Cancer and Heart Failure—More than Meets the Eye: Common Risk Factors and Co-Morbidities

Worldwide more than 32 million patients suffer from cancer,1 and more than 23 million from heart failure.2 Both diseases represent a major challenge for today's health care and economic systems. In the industrialized world about 4% of all medical expenditure is related to anti-cancer3 and more than 2% to heart failure treatments.4, 5 Cancer and heart failure are interrelated on many levels, share some of the same risk factors such as hypertension, obesity, diabetes, and tobacco smoking,6, 7 and frequently show similar symptoms such as fatigue, dyspnoea, weight loss, muscle wasting, and oedema.8-12 Furthermore, several modern anti-cancer therapies can cause transient or permanent left ventricular dysfunction (defined as a reduction of left ventricular ejection fraction by more than 10 percentage points and under 50%) in up to 48% of patients,13 depending on the kind of chemo-, immuno- or radio-therapy selected and the dose provided. Consequently, left ventricular dysfunction can lead to the development of heart failure, which ultimately reduces the chance for affected cancer patients to receive life-prolonging therapies. This ultimately could result in an increased risk of cardiovascular death. Therefore, cancer can cause cardiovascular problems and, together with anti-cancer therapy, heart failure.14 Despite an earlier study,15 the reverse, however, has recently been refuted. It appears that heart failure itself is not a cause of cancer development.16 Life expectancy in cancer patients can vary greatly between different cancer types. Five-year survival rates range from 99% in prostate to 8% in pancreatic cancer.17 Also symptoms vary greatly depending on how aggressive the cancer is and whether the patients are in remission, partial or complete, or under treatment, curative or palliative. In heart failure patients with severely reduced left ventricular ejection fraction, 1-year and 5-year survival rates have improved over the past few decades, but remain low at about 85% and 50%, respectively.18-21 Independent of optimal medical therapy, muscle strength and physical activity in both cancer and heart failure have proven to be an important component in improvement of survival.22-24 In the industrialized world cardiovascular disease and cancer are the leading causes of death in the ageing population and together they account for 50% of all deaths.25 This separation may, however, be a false dichotomy, for cancer patients can actually die a cardiovascular death and vice versa. Regarding the cause of deaths in cancer patients, Brown et al.26 analysed data from 1.2 million cancer patients from the SEER database with a follow-up time of up to 14 years and observed 470 000 deaths. On average, 21% of these deaths were non-cancer-related (ranging from 10% in lung cancer, 25% in colon cancer, 28% in female breast cancer, to 45% in prostate cancer patients). Cardiovascular disease was the most frequent non-cancer cause of death (Figure 1).26 One of the larger studies that conducted autopsies in cancer patients was that of Inagaki et al.27 who evaluated the deaths of 816 cancer patients. The four most common causes of death were infection, organ failure, infarction (mostly of heart and lung), and haemorrhage. In female breast cancer patients, the most frequent non-cancer cause of death was also shown to be due to cardiovascular disease28 (15% in survivors younger than 50 years and up to 40% in survivors older than 70 years). The prediction of death using clinical variables (size of tumour, lymph node invasion, and tumour grade29) or blood biomarkers, may serve to guide clinical decision making and it may—if the particular prognosticator allows for such conclusions—allow pathophysiologic analyses or even permit identification of a therapeutic target. Heart rate may be such a particularly informative prognosticator. Our research group was the first to show prospectively in a long-term cardiovascular follow-up study in 145 patients with pancreatic, colon, and non-small cell lung cancer that heart rate > 75 b.p.m. independently predicted mortality.30 A retrospective analysis by Lee et al.31 in 4786 breast cancer patients showed similar associations between elevated resting heart rate and increased all-cause mortality. A recent study in 300 colorectal cancer patients showed that elevated heart rate was also independently associated with cancer recurrence in long-term cancer survivors.32 It is our opinion, that in this setting, an elevated heart rate is a biomarker for increased sympathetic nervous system activation, that may have prognostic implications. In breast cancer mouse models, it has already been shown that increased sympathetic nervous system activation is associated with a 38-times elevated rate of metastasis growth.33 At the same time this highly elevated growth rate could be reduced by beta-blocker therapy.33 In heart failure the autonomic nervous system has already been identified as a therapeutic target.34 Therefore, we think that future trials should also assess the potential of beta-blocker therapy in cancer patients with an elevated heart rate. Increased basal metabolism, and thereby whole body and cardiac wasting, may also be favoured by tachycardia. It is also known that cardiac wasting occurs in advanced cancer, which has been documented in preclinical models35-37 and humans.38 Barkhudaryan et al.38 analysed pathology reports from 177 cancer patients with pancreatic, gastrointestinal, and lung cancer and demonstrated that body mass index and heart weight correlated well and showed that overall body weight loss was associated with a decrease in heart weight.38 In rat models cardiac muscle wasting has been shown to be associated with fibrotic remodelling, left ventricular dysfunction, and increased mortality.35 This might be due to local wasting processes involving neurohormonal activation and inflammatory cytokines.39 In addition, in animal models, onco-metabolites have been shown to cause cardiac dysfunction.40 Such mechanisms could induce left ventricular dysfunction in patients suffering from malignant carcinomas. In conclusion, research in the field of cardio-oncology has markedly increased in the last few years and we are rapidly gaining a better understanding of the underlying mechanisms and possible clinical targets. We think that more research into this field is promising and new treatment strategies to prevent cardiac death in cancer patients are urgently needed. Similarly to what is happening in heart failure therapeutic research, where treatment of common co-morbidities is thought to be able to improve outcomes, new cardiovascular therapies may indeed be the next step to improve outcomes of cancer patients. Conflict of interest: S.v.H. has received honoraria for consultancy from Vifor, BRAHMS, Roche, Bayer, Novartis, Boehringer Ingelheim, and Chugai. A.J.S.C. has received honoraria for consultancy and lecture fees from Respicardia, Resmed, Actimed Therapeutics, Novartis, Servier, Impulse Dynamics, Verona and Vifor. S.D.A. has received honoraria for clinical trial committee work, consultancy and lectures from Bayer, Boehringer Ingelheim, BRAHMS, Actimed Therapeutics, V-Wave, Impulse Dynamics, Novartis, Servier, and Vifor. S.D.A. reports grant support for IITs from Abbott Vascular and Vifor. M.S.A. and U.L. report no conflict of interest.