Machine Learning Approach to Metabolomic Data Predicts Type 2 Diabetes Mellitus Incidence.

Metabolomics, with its wealth of data, offers a valuable avenue for enhancing predictions and decision-making in diabetes. This observational study aimed to leverage machine learning (ML) algorithms to predict the 4-year risk of developing type 2 diabetes mellitus (T2DM) using targeted quantitative metabolomics data. A cohort of 279 cardiovascular risk patients who underwent coronary angiography and who were initially free of T2DM according to American Diabetes Association (ADA) criteria was analyzed at baseline, including anthropometric data and targeted metabolomics, using liquid chromatography (LC)-mass spectroscopy (MS) and flow injection analysis (FIA)-MS, respectively. All patients were followed for four years. During this time, 11.5% of the patients developed T2DM. After data preprocessing, 362 variables were used for ML, employing the Caret package in R. The dataset was divided into training and test sets (75:25 ratio) and we used an oversampling approach to address the classifier imbalance of T2DM incidence. After an additional recursive feature elimination step, identifying a set of 77 variables that were the most valuable for model generation, a Support Vector Machine (SVM) model with a linear kernel demonstrated the most promising predictive capabilities, exhibiting an F1 score of 50%, a specificity of 93%, and balanced and unbalanced accuracies of 72% and 88%, respectively. The top-ranked features were bile acids, ceramides, amino acids, and hexoses, whereas anthropometric features such as age, sex, waist circumference, or body mass index had no contribution. In conclusion, ML analysis of metabolomics data is a promising tool for identifying individuals at risk of developing T2DM and opens avenues for personalized and early intervention strategies.

Evaluation of SARS-CoV-2 antibody levels on hospital admission as a correlate of protection against mortality.

BACKGROUND: Millions of people have now been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, it is still unclear which antibody levels provide protection against mortality. It is further unknown whether measuring antibody concentrations on hospital admission allows for identifying patients with a high risk of mortality. OBJECTIVES: To evaluate whether anti-SARS-CoV2-spike antibodies on hospital admission predict in-hospital mortality in patients with coronavirus disease 2019. METHODS: We conducted a prospective, multicentre cohort study on 1152 hospitalized patients who tested positive for SARS-CoV-2 with a polymerase chain reaction-based assay. Patients were classified by vaccination status. Anti-SARS-CoV-2 spike antibodies were determined on hospital admission. The investigated end point was in-hospital mortality for any cause. RESULTS: Spike antibodies on hospital admission were significantly lower in non-survivors in both non-vaccinated (73 U/ml, 95%CI 0-164 vs. 175 U/ml, 95%CI 124-235, p = 0.002) and vaccinated patients (1056 U/ml, 95%CI 701-1411 vs. 1668 U/ml, 95%CI 1580-1757, p < 0.001). Further, spike antibodies were significantly lower in fully vaccinated and boostered patients who died compared to those who survived (mean 883 U/ml, 95%CI 406-1359 vs. 1292 U/ml, 95%CI 1152-1431, p = 0.017 and 1485 U/ml, 95%CI 836-2133 vs. 2050 U/ml, 95%CI 1952-2149, p = 0.036). Patients infected with the currently prevailing Omicron variant were three times more likely to die if spike antibodies were <1200 U/ml (OR 3.458, 95%CI 1.562-7.656, p = 0.001). After adjusting for potential confounders, this value increased to an aOR of 4.079 (95%CI 1.809-9.198, p < 0.001). CONCLUSION: Anti-SARS-CoV2 spike-antibody levels on hospital admission are inversely associated with in-hospital mortality. Hospitalized patients with lower antibody levels have a higher risk of mortality.

Empagliflozin in acute myocardial infarction: the EMMY trial.

AIMS: Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking. METHODS AND RESULTS: In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757-2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) -4.4% to -23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2-2.9%, P = 0.029), mean E/e' reduction was 6.8% (95% CI 1.3-11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4-11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7-15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups. CONCLUSION: In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters. CLINICALTRIALS.GOV REGISTRATION: NCT03087773.

Impact of ezetimibe on markers of inflammation in patients treated with statins: a systematic review.

