Faculty Bibliography

Background and aims: Atherosclerosis is an important cause of clinical cardiovascular events. Atherosclerotic plaques are hypoxic, and reoxygenation improves plaque phenotype. Central players in hypoxia are hypoxia inducible factors (HIF) and their regulators, HIF-prolyl hydroxylase (PHD) isoforms 1, 2, and 3. PHD inhibitors, targeting all three isoforms, are used to alleviate anemia in chronic kidney disease. Likewise, whole-body PHD1 and PHD2ko ameliorate hypercholesterolemia and atherogenesis. As the effect of whole-body PHD3 is unknown, we investigated the effects of germline whole-body PHD3ko on atherosclerosis. Approach and Results: To initiate hypercholesterolemia and atherosclerosis low-density lipoprotein receptor knockout (LDLrko) and PHD3/LDLr double knockout (PHD3dko), mice were fed a high-cholesterol diet. Atherosclerosis and hypoxia marker pimonidazole were analyzed in aortic roots and brachiocephalic arteries. In contrast to earlier reports on PHD1- and PHD2-deficient mice, a small elevation in the body weight and an increase in the plasma cholesterol and triglyceride levels were observed after 10 weeks of diet. Dyslipidemia might be explained by an increase in hepatic mRNA expression of Cyp7a1 and fatty acid synthase, while lipid efflux of PHD3dko macrophages was comparable to controls. Despite dyslipidemia, plaque size, hypoxia, and phenotype were not altered in the aortic root or in the brachiocephalic artery of PHD3dko mice. Additionally, PHD3dko mice showed enhanced blood hematocrit levels, but no changes in circulating, splenic or lymphoid immune cell subsets. Conclusion: Here, we report that whole-body PHD3dko instigated an unfavorable lipid profile and increased hematocrit, in contrast to other PHD isoforms, yet without altering atherosclerotic plaque development.

BACKGROUND AND AIMS/OBJECTIVE:Peripheral artery disease (PAD) is a systemic manifestation of atherosclerosis that is associated with a high risk of major adverse cardiovascular events (MACE). LDL aggregation contributes to atherosclerotic plaque progression and may contribute to plaque instability. We aimed to determine if LDL aggregation is associated with MACE in patients with PAD undergoing lower extremity revascularization (LER). METHODS:Two hundred thirty-nine patients with PAD undergoing LER had blood collected at baseline and were followed prospectively for MACE (myocardial infarction, stroke, cardiovascular death) for one year. Nineteen age, sex and LDL-C-matched control subjects without cardiovascular disease also had blood drawn. Subject LDL was exposed to sphingomyelinase and LDL aggregate size measured via dynamic light scattering. RESULTS:Mean age was 72.3 ± 10.9 years, 32.6% were female, and LDL-cholesterol was 68 ± 25 mg/dL. LDL aggregation was inversely associated with triglycerides, but not associated with demographics, LDL-cholesterol or other risk factors. Maximal LDL aggregation occurred significantly earlier in subjects with PAD than in control subjects. 15.9% of subjects experienced MACE over one year. The 1st tertile (shortest time to maximal aggregation) exhibited significantly higher MACE (25% vs. 12.5% in tertile 2 and 10.1% in tertile 3, p = 0.012). After multivariable adjustment for demographics and CVD risk factors, the hazard ratio for MACE in the 1st tertile was 4.57 (95% CI 1.60-13.01; p = 0.004) compared to tertile 3. Inclusion of LDL aggregation in the Framingham Heart Study risk calculator for recurrent coronary heart disease events improved the c-index from 0.57 to 0.63 (p = 0.01). CONCLUSIONS:We show that in the setting of very well controlled LDL-cholesterol, patients with PAD with the most rapid LDL aggregation had a significantly elevated MACE risk following LER even after multivariable adjustment. This measure further improved the classification specificity of an established risk prediction tool. Our findings support broader investigation of this assay for risk stratification in patients with atherosclerotic CVD.

