Lower Extremity Arterial Calcification Research Articles

Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Association between lower extremity arterial calcification and coronary arterial calcification in a population at increased risk of cardiovascular disease

IntroductionThere is conflicting evidence whether lower extremity arterial calcification coincides with coronary arterial calcification (CAC). The aims of this study were to investigate the associations between (1) femoral and crural...

Abstract 15138: Lower Extremity Arterial Calcification: Association With Walking Impairment in Patients With Peripheral Arterial Disease

Introduction: Increasing prevalence of arterial calcium in the lower extremities of patients with peripheral arterial disease (PAD) is associated with worsening clinical outcomes. Calcium burden can be detected in patients using standard imaging methods. However, quantitative evaluation of calcium burden in specific arteries of the leg in PAD patients is uncommon in the clinical setting, and the association between quantified levels of vessel-specific calcium burden and functional capacity in PAD remains understudied. We hypothesized that x-ray computed tomography (CT) imaging could quantify calcium mass of the superficial femoral (SFA) and popliteal artery and CT-derived measures of calcium burden would be associated with walking impairment scores. Methods: Healthy controls (n=8) and patients with PAD (n=44) underwent CT imaging of the legs. Calcium mass was quantified from CT images by manual segmentation of the combined SFA and popliteal artery from axial images, with established calcium defined as arterial segments with CT image intensities >130 Hounsfield units. To assess functional capacity, the Walking Impairment Questionnaire (WIQ) was administered at the time of imaging. Univariate and multivariate analyses were performed to assess the association between calcium measures and walking impairment scores. Results: WIQ scores for distance, speed, and stairs significantly differed between healthy controls and PAD patients (all scores, p<0.0001). Calcium mass values for the SFA-popliteal artery were significantly higher in PAD patients versus healthy controls (p=0.0005). In univariate analysis, WIQ scores for distance (p=0.004), speed (p<0.001), and stairs (p=0.002) were significantly associated with calcium mass of the SFA-popliteal artery. Associations between WIQ scores and SFA-popliteal artery calcium mass remained significant after adjusting for age and body mass index in multivariate analyses. Conclusions: These results suggest that calcium burden above the knee is significantly associated with walking impairment. Implementation of arterial calcium scoring for the lower extremities in PAD patients may provide novel insight into the relationships between calcium burden, PAD symptoms, and functional limitations.

Different Lower Extremity Arterial Calcification Patterns in Patients with Chronic Limb-Threatening Ischemia Compared with Asymptomatic Controls.

Objectives: The most severe type of peripheral arterial disease (PAD) is critical limb-threatening ischemia (CLI). In CLI, calcification of the vessel wall plays an important role in symptoms, amputation rate, and mortality. However, calcified arteries are also found in asymptomatic persons (non-PAD patients). We investigated whether the calcification pattern in CLI patients and non- PAD patients are different and could possibly explain the symptoms in CLI patients. Materials and Methods: 130 CLI and 204 non-PAD patients underwent a CT of the lower extremities. This resulted in 118 CLI patients (mean age 72 ± 12, 70.3% male) that were age-matched with 118 non-PAD patients (mean age 71 ± 11, 51.7% male). The characteristics severity, annularity, thickness, and continuity were assessed in the femoral and crural arteries and analyzed by binary multiple logistic regression. Results: Nearly all CLI patients have calcifications and these are equally frequent in the femoropopliteal (98.3%) and crural arteries (97.5%), while the non-PAD patients had in just 67% any calcifications with more calcifications in the femoropopliteal (70.3%) than in the crural arteries (55.9%, p < 0.005). The crural arteries of CLI patients had significantly more complete annular calcifications (OR 2.92, p = 0.001), while in non-PAD patients dot-like calcifications dominated. In CLI patients, the femoropopliteal arteries had more severe, irregular/patchy, and thick calcifications (OR 2.40, 3.27, 1.81, p ≤ 0.05, respectively) while in non-PAD patients, thin continuous calcifications prevailed. Conclusions: Compared with non-PAD patients, arteries of the lower extremities of CLI patients are more frequently and extensively calcified. Annular calcifications were found in the crural arteries of CLI patients while dot-like calcifications were mostly present in non-PAD patients. These different patterns of calcifications in CLI point at different etiology and can have prognostic and eventually therapeutic consequences.

Does Presence of Femoral Arterial Calcification Have an Effect on Postoperative Complication and Mortality in Patients With Hip Fracture?

