Toward Ultrasound Molecular Imaging of Endothelial Dysfunction in Diabetes: Targets, Strategies, and Challenges.

Diabetes vasculopathy is a significant complication of diabetes mellitus (DM), and early identification and timely intervention can effectively slow the progression. Accumulating studies have shown that diabetes causes vascular complications directly or indirectly through a variety of mechanisms. Direct imaging of the endothelial molecular changes not only identifies the early stage of diabetes vasculopathy but also sheds light on the precise treatment. Targeted ultrasound contrast agent (UCA)-based ultrasound molecular imaging (UMI) can noninvasively detect the expression status of molecular biomarkers overexpressed in the vasculature, thereby being a potential strategy for the diagnosis and treatment response evaluation of DM. Amounts of efforts have been focused on identification of the molecular targets expressed in the vasculature, manufacturing strategies of the targeted UCA, and the clinical translation for the diagnosis and evaluation of therapeutic efficacy in both micro- and macrovasculopathy in DM. This review summarizes the latest research progress on endothelium-targeted UCA and discusses their promising future and challenges in diabetes vasculopathy theranostics.

Diabetic microvascular complications are associated with left atrial structural alterations in asymptomatic type 2 diabetes patients: A cross-sectional study.

AIMS: We used 4D-Auto LAQ to quantitatively evaluate the morphological and functional changes of left atrium in patients with asymptomatic type 2 diabetes mellitus (T2DM), and explored its correlations with diabetic microvascular complications (MICRO). METHODS: This study included 319 patients with asymptomatic T2DM. According to the occurrence of MICRO, these patients were divided into 3 groups: patients with no complication, 1 complication, and 2-3 complications. 4D-Auto LAQ was used to evaluate left atrial volume (LAVImin, LAVImax, LAVIpre) and calculate the left atrial function (DEI, PEI, AEI) in different phases. Multiple linear regression was used to analyze the correlation between changes in left atrial volume and function and the number of MICROs in DM patients. RESULTS: A total of 279 patients with asymptomatic T2DM were included in this study. (1) The ultrasound data of the three T2DM groups showed that there was no significant difference in left ventricular size and function among the three groups; (2) with the increase of MICRO number, the left atrial volume (LAVImin, LAVImax, LAVIpre) progressively increased, the left atrial storage function index (DEI) gradually decreased, and the differences were significant (P < 0.05). (3) Multiple linear regression analysis showed that: with the increase of MICRO number (no complication→1 complication→2-3 complications), the left atrial volume (LAVImin, LAVIpre) showed an increasing trend (both P < 0.05). CONCLUSION: In asymptomatic T2DM patients, MICRO number showed a significant positive correlation with LAVImin and LAVIpre (P < 0.05). Therefore, the increase in left atrial volume can dynamically reflect the severity of microvascular lesions in patients with asymptomatic T2DM.

Clinical significance and influencing factors of carotid pulse wave velocity in patients with diabetic microangiopathy.

PURPOSE: To evaluate the utility of carotid ultrafast pulse wave velocity (PWV) and explore its influencing factors in patients with type 2 diabetes mellitus (T2DM) microangiopathy. METHODS: Seventy-seven patients with T2DM were divided into two groups according to the absence (Group A, n = 45) or presence (Group B, n = 32) of microangiopathy. The control group comprised 1544 healthy volunteers. Two-dimensional ultrasonography was used to measure intima-media thickness (IMT) of the carotid arteries, and ultrafast ultrasound imaging was used to measure PWV of the carotid arteries at the beginning of systole (PWV-BS) and the end of systole (PWV-ES). RESULTS: The IMT, PWV-BS, and PWV-ES were higher in the T2DM group than in the control group, and the values in T2DM Group B were higher than those in Group A. IMT was positively correlated with PWV-BS and PWV-ES. Age and uric acid were influencing factors of PWV-ES, while age, uric acid, body mass index, glycated hemoglobin, and urine albumin/creatinine ratio were influencing factors of PWV-BS. PWV-ES was a more sensitive predictor than PWV-BS, and a PWV-ES critical value predicted carotid elasticity in patients with T2DM microangiopathy. CONCLUSION: Ultrafast PWV can reflect early atherosclerosis and provide a noninvasive assessment of microangiopathy in patients with T2DM.

