Faculty Bibliography

Introduction - Critical limb ischemia (CLI) implies a heightened risk for cardiovascular morbidity and mortality. Methods - The EUCLID trial (NCT01732822) investigated the effect of antithrombotic monotherapy, ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily, in patients with symptomatic peripheral arterial disease (PAD). Inclusion criteria were previous lower extremity revascularization (LER) or ankle-brachial index (ABI) <=0.80, randomizing 13,885 patients. Ticagrelor was not superior to clopidogrel in the reduction of cardiovascular events, nor did major bleeding differ between groups. The present study focuses on patients with CLI at baseline, defined by rest pain, minor or major tissue loss. Results - At baseline 643 patients (4.6 %) had CLI (Rutherford 4 (58.8%), Rutherford 5-6 (41.2%)). The proportion of patients with CLI in the LER group (351/7873, 4.5%) or low ABI group (292/6009, 4.9%) was similar.Diabetes mellitus was more common in the CLI group (49.3% vs 38.0%, p<0.0001), while a history of coronary artery disease was more common for the non-CLI group (29.2% vs 25.3%, p=0.035). A history of carotid disease was more frequent in non-CLI patients (18.0% vs 12.1%, p=0.0002) and a corresponding relationship was recorded for hypertension (non-CLI 78.4%, CLI 74.2%, p=0.01). Before randomization, more CLI than non-CLI patients were on clopidogrel (40.0% vs 31.8%, p<0.0001) whereas aspirin treatment was more common in the non-CLI group (67.3% vs 55.5%, p<0.0001). Dual antiplatelet therapy (aspirin and clopidogrel) was used by 16.2 % of CLI patients and 16.3 % of the non-CLI group. Statins were used by 73.8% of non-CLI patients, and 64.1% of the CLI group (p<0.0001). A history of major amputation was more common in patients with CLI (10.3%) compared to non-CLI patients (2.1%), p<0.0001. The primary efficacy endpoint, cardiovascular death, MI or ischemic stroke occurred significantly more frequently among CLI patients with a rate of 8.85 versus 4.28 per 100 patient-years (HR 2.07(1.72-2.48), p<0.0001; Fig), and this difference remained significant after adjustment for baseline characteristics (HR 1.43(1.16-1.76), p=0.0009). When including acute limb ischemia requiring hospitalization with MACE, significant differences remained, also after adjustment for baseline characteristics (HR 1.38(1.13-1.69), p=0.0016). LER was more common in CLI compared with non-CLI patients (HR 1.29(1.05-1.59), p=0.018), the difference not remaining significant after adjustment (HR 1.19(0.96-1.49), p=0.12). Bleeding did not differ between patients with and without CLI.The primary efficacy endpoint did not differ between ticagrelor and clopidogrel treated patients in the respective CLI and non-CLI groups, nor did bleeding. [Formula presented] Conclusion - Patients suffering CLI represented nearly 5% of patients enrolled in the EUCLID trial. The low amputation rate at baseline suggests milder forms of CLI dominated. CLI patients had a 2-fold higher rate of cardiovascular mortality and morbidity compared to non-CLI patients. Further efforts are required to reduce the risk for cardiovascular events in PAD, especially in patients with CLI.
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New-onset heart failure (HF) is associated with cardiovascular morbidity and mortality. It is uncertain to what extent HF confers an increased risk of venous thromboembolism (VTE). Adults ≥65 years old hospitalized with a new diagnosis of HF were identified from Medicare claims from 2007-2013. We identified the incidence, predictors and outcomes of VTE in HF. We compared VTE incidence during follow-up after HF hospitalization with a corresponding period 1-year prior to the HF diagnosis. Among 207,535 patients with a new HF diagnosis, the cumulative incidence of VTE was 1.4%, 2.5%, and 10.5% at 30 days, 1 year, and 5 years, respectively. The odds of VTE were greatest immediately after new-onset HF and steadily declined over time (OR 2.2 [95% CI 2.0-2.3], OR 1.5 [1.4-1.7], and OR 1.2 [1.2-1.3] at 0-30 days, 4-6 months, and 7-9 months, respectively). Over 26-month follow-up, patients with HF were at two-fold higher risk of VTE than patients without HF (adjusted HR 2.31 [2.18-2.45]). VTE during follow-up was associated with long-term mortality (adjusted HR 1.60, 95% CI 1.56-1.64). In conclusion, patients with HF are at increased risk of VTE early after a new HF diagnosis. VTE in patients with HF is associated with long-term mortality.

BACKGROUND:Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events. METHODS:EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined. RESULTS:TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event. CONCLUSIONS:In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In Ldlr^-/- mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.

BACKGROUND AND AIMS/OBJECTIVE:An independent association of body mass index (BMI) with atherosclerotic cardiovascular disease is somewhat controversial and may differ by vascular bed. Sex-specific risk factors for atherosclerosis may further modify these associations. Obesity and peripheral artery disease (PAD) are both more prevalent in women. We sought to determine the association between PAD and BMI using a very large population-based study. METHODS:Self-referred individuals at >20,000 US sites completed medical questionnaires including height and weight, and were evaluated by screening ankle brachial indices (ABI) for PAD (ABI<0.9). RESULTS:). CONCLUSIONS:Our study suggests that increasing BMI is a robust independent risk factor for PAD only in women. This observation requires validation, but highlights the need for further research on sex-specific risk and mechanisms of atherosclerosis.

