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The article discusses the results of the VOYAGER PAD clinical trial, which investigated the use of low-dose rivaroxaban plus aspirin in patients with peripheral artery disease (PAD) undergoing lower extremity revascularization. The trial found that rivaroxaban reduced the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) by 15% compared to placebo. The study also examined the effects of rivaroxaban in patients with concomitant coronary artery disease (CAD) and found consistent benefits in both groups. However, the risk of major bleeding was higher in patients with CAD. The findings suggest that rivaroxaban plus aspirin may be an effective treatment option for patients with PAD, but shared decision-making between clinicians and patients is important. [Extracted from the article]

BACKGROUND: Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER. METHODS: The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included. RESULTS: Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76–0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76–1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67–0.98]; P interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54–0.90]; P =0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30–58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06–2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40–1.87]; P =0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02–1.52]), although this finding was isolated to specific regions. CONCLUSIONS: Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease. [ABSTRACT FROM AUTHOR]

Peripheral Artery Disease (PAD) affects millions of people worldwide and can range from asymptomatic to severe limb-threatening ischemia. Those with PAD have higher rates of cardiovascular events and major adverse limb events compared to those without PAD. Recent clinical trials have shown the benefits of intensive low-density lipoprotein-lowering therapy and antithrombotic therapies for PAD. Guidelines recommend supervised exercise and lower-extremity revascularization as first-line treatments for walking impairment in PAD. However, the uptake of supervised exercise is low, and there is a need for more effective home-based exercise interventions. Endovascular revascularization procedures are common but carry risks, and optimal timing and procedures are still being studied. Disparities in diagnosis and treatment have been identified, particularly among different racial and socioeconomic groups. Current drug therapies for improving walking performance in PAD are limited, and more research is needed to identify effective treatments. [Extracted from the article]

The article titled "Unplanned Index Limb Revascularization With Rivaroxaban Versus Placebo in Patients With Critical Limb-Threatening Ischemia After Endovascular and Surgical Treatment: Insights From VOYAGER PAD" discusses the results of the VOYAGER PAD study, which examined the efficacy of rivaroxaban in reducing ischemic events, including unplanned index limb revascularization (UILR), in patients undergoing lower-extremity revascularization (LER) for symptomatic peripheral artery disease (PAD). The study found that rivaroxaban reduced UILR by 22% in patients with critical limb-threatening ischemia (CLTI), regardless of the initial LER method (surgical or endovascular). The findings suggest that rivaroxaban may be beneficial in reducing repeat revascularization in patients with CLTI. However, it is important to note that the trial was not powered to show statistical significance for the UILR endpoint within the subgroups presented. [Extracted from the article]

This document discusses the challenges and benefits of implementing low-dose anticoagulant use in patients with peripheral artery disease (PAD). The article highlights the prevalence and seriousness of PAD, as well as the underutilization of guideline-recommended therapies. The VOYAGER PAD and COMPASS trials have provided evidence supporting the use of low-dose anticoagulation in PAD patients, particularly those who have undergone endovascular revascularization procedures. The article emphasizes the need for further research, safety studies, and implementation efforts to ensure the effective use of low-dose anticoagulants in clinical practice. Additionally, barriers such as high drug prices and prescriber behavior are discussed, and potential interventions to increase anticoagulation use are suggested. [Extracted from the article]

Peripheral artery disease (PAD) affects 200 million individuals worldwide. In the United States, certain demographic groups experience a disproportionately higher prevalence and clinical effect of PAD. The social and clinical effect of PAD includes higher rates of individual disability, depression, minor and major limb amputation along with cardiovascular and cerebrovascular events. The reasons behind the inequitable burden of PAD and inequitable delivery of care are both multifactorial and complex in nature, including systemic and structural inequity that exists within our society. Herein, we present an overview statement of the myriad variables that contribute to PAD disparities and conclude with a summary of potential novel solutions. [ABSTRACT FROM AUTHOR]

B Conclusions: b Compared with nonoperative myocardial infarction patients, perioperative myocardial infarction patients had elevated risk of all-cause mortality, venous thromboembolism, and acute kidney failure. The 5-year risk of all-cause mortality was 67.5% (95% CI, 66.1%-69.0%) for perioperative myocardial infarction patients and 38.0% (95% CI, 37.7%-38.3%) for nonoperative myocardial infarction patients. B Results: b We identified 5068 patients with perioperative myocardial infarction and 137 862 patients with nonoperative myocardial infarction. [Extracted from the article]

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER.Methods: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee.Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased.Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216. [ABSTRACT FROM AUTHOR]

Background: Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization.Methods: We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities.Results: Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004.Conclusions: Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations. [ABSTRACT FROM AUTHOR]

Background: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis.Methods: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer.Results: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively).Conclusions: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534. [ABSTRACT FROM AUTHOR]

Background: Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C.Methods: This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a).Results: At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events.Conclusions: In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402. [ABSTRACT FROM AUTHOR]

Background: Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.Methods: The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: <5%, 5% to 20%, and >20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT5) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH5) estimations.Results: Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants <70 years of age not at high risk of bleeding (n=3540). The overall NNT5 with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH5 was 355. The NNT5 was also greater than or similar to the NNH5 among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT5 was lower than NNH5. This was true both overall (for CAC≥100, NNT5=140 versus NNH5=518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT5 was much higher than the NNH5 (overall, NNT5=1190 versus NNH5=567).Conclusions: CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis evaluated the efficacy and safety of catheter ablation versus medical therapy in patients with atrial fibrillation. Patients who score <=6 have a negative likelihood ratio of 0.42 for obstructive CAD, whereas those who score >=14 have a positive likelihood ratio of >5.5 for obstructive CAD. We sought to assess contemporary outcomes after PCI and CABG in patients with left main CAD according to SS and revascularization type from a large randomized trial. B Methods: b The EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized patients with left main CAD and site-assessed SS<=32 to PCI with everolimus-eluting stents or CABG. [Extracted from the article]

