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Changes in Lipid Profile of Obese Patients following Contemporary Bariatric Surgery: A Meta-Analysis

Heffron, Sean P; Parikh, Amar; Volodarskiy, Alexandar; Ren-Fielding, Christine; Schwartzbard, Arthur; Nicholson, Joseph; Bangalore, Sripal
BACKGROUND: Although metabolic surgery was originally performed to treat hypercholesterolemia, the effects of contemporary bariatric surgery on serum lipids have not been systematically characterized. METHODS AND RESULTS: MEDLINE, EMBASE and Cochrane databases were searched for studies with >/=20 obese adults undergoing bariatric surgery [Roux-en-Y Gastric Bypass (RYGBP), Adjustable Gastric Banding, Bilio-Pancreatic Diversion (BPD), or Sleeve Gastrectomy]. The primary outcome was change in lipids from baseline to one-year after surgery. The search yielded 178 studies with 25,189 subjects (pre-operative BMI 45.5+/-4.8kg/m2) and 47,779 patient-years of follow-up. In patients undergoing any bariatric surgery, compared to baseline, there were significant reductions in total cholesterol (TC; -28.5mg/dL), low density lipoprotein cholesterol (LDL-C; -22.0mg/dL), triglycerides (-61.6mg/dL) and a significant increase in high density lipoprotein cholesterol (6.9mg/dL) at one year (P<0.00001 for all). The magnitude of this change was significantly greater than that seen in non-surgical control patients (eg LDL-C; -22.0mg/dL vs -4.3mg/dL). When assessed separately, the magnitude of changes varied greatly by surgical type (Pinteraction<0.00001; eg LDL-C: BPD -42.5mg/dL, RYGBP -24.7mg/dL, Adjustable Gastric Banding -8.8mg/dL, Sleeve Gastrectomy -7.9mg/dL). In the cases of Adjustable Gastric Banding (TC and LDL-C) and Sleeve Gastrectomy (LDL-C), the response at one year following surgery was not significantly different from non-surgical control patients. CONCLUSIONS: Contemporary bariatric surgical techniques produce significant improvements in serum lipids, but changes vary widely, likely due to anatomic alterations unique to each procedure. These differences may be relevant in deciding the most appropriate technique for a given patient.
PMID: 26899751
ISSN: 1555-7162
CID: 1965332

Greater Frequency of Nut Consumption is Associated with Lower Prevalence of Peripheral Arterial Disease

Heffron, Sean P; Rockman, Caron B; Gianos, Eugenia; Guo, Yu; Berger, Jeffrey S
Nut consumption has been associated with lower risk of coronary heart disease and all-cause mortality. The association between nut intake and peripheral arterial disease (PAD) is uncertain. OBJECTIVE: We sought to investigate the association between nut consumption and presence of prevalent PAD in a large cross-sectional sample. METHODS: Self-referred participants at >20,000 US sites who completed a medical and lifestyle questionnaire were evaluated by screening ankle brachial indices for PAD. Multivariable logistic regression analysis was used to estimate odds of PAD in different nut consumption categories. RESULTS: Among 3,312,403 individuals, mean age was 63.6+/-10.6years and 62.8% were female. There were 219,527 cases of PAD. After multivariable adjustment there was an inverse association of nut intake with PAD. Compared to subjects with consumption of nuts
PMID: 25532677
ISSN: 0091-7435
CID: 1416232

Laparoscopic gastric banding resolves the metabolic syndrome and improves lipid profile over five years in obese patients with body mass index 30-40 kg/m

