One of the few advantages of the Covid-19 pandemic is a renewed focus on the benefits of a healthy lifestyle, as a way to reduce both the risk of contracting SARS-CoV-2 infection and, in case of Covid-19, to improve the chance of survival [
[1]
]. In those not infected, living a healthy life is important anyway, in order to reduce the “corona” weight gain due to social deprivation, isolation and depression, leading to inactivity and increase in unhealthy eating habits. An associated response to this pandemic is a reorientation towards the way that we want to shape society, involving fundamental issues like durability, bioindustry, air pollution and the impact it all has on climate.- Lange KW
- Nakamura Y.
Lifestyle factors in the prevention of COVID-19.
Glob Health J. 2020 Dec;; 4 (Epub 2020 Nov 9. PMID:33520339PMCID: PMC7834031): 146-152https://doi.org/10.1016/j.glohj.2020.11.002
Interestingly, common diseases including malignancies and cardiovascular diseases (CVD), both leading causes of global morbidity and mortality, are for a substantial part driven by the same factors that threaten a healthy life, including lack of exercise/obesity/diabetes, smoking, poor food habits/diet and environmental pollution [
[2]
,GBD 2016 Causes of Death Collaborators
Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Lancet. 2017 Sep 16; 390 (Erratum in: Lancet. 2017 Oct 28;390(10106):e38. PMID:28919116PMCID: PMC5605883): 1151-1210https://doi.org/10.1016/S0140-6736(17)32152-9
[3]
]. The interaction between CVD risk profile and cancer and vice versa is widely recognized and inspired calls for action to address this dangerous liaison [- Münzel T
- Miller MR
- Sørensen M
- Lelieveld J
- Daiber A
- Rajagopalan S.
Reduction of environmental pollutants for prevention of cardiovascular disease: it's time to act.
Eur Heart J. 2020 Nov 1; 41 (PMID:33141181PMCID: PMC7672530): 3989-3997https://doi.org/10.1093/eurheartj/ehaa745
[4]
]. In this issue of the Journal, Whelton and colleagues from Europe and the United States of America focus the attention to the specific interactions between colorectal cancer, a highly prevalent malignant disease, and CVD [- Handy CE
- Quispe R
- Pinto X
- Blaha MJ
- Blumenthal RS
- Michos ED
- et al.
Synergistic opportunities in the interplay between cancer screening and cardiovascular disease risk assessment: together we are stronger.
Circulation. 2018 Aug 14; 138 (PMID:30359131): 727-734https://doi.org/10.1161/CIRCULATIONAHA.118.035516
[5]
]. In a comprehensive narrative review paper, the authors address common pathophysiological risk factors and mechanisms as a basis for improvements in the therapeutic management of the patient with colorectal cancer, at risk of CVD.- Whelton SP
- Berning P
- Blumenthal RS
- Marshall CH
- Martin SS
- Mortensen MB
- et al.
Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.
Eur J Intern Med. 2021 Feb 17; (S0953-6205(21)00040-6Epub ahead of print. PMID:33610416)https://doi.org/10.1016/j.ejim.2021.02.003
In the list of common risk factors for colorectal cancer and CVD (figure 1 in [
[5]
]), “chronic inflammation” probably is the common denominator for most, if not all, other single risk factors as the pathways that link each risk factor to cancer or CVD, typically involve inflammation [- Whelton SP
- Berning P
- Blumenthal RS
- Marshall CH
- Martin SS
- Mortensen MB
- et al.
Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.
Eur J Intern Med. 2021 Feb 17; (S0953-6205(21)00040-6Epub ahead of print. PMID:33610416)https://doi.org/10.1016/j.ejim.2021.02.003
[6]
]. Additional mechanisms include hormonal challenges (eg hyperinsilunemia, hyperglycemia, IGF-1 in diabetes; angiotensin and vascular endothelial growth factor in hypertension), direct or indirectly connected through inflammatory pathways [- Koene RJ
- Prizment AE
- Blaes A
- Konety SH.
Shared risk factors in cardiovascular disease and cancer.
Circulation. 2016 Mar 15; 133 (PMID:26976915PMCID: PMC4800750): 1104-1114https://doi.org/10.1161/CIRCULATIONAHA.115.020406
[6]
].- Koene RJ
- Prizment AE
- Blaes A
- Konety SH.
Shared risk factors in cardiovascular disease and cancer.
