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Patients with HF after MI at elevated risk for cancer
Patients who develop HF after MI face an increased risk for cancer, according to study data published in the Journal of the American College of Cardiology.
Researchers analyzed data on 1,081 patients with MI in Olmstead County, Minnesota, from November 2002 to December 2010 (mean age, 64; 60% men) who participated in the Rochester Epidemiology Project. There were 5,327 person-years of follow-up (mean, 4.9 years).
Association suggested
“Our research suggests an association between [cancer and HF], and it’s possible that as we learn more about how this connection works, we can prevent deaths,” Veronique L. Roger, MD, director of the Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery at Mayo Clinic, said in a press release. “In the meantime, physicians should recognize this increased cancer risk for [patients with HF] and follow guideline-recommended surveillance and early detection practices.”
Veronique L. Roger
During the study period, 228 (21%) patients with MI progressed to HF and 98 developed cancer, excluding non-melanoma skin cancer. Median time to HF diagnosis was 3 days. The incidence density rates for a diagnosis of cancer were 33.7 per 1,000 patient-years for patients with HF and 15.6 per 1,000 patient-years for those without HF (P = .0002).
According to the researchers, those with HF had an elevated unadjusted risk for cancer (HR = 2.16, 95% CI, 1.39-3.35), which persisted after adjustment for age, sex and Charlson comorbidity index (HR = 1.71; 95% CI, 1.07-2.73).
HRs for mortality linked to cancer were 4.9 (95% CI, 3.1-7.74) for patients without HF and 3.91 (95% CI, 1.88-8.12) for those with HF (P for interaction = .76), the researchers found.
“The association between HF and cancer raises concerns regarding the effects of specific [CV] medications, including angiotensin receptor blockers, cardiac glycosides, diuretic agents, statins and prasugrel (Effient, Daiichi Sankyo/Eli Lilly),” Roger and colleagues wrote.
Age, sex and infarct size were among the factors contributing to HF onset, according to the researchers, who wrote, “Patients with subsequent HF were, on average, 10 years older, more likely to be women [and] with adverse risk factors and larger infarctions. They were also less likely to receive reperfusion/revascularization.”
Causation unlikely
In a related editorial, Jyoti Malhotra, MD, MPH, from Rutgers Cancer Institute of New Jersey, New Brunswick, and Paolo Boffetta, MD, MPH, from Icahn School of Medicine at Mount Sinai, wrote that “... it is unlikely that HF is playing a causative role in carcinogenesis because cancer has a latent period of at least a few years. ... However, a role in the late stages of the carcinogenic process ... cannot be excluded.”
Malhotra and Boffetta highlighted a potential limitation of the study regarding cancer diagnoses.
“Another factor to consider is that patients with MI who get HF may experience a more intense medical surveillance than other patients,” they wrote. “This could cause overdiagnosis and lead-time bias, with participants in the HF group getting diagnosed either with clinically irrelevant cancers or at an earlier stage of clinically relevant cancers.” – by James Clark
Disclosure: The researchers, Malhotra and Boffetta report no relevant financial disclosures.
Perspective
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HF and cancer have always had an ominous alliance, sharing not only common risk factors such as age and smoking, but also the potentiation of CV risk by various cancer therapeutics. However, this interesting study highlights the flip side of the coin, where HF post-MI might be an independent predictor of cancer incidence over a 5-year period following HF diagnosis.
Despite the limitations already highlighted by the authors in terms of sample size, observational study design, missing ejection fraction values and other factors, the study generates several important hypotheses such as, No. 1, the onco-protective effect of certain cardiac drugs such as aspirin; No. 2, common pathways mediated by angiotensin II and cyclooxygenases in increasing cancer risk in patients with HF; and, No. 3, the role of lifestyle in patients with HF that may be an independent oncological risk.
The study shows that that the patients with HF were less likely to be on aspirin. Interestingly, long-term aspirin use has been shown in several studies to reduce the risk for cancers such as colorectal cancer via the inhibition of cyclooxygenases COX-1 and COX-2, which have been proposed as one of the mechanisms for colorectal cancers. (Rothwell PM, et al. Lancet. 2010;doi:10.1016/S0140-6736(10)61543-7; Williams CS, et al. J Clin Invest. 1997;doi:10.1172/JCI119651.) A similar protective effect has been proposed in other cancers such as breast, prostate and lung, with a 2011 meta-analysis of eight randomized clinical trials showing that participants who took daily aspirin for 4 years or more had a 20% lower risk for dying from cancer vs. those who took no aspirin. (Rothwell PM, et al. Lancet. 2011;doi:10.1016/S0140-6736(10)62110-1.)
Among similar causal mechanisms for cancer and HF, besides altered immunity involving the monocyte system as suggested by the authors, is the role of angiotensin II. Cardiac angiotensin II levels increase after MI, and greatly so in response to pressure and volume overload such as that seen in patients with HF. The potentiation of vascular endothelial growth factor-induced proliferation and network formation of endothelial progenitor cells by angiotensin II is also one of the mechanisms for cancer-cell proliferation. (Imanishi T, et al. Hypertens Res. 2004;doi:10.1291/hypres.27.101.) Moreover, angiotensin II inhibition has been shown to enhance the anti-tumor effect of COX2 inhibitors such as aspirin and other nonsteroidal anti-inflammatory drugs. (Yasumaru M, et al. Cancer Res. 2003;63:6726-6734.)
Therefore, the role of increased angiotensin II levels is certainly hypothesis-generating for the increased incidence of cancer in patients with HF. The role of chronic inflammation, which has been seen in HF over time, can also cause changes such as formation of new blood vessels and DNA mutations that can promote tumor development and growth — hence, the proposed anti-cancer effect of COX-2 inhibitors.
From a non-pharmacological and non-mechanistic standpoint, there is the role of lifestyle. Patients with HF predictably have worse functional performances depending on their NYHA classification, and the reduced physical activity in patients with HF could be an independent factor for increased cancer risk. The inverse relationship between physical activity and cancer risk has been studied and suggested in 60 breast-cancer studies, 21 lung-cancer studies and 50 colorectal-cancer studies. (Wannamethee SG, et al. Br J Cancer. 2001;doi:10.1054/bjoc.2001.2096; Samad AK, et al. Colorectal Dis. 2005;doi: 10.1111/j.1463-1318.2005.00747.x.)
Further research into the above hypotheses regarding the association of increased cancer risk in post-MI HF patients would be exciting to see in larger, prospective trials.