Endothelial dysfunction in patients with spontaneous venous thromboembolism

Background and Objectives A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism.Design and Methods Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age-(±5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured.Results Twenty-eight cases (8 females; mean age 59±15 years) and 28 controls (8 females; mean age 58±15) were studied. Flow-mediated vasodilation was 3.5±0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7±0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls.Interpretation and Conclusions Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis

Prevalence of peripheral artery disease by abnormal ankle-brachial index in atrial fibrillation: implications for risk and therapy.

To the Editor: Nonvalvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a 5-fold increased risk for stroke (1). Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial infarction (AMI) (2). Peripheral artery disease (PAD) is an established marker of systemic atherosclerosis but its prevalence in NVAF is still unclear. We reasoned that inclusion of ankle-brachial index (ABI), which is an established tool for diagnosis of PAD (3), in the CHA2DS2-VASc (4) score would better define the prevalence of vascular disease. To address this issue, the Italian Society of Internal Medicine (SIMI) established an Italian registry documenting ABI in NVAF patients. The Atrial Fibrillation Registry for the ARAPACIS (Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study) study is an independent research project involving all Regional Councils of SIMI. The first objective of the study was to estimate the prevalence of ABI 640.90 in NVAF patients. Consecutive patients with NVAF referred to internal medicine wards were eligible for the enrollment. Enrollment started in October 2010 and continued until October 30, 2012. Patients were enrolled if they were 18 years or older and had a diagnosis of NVAF, recording during the qualifying admission/consultation or in the preceding 12 months, and if it was possible to obtain the ABI measurement. Exclusion criteria included the following: acquired or congenital valvular AF, active cancer, disease with life expectancy <3 years, hyperthyroidism and pregnancy. We initially planned to include 3,000 patients. The Data and Safety Monitoring Board (Online Appendix) decided to perform an interim analysis to assess the prevalence of ABI in the enrolled populations\u2014as a higher than expected prevalence of low ABI was detected\u2014and decided to interrupt the patients' enrollment. The sample size was amended as follows: a sample of 2,027 patients leads to the expected prevalence of 21% with a 95% confidence interval width of 3.5% (StataCorp LP, College Station, Texas). Among the 2,027 NVAF patients included in the study, hypertension was detected in 83%, diabetes mellitus in 23%, dyslipidemia in 39%, metabolic syndrome in 29%, and smoking in 15%. At least 1 atherosclerotic risk factor was detected in 90% of patients. The NVAF population was at high risk for stroke, with only 18% having a CHA2DS2-VASc score of 0 to 1, while 82% had a risk 652. Despite this, 16% were untreated with any antithrombotic drug, 19% were treated with antiplatelet drugs (APs), and 61% with oral anticoagulants (OAC); 4% of patients were treated with both APs and OAC. Among the AF population, 428 patients (21%) had ABI 640.90 compared with 1,381 patients, who had an ABI of 0.91 to 1.39 (69%); 204 patients (10%) had ABI 651.40 (Fig. 1). ABI recorded only in 1 leg was excluded from the analysis (n = 14). ABI 