Paclitaxel drug-coated balloons and drug-eluting stents became commercially available for the treatment of intermittent claudication in 2015 and 2012, respectively. Both devices demonstrated superiority in limb revascularization compared with non-paclitaxel-coated devices and were rapidly accepted into clinical practice. In a recent systematic review and study-level meta-analysis, Katsanos et al reported a late all-cause mortality signal for patients in the drug-coated balloon and drug-eluting stent arms of randomized clinical trials for both devices. As a result of this safety signal, Vascular InterVentional Advances Physicians (VIVA), a not-for-profit 501c(3) organization, convened the Vascular Leaders Forum on March 1 and 2, 2019, in Washington, DC, to initiate an open and collaborative process of investigation into this finding. The Vascular Leaders Forum brought together 100 stakeholders, including an international group of representatives of cardiovascular medicine, interventional radiology, vascular medicine, and vascular surgery; oncologists; basic scientists; the Food and Drug Administration; the Centers for Medicare and Medicaid Services; and commercial manufacturers of these products. The Vascular Leaders Forum reviewed the natural history of peripheral arterial disease, the use of paclitaxel in peripheral arterial disease and other conditions, the harm signal noted by Katsanos et al, the impact of the methods chosen by Katsanos et al, possible mechanisms of harm, the role of the Food and Drug Administration in a setting like this one, and guidance for clinicians taking care of patients with symptomatic peripheral arterial disease. This document integrates the most current data to help establish an appropriate path forward to understand the risks and benefits associated with these technologies while ensuring the best treatment paradigm for patients. [ABSTRACT FROM AUTHOR]

There are >12 million patients with peripheral artery disease in the United States. The most severe form of peripheral artery disease is critical limb ischemia (CLI). The diagnosis and management of CLI is often challenging. Ethnic differences in comorbidities and presentation of CLI exist. Compared with white patients, black and Hispanic patients have higher prevalence rates of diabetes mellitus and chronic renal disease and are more likely to present with gangrene, whereas white patients are more likely to present with ulcers and rest pain. A thorough evaluation of limb perfusion is important in the diagnosis of CLI because it can not only enable timely diagnosis but also reduce unnecessary invasive procedures in patients with adequate blood flow or among those with other causes for ulcers, including venous, neuropathic, or pressure changes. This scientific statement discusses the current tests and technologies for noninvasive assessment of limb perfusion, including the ankle-brachial index, toe-brachial index, and other perfusion technologies. In addition, limitations of the current technologies along with opportunities for improvement, research, and reducing disparities in health care for patients with CLI are discussed. [ABSTRACT FROM AUTHOR]

Background: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated.Methods: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized patients with peripheral artery disease to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index ≤0.80 or previous lower extremity revascularization. Patients were grouped according to the primary outcome, postrandomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation.Results: Among 13 885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had previous peripheral revascularization and lower baseline ankle-brachial index. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any previous peripheral revascularization (Hazard Ratio [HR] 4.7, 95% CI 3.3-6.8, P<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, P=0.03), and baseline ankle-brachial index ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, P<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, P=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, P<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with previous revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, P=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, P<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, P<0.01).Conclusions: Previous peripheral revascularization, baseline atrial fibrillation, and lower ankle-brachial index identify peripheral artery disease patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01732822. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Intraplaque hemorrhage promotes atherosclerosis progression, and erythrocytes may contribute to this process. In this study we examined the effects of red blood cells on smooth muscle cell mineralization and vascular calcification and the possible mechanisms involved. Methods: Erythrocytes were isolated from human and murine whole blood. Intact and lysed erythrocytes and their membrane fraction or specific erythrocyte components were examined in vitro using diverse calcification assays, ex vivo by using the murine aortic ring calcification model, and in vivo after murine erythrocyte membrane injection into neointimal lesions of hypercholesterolemic apolipoprotein E–deficient mice. Vascular tissues (aortic valves, atherosclerotic carotid artery specimens, abdominal aortic aneurysms) were obtained from patients undergoing surgery. Results: The membrane fraction of lysed, but not intact human erythrocytes promoted mineralization of human arterial smooth muscle cells in culture, as shown by Alizarin red and van Kossa stain and increased alkaline phosphatase activity, and by increased expression of osteoblast-specific transcription factors (eg, runt-related transcription factor 2, osterix) and differentiation markers (eg, osteopontin, osteocalcin, and osterix). Erythrocyte membranes dose-dependently enhanced calcification in murine aortic rings, and extravasated CD235a-positive erythrocytes or Perl iron-positive signals colocalized with calcified areas or osteoblast-like cells in human vascular lesions. Mechanistically, the osteoinductive activity of lysed erythrocytes was localized to their membrane fraction, did not involve membrane lipids, heme, or iron, and was enhanced after removal of the nitric oxide (NO) scavenger hemoglobin. Lysed erythrocyte membranes enhanced calcification to a similar extent as the NO donor diethylenetriamine-NO, and their osteoinductive effects could be further augmented by arginase-1 inhibition (indirectly increasing NO bioavailability). However, the osteoinductive effects of erythrocyte membranes were reduced in human arterial smooth muscle cells treated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide or following inhibition of NO synthase or the NO receptor soluble guanylate cyclase. Erythrocytes isolated from endothelial NO synthase–deficient mice exhibited a reduced potency to promote calcification in the aortic ring assay and after injection into murine vascular lesions. Conclusions: Our findings in cells, genetically modified mice, and human vascular specimens suggest that intraplaque hemorrhage with erythrocyte extravasation and lysis promotes osteoblastic differentiation of smooth muscle cells and vascular lesion calcification, and also support a role for erythrocyte-derived NO. [ABSTRACT FROM AUTHOR]