Assessment of Tissue Viability Following Amputation Surgery Using Near-Infrared Fluorescence Imaging With Indocyanine Green.

BACKGROUND: Patients with chronic limb threatening ischemia have a risk of undergoing a major amputation within 1 year of nearly 30% with a substantial risk of re-amputation since wound healing is often impaired. Quantitative assessment of regional tissue viability following amputation surgery can identify patients at risk for impaired wound healing. In quantification of regional tissue perfusion, near-infrared (NIR) fluorescence imaging using Indocyanine Green (ICG) seems promising. METHODS: This pilot study included adult patients undergoing lower extremity amputation surgery due to peripheral artery disease or diabetes mellitus. ICG NIR fluorescence imaging was performed within 5 days following amputation surgery using the Quest Spectrum PlatformⓇ. Following intravenous administration of ICG, the NIR fluorescence intensity of the amputation wound was recorded for 10 minutes. The NIR fluorescence intensity videos were analyzed and if a fluorescence deficit was observed, this region was marked as "low fluorescence." All other regions were marked as "normal fluorescence." RESULTS: Successful ICG NIR fluorescence imaging was performed in 10 patients undergoing a total of 15 amputations. No "low fluorescence" regions were observed in 11 out of 15 amputation wounds. In 10 out of these 11 amputations, no wound healing problems occurred during follow-up. Regions with "low fluorescence" were observed in 4 amputation wounds. Impaired wound healing corresponding to these regions was observed in all wounds and a re-amputation was necessary in 3 out of 4. When observing time-related parameters, regions with low fluorescence had a significantly longer time to maximum intensity (113 seconds vs. 32 seconds, P = 0.003) and a significantly lesser decline in outflow after five minutes (80.3% vs. 57.0%, P = 0.003). CONCLUSIONS: ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Quantitative assessment of regional perfusion remains challenging due toinfluencing factors on the NIR fluorescence intensity signal, including camera angle, camera distance and ICG dosage. This was also observed in this study, contributing to a large variety in fluorescence intensity parameters among patients. To provide surgeons with reliable NIR fluorescence cut-off values for prediction of wound healing, prospective studies on the intra-operative use of this technique are required. The potential prediction of wound healing using ICG NIR fluorescence imaging will have a huge impact on patient mortality, morbidity as well as the burden of amputation surgery on health care.

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes.

BACKGROUND: Prospective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. METHODS: In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. RESULTS: In patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. CONCLUSION: With the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. TRIAL REGISTRATION: Trial registration number: NCT02383238 Date of registration: March 9, 2015.

Relationship of musculoskeletal diseases with microvascular and macrovascular complications in patients with diabetes in Iran.

BACKGROUND AND AIMS: Musculoskeletal manifestations (carpal tunnel syndrome, Dupuytren's contracture, etc.) may occur in poorly controlled and longstanding diabetes. In this study, we evaluated the relationship of musculoskeletal diseases with microvascular and macrovascular complicationsin patients with diabetes. METHODS: A total of 600 patients with diabetes were enrolled in this cross-sectional study. Demographic data and historical records of the patients were retrieved. Musculoskeletal diseases were assessed by clinical examinations and then confirmed by a rheumatologist. RESULTS: Out of the 600 patients with diabetes, 61.5% (369/600) were female and 38.5% (231/600) were male. Diabetic retinopathy, diabetic nephropathy, diabetic peripheral neuropathy, CVA, and diabetes related ischemic heart disease were rated as 43.1%, 33.2%, 7.8%, 7.5%, and 39.6%, respectively. Significant gender differences were observed in the rates of diabetic nephropathy [56.28% for women and 43.71% for men (p value < 0.000)], diabetic peripheral neuropathy [72.34% for women and 27.65% for men (p value < 0.002)], and ischemic heart disease [57.98% for women and 42.01% for men(p value < 0.001)]. CONCLUSION: Musculoskeletal diseases usually occur in patients with poorly controlled and long-term diabetes. Due to the clear association of microvascular complications with musculoskeletal disease, more attention should be paid to the early detection of these complications in patients with diabetes.

Assessment of toe brachial index validity in diabetic patients - interim results.