Heffron, Sean P; Singh, Amita; Zagzag, Jonathan; Youn, Heekoung A; Underberg, James A; Fielding, George A; Ren-Fielding, Christine J
BACKGROUND: Obesity, metabolic syndrome (MS) and dyslipidemia are independent risk factors for cardiovascular disease. Bariatric surgery is increasingly recognized as an effective intervention for improving each of these risk factors. There are sparse data on the long-term durability of metabolic changes associated with bariatric surgery, in particular with laparoscopic gastric banding (LGB). Our objective was to evaluate the durability of metabolic changes associated with LGB in nonmorbid obesity. METHODS: Fifty obese patients (BMI 30-40) with >/=1 obesity-related comorbidity were prospectively followed for five years. At follow-up, subjects underwent fasting blood measures, including lipid NMR spectroscopy and standard lipid profile. RESULTS: Forty-seven patients (45 female, mean age 43.8 years) completed four years follow-up (46 completed five years). Baseline BMI was 35.1 +/- 2.6. Subjects exhibited mean weight loss of 22.3 +/- 7.9 kg (22.9 +/- 7.4%) at year one and maintained this (19.8 +/- 10.2%) over five years. At baseline, 43% (20/47) of subjects met criteria for MS. This was reduced to 15% (7/47) at year one and remained reduced over five years (13%, 6/46) (p < 0.001). There were reductions in triglycerides (p < 0.001) and increases in HDL cholesterol (HDL-C, p < 0.001) and HDL particle concentration (p = 0.02), with a trend toward increased HDL particle size (p = 0.06) at year five. Changes in triglycerides and HDL-C were more prominent in patients with MS at baseline, but unassociated with weight loss or waist circumference. Changes in HDL particle size and concentration were not associated with MS status, weight loss, waist circumference, or statin use. CONCLUSIONS: LGB produces significant weight loss, resolution of MS and changes in lipid profile suggestive of beneficial HDL remodeling. These changes persist five years following LGB.
PMID: 25240114
ISSN: 0021-9150
CID: 1259062

Implementing the physical activity vital sign in an academic preventive cardiology clinic

McCarthy, Margaret M; Fletcher, Jason; Heffron, Sean; Szerencsy, Adam; Mann, Devin; Vorderstrasse, Allison
The aims were to implement physical activity (PA) screening as part of the electronic kiosk check-in process in an adult preventive cardiology clinic and assess factors related to patients' self-reported PA. The 3-question physical activity vital sign (PAVS) was embedded in the Epic electronic medical record and included how many days, minutes and intensity (light, moderate, vigorous) of PA patients conducted on average. This is a data analysis of PAVS data over a 60-day period. We conducted multivariable logistic regression to identify factors associated with not meeting current PA recommendations. Over 60 days, a total of 1322 patients checked into the clinic using the kiosk and 72% (n = 951) completed the PAVS at the kiosk. The majority of those patients were male (58%) and White (71%) with a mean age of 64 ± 15 years. Of the 951 patients completing the PAVS, 10% reported no PA, 55% reported some PA, and 35% reported achieving at least 150 min moderate or 75 min vigorous PA/week. In the logistic model, females (AOR = 1.4, 95%CI: 1.002-1.8, p = .049) vs. males, being Black (AOR = 2.0, 95%CI: 1.04-3.7, p = .038) or 'Other' race (AOR = 1.5, 95%CI: 1.02-2.3, p = .035) vs. White, unknown or other types of relationships (AOR = 0.0.26, 95%CI: 0.10-0.68, p = .006) vs. being married/partnered, and those who were retired (AOR = 1.9, 95% CI: 1.4-2.8, p < .001) or unemployed (AOR = 2.2, 95%CI: 1.3-3.7, p = .002) vs. full-time workers were associated with not achieving recommended levels of PA. The PAVS is a feasible electronic tool for quickly assessing PA and may prompt providers to counsel on this CVD risk factor.
PMID: 34150483
ISSN: 2211-3355
CID: 4936852

Medical and Surgical Obesity Treatments and Atherosclerosis: Mechanisms beyond Typical Risk Factors

Bostrom, John A; Mottel, Beth; Heffron, Sean P
PURPOSE OF REVIEW/OBJECTIVE:This study aims to discuss the mechanisms by which GLP-1 agonists and bariatric surgery improve cardiovascular outcomes in severely obese patients. RECENT FINDINGS/RESULTS:Recent studies have demonstrated that both GLP-1 agonist use and bariatric surgery reduce adverse cardiovascular outcomes. Improvements in traditional atherosclerosis risk factors in association with weight loss likely contribute, but weight loss-independent mechanisms are also suggested to have roles. We review the clinical and preclinical evidence base for cardiovascular benefit of LP-1 agonists and bariatric surgery beyond traditional risk factors, including improvements in endothelial function, direct impacts on atherosclerotic plaques, and anti-inflammatory effects.
PMID: 34351556
ISSN: 1534-6242
CID: 5004252

