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1 CURRENT OPINION European Heart Journal (2015) 36 , 1157–1162 doi:10.1093/eurheartj/ehu457 What is good for the circulation also lessens cancer risk 1 2 * and Gary D. Lopaschuk Lionel H. Opie Downloaded from https://academic.oup.com/eurheartj/article-abstract/36/19/1157/2293187 by guest on 08 May 2019 1 Department of Medicine, Groote Schuur Hospital and Hatter Institute for Cardiovascular Research in Africa, Observatory, Cape Town, South Africa; a nd 2 Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada Received 18 June 2014; revised 9 October 2014; accepted 6 November 2014; online publish-ahead-of-print 16 March 2015 5 metrics. The trend towards a lower cancer incidence with higher Hypothesis: what is good for the numbers of ideal health metrics was highly significant ( P for 5 circulation also lessens cancer risk 0.0001). , trend How was cancer incidence assessed? Incident cancer cases from 1987 – 2006 were obtained by linking to cancer Although there have been substantial advances in the prevention and registries. Hospital surveillance was used to identify additional management of cardiovascular disease (CVD) and its complications, cancer cases. There was an inverse, graded combined cancer inci- a new player and concept has entered the scene, namely an associ- dence rate in relation to a larger number of ideal health metrics; par- ation between CVD and cancer. There were two alerting signals to ticipants with three ideal health metrics had 25% lower risk of this remarkable coupling. On the one hand, disconcerting evidence incident cancer and participants with 6 – 7 ideal health metrics had has been provided that suggests that the use of angiotensin receptor . 50% lower risk of incident cancer than those with no ideal health – 1 3 blockers could be increasing the development of cancers. On the ). In the proportional hazards regression model Table metrics ( 1 other hand, evidence has been provided that the preventative effects adjusting for age, sex, race, and ARIC centre, results were similar of aspirin both as an antithrombotic agent in CVD prevention and when cases of cancer occurring in the first 3 years after follow-up the subsequent discovery of its effects in lessening the development were removed from the analysis. of cancer, especially but not only primary gastrointestinal and distant The association of ideal health metrics with new CVD was stron- 4 metastases. In addition, ideal cardiovascular health has been shown ger than that for combined cancer. Thus, the hazard ratio for CVD to be inversely associated with incident cancer in the Atherosclerosis comparing individuals with five ideal metrics at baseline with those 5 Risk In Communities (ARIC) study. The American Heart Associ- with 0 was 0.18, whereas that for combined cancer was 0.61. None- ation (AHA) has now widened its health goals to adherence to theless, combined cancer was strongly and significantly associated seven ideal heart health metrics that are aimed at lessening the inci- 6 ideal health metrics ≥ with ideal health metrics, so that having 6 dence of both CVD and cancer as part of its 2020 goals. To ). was associated with a 51% reduction in cancer risk ( 1 Table achieve this goal, the AHA is therefore pursuing partnerships with Could the links between health metrics and cancer be explained cancer advocacy groups to achieve reductions in chronic disease solely by one of health metrics such as smoking for lung cancer? prevalence. The ideal health factors are four ideal self-help health The authors conducted additional analyses removing smoking from metrics and three ideal measured health metrics (an untreated total the score of ideal health metrics and repeated the analyses for the cholesterol , 200 mg/dL, untreated blood pressure , 120 mmHg four most common incident cancers individually. The association systolic and 80 mm Hg diastolic, and untreated fasting serum glucose remained statistically significant, especially for those with ideal high 1 100 mg/dL) ( ). Ambitious plans to reduce both CVD and Table , health metrics of 4 – 6 score, representing ≈ 15% of the sample. cancer will be communicated to the American public through the Even when correcting for the relatively high levels of smoking, ‘Life’s Simple Seven campaign’. Fundamental to the current ‘war on there was still a relationship between the numbers of health cancer’ is the role of lifestyle measures in primary prevention, metrics in the 4 – 6 group, meaning that only about 25% of the 7 whereby between one-third and one-half of cancers are preventable. ARIC population, those with a healthy