Pathophysiologic Convergence in Cardiovascular and Oncologic Disease
- Inflammatory pathways involving IL-1, IL-6 and NLRP3 inflammasome likely represent overlapping mechanisms in cardiovascular and oncologic disease.
- A similar risk profile for cardiovascular and oncologic disease, as well as cardiotoxicity of cancer-directed cardiotoxicity, support collaborative screening guidelines.
- Patients with cancer and atrial fibrillation have uniquely complex thrombotic and bleeding risk requiring thoughtful risk/benefit assessment.
Commentary based on Leiva O, AbdelHameid D, Connors JM, Cannon CP, Bhatt DL. Common pathophysiology in cancer, atrial fibrillation, atherosclerosis, and thrombosis. JACC CardioOncol 2021;3:619-34.
There has been a steady improvement in the overall survival of cancer patients. However, among cancer survivors, cardiovascular disease (CVD) remains the leading cause of death.1 Optimal patient management demands consideration of multiple coexisting disease states. Progression in our understanding of CV and oncologic disease reveals overlapping risk factors and unifying pathophysiologic features.2,3 Inflammatory markers including interleukin (IL)-6, interleukin (IL)-1, and C-reactive protein (CRP) are associated with coronary artery disease and atrial fibrillation (AF),4 while also clearly implicated in malignant processes like metastasis, angiogenesis, immune evasion, and cancer cell invasion.5
Inflammatory processes convergent on IL-1 and activation of the NLRP3 inflammasome have generated therapeutic interest. This was showcased in the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Studies) trial, which randomized patients with prior myocardial infarction (MI) and elevated CRP to the IL-1B inhibitor or placebo and demonstrated significant reduction in nonfatal MI, nonfatal stroke, and CV death in the treatment arm.6 Early mechanistic studies invoke reactive oxygen species as an important cause of atherosclerosis and myocardial remodeling.7
Increasing age, obesity, diabetes mellitus, and cardiometabolic disease are independently associated with both AF and cancer.8 However, large epidemiologic studies have recognized a direct and possibly bidirectional link between cancer diagnosis and new onset AF.9
Treatment-related predisposition to sepsis and post-surgical AF are intuitive explanations for this link.10 Nuanced relationships between targeted therapies and new onset AF have emerged, such as that between ibrutinib, a Bruton tyrosine kinase inhibitor, where up to 16% of patients are diagnosed with AF after initiation of therapy.11
Similarly, risk factors such as age, obesity, and diabetes predispose to both coronary atherosclerosis and malignancy.12 Clonal hematopoiesis of indeterminate potential (CHIP) has transformed the landscape of study regarding hematologic malignancies; somatic mutations common to CHIP have been implicated in CVD risk.13
Most emblematic is the strong association between Janus kinase 2 (JAK2) mutations, arterial thrombophilia and atherosclerosis, which may be mediated by altered characteristics of platelets and endothelial cells in addition to proinflammatory cytokine signaling.14 Thus, a patient's atherosclerotic burden as measured by coronary artery calcium (CAC) could represent an association between CVD and CHIP that may be useful in determining CV risk of patients with CHIP mutations.
CAC is a measure of subclinical atherosclerotic burden and improves CVD risk prediction beyond both traditional and novel factors.15 Elevated CAC scores are associated with a higher incidence of cancer, and may aid in determining whether a person is more likely to die from CVD or cancer.16 Accordingly, CAC can be considered a marker of both vascular and overall health status.
Cardiotoxicity of cancer directed treatments such as radiation and platinum-based chemotherapeutics have been associated with worsening burden of CAC and higher risk of coronary plaque erosion, respectively.17 Extensive use of vascular endothelial growth factor inhibitors in oncologic therapy exposed a relationship between vascular endothelial growth factor (VEGF) inhibition and subsequent hypertension and arterial thromboses, likely mediated by endothelial dysfunction.
Tyrosine kinase inhibitors, on the other hand, are also widely used, but exhibit more complex and variable relationships with atherosclerosis. This may be dependent on the degree of nonspecific tyrosine kinase inhibition in comparison to the anti-inflammatory effect on plaques. A signal for immunotherapy related atherosclerosis has also been identified.18 This supports a need for careful attention to CV risk prior to oncologic treatment and monitoring for development of new disease afterwards.