Keywords: cardiovascular risk; computed tomography; coronary artery disease EN cardiovascular risk computed tomography coronary artery disease 585 586 2 08/22/22 20220823 NES 220823 According to the American Heart Association (AHA) and the American College of Cardiology (ACC), coronary artery calcium (CAC) scanning is the best way to improve selection of patients for lipid-lowering drug treatment when the initial risk assessment by the Pooled Cohort Equations is inconclusive.[1] Similar recommendations have been issued by the Canadian Cardiovascular Society and the Cardiac Society of Australia and New Zealand. Cardiology organizations have recommended CAC as a reasonable test in intermediate risk primary prevention patients to improve selection of patients for more intensive and safe statin therapy for prevention. [Extracted from the article]

Although rates of ischemic complications in type 2 diabetes mellitus seem to be declining, some of the most feared and costly complications, namely end-stage kidney disease, heart failure, and lower limb amputations, remain on the rise. The development of chronic kidney disease in type 2 diabetes mellitus marks the beginning of a sharp increase in cardio-renal complications.[2] Indeed, in type 2 diabetes mellitus, chronic kidney disease is one of the strongest determinants of atherosclerotic vascular events and heart failure, with a hazard that parallels the degree/stage of kidney insufficiency. Thus, it is imperative that treatment goals of diabetic kidney disease (DKD) involve both kidney protection and cardiovascular risk reduction, particularly because many patients with DKD will have a cardiovascular event before developing end-stage kidney disease. [Extracted from the article]

First, a detailed analysis of the specific causes of death in all patients enrolled in all PTX-based trials for PAD treatment needs to be performed. Third, all ongoing PTX-based clinical trials need to determine and monitor the cause of mortality and possible link to PTX therapy. [Extracted from the article]

Background—Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow—derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results—The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62-3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63-3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22-2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions—Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. [ABSTRACT FROM AUTHOR]

2-4 Given that alirocumab lowered Lp(a) by 23.5% but LDL cholesterol by about 60%, 2-4 it is predictable that patients with higher Lp(a) at baseline were less likely to achieve an LDL below the action threshold and consequently less likely to be withdrawn from active treatment (as alluded to in Bittner et al 3). Because of a concern about low LDL cholesterol levels, participants who achieved a consistent LDL cholesterol <15 mg/dL during the trial were withdrawn from study treatment (most likely alirocumab) and switched to placebo. [Extracted from the article]

The article discusses ankle-brachial index (ABI) which is the ratio of the systolic blood pressure (SBP) measured at the ankle to that measures at the brachial artery. The authors state that ABI was initially proposed for the noninvasive diagnosis of lower-extremity peripheral artery disease (PAD). They provide recommendations for a standardized method to determine the ABI, and provide guidance on the interpretation of the ABI in the clinical setting.

Background--Hypoxia-inducible factor-la (HIF-l&agr;) is a transcriptional regulatory factor that orchestrates cellular responses to hypoxia. It increases collateral vessel growth and blood flow in models of hind-limb ischemia. This study tested whether intramuscular administration of Ad2/HIF-1 &agr;/VP 16, an engineered recombinant type 2 adenovirus vector encoding constitutively active HIF-l&agr;, improves walking time in patients with peripheral artery disease and intermittent claudication. Methods and Results--Two hundred eighty-nine patients with claudication were randomized in a double-blind manner to 1 of 3 doses of Ad2/HIF-l&agr;/VP 16 (2×109 2×1010, or 2×1011 viral particles) or placebo, administered by 20 intramuscular injections to each leg. Graded treadmill tests were performed at baseline and then 3,6, and 12 months after treatment. The primary end point was the change in peak walking time from baseline to 6 months. The secondary end point was change in claudication onset time, and tertiary end points included changes in ankle-brachial index and quality-of-life assessments. Median peak walking time increased by 0.82 minutes (interquartile range, --0.05-1.93 minutes) in the placebo group and by 0.82 minutes (interquartile range, -0.07-2.12 minutes), 0.28 minutes (interquartile range, -0.37-1.70 minutes), and 0.78 minutes (interquartile range, --0.02-2.10 minutes) in the HIF-l&agr; 2×109, 2×1010, and 2×1011 viral particle groups, respectively (P=NS between placebo and each HIF-la treatment group). There were no significant differences in claudication onset time, ankle-brachial index, or quality-of-life measurements between the placebo and each HIF-la group. Conclusions--Gene therapy with intramuscular administration of Ad2/HIF-l&agr;/VP16 is not an effective treatment for patients with intermittent claudication. [ABSTRACT FROM AUTHOR]

The authors have proposed that SGLT2 inhibition with empagliflozin leads to a significant reduction in LVMi, which may contribute to the beneficial cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. Further studies should be performed to assess more precisely the possible link between SGLT2 inhibitors and NO bioavailability and its contribution to the therapeutic approach to cardiac hypertrophy in patients with type 2 diabetes mellitus and coronary artery disease. [Extracted from the article]

