PDF icon Download PDF
Thromb Haemost 2019; 119(09): 1471-1480
DOI: 10.1055/s-0039-1692442
Blood Cells, Inflammation and Infection

Sex Differences in the Association between Inflammation and Ischemic Heart Disease

Michael Fiechter 
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
3   Swiss Paraplegic Center, Nottwil, Switzerland
,
Achi Haider 
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
,
Susan Bengs
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
,
Monika Marȩdziak
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
,
Irene A. Burger
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Andrea Roggo
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Angela Portmann
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
,
Geoffrey I. Warnock
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
,
Katharina Schade
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Valerie Treyer
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Anton S. Becker
4   Department of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland
,
Michael Messerli
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Elia von Felten
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Dominik C. Benz
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Tobias A. Fuchs
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Christoph Gräni
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Aju P. Pazhenkottil
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Ronny R. Buechel
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Philipp A. Kaufmann
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
,
Catherine Gebhard
1   Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2   Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
› Author Affiliations
Funding C.G. was supported by grants from the Swiss National Science Foundation (SNSF), the Olga Mayenfisch Foundation, Switzerland, the OPO Foundation, Switzerland, the Novartis Foundation, Switzerland, the Swissheart Foundation, and the Helmut Horten Foundation, Switzerland. M.F. was supported by the Swiss Paraplegic Center, Nottwil, Switzerland. M.M. was supported by the Iten-Kohaut Foundation, Switzerland.
› Further Information
   Permissions and Reprints
Preview

Abstract

Background

Inflammation plays a fundamental role in mediating all stages of atherosclerosis. Given the higher prevalence of inflammatory rheumatologic conditions in women and the female propensity towards worse cardiovascular outcomes, refined strategies are needed to better identify the high-risk female cardiovascular phenotype.

Objectives

This article aims to assess sex-specific links between inflammatory processes and the development and progression of ischemic heart disease.

Patients and Methods

The relationship between vertebral bone marrow metabolism—a marker of inflammation—and myocardial injury was retrospectively assessed in 294 patients (28.6% women, mean age: 66.9 ± 10.0 years) who underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI).

Results

A significant increase in 18F-FDG bone marrow uptake was observed in women with impaired myocardial perfusion (SPECT-MPI) as compared to women with normal myocardial perfusion (standardized uptake value [SUV]: 2.2 ± 1.2 vs. 1.7 ± 0.5, p = 0.013), while no such difference was observed in men (SUV: 1.6 ± 0.8 vs. 1.6 ± 0.4, p = 0.372). Furthermore, a significant inverse correlation between left ventricular ejection fraction (LVEF) and bone marrow metabolism was seen in women (r = −0.229, p = 0.037), but not in men (r = −0.075, p = 0.289). Accordingly, in women, but not in men, bone marrow activity was identified as an independent predictor of both, reduced LVEF (β-coefficient, −4.537; p = 0.040) and impaired myocardial perfusion (β-coefficient, 0.138; p = 0.014).

Conclusion

A strong link between bone marrow metabolism and impaired myocardial function and perfusion was observed in women, but not in men. Our data suggest that novel biomarkers of inflammation might help to identify women at risk for ischemic cardiomyopathy and to tailor disease management to the female cardiovascular phenotype.

Keywords

bone marrow activity - PET/CT - inflammation - myocardial perfusion imaging - sex


Publication History

Received: 20 February 2019

Accepted: 01 May 2019

Publication Date:
21 June 2019 (online)