Myocardial injury after non-cardiac surgery (MINS) is a common post-operative complication associated with adverse cardiovascular outcomes. The purpose of this systematic review was to determine the incidence, clinical features, pathogenesis, management, and outcomes of MINS. We searched PubMed, Embase, Central and Web of Science databases for studies reporting the incidence, clinical features, and prognosis of MINS. Data analysis was performed with a mixed-methods approach, with quantitative analysis of meta-analytic methods for incidence, management, and outcomes, and a qualitative synthesis of the literature to determine associated pre-operative factors and MINS pathogenesis. A total of 195 studies met study inclusion criteria. Among 169 studies reporting outcomes of 530,867 surgeries, the pooled incidence of MINS was 17.9% (95% CI 16.2%-19.6%). Patients with MINS were older, more frequently men, and more likely to have cardiovascular risk factors and known coronary artery disease. Post-operative mortality was higher among patients with MINS than those without MINS, both in-hospital (8.1%, 95% CI 4.4%-12.7% versus 0.4%, 95% CI 0.2%-0.7%; relative risk 8.3, 95% CI 4.2 - 16.6, p<0.001) and at 1-year after surgery (20.6%, 95% CI 15.9%-25.7% versus 5.1%, 95% CI 3.2%-7.4%; relative risk 4.1, 95% CI 3.0 - 5.6, p<0.001). Few studies reported mechanisms of MINS or the medical treatment provided. In conclusion, MINS occurs frequently in clinical practice, is most common in patients with cardiovascular disease and its risk factors, and is associated with increased short- and long-term mortality. Additional investigation is needed to define strategies to prevent MINS and treat patients with this diagnosis.

Stroke is a serious complication of noncardiac surgery. Congenital defects of the interatrial septum may be a potent risk factor for perioperative stroke. The aim of the present study was to determine the association between atrial septal defect (ASD) or patent foramen ovale (PFO) and in-hospital perioperative ischemic stroke after non-cardiac surgery in a large nationwide cohort of patients hospitalized in the United States. Patients undergoing noncardiac surgery between 2004 and 2014 were identified using the Healthcare Cost and Utilization Project's National Inpatient Sample. Patients without an in-hospital echocardiogram were excluded. The presence of an ostium secundum-type ASD or PFO was identified by ICD-9 diagnosis code 745.5. The primary study outcome was perioperative acute ischemic stroke. Between 2004 and 2014, there were 639,985 admissions for noncardiac surgery with an in-hospital echocardiogram. An ASD or PFO was documented in 9,041 (1.4%) hospitalizations. Perioperative ischemic stroke occurred more frequently in patients with an ASD or PFO compared with those without an ASD or PFO (35.1% vs 6.0%, p <0.001). The association between ASD or PFO and ischemic stroke persisted after adjustment for demographics and clinical covariates (adjusted odds ratio 6.30, 95% confidence interval, 5.59 to 7.10) and in all non-cardiac surgery subtypes. In conclusion, in a large, nationwide analysis of patients undergoing noncardiac surgery, a diagnosis of ASD or PFO was associated with an increased risk of acute ischemic stroke overall and in all surgical subtypes. Additional measures are necessary to mitigate stroke risk in patients with septal defects who are planned for non-cardiac surgery.

BACKGROUND:The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure. METHODS:EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point classification group. RESULTS:Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%-4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%-5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%-3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation. CONCLUSIONS:The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

Background: Hypertension is a risk factor for major adverse cardiac events (MACE) in patients with symptomatic peripheral artery disease (PAD).
Purpose(s): The effects of a history of hypertension and baseline systolic blood pressure (SBP) on MACE and major adverse limb events (MALE), including acute limb ischemia and major amputation, were evaluated in the Examining Use of tiCagreLor In paD (EUCLID) trial.
Method(s): EUCLID randomized 13,885 patients with PAD and found no benefit of ticagrelor compared with clopidogrel on risk of MACE or MALE. The median duration of follow up was approximately 30 months. This post hoc, subgroup analysis evaluated the effects of hypertension history at baseline on the hazard for MACE and MALE. An adjusted restricted cubic spline regression analysis evaluated the association of SBP with MACE and MALE.
Result(s): A clinical history of hypertension was present in 10,857 (78%) patients at baseline and these patients were more likely to be older, female, white or African American, and reside in North America compared with the 3026 without hypertension. Hypertension was associated with a higher prevalence of concomitant cardiovascular diseases, polyvascular disease, diabetes, and prior coronary interventions. MACE occurred at a rate of 4.63 events/100 pt-yrs in participants with hypertension and 3.64 events/100 ptyrs in participants without hypertension, (adjusted hazard ratio [aHR] 0.94, 95% CI 0.82-1.08; p=0.38). MALE occurred at a rate of 1.11 events/100 ptyrs in those with hypertension and 1.38 events/100 pt-yrs in those without hypertension (p=0.054) (aHR 0.93 (95% CI 0.73, 1.18) p=0.55. The adjusted spline model for MACE and SBP demonstrated a significantly nonlinear relationship with a HR 1.08 (95% CI 1.01, 1.15), p=0.0275 for every 10-unit decrease <135 mmHg SBP and HR 1.11 (1.06, 1.16), p<0.0001 for every 10-unit increase >135 mmHg (figure). There was no association between baseline SBP and MALE events.
Conclusion(s): A history of hypertension was not associated with a higher adjusted hazard for MACE or MALE in participants with PAD. In contrast, SBP at baseline was associated with increased risk of MACE at values both above and below 135 mmHg

BACKGROUND:Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS:mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS:Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS:Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.