Background: The FOURIER trial of a PCSK9 inhibitor in patients with prevalent cardiovascular disease reported that patients with peripheral artery disease (PAD) without myocardial infarction (MI) or stroke (MI/stroke) had worse prognosis than those with MI/stroke without PAD. However, whether this observation holds in the general population is unknown. Methods: We conducted a prospective analysis of 5,858 participants aged 40 years or older from the 1999-2004 National Health and Nutrition Examination Survey and compared overall mortality among four categories by PAD (ankle-brachial index ≤0.9) and MI/stroke (self-report) status at baseline using Kaplan-Meier curves and multivariable Cox models adjusted for potential confounders such as age, sex, race, diabetes, smoking, blood pressure, and lipids. Results: There were 125 participants (2.1%) with both PAD and MI/stroke, 323 (5.5%) with PAD without MI/stroke, and 571 (9.7%) with MI/stroke without PAD (4,785 participants without MI/stroke or PAD). During a median follow-up of 9.5 years, 1,133 participants died. Compared to those without PAD or MI/stroke, participants with both MI/stroke and PAD had the worst survival (36.8% at 10 years), followed by those with PAD without MI/stroke (56.4%) and then those with MI/stroke without PAD (71.0%) (Figure). Multivariable Cox models showed similar patterns: adjusted hazard ratios of 2.81 [95% CI 2.16-3.66] in MI/stroke with PAD, 1.85 (1.41-2.43) in PAD without MI/stroke, and 1.59 [1.30-1.95] in MI/stroke without PAD. Conclusions: In the general population, the presence of PAD contributed to significantly higher mortality in those with and without MI/stroke. PAD without MI/stroke showed similar or even worse prognosis than MI/stroke without PAD. These results suggest the importance of recognizing the presence of PAD in the community. [ABSTRACT FROM AUTHOR]

Introduction: Hypertension is associated with several circulatory biomarkers and target organ damage. Hypothesis: The present study investigated the relationship between circulatory biomarkers with markers of TOD in never-treated hypertensives. Methods: We enrolled 896 consecutive essential hypertensives (mean age 52.9±12.0 years, 472 males). Markers of TOD [left ventricular mass index (LVMI), pulse wave velocity (PWV), estimated glomerular filtration rate (eGFR), ankle-brachial index (ABI), and microalbuminuria] were evaluated in all patients. LVMI was assessed echocardiographically using the Devereux formula. eGFR was estimated using the MDRD formula. Microalbuminuria was measured with the albumin-creatinine ratio. Organ damage was defined as described in the 2013 European Hypertension Guidelines. Circulatory biomarkers were assessed by measurement of high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), glycated haemoglobin (HbA1c) and thyroid-stimulating hormone (TSH) in blood samples. Results: In multivariable regression analysis, hsCRP exhibited significant association with LVMI (p=0.018), PWV (p<0.001), eGFR (p=0.006) and urine microalbumin (p<0.001), which was independent of relevant confounders. In identical analysis, associations were observed for SAA with PWV (p<0.001), urine microalbumin (p<0.001), LVMI (p<0.001), eGFR (p=0.008) and for HbA1c with LVMI (p=0.001), ABI (p=0.046), PWV (p=0.003). No associations were observed between TSH and TOD. In further analysis, receiver operating characteristic (ROC) curves were generated to evaluate the ability of hsCRP, SAA and HbA1c to discriminate subjects with extended TOD. The area under the curve (AUC) and 95% CIs of the ROC curves for concurrent TOD in 4 or more organs were AUC=0.71 (95% CI: 0.64-0.78, p<0.001) for SAA, AUC=0.68 (95% CI: 0.61-0.75, P<0.001) for HbA1c and AUC=0.65 (95% CI: 0.57-0.74, p<0.001) for hsCRP, respectively. (Figure) Conclusions: Our findings support the close relationship between circulatory biomarkers and TOD in hypertension, as well as, the predictive ability of hsCRP, SAA and HbA1c levels for TOD. However, the exact role of these biomarkers in the development of TOD in hypertension warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Compared to coronary and carotid arteries, there is much less knowledge on atherosclerotic plaque characteristics and their clinical relevance in lower-extremity arteries. Magnetic resonance (MR) vessel wall imaging allows for in vivo detection of intraplaque hemorrhage (IPH), which has been consistently associated with increased risks for clinical events in coronary and carotid artery disease. Objective: In a pilot study, we sought to estimate the prevalence of IPH in peripheral artery disease and examine plaque progression in the presence of IPH. Methods: Ten patients with ankle brachial index <0.90 in one or both legs were recruited. A 3D MR imaging protocol with a large coverage (30 or 45 cm in the head-feet direction) and isotropic resolution (voxel size: 0.8x0.8x0.8 mm3) was used to scan bilateral legs in the coronal plane from the common femoral artery bifurcation to the popliteal artery at baseline and 6 months later. Images were reformatted into axial slices for detailed visualization of vessel wall. Following previous publications on carotid MRI, IPH was detected as hyperintense signals on heavily T1-weighted images. Superficial femoral artery (SFA) segments (3 cm in length) with IPH were identified, of which lumen and outer wall were segmented on black-blood images (motion-sensitized flow suppression for improved vessel wall delineation) to measure plaque progression and remodeling. Image analysis was performed in a blinded fashion without knowing time relationship between serial images. Results: Twenty SFAs were analyzed. After excluding 4 arteries with total occlusion, 5 out of the 16 arteries (31%) or 50% of the subjects showed IPH in 1 or more SFA segments. After 6 months, there was significant progression in vessel wall area in SFA segments with IPH (mean ± standard deviation: 43.5 ± 13.9 mm2 versus 47.3 ± 17.3 mm2, p=0.045), which resulted in outer wall expansion (mean [95% confidence intervals]: +3.9 mm2 [+0.4, +7.4], p=0.035) rather than lumen reduction (-0.02 mm2 [-2.6, +2.5], p=0.99). Conclusions: MR vessel wall imaging revealed that IPH is likely a common feature in femoral atherosclerosis. SFA segments with IPH showed expansive remodeling in 6 months, of which the clinical significance needs to be further studied. [ABSTRACT FROM AUTHOR]