© 2019. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32 (09) 2045-2051
    Search in Google Scholar
  • 2 Gebhard C, Toma A, Min Z. , et al. Preprocedural leucocyte count predicts risk in patients with coronary chronic total occlusion. Thromb Haemost 2017; 117 (11) 2105-2115
    Search in Google Scholar
  • 3 de Lemos JA, Morrow DA, Sabatine MS. , et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 2003; 107 (05) 690-695
    Search in Google Scholar
  • 4 Kalkman DN, Aquino M, Claessen BE. , et al. Residual inflammatory risk and the impact on clinical outcomes in patients after percutaneous coronary interventions. Eur Heart J 2018; 39 (46) 4101-4108
    Search in Google Scholar
  • 5 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
    Search in Google Scholar
  • 6 Fava C, Montagnana M. Atherosclerosis is an inflammatory disease which lacks a common anti-inflammatory therapy: how human genetics can help to this issue. A narrative review. Front Pharmacol 2018; 9: 55
    Search in Google Scholar
  • 7 Ridker PM, Everett BM, Pradhan A. , et al; CIRT Investigators. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019; 380 (08) 752-762
    Search in Google Scholar
  • 8 Vaidya K, Martínez G, Patel S. The role of colchicine in acute coronary syndromes. Clin Ther 2019; 41 (01) 11-20
    Search in Google Scholar
  • 9 Khera A, McGuire DK, Murphy SA. , et al. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol 2005; 46 (03) 464-469
    Search in Google Scholar
  • 10 Lew J, Sanghavi M, Ayers CR. , et al. Sex-based differences in cardiometabolic biomarkers. Circulation 2017; 135 (06) 544-555
    Search in Google Scholar
  • 11 Thorand B, Baumert J, Döring A. , et al; KORA Group. Sex differences in the relation of body composition to markers of inflammation. Atherosclerosis 2006; 184 (01) 216-224
    Search in Google Scholar
  • 12 Kurmann RD, Mankad R. Atherosclerotic heart disease in women with autoimmune rheumatologic inflammatory conditions. Can J Cardiol 2018; 34 (04) 381-389
    Search in Google Scholar
  • 13 Potts J, Sirker A, Martinez SC. , et al. Persistent sex disparities in clinical outcomes with percutaneous coronary intervention: insights from 6.6 million PCI procedures in the United States. PLoS One 2018; 13 (09) e0203325
    Search in Google Scholar
  • 14 Gabet A, Danchin N, Juillière Y, Olié V. Acute coronary syndrome in women: rising hospitalizations in middle-aged French women, 2004-14. Eur Heart J 2017; 38 (14) 1060-1065
    Search in Google Scholar
  • 15 Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J 2016; 37 (42) 3232-3245
    Search in Google Scholar
  • 16 Murata Y, Kubota K, Yukihiro M, Ito K, Watanabe H, Shibuya H. Correlations between 18F-FDG uptake by bone marrow and hematological parameters: measurements by PET/CT. Nucl Med Biol 2006; 33 (08) 999-1004
    Search in Google Scholar
  • 17 Inoue K, Goto R, Okada K, Kinomura S, Fukuda H. A bone marrow F-18 FDG uptake exceeding the liver uptake may indicate bone marrow hyperactivity. Ann Nucl Med 2009; 23 (07) 643-649
    Search in Google Scholar
  • 18 Pazhenkottil AP, Nkoulou RN, Ghadri JR. , et al. Prognostic value of cardiac hybrid imaging integrating single-photon emission computed tomography with coronary computed tomography angiography. Eur Heart J 2011; 32 (12) 1465-1471
    Search in Google Scholar
  • 19 Verberne HJ, Acampa W, Anagnostopoulos C. , et al; European Association of Nuclear Medicine (EANM). EANM procedural guidelines for radionuclide myocardial perfusion imaging with SPECT and SPECT/CT: 2015 revision. Eur J Nucl Med Mol Imaging 2015; 42 (12) 1929-1940
    Search in Google Scholar
  • 20 Dahlbom M, Hoffman EJ, Hoh CK. , et al. Whole-body positron emission tomography: part I. Methods and performance characteristics. J Nucl Med 1992; 33 (06) 1191-1199
    Search in Google Scholar
  • 21 Boellaard R, Delgado-Bolton R, Oyen WJ. , et al; European Association of Nuclear Medicine (EANM). FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 2015; 42 (02) 328-354
    Search in Google Scholar
  • 22 Signore A, Glaudemans AW. The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med 2011; 25 (10) 681-700
    Search in Google Scholar
  • 23 Siegrist PT, Gaemperli O, Koepfli P. , et al. Repeatability of cold pressor test-induced flow increase assessed with H(2)(15)O and PET. J Nucl Med 2006; 47 (09) 1420-1426
    Search in Google Scholar
  • 24 Shirazi LF, Bissett J, Romeo F, Mehta JL. Role of inflammation in heart failure. Curr Atheroscler Rep 2017; 19 (06) 27
    Search in Google Scholar
  • 25 Ndrepepa G, Braun S, Iijima R. , et al. Total leucocyte count, but not C-reactive protein, predicts 1-year mortality in patients with acute coronary syndromes treated with percutaneous coronary intervention. Clin Sci (Lond) 2009; 116 (08) 651-658
    Search in Google Scholar
  • 26 Rasouli M, Kiasari AM, Bagheri B. Total and differential leukocytes counts, but not hsCRP, ESR, and five fractioned serum proteins have significant potency to predict stable coronary artery disease. Clin Chim Acta 2007; 377 (1-2): 127-132
    Search in Google Scholar
  • 27 Anderson JL, Ronnow BS, Horne BD. , et al; Intermountain Heart Collaborative (IHC) Study Group. Usefulness of a complete blood count-derived risk score to predict incident mortality in patients with suspected cardiovascular disease. Am J Cardiol 2007; 99 (02) 169-174
    Search in Google Scholar
  • 28 Horne BD, May HT, Kfoury AG. , et al. The Intermountain Risk Score (including the red cell distribution width) predicts heart failure and other morbidity endpoints. Eur J Heart Fail 2010; 12 (11) 1203-1213
    Search in Google Scholar
  • 29 Mentzer G, Hsich EM. Heart failure with reduced ejection fraction in women: epidemiology, outcomes, and treatment. Heart Fail Clin 2019; 15 (01) 19-27
    Search in Google Scholar
  • 30 Hsich EM, Piña IL. Heart failure in women: a need for prospective data. J Am Coll Cardiol 2009; 54 (06) 491-498
    Search in Google Scholar
  • 31 Xiao H, Li H, Wang JJ. , et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult. Eur Heart J 2018; 39 (01) 60-69
    Search in Google Scholar
  • 32 Karakas M, Haase T, Zeller T. Linking the sympathetic nervous system to the inflammasome: towards new therapeutics for atherosclerotic cardiovascular disease. Eur Heart J 2018; 39 (01) 70-72
    Search in Google Scholar
  • 33 Sullivan S, Hammadah M, Wilmot K. , et al. Young women with coronary artery disease exhibit higher concentrations of interleukin-6 at baseline and in response to mental stress. J Am Heart Assoc 2018; 7 (23) e010329
    Search in Google Scholar
  • 34 Mitoff PR, Gam D, Ivanov J. , et al. Cardiac-specific sympathetic activation in men and women with and without heart failure. Heart 2011; 97 (05) 382-387
    Search in Google Scholar
  • 35 O'Brien PD, Hinder LM, Callaghan BC, Feldman EL. Neurological consequences of obesity. Lancet Neurol 2017; 16 (06) 465-477
    Search in Google Scholar
  • 36 Wong ND, Pio J, Valencia R, Thakal G. Distribution of C-reactive protein and its relation to risk factors and coronary heart disease risk estimation in the National Health and Nutrition Examination Survey (NHANES) III. Prev Cardiol 2001; 4 (03) 109-114
    Search in Google Scholar
  • 37 Shanahan L, Freeman J, Bauldry S. Is very high C-reactive protein in young adults associated with indicators of chronic disease risk?. Psychoneuroendocrinology 2014; 40: 76-85
    Search in Google Scholar
  • 38 Pruijm M, Vollenweider P, Mooser V. , et al. Inflammatory markers and blood pressure: sex differences and the effect of fat mass in the CoLaus Study. J Hum Hypertens 2013; 27 (03) 169-175
    Search in Google Scholar
  • 39 Qasim AN, Budharaju V, Mehta NN. , et al. Gender differences in the association of C-reactive protein with coronary artery calcium in type-2 diabetes. Clin Endocrinol (Oxf) 2011; 74 (01) 44-50
    Search in Google Scholar
  • 40 Miao C, Chen S, Ding J. , et al. The association of pericardial fat with coronary artery plaque index at MR imaging: the Multi-Ethnic Study of Atherosclerosis (MESA). Radiology 2011; 261 (01) 109-115
    Search in Google Scholar
  • 41 Diouf I, Charles MA, Ducimetière P, Basdevant A, Eschwege E, Heude B. Evolution of obesity prevalence in France: an age-period-cohort analysis. Epidemiology 2010; 21 (03) 360-365
    Search in Google Scholar
  • 42 Hirata Y, Tabata M, Kurobe H. , et al. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 2011; 58 (03) 248-255
    Search in Google Scholar
  • 43 Mazurek T, Zhang L, Zalewski A. , et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003; 108 (20) 2460-2466
    Search in Google Scholar
  • 44 Yerramasu A, Dey D, Venuraju S. , et al. Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis. Atherosclerosis 2012; 220 (01) 223-230
    Search in Google Scholar
  • 45 Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014; 114 (12) 1867-1879
    Search in Google Scholar
  • 46 Kannel WB, Anderson K, Wilson PW. White blood cell count and cardiovascular disease. Insights from the Framingham Study. JAMA 1992; 267 (09) 1253-1256
    Search in Google Scholar
  • 47 Gillum RF, Ingram DD, Makuc DM. White blood cell count, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study. Am Heart J 1993; 125 (03) 855-863
    Search in Google Scholar
  • 48 Drakopoulou M, Toutouzas K, Stefanadi E, Tsiamis E, Tousoulis D, Stefanadis C. Association of inflammatory markers with angiographic severity and extent of coronary artery disease. Atherosclerosis 2009; 206 (02) 335-339
    Search in Google Scholar
  • 49 Sönmez O, Ertaş G, Bacaksız A. , et al. Relation of neutrophil-to-lymphocyte ratio with the presence and complexity of coronary artery disease: an observational study. Anadolu Kardiyol Derg 2013; 13 (07) 662-667
    Search in Google Scholar