IntroductionIn this study, we investigated the relationship between femoral arterial calcification on preoperative hip radiography and post-operative complications and all-time mortality rates in patients with hip fracture >65 years old.MethodsThis retrospective study was conducted by evaluating the records of patients who were operated for hip fractures. All patients were divided into two groups according to the presence of lower extremity arterial calcification (LEAC) at the femoral artery which was diagnosed using the hip radiograph. The patients with and without the presence of LEAC were assigned as groups 1 and 2, respectively. A multivariate Cox algorithm was applied to recognize whether this radiological factor is independently associated with survival.ResultsThe study included 530 patients (540 hips; 191 males and 339 females) with an average age of 80.8 ± 7.6 years. In the study after 24.8±19.9 months (range:0-65 months) follow-up period, 336 (63.3%) patients had expired. Conversely, 194 (36.7%) patients are surviving. Survival rates at one month and one year after surgery were 89.5% and 65.7%, respectively. 234 of 540 hips (230 patients) have LEAC on the femoral artery. The survival rate at one month, one year, and overall survival were significantly higher in patients with LEAC. The postoperative infection rate was also two times higher in patients with LEAC than without LEAC (p = 0.021). Multivariate analysis demonstrated that age, treatment modality (hemiarthroplasty), and the presence of femoral arterial calcification were independently associated with poor overall survival.ConclusionsIn our study, we found that the presence of femoral arterial calcification on the affected side of the hip identified on hip radiograph was independently associated with poor one month, one year, and overall survival as the patients had 1.5 times higher mortality rate. Additionally, a significant correlation was found between age and survival of patients with hip fracture, especially patients >80 years old.

Calcification of lower extremity arteries is related to the presence of osteoporosis in postmenopausal women with type 2 diabetes mellitus: a cross-sectional observational study

SummaryIt is unknown whether there is any relationship between extremity arterial macroangiopathy and osteoporosis in type 2 diabetic mellitus (T2DM) patients. We provide evidence to show the association between lower extremity arterial calcification and the presence of osteoporosis in postmenopausal T2DM women, but not in T2DM men of similar age.PurposeTo investigate the relationship between lower extremity arterial calcification and the presence of osteoporosis in type 2 diabetic mellitus (T2DM) patients.MethodsWe performed a retrospective cross-sectional study in patients with T2DM. They were assigned into two groups (patients with or without vascular calcification) in both sexes. Clinical characteristics, presence of osteoporosis, and bone metabolic markers were compared. Arterial calcification was determined by ultrasonography examination. Osteoporosis was defined based on the measurements from dual-energy X-ray absorptiometry. The relationship between the lower extremity arterial calcification and the presence of osteoporosis was analyzed. Statistical analysis was performed in SPSS 26.0.ResultsA total of 933 T2DM patients (535 men ≥ 50 years old, and 398 postmenopausal women) were identified and analyzed. A significant association between arterial calcification and osteoporosis was only observed in women, with a higher prevalence of osteoporosis observed in women with calcification (40.8%) than in women without calcification (26.9%) (P = 0.004). Compared to women without calcification, women with calcification had lower bone mineral densities in the hip (P < 0.001) and femoral neck (P < 0.001). Ordinal logistic regression analysis showed that women with calcification had a nearly 2-fold increased risk for osteoporosis, even after adjusting for age, duration of T2DM, body mass index, pulse pressure, clearance of creatinine, glycosylated hemoglobin, and fasting C-peptide. Similar differences were not identified between men with and without calcification.ConclusionCalcification of lower extremity arteries is related with the presence of osteoporosis in postmenopausal T2DM women.

Arterial calcification and long-term outcome in chronic limb-threatening ischemia patients

PurposeWithin five years after presentation 50–60% of patients with chronic limb-threatening ischemia (CLI) have died or had an amputation. We assessed the predictive value of lower extremity arterial calcification on computed tomography (CT) characteristics on both 7-years amputation-free survival and 10-years all-cause mortality in patients with CLI. MethodIncluded were 89 CLI patients (mean age 73.1 ± 11.6 years) who underwent a CT angiography of the lower extremities. In the femoropopliteal and crural arteries based on a CT score the following calcification characteristics were assessed: severity, annularity, thickness and continuity. The predictive value of different arterial calcification characteristics was analysed by age- and sex-adjusted multivariate Cox regression analysis. ResultsComplete annular calcifications were common (femoropopliteal 43.7%, n = 38; crural, 63.2%, n = 55). Mean survival was 278.4 weeks (95% CI 238.77–318.0 weeks). Patients with complete annular calcifications had a higher all-cause 10-year mortality (femoropopliteal unadjusted HR 1.64, p = 0.04 and adjusted for age and sex HR 1.68, p = 0.04; crural unadjusted HR 1.92, p = 0.02, adjusted for age and sex HR 2.29, p = 0.006) than patients with other calcification characteristics. ConclusionsAnnularity of calcification of both femoropopliteal and crural arteries is a predictor for 10-year all-cause survival, its hazard being even higher than the traditional prognostic risk factors for CLI and therefore could be involved in the poor survival of these patients.