Circulation. 2016 Mar 15; 133 (PMID:26976915PMCID: PMC4800750): 1104-1114https://doi.org/10.1161/CIRCULATIONAHA.115.020406
“Chronic inflammation” is a container concept for different inflammatory networks, combining cellular and humoral pathways, that are also intertwined with blood coagulation (thrombo-inflammation) and complement. “Inflammageing” is the name used to describe the age-related increase in chronic inflammation [
[7]
]. In real life, a combination of acute inflammatory stimuli (such as smoking, changes in air pollution status, noise, heavy caloric intake etc) superimposed on chronic inflammatory challenges, provide the biological determinants of many multifactorial diseases. The best way to manage these inflammatory challenges is to reduce the burden of triggers, accomplished by living healthier in general; however, this is not always feasible, as in particular the environment cannot be simply optimized for many people.- Ferrucci L
- Fabbri E.
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty.
Nat Rev Cardiol. 2018 Sep; 15 (PMID:30065258PMCID: PMC6146930): 505-522https://doi.org/10.1038/s41569-018-0064-2
In epidemiological research as well as interventional studies in CVD, high sensitivity C reactive protein (hsCRP) is a key inflammation biomarker. Elevated levels of hsCRP (and also interleukin-6) are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors [
[8]
]. HsCRP, a marker of residual inflammatory risk, is also a useful tool to assess risk and direct medication including the use of statins and more recently anti-Il1beta therapy [- Aday AW
- Ridker PM.
Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease.
Front Cardiovasc Med. 2019 Feb 28; 6 (PMID:30873416PMCID: PMC6403155): 16https://doi.org/10.3389/fcvm.2019.00016
[8]
]. Chronic inflammation, characterized by detectable low levels of hsCRP, is a marker for severity of atherosclerosis, but also indicative of a higher risk of cancer, particularly lung cancer [- Aday AW
- Ridker PM.
Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease.
Front Cardiovasc Med. 2019 Feb 28; 6 (PMID:30873416PMCID: PMC6403155): 16https://doi.org/10.3389/fcvm.2019.00016
[9]
]. However, the association between elevated hsCRP and cancer is not consistent and absent for colorectal cancer [- Van't Klooster CC
- Ridker PM
- Hjortnaes J
- van der Graaf Y
- Asselbergs FW
- Westerink J
- et al.
The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study.
Eur Heart J. 2019 Dec 21; 40 (PMID:31504409PMCID: PMC6925382): 3901-3909https://doi.org/10.1093/eurheartj/ehz587
[10]
], although colon cancer is considered a disease driven and aggravated by chronic inflammation [- Zhang SM
- Buring JE
- Lee IM
- Cook NR
- Ridker PM.
C-reactive protein levels are not associated with increased risk for colorectal cancer in women.
Ann Intern Med. 2005 Mar 15; 142 (PMID:15767620): 425-432https://doi.org/10.7326/0003-4819-142-6-200503150-00008
[11]
].A broader scope would also include markers for thrombo-inflammation; the links between inflammation and hypercoagulability are well established and of pivotal significance in both CVD [
[12]
] and cancer. A simple marker that reflects thrombo-inflammation is D-dimer, a fibrin cleavage fragment [- d'Alessandro E
- Becker C
- Bergmeier W
- Bode C
- Bourne JH
- Brown H
- et al.
Scientific Reviewer Committee. Thrombo-inflammation in cardiovascular disease: an expert consensus document from the third maastricht consensus conference on thrombosis.
Thromb Haemost. 2020 Apr; 120 (Epub 2020 Apr 14. PMID:32289858): 538-564https://doi.org/10.1055/s-0040-1708035
[13]
]. Elevated D-dimer levels are predictive of venous thromboembolism but also total mortality in a broader context [- Favresse J
- Lippi G
- Roy PM
- Chatelain B
- Jacqmin H
- Ten Cate H
- Mullier F
D-dimer: Preanalytical, analytical, postanalytical variables, and clinical applications.
Crit Rev Clin Lab Sci. 2018 Dec; 55 (PMID:30694079): 548-577https://doi.org/10.1080/10408363.2018.1529734
[14]
]. D-dimer levels are associated with risk of atherothrombotic events in patients with systemic atherosclerosis [- Halaby R
- Popma CJ
- Cohen A
- Chi G
- Zacarkim MR
- Romero G
D-Dimer elevation and adverse outcomes.
J Thromb Thrombolysis. 2015 Jan; 39 (PMID:25006010PMCID: PMC4300425): 55-59https://doi.org/10.1007/s11239-014-1101-6
[15]
]. Elevated D-dimer levels are predictive of poor outcome in patients with solid tumors [- Kleinegris MC
- ten Cate H
- ten Cate-Hoek AJ.
