Endothelial Dysfunction Linked to Risk for
Future Cancer

November 01, 2019

Microvascular endothelial dysfunction, a common early sign of cardiovascular disease, could also be a marker for predicting risk for solid-tumor cancer, a new study suggests.

Researchers found that patients who had microvascular endothelial dysfunction as measured with reactive hyperemia peripheral arterial tonometry (RH-PAT) — a technique that measures blood flow to the fingers during blood pressure cuff inflation and release — had more than double the risk of developing a solid-tumor cancer over a median period of 6 years follow-up compared with similar patients who did not have microvascular endothelial dysfunction.

The study was published online yesterday in the European Journal of Preventive Cardiology.

"This abnormal vasoreactivity should alert clinicians not only to the