Statins are the primary pharmacological intervention to reduce LDL cholesterol; they significantly reduce inflammatory markers. Ezetimibe also reduces LDL cholesterol and reduces cardiovascular events when given on top of statin therapy. Whether ezetimibe, like statins, reduces markers of inflammation is less clear. We, therefore, conducted a systematic literature research addressing the impact of ezetimibe on CRP, TNFα and IL-6 when given on top of statin therapy. Our work indicates that overall ezetimibe reduces inflammation on top of statin treatment. However, available data are limited for CRP and even more so for TNFα and IL-6.

Evaluation of the associations between circulating microRNAs and kidney function in coronary angiography patients.

Circulating microRNAs (miRNAs) have been linked to chronic kidney disease. Little is known about the association between circulating miRNAs and kidney function in patients at high cardiovascular risk. We therefore investigated the association between a panel of candidate miRNAs and kidney function, based on estimated glomerular filtration rate (eGFR), in two independent cohorts of patients undergoing coronary angiography. The present study totally included 438 patients undergoing coronary angiography, who were divided into a discovery cohort (n = 120) and a validation cohort (n = 318). A candidate miRNA panel comprising 50 renal miRNAs was selected from the literature, and expression levels of circulating miRNAs were determined by real-time PCR. Out of the initially tested candidate miRNAs, 38 miRNAs were sufficiently detectable in plasma. Their association with kidney function was evaluated in the discovery cohort. Associations of seven of these miRNAs with eGFR were significant after multiple testing correction via false discovery rate estimation. To verify obtained results, miRNAs with significant false discovery rates were further analyzed in the validation cohort. miR-106b-5p, miR-16-5p, miR-19b-3p, miR-20a-5p, miR-25-3p, and miR-451a proved to be significantly associated with eGFR also in the validation cohort (all P < 0.001). Association between the identified renal miRNAs and kidney function was confirmed by analysis of covariance adjusting for age, sex, type 2 diabetes, hypertension, and albumin-to-creatinine ratio. In conclusion, our study showed that miR-16-5p, miR-19b-3p, miR-20a-5p, miR-25-3p, miR-106b-5p, and miR-451a are significantly linked to kidney function in patients undergoing coronary angiography.

Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction-The EMMY trial.

BACKGROUND: Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI. METHODS: Within a multicenter, randomized, double-blind, placebo-controlled, phase 3b trial we will enroll patients with AMI and characteristics suggestive of severe myocardial necrosis are randomized in a 1:1 ratio to empagliflozin (10 mg once daily) or matching placebo. The primary endpoint is the impact of empagliflozin on changes in NT-proBNP within 6 months after AMI. Secondary endpoints include changes in echocardiographic parameters, levels of ketone body concentrations, HbA1c levels and body weight, respectively. Hospitalization rate due to heart failure or other causes, the duration of hospital stay and all-cause mortality will be assessed as exploratory secondary endpoints. DISCUSSION: The EMMY trial will test empagliflozin in patients with AMI regardless of their diabetic status. The EMMY trial may therefore underpin the concept of SGLT2 inhibition to improve cardiac remodeling, pre-and afterload reduction and cardiac metabolism regardless of its antidiabetic effects. Results will provide the rationale for the conduct of a cardiovascular outcome trial to test the effect of empagliflozin in patients with AMI.

Comparison of preoperative continuation and discontinuation of aspirin in patients undergoing total hip or knee arthroplasty.

