Risk Of Peripheral Arterial Disease Research Articles

A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations.

Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.

The causal relationship between human blood metabolites and risk of peripheral artery disease: a Mendelian randomization study.

Peripheral Artery Disease (PAD) is a common vascular disorder typically caused by atherosclerosis, leading to impaired blood supply to the lower extremities, resulting in pain, necrosis, and even amputation. Despite extensive research into the pathogenesis of PAD, many mysteries remain, particularly regarding its association with human blood metabolites. To explore the causal relationship between 1,400 serum metabolites and PAD, a two-sample Mendelian randomization (MR) analysis was conducted. The Inverse Variance-Weighted (IVW) method was the primary technique used to estimate the causal impact of the metabolites on PAD. To enhance the analysis, several additional methods were employed: MR-Egger regression, weighted median, simple mode, and weighted mode. These methods provided a comprehensive evaluation beyond the primary IVW estimation. To ensure the validity of the MR findings, sensitivity analysis was performed. Furthermore, a bidirectional MR approach was applied to explore the possibility of a reverse causal effect between PAD and potential candidate metabolites. After rigorous selection, significant associations were found between 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 levels with PAD. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) was positively associated with increased PAD risk (IVW OR = 1.13, 95% CI, 1.06-1.21; P < 0.001). X-17653 levels were associated with decreased PAD risk (IVW OR = 0.88, 95% CI, 0.83-0.94; P < 0.001). In the reverse direction, PAD was positively associated with increased 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) levels (IVW OR = 1.16, 95% CI, 1.01-1.34; P = 0.036). PAD was not associated with X-17653. Among 1,400 blood metabolites, 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 are significantly associated with PAD risk. Importantly, in the reverse direction, PAD was found to be positively associated with increased levels of 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4). This highlights the bidirectional nature of the association and suggests a potential feedback mechanism between PAD and this specific lipid species. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) may serve as potential biomarkers for PAD, aiding early diagnosis and providing novel avenues for personalized treatment and management. However, further validation and research are warranted despite the promising results.

Association between grip strength, walking pace and incident peripheral artery disease: A prospective study of 430,886 UK biobank participants

Background and aimsPatients with peripheral artery disease (PAD) presented overall muscle weakness and reduced physical performance. Previous study focused on the impact of muscle weakness on outcomes of established PAD, however the relationship between compromised muscle function and incident PAD remained unclear. MethodsA prospective study involving 430,886 participants aged 40–69 y from UK biobank was conducted. The main outcome was incident PAD. Grip strength and walking pace were used as indicators for muscle function. Grip strength was measured using a Jamar J00105 hydraulic hand dynamometer, while walking pace was self-reported by the participants. Cox proportional hazard models were employed to investigate the relationship between grip strength, walking pace, and incident PAD. ResultsA total of 430,886 individuals were included in the final analysis. The mean age of the participants were 56.44 years, and 55.3 % were female. Over a median follow-up period of 13.81 years, 5,661 participants developed PAD. Higher grip strength, whether absolute or relative, exhibited a dose-dependent inverse association with incident PAD. Each 1 kg increment in absolute grip strength and each 0.01 kg/kg increase in relative grip strength were associated with reduced PAD risk by 2 % (HR: 0.98; 95 % CI [0.97–0.98]) and 83 % (HR: 0.17; 95 % CI [0.13–0.23]), respectively. Slow walking pace significantly correlated with increased PAD risk, while brisk walking pace was associated with decreased PAD risk. ConclusionAbsolute grip strength, relative grip strength and walking pace were inversely associated with the risk of incident PAD.

Competing risk analysis to estimate amputation incidence and risk in lower-extremity peripheral artery disease.

