Faculty Bibliography

Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.

BACKGROUND:Psoriasis is associated with increased cardiovascular risk that is not captured by traditional pro-inflammatory biomarkers. OBJECTIVE:To investigate the relationship between psoriasis area and severity index (PASI), circulating pro-inflammatory biomarkers, and vascular health in psoriasis. METHODS:In psoriasis and age, sex-matched controls, 273 proteins were analyzed utilizing the OLINK platform, while vascular endothelial inflammation and health was measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS:= 48.18, p<0.001) in predicting vascular endothelial inflammation. LIMITATIONS/CONCLUSIONS:Our study was observational and does not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION/CONCLUSIONS:We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.

OBJECTIVE:<0.05, |log2foldchange| >0.5) and analyzed using weighted gene co-expression network analysis. Weighted gene co-expression network analysis revealed blood modules enriched for immune activation, secretory granules, and coagulation in patients with PAD. Of these 127 differentially expressed transcripts, 40 were significantly associated with MACLE (log-rank false discovery rate <0.1). MicroRNA-4477b was significantly increased in patients with PAD with subsequent MACLE and in a mouse hindlimb ischemia model. CONCLUSIONS:A whole blood transcript signature identified patients with symptomatic PAD and PAD patients at increased risk of MACLE. A previously uncharacterized transcript microRNA-4477b was overexpressed in prevalent PAD, incident MACLE, and in a mouse hindlimb ischemia model. Our novel transcriptomic signature provides insight into potential mechanisms of patients with severe symptomatic PAD.

OBJECTIVE:Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS:Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS:Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION/CONCLUSIONS:HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

Background: In ISCHEMIA, an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular endpoints was myocardial infarction. Methods: ISCHEMIA prespecified that the primary and major secondary composite endpoints of the trial be analyzed using two MI definitions. For procedural MI, the primary MI definition used CK-MB as the preferred biomarker whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times URL for PCI and >10 times for CABG. Procedural MI definitions included (i) a category of elevated biomarker only events with much higher biomarker thresholds (ii) new ST segment depression of ≥ 1mm for the primary and ≥ 0.5 mm for the secondary definition and (iii) new coronary dissections ≥ NHLBI grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. Results: Procedural MI's accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive vs conservative strategy using the primary [2.7% vs. 1.1%; adjusted HR 2.98 (95% CI 1.87, 4.73)] and secondary [8.2% vs. 2.0%; adjusted HR 5.04 (95% CI 3.64, 6.97)] MI definitions. Type 1 MI's were less frequent with the invasive vs conservative strategy using the primary [3.40% vs. 6.89%; adjusted HR 0.53 (95% CI 0.41,0.69); p<0.0001], and secondary [3.48% vs 6.89%; adjusted HR 0.53 (95% CI 0.41, 0.69); p<0.0001] definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI compared to no MI using the primary [adjusted HR 3.38 (95% CI 2.03,5.61); p<0.001] or secondary MI definition [adjusted HR 3.52 (2.11, 5.88); p<0.001]. Conclusions: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and using the secondary MI definition. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01471522.

Thrombosis is a major concern in respiratory infections. Our aim was to investigate the magnitude and duration of risk for arterial and venous thrombosis following discharge after respiratory infection. Patients with respiratory infections were identified using the United States Nationwide Readmission Database from 2012 to 2014. Patients admitted with asthma or cellulitis served as comparators. Readmissions for acute myocardial infarction (MI) and venous thromboembolism (VTE) were evaluated at 30 to 180 days. The likelihood of a first thrombotic event after discharge was compared with a 30-day period prior to hospitalization. Among 5,271,068 patients discharged after a respiratory infection, 0.56% and 0.78% were readmitted within 30-days with MI and VTE, respectively. Relative to asthma and cellulitis, respiratory infection was associated with a greater age and sex-adjusted hazard of 30-day readmission for MI (adjusted HR [aHR] 1.48 [95% CI 1.42-1.54] vs. asthma; aHR 1.36 [95% CI 1.31-1.41] vs. cellulitis) and VTE (aHR 1.28 [95% CI 1.24-1.33] vs. asthma; aHR 1.26, [95% CI 1.22-1.30] vs. cellulitis). Risks of MI and VTE attenuated over time. In a crossover-cohort analysis, the odds of MI (OR 1.68 [95% CI 1.62-1.73]) and VTE (OR 3.30 [95% 3.19-3.41]) were higher in the 30 days following discharge after respiratory infection than during the 30-day baseline period. Hospitalization for respiratory infection was associated with increased risks of thrombosis that were highest in the first 30-days after discharge and declined over time.

BACKGROUND:Perioperative cardiovascular events are a leading cause of morbidity and mortality after non-cardiac surgery. We propose a simplified method for perioperative risk stratification. METHODS:A retrospective cohort study identified patients undergoing non-cardiac surgery between 2009-2015 in the United States National Surgical Quality Improvement Program. Multivariable logistic regression models adjusted for age, sex, race and surgery type were generated to estimate the impact of traditional cardiovascular risk factors (hypertension, diabetes mellitus, current smoking) on odds of perioperative myocardial infarction (MI). Time to event analysis was conducted using competing risk analysis, with MI as the outcome event and death as the competing risk. RESULTS:A total of 3,848,501 non-cardiac surgeries were identified. Post-operative MI occurred in 0.37% of patients and 1.04% of patients died. The 30-day event rate of perioperative MI increased in a stepwise fashion with additional risk factors (0.41% for one, 0.81% for two, and 1.07% for three; P-for-trend < 0.001) after accounting for the competing risk of death. In comparison to those with no risk factors, patients with one, two and three risk factors had increased odds of MI (aOR 2.07; 95% CI 1.96-2.19; aOR 3.63 95% CI 3.43-3.85; aOR 5.54 95% CI 5.09-6.04). Perioperative MI was rare (0.10%) in patients without risk factors. CONCLUSIONS:Patients with cardiovascular risk factors are at increased risk of perioperative MI, those without risk factors are at low risk. Further evaluation is needed to determine the impact of a simplified risk score in the perioperative setting.

Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57-0.88] and 0.83 [95% CI, 0.68-1.01], respectively; P-trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.