Factors associated with sclerostin levels – A calcification inhibitor – In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BackgroundSclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. MethodsA total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. ResultsPlasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. ConclusionPlasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

The risk factors for calcification vary among the different sections of the lower extremity artery in patients with symptomatic peripheral arterial disease

BackgroundPeripheral arterial disease (PAD) is associated with considerable mortality and morbidity worldwide. The present study explored the risk factors for arterial calcification among the different sections of the lower extremity in patients with PAD and analyzed their correlations with the extent of arterial stenosis at the corresponding section.MethodsThis study enrolled symptomatic PAD patients from our hospital from March 2017 to March 2018. The lower extremity arterial calcification score (LEACS) and lower extremity arterial stenosis index (LEASI), representing the extent of arterial stenosis, were measured on computed tomography (CT) and the correlations between them were analyzed using Spearman’s correlation analysis. The relationships between risk factors and calcification were analyzed among the different sections of the lower extremity artery.ResultsIn total, 209 patients were included. The LEACSs of the total lower extremity, aortoiliac artery, and femoropopliteal and infrapopliteal arteries were correlated with the LEASI (all P < 0.05), but their correlation was relatively weak in the aortoiliac artery. Univariate analysis showed that hypertension was associated with the total (P = 0.019) and aortoiliac (P = 0.012) LEACSs. Diabetes was related to both femoropopliteal (P = 0.001) and infrapopliteal (P = 0.002) LEACSs. The infrapopliteal LEACS was higher in male patients (P = 0.011). After adjustment for age, the above relationships were maintained among the different sections, but not in the total lower extremity artery.ConclusionsThe LEACS is associated with the LEASI in all arterial sections, but that of the aortoiliac artery was relatively weak. Different factors have different effects on calcification among the various sections of the lower extremity artery.

Prevalence of Lower-Extremity Arterial Calcification in Patients with Diabetes Mellitus Complicated by Foot Disease at an Urban US Tertiary-Care Center.

We sought to determine the prevalence of lower-extremity arterial calcification in a cohort of patients with diabetes and associated foot pathology receiving inpatient treatment at an urban US tertiary health-care system. The primary outcome measure was defined as either radiographic evidence of vessel calcification or noninvasive vascular testing that resulted in any reporting of vessel noncompressibility or an ankle-brachial index greater than 1.1. Radiographic evidence of vessel calcification was defined as radiodense calcification in the proximal first intermetatarsal space (deep plantar perforating artery), anterior ankle (anterior tibial artery), or posterior ankle (posterior tibial artery) on dorsoplantar and lateral foot projections. Of the 367 individuals included in the study, 359 underwent radiography, with radiographic evidence of calcification in 192 (53.5%). Noninvasive vascular testing was performed on 265 participants, with any reporting of noncompressibility or an ankle-brachial index greater than 1.1 observed in 153 (57.7%). Ninety-four participants (25.6%) demonstrated evidence of arterial calcification on the radiographs and noninvasive testing, meaning that 251 participants (68.4%) demonstrated evidence of arterial calcification on at least one test, including 63.6% of participants classified as black/African American race, 65.4% as white race, and 78.3% as Hispanic/Latino ethnicity. The results of this investigation increase the body of knowledge with respect to the evaluation and treatment of diabetic foot disease and may lead to future investigations on the topic of lower-extremity arterial calcification.

