Decoding the Link Between Heart Failure and Incident Cancer

Sanjay Divakaran; Anju Nohria

Disclosures

Eur Heart J. 2021;42(32):3060-3062. 

Graphical Abstract: Potential common pathways between heart failure and cancer and how statin therapy may affect them. Adapted with permission from de Boer et al.[2]

Several studies have described a link between cardiovascular risk factors or established cardiovascular disease and incident cancer. For example, in a recent study that included 20 305 participants from the Framingham Heart Study and the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, traditional cardiovascular risk factors (including age, sex, and tobacco use), 10-year atherosclerotic risk score, and natriuretic peptide concentrations were associated with an increased risk of incident cancer.[1]

More specifically, overlapping risk factors for heart failure (HF) and cancer have also been described, such as age, hypertension, diabetes, tobacco use, lack of physical activity, and obesity.[2] Inflammation, oxidative stress, and metabolic remodelling are all thought to be among overlapping contributors to the pathophysiology of HF and cancer.[3] Emerging data also implicate clonal haematopoiesis of indeterminate potential in both diseases.[2,4] There are also some data that suggest that HF may beget incident cancer: a pre-clinical study in a mouse strain prone to developing colonic polyps found increased tumour growth in mice with anterior myocardial infarction-induced HF compared with sham-operated animals. Proteins secreted by the failing heart, such as SerpinA1 and SerpinA3, were shown to increase tumour proliferation in human colon cancer cells in vitro.[5]

However, the clinical existence of a link between the presence of HF and incident cancer remains controversial. In a case–control study from Olmsted County, Minnesota, HF patients were found to have a 68% higher adjusted risk of developing cancer when compared with age-, sex-, and date-matched community controls without HF.[6] A study that compared incident cancer rates in 9307 outpatients (left ventricular ejection fraction <45%), referred to 26 Danish HF clinics between April 2002 and December 2009, and the general Danish population without HF, found that the risk of any type of cancer was increased (incidence rate ratio of 1.24) in those with HF.[7] In contrast, a study that included a cohort from the Physicians' Health Studies I and II found that a self-reported diagnosis of HF was not associated with an increased risk of cancer among male physicians [adjusted hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.86–1.29].[8]

Additionally, several observational studies have shown that statin use lowers the risk of cancer and cancer-related mortality. A medical administrative database study from Canada compared incidence rates for hospital admission with any type of cancer among 30 076 patients discharged after an acute myocardial infarction on high-dose, low-dose, or no statin therapy, and found that high-dose, but not low-dose, statin therapy was associated with a reduced risk of incident cancer (HR 0.75, 95% CI 0.60–0.95).[9] In a Danish population-wide study of patients 40 years and older diagnosed with cancer between 1995 and 2007, those using statins prior to their cancer diagnosis were less likely to die from cancer compared with non-statin users (HR 0.85, 95% CI 0.82–0.87).[10]

The proposed mechanisms for the salutary effects of statins in cancer are centred on inhibition of HMG-CoA reductase. In addition to decreased proliferation and migration of cancer cells due to a reduction in cholesterol availability,[10] statin-mediated inhibition of HMG-CoA reductase inhibits the mevalonate pathway (which is up-regulated by mutated p53). Effects of inhibiting the mevalonate pathway include interfering with cell cycle progression and suppressing cell proliferation by inducing G1 arrest, inducing apoptosis via depletion of mevalonic acid, release of cytochrome c, activation of caspase-3, and reduction in inflammation (Graphical Abstract).[11]

In this issue of the European Heart Journal, Ren et al.[12] report the findings from their retrospective cohort study that aimed to investigate the association between statin use and the risk of incident cancer and cancer-related mortality in patients with HF, using data from the Hong Kong Hospital Authority Clinical Data Analysis Reporting System. The cohort consisted of 87 102 adult patients with a first HF hospitalization between January 2003 and January 2015. Statin exposure was defined as at least 90 consecutive days of statin therapy beginning within the first year after the index date (date of first diagnosis of HF). There were a total of 36 176 statin users (41.5%) and 50 926 (58.5%) statin non-users. The indications for therapy among statin users were atherosclerotic disease (n = 21 894, 60.5%), hypercholesterolaemia (n = 8326, 23.0%), and undefined (n = 5956, 16.5%).

Inverse probability of treatment weighting was used to balance baseline covariates between statin users and non-users. Competing risk regression with Cox proportional hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. After multivariable adjustment, statin users had a 16% lower risk of cancer than statin non-users [subdistribution hazard ratio (SDHR) 0.84, 95% CI 0.80–0.89]. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among statin non-users (adjusted SDHR 0.74, 95% CI 0.67–0.81). In additional analyses, incident cancer in statin users was not related to the indication for statin therapy or time-weighted LDL control, and the inverse association between incident cancer and statin use was duration dependent.

This is an important study that demonstrates, for the first time, the potential anticancer benefits of statin therapy in patients with HF. Furthermore, it expands the patient demographics of the existing literature on the association between statins and cancer outcomes by using a large, validated database of Asian patients with HF.

This study raises as many questions as it answers. The available data did not allow the investigators to differentiate between the effects of statins on incident cancer in patients with HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). While statin use was associated with reduced all-cause mortality in this study, previous studies have shown that statins improve overall mortality in patients with HFpEF[13] but not in those with HFrEF.[14] It is possible that the cancer-related benefits of statins may not apply equally to those with HFrEF and HFpEF. Similarly, subgroup analyses did not evaluate the association of statin use and lower risk of incident cancer in those with and without coronary artery disease, although the authors did attempt to address this by demonstrating no differences by indication for statin use.

Although the proposed pleotropic effects of statin therapy in cardiovascular disease centre on its anti-inflammatory effects, the mechanisms for cancer prevention/cancer mortality remain unclear. The authors describe that 'cancer incidence in statin users was not related to…time-weighted LDL control', but they were not able to dig deeper into other potential mechanisms for the effect of statin therapy on incident cancer. If available, data on inflammatory biomarkers, such as C-reactive protein (CRP), pre- and post-therapy would have been informative. These assessments could potentially help differentiate between the effects of mevalonate pathway inhibition and reduction in systemic inflammation by statin therapy on the incidence of cancer in patients with HF.

In this study, the benefits of statin therapy were not uniform, but were specific to certain types of cancer. An analysis of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), conducted in patients with a prior myocardial infarction and elevated CRP, also found a reduction in incident lung cancer and lung cancer mortality with inhibition of interleukin-1β by canakinumab.[15] The results of CANTOS and the current study suggest that different anti-inflammatory pathways may be potential targets for therapy in different forms of cancer. However, the role of inflammation in cancer biology is complex. Immune activation, and hence increased inflammation, with adoptive T-cell therapies has significantly improved outcomes in many types of cancers. We should also derive caution from the lack of benefit with statins[14] and antibodies against tumour necrosis factor-α[16] in patients with HF.

In summary, the results of the study by Ren and colleagues should motivate us to prospectively examine the effect of statins on incident cancer and cancer mortality in patients with established cardiovascular disease, including HF. Further basic and translational studies are also needed to learn more about the link between cardiovascular disease and incident cancer.

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