Background: Patients with peripheral artery disease face high amputation and mortality risk. When assessing vascular outcomes, consideration of mortality as a competing risk is not routine. We hypothesize standard time-to-event methods will overestimate major amputation risk in chronic limb-threatening ischemia (CLTI) and non-CLTI. Methods: Patients undergoing peripheral vascular intervention from 2017 to 2018 were abstracted from the Vascular Quality Initiative registry and stratified by mean age (⩾ 75 vs < 75 years). Mortality and amputation data were obtained from Medicare claims. The 2-year cumulative incidence function (CIF) and risk of major amputation from standard time-to-event analysis (1 - Kaplan-Meier and Cox regression) were compared with competing risk analysis (Aalen-Johansen and Fine-Gray model) in CLTI and non-CLTI. Results: A total of 7273 patients with CLTI and 5095 with non-CLTI were included. At 2-year follow up, 13.1% of patients underwent major amputation and 33.4% died without major amputation in the CLTI cohort; 1.3% and 10.7%, respectively, in the non-CLTI cohort. In CLTI, standard time-to-event analysis overestimated the 2-year CIF of major amputation by 20.5% and 13.7%, respectively, in patients ⩾ 75 and < 75 years old compared with competing risk analysis. The standard Cox regression overestimated adjusted 2-year major amputation risk in patients ⩾ 75 versus < 75 years old by 7.0%. In non-CLTI, the CIF was overestimated by 7.1% in patients ⩾ 75 years, and the adjusted risk was overestimated by 5.1% compared with competing risk analysis. Conclusions: Standard time-to-event analysis overestimates the incidence and risk of major amputation, especially in CLTI. Competing risk analyses are alternative approaches to estimate accurately amputation risk in vascular outcomes research.

Associations between physical activity and ankle-brachial index: the Swedish CArdioPulmonary bioImage Study (SCAPIS)

BackgroundThe ankle–brachial index (ABI) is the ratio of the ankle and brachial systolic blood pressures. In the clinical setting, low ABI (< 0.9) is an indicator of peripheral atherosclerosis, while high ABI (> 1.4) is a sign of arterial stiffness and calcification. The purpose of the current study was to investigate the association between ABI and physical activity levels, measured by accelerometer.MethodsThe Swedish CArdioPulmonary bioImage Study (SCAPIS) is a Swedish nationwide population-based cross-sectional cohort for the study of cardiovascular and pulmonary diseases, in which individuals aged 50–64 years were randomly invited from the general population. The study population with data on ABI, physical activity, and sedentary time based on accelerometry was 27,737. Differences between ABI categories and associations to sedentary behavior, moderate to vigorous physical activity (MVPA), and other metabolic characteristics were compared. ABI was categorized as low, ABI ≤ 0.9, borderline, ABI 0.91–0.99, normal, ABI 1.0-1.39, and high, ABI ≥ 1.4.ResultsPrevalence of low ABI was higher in the most sedentary quartiles compared to the least sedentary (0.6% vs. 0.1%, p < 0.001). The most sedentary individuals also exhibited higher BMI, higher prevalence of diabetes and hypertension. The proportion of wake time spent in MVPA was lowest in those with low ABI (0.033 ± 0.004; p < 0.001) and highest in those with ABI > 1.4 (0.069 ± 0.001; p < 0.001) compared to those with normal ABI. Compared to normal ABI, the proportion of sedentary time was highest in those with low ABI (0.597 ± 0.012; p < 0.001) and lowest in those with ABI > 1.4 (0.534 ± 0.002; p = 0.004).ConclusionThis population-based study shows that middle-aged individuals with ABI > 1.4 have the highest level of physical activity, while individuals with a lower ABI, especially those with ABI < 0.9, are less active and spend more time sedentary. Future studies are needed to understand the relationships between ABI, physical activity, and the risk of peripheral arterial and cardiovascular disease in the general population.

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Peripheral Arterial Disease prevalence and risk factors in the Eastern Caribbean Health Outcomes Research Network (ECHORN) cohort.

Peripheral arterial disease (PAD) indicates generalised atherosclerotic disease but is often asymptomatic. The prevalence and potential risk factors of PAD were studied in ECHORN cohort study participants. Representative samples of community-dwelling people ≥40 years of age residing in Barbados, Puerto Rico, Trinidad, and the USVI were recruited. The survey included questions on diabetes, hypertension, heart disease and smoking status. Body Mass Index, HbA1c, blood glucose and lipids were determined. Ankle brachial index (ABI) was evaluated in one leg. An oscillometric device measured arm and leg systolic BP simultaneously. ABI classifications were PAD ≤0.90, borderline 0.91 to 0.99, normal 1.00 to 1.40, and non-compressible >0.40. Multivariable logistic regression tested associations of potential risk factors with PAD. Of 2772 participants (mean age 57.3, 65.2% female), 35.8% were overweight, 38.1% obese, 32.4% had diabetes, 60% hypertension, and 15.4% reported heart. ABI prevalence (95% CI) by category was PAD 4.4% (3.6%, 5.1%), borderline 5.2% (4.4%, 6.1%), normal 87.0% (85.8%, 88.3%) and noncompressible 3.4% (2.7%, 4.0%). Female sex (OR 1.72, 95% CI 1.07 to 2.77), diabetes (OR 2.23, 95% CI 1.47 to 3.4), heart disease history (OR 1.74, 95% CI 1.07 to 2.83) and less than high school education vs having a university degree (OR 2.49, 95% CI 1.19 to 5.22) were independently associated with PAD. Testing one leg only would underestimate PAD prevalence. Increasing the ABI cutoff for identifying PAD to <1.0 when using oscillometric devices is suggested by some studies but would more than double the estimated prevalence. Guidelines need to address this issue. Female sex and lower educational attainment are important considerations when screening. While diabetes and a history of heart disease were confirmed as risk factors, the lack of association of increasing age and cigarette smoking with PAD was unexpected.

