Cardio-oncology: low-grade inflammation as a common pathway of cancer and cardiovascular disease

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Cardiac diseases and cancer are still the major causes of death.1 Of note, with the impressive reduction in cardiovascular mortality, in particular due to prevention and modern management of acute coronary syndromes, cancer mortality has surpassed death rates from cardiac causes in some countries. However, an increasing number of cancer patients can be successfully treated, albeit increasingly so at the price of cardiovascular side effects such as pump failure,2 coronary disease,3 acute coronary syndromes,4 and arrythmias. Furthermore, cancer and cardiac diseases are in large part age dependent and hence may occur incidentally together in the same patient. There is also evidence that some cancers and myocardial infarction share similar inflammatory pathways.5 Thus, it is timely that Kathleen Sturgeon and colleagues from the Pennsylvania State University in the USA report ‘A population-based study of cardiovascular disease mortality risk in US cancer patients’.6 The Surveillance, Epidemiology, and End Results (SEER) program was used to compare the US general population with 3 234 256 US cancer survivors. Among 28 cancer types, 1 228 328 patients or 38% died from cancer and 365 689 patients or 11% died from cardiovascular diseases. Among the latter, 76% of deaths were due to heart disease (Figure 1). In eight cancer sites, cardiovascular mortality risk surpassed index cancer mortality risk and was highest in survivors diagnosed at <35 years of age. Further, cardiovascular mortality risk was highest within the first year after cancer diagnosis, and cardiovascular disease mortality risk remained elevated throughout follow-up compared with the general population. Thus, the authors conclude that the majority of cardiovascular deaths occur in patients with breast, prostate, or bladder cancer. Of note, from the point of cancer diagnosis forward into survivorship, cancer patients are at elevated risk of dying from cardiovascular diseases, particularly those with childhood cancer,7 compared with the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from cardiovascular diseases, supporting early involvement of cardiologists in such patients and the establishment of cardio-oncology services.8 These important findings are put into context in an interesting Editorial by Joerg Herrmann from the Mayo Clinic Rochester in Minnesota, USA.9 Standardized morality ratios for cancer sites with both ≤30% risk of death from the index-cancer and ≥20% risk of mortality from heart disease were calculated and binned by follow-up time. Cancers sites with at least 1000 person-years of risk for death from heart disease between 2000 and 2015 are displayed. (from Sturgeon KM, Deng L, Bluethmann SM, Zhou S, Trifiletti DM, Jiang C, Kelly SP, Zaorsky NG. A population-based study of cardiovascular disease mortality risk in US cancer patients. See pages 3889–3897) Low-grade inflammation, measured by elevated plasma concentrations of high sensitive C-reactive protein or CRP is a risk factor for cardiovascular disease10 before and after percutaneous coronary interventions.11 Indeed, inflammatory markes and in particular the inflammasome NLRP3 and its downstream cytokines such as the interleukins (ILs)12–14 represent a novel therapeutic target. In their FAST TRACK ‘The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study’ Frank L.J. Visseren and colleagues of the UCC-SMART study group suggest that there is evidence that low-grade inflammation is also related to a higher risk of cancer.15 In total, 7178 patients with stable cardiovascular disease and plasma CRP ≤10 mg/L were included and followed for 4.6 years up to 12.3 years, 15% or 1072 patients received a cancer diagnoses. CRP was related to total cancer (Figure 2). Lung cancer in particular, independent of histopathological subtype, was related to CRP, as were epithelial neoplasms and especially squamous cell neoplasms, irrespective of anatomical location. Thus, in patients with stable cardiovascular disease, chronic systemic low-grade inflammation as reflected by increased levels of CRP is a risk factor for cancer, in particular lung cancer. However, the relationship between inflammation and cancer is seen in former and current smokers and is uncertain in never smokers, suggesting that oxidative stress may be a common molecular pathway. These intruiging findings are further discussed in a thought-provoking Editorial by Patrizio Lancellotti from the University Hospital of Liège in Belgium.16 Low grade systemic inflammation and risk of incident cancer in patients with established vascular disease. CI, confidence interval; CRP, C-reactive protein; HR, hazard ratio; IQR, interquartile range. *Hazard ratios are adjusted for age, sex, body mass index, smoking status, pack-years of smoking, low-density lipoprotein cholesterol, diabetes mellitus, systolic blood pressure, and kidney function. Hazard ratios per 1 mg/L higher C-reactive protein are presented (from van't Klooster CC, Ridker PM, Hjortnaes J, van der Graaf Y, Asselbergs FW, Westerink J, Aerts JGJV, Visseren FLJ, On behalf of the UCC-SMART study group. The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study. See pages 3901–3909). Based on these findings, cancer has to be considered an independent risk factor for cardiovascular disease and hence should be considered in risk scores. In their article entitled ‘Development and validation of a multivariable prediction model for major adverse cardiovascular events after early stage breast cancer: a population-based cohort study’, Husam Abdel-Qadir and colleagues from the Women’s College Hospital in Toronto, Ontario, Canada indeed developed such a score.17 The risk score was derived in 60 294 women and validated in 29 810 women. Age, hypertension, diabetes, ischaemic heart disease, atrial fibrillation, heart failure, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and chronic kidney disease were significantly associated with major adverse cardiac events (MACE) and incorporated into the score. Ten-year MACE incidence was >40-fold higher in patients in the highest score decile compared with the lowest. The c-index was 81.9% at 5 years and 79.8% at 10 years in the validation cohort, with good agreement between predicted and observed MACE incidence. Thus, cardiovascular prognosis after early-stage breast cancer can be estimated using patients’ pre-treatment characteristics. Whether such a score is of use for practising cardio-oncologists is outlined in a stimulating Editorial by Alexander Lyon from the Imperial College and Royal Brompton Hospital in London, UK.18 The immune system is equally involved in cancer and cardiovascular disease. For instance, a persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. In their Basic Science article ‘Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization’ Xiang Cheng and colleagues from the Institute of Cardiology in Wuhan, China remind us that no data exist on T-cell receptor repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts.19 Analysis of the T-cell receptor repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded T-cell receptor repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded T-cell receptor repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, T-cell receptor clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen alleles. Furthermore, ischaemic heart failure heart-associated clonotypes were more frequent in peripheral blood of ischaemia heart failure patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ (IFN-γ), granzyme B, and perforin.Thus, here is novel evidence for a tissue-specific T-cell response dominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure. These novel findings are put into context in an educational Editorial by Stefan Frantz from the Universitatsklinikum Wurzburg in Germany.20 This topic is further expanded in a comprehensive review entitled ‘Immunotherapy for cardiovascular disease’ by Christian Weber and colleagues from the Ludwig-Maximilians-University in Munich, Germany.21 They remind us that the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial using an anti-IL-1β antibody as well as the most recent COLCOT trial using colchicine have proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves outcomes, especially in patients in a pro-inflammatory state. However, such an approach also increases the risk of infections. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways and exhibit limited immune-suppressive side effects are required to optimize immunotherapy for cardiovascular disease. The authors highlight the potential of novel immunotherapeutic targets that are currently considered to become a future treatment for cardiovascular disease. The issue is also complemented by two Discussion Forum contributions. In a first piece ‘Distracting factors involving the high-intensity interval training as modulator of retinal microvascular phenotype and DNA methylation of SHC1 gene’ Leonardo Vidal Andreato and colleagues from the Universidade do Estado de Santa Catarina in Florianópolis, Brazil comment on the recently published contribution entitled ‘High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE)’ by Francesco Cosentino and colleagues from the University Hospital Solna in Stockholm, Sweden,22,23 Cosentino et al. respond in a separate contribution.24 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.