INTRODUCTION: The toe brachial index (TBI) is recommended for the detection of lower extremity arterial disease (LEAD) in case of reduced efficacy of the ankle brachial index (ABI), which most often occurs in diabetics. In this case, TBI is expected to give more accurate results. There are not many studies dealing with the use of TBI specifically in diabetics and the results are different. OBJECTIVE: The purpose of this work is to present the interim results of the study, whose main objective is to assess the validity of TBI in diabetics and to determine whether this method provides improvements over the ABI. METHODS: In the first phase of the study, 42 limbs were examined in 21 patients with type 2 diabetes. ABI was measured using the automatic oscillometric method (ABI OSC) and the manual method using the pencil doppler (ABI DPP). TBI was determined using an automatic plethysmographic method. The reference examination of the arteries of the lower limbs was performed using duplex ultrasonography (DUS). A paired t-test was used to compare the individual TBI and ABI methods. Cut-off points ABI < 0.9; TBI < 0.7; and DUS stenosis > 50 % were used to evaluate validity parameters. RESULTS: The individual ABI and TBI methods gave different results (p < 0.05). In eight limbs of the total number, LEAD was demonstrated using DUS. The best validity parameters were demonstrated by the TBI - sensitivity 0.88; specificity 0.88; positive predictive value 0.64; negative predictive value 0.97, positive likelihood ratio 7.44; negative likelihood ratio 0.14. The ABI method of calculation, that uses lower systolic blood pressure determined from two measurement sites on the ankle as a numerator, had a higher validity parameters. The ABI OSC did not correctly detect a single limb with stenosis > 50 % in this cohort. CONCLUSION: According to the interim results of this work, the TBI was more suitable for the detection of LEAD in diabetics in comparison with ABI.

Deteriorated regional calf microcirculation measured by contrast-free MRI in patients with diabetes mellitus and relation with physical activity.

OBJECTIVE: To evaluate regional calf muscle microcirculation in people with diabetes mellitus (DM) with and without foot ulcers, compared to healthy control people without DM, using contrast-free magnetic resonance imaging methods. METHODS: Three groups of subjects were recruited: non-DM controls, DM, and DM with foot ulcers (DM + ulcer), all with ankle brachial index (ABI) > 0.9. Skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in calf muscle were measured at rest and during a 5-min isometric ankle plantarflexion exercise. Subjects completed the Yale physical activity survey. RESULTS: The exercise SMBF (ml/min/100 g) of the medial gastrocnemius muscle were progressively impaired: 63.7 ± 18.9 for controls, 42.9 ± 6.7 for DM, and 36.2 ± 6.2 for DM + ulcer, p < 0.001. Corresponding exercise SMOEF was the lowest in DM + ulcers (0.48 ± 0.09). Exercise SMBF in the soleus muscle was correlated moderately with the Yale physical activity survey (r = 0.39, p < 0.01). CONCLUSIONS: Contrast-free MR imaging identified progressively impaired regional microcirculation in medial gastrocnemius muscles of people with DM with and without foot ulcers. Exercise SMBF in the medial gastrocnemius muscle was the most sensitive index and was associated with HbA1c. Lower exercise SMBF in the soleus muscle was associated with lower Yale score.

Diabetic microvascular complications are associated with reduced global longitudinal strain independent of atherosclerotic coronary artery disease in asymptomatic patients with diabetes mellitus: a cross-sectional study.