640.90 progressively increased from paroxysmal to permanent NVAF (18%, 21%, 24%; p = 0.0315). Figure 1. ABI Distribution of Any Category and CHA2DS2-VASc Score Including ABI 640.90 C = congestive heart failure (or left ventricular systolic dysfunction) (Points: 1), H = hypertension (Points: 1), A2 = Age 6575 years (Points: 2), D = diabetes mellitus (Points: 1), S2 = prior stroke or transient ischemic attack or thromboembolism (Points: 2); V = vascular disease (previous acute myocardial infarction, peripheral arterial disease, or aortic plaque) (Points: 1); A = age 65 to 74 years (Points: 1); Sc = sex category (female) (Points: 1). ABI = ankle brachial index. Figure optionsDownload full-size imageDownload high-quality image (447 K)Download as PowerPoint slide NVAF patients with ABI 640.90 were more likely to be hypertensive (88% vs. 82%; p = 0.032), diabetic (34% vs. 20%; p 0.90 (93% vs. 82%; p < 0.0001). Logistic regression analysis demonstrated that ABI 640.90 was significantly associated with a smoking habit (odds ratio [OR]: 1.99; 95% confidence interval [CI]: 1.48 to 2.66; p < 0.0001), diabetes (OR: 1.93; 95% CI: 1.51 to 2.46; p < 0.0001), age class 65 to 74 years (OR: 2.05; 95% CI: 1.40 to 3.07; p < 0.0001), age class 6575 years (OR: 3.12; 95% CI: 2.16 to 4.61; p < 0.0001), and history of previous transient ischemic attack/stroke (OR: 1.64; 95% CI: 1.20 to 2.24; p = 0.002). Vascular disease, as assessed by the history elements of CHA2DS2VASc score, was recorded in 17.3% of patients; inclusion of ABI 640.90 in the definition of vascular disease yielded a total prevalence of 33%. A higher prevalence of vascular disease was detected if ABI 640.90 was included in the CHA2DS2VASc score (Fig. 1). CHA2DS2VASc including ABI 640.90 was more associated with previous stroke (43%; OR: 1.85; 95% CI: 1.41 to 2.44; p < 0.0001) compared to CHA2DS2VASc with ABI 0.91 to 1.39 (23%; OR: 1.52; 95% CI: 1.10 to 2.11; p = 0.0117). To the best of our knowledge, there is no large-scale study that specifically examined the prevalence of ABI 640.90 in NVAF. In our population, 21% had ABI 640.90 indicating that NVAF is often associated with systemic atherosclerosis. The CHADS2 has been recently refined with the CHA2DS2-VASc score, which includes vascular disease as documented by a history of AMI, symptomatic PAD, or detection of atherosclerotic plaque in the aortic arch (4). Comparison of vascular prevalence as assessed by CHA2DS2-VASc score and/or ABI 640.90 is of interest to define the potentially positive impact of measuring ABI in the management of NVAF patients. Inclusion of ABI 640.90 in the definition of vascular disease greatly increased the prevalence of vascular disease, which increased from 17.3% (based on history alone) to 33% (based on ABI) in the entire population. If ABI 640.90 was encompassed in the definition of vascular disease of CHA2DS2-VASc score the prevalence of vascular disease increased in every risk class. Inclusion of ABI 640.90 in the CHA2DS2-VASc score allowed us to better define the risk profile of NVAF patients with an up-grading of the risk score in each CHA2DS2-VASc score category. This may have important therapeutic implications if the new score could be tested prospectively, as a higher number of NVAF patients would potentially be candidates for an anticoagulant treatment by measuring ABI. A prospective study is, therefore, necessary to validate the risk score of this new definition of vascular disease. In conclusion, this study provides the first evidence that one-fifth of NVAF patients had an ABI 640.90, indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF

Prevalence of peripheral artery disease by abnormal ankle-brachial index in atrial fibrillation: Implications for risk and therapy

To the Editor: Nonvalvular atrial fibrillation (NVAF) is the most common sustained arrhythmia encountered in clinical practice and is associated with a 5-fold increased risk for stroke (1). Moreover, patients with NVAF often suffer from atherosclerotic complications such as acute myocardial infarction (AMI) (2). Peripheral artery disease (PAD) is an established marker of systemic atherosclerosis but its prevalence in NVAF is still unclear. We reasoned that inclusion of ankle-brachial index (ABI), which is an established tool for diagnosis of PAD (3), in the CHA2DS2-VASc (4) score would better define the prevalence of vascular disease. Toaddress this issue, the ItalianSociety of InternalMedicine (SIMI) established an Italian registry documenting ABI inNVAF patients. The Atrial Fibrillation Registry for the ARAPACIS (Ankle- brachial Index Prevalence Assessment: Collaborative Italian Study) study is an independent research project involving all Regional Councils of SIMI. The first objective of the study was to estimate the prevalence of ABI 0.90 in NVAF patients. Consecutive patients with NVAF referred to internal medicine wards were eligible for the enrollment. Enrollment started in October 2010 and continued until October 30, 2012. Patients were enrolled if they were 18 years or older and had a diagnosis of NVAF, recording during the qualifying admission/consultation or in the preceding 12 months, and if it was possible to obtain the ABI measurement. Exclusion criteria included the following: acquired or congenital valvular AF, active cancer, disease with life expectancy &lt;3 years, hyperthyroidism and pregnancy. We initially planned to include 3,000 patients. The Data and Safety Monitoring Board (Online Appendix) decided to perform an interim analysis to assess the prevalence of ABI in the enrolled populationsdas a higher than expected prevalence of low ABI was detecteddand decided to interrupt the patients’ enrollment. The sample size was amended as follows: a sample of 2,027 patients leads to the expected prevalence of 21% with a 95% confidence interval width of 3.5% (StataCorp LP, College Station, Texas). Among the 2,027 NVAF patients included in the study, hyper- tension was detected in 83%, diabetes mellitus in 23%, dyslipidemia in 39%, metabolic syndrome in 29%, and smoking in 15%. At least 1 atherosclerotic risk factor was detected in 90% of patients. The NVAF population was at high risk for stroke, with only 18% having a CHA2DS2-VASc score of 0 to 1, while 82% had a risk 2. Despite this, 16% were untreated with any antith- rombotic drug, 19% were treated with antiplatelet drugs (APs), and 61% with oral anticoagulants (OAC); 4% of patients were treated with both APs and OAC. Among the AF population, 428 patients (21%) had ABI 0.90 (69%); 204 patients (10%) had ABI 1.40 (Fig. 1). ABI recorded only in 1 leg was excluded from the analysis (n ¼ 14). ABI 0.90 progressively increased from paroxysmal to permanent NVAF (18%, tensive (88% vs. 82%; p ¼ 0.032), diabetic (34% vs. 20%; p &lt; 0.0001), or smokers (20% vs. 14%; p ¼ 0.0008), or to have experi- enced transient ischemic attack or stroke (17% vs. 10%; p &lt; 0.001). 21%, 24%; p ¼ 0.0315). NVAF patients with ABI 0.90 were more likely to be hyper- NVAF patients with ABI 0.90 had a higher percentage of CHA2DS2-VASc score 2 compared with those with ABI &gt;0.90 (93% vs. 82%; p &lt; 0.0001). significantly associated with a smoking habit (odds ratio [OR]: 1.99; 95% confidence interval [CI]: 1.48 to 2.66; p &lt; 0.0001), diabetes (OR: 1.93; 95% CI: 1.51 to 2.46; p &lt; 0.0001), age class 65 to 74 years (OR: 2.05; 95% CI: 1.40 to 3.07; p &lt; 0.0001), age Logistic regression analysis demonstrated that ABI 0.90 was class 75 years (OR: 3.12; 95% CI: 2.16 to 4.61; p &lt; 0.0001), and history of previous transient ischemic attack/stroke (OR: 1.64; 95% CI: 1.20 to 2.24; p ¼ 0.002). Vascular disease, as assessed by the history elements of CHA2DS2VASc score, was recorded in 17.3% of patients; inclu- sion of ABI 0.90 in the definition of vascular disease yielded a total prevalence of 33%. A higher prevalence of vascular disease was detected if ABI 0.90 was included in the CHA2DS2VASc score (Fig. 1). CHA2DS2VASc including ABI 0.90 was more associated with previous stroke (43%; OR: 1.85; 95% CI: 1.41 to 2.44; p &lt; 0.0001) compared to CHA2DS2VASc with ABI 0.91 to 1.39 (23%; OR: 1.52; 95% CI: 1.10 to 2.11; p ¼ 0.0117). To the best of our knowledge, there is no large-scale study that specifically examined the prevalence of ABI 0.90 in NVAF. In our population, 21% had ABI 0.90 indicating that NVAF is often associated with systemic atherosclerosis. The CHADS2 has been recently refined with the CHA2DS2- VASc score, which includes vascular disease as documented by a history of AMI, symptomatic PAD, or detection of atheroscle- rotic plaque in the aortic arch (4). Comparison of vascular prevalence as assessed by CHA2DS2- NVAF patients. Inclusion of ABI 0.90 in the definition of vascular disease greatly increased the prevalence of vascular disease, which increased from 17.3% (based on history alone) to 33% (based compared with 1,381 patients, who had an ABI of 0.91 to 1.39 to better define the risk profile ofNVAFpatients with an up-grading of the risk score in each CHA2DS2-VASc score category. This may have important therapeutic implications if the new score could be tested prospectively, as a higher number of NVAF patients would on ABI) in the entire population. If ABI 0.90 was encompassed in the definition of vascular disease of CHA2DS2-VASc score the prevalence of vascular disease increased in every risk class. Inclusion of ABI0.90 in theCHA2DS2-VASc score allowed us VASc score and/or ABI 0.90 is of interest to define the poten- tially positive impact of measuring ABI in the management of potentially be candidates for an anticoagulant treatment by measuring ABI. A prospective study is, therefore, necessary to validate the risk score of this new definition of vascular disease. In conclusion, this study provides the first evidence that one-fifth of NVAF patients had an ABI 0.90, indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF

Frequency of Left Ventricular Hypertrophy in Non-Valvular Atrial Fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p <0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p <0.0001), age (OR 1.03 per year, p <0.001), hypertension (OR 2.30, p <0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention