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Inflammation, Calcification, and Risk Prediction in Patients with Stable Cardiovascular Disease Cilie C

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Inflammation, Calcification, and Risk Prediction in Patients with Stable Cardiovascular Disease Cilie C Cilie C. van ‘t Klooster Beyond the scope of usual care Beyond the scope of in patients with stable cardiovascular disease cardiovascular with stable in patients Inflammation, calcification, and risk prediction and risk prediction calcification, Inflammation, Inflammation, calcification, and risk prediction in patients with stable cardiovascular disease Cilie C. van ‘t Klooster INFLAMMATION, CALCIFICATION, AND RISK PREDICTION IN PATIENTS WITH STABLE CARDIOVASCULAR DISEASE Beyond the scope of usual care Cilie Christina van ‘t Klooster Inflammation, calcification, and risk prediction in patients with stable cardiovascular disease Beyond the scope of usual care ISBN 978-94-6416-017-8 Cover design and layout by Evelien Jagtman, © evelienjagtman.com Printed by Ridderprint, www.ridderprint.nl © CC van ‘t Klooster, Utrecht, the Netherlands 2020 All rights reserved. No part of this dissertation may be reproduced or transmitted, in any form or by any means, without prior permission of the author. INFLAMMATION, CALCIFICATION, AND RISK PREDICTION IN PATIENTS WITH STABLE CARDIOVASCULAR DISEASE Beyond the scope of usual care Inflammatie, calcificatie en risicopredictie in patiënten met bestaande hart- en vaatziekte Buiten het kader van de reguliere zorg (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 22 oktober 2020 des middags te 2.30 uur door Cilie Christina van ’t Klooster geboren op 9 maart 1991 te Haarlem Promotoren: Prof.dr. F.L.J. Visseren Prof.dr. Y. van der Graaf Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Contents Chapter 1 General introduction 7 Part I Systemic low-grade inflammation Chapter 2 The relation between systemic inflammation and incident cancer in 23 patients with stable cardiovascular disease, a cohort study European Heart Journal. 2019;40(48):3901-3909 Chapter 3 The relation between healthy lifestyle changes and decrease in 57 systemic inflammation in patients with stable cardiovascular disease Atherosclerosis 2020;301:37-43. Part II Cardiovascular calcification Chapter 4 Multifocal cardiovascular calcification in patients with established 85 cardiovascular disease; prevalence, risk factors, and relation with recurrent cardiovascular disease Int J Cardiol Heart Vasc 2020; 27: 100499. Chapter 5 Cardiovascular calcification and prediction of cardiovascular events 109 and interventions in patients with stable cardiovascular disease Submitted Part III Individualized risk prediction Chapter 6 Predicting 10-year risk of recurrent cardiovascular events and 141 cardiovascular interventions in patients with established cardiovascular disease: results from UCC-SMART and REACH In revision Chapter 7 Prediction of lifetime and 10-year risk of cancer in patients with 171 established cardiovascular disease Accepted JACC CardioOncology Chapter 8 General discussion 211 Appendix Summary 231 Samenvatting (voor niet ingewijden) 235 Contributing authors 239 Dankwoord 245 List of publications 251 Curriculum Vitae 253 Chapter 1 General introduction General introduction General introduction 1 Cardiovascular disease and cancer, the two leading non-communicable diseases worldwide,1,2 account for 31% and 16% of all global deaths respectively.2 For several years, cardiovascular mortality rates have declined substantially due to improved detection and interventions of acute cardiovascular events and due to advanced preventive treatment strategies.1,3 Although the trends in cardiovascular mortality have plateaued in recent years4 and cardiovascular disease is still the number one cause of death globally, a transition in the predominant causes of death in the middle-aged is observed in which mortality from cancer will apparently become the leading cause of death.5 In fact, in some high and upper middle income countries cancer mortality has already outranked fatal cardiovascular disease.5,6 The number of patients with established cardiovascular disease in a chronic phase is growing as a consequence of several factors, including the increased survival of patients with an acute manifestation of cardiovascular disease, population growth and ageing, and lifestyle habits such as sedentary behavior and obesity.1,4,7 Globally, a number of 422.7 million prevalent cases of cardiovascular disease in 2015 was estimated.4 Recent evaluations estimate the number of patients with some form of established cardiovascular disease in the United States on 24.3 million adults (9% of total adult population).8 In the Netherlands, 1.55 million patients had chronic cardiovascular disease (also including congenital heart disease) in 2018,7,9 with an expected number of 1.9 million in 2030.9 Patients with established cardiovascular disease are at risk of recurrent cardiovascular disease, and are generally classified as very high risk (≥10% risk of fatal cardiovascular event within 10 years) according to guidelines.10 Preventing second cardiovascular events in these patients is needed from a patient’s, as well as an economic11 perspective. 9 Chapter 1 Part I Low-grade systemic inflammation Cardiovascular disease and cancer; two pieces of the same puzzle? In addition to the risk of recurrent cardiovascular disease, patients with established cardiovascular disease are also at a higher risk for cancer compared to the general population12-15 (standardized incidence ratio of 1.19; 95%CI 1.10-1.29 adjusted for age, sex and calendar year14). Especially cancer of the respiratory tract, bladder, colorectum, and kidney are more common in patients with cardiovascular disease.14 Although generally regarded as two separate entities, increasing evidence shows an overlap in risk factors for cardiovascular disease and cancer, suggesting common pathways of etiology and progression of disease.16-18 Shared risk factors for cardiovascular disease and cancer include lifestyle habits such as smoking, diet, and physical activity, diabetes mellitus, obesity, and hypertension.16 Underlying proposed pathophysiological pathways leading from these well-established cardiovascular risk factors to cancer are several. One of the mechanisms through which diabetes and obesity are related to the development of certain malignancies, is chronic hyperinsulinemia and consequent elevated unbounded insulin-like growth factor (IGF-1) levels, resulting in promotion of cell proliferation.12,16,18 Hypertension in turn, is associated with elevated levels of plasma vascular endothelial growth factor, a hormone that enables tumor cells to induce new blood-vessel formation.16 Most importantly, inflammation is thought be one of the major common pathways leading from several risk factors such as diabetes mellitus, obesity, hypertension, and lifestyle habits to development and progression of both cardiovascular disease and cancer.16 Inflammation, cardiovascular disease, and cancer Chronic low-grade systemic inflammation is a well established risk factor for cardiovascular disease, and plays a role in the etiology and progression of disease by initiating and accelerating arterial plaque formation and destabilization, causing acute atherosclerotic events.19 The interleukin (IL) 1β, IL-6, C-reactive protein (CRP) pathway is involved in the pathogenesis; cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome resulting in production of pro-IL1β and IL1β.20 Moving downstream, IL-1β leads to IL-6 activation and consequent CRP production by the liver.20 IL-6 signaling has been linked to plaque initiation and transformation to vulnerable plaques,20-22 and microvascular flow dysfunction.20,23 The involvement of the IL1β, IL-6, CRP pathway in the pathophysiology of atherothrombosis is illustrated by the combined results of two trials; the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) and the Cardiovascular Inflammation Reduction Trial (CIRT), both enrolling patients with established cardiovascular disease.20,24 In the CANTOS trial, canakinumab, an IL1β inhibitor, reduced CRP levels by 26-41% as well as recurrent cardiovascular disease incidence with a hazard ratio (HR) of 0.85 (95%CI 0.74-0.98) (150 mg canakinumab),25 whereas methotrexate in CIRT had no influence on CRP levels nor incident cardiovascular disease.24 10 General introduction Another finding of the CANTOS trial was the reduced incidence of lung cancer, lung cancer death, 1 and total cancer mortality in the treatment arm with HRs for the 300 mg canakinumab treatment arm of 0.33 (95%CI 0.18-0.59), 0.23 (95%CI 0.10-0.54), 0.49 (95%CI 0.31-0.75) respectively.26 This finding supports the involvement of that same inflammatory pathway in (lung) cancer development and progression. Inflammation and cancer have been connected since 1863, when Rudolph Virchow noticed leucocytes in neoplastic tissues and linked chronic inflammation to cancer,27 however, exact pathophysiological mechanisms are yet unclear. Hypothesized mechanisms of the role of inflammation in the development of cancer are focused on the promotion phase, and include stimulation of angiogenesis, vascular permeability, tumour cell survival and proliferation, and promotion of metastatic spread induced by IL-1β signaling pathways.27-30 In both cardiovascular disease and cancer,
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