Remnant cholesterol, not LDL cholesterol, explains peripheral artery disease risk conferred by apolipoprotein B: A cohort study

Remnant cholesterol, not LDL cholesterol, explains peripheral artery disease risk conferred by apolipoprotein B: A cohort study

Association between dietary fiber intake and peripheral artery disease in hypertensive patients

BackgroundAt present, no studies explored whether dietary fiber intake was associated with the risk of peripheral artery disease (PAD) in hypertensive patients. This study assessed the association between dietary fiber intake and PAD in hypertensive patients.MethodsThis cross-sectional study collected the data of 4628 participants with the measurement of ankle-brachial pressure index in the National Health and Nutrition Examination Surveys database. Univariate logistic regression analysis was applied to identify variables associated with PAD as confounding factors. Univariate and multivariable logistic regression analyses were used to explore the association between dietary fiber intake and PAD in hypertensive patients. Subgroup analysis was stratified by age, cardiovascular disease, dyslipidemia, diabetes, smoking, and physical activity.ResultsAfter adjusting for confounding factors, decreased risk of PAD was observed in hypertensive patients with dietary fiber intake > 21 g [odds ratio (OR) = 0.67, 95% confidence interval (CI) 0.46–0.99]. Compared with people with dietary fiber intake ≤ 21 g, those with dietary fiber intake > 21 g were associated with decreased risk of PAD in hypertensive patients < 60 years (OR = 0.23, 95%CI 0.08–0.66). In hypertensive patients without dyslipidemia, dietary fiber intake > 21 g were associated with reduced risk of PAD (OR = 0.33, 95%CI 0.12–0.95). Decreased risk of PAD was also found in hypertensive patients without diabetes in dietary fiber intake > 21 g group (OR = 0.50, 95%CI 0.31–0.78). Dietary fiber intake > 21 g was linked with reduced risk of PAD in hypertensive patients in never smoke group (OR = 0.46, 95%CI 0.24–0.86).ConclusionHigher dietary fiber intake was associated with reduced risk of PAD in hypertensive patients, suggesting the importance of increase the daily dietary quality especially fiber intake in hypertensive people.

The Promoter Polymorphism rs3918226 of the Endothelial Nitric Oxide Synthase Gene as a Novel Susceptibility Marker for Peripheral Artery Disease

This pilot study aimed to investigate the association between the single nucleotide polymorphism (SNP) rs3918226 in the promoter of the nitric oxide synthase (NOS3) gene and the risk of peripheral artery disease (PAD). DNA samples from 1,263 unrelated subjects of Slavic origin, including 620 patients with PAD and 643 controls, were genotyped for the SNP rs3918226 using the MassArray-4 system. The rs3918226 polymorphism was found to be strongly associated with an increased risk of PAD regardless of coronary artery disease, hypertension, or cigarette smoking (odds ratio [OR]=2.86; 95% confidence interval [CI] 1.89-4.32; Pperm < 0.0001). The SNP-PAD association was almost 3 times stronger in females (OR=8.31; 95% CI 3.07-22.48) than in males (OR=1.79; 95% CI 1.10-2.93). SNP rs3918226 was correlated with ankle-brachial index and total plasma cholesterol in patients with PAD (Рperm < 0.05). The NOS3 polymorphism was closely associated with SNPs rs7692387 and rs13139571 in guanylate cyclase soluble subunit alpha-3 (GUCY1A3) to determine the risk of PAD, suggesting that the rs3918226 polymorphism may disrupt signaling in the NO-soluble guanylyl cyclase pathway. Diplotypes with wild-type alleles, such as NOS3 rs3918226-C/C×GUCY1A1 rs7692387G/G and NOS3 rs3918226-C/C×GUCY1A1 rs13139571C/C, showed strong protection against disease risk (false discovery rate ≤ 0.001). Functional SNP annotation revealed that the allele rs3918226-T was associated with decreased expression of NOS3, most strongly in the tibial arteries than in the coronary artery or aorta. The present study is the first to show that the rs3918226 polymorphism of NOS3 is a novel susceptibility marker for PAD. Further research in independent populations is necessary to reproduce the association between polymorphism rs3918226 and disease risk.