INTRODUCTION: Preoperative discontinuation of aspirin (acetylsalicylic acid) can reduce bleeding risk but may increase the risk of perioperative cardiovascular events. MATERIALS AND METHODS: We retrospectively assessed the impact of preoperative continuation versus discontinuation of aspirin compared with a control group in a cohort of 739 consecutive patients undergoing total hip (THA) (n = 396) or knee arthroplasty (TKA) (n = 343) at a tertiary hospital. Bleeding risk, local complications, orthopaedic outcome, and cardiac and cerebral complications were assessed. RESULTS: Four hundred and sixty-five patients did not receive antithrombotic or full-dose anticoagulant medication, 175 patients were taking low-dose aspirin, 99 vitamin K antagonists, clopidogrel, or a combination of these drugs. Of the patients taking aspirin, 139 discontinued and 36 continued aspirin. Blood loss and local bleeding complications were comparable in these two groups. TKA patients who continued aspirin more frequently showed marked knee swelling after 1 week than those discontinuing aspirin (35.1 vs. 81.3 %; p = 0.001). However, orthopaedic outcome did not differ significantly between the two groups. There was a trend towards an increased risk of cardiac complications in patients who discontinued aspirin (6.5 vs. 0.0 %; p = 0.107). CONCLUSIONS: Continuation or discontinuation of aspirin did not show a statistically significant difference in the risk of relevant perioperative bleeding complications in our study. Continuation of aspirin was associated with a transitory increase in knee swelling, but had no effect on orthopaedic outcome. Continuation of aspirin may be associated with a favourable perioperative cardiac outcome. Our data support perioperative continuation of aspirin intake in patients undergoing THA or TKA.

Lipid parameters in patients with acute coronary syndromes versus stable coronary artery disease.

BACKGROUND: Differences in lipid parameters between patients with acute coronary syndromes (ACS) and patients with stable coronary artery disease (CAD) are unclear and are addressed in this study. METHODS: We enrolled 582 patients with angiographically proven stable CAD (of whom 26·9% had diabetes mellitus type 2 (T2DM)) and 182 patients with ACS (of whom 35·8% had T2DM). RESULTS: HDL cholesterol and apolipoprotein A1 levels were significantly lower in patients with ACS than in patients with CAD (46 ± 16 mg/dL vs. 50 ± 16 mg/dL, P < 0·001, and 139 ± 30 mg/dL vs. 155 ± 31 mg/dL, P < 0·001, respectively). Analysis of covariance (ancova) adjusting for age, gender, smoking, BMI, statin therapy, alcohol use, hypertension and diabetic state confirmed an independent impact of ACS on HDL cholesterol and apolipoprotein A1 levels (F = 24·1; P < 0·001). In contrast, total cholesterol, LDL cholesterol, non-HDL cholesterol and apolipoprotein B levels did not differ significantly between patients with ACS and patients with stable CAD. CONCLUSION: HDL cholesterol and apolipoprotein A1 levels are lower in patients with ACS than in patients with stable CAD.

Occurrence of the JAK2 V617F mutation in patients with peripheral arterial disease.

The acquired JAK2 V617F mutation is common in patients with myeloproliferative neoplasms. We previously showed that JAK2 V617F is also found in coronary patients, most of them affected by coronary atherosclerosis. Peripheral arterial disease (PAD) is another important manifestation of atherosclerosis. However, prevalence of the JAK2 V617F mutation and its effect on clinical or hematologic characteristics is unknown in PAD patients. In the present study we determined the prevalence of JAK2 V617F in a cohort of 287 patients with sonographically proven PAD and compared mutation frequency with mutational status of 997 healthy people from the KORA F4 study. JAK2 V617F screening and quantification of allele burden in both cohorts was performed with same allele-specific quantitative real-time PCR method. From a total of 287 PAD patients, 9 individuals were tested positive for the JAK2 V617F mutation. One patient showed elevated hemoglobin values, indicating polycythemia vera. Observed JAK2 V617F frequency (3.1%) in PAD patients showed a 5-fold, highly significant increase compared with healthy people (P < 0.001). Furthermore, occurrence of the mutation in PAD patients was significantly decreased in patients using aspirin (P = 0.003). We conclude that the prevalence of JAK2 V617F mutation is significantly increased in PAD patients compared to the general population. Future studies are warranted to confirm our observations and to define the underlying mechanisms behind our findings.

Evaluation of the prevalence and prospective clinical impact of the JAK2 V617F mutation in coronary patients.