Lower Extremity Arterial Calcification on Preoperative Knee Radiographs as a Predictor of Postoperative Cardiovascular Events After Primary Total Knee Arthroplasty

BackgroundA cross-sectional study of total knee arthroplasty (TKA) patients was conducted to determine the association of lower-extremity arterial calcification (LEAC) with acute perioperative cardiovascular events (CVEs). MethodsRegression modeling was used to examine the association of radiographic presence of LEAC and acute myocardial infarction (MI), perioperative CVE, 30-day CVE readmit, and 30-day and 1-year mortality. ResultsOf 900 TKA patients, LEAC was identified in 21.1%. Of LEAC cases, 1.6% had an acute MI vs 0.1% of non-LEAC cases (P = .031). Perioperative CVE rate was 5.8% for LEAC vs 1.5% for non-LEAC (P = .002). Having LEAC was identified as a significant risk factor for a perioperative CVE (odds ratio [OR] 2.83; 95% confidence interval [CI] 1.09-7.35). Because of limited number of acute MI events, absence of 30-day CVE readmit, 30-day mortality, and few 1-year mortality events, computing OR for these was not possible. Likewise, because of small number of events (n = 3), estimates for the odds of LEAC cases having an acute MI are less reliable, yielding extremely large random errors (OR 11.37; 95% CI 0.09-597.93) and must be interpreted with caution. The OR for 1-year mortality was 1.88 (95% CI 0.17-13.20), but again with large random errors. ConclusionOur study shows that LEAC around the knee is associated with an increased risk of having a perioperative CVE. Crude radiographic detection of LEAC around the knee has the potential to improve risk stratification for TKA patients by informing the surgeon of the need for further preoperative cardiac workup.

Association of plasma fetuin-a levels with peripheral arterial disease and lower extremity arterial calcification in subjects with type 2 diabetes mellitus

AimsFetuin-A is a hepatic glycoprotein that is involved in insulin resistance and atherosclerosis. Herein we examined the association of plasma fetuin-A levels with peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). Material and MethodsA total of 71 patients with T2DM and 57 non-diabetic individuals were recruited. Diagnosis of PAD was based on the absence of triphasic waveform at pedal arteries, while ankle–brachial index (ABI) was calculated. Radiographs of both feet and ankles were taken for the assessment of lower extremity arterial calcification (LEAC). Plasma fetuin-A levels were measured using ELISA. ResultsPatients with T2DM had higher fetuin-A levels than non-diabetic participants. Participants with diabetes and PAD had lower fetuin-A levels than non-PAD diabetic patients. In subjects with T2DM fetuin-A levels were associated with ABI. Multivariate analysis demonstrated that in patients with T2DM the odds of PAD increased with long diabetes duration, smoking, presence of arterial hypertension and dyslipidemia, as well as with lower fetuin-A levels. A trend towards higher fetuin-A levels in subjects with less severe LEAC was found. ConclusionPlasma fetuin-A levels are lower in patients with T2DM and PAD and are associated with PAD, irrespective of traditional cardiovascular risk factors. Moreover, fetuin-A may be involved in arterial calcification.

Lower Extremity Arterial Calcification as a Predictor of Coronary Atherosclerosis in Patients with Peripheral Arterial Disease.

BackgroundUntil now, there has been no study on the relationship between the calcification of the lower extremity arteries and significant coronary arterial disease (CAD).ObjectivesTo evaluate whether lower extremity calcium scores (LECS) are associated with CAD and whether this can predict multivessel-CAD in patients with peripheral arterial disease (PAD).Patients and MethodsWe retrospectively enrolled 103 PAD patients without cardiac symptoms or known CAD. All patients underwent cardiac computed tomography (CT) and lower extremity CT within 1 month and were categorized as nonsignificant CAD, single-CAD, or multivessel-CAD. The coronary calcium scores (CCS) were quantitatively measured according to the Agatston method and LECS were semi-quantitatively measured according to the presence of lower extremity calcification in the segment. The extent of CAD was evaluated according to the presence of ≥ 50% luminal diameter stenosis in the segment of CAD.ResultsLECS in multivessel-CAD were significantly higher than those in nonsignificant CAD (10.0 ± 5.8 versus 4.0 ± 3.1, P < 0.001). LECS significantly correlated with CCS (r = 0.831, P < 0.001) and the extent of CAD (r = 0.631, P < 0.001). Multivariate regression analysis demonstrated LECS and log-transformed CCS were independent predictors for multivessel-CAD. In receiver operating characteristic curve analysis, the diagnostic performance of LECS was 0.807 (95% confidence interval = 0.724-0.891, P < 0.001) for predicting multivessel-CAD.ConclusionPeripheral arterial calcification is significantly correlated with CAD extent in patients with PAD. Peripheral arterial calcification can be a useful marker for predicting multivessel-CAD.

Increased Peripheral Arterial Calcification in Patients Receiving Warfarin.