Peripheral arterial disease in women.

Peripheral arterial disease (PAD) represents one of the most frequent manifestations of atherosclerosis in men and women. In both sexes, PAD is related to classical risk factors of atherosclerosis, which are similarly distributed, but some additional factors determine differences between men and women. More frequent asymptomatic disease in women than in men and less frequent screening in women may result in a false underestimation of the prevalence of PAD in women. All these factors may cause delayed diagnosis and treatment of PAD in women. Estrogen hormones have vasoprotective properties that lower the prevalence of atherosclerosis in women of younger age. However, estrogen probably does not have a protective role against the development of cardiovascular disease in women of an older age. Hormone replacement therapy (HRT) of less than one year does not appear to reduce the odds of developing PAD in postmenopausal women. It may even increase the risk of morbidity from vascular interventions. However, some studies indicated that HRT for more than one year significantly decreases the risk of PAD if administered early after the last menstruation. Also, treatment of PAD in women differs to some extent from men.

Aryl hydrocarbon receptor repressor (AHRR) methylation predicts risk of vascular disease: A cohort study of the general population.

Smoking is a risk factor for cardiovascular disease, but there is currently no clinically established biomarker for its cardiovascular damage. We aimed to investigate the hypothesis that aryl hydrocarbon receptor repressor (AHHR) methylation at CpG site cg05575921, a biomarker of smoking behavior, is associated with the risk of peripheral artery disease (PAD) and aortic aneurysm (AA) in the general population. In this prospective cohort study of the general population, we measured AHRR methylation in individuals from three visits of the Copenhagen City Heart Study. Information on risk factors were collected at visits with ten years intervals; visit 1 (1991-94), visit 2 (2001-03), and visit 3 (2011-15). Individuals were followed up in the Danish National Patient Register for PAD and AA until December 2018. Subhazard ratios were calculated using Fine and Gray competing risk regression. In 11,332 individuals from visit 1 (n=9,234), visit 2 (n=5,384), and visit 3 (n=4,387) there were 613 and 219 events of PAD and AA during up to 26.5 years of follow-up. AHRR hypomethylation was associated with higher risk of PAD and AA with multivariable adjusted subhazard ratios of 2.82 (1.91; 4.15) for PAD and 2.88 (1.42; 5.88) for AA in individuals within the lowest versus highest methylation quintile. We found that AHRR methylation, a strong biomarker for smoking, was associated with risk of PAD and AA. AHRR methylation could be a useful tool in more personalized risk prediction of PAD and AA.

APOC1 rs445925 and rs4420638 polymorphic variants as genetic predictors of occlusive peripheral arterial disease of lower extremities

Aim. To study the involvement of APOC1 rs445925 and rs4420638 single nucleotide polymorphisms (SNP) in the development of occlusive peripheral arterial disease (PAD) of lower extremities.Material and methods. The study included 1278 people, including 630 patients with occlusive PAD and 648 relatively healthy individuals. Genotyping of APOC1 rs445925 and rs4420638 SNPs was performed using the MassARRAY-4 genomic mass spectrometer. The analysis of the association of alleles, genotypes, haplotypes and diplotypes with the risk of occlusive PAD was performed using the statistical programs SNPStats, PLINK, v1.9 and STATISTICA 13.3. The adaptive permutation test was used to assess statistical significance of associations (Pperm).Results. The rs445925-A (Pperm=1,0×10-6) and rs4420638-G (Pperm=0,006) alleles, as well as the rs445925-G/A-A/A (Pperm=1,0×10-6) and rs4420638-A/G-G/G (Pperm=0,006) genotypes were associated with an increased risk of occlusive PAD. The rs445925 polymorphism was also associated with the blood cholesterol level in patients with occlusive PAD (Pperm=0,04). The rs445925A-rs4420638A and rs445925A-rs4420638G haplotypes, as well as three APOC1 diplotypes, showed a pronounced relationship with a predisposition to occlusive PAD. In particular, the rs445925G/A×rs4420638A/A (odds ratio (OR) 6,59, 95% confidence interval (CI) 4,20-10,35, P=2,4×10-19) and rs445925G/A×rs4420638A/G (OR 4,24, 95% CI 2,23-8,03, P=2,0×10-6) diplotypes were associated with an increased risk of occlusive PAD. The rs445925G/G×rs4420638A/A diplotype had a protective effect on the disease development (OR 0,26, 95% CI 0,20-0,35, P=1,3×10-20). Associations of haplotypes with the severity of peripheral arterial stenosis of various locations were also revealed (P&lt;0,05).Conclusion. The study results established for the first time that APOC1 rs445925 and rs4420638 polymorphic variants are part of a genetic predisposition to occlusive PAD and have a significant effect on the severity of peripheral arterial stenosis. The molecular mechanisms underlying the identified genotypic associations can affect not only lipid metabolism disorders, but also the proliferation of immunocompetent cells, platelet activation and aggregation processes, inflammation and apoptosis.