The JAK2 V617F mutation is not only found in the majority of patients with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), but also has been reported in individuals without overt MPN. A close relation of the JAK2 V617F mutation to atherothrombotic events has been described, at least in patients with MPN. The prevalence of the JAK2 V617F mutation and its clinical impact in coronary patients is unknown. To address this issue, DNA samples from 1,589 subjects undergoing coronary angiography with up to 11 years of follow up were genotyped using allele-specific real-time PCR assays. Prevalence of the JAK2 V617F mutation was 1.32% (n = 21) in coronary patients. Two JAK2 V617F positive patients showed baseline platelet counts indicative for ET and a third patient developed ET during follow up, finally resulting in a percentage of 0.188% of ET cases. This corresponds to an up to fivefold accumulation of ET cases in coronary patients compared with the general population. Our study showed no impact of the JAK2 V617F mutation on future atherothrombotic events or overall survival (HR = 1.04 [0.33-3.27]; P = 0.949 and HR = 0.35 [0.05-2.46]; P = 0.288, respectively). Therefore, our data suggest that JAK2 V617F positive coronary patients are not at increased risk for future atherothrombotic complications. Routine mutation screening in coronary patients is, therefore, not warranted. However, number of ET cases appears to be accumulated in coronary patients. For this reason, we recommend JAK2 V617F testing only in coronary patients showing abnormal blood cell counts for further clarification.

Ceramides improve cardiovascular risk prediction beyond low-density lipoprotein cholesterol.

Aims: Low-density lipoprotein cholesterol (LDL-C) is the best documented cardiovascular risk predictor and at the same time serves as a target for lipid-lowering therapy. However, the power of LDL-C to predict risk is biased by advanced age, comorbidities, and medical treatment, all known to impact cholesterol levels. Consequently, such biased patient cohorts often feature a U-shaped or inverse association between LDL-C and cardiovascular or overall mortality. It is not clear whether these constraints for risk prediction may likewise apply to other lipid risk markers in particular to ceramides and phosphatidylcholines. Methods and results: In this observational cohort study, we recorded cardiovascular mortality in 1195 patients over a period of up to 16 years, comprising a total of 12 262 patient-years. The median age of patients at baseline was 67 years. All participants were either consecutively referred to elective coronary angiography or diagnosed with peripheral artery disease, indicating a high cardiovascular risk. At baseline, 51% of the patients were under statin therapy. We found a U-shaped association between LDL-C and cardiovascular mortality with a trough level of around 150 mg/dL of LDL-C. Cox regression analyses revealed that LDL-C and other cholesterol species failed to predict cardiovascular risk. In contrast, no U-shaped but linear association was found for ceramide- and phosphatidylcholine-containing markers and these markers were able to significantly predict the cardiovascular risk even after multivariate adjustment. Conclusion: We thus suggest that ceramides- and phosphatidylcholine-based predictors rather than LDL-C may be used for a more accurate cardiovascular risk prediction in high-risk patients.

Interplay of inflammatory markers and anti-SARS-CoV-2 antibodies in COVID-19 mortality: A prospective cohort study.

OBJECTIVES: Despite high global vaccination coverage, it remains unclear how vaccination and anti-SARS-CoV-2 antibodies affect immune responses and inflammation levels in patients with COVID-19. It is further unclear whether the inflammatory response differs depending on antibody levels and whether the combination of antibody and inflammation levels in COVID-19 patients affects mortality rates. METHODS: We conducted a prospective multicenter cohort study that included 1031 hospitalized COVID-19 patients from five hospitals. Anti-SARS-CoV-2-spike antibodies, interleukin-6 (IL6), and CRP were measured on hospital admission. The prespecified endpoint was all-cause in-hospital mortality. RESULTS: We observed significantly lower levels of CRP (P<0.001) and IL6 (P<0.001) in patients with antibody levels above 1200 BAU/ml. After adjusting for potential confounders, patients with high levels of inflammatory markers (CRP>6 mg/dl or IL6>100 pg/ml) combined with low levels of anti-SARS-CoV-2-spike antibodies (<1200 BAU/ml) were approximately 8 times more likely to die than patients with low inflammatory responses and high antibody levels (CRP: aHR 7.973, 95% CI 2.744-23.169, P<0.001; IL6: aHR 8.973, 95% CI 3.549-22.688, P<0.001). CONCLUSION: Hospitalized COVID-19 patients presenting with high inflammatory markers and low antibody levels exhibited the highest mortality risks. Higher antibody levels are associated with lower levels of inflammation in hospitalized COVID-19 patients.

