripheral artery disease (PAD) or outcomes after treatment. Materials and Methods: A retrospective review was conducted of 259 limbs with tissue loss among 223 CLTI patients (mean age 72.2±11.4 years; 194 men) having an angiographic foot vessel study, foot radiography, and at least 6 months of follow-up after intervention. SAD and MAC were quantified using a 3-level score (0=absent, 1=moderate, 2=severe) based on angiography for SAD and foot radiographs for MAC. The MAC score was validated and compared with the SAD score, evaluating their associations with PAD distribution and clinical outcomes. Results: Based on the MAC score, the 259 limbs were classified as 55 group 0 (21.2%), 89 group 1 (34.4%), and 115 group 2 (44.4%). The SAD score stratified the 259 limbs as 67 group 0 (25.9%), 76 group 1 (29.3%), and 116 group 2 (44.8%). Interobserver reproducibility of the MAC score was high (correlation coefficient 0.96). Sensitivity and specificity of the MAC score in detecting SAD was 100% and 98.1%, respectively, in SAD groups 0 and 2 vs 99.1% and 92.7%, respectively, for SAD group 1. PAD was more proximal in MAC and SAD groups 0 and more distal in groups 1 and 2. Both MAC and SAD scores were able to predict clinical endpoints. Multivariable analysis demonstrated that the MAC score represents an independent risk factor for adverse limb events. Conclusion: SAD and MAC must be considered expressions of the same obstructing disease, able to adversely impact the fate of CLTI patients. SAD and MAC scores are powerful prognostic indicators of major adverse limb events in CLTI patients.