The Identification and Evaluation of Interleukin-7 as a Myokine Biomarker for Peripheral Artery Disease Prognosis.

Background/Objectives: Myokines have been demonstrated to be associated with cardiovascular diseases; however, they have not been studied as biomarkers for peripheral artery disease (PAD). We identified interleukin-7 (IL-7) as a prognostic biomarker for PAD from a panel of myokines and developed predictive models for 2-year major adverse limb events (MALEs) using clinical features and plasma IL-7 levels. Methods: A prognostic study was conducted with a cohort of 476 patients (312 with PAD and 164 without PAD) that were recruited prospectively. Their plasma concentrations of five circulating myokines were measured at recruitment, and the patients were followed for two years. The outcome of interest was two-year MALEs (composite of major amputation, vascular intervention, or acute limb ischemia). Cox proportional hazards analysis was performed to identify IL-7 as the only myokine that was associated with 2-year MALEs. The data were randomly divided into training (70%) and test sets (30%). A random forest model was trained using clinical characteristics (demographics, comorbidities, and medications) and plasma IL-7 levels with 10-fold cross-validation. The primary model evaluation metric was the F1 score. The prognostic model was used to classify patients into low vs. high risk of developing adverse limb events based on the Youden Index. Freedom from MALEs over 2 years was compared between the risk-stratified groups using Cox proportional hazards analysis. Results: Two-year MALEs occurred in 28 (9%) of patients with PAD. IL-7 was the only myokine that was statistically significantly correlated with two-year MALE (HR 1.56 [95% CI 1.12-1.88], p = 0.007). For the prognosis of 2-year MALEs, our model achieved an F1 score of 0.829 using plasma IL-7 levels in combination with clinical features. Patients classified as high-risk by the predictive model were significantly more likely to develop MALEs over a 2-year period (HR 1.66 [95% CI 1.22-1.98], p = 0.006). Conclusions: From a panel of myokines, IL-7 was identified as a prognostic biomarker for PAD. Using a combination of clinical characteristics and plasma IL-7 levels, we propose an accurate predictive model for 2-year MALEs in patients with PAD. Our model may support PAD risk stratification, guiding clinical decisions on additional vascular evaluation, specialist referrals, and medical/surgical management, thereby improving outcomes.

Variability of flow-mediated dilation across lower and upper limb conduit arteries

Endothelial dysfunction is an early predictor of atherosclerosis and cardiovascular disease. Flow-mediated dilation (FMD) is the gold standard to assess endothelial function in humans. FMD reproducibility has been mainly assessed in the brachial artery (BA) with limited research in lower limb arteries. The purpose of this study was to compare FMD reproducibility in the upper limb BA and lower limb superficial femoral artery (SFA) in young healthy adults.Fifteen young healthy adults (nine males; six females) underwent FMD, resting diameter, velocity, and shear rate measurements on three occasions to determine intra-and inter-day reproducibility in both BA and SFA, assessed by coefficient of variation (CV), intraclass correlation coefficient (ICC), and Bland–Altman plots.BA FMD CVs (intra-day: 4.2%; inter-day: 8.7%) and ICCs (intra-day: 0.967; inter-day: 0.903) indicated excellent reproducibility and reliability, while for SFA FMD, both CVs (intra-day: 11.6%; inter-day: 26.7%) and ICCs (intra-day: 0.898; inter-day: 0.651) showed good/moderate reproducibility and reliability. BA FMD was significantly more reproducible than SFA FMD (p < 0.05). Diameter reproducibility was excellent and similar between arteries, while resting velocity and shear rate have lower reproducibility in the BA compared to SFA. Bland–Altman plots displayed no proportional and fixed bias between measurements.In summary, SFA FMD is less reproducible than BA FMD, with identical volume of ultrasound training. Given the increasing interest in using SFA FMD to test the efficacy of interventions targeting lower limb’s vascular health and as a potential biomarker for peripheral arterial disease risk, future studies should ensure higher levels of training for adequate reproducibility.