Background: Peripheral artery disease (PAD) is a prevalent condition affecting one in four patients with end stage renal disease (ESRD). Intermittent pneumatic compression (IPC) has proven benefits in PAD. We are conducting a trial testing the utility of IPC in the ESRD population by assessing the improvement in quality of life (QOL), functional limitation and walking performance from PAD-related symptoms. We aim to present our pilot results. Methods: Prospective single cohort study undergoing recruitment of outpatients at the hemodialysis (HD) unit of John H. Stroger Hospital. The calculated sample size is 78. PAD is confirmed by ankle-brachial index (ABI) and demographics obtained from interview and chart review. At baseline and post intervention, a Six-minute Walk Test (6MWT), Peripheral Artery Questionnaire (PAQ) and Walking Impairment Questionnaire (WIQ) are administered. The IPC device (Bio Arterial Plus) is used for intervention during HD. We present continuous variables as median (IQR) and categorical variables as percentage. Wilcoxon signed rank test was performed for comparison of results. Results: So far, 9 patients have completed intervention for the pilot study, 44% are men, the majority hispanic (66%), with age 48 (41-63) years. At baseline 66% of ABI were abnormal, all due to non-compressible PAD 1.46 (1.20-1.62). All patients have HTN, 44% diabetes, 33% hyperlipidemia and 33% heart failure. The median time of intervention is 70 (60-83) days. There was a significant difference in QOL measured by the WIQ (Fig.1), PAQ physical limitation (p=0.011), and PAQ social limitation (p=0.018). Although there was a trend towards benefit, no statistical difference was found on rest of objective and subjective measured parameters (p>0.05) Conclusions: Preliminary, IPC shows to improve many subsets of QOL in patients with ESRD and PAD. Given the small sample, improvement of walking distance remains elusive but with trends towards benefit. [ABSTRACT FROM AUTHOR]

Introduction: Recently medical therapies have shown benefit in reducing major adverse limb events (MALE) including acute limb ischemia (ALI), urgent revascularization for ischemia, and ischemic amputation in patients with atherosclerotic vascular disease. Defining predictors of MALE may facilitate patient selection for application of novel therapies. Hypothesis: Clinical characteristics can be used to develop a risk score that will predict MALE Methods: Clinical characteristics independently predictive of ALI were identified among 3,985 patients with PAD randomized to placebo in TRA 2°P-TIMI 50 and were used to develop a risk score (c-statistic 0.82). This score was prospectively validated in 7,053 and 13,723 placebo patients from the PEGASUS-TIMI 54 and FOURIER trials respectively. Risk in each trial was evaluated stratified by the investigational treatment (vorapaxar, ticagrelor, or evolocumab). Results: In the broad PAD placebo population of TRA 2°P-TIMI 50, seven independent predictors of ALI with relative risks ranging from 1.69 to ~10 fold were identified including claudication, prior peripheral revascularization or amputation, ankle brachial index ≤ 0.5, heart failure, low body weight, elevated CRP and ASA monotherapy and assigned a point score.There was a gradient of MALE risk in placebo treated patients from 0.1% to 19.7% with increasing score (p<0.0001; Figure, Top). When validated in PEGASUS-TIMI 54 and FOURIER, discrimination remained high (c-statistic of 0.81 in both datasets). A risk of 4 generally correlated to an annualized risk of MALE of ~ 1% (1.1% TRA2P-TIMI 50, 0.93% PEGASUS-TIMI 54, 1.2% FOURIER). A score <4 identified patients at low risk of MALE, whereas those with a score ≥ 4 had greater baseline risk and benefit of randomized therapy (Figure, Bottom). Conclusions: A simple risk score can identify patients at greater risk of MALE who derive greater absolute reductions with effective therapies. [ABSTRACT FROM AUTHOR]

Introduction: PAD is twice as common in carotid stenosis patients with an associated higher stroke and myocardial infarction (MI) risk, suggesting a more aggressive phenotype for atherosclerosis in these individuals. We identified blood biomarkers of PAD risk among patients with ≥50% carotid stenosis to explore inflammatory and thrombotic mechanisms of atherosclerosis development in multiple vascular beds. Methods: Asymptomatic patients with ≥50% carotid stenosis were tested for 58 plasma markers of inflammation, cell adhesion, angiogenesis and coagulation (Thermo Scientific and Bio-Rad Laboratories). Demographics, comorbidities, PAD symptoms [claudication, rest pain or equivalent (ulceration, gangrene or amputation)] and diagnostic tests (ankle-brachial index, arterial physiologic testing, duplex ultrasound and arterial CT) were identified by medical record review. Variables associated with PAD presence and severity (p<0.15) were included for multivariate analysis. Results: We enrolled 117 patients (97% male, 39% smokers, 82% hyperlipidemic). Thirty-four (29%) had PAD symptoms (12 at rest). PAD was moderate to severe in 23 (20%) and severe in 11 (9%) by testing. Monocyte chemoattractant protein-1 (MCP-1) inversely associated with symptom presence (p = 0.0024). Age (p=0.0051), triglycerides (p=0.0650), and MCP-1 (0.0055) inversely and D-dimer (0.0018) directly associated with symptom severity. Plasma creatinine (p=0.03) and IL12p70 (0.04) associated with PAD presence and IL12p70 (p = 0.009) and soluble intercellular adhesion moliecule-1 (sICAM1) (p = 0.038) associated with PAD severity by testing. Conclusions: In our carotid stenosis cohort, lower MCP-1 levels, younger age and higher D-dimer levels were associated with PAD presence and/or more severe symptoms. Higher IL-12p70 and plasma creatinine were associated with PAD presence by testing, with higher IL-12p70 and sICAM1 levels in more severe disease. In patients with established carotid atherosclerosis, presence of and more severe PAD symptoms may rely less on monocyte recruitment and tissue factor regulation by MCP-1. The association between IL-12p70 and PAD supports a role for Th1 cell mediated immunity in mechanisms of atherosclerosis development in multiple vascular beds. [ABSTRACT FROM AUTHOR]