lifestyle and ideal BP, blood sugar, and cholesterol, were adequately protecting themselves The ARIC study from both CVD and cancer. The important overall message is that adherence to Life’s Simple The ARIC (Atherosclerosis Risk In Communities) linked the ideal Seven health metrics of the American Heart Association is associated seven health metrics in 13 753 persons to these seven health or of the European Society of Cardiology. European Heart Journal The opinions expressed in this article are not necessarily those of the Editors of the * [email protected] 27 21 406 6358, Email: + Corresponding author. Tel: Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2015. For permissions please email: [email protected] &

2 1158 L.H. Opie and G.D. Lopaschuk 5 Table 1 Incident combined cancer rates by number of ideal health metrics: The ARIC Study, 1987 – 2006 Ideal health metrics Sample % ( n 5 13 253) Cancer cases Rate/1000 years HR (95% CI) ... ... 0 2.8 95 17.3 1.0 (referent) 1 15.7 475 0.79 (0.64 – 0.98) 14.3 815 25.9 2 0.79 (0.64 – 0.98) 14.3 26.3 779 13.4 0.74 (0.59 – 0.91) 3 12.3 17.8 4 0.67 (0.54 – 0.84) 463 5 203 11.3 0.61 (0.48 – 0.79) 8.8 6 – 7 2.7 50 9.0 0.49 (0.35 – 0.69) Downloaded from https://academic.oup.com/eurheartj/article-abstract/36/19/1157/2293187 by guest on 08 May 2019 5 Cardiovascular disease (CVD) benefit vs. cancer benefit in ARIC. with lower incidence of total mortality, CVD, and cancer. Promotion of these ideal health metrics could reduce both CVD and cancer incidence. Nurses’ health study In a much larger and longer study, the Prospective Cohort study on 8 Nurses Health over 24 years, 77 782 US Health Professionals, ana- lysed five adverse lifestyle factors. These were: cigarette smoking, being overweight, not taking enough moderate to vigorous physical activity, a low diet quality score, and not taking a light-to-moderate alcohol intake (the least important). A total of 8882 deaths were documented, including 1790 from cardiovascular disease and 4527 from cancer. Each lifestyle factor independently and significantly pre- dicted mortality. Relative risks for five compared with zero lifestyle Note the number of increased deaths from cardiovasu- Figure1 risk factors were 3.26 (95% confidence interval 2.45 – 4.34) for lar disease (dashed line) and deaths from cancer (middle line) with cancer mortality, 8.17 (4.96 – 13.47) for cardiovascular mortality, an almost five-fold increase in all-cause mortality (top line). ( Figure 8 and 4.31 (3.51 – 5.31) for all-cause mortality. A total of 28% (25 – modified from van Dam et al . ). 31%) of deaths during follow-up could be attributed to smoking and 55% (47 – 62%) to the combination of smoking, being over- factors were 0.53 (0.43 – 0.63) for total mortality, 0.31 (0.20 – 0.48) weight, lack of physical activity, and a low diet quality. These results for CVD mortality, and 0.76 (0.59 – 0.97) for cancer mortality. indicate that in middle-aged American women adherence to healthy lifestyle patterns was associated with markedly lower mortal- A diet-cancer-cardiovascular disease relationship in India ity from cardiovascular disease and from cancer ( ). 1 Figure India has very large population with differing dietary and lifestyle patterns from those found in the USA or China. A detailed case control study at Puducherry found that consumption of fats more than 30 g/day resulted in a 2.4 increased relative risk of breast Links between lifestyle and cancer cancer (CI,1.14 – 5.45) and consumption of oils containing more in Asian populations 10 saturated fats doubled the risk (CI,1.03 – 4.52). Unfortunately, such observational studies make it difficult to establish causality Lifestyle and cancer in Chinese women between diet and cancer. As such, well-controlled population As lifestyle and diet are very different from those of Western studies will be needed to establish causality, recognizing the difficul- nations, data from China and India become relevant. In a major ties is establishing causality between health outcomes and diet. study, the healthy lifestyle score based on lifestyle-related factors was independently associated with mortality outcomes (normal Possible mechanisms for links weight, lower waist-hip ratio, daily exercise, non-smoking, and never 9 exposed to spouse’s smoking, higher daily fruit and vegetable intake. between cardiovascular disease Two additional factors were: body weight and no alcohol intake. A and cancer total of 71 243 women from the Shanghai Women’s Health Study were followed for an average of 9 years. Compared with women First, there are common predisposing factors, of which obesity is with a score of zero, hazard ratios for women with seven health one of the best studied. Specifically, ectopic visceral fat is the link