Leveraging the Cardiovascular Team in Peripheral Artery Disease Diagnosis: A Call to Action.

Lower extremity peripheral artery disease (PAD) is a common atherosclerotic cardiovascular disease (ASCVD) involving the aortoiliac, femoropopliteal, and infrapopliteal arterial segments. PAD remains a largely underdiagnosed and undertreated condition. The ankle-brachial index (ABI) is a simple and widely available test that is key detection tool in the diagnosis of PAD and is prognostic for mortality and morbidity. The cardiovascular (CV) team is a diverse array of health care clinicians (eg, nurses, nurse practitioners, physician assistants/associates, pharmacists, podiatrists) who have the qualifications and skills to be able to recognize when patients are at risk for PAD and perform an ABI. It is critical that the healthcare community recognize the critical role the CV team could play in improving outcomes and reducing disparities for patients with PAD.

Randomized Trial of a Vascular Care Team vs Education for Patients With Peripheral Artery Disease

BackgroundUnderutilization of therapies to reduce ischemic risk in peripheral artery disease (PAD) persists. ObjectivesThe purpose was to conduct an implementation trial of lipid management in vascular disease. MethodsThe OPTIMIZE PAD-1 (Implementation of Vascular Care Team to Improve Medical Management of PAD Patients) trial randomized patients with peripheral artery disease with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL to management via a vascular care team including a clinical pharmacist and an algorithm of intensive lipid management to achieve goal LDL-C in 1 step vs usual care plus provider education. Medications were obtained using commercial insurance. The primary endpoint was percent change in LDL-C at 12 months. ResultsOf 166 enrolled patients, 74.2% did not have an LDL-C level at goal. Among 114 randomized patients (mean age 66 years, 36.0% women, and 15.8% Black), 50.9% received high-intensity statin, and 7.9% received ezetimibe at baseline. The mean 12-month LDL-C change was −49.1% (95% CI: −58.7% to −39.5%) with vascular care team management and −5.4% (95% CI: −15.3% to 4.6%) with usual care; the between-group least-squares mean difference was −43.7% (95% CI: −57.6% to −29.9%; P < 0.0001). Mean LDL-C was reduced in vascular care team patients from 100.6 mg/dL at baseline to 54.8 and 50.1 mg/dL by week 4 and month 12, respectively. At 12 months, vascular care team patients were >3 times as likely to achieve LDL-C <70 mg/dL and 8 times as likely to achieve LDL-C <55 mg/dL (P < 0.0001) than usual care. ConclusionsOPTIMIZE PAD-1 showed that an interprofessional, algorithm-based program can achieve rapid LDL-C lowering in vascular patients using available insurance and therapies, and LDL-C targets can be met in most patients if enabled by optimized systems of care.

Association between the triglyceride glucose index and atherosclerotic cardiovascular disease in the general population: analysis of the national health and nutrition examination survey 1999-2004.