D-dimer as a marker for cardiovascular and arterial thrombotic events in patients with peripheral arterial disease. a systematic review.
Thromb Haemost. 2013 Aug; 110 (Epub 2013 Jun 20. PMID:23784703): 233-243https://doi.org/10.1160/TH13-01-0032
[16]
]. Other biomarkers of thrombo-inflammation with potential not only to detect thrombosis but also recurrence of (breast) cancer, include thrombin generation analysis [- Li W
- Tang Y
- Song Y
- Chen SH
- Sisliyan N
- Ni M
- et al.
Prognostic Role of Pretreatment Plasma D-Dimer in Patients with Solid Tumors: a Systematic Review and Meta-Analysis.
Cell Physiol Biochem. 2018; 45 (Epub 2018 Feb 22. PMID:29490291): 1663-1676https://doi.org/10.1159/000487734
[17]
]. In the Vienna risk score for prediction of cancer associated thrombosis (CAT), D-dimer is an important element and its time course in patients with different cancer types identifies highest risk for VTE patients [- Marchetti M
- Giaccherini C
- Masci G
- Verzeroli C
- Russo L
- Celio L
- et al.
HYPERCAN Investigators. Thrombin generation predicts early recurrence in breast cancer patients.
J Thromb Haemost. 2020 Sep; 18 (Epub 2020 Aug 11. PMID:32397009): 2220-2231https://doi.org/10.1111/jth.14891
[18]
]. One can imagine that a combination of different biomarkers reflecting thrombo-inflammation could be helpful for risk stratification in patients with cancer and increased risk of CVD, allowing individual optimization of preventive measures including pharmacotherapy.- Posch F
- Riedl J
- Reitter EM
- Crowther MJ
- Grilz E
- Quehenberger P
- Jilma B
- Pabinger I
- Ay C.
Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D-Dimer analysis: a prospective study.
J Thromb Haemost. 2020 Jun; 18 (Epub 2020 Apr 15. PMID:32073229PMCID: PMC7317804): 1348-1356https://doi.org/10.1111/jth.14774
As discussed by Whelton and colleagues, in addition to lifestyle changes aimed at reducing the burden of inflammatory challenges (including diet induced modifications of the microbiome), specific pharmacological interventions may be considered [
[5]
]. These include prescription of acetylsalicylic acid (aspirin) and other anti-inflammatory agents, like colchicine. These agents are prescribed to reduce the risk of CVD, but may also have some antitumor effects, although the evidence is still inconsistent. Other agents, like antihypertensive drugs and statins may similarly reduce the burden of chronic inflammation, but the evidence for anti-tumor effects is weak. Anti-Il 1 beta appeared to have some protective effects against lung cancer, but not against other malignancies [- Whelton SP
- Berning P
- Blumenthal RS
- Marshall CH
- Martin SS
- Mortensen MB
- et al.
Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.
Eur J Intern Med. 2021 Feb 17; (S0953-6205(21)00040-6Epub ahead of print. PMID:33610416)https://doi.org/10.1016/j.ejim.2021.02.003
[19]
]. Considering (thrombo) inflammation as a leading mechanism in CVD and cancer: can one imagine a single pharmacological approach to dampen its impact on these complex diseases? The simple answer is “no”. The presented summary of data [- Wong CC
- Baum J
- Silvestro A
- Beste MT
- Bharani-Dharan B
- Xu S
- et al.
Inhibition of IL1β by canakinumab may be effective against diverse molecular subtypes of lung cancer: an exploratory analysis of the CANTOS trial.
Cancer Res. 2020 Dec 15; 80 (Epub 2020 Oct 6. PMID:33023946): 5597-5605https://doi.org/10.1158/0008-5472.CAN-19-3176
[5]
] does not reveal any major impact of agents that potentially target both atherosclerosis and cancer in all subjects. The same sobering conclusion was obtained regarding attempts to cure cancer with anticoagulant therapy. While animal studies provided strong evidence for antitumor effects of diverse anticoagulants, but in particular (low molecular weight) heparins, studies with these agents failed to reduce cancer burden in patients with solid tumors [- Whelton SP
- Berning P
- Blumenthal RS
- Marshall CH
- Martin SS
- Mortensen MB
- et al.
Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.
Eur J Intern Med. 2021 Feb 17; (S0953-6205(21)00040-6Epub ahead of print. PMID:33610416)https://doi.org/10.1016/j.ejim.2021.02.003
[20]
]. Newer strategies may include non-anticoagulant heparins, amongst other compounds, for their inhibitory potential against heparinase, a naturally occurring enzyme that degrades glycosaminoglycans and may thus facilitate tumor growth and metastasis [- Mulloy B.