BACKGROUND: Reduced left ventricular function, assessed by global longitudinal strain (GLS), is sometimes observed in asymptomatic patients with diabetes mellitus (DM) and is often present in patients with diabetes-related microvascular complications. Our aim was to assess the association between microvascular complications, coronary artery plaque burden (PB) and GLS in asymptomatic patients with DM and non-obstructive coronary artery disease (CAD). METHODS: This cross-sectional study included patients with DM without any history, symptoms or objective evidence of obstructive CAD. All patients were identified in the outpatient Clinic of Endocrinology at Odense University Hospital Svendborg. An echocardiography and a coronary computed tomography angiography were performed to assess GLS and the degree of CAD, respectively. A coronary artery stenosis < 50% was considered non-obstructive. A linear regression model was used to evaluate the impact of potential confounders on GLS with adjustment of body mass index (BMI), mean arterial pressure (MAP), microvascular complications, type of diabetes, tissue Doppler average early diastolic mitral annulus velocity (e') and PB. RESULTS: Two hundred and twenty-two patients were included, of whom 172 (77%) had type 2 DM and 50 (23%) had type 1 diabetes. One hundred and eleven (50%) patients had microvascular complications. GLS decreased as the burden of microvascular complications increased (P-trend = 0.01): no microvascular complications, GLS (- 16.4 ± 2.5%), 1 microvascular complication (- 16.0 ± 2.5%) and 2-3 microvascular complications (- 14.9 ± 2.8%). The reduction in GLS remained significant after multivariable adjustment (ß 0.50 [95% CI 0.11-0.88], p = 0.01). BMI (ß 0.12 [95% CI 0.05-0.19]) and MAP (ß 0.05 [95% CI 0.01-0.08]) were associated with reduced GLS. In addition, an increased number of microvascular complications was associated with increased PB (ß 2.97 [95% CI 0.42-5.51], p = 0.02) in a univariable linear regression model, whereas there was no significant association between PB and GLS. CONCLUSIONS: The burden of microvascular complications was associated with reduced GLS independent of other cardiovascular risk factors in asymptomatic patients with DM and non-obstructive CAD. In addition, the burden of microvascular complications was associated with increasing PB, whereas PB was not associated with GLS.

The Global Anatomic Staging System Does Not Predict Limb Based Patency of Tibial Endovascular Interventions.

OBJECTIVE: Anatomic grading systems have historically been poor predictors of patency after endovascular tibial interventions. The Global Vascular Guidelines proposed a new Global Anatomic Staging System (GLASS) to estimate one-year limb-based patency (LBP). The purpose of this study was to determine the association of GLASS with LBP following endovascular tibial interventions. METHODS: We included all patients presenting to our multidisciplinary diabetic limb preservation service between 01/2012 and 8/2020 who underwent first-time endovascular tibial revascularization for chronic limb-threatening ischemia. Diagnostic angiograms were reviewed to define the preferred target artery pathway and assign a GLASS stage to each treated limb. One-year LBP was calculated and compared across GLASS stages using Kaplan-Meier curves with log-rank tests and Cox proportional hazards models. RESULTS: We performed tibial revascularization in 96 limbs (5.2% rest pain, 56.3% ulcer, 37.5% gangrene), including isolated tibial interventions in 61.5% and tibial + femoropopliteal interventions in 38.5%. 15.6% of limbs were GLASS stage 1, 28.1% were GLASS stage 2, and 56.3% were GLASS stage 3. Overall, one-year LBP was 43.2 ± 6.3%, and did not differ significantly across GLASS stages (P = 0.42). The hazard ratio for failed LBP was 1.94 (95% CI 0.70-5.41) for GLASS stage 2 and 1.49 (95% CI 0.56-3.94) for GLASS stage 3 limbs (versus GLASS stage 1). When analyzed excluding the calcium modifier, LBP remained similar across GLASS stages (P = 0.72). Major amputation was uncommon, occurring in 9.3 ± 3.4% of limbs at one year, and did not significantly differ by GLASS stage (P = 0.98). CONCLUSION: The Global Anatomic Staging System did not predict limb-based patency following tibial endovascular interventions. Given the low major amputation rates in this cohort, anatomic complexity should not preclude endovascular limb salvage efforts below the knee.

Endovascular Treatment for Critical Limb Ischemia in Type II Diabetes Mellitus Involving Femoropopliteal and Infrapopliteal Segments: Revascularization Strategy.