Current Practices of Medication Plans in Austrian Patients Undergoing Coronary Angiography: An In-Depth Analysis.

A complete medication plan (MPlan) increases medication safety and adherence and is crucial in care transitions. Countries that implemented a standardized MPlan reported benefits on patients' understanding and handling of their medication. Austria lacks such a standardization, with no available data on the issue. Objective: This study aimed to investigate the current state of all medication documentations (MDocs) at hospital admission in a population at high risk for polypharmacy in Austria. Methods: We enrolled 512 consecutive patients undergoing elective coronary angiography. Their MDocs and medications were recorded at admission. MDocs were categorized, whereby a MPlan was defined as a tabular list including medication name, dose, route, frequency and patient name. Results: Out of 485 patients, 55.1% had an MDoc (median number of drugs: 6, range 2-17), of whom 24.7% had unstructured documentation, 18.0% physicians' letters and 54.3% MPlans. Polypharmacy patients did not have a MDoc in 31.3%. Crucial information as the patients's name or the originator of the MDoc was missing in 31.1% and 20.4%, respectively. Patients with MDoc provided more comprehensive medication information (p = 0.019), although over-the-counter-medication was missing in 94.5% of MDocs. A discrepancy between the MPlan and current medication at admission existed in 64.4%. In total, only 10.7% of our patient cohort presented an MPlan that was in accordance with their current medication. Conclusion: The situation in Austria is far from a standardized MPlan generated in daily routine. Numerous MPlans do not represent the current medication and could pose a potential risk for the effectiveness and safety of pharmacotherapy.

Anti-SARS-CoV-2 Antibodies versus Vaccination Status in CAD Patients with COVID-19: A Prospective, Propensity Score-Matched Cohort Study.

OBJECTIVES: Despite the currently prevailing, milder Omicron variant, coronary artery disease (CAD) patients constitute a major risk group in COVID-19, exhibiting 2.6 times the mortality risk of non-CAD patients and representing over 22% of non-survivors. No data are currently available on the efficacy of antibody levels in CAD patients, nor on the relevance of vaccination status versus antibody levels for predicting severe courses and COVID-19 mortality. Nor are there definitive indicators to assess if individual CAD patients are sufficiently protected from adverse outcomes or to determine the necessity of booster vaccinations. METHODS: A prospective, propensity-score-matched, multicenter cohort study comprising 249 CAD patients and 903 controls was conducted. Anti-SARS-CoV-2-spike antibodies were measured on hospital admission. Prespecified endpoints were in-hospital mortality, intensive care, and oxygen administration. RESULTS: After adjustment for potential confounders, CAD patients exhibited 4.6 and 6.1-times higher mortality risks if antibody levels were <1200 BAU/mL and <182 BAU/mL, respectively, compared to CAD patients above these thresholds (aOR 4.598, 95%CI 2.426-8.714, p < 0.001; 6.147, 95%CI 2.529-14.941, p < 0.001). Risk of intensive care was 3.7 and 4.0 (p = 0.003; p < 0.001), and risk of oxygen administration 2.6 and 2.4 times higher below these thresholds (p = 0.004; p = 0.010). Vaccination status was a weaker predictor of all three outcomes than both antibody thresholds. CONCLUSION: Antibody levels are a stronger predictor of outcome in CAD patients with COVID-19 than vaccination status, with 1200 BAU/mL being the more conservative threshold. Measuring anti-SARS-CoV-2 antibodies in CAD patients may ensure enhanced protection by providing timely booster vaccinations and identifying high-risk CAD patients at hospital admission.

The value of earlier-in-life systolic and diastolic blood pressure for cardiovascular risk prediction.

