Vascular Risk Reduction in Obesity through Reduced Granulocyte Burden and Improved Angiogenic Monocyte Content following Bariatric Surgery

David A Hess, Justin Z Trac, Stephen A Glazer, Daniella C Terenzi, Adrian Quan, Hwee Teoh, Mohammed Al-Omran, Deepak L Bhatt, C David Mazer, Ori D Rotstein, Subodh Verma, David A Hess, Justin Z Trac, Stephen A Glazer, Daniella C Terenzi, Adrian Quan, Hwee Teoh, Mohammed Al-Omran, Deepak L Bhatt, C David Mazer, Ori D Rotstein, Subodh Verma

Abstract

Bariatric surgery, in addition to the benefit of sustained weight loss, can also reduce cardiometabolic risk and mortality. Lifelong vessel maintenance is integral to the prevention of cardiovascular disease. Using aldehyde dehydrogenase activity, an intracellular detoxifying enzyme present at high levels within pro-vascular progenitor cells, we observed an association between chronic obesity and "regenerative cell exhaustion" (RCE), a pathology whereby chronic assault on circulating regenerative cell types can result in adverse inflammation and diminished vessel repair. We also describe that, at 3 months following bariatric surgery, systemic inflammatory burden was reduced and pro-angiogenic macrophage precursor content was improved in subjects with severe obesity, suggesting the restoration of a microenvironment to support vessel homeostasis. These data suggest that bariatric surgery may reverse deleterious events that predispose patients with morbid obesity to cardiovascular risk.

Trial registration: ClinicalTrials.gov NCT04132531.

Keywords: bariatric surgery; blood vessels; cardiovascular disease; granulocytes; inflammation; monocytes; obesity; progenitor cells; regenerative; vascular disease.

Conflict of interest statement

H.T. reports receiving an honorarium from Boehringer Ingelheim and manuscript writing fees from Merck and Servier. D.L.B. discloses the following relationships: advisory board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; chair: American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the EXCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; honoraria: American College of Cardiology (ACC) (senior associate editor, Clinical Trials and News, ACC.org; vice chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Medtelligence/ReachMD (continuing medical education [CME] steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. C.D.M. reports receiving honoraria from Amgen, Boehringer Ingelheim, and OctaPharma. S.V. reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; he is also the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization.

© 2020 The Author(s).

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Bariatric Surgery Was Associated with a Decreased Circulating Pro-inflammatory Granulocyte Burden and Increased Pro-angiogenic Monocyte Content (A) Representative flow cytometry plot showing inhibition of ALDH activity to establish gates marking cells with low versus high ALDH activity. (B) Cells with high ALDH activity (right shift) were separated into subgroups based on side scatter properties (R1 = ALDHhiSSChi granulocyte precursors, R2 = ALDHhiSSCmid monocyte/macrophage precursors, R3 = ALDHhiSSClow primitive progenitor cells). (C) Representative flow cytometry plots showing the frequency of ALDHhi cell subsets in normal-weight individuals and in patients before and 3 months after bariatric surgery. (D) The frequency of circulating ALDHhiSSChi granulocyte precursors was higher in patients before bariatric surgery compared to normal-weight individuals and was normalized after bariatric surgery. (E) The frequency of circulating ALDHhiSSCmid monocyte/macrophage precursors was increased after bariatric surgery. (F) The frequency of circulating ALDHhiSSClow progenitor cells was decreased after bariatric surgery. Data are presented as means ± SEMs. ∗p †p < 0.01 per the Student’s t test.
Figure 2
Figure 2
Bariatric Surgery Normalized the Balance of Circulating ALDHhiSSCmid Monocyte/Macrophage Precursors with M1 versus M2 Polarization (A) Representative flow cytometry plots showing the frequency of ALDHhiSSCmid cells with CD14 and CD80 (M1) co-expression in normal-weight individuals and in patients before and 3 months after bariatric surgery. (B) The frequency of circulating ALDHhiSSCmid cells with CD14 and CD80 co-expression was higher in patients before bariatric surgery compared to normal-weight individuals and was normalized after bariatric surgery. (C) Representative flow cytometry plots showing the frequency of ALDHhiSSCmid cells with CD14 and CD163 (M2) co-expression in normal-weight controls and in patients before and 3 months after bariatric surgery. (D) The frequency of circulating ALDHhiSSCmid cells with CD14 and CD163 co-expression was lower in patients before bariatric surgery compared to normal-weight individuals and was normalized after bariatric surgery. Data are presented as means ± SEMs. ∗p ‡p < 0.001 per the Student’s t test.
Figure 3
Figure 3
Bariatric Surgery Was Associated with an Increased Frequency of Circulating ALDHhiSSClow Progenitor Cells with CD133 and CD34 Co-expression (A) Representative flow cytometry plots showing the frequency of ALDHhiSSClow progenitor cells with CD34 co-expression in normal-weight individuals and in patients before and 3 months after bariatric surgery. (B) The frequency of circulating ALDHhiSSClow progenitor cells with CD34 co-expression was equal in patients before bariatric surgery compared to normal-weight individuals and was not changed after bariatric surgery. (C) Representative flow cytometry plots showing the frequency of ALDHhiSSClow progenitor cells with CD133 co-expression in normal-weight individuals and in patients before and 3 months after bariatric surgery. (D) The frequency of circulating ALDHhiSSClow progenitor cells with CD133 co-expression was lower in patients before bariatric surgery compared to normal-weight individuals and was normalized after bariatric surgery. (E) Representative flow cytometry plots showing the frequency of ALDHhiSSClow progenitor cells with CD34 and CD133 co-expression in normal-weight individuals and in patients before and 3 months after bariatric surgery. (F) The frequency of circulating ALDHhiSSClow progenitor cells with CD34 and CD133 co-expression was lower in patients before bariatric surgery compared to normal-weight individuals and was normalized after bariatric surgery. Data are presented as means ± SEMs. †p < 0.01 and ‡p < 0.001 per the Student’s t test.