PURPOSE: To determine if further endovascular infrapopliteal angioplasty in combination with femoropopliteal revascularization improves the clinical outcomes regarding major amputation rate, rate of secondary interventions, and mortality in diabetic type-II patients presented with critical lower limb ischemia (CLI). PATIENTS AND METHODS: This is a retrospective study in which all type-II diabetic patients with CLI at King Abdullah University Hospital between October 2015 and September 2019 were identified. Patients with concomitant femoropopliteal and infrapopliteal vessels atherosclerotic lesions (total occlusion or more than 50% stenosis) who received successful endovascular treatment were included. Patients were divided into 2 groups. Group-I included patients treated for femoropopliteal segment alone, while Group-II included patients treated for both femoropopliteal and infrapopliteal segments. The outcomes of the two groups were compared regarding major amputation rate, rate of secondary interventions, and mortality. In addition, demographic data, atherosclerotic lesions distributions and cardiovascular risk factors were also collected and analyzed. RESULTS: In all, 90 patients (65 males and 25 females) with a mean age of 67.5±12 years were included. In Group-I; 44 patients (48.9%) were included (36 males and 8 females) with a mean age of 67±12 years. In group-II; 46 patients (51.1%) were included (29 males and 17 females) with a mean age of 68±13 years. The major amputation rate was higher and statistically significant in Group-I (38.6% vs 17.4%, p-value = 0.034). However, the secondary interventions and the mortality rates showed no statistically significant differences (56.8% vs 39.1%, p-value = 0.139) and (22.7% vs 28.3%, p-value = 0.632), respectively. CONCLUSION: Endovascular infrapopliteal angioplasty in combination with femoropopliteal revascularization in diabetic type-II patients with CLI improves the clinical outcome regarding major amputation rate. However, there were no significant differences regarding the rate of secondary interventions and the mortality rate.

Lack of evidence of the correlation between plasma Asymmetrical Dimethylarginine correlation and IMT in type 2 diabetic patients with chronic vascular complication.

INTRODUCTION: Patients with type 2 diabetes represent 50% of all sudden cardiac deaths. Disseminated arteriosclerotic lesions are the cause of vascular incidents that cause permanent disability resulting from lower limb amputations. OBJECTIVES: Our study was designed to investigate the relationship between asymmetrical dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) plasma concentration and intima-media thickness (IMT) in subjects with diabetes mellitus without vascular complications (group A) and a group of diabetic patients diagnosed with diabetes micro- and macroangiopathy (group B). PATIENTS AND METHOD: The experimental groups included 42 diabetic patients. Group A - 22 patients (9 W and 13 M), free from vascular complications (mean age 55.83±7.37 years), group B - 20 patients (6 W, 14 M) with accompanying micro- and macropathic changes (mean age 63.80±8.79 years). Group C (n=22), the control group, consisted of healthy volunteers (12 W and 10 M), between the ages of 40 to 60 (mean age 51.16±6.39), selected in reference to the age and sex of the research group. The carotid artery intima-media complex thickness (IMT) was evaluated with the use of a duplex ultrasound. CONCLUSIONS: There was no correlation between ADMA and the maximal or mean intima-media thickness (IMT) of the common carotid artery (CCA) and internal carotid artery (ICA). We demonstrated a correlation between symmetric dimethylarginine (SDMA) concentration and CCA IMT. The results suggest that ICA IMT may serve as a marker of vascular complication among patients with diabetes.

Determinants of 18F-NaF uptake in femoral arteries in patients with type 2 diabetes mellitus.

BACKGROUND: The goal of this study was to investigate the potential determinants of 18F-NaF uptake in femoral arteries as a marker of arterial calcification in patients with type 2 diabetes and a history of arterial disease. METHODS AND RESULTS: The study consisted of participants of a randomized controlled trial to investigate the effect of vitamin K2 (NCT02839044). In this prespecified analysis, subjects with type 2 diabetes and known arterial disease underwent full body 18F-NaF PET/CT. Target-to-background ratio (TBR) was calculated by dividing the mean SUVmax from both superficial femoral arteries by the SUVmean in the superior vena cava (SVC) and calcium mass was measured on CT. The association between 18F-NaF TBR and cardiovascular risk factors was investigated using uni- and multivariate linear regression corrected for age and sex. In total, 68 patients (mean age: 69 ± 8 years; male: 52) underwent 18F-NaF PET/CT. Higher CT calcium mass, total cholesterol, and HbA1c were associated with higher 18F-NaF TBR after adjusting. CONCLUSION: This study shows that several modifiable cardiovascular risk factors (total cholesterol, triglycerides, HbA1c) are associated with femoral 18F-NaF tracer uptake in patients with type 2 diabetes.

Functional capacity and left ventricular diastolic function in patients with type 2 diabetes.