The non-anticoagulant promise of heparin and its mimetics.
Curr Opin Pharmacol. 2019 Jun; 46 (Epub 2019 Apr 19. PMID:31009826): 50-54https://doi.org/10.1016/j.coph.2019.03.009
[21]
]. Nonanticoagulant heparins are probably safer with regard to bleeding complications, a major side effect of all current antithrombotic agents. Theoretically, novel antithrombotic agents that target coagulation or platelets and lack substantial impact on hemostasis (ie bleeding risk; [- Cassinelli G
- Torri G
- Naggi A.
Non-Anticoagulant Heparins as Heparanase Inhibitors.
Adv Exp Med Biol. 2020; 1221 (PMID:32274724PMCID: PMC7142274): 493-522https://doi.org/10.1007/978-3-030-34521-1_20
[22]
]) may be of interest both for preventing thrombosis in patients with cancer and perhaps by modifying the risks of atherosclerosis. A recently introduced combined antithrombotic regimen, comprising of the factor Xa inhibitor rivaroxaban and aspirin, successfully reduced cardiovascular mortality, albeit at a price of bleeding complications [- Fredenburgh JC
- Weitz JI.
New anticoagulants: Moving beyond the direct oral anticoagulants.
J Thromb Haemost. 2021 Jan; 19 (Epub 2020 Nov 3. PMID:33047462): 20-29https://doi.org/10.1111/jth.15126
[23]
]. Combining anti-inflammatory and safer antithrombotic agents could become a feasible strategy to reduce thrombo-inflammatory burden in the future.- Gurbel PA
- Fox KAA
- Tantry US
- Ten Cate H
- Weitz JI
Combination antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease.
Circulation. 2019 Apr 30; 139 (PMID:31034291): 2170-2185https://doi.org/10.1161/CIRCULATIONAHA.118.033580
Whereas cancer used to be an ominous diagnosis, several decades ago, the chances of survival have substantially increased and fortunately, in many cases, cancer can be cured or reversed to a manageable, chronic condition. This brings along new challenges as cancer and its treatment put a burden on the cardiovascular system, with increased cardiovascular morbidity and mortality. Survivors of cancer therefore require extra attention for CV risk factors, even more so as cancer occurs more often in individuals with a suboptimal lifestyle, being exposed to risk factors like smoking, poor diet and overweight.
A way forward requires more precise individual characterization of patients, in order to find the best management of CVD; precision medicine will become important, like it is increasingly in cancer treatment. This strategy will ultimately need to make smart use of data from epigenetics, transcriptomics and proteomics analyses to characterize relevant pathways and networks for individual patient endotyping, in relation to outcomes.
Conflict of interest
HtC received research support from Bayer and Pfizer and is consultant for Aleveron and stockholder for Coagulation Profile.
Acknowledgements
Research by the author is sponsored through grants from the Netherlands Heart Foundation (RACE-5 and CONTRAST), the Netherlands Thrombosis Foundation (Dutch Covid and Thrombosis Coalition) and REG-MED XB (consortium sponsoring the Cardiovascular Moonshot).