Platelets function as a physiologic conduit of inflammatory signaling within the vascular bed. Activated platelets release chemokines and cytokines, which recruit monocytes and propagate local inflammatory cascades at the site of atherosclerotic plaques. Active platelets are essential to oxidation of low-density lipoprotein and promotion of neutrophil extracellular trap formation in active areas.
Thrombocytosis is a common feature of poor prognosis in malignancy and is thought to aid tumor progression via immune cell recruitment. Receptors on platelets such as P-selectin and C-type lectin-like receptor 2 (CLEC-2) mediate direct cellular interactions between leukocytes and tumor respectively, predisposing to thrombi and metastasis.19 CLEC-2 in particular has garnered interest as a therapeutic target given its role in mediating tumor-platelet interaction. Platelets also depend on CLEC-2 for binding to advanced atherosclerotic plaques, and targeted inhibition may hold promise clinically.
Low-dose aspirin use has been associated in some studies with reduced cancer metastasis and incidence of prostate and colorectal cancers;20 however this observation has not been consistent.21 Some studies have signaled an overall reduction of cancer incidence and mortality, though pragmatically adaptation of antiplatelet therapy in malignancy is limited by bleeding risk.
A body of research dedicated to novel platelet inhibitors is underway, with the objective of reducing pro-inflammatory platelet signaling without increasing bleeding risk. Lysyl oxidase, a proangiogenic and pro-adhesion factor is one such candidate,22 in addition to CLEC-2.
Thrombophilia is of principal concern in patients with both CV and oncologic disease. Venous thromboembolism (VTE) is highly prevalent in patients with malignancy, manifesting as a complication in nearly 25% of patients.23 The landscape of both anti-thrombotic therapy and anti-tumor therapies has transformed in the era of direct oral anticoagulants (DOAC) and immunotherapy, and this merits reframing of risk/benefit profiling. Interestingly, large cohorts do not definitively show elevated risk of ischemic stroke to be associated with malignancy or ongoing chemotherapy treatment.
A diagnosis of AF in addition to malignancy appears to be associated with higher overall mortality, but not necessarily greater risk of ischemic stroke.24 There is heterogeneity observed in bleeding/thrombotic risk with and without AF across malignancy types. This conclusion merits further examination of how risk is measured in complex populations in the modern era.
Risk scores such as CHA2DS2-VASc and HAS-BLED may not accurately reflect the altered physiology in patients with advanced coronary and peripheral artery disease as well as hematologic malignancy. Great efforts in VTE risk research are working to better quantify differential risk, and parallel studies for CV risk are in need.
Differential bleeding/thrombosis risk profiles are relevant to interventional cardiology practices. A recent study of a nationwide database of patients who underwent percutaneous coronary intervention (PCI) demonstrated that lung and colon cancer patients were nearly twice as likely to be readmitted for acute MI as compared to patients without malignancy.25 Similar phenomena have been observed in other large databases.
Major strides within oncologic management, CVD intervention, arrhythmia management and thrombosis reveal inter-related disease states that warrant new framing of risk and treatment paradigms. Mechanistic studies have revealed the convergence of pro-inflammatory signaling and damaged vascular integrity in each pathologic process, which might be targeted using thoughtful application of available biologic therapies.
Cancer treatments, whether it be conventional radiation and chemotherapy or immunotherapy, often have disseminated effects involving the CV system which should heighten clinicians' suspicion for development of arrhythmias, thrombosis, or atherosclerosis. Large epidemiologic studies suggest that clotting and bleeding risk is nuanced and would benefit from more detailed risk modeling. This restructuring, while a consequence of scientific progress, will be critical to adapt rapidly as advancements continue to prolong life and create a patient population in need of thoughtful personalized care.
In the light of steadily improving cancer survival rates, multidisciplinary approaches merging the expertise of oncologists and cardiologists will become more important and warrant the development of specific collaborative clinical guidelines.
- Leiva O, AbdelHameid D, Connors JM, Cannon CP, Bhatt DL. Common pathophysiology in cancer, atrial fibrillation, atherosclerosis, and thrombosis. JACC CardioOncol 2021;3:619-34.
- Bhatt, DL. Birth and maturation of cardio-oncology. JACC CardioOncology 2019;1:114–16.
- Gervaso, L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2021;3:173–90.
- Ridker PM, Rane M. Interleukin-6 signaling and anti-Interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021;128:1728–46.
- Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–67.
- Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31.
- Cristina V. Oxidative stress and cardiovascular risk prediction: the long way towards a "radical" perspective. Int J Cardiol 2018;273:252–53.