References

    1. Ng M., Fleming T., Robinson M., Thomson B., Graetz N., Margono C., Mullany E.C., Biryukov S., Abbafati C., Abera S.F. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–781.
    1. Poirier P., Giles T.D., Bray G.A., Hong Y., Stern J.S., Pi-Sunyer F.X., Eckel R.H., American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity and Metabolism Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898–918.
    1. Flegal K.M., Kit B.K., Orpana H., Graubard B.I. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71–82.
    1. Schauer P.R., Bhatt D.L., Kirwan J.P., Wolski K., Aminian A., Brethauer S.A., Navaneethan S.D., Singh R.P., Pothier C.E., Nissen S.E., Kashyap S.R., STAMPEDE Investigators Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-Year Outcomes. N. Engl. J. Med. 2017;376:641–651.
    1. Terenzi D.C., Trac J.Z., Teoh H., Gerstein H.C., Bhatt D.L., Al-Omran M., Verma S., Hess D.A. Vascular Regenerative Cell Exhaustion in Diabetes: Translational Opportunities to Mitigate Cardiometabolic Risk. Trends Mol. Med. 2019;25:640–655.
    1. Hutch C.R., Sandoval D. The Role of GLP-1 in the Metabolic Success of Bariatric Surgery. Endocrinology. 2017;158:4139–4151.
    1. Terenzi D.C., Al-Omran M., Quan A., Teoh H., Verma S., Hess D.A. Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into the Prevention of Ischemic Complications in Diabetes. JACC Basic Transl. Sci. 2018;4:98–112.
    1. Capoccia B.J., Robson D.L., Levac K.D., Maxwell D.J., Hohm S.A., Neelamkavil M.J., Bell G.I., Xenocostas A., Link D.C., Piwnica-Worms D. Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. Blood. 2009;113:5340–5351.
    1. Hess D.A., Terenzi D.C., Trac J.Z., Quan A., Mason T., Al-Omran M., Bhatt D.L., Dhingra N., Rotstein O.D., Leiter L.A. SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus. Cell Metab. 2019;30:609–613.
    1. Zinman B., Wanner C., Lachin J.M., Fitchett D., Bluhmki E., Hantel S., Mattheus M., Devins T., Johansen O.E., Woerle H.J., EMPA-REG OUTCOME Investigators Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015;373:2117–2128.
    1. Putman D.M., Liu K.Y., Broughton H.C., Bell G.I., Hess D.A. Umbilical cord blood-derived aldehyde dehydrogenase-expressing progenitor cells promote recovery from acute ischemic injury. Stem Cells. 2012;30:2248–2260.
    1. Poitou C., Dalmas E., Renovato M., Benhamo V., Hajduch F., Abdennour M., Kahn J.-F., Veyrie N., Rizkalla S., Fridman W.-H. CD14dimCD16+ and CD14+CD16+ Monocytes in Obesity and During Weight Loss: Relationships with Fat Mass and Subclinical Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2011;31:2322–2330.
    1. Sidibe A., Ropraz P., Jemelin S., Emre Y., Poittevin M., Pocard M., Bradfield P.F., Imhof B.A. Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours. Nat. Commun. 2018;9:355.
    1. Fadini G.P., Rigato M., Cappellari R., Bonora B.M., Avogaro A. Long-term Prediction of Cardiovascular Outcomes by Circulating CD34+ and CD34+CD133+ Stem Cells in Patients With Type 2 Diabetes. Diabetes Care. 2017;40:125–131.
    1. Dalmas E., Rouault C., Abdennour M., Rovere C., Rizkalla S., Bar-Hen A., Nahon J.-L., Bouillot J.-L., Guerre-Millo M., Clément K., Poitou C. Variations in circulating inflammatory factors are related to changes in calorie and carbohydrate intakes early in the course of surgery-induced weight reduction. Am. J. Clin. Nutr. 2011;94:450–458.
    1. Laferrère B., Teixeira J., McGinty J., Tran H., Egger J.R., Colarusso A., Kovack B., Bawa B., Koshy N., Lee H. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 2008;93:2479–2485.
    1. Noordzij M., Tripepi G., Dekker F.W., Zoccali C., Tanck M.W., Jager K.J. Sample size calculations: basic principles and common pitfalls. Nephrol. Dial. Transplant. 2010;25:1388–1393.

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