Blood pressure (BP) varies over a lifetime. This cardiovascular observation study (OS) compared the predictive value of earlier- and later-in-life blood pressure (BP) in 1,497 cardiovascular disease patients utilizing readings taken during a health survey (HS) and 15 years later from the same subjects at the baseline of this OS. Prediction of the cardiovascular risk during the OS follow-up (21 years) was significantly more effective if the earlier BP readings at HS were used instead of recent OS readings (NRI = 0.30, p < 0.001). For HS readings, each 10 mm Hg increase of systolic and diastolic BP was associated with a 17% and 20% higher risk, respectively. At OS, systolic BP lost significance and diastolic BP reversed its association. Noteworthy, different BP categorizations (European vs. US guidelines) yielded similar results. This study highlights the poor predictive power of BP readings in elderly cardiovascular disease patients but emphasizes the significant prognostic value of earlier-in-life BP.

Antibody levels versus vaccination status in the outcome of older adults with COVID-19.

BACKGROUNDDespite the currently prevailing, milder Omicron variant of COVID-19, older adults remain at elevated risk of hospital admission, critical illness, and death. Loss of efficacy of the immune system, including reduced strength, quality, and durability of antibody responses, may render generalized recommendations on booster vaccinations inadequate. There is a lack of data on the efficacy of antibody levels in older adults and on the utility of vaccination status versus antibody levels as a correlate of protection. It is further unclear whether antibody levels may be used to guide the timing of booster vaccinations in older adults.METHODSWe conducted a prospective multicenter cohort study comprising hospitalized patients with COVID-19. Anti-SARS-CoV-2 spike antibodies were measured on hospital admission. The primary endpoint was in-hospital mortality. Patients were stratified by age, antibody levels, and vaccination status. Multiple logistic regression and Cox regression analyses were conducted.RESULTSIn total, 785 older patients (≥60 years of age [a]) and 367 controls (<60a) were included. After adjusting for confounders, risk of mortality, ICU admission, endotracheal intubation, and oxygen administration was 4.9, 2.6, 6.5, and 2.3 times higher, respectively, if antibody levels were < 1,200 BAU/mL (aOR, 4.92 [95%CI, 2.59-9.34], P < 0.0001; aOR, 2.64 [95%CI, 1.52-4.62], P = 0.0006; aOR, 6.50 [95%CI, 1.48-28.47], P = 0.013; aOR, 2.34 [95%CI, 1.60-3.343], P < 0.0001). Older adults infected with the Omicron variant were approximately 6 times more likely to die if antibody levels were < 1,200 BAU/mL (aOR, 6.3 [95% CI, 2.43-16.40], P = 0.0002).CONCLUSIONAntibody levels were a stronger predictor of in-hospital mortality than vaccination status. Monitoring antibody levels may constitute a better and more direct approach for safeguarding older adults from adverse COVID-19 outcomes.

Insulin resistance is significantly associated with the metabolic syndrome, but not with sonographically proven peripheral arterial disease.

OBJECTIVE: Insulin resistance (IR) is the key feature of the metabolic syndrome (MetS); its association with peripheral arterial disease (PAD) is unclear. We hypothesized that IR is associated with both the MetS and sonographically proven PAD. METHODS: IR was determined by the Homeostasis Model Assessment (HOMA) index in 214 patients with sonographically proven PAD as well as in 197 controls, who did not have a history of PAD and in whom coronary artery disease was ruled out angiographically; the MetS was defined according to NCEP-ATPIII criteria. RESULTS: HOMA IR scores were significantly higher in MetS patients than in subjects without the MetS (5.9 ± 6.2 vs. 2.9 ± 3.9; p <0.001). However, HOMA IR did not differ significantly between patients with PAD and controls (4.2 ± 5.4 vs. 3.3 ± 4.3; p = 0.124). When both, the presence of MetS and of PAD were considered, HOMA IR was significantly higher in patients with the MetS both among those with PAD (6.1 ± 5.7 vs. 3.6 ± 5.2; p<0.001) and among controls (5.8 ± 6.8 vs. 2.3 ± 1.8; p <0.001), whereas it did not differ significantly between patients with PAD and controls among patients with the MetS (5.8 ± 6.8 vs. 6.1 ± 5.7; p = 0.587) nor among those without the MetS (2.3 ± 1.8 vs. 3.6 ± 5.2; p = 0.165). Similar results were obtained with the International Diabetes Federation definition of the MetS. CONCLUSION: IR is significantly associated with the MetS but not with sonographically proven PAD.