AIMS: The study sought to evaluate cardiorespiratory fitness in patients with type 2 diabetes mellitus (DM) with different levels of left ventricular (LV) diastolic dysfunction (LVDD). METHODS: This investigation included 55 controls and 85 uncomplicated diabetic patients, who underwent laboratory analysis, echocardiographic evaluation and cardiopulmonary exercise testing. All DM subjects were separated into 3 groups using the level of LV diastolic function as main criterion: normal, intermediate and LVDD. RESULTS: Echocardiographic parameters of LV hypertrophy were significantly higher in DM subjects, particularly those with intermediate LV diastolic function and LVDD comparing with controls. The same is valid for parameters of LV diastolic function (E/e', left atrial volume index and tricuspid regurgitation velocity). Peak oxygen uptake was lower, whereas ventilation/carbon dioxide slope was higher, in DM subjects with intermediate LV diastolic function and LVDD in comparison to controls. In the whole study population HbA1c, LV mass index and mitral E/e' were independently related with peak oxygen uptake and ventilation/carbon dioxide slope. CONCLUSIONS: LVDD significantly impacted functional capacity in DM patients. Glycemic control, LV mass index and LVDD were independently related with peak oxygen consumption and ventilation/carbon dioxide slope in the study population. These results show that timely diagnosis of LVDD and more intensive antidiabetic treatment could prevent target organ damage in DM patients.

An Extension of the Bollinger Scoring System to Analyse the Distribution of Macrovascular Disease of the Lower Limb in Diabetes.

OBJECTIVE: While it is generally considered that patients with diabetes mellitus (DM) have more distal peripheral arterial disease (PAD), there is little information on how individual vessels are affected. The aim of this study was to adapt Bollinger's scoring system for lower limb angiograms (DSAs) to include the distal and planter vessels. The reliability of this extension was tested and was used to compare the distribution of disease in two cohorts of patients with and without DM. METHODS: Patients who had undergone DSA ± angioplasty for PAD at a single centre between September 2010 and April 2014 were identified. Twenty-five patients' images were reviewed by four clinicians and scored using an extended version of the Bollinger score. A total of 153 patients with DM were matched, for age, sex, ethnicity, smoking, and hypertension, with 153 patients without DM. The infrainguinal vessels were divided into 16 arterial segments, including plantar vessels, and scored using the Bollinger score. The score ranges from 0 to 15. Fifteen represents an arterial segment with more than 50% of its length occluded. Interobserver reliability was tested using interclass correlation (ICC) and Cohen's kappa coefficient. RESULTS: The ICC demonstrated good agreement between observers (0.76 [0.72-0.79]) with good internal consistency (Cronbach's alpha 0.93). When the Bollinger scores were categorised, the results were weaker, Cohen's kappa ranged from 0.39 (standard error 0.033) to 0.54 (0.030). Patients with DM had a higher burden of disease in the anterior tibial and posterior tibial arteries with relative sparing of the peroneal artery and no difference in the plantar vessels. CONCLUSION: It has been demonstrated that the Bollinger score can be extended to include the distal vessels. This amended scoring system can be used to compare the burden of distal disease in patients with PAD. How the score relates to clinical presentation and outcomes needs further investigation.

Improving the Assessment of Flow-Mediated Dilation Through Detection of Peak Time in Healthy Subjects and Subjects With Type 2 Diabetes.

The assessment of flow-mediated dilation (FMD) is widely used to quantify endothelial function. Historically, FMD was determined at 60 seconds post-cuff deflation. We investigated whether FMD would be more accurate if determined at maximum dilatory peak (MDP) than at 60 seconds in healthy subjects and subjects with type 2 diabetes mellitus (T2DM). We studied 95 healthy and 72 subjects with T2DM and assessed FMD at MDP, 60 and 90 seconds. Twenty-four healthy and 12 subjects with T2DM underwent a repeat FMD after 28 days. In healthy subjects, FMD at MDP was higher than at 60 and 90 seconds, with mean difference MDP versus 60 seconds 1.14% (95% CI: 0.6-1.7); P < .0001 and MDP versus 90 seconds 1.9% (95% CI: 1.3-2.5) with similar results in T2DM, that is, 1.0% (95% CI: 0.1-1.9) and 2.3% (95% CI: 1.3-3.2), respectively. Intraindividual variability was lowest with MDP compared with 60 and 90 seconds, that is, 15.0 versus 23.2% and 40.0%, respectively, resulting in a more than 2-fold reduction in necessary sample size. In healthy subjects and subjects with T2DM, assessment of FMD using MDP results in a more accurate and precise assessment leading to a substantial reduction in sample size.