Factors associated with participation in a short-term dietary intervention study among patients with established coronary artery disease: insights from the EVADE CAD trial

Rubinfeld, Gregory; Driggin, Elissa; Woolf, Kathleen; Slater, James; Newman, Jonathan D; Heffron, Sean; Shah, Binita
PMID: 32639244
ISSN: 1473-5830
CID: 4552562

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Weinstock, Ada; Rahman, Karishma; Yaacov, Or; Nishi, Hitoo; Menon, Prashanthi; Nikain, Cyrus A; Garabedian, Michela L; Pena, Stephanie; Akbar, Naveed; Sansbury, Brian E; Heffron, Sean P; Liu, Jianhua; Marecki, Gregory; Fernandez, Dawn; Brown, Emily J; Ruggles, Kelly V; Ramsey, Stephen; Giannarelli, Chiara; Spite, Matthew; Choudhury, Robin P; Loke, P'ng; Fisher, Edward A
Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.
PMID: 33720008
ISSN: 2050-084x
CID: 4817422

Platelet Conditioned Media Induces an Anti-inflammatory Macrophage Phenotype through EP4

Heffron, Sean P; Weinstock, Ada; Scolaro, Bianca; Chen, Shiyu; Sansbury, Brian E; Marecki, Greg; Rolling, Christina C; El Bannoudi, Hanane; Barrett, Tessa; Canary, James W; Spite, Matthew; Berger, Jeffrey S; Fisher, Edward A
BACKGROUND:Platelets are increasingly recognized as immune cells. As such, they are commonly seen to induce and perpetuate inflammation, however, anti-inflammatory activities are increasingly attributed to them. Atherosclerosis is a chronic inflammatory condition. Similar to other inflammatory conditions, the resolution of atherosclerosis requires a shift in macrophages to an M2 phenotype, enhancing their efferocytosis and cholesterol efflux capabilities. OBJECTIVES/OBJECTIVE:To assess the effect of platelets on macrophage phenotype. METHODS:In several in vitro models employing murine (RAW264.7 and bone marrow derived macrophages) and human (THP-1 and monocyte-derived macrophages) cells, we exposed macrophages to media in which non-agonized human platelets were cultured for 60 minutes (platelet conditioned media; PCM) and assessed the impact on macrophage phenotype and function. RESULTS:). CONCLUSIONS:PCM induces an anti-inflammatory, pro-resolving phenotype in macrophages. Our findings suggest that therapies targeting hemostatic properties of platelets, while not influencing pro-resolving, immune-related activities, could be beneficial for the treatment of atherothrombotic disease.
PMID: 33171016
ISSN: 1538-7836
CID: 4662992

Whole-Body Prolyl Hydroxylase Domain (PHD) 3 Deficiency Increased Plasma Lipids and Hematocrit Without Impacting Plaque Size in Low-Density Lipoprotein Receptor Knockout Mice

Demandt, Jasper A F; van Kuijk, Kim; Theelen, Thomas L; Marsch, Elke; Heffron, Sean P; Fisher, Edward A; Carmeliet, Peter; Biessen, Erik A L; Sluimer, Judith C
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.
PMID: 34055796
ISSN: 2296-634x
CID: 4890912

Low-density lipoprotein aggregation predicts adverse cardiovascular events in peripheral artery disease

Heffron, Sean P; Ruuth, Maija K; Xia, Yuhe; Hernandez, Gustavo; Äikäs, Lauri; Rodriguez, Crystalann; Öörni, Katariina; Berger, Jeffrey S
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.
PMID: 33307457
ISSN: 1879-1484
CID: 4709522