Introduction: With the increasing prevalence of peripheral artery disease (PAD) and impairment of quality of life, lower extremity revascularization is commonly performed to improve patient morbidity and quality of life; however, adverse cardiovascular and limb events are major concerns. We and others have shown that platelet aggregation in response to submaximal epinephrine can identify a population with a hyperreactive platelet phenotype. We tested the hypothesis that an increase in platelet aggregation in response to submaximal epinephrine ex vivo measured prior to revascularization predicts major adverse cardiac and limb events (MACLE) within 30-days. Methods: A cohort of 300 patients with symptomatic PAD undergoing lower extremity revascularization was recruited in the Platelet Activity and Cardiovascular Events (PACE) study. Immediately prior to revascularization, platelet hyperreactivity was investigated via light transmission aggregation in response to epinephrine 0.4uM. Aggregation is reported as percent aggregation at 180 seconds. The composite of MACLE consisted of death, myocardial infarction (MI), stroke or major amputation up to 30-days. Odds ratios (ORs) and 95% CIs were assessed using logistic regression modeling. Results: At 30-days, MACLE occurred in 31 of 289 (10.7%) patients. Patients with versus without MACLE had higher platelet aggregation (36% [18, 45) vs. 27% [15, 39], P=0.13). After adjustment for age, sex, race, and prior MI, platelet aggregation was associated with MACLE (for every 1% increase OR 1.02, 95% CI 1.0 to 1.04, P=0.049). Overall, 10% of patients with PAD had a hyperreactive platelet phenotype (>60% aggregation). Patients with an event were more frequently hyperreactive than patients without an event (23.1% vs. 8.5%, P=0.019). After multivariable adjustment, patients with platelet hyperreactivity were more likely to experience MACLE at 30-days (OR 3.6, 95% CI 1.2 to 10.6, P=0.02). Conclusions: Platelet aggregation in response to submaximal epinephrine is a useful biologic marker for the prediction of MACLE in PAD patients undergoing lower extremity revascularization. [ABSTRACT FROM AUTHOR]

Introduction: Simultaneous measurements of central and peripheral blood pressure (BP) throughout 24 hours (24-h) has become possible due to technological advances. We investigated the association between circadian hemodynamic characteristics and the presence and degree of target organ damage (TOD) in essential hypertension. Methods: Circadian hemodynamics, including 24-h brachial and central systolic BP (SBP), cardiac index (CI), and total vascular resistance (TVR), were evaluated using an oscillometric device, Mobil-O-Graph, in 272 hypertensive patients (67.8±16.0 years, 54% women). TOD, namely carotid wall thickening, left ventricular (LV) hypertrophy, and albuminuria, was assessed in all patients. Results: The prevalence of having carotid wall thickening, LV hypertrophy, and albuminuria were 21.5, 26.8, and 46.5%, respectively. All SBP estimates [office, 24-h brachial (TOD 0: 123±13, TOD 1: 129±14, TOD ≥2: 136±14 mmHg) and central], and the difference between 24-h brachial and central SBP (TOD 0: 9±3, TOD 1: 12±5, TOD ≥2: 15±7 mmHg), an index of pressure amplification, increased significantly with increasing the number of having TOD (all p <0.01 for trend). Multivariate logistic regression analysis showed that, 24-h brachial (p <0.05) and central SBP [odds ratio (OR) 1.03 for 1 mmHg increase, p <0.05), and the difference between 24-h brachial and central SBP (OR 1.16 for 1 mmHg increase, p <0.01), but not office, were associated with the presence of at least one sign of TOD. In all subgroups, CI decreased from daytime to nighttime (all p <0.05), but this decrease did not different among subgroups. Both in daytime and nighttime period, TVR increased significantly with increasing the number of having TOD (all p <0.01 for trend). In patients without TOD, TVR did not change significantly from daytime to nighttime; however, a significant increase in TVR was found in those with TOD (TOD 1: 1358±167 to 1415±191, TOD ≥2: 1427±188 to 1492±210 dyn*s/cm5, p <0.05, respectively). Conclusions: These results showed that, in essential hypertension, the 24-h peripheral and central SBP could be a marker of subclinical TOD, and further, circadian hemodynamics in patients with TOD are characterized by increased pressure amplification and disturbed circadian hemodynamic variation. [ABSTRACT FROM AUTHOR]

Objective: The TIMI Risk Score for secondary prevention (TRS2°P), a simple scoring system based on presence/absence of nine clinical factors, was developed to stratify the risk of secondary events in patients with a history of myocardial infarction (MI), but its performance has not been evaluated in patients with peripheral artery disease (PAD). Since MI and PAD are caused by similar biology and underlying atherosclerotic disease it is possible that TRS2°P is also informative in PAD patients. Methods: TRS2°P was calculated with a point value of 1 assigned for heart failure, hypertension, age ≥75 years, diabetes, stroke, coronary artery bypass graft, PAD, kidney dysfunction, and current smoking (since all patients had PAD, the lowest possible score was 1). We evaluated prediction statistics of TRS2°P for major adverse cardiovascular disease (MACE) (a composite of cardiovascular death, myocardial infarction, or ischemic stroke) in 386,458 patients with PAD in five international cohorts from New Zealand, South Korea, Sweden, and the US participating in the Chronic Kidney Disease Prognosis Consortium. Results: Overall, there were 134,827 cases of MACE outcomes reported across five cohorts over a mean follow-up of 5 years, and overall MACE rate ranged from 1.5 to 8.6 (per 100 person-years). The TRS2°P showed modest calibration (Brier score ranged from 0.061 to 0.160) and discrimination (c-statistics ranged from 0.59 to 0.69) across cohorts (Brier score was 0.098 and c-statistic was 0.67 in the TRS2°P derived dataset). Although there was some heterogeneity across cohorts, the predictors in the TRS2°P were generally associated with MACE in patients with PAD, with the strongest association for a history of heart failure (meta-analyzed adjusted hazard ratio [HR] 2.1), followed by age ≥75 years (HR 1.8), stroke (HR 1.7), kidney dysfunction (HR 1.4), and current smoking (HR 1.2). Hypertension and coronary artery bypass graft surgery did not reach statistical significance. Conclusion: TRS2°P was reasonably predictive of MACE outcomes when applied in patients with PAD and thus can be a reasonable tool for risk assessment in two common leading atherosclerotic diseases, MI and PAD. [ABSTRACT FROM AUTHOR]