3 Aspirin and cancer prevention 1159 between cancer and cardiovascular disease as shown in a sub- A key enzyme involved in the mitochondrial oxidation of glucose is 11 population of the Framingham Heart Study. pyruvate dehydrogenase (PDH). This enzyme limits the rate of More generally, and glucose oxidation and is responsible for the mitochondrial decarb- secondly, obesity in young adulthood is linked to diabetes in 12 19 oxylation of pyruvate to acetyl CoA. middle age, In turn, PDH can be phos- while diabetes is linked to cancer in that circulating markers of peripheral insulin resistance are independently asso- phorylated and inhibited by PDH kinases (PDK). In ischaemic heart 13 ciated with pancreatic cancer risk. disease, cardiac hypertrophy and heart failure, PDKs are up-regulated Poorer prognosis in breast , 29 , 30 19 and PDH is phosphorylated and inhibited. cancer is related to increasing levels of obesity, and metabolic dys- A similar 14 function. up-regulation of PDK and inhibition of PDH also occurs in tumour Thirdly, there are links between heart failure (HF) and , 31 , 28 32 33 cells cancer. In a study at the Mayo Clinic, HF patients had a 68% higher In addition and in the pulmonary vasculature in PAH. risk of developing cancer [hazard ratio (1.68; 95% CI: 1.13 – 2.50)] to the up-regulation of PDK and phosphorylation of PDH, the 35 34 15 adjusted for body mass index, smoking, and comorbidities. PDH in both muscle Fourth- and tumour cells also has an increase in Downloaded from https://academic.oup.com/eurheartj/article-abstract/36/19/1157/2293187 by guest on 08 May 2019 ly, there appear to be common mechanisms at the cellular metabolic lysine acetylation, which leads to an inhibition of PDH activity. This contributes to the inhibition of PDH and decrease in glucose oxida- level. For example, in obesity, the circulating blood free fatty acid 16 levels are high tion seen in both diseased heart cells and tumour cells. which in turn inhibits the flow of glucose through Since in many cardiovascular diseases mitochondrial oxidative glycolysis to oxidation, while in cancer there are also inhibitions at phosphorylation is impaired, and the heart switches to a more the level of the same pathway which explains the most common foetal metabolic phenotype involving increased glycolysis as a metabolic hallmark of malignant tumours, i.e. the ‘Warburg effect’ 17 19 24 source of energy, (see next section). as also occurs in tumour cell proliferation, a po- This effect is the propensity of cancer cells to tential therapeutic approach to treating both heart disease and metabolize glucose to lactic acid at a high rate even in the presence of oxygen. In the future, there may be biomarkers that could predict cancer could involve stimulating PDH activity. In support of this, a which patients would be likely to suffer from both CHD and number of studies have shown that PDK inhibition (with dichloroace- 18 tate) can improve the coupling of glycolysis to glucose oxidation and cancer. Fifthly, the strongest links between CVD and cancer prob- 37 , 36 , 19 lessen ischaemic injury ably come from the preventative capacity of regular aspirin intake to and improve heart function in heart 39 37 – reduce both CVD and some types of cancer and their metastases failure. PDK inhibition (again with dichloroacetate) also , 31 32 (next section). decreases tumourogenesis, and improves vascular and heart 39 function in PAH. As a result, stimulating mitochondrial glucose oxi- dation has a potential dual role in treating both cardiovascular dis- The Warburg effect eases and cancer. In many cardiovascular diseases, the metabolic characteristics of the cardiomyocyte mimic the metabolic characteristics of tumour cells. Aspirin and cancer: are there The normal heart has a very high energy demand which it obtains common mechanisms? primarily from mitochondrial oxidative phosphorylation (for 19 review see Lopaschuk et al. ). However, in many CVD disease Aspirin and cancer prevention states, mitochondrial oxidative phosphorylation is impaired and the heart switches to a more foetal metabolic profile, involving Observational studies show that regular use of aspirin reduces the 20 increased glycolysis as a source of energy. long-term risk of several cancers and the risk of distant metastasis. While glycolysis is Results of methodologically rigorous studies are consistent with increased, glucose oxidation is often impaired, especially in ischae- 23 – 21 , 19 4 those obtained from randomized controlled trials. mic