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

Risks and Risk Factors for Ipsilateral Re-Amputation in the First Year Following First Major Unilateral Dysvascular Amputation.

OBJECTIVE: To identify timing, incidence, and risk factors for ipsilateral re-amputation within 12 months of first dysvascular amputation and to determine specific subgroups of patients at each amputation level that are at increased risk. METHODS: A retrospective cohort study evaluating 7187 patients with first unilateral transmetatarsal (TM), transtibial (TT), or transfemoral (TF) amputation secondary to diabetes and/or peripheral artery disease (PAD) were identified in the VA Surgical Quality Improvement Program database between 2004 and 2014. Re-amputation was defined as any subsequent ipsilateral soft tissue/bony revision or amputation to a higher level. Twenty-three potential pre-operative risk factors (and nine potential interactions) were identified. A backward stepwise Cox regression was used to identify risk factors. Incidence rates and hazard ratios (HR) with 95% confidence intervals (CI) were computed. RESULTS: The median time to highest level of re-amputation in the first year was 33 (interquartile range, 13-73) days. Risk of requiring at least one re-amputation was 41% (TM), 25% (TT), and 9% (TF). Risk factors associated with requiring re-amputation included chronic obstructive pulmonary disease, elevated white blood cell count, abnormal ankle brachial index (ABI), history of revascularisation, and alcohol misuse. TM patients who had diabetes only (HR 1.9; 95% CI 1.4-2.5), diabetes with an abnormal ankle brachial index (ABI) score (HR 2.4; 95% CI 1.8-3.2), and kidney failure (HR 1.7; 95% CI 1.3-2.1) were at the greatest risk of re-amputation. TT amputees who were smokers were also at an increased risk (HR 1.4; 95% CI 1.2-1.6). CONCLUSION: This research identified important risk factors for failure of primary healing and need for re-amputation at the TM and TT level. If considering a TM amputation, caution should be exercised in patients with diabetes, in particular those with an abnormal ABI and/or renal failure. At the TT level, caution should be exercised in those who smoke.

Efficacy of Zotarolimus-Eluting Stents in Treating Diabetic Coronary Lesions: An Optical Coherence Tomography Study.

BACKGROUND: Diabetes mellitus (DM) plays an important role in restenosis and late in-stent thrombosis (ST). The current study using optical coherence tomography (OCT) aims to compare target lesion neointima in patients with or without diabetes after zotarolimus-eluting stent (ZES) treatment. METHODS: OCT images of 90,212 struts and quantitative coronary angiography (QCA) in 62 patients (32 with DM and 30 without DM) with 69 de novo coronary lesions (34 DM and 35 non-DM) both after ZES implantation and 12 ± 1 month angiographic follow-up were recorded. Patient characteristics, lesion characteristics, clinical outcomes, and OCT findings including neointimal thickness, coverage, malapposition, and intimal morphology were analyzed. RESULTS: Baseline patient characteristics and lesion characteristics data were similar between the two groups. Higher neointimal thickness (0.14 ± 0.09 mm vs. 0.09 ± 0.04 mm, p = 0.021), more neovascularization (3.03 ± 6.24 vs. 0.52 ± 1.87, p = 0.017) and higher incidence of layered signal pattern (12.19 ± 19.91% vs. 4.28 ± 9.02%, p = 0.049) were observed in diabetic lesions comparing with non-diabetic lesions. No differences were found in malapposition, uncovered percentage, and thrombus between the two groups (all p > 0.05). Occurrence of clinical adverse events was also similar during the follow-up period (p > 0.05). CONCLUSION: Although more neointimal proliferation and more neovascularization were found in diabetic coronary lesions when compared with non-diabetic lesions, treatment with ZES showed similar stent malapposition rate at 1-year follow-up. The data indicated that ZES treatment could possibly be effective in treating diabetic coronary lesions. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01747356.