Introduction: Experimental evidence suggests sedentary time (ST), in part, contributes to cardiovascular disease risk by eliciting detrimental hemodynamic changes (blood pooling, turbulent blood flow) in the lower limbs. However, few studies have examined the association of ST and peripheral artery disease (PAD). Hypothesis: We hypothesized that longer daily ST is associated with higher odds of PAD, independent of moderate-to-vigorous physical activity (MVPA). Methods: We examined cross-sectional associations of accelerometer-measured ST (measured over 7 days) and the ankle brachial index (ABI) among 7,677 Hispanic adults (ages 45-74) who were enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). ST (<100 counts/min) was standardized to 16 hours/d of wear time. Using multivariable logistic regression accounting for the complex survey design, we analyzed quartiles of ST then used restricted cubic splines (RCS) to assess non-linear associations of ST with odds of PAD (ABI ≤ 0.9), all models controlled for claudication, MVPA, and traditional cardiovascular risk factors. Results: Median ST was 12.2 hours/day (76% of wear time) and 366 (5%) participants had PAD. Using RCS with 3 knots (10th, 50th & 90th percentile), ST had a significant non-linear association with PAD (p= 0.004). As seen in the dose-response figure, a threshold effect was seen such that time spent above median ST was associated with significantly higher odds of PAD. For example, compared to median ST, 2 hours above median ST (14.2 hours/day) was associated with 1.60 times the odds of PAD (OR 1.60, 1.24-2.07). Conclusions: Among Hispanic/Latino adults, higher ST is associated with higher odds of PAD, independent of claudication, MVPA, and traditional cardiovascular risk factors. Importantly, this effect was only observed at higher levels of ST. Further study is warranted to determine if reducing high levels of ST may reduce risk of PAD or prevent progression of the disease. [ABSTRACT FROM AUTHOR]

Betatrophin, also called angiopoietin-llike protein 8, is a recently identified adipokine, mainly produced in liver and adipose tissue, which is recognized to play a dual role in lipid and glucose metabolism. However, any association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated yet. We investigated plasma betatrophin levels by ELISA in 457 patients (pts) undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening. Pts with ACS or a history of PCI were excluded. Results: Of the 457 study pts, CAD was present in 241 (53%), of whom 99 had 1-vessel, 71 had 2-vessel, 71 had 3-vessel disease (3-VD). Plasma betatrophin levels were higher in 241 pts with CAD than in 216 without CAD (median 1120 vs. 909 pg/mL, P<0.001). A stepwise increase in betatrophin levels was found depending on the number of >50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD and 1393 pg/mL in 3-VD (P<0.001). Betatrophin levels also correlated with the numbers of >50% and >25% stenotic coronary segments (r=0.22 and r=0.24, P<0.001). Moreover, betatrophin levels correlated with HbA1c (r=0.18, P<0.001) but not with FPG and triglyceride levels. In multivariate analysis, betatrophin levels were not a factor for CAD but were a significant factor for 3-VD independent of atherosclerotic risk factors. Odds ratio for 3-VD was 1.06 (95%CI=1.01-1.11, P<0.02) for a 100 pg/mL increase in betatrophin levels. Of the 457 pts, PAD (ABI<0.9) was found in 41 (9%). Betatrophin levels were also higher in 41 pts with PAD than in 416 without PAD (median 1354 vs. 981 pg/mL, P<0.001). Notably, pts with PAD more often had CAD (85% vs. 65%), especially 3-VD (46% vs. 13%) (P<0.001). In multivariate analysis, betatrophin levels were a significant factor for PAD independent of atherosclerotic risk factors and CAD. Odds ratio for PAD was 1.08 (95%CI=1.01-1.14, P<0.02) for a 100 pg/mL increase in betatrophin levels. Conclusions: Plasma betatrophin levels were found to be associated with the presence and severity of CAD as well as PAD independent of atherosclerotic risk factors. Betatrophin may play a role in the development of atherosclerotic diseases. [ABSTRACT FROM AUTHOR]

Background: Acute limb ischemia (ALI) in peripheral artery disease (PAD) is an important clinical event and an emerging cardiovascular endpoint in clinical trials that has not been fully evaluated. Methods: The EUCLID (Examining Use of Ticagrelor in PAD, NCT01732822) trial randomized 13,885 PAD patients to ticagrelor versus clopidogrel. Enrollment was based on an ankle-brachial index (ABI) ≤0.80 or prior lower extremity revascularization (LER). Patients were grouped according to post-randomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were also developed for major adverse cardiac events (MACE: myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation. Results: 232 patients (1.7%) had 293 ALI hospitalizations post-randomization. Compared with patients without ALI, ALI patients were younger, more often male, more often had prior LER and amputation, and had a lower baseline ABI. Endovascular revascularization, surgical bypass, and above-knee amputation were performed in 39.2% (n=115), 24.6% (n=72), and 10.9% (n=32) of ALI events, respectively. After multivariable adjustment, prior peripheral revascularization (HR 4.77, 95% CI 3.32-6.86) and baseline ABI ≤0.60 (HR 1.31 per 0.1 decrease, 95% CI 1.16-1.46) were associated with ALI. Among prior revascularization patients, surgical (HR 1.90, 95% CI 1.42-2.56) and recent (≤6 months, HR 1.60, 95% CI 1.19-2.16) procedures were associated with ALI. Post-randomization ALI was associated with increased risk for MACE, all-cause mortality, and major amputation (Figure). Conclusions: In PAD patients, ALI is associated with cardiac and limb-related morbidity and mortality. Prior peripheral revascularization and lower ABI values identify high-risk patients who may warrant aggressive secondary prevention and monitoring. [ABSTRACT FROM AUTHOR]