- Freisling H, Viallon V, Lennon H, et al. Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study. BMC Med 2020;18:5.
- Jakobsen, CB, Lamberts M, Carlson N, et al. Incidence of atrial fibrillation in different major cancer subtypes: a nationwide population-based 12 year follow up study. BMC Cancer 2019;19:1105.
- Higuchi S, Kabeya Y, Matsushita K, et al. Incidence and complications of perioperative atrial fibrillation after non-cardiac surgery for malignancy. PLoS One 2019;14:e0216239.
- Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol 2018;4:1491–1500.
- Lauby-Secretan, B, Scoccianti C, Loomis D, et al. Body fatness and cancer--viewpoint of the IARC Working Group. N Engl J Med 2016;375:794–98.
- Calvillo-Argüelles O, Jaiswal S, Shlush LI, et al. Connections between clonal hematopoiesis, cardiovascular disease, and cancer: a review. JAMA Cardiol 2019;4:380–87.
- Wolach O, Sellar RS, Martinod K, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med 2018;10:eaan8292.
- Peng AW, Mirbolouk M, Orimoloye OA, et al. Long-term all-cause and cause-specific mortality in asymptomatic patients with CAC ≥1,000: results from the CAC Consortium. JACC Cardiovasc Imaging 2020;13:83–93.
- Dzaye O, Al Rifai M, Dardari Z, et al. Coronary artery calcium as a synergistic tool for the age- and sex-specific risk of cardiovascular and cancer mortality: he Coronary Artery Calcium Consortium. J Am Heart Assoc 2020;9:e015306.
- Herrmann, J, Yang EJ, Iliescu CA, et al. Vascular toxicities of cancer therapies: the old and the new--an evolving avenue. Circulation 2016;133:1272–89.
- Drobni, ZD, Alvi RM, Taron J, et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020;142:2299–2311.
- Olsson AK, Cedervall J. The pro-inflammatory role of platelets in cancer. Platelets 2018;29:569–73.
- Bosetti C, Santucci C, Gallus, S, Martinetti M, La Vecchia C. Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann Oncol 2020;31:558–68.
- Jacobsen AP, Khiew YC, Blumenthal RS, Martin SS. Aspirin to prevent gastrointestinal cancer - but recent trial data do not fit. Ann Oncol 2020;31:1262–63.
- De Vita A, Liverani C, Molinaro R, et al. Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer. Sci Rep 2021;11:5107.
- Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013;122:1712–23.
- Pastori D, Marang A, Bisson A, et al. Thromboembolism, mortality, and bleeding in 2,435,541 atrial fibrillation patients with and without cancer: a nationwide cohort study. Cancer 2021;127, 2122–29.
- Kwok CS, Wong CW, Kontopantelis E, et al. Percutaneous coronary intervention in patients with cancer and readmissions within 90 days for acute myocardial infarction and bleeding in the USA. Eur Heart J 2021;42:1019–34.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Cardiovascular Care Team, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Hypertension
Keywords: Platelet Aggregation Inhibitors, Vascular Endothelial Growth Factor A, C-Reactive Protein, Calcium, Coronary Artery Disease, Inflammasomes, Janus Kinase 2, NLR Family, Pyrin Domain-Containing 3 Protein, P-Selectin, Protein-Lysine 6-Oxidase, Reactive Oxygen Species, Venous Thromboembolism, Atrial Fibrillation, Cause of Death, Cardiovascular Diseases, Survival Rate, Blood Platelets, Brain Ischemia, Cancer Survivors, Cardiotoxicity, Clonal Hematopoiesis, Endothelial Cells, Extracellular Traps, Immune Evasion, Monocytes, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Prostate, Stroke, Anticoagulants, Risk Factors, Interleukin-1, Sepsis, Protein Kinase Inhibitors, Peripheral Arterial Disease, Hematologic Neoplasms, Lipoproteins, LDL, Myocardial Infarction, Epidemiologic Studies, Neoplasm Invasiveness, Biological Therapy, Colorectal Neoplasms, Anti-Inflammatory Agents, Diabetes Mellitus, Ischemic Stroke, Atherosclerosis, Outcome Assessment, Health Care, Lectins, C-Type, Thrombocytosis, Thrombophilia, Colonic Neoplasms, Health Status, Immunotherapy, Hypertension, Interleukins, Chemokines, Thrombosis, Cytokines, Mutation, Fibrinogen, Aspirin, Obesity
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