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Demographic predictors of nonHDL-C increase during COVID-19 pandemic stay-at-home period

Manmadhan, Arun; Kozloff, Samuel J; Heffron, Sean P
The onset of the coronavirus 2019 (COVID-19) pandemic prompted unique public health measures including stay-at-home (SAH) orders that provoked altered dietary and exercise patterns and may have affected medication access and use. Although these impacts have the potential to influence lipid levels, little is known of the consequences of COVID-19 SAH on objective atherosclerotic cardiovascular disease (ASCVD) risk factors. We performed a patient-level analysis of the primary measure of atherogenic lipid-associated risk, nonHDL-C during the 2020 SAH period and the same time period in 2019, in patients within a large health system in New York City. We found that women and racial and ethnic minority group members were more likely to exhibit substantial worsening of atherogenic lipid profile (≥38 mg/dL increase in nonHDL-C) during this period. Our results suggest that the pandemic and subsequent public health measures may have produced unintended negative consequences on already at-risk groups.
PMCID:8503967
PMID: 34661184
ISSN: 2666-6677
CID: 5081552

More frequent olive oil intake is associated with reduced platelet activation in obesity

Zhang, Ruina; Moscona, Alberto; Myndzar, Khrystyna; Luttrell-Williams, Elliot; Vanegas, Sally; Jay, Melanie R; Calderon, Karry; Berger, Jeffrey S; Heffron, Sean P
BACKGROUND AND AIMS/OBJECTIVE:Obesity is an independent risk factor for atherosclerotic cardiovascular disease (CVD), and platelet hyperactivation in obesity may contribute to this association. Olive oil consumption is associated with lower cardiovascular disease (CVD) risk in the general population. However, little is known for individuals with obesity. We investigated whether olive oil intake is associated with platelet activation in obesity. METHODS AND RESULTS/RESULTS:. Olive oil intake was stratified into <1 time/week (n = 21), 1-3 times/week (n = 18), ≥4 times/week (n = 24). Strata did not differ by age, BMI or platelet count. Unstimulated P-selectin expression did not differ by olive oil consumption. Subjects with more frequent olive oil intake exhibited lower P-selectin expression on submaximal thrombin exposure. CONCLUSIONS:More frequent olive oil intake is associated with reduced thrombin-induced platelet activation in obesity.
PMID: 34627691
ISSN: 1590-3729
CID: 5027102

Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association

Reyes-Soffer, Gissette; Ginsberg, Henry N; Berglund, Lars; Duell, P Barton; Heffron, Sean P; Kamstrup, Pia R; Lloyd-Jones, Donald M; Marcovina, Santica M; Yeang, Calvin; Koschinsky, Marlys L
High levels of lipoprotein(a) [Lp(a)], an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.
PMID: 34647487
ISSN: 1524-4636
CID: 5081542

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.
PMCID:8193127
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.
PMCID:8160238
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