Introduction: The ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) has been widely used as a non-invasive index of arterial stiffness and arteriosclerosis. Arterial stiffness is considered causes of left ventricular (LV) diastolic dysfunction. This study evaluated prevalence of LV diastolic dysfunction by combining ABI and baPWV. Methods: This study consisted of 923 patients (male 55 %, mean age 68±13 years) with ejection fraction ≥50% on echocardiography. Low ABI was identified as ABI ≤0.9 and high PWV as PWV ≥1800. Patients were divided into 4 groups on ABI and baPWV: normal ABI and low PWV (group 1, n=495), normal ABI and high PWV (group 2, n=283), low ABI and low PWV (group 3, n=79) and low ABI and high PWV (group 4, n=66). LV diastolic dysfunction was diagnosed according to the American Society of Echocardiography criteria. Results: Each echocardiographic parameter of LV diastolic dysfunction was significantly difference among four groups: Septal e' < 7 cm/sec (58% in group 1, 84% in group 2, 78% in group 3, 85% in group4; P < 0.01), E/e' > 15 (septal) (11%, 26%, 37%, 45%; P < 0.01), LAVI > 34 mL/m2 (24%, 39%, 54%, 56%; P < 0.01), and TR velocity > 2.8 m/sec (1%, 3%, 9%, 11%; P < 0.01), respectively. Prevalence of LV diastolic dysfunction was 6%, 17%, 30% and 35% in group 1, 2, 3 and 4 (P<0.01) (Figure). Conclusions: This study shows that combination of baPWV and ABI would be useful for risk stratification of prevalence of LVDD. [ABSTRACT FROM AUTHOR]

Background: The 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral arterial disease (PAD) recommends antihypertensive therapy to lower the risk of cardiovascular events in patients with PAD and hypertension. However, the choice of antihypertensive therapy in these patients remains uncertain. Clinical studies have shown calcium channel blockers (CCB) can mitigate the development of atherosclerosis; an effect that is considered independent of its blood pressure lowering properties. Aim: To evaluate the effect of CCB on primary prevention of PAD in patients with hypertension. Method: A review of literature was performed in MEDLINE and Cochran Central Register of Controlled Trials published between 1982 and 2018. Studies were included for review provided they were randomized controlled trials, study duration of over 6 months and availability of outcome data on PAD. Treatment group received either class of CCB i.e., dihydropyridines or non-dihydropyridines. Control group received placebo or active treatment with ACE-I, beta blocker or a diuretic. A meta-analysis was performed using random effect model. Results: 928 randomized trials were identified for review, of which 8 studies (72,442 patients) were included in the analysis. In patients receiving CCB, PAD events occurred in 547 out of 27,737 patients (2%), in comparison to 1264 out of 42,894 patients in the control group (3%). Based on the random effect model, there was a relative risk reduction of 30% (95% confidence interval, 14% to 42%, p<0.001) for development of PAD in hypertensive patients treated with CCB when compared to the control group (table 1). Conclusion: Our findings suggest that calcium channel blockers can be effective in preventing PAD in hypertensive patients. Table 1. Forest plot of the incidence of PAD in hypertensive patients treated with CCB versus control. [ABSTRACT FROM AUTHOR]

Introduction: The protective relation of high density lipoprotein-cholesterol (HDLC) with coronary heart disease may be weakened in the presence of inflammation; however, whether inflammation may attenuate any association of HDL-C with peripheral arterial disease (PAD) is unknown. Hypothesis: We hypothesized that inflammation measured by high-sensitivity Creactive protein (hs-CRP) will attenuate any inverse association of HDL-C with PAD. Methods: We studied 6512 men and women aged ≥ 40 years who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999-2004 who had measures of ankle brachial index (positive for PAD defined as <0.9 or ≥1.5), lipids, high-sensitivity CRP (hs-CRP) and other risk factors. Groups were categorized by low (<40 mg/dL for men or <50 mg/dl or women), intermediate (40 or 50-59 mg/dL), and high (≥60 mg/dL) HDL-C, and low (<1 mg/L), normal (1-3), and high (3 mg/L) hs-CRP levels. We evaluated the odds ratio (ORs) for PAD by logistic regression adjusted for age, race, gender, low density lipoproteincholesterol, smoking, diabetes, body mass index, systolic blood pressure waist circumference and triglycerides. Results: Those with the highest hs-CRP levels had the highest prevalence of PAD (8.5-10.8%), regardless of level of HDL-C (figure 1). Using high HDL-C/low hs-CRP as the reference, the likelihood of PAD was significantly increased among those with normal and high hs-CRP within the intermediate HDL-C group: OR 4.7 (95%CI 1.6, 14.1) and OR 4.5 (95% CI 1.4,14.2), respectively. Among those with normal and high hs-CRP within the low HDL-C group, the likelihood of PAD was also increased:OR 5.0 (95% CI 2.1,12,1) and OR 6.4 (95% CI 2.2,18.1), respectively. Conclusion: High hs-CRP is associated with higher likelihood of PAD across all ranges of HDL-C, but especially when HDL-C is normal or low. These results support the value of combined hs-CRP and HDL-C in risk stratification for PAD which should be validated by prospective studies. [ABSTRACT FROM AUTHOR]