BackgroundMatrix Gla protein is a vitamin K–dependent inhibitor of vascular calcification. Warfarin use is associated with increased breast arterial calcification, but whether this is reflective of other arteries or occurs in men is unclear. In this study, the prevalence of calcification in peripheral arteries was compared in patients with and without warfarin therapy.Methods and ResultsThis retrospective matched cohort study assessed 430 patients with radiographs performed during or after warfarin therapy who were identified by a computerized search of medical records. Each patient was matched to a patient without warfarin exposure based on age, sex, and diabetes status. Patients with warfarin exposure <1 month, history of end‐stage renal disease, or serum creatinine >2.0 mg/dl were excluded. Radiographs were reviewed visually for arterial calcification. The prevalence of arterial calcification was 44% greater in patients with versus without warfarin use (30.2% versus 20.9%, P=0.0023) but not on radiographs performed before warfarin therapy (26.4% versus 22.4%, n=156) or prior to 5 years of warfarin therapy. The increase was noted only in the ankle and foot, was limited to a medial pattern of calcification, and was similar in men and women.ConclusionsWarfarin use is associated with lower extremity arterial calcification in both men and women independent of age, sex, diabetes status, and other patient characteristics. This may have implications for the choice of therapies for long‐term anticoagulation.

Association of Lower Extremity Arterial Calcification with Amputation and Mortality in Patients with Symptomatic Peripheral Artery Disease

ObjectiveThe clinical implication of the coronary artery calcium score (CS) is well demonstrated. However, little is known about the association between lower extremity arterial calcification and clinical outcomes.Methods and ResultsEighty-two patients with symptomatic peripheral artery disease (age 61.0±12.4 years) were followed for 21±11 months. CSs, ranging from the common iliac artery bifurcation to the ankle area, were analyzed through noncontrast multidetector computed tomography images retrospectively. The primary endpoints of this study were amputation and mortality. Old age, diabetes, hyperlipidemia, and end-stage renal disease were associated with higher CSs. Patients with more advanced Fontaine stages also tended to have significantly higher CSs (p = 0.03). During the follow-up period (21±11 months), 29 (35%) patients underwent amputation, and 24 (29%) patients died. Among the patients who underwent amputation, there were no significant differences in CSs between the amputated legs and the non-amputated legs. In the Cox proportional hazard model with CS divided into quartiles, patients with CS in the highest quartile had a 2.88-fold (95% confidence interval [CI] 1.18–12.72, p = 0.03) and a 5.16-fold (95% CI 1.13–21.61, p = 0.04) higher risk for amputation and all-cause mortality, respectively, than those with CS in the lowest quartile. These predictive effects remained after conventional risk factor adjustment.ConclusionLower extremity arterial CSs are associated with disease severity and outcomes, including amputation and all-cause mortality, in patients with symptomatic peripheral artery disease. However, the independent predictive value needs further investigation in large scale, prospective studies.

Tibial Artery Calcification Score Predicts Amputation Free Survival

Lower extremity arterial calcification has been shown to predict amputation risk better than traditional cardiovascular risk factors and the ankle brachial index. The purpose of this study was to determine whether the predictive ability of extremity arterial calcification on amputation free survival was independent of occlusive disease.

Lower-extremity arterial calcification as a correlate of coronary artery calcification

Coronary artery calcification (CAC) has been used as a testing modality for coronary atherosclerosis burden. In diabetes, arterial calcification in the tunica media is common and predicts renal and cardiovascular mortality. It is unknown whether the 2 calcification processes are related. We identified risk factors associated with lower-extremity arterial calcification (LEAC) and determined its relationship to the presence of CAC 6 years later and the incidence of complications in type 1 diabetes mellitus. A random sample of 190 participants from the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective cohort of childhood-onset type 1 diabetes mellitus, received radiographs of their ankles and feet at the 4-year follow-up examination (1990-1992) and was followed up for approximately 6 years. At the 10-year examination, 121 of these individuals received an electron beam tomography scan. Male sex (odds ratio [OR] = 12.72, P < .0001), diabetes duration (OR = 4.53, P < .0001), and autonomic neuropathy (AN; OR = 5.92, P = .007) independently increased the odds of LEAC. Controlling for other known risk factors (duration and high-density lipoprotein cholesterol), we found that LEAC correlated with the presence of CAC 6 years later (OR = 1.12, P = .03), although adjusting for neuropathy attenuated this relationship ( P = .08). LEAC also independently predicted AN but not the onset of other diabetes complications. Although arterial calcification in the lower extremities and the heart share many of the same risk factors, LEAC is an independent correlate of the later presence of CAC and AN. Thus, factors related to the calcification process in addition to vascular risk factors may play a role in determining the extent of CAC.