heart disease and heart failure. Benefit was ap- This results in a scenario 7.5 ≥ parent only after 5 years’ follow-up, and with longer duration, whereby glycolysis becomes uncoupled from glucose oxidation, 19 resulting in the production of lactate and protons. years, solid cancers were reduced by 31% and gastrointestinal This energy cancers by 59% ( 0.0001). The 20-year risk of cancer death was ¼ P metabolic profile is shared with cancerous cells. The hallmark of lower in the aspirin groups. Even though this study is a retrospective cancer cells is a defect in mitochondrial oxidative metabolism and analysis, in three large UK trials long-term post-trial follow-up had an increase in aerobic glycolysis compared with normal cells (for 24 been obtained from death certificates and cancer registries. review see Boland . et al ). This uncoupling of high glycolysis rates Strong support for the inhibitory effect of aspirin on colorectal from glucose oxidation was first observed by Otto Warburg, and 25 26 , cancer comes from a prospective randomized study in which 2 Figure is now known as the ‘Warburg Effect’ ( ). While the aspirin 600 mg daily (a dose normally not used because of the bleed- phenotype of high glycolysis uncoupled from glucose oxidation is ing risk) for a mean of 25 months substantially reduced cancer inci- a phenomenon normally associated with rapidly proliferating cells 40 dence in carriers of hereditary colorectal cancer. (such as tumour cells), this same metabolic phenotype can also be seen in terminally differentiated cardiomyocytes from hypertro- In contrast, a recent meta-analysis of nine primary prevention phied and failing hearts. Interestingly, this metabolic profile also studies claimed that there was no statistically significant effect on 41 occurs in vascular disorders such as pulmonary arterial hyperten- cancer mortality. The analysis involved over 100 000 participants, 28 sion (PAH) (see Sutendra and Michelakis and covered a mean follow- up period of 6.0 years. However, for review). Mitochon- effects of aspirin on cancer may take 20 years for effects on solid drial oxidation of pyruvate derived from glycolysis is impaired in tumours. These authors were unable to confirm the links between the pulmonary vasculature of PAH patients, and similar to tumour aspirin and cancer reduction because cancer mortality failed to cells, glycolytic mediators such as hypoxia inducible factor-1 a 28 reach statistical significance even after excluding studies that had a (HIF-1 ) are also up-regulated.

4 L.H. Opie and G.D. Lopaschuk 1160 Downloaded from https://academic.oup.com/eurheartj/article-abstract/36/19/1157/2293187 by guest on 08 May 2019 The Warburg Effect. In tumour cells, the mitochondrial metabolism of pyruvate ( A ) is blocked, resulting in the shunting of pyruvate to Figure 2 ). This is due to a decrease in mitochondrial oxidative metabolism, resulting in the aerobic production of lactate. A similar scenario can occur B lactate ( in many forms of cardiovascular disease, where an impaired mitochondrial oxidative metabolism of pyruvate results in an uncoupling of glycolysis 27 Figure from Mathupala et al . from glucose oxidation. used alternate-day aspirin treatment (OR, 0.88; 95% CI, 0.76 – 1.01). cardiovascular events as the primary endpoint were excluded. However, it may be noted that mortality over a mean of 6 years Observational studies indicated a beneficial role of aspirin on colo- was in the same direction as the Rothwell results. Also of note, the rectal and other digestive tract cancers; modest risk reductions 4 anti-cancer benefit of aspirin described by Algra and Rothwell were also observed for breast and prostate cancer. Regular aspirin was was associated with reduced risk of colorectal cancer [confidence apparent only after 5 years’ of follow-up and became more evident ¼ interval (CI) 0.67 – 0.79], and of other digestive tract cancers (CI the longer the follow-up. The Seshasai study had a mean follow-up 41 0.52 – 0.78) ¼ 0.50 – 0.76), for squamous cell esophageal cancer (CI time of only 6 years. for esophageal and gastric cardiac adenocarcinoma; and RR ¼ 0.67 To test the hypothesis that aspirin use is associated with a 42 0.54 – 0.83) for gastric cancer, ¼ (CI . et al reduced risk of colorectal cancer, Bosetti conducted a In the Lynch syndrome (a rare inherited form of non-polyposis meta-analysis of all observational studies on aspirin in 12 selected 40 , 41 4 colorectal cancer), cancer sites. Randomized controlled trials of aspirin, aspirin 600 mg daily for 2 years of intervention with