BACKGROUND:Lipoprotein insulin resistance (LPIR) score is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. It is elevated in obesity and may provide information not captured in glycosylated hemoglobin and homeostatic model assessment for insulin resistance. While bariatric surgery reduces diabetes incidence and resolves metabolic syndrome, the effect of bariatric surgery on LPIR is untested. OBJECTIVES/OBJECTIVE:We sought to assess the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on LPIR in nondiabetic women with obesity. SETTING/METHODS:Nonsmoking, nondiabetic, premenopausal Hispanic women, age ≥18 years, undergoing Roux-en-Y gastric bypass or sleeve gastrectomy at Bellevue Hospital were recruited for a prospective observational study. METHODS:Anthropometric measures and blood sampling were performed preoperatively and at 6 and 12 months postoperatively. LPIR was measured by nuclear magnetic resonance spectroscopy. RESULTS:. LPIR was reduced by 35 ± 4% and 46 ± 4% at 6 and 12 months after surgery, respectively, with no difference by procedure. Twenty-seven of 53 patients met International Diabetes Federation criteria for metabolic syndrome preoperatively and had concomitant higher homeostatic model assessment for insulin resistance, glycosylated hemoglobin, nonhigh-density lipoprotein-cholesterol and LPIR. Twenty-five of 27 patients experienced resolution of metabolic syndrome postoperatively. Concordantly, the preoperative differences in homeostatic model assessment for insulin resistance, glycosylated hemoglobin, and nonhigh-density lipoprotein-cholesterol between those with and without metabolic syndrome resolved at 6 and 12 months. In contrast, patients with metabolic syndrome preoperatively exhibited greater LPIR scores at 6 and 12 months postoperatively. CONCLUSION/CONCLUSIONS:This is the first study to demonstrate improvement in insulin resistance, as measured by LPIR, after bariatric surgery with no difference by procedure. This measure, but not traditional markers, was persistently higher in patients with a preoperative metabolic syndrome diagnosis, despite resolution of the condition.

Through diverse mechanisms, obesity contributes to worsened cardiometabolic health and increases rates of cardiovascular events. Effective treatment of obesity is necessary to reduce the associated burdens of diabetes mellitus, cardiovascular disease, and death. Despite increasing cardiovascular outcome data on obesity interventions, only a small fraction of the population with obesity are optimally treated. This is a primary impetus for this article in which we describe the typical weight loss, as well as the associated impact on both traditional and novel cardiovascular disease risk factors, provided by the 4 primary modalities for obtaining weight loss in obesity-dietary modification, increasing physical activity, pharmacotherapy, and surgery. We also attempt to highlight instances where changes in metabolic risk are relatively specific to particular interventions and appear at least somewhat independent of weight loss. Finally, we suggest important areas for further research to reduce and prevent adverse cardiovascular consequences due to obesity.

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.

Chronic inflammation drives many obesity-associated conditions, including atherosclerosis. GlycA, a marker of systemic inflammation with lower intraindividual variability than hsCRP, is independently associated with incident cardiovascular events and mortality. Although GlycA is elevated in obesity, correlations with anthropometric measures are modest and the effect of weight loss on GlycA is untested. Obese (BMI 44.6±6.6kg/m² ), non-diabetic women (33.7±8.2 years) undergoing Roux-en-Y gastric bypass (n=23) or sleeve gastrectomy (n=31) were prospectively studied at baseline, 6 and 12 months post-procedure. Women with normal BMI (n=14) served as controls. Bariatric surgery significantly reduced GlycA by 6 months (451±47umol/L vs 383±50umol/L; p<0.001) with further reduction at 12 months (348±41umol/L; p<0.001) and no difference between procedures. At 12 months, despite 41% of surgical subjects maintaining BMI >30kg/m² , GlycA levels did not differ between surgical and control subjects (p=0.13). Increased HDL particle size was strongly associated with reduced GlycA (r=-0.49; p<0.001) and was found to mediate up to 43% of its weight-loss-associated fall. This is the first study to demonstrate that surgical weight loss markedly reduces levels of GlycA.

Mechanisms explaining the relationship between obesity and cardiovascular disease (CVD) are needed. Despite growing recognition of the importance of the anucleate platelet transcriptome, low levels of RNA in platelets make assessment difficult. We sought to perform unbiased platelet RNA profiling in obesity by performing a prospective study of severe obesity and weight loss via bariatric surgery on platelet characteristics and mRNA profile in 26 pre-menopausal, non-diabetic women (31.6 ± 8.4 years; BMI 43.0 ± 6.5 kg/m²) who underwent sleeve gastrectomy. Totally, 10 women of similar age with normal BMI served as controls. Platelet activation via flow cytometry was assessed before and after surgery. RNA-sequencing (RNAseq) was performed on platelet isolates from a subset of 13 subjects (eight obese women and five normal-BMI subjects). Platelet count, size, and age did not differ between control and obese women. However, platelet surface P-selectin and CD40 were higher in obesity. RNAseq demonstrated 629 differentially abundant transcripts in obesity. Notably, S100A9 and AGER, established markers of cardiovascular risk, were two of the most highly upregulated transcripts (each > 2.5 fold). At 6 months post-operatively, subjects lost 26.1 ± 5.8% body weight and inducible platelet P-selectin expression was reduced. Expression of 170 transcripts was affected by surgery, but only a small fraction (46/629) were genes found altered in obesity. We demonstrate that obesity is associated with an altered platelet transcriptome and increased platelet activation, which is partly attenuated by bariatric surgery. These observations suggest that platelets may contribute to increased cardiovascular risk in obesity through a variety of mechanisms.

OBJECTIVE:Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS:First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12. RESULTS:First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% ± 3.7, P = .002) and C-reactive protein (-35.5% ± 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS:Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, NCT02732223.