The triglyceride-glucose (TyG) index, a reliable substitute indicator of insulin resistance (IR), is considered an independent risk factor for long-term outcomes in patients with cardiovascular disease. However, studies investigating the association between TyG and atherosclerotic cardiovascular disease (ASCVD) are limited and lack direct evidence. We aim to examine the relationship between the TyG index and ASCVD through a comprehensive cross-sectional study. Overall, 7212 participants from the 1999-2004 National Health and Nutrition Examination Survey were included. The baseline TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. Restricted cubic spline (RCS) regression, univariate logistic regression, and multivariate logistic regression analysis were used to evaluate the association between the TyG index and ASCVD. In the overall population, a multivariate logistic regression analysis showed that the TyG level was not only positively associated with ASCVD [OR (95%CI): 1.29 (1.01,1.64), P=0.042], coronary artery disease (CAD) [OR (95%CI): 1.82(1.33,2.48), P<0.001], and stroke [OR (95%CI): 2.68(1.54,4.69), P=0.002], but also linearly correlated with all three (P-overall<0.001; P-non-linear >0.05). Although the TyG index was not associated with peripheral arterial disease (PAD) [OR (95%CI): 1.00 (0.73,1.36), P>0.900], it showed a U-shaped correlation with PAD (P-overall <0.001; P-non-linear= 0.0085), and the risk of PAD was minimized when TyG=8.67. By incorporating the TyG index into the baseline risk model, the accuracy of ASCVD prediction was improved [AUC: baseline risk model, 0.7183 vs. baseline risk model + TyG index, 0.7203, P for comparison=0.034]. The results of the subgroup analysis were consistent with those of the main analysis. The TyG index was independently associated with ASCVD, CAD, and stroke, suggesting that it may serve as a valid indicator for predicting ASCVD in the entire population.

Sex and age significantly modulate cardiovascular disease presentation in type 2 diabetes: a large population-based cohort study.

We aimed to describe and compare the incidence of the first cardiovascular event and its major subtypes, coronary heart disease (CHD), cerebrovascular disease, heart failure (HF), or peripheral artery disease (PAD), according to age and sex in a population-based cohort of individuals with type 2 diabetes (T2D) from a Mediterranean region. We used linked primary care electronic medical reports, pharmacy-invoicing data, and hospital admission disease registry records from the SIDIAP database, which contains linked data for 74% of the Catalonian population. We selected individuals with T2D aged 30 to 89 years free of cardiovascular disease (CVD). The primary outcome was the first presentation of CVD. The study cohort included 247,751 individuals (48.6% women, 66.8 ± 11.9 years). During a 6.99-year follow-up, the cumulative incidence of the first cardiovascular event was 23.4%. Men were at higher risk for CVD (hazard ratio [HR]: 1.47 95%CI: 1.45-1.50), CHD (HR: 1.52 95%CI: 1.47-1.57), cerebrovascular disease (HR:1.07 95%CI: 1.03-1.10) and PAD (HR: 2.30 95%CI: 2.21-2.39) than women but at a lower risk for HF (HR:0.70 95%CI: 0.68-0.73). CHD and PAD were the most frequent CVD presentations among men (28.1% and 27.5%) and HF (40.1%) in women. CHD predominated among young participants of both sexes, while HF predominated among women older than 65 and men older than 75. In individuals with T2D, the overall risk and the type of first CVD manifestation largely varied by sex and age. This epidemiological evidence should be considered in clinical practice.

Relationship of apolipoprotein C-III proteoform composition with ankle-brachial index and peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aimsApolipoprotein C-III (apoC-III) proteoform composition shows distinct relationships with plasma lipids and cardiovascular risk. The present study tested whether apoC-III proteoforms are associated with risk of peripheral artery disease (PAD). MethodsApoC-III proteoforms, i.e., native (C-III0a), and glycosylated with zero (C-III0b), one (C-III1) or two (C-III2) sialic acids, were measured by mass spectrometry immunoassay on 5,734 Multi-Ethnic Study of Atherosclerosis participants who were subsequently followed for clinical PAD over 17 years. Ankle-brachial index (ABI) was also assessed at baseline and then 3 and 10 years later in 4,830 participants. ResultsHigher baseline C-III0b/C-III1 and lower baseline C-III2/C-III1 were associated with slower decline in ABI (follow-up adjusted for baseline) over time, independently of cardiometabolic risk factors, and plasma triglycerides and HDL cholesterol levels (estimated difference per 1 SD was 0.31 % for both, p < 0.01). The associations between C-III2/C-III1 and changes in ABI were stronger in men (−1.21 % vs. −0.27 % in women), and in Black and Chinese participants (−0.83 % and −0.86 % vs. 0.12 % in White). Higher C-III0b/C-III1 was associated with a trend for lower risk of PAD (HR = 0.84 [95%CI: 0.67–1.04]) that became stronger after excluding participants on lipid-lowering medications (0.73 [95%CI: 0.57–0.94]). Neither change in ABI nor clinical PAD was related to total apoC-III levels. ConclusionsWe found associations of apoC-III proteoform composition with changes in ABI that were independent of other risk factors, including plasma lipids. Our data further support unique properties of apoC-III proteoforms in modulating vascular health that go beyond total apoC-III levels.