5 Aspirin and cancer prevention 1161 non-users, they found improved survival with statin exposure for (258 aspirin, 250 aspirin placebo), the hazard ratio for aspirin vs. con- 13 cancers, including the four most common cancers: lung (HR: ¼ trols was 0.41 (0.19 – 0.86, P 0.02) and the incidence rate ratio was 0.87; CI: 0.83 – 0.92), colorectal (HR: 0.79; CI: 0.75 – 0.85), prostate 0.008). P 0.37 (0.18 – 0.78, ¼ (HR: 0.81; CI: 0.75 – 0.88), and breast (HR: 0.88; CI: 0.80 – 0.99). While aspirin has been linked to a decrease in gastrointestinal The strict design of the study adjusted for multiple confounding cancers, it cannot be complete discounted that some of the beneficial factors, yet unfortunately no allowance was made for the carcino- effects of aspirin are attributable to an earlier detection of the genic effects of smoking which was not recorded in the Danish cancers. This may occur due to early diagnosis due to the increased data base, although expected to be very low. The basic protective incidence of bleeding with aspirin. mechanism could include statin-mediated down-regulation of the mevalonate pathway. Studies have suggested that suppression of Mechanism of anti-cancer effect mevalonate synthesis depletes tumour tissues of two intermediate Downloaded from https://academic.oup.com/eurheartj/article-abstract/36/19/1157/2293187 by guest on 08 May 2019 products, farnesyl pyrophosphate and geranylgeranyl pyrophos- of aspirin 52 phate, which are critical in cell growth. Colorectal cancer and atherothrombosis may share a common Statins reduce progression of prostate cancer, the second most 51 mechanism of disease, i.e. platelet activation in response to epithelial common malignancy in men worldwide but by which mechanism (in tumourigenesis) and endothelial (in tumourigenesis and athero- is unknown. If bone marrow stroma, PC-3 cells were isolated from 43 thrombosis) injury. Even at low-doses, aspirin acts mainly by irre- patients and the binding, invasion, and colony formation of these versible inactivation of platelet cyclooxygenase (COX)-1 in the was assessed by co-cultures in the presence of different in vitro presystemic circulation, which translates into a long-lasting inhibition statins. The statins that acted directly on PC-3 cells were the lipophilic of platelet function. Aspirin also appears to have a direct inhibitory statins (atorvastatin, mevastatin, and simvastatin), but not the non- effect on early stages of development of cancer cells. Salicylates P lipophilic pravastatin. There were reductions both in number ( ¼ reduced the formation of tetraploid cells from the culture of P 0.0055) and size ( ¼ 0.0019) of colonies formed within the isolated 51 human colon carcinoma cell lines or primary mouse epithelial cells bone marrow stroma. 44 lacking tumour protein p53. Over half of human cancers have a 45 loss of function of the p53 gene. These data explain the anti-cancer , 47 46 Summary properties of p53 feedback loop. Cycloxygenase 2 expression is increased in cancers, likely due to There are increasing links between cardiovascular disease and post-translational mechanisms, and is an independent risk factor cancer, starting with optimal lifestyle, including diet, and extending 49 , 48 for cancer development. For instance, COX-2 overexpression to statin-induced reductions in the incidences of both cardiovascular 50 is associated with worse survival among colon cancer patients. disease and cancer. Furthermore, there are plausible mechanisms This effect of COX-2 on clinical outcome may be modified by p53 that are being explored. 49 status. In addition, the cyclooxygenase product PGE2, via the EP2 PGE receptor, displays heightened p53 transcription and increased 2 Funding 50 risk of p53 mutagenesis. As a result, COX-2 inhibition has the po- L.H.O. was supported by the University of Cape Town and G.D.L. by the tential to decrease p53 and tumour formation. University of Alberta. These molecular mechanisms underlying the anti-cancer effect of aspirin suggest that aspirin, in addition to being taken for cardiovascu- Conflict of interest: none declared. lar protection, may have potential anti-cancer effects. However, further studies are needed to determine if the benefits of aspirin in References 1. Sipahi I, debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor block- cancer prevention outweigh the potential side effects of aspirin ade and the risk of cancer: meta-analysis of randomised control trials. Lancet Oncol (such as increased risk of bleeding). There are no data to recommend 11 :627 – 636. 2010; a specific starting age. Arguably, in those persons middle-aged and 2. Pfeffer MA. 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