References
- Lifestyle factors in the prevention of COVID-19.Glob Health J. 2020 Dec;; 4 (Epub 2020 Nov 9. PMID:33520339PMCID: PMC7834031): 146-152https://doi.org/10.1016/j.glohj.2020.11.002
- Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2017 Sep 16; 390 (Erratum in: Lancet. 2017 Oct 28;390(10106):e38. PMID:28919116PMCID: PMC5605883): 1151-1210https://doi.org/10.1016/S0140-6736(17)32152-9
- Reduction of environmental pollutants for prevention of cardiovascular disease: it's time to act.Eur Heart J. 2020 Nov 1; 41 (PMID:33141181PMCID: PMC7672530): 3989-3997https://doi.org/10.1093/eurheartj/ehaa745
- Synergistic opportunities in the interplay between cancer screening and cardiovascular disease risk assessment: together we are stronger.Circulation. 2018 Aug 14; 138 (PMID:30359131): 727-734https://doi.org/10.1161/CIRCULATIONAHA.118.035516
- Multidisciplinary prevention and management strategies for colorectal cancer and cardiovascular disease.Eur J Intern Med. 2021 Feb 17; (S0953-6205(21)00040-6Epub ahead of print. PMID:33610416)https://doi.org/10.1016/j.ejim.2021.02.003
- Shared risk factors in cardiovascular disease and cancer.Circulation. 2016 Mar 15; 133 (PMID:26976915PMCID: PMC4800750): 1104-1114https://doi.org/10.1161/CIRCULATIONAHA.115.020406
- Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty.Nat Rev Cardiol. 2018 Sep; 15 (PMID:30065258PMCID: PMC6146930): 505-522https://doi.org/10.1038/s41569-018-0064-2
- Targeting residual inflammatory risk: a shifting paradigm for atherosclerotic disease.Front Cardiovasc Med. 2019 Feb 28; 6 (PMID:30873416PMCID: PMC6403155): 16https://doi.org/10.3389/fcvm.2019.00016
- The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study.Eur Heart J. 2019 Dec 21; 40 (PMID:31504409PMCID: PMC6925382): 3901-3909https://doi.org/10.1093/eurheartj/ehz587
- C-reactive protein levels are not associated with increased risk for colorectal cancer in women.Ann Intern Med. 2005 Mar 15; 142 (PMID:15767620): 425-432https://doi.org/10.7326/0003-4819-142-6-200503150-00008
- Role of inflammation in pathophysiology of colonic disease: an update.Int J Mol Sci. 2020; 21: 4748https://doi.org/10.3390/ijms21134748
- Scientific Reviewer Committee. Thrombo-inflammation in cardiovascular disease: an expert consensus document from the third maastricht consensus conference on thrombosis.Thromb Haemost. 2020 Apr; 120 (Epub 2020 Apr 14. PMID:32289858): 538-564https://doi.org/10.1055/s-0040-1708035
- D-dimer: Preanalytical, analytical, postanalytical variables, and clinical applications.Crit Rev Clin Lab Sci. 2018 Dec; 55 (PMID:30694079): 548-577https://doi.org/10.1080/10408363.2018.1529734
- D-Dimer elevation and adverse outcomes.J Thromb Thrombolysis. 2015 Jan; 39 (PMID:25006010PMCID: PMC4300425): 55-59https://doi.org/10.1007/s11239-014-1101-6
- D-dimer as a marker for cardiovascular and arterial thrombotic events in patients with peripheral arterial disease. a systematic review.Thromb Haemost. 2013 Aug; 110 (Epub 2013 Jun 20. PMID:23784703): 233-243https://doi.org/10.1160/TH13-01-0032
- Prognostic Role of Pretreatment Plasma D-Dimer in Patients with Solid Tumors: a Systematic Review and Meta-Analysis.Cell Physiol Biochem. 2018; 45 (Epub 2018 Feb 22. PMID:29490291): 1663-1676https://doi.org/10.1159/000487734
- HYPERCAN Investigators. Thrombin generation predicts early recurrence in breast cancer patients.J Thromb Haemost. 2020 Sep; 18 (Epub 2020 Aug 11. PMID:32397009): 2220-2231https://doi.org/10.1111/jth.14891
- Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D-Dimer analysis: a prospective study.J Thromb Haemost. 2020 Jun; 18 (Epub 2020 Apr 15. PMID:32073229PMCID: PMC7317804): 1348-1356https://doi.org/10.1111/jth.14774
- Inhibition of IL1β by canakinumab may be effective against diverse molecular subtypes of lung cancer: an exploratory analysis of the CANTOS trial.Cancer Res. 2020 Dec 15; 80 (Epub 2020 Oct 6. PMID:33023946): 5597-5605https://doi.org/10.1158/0008-5472.CAN-19-3176
- The non-anticoagulant promise of heparin and its mimetics.Curr Opin Pharmacol. 2019 Jun; 46 (Epub 2019 Apr 19. PMID:31009826): 50-54https://doi.org/10.1016/j.coph.2019.03.009
- Non-Anticoagulant Heparins as Heparanase Inhibitors.Adv Exp Med Biol. 2020; 1221 (PMID:32274724PMCID: PMC7142274): 493-522https://doi.org/10.1007/978-3-030-34521-1_20
- New anticoagulants: Moving beyond the direct oral anticoagulants.J Thromb Haemost. 2021 Jan; 19 (Epub 2020 Nov 3. PMID:33047462): 20-29https://doi.org/10.1111/jth.15126
- Combination antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease.Circulation. 2019 Apr 30; 139 (PMID:31034291): 2170-2185https://doi.org/10.1161/CIRCULATIONAHA.118.033580
Article info
Publication history
Published online: March 26, 2021
Accepted:
March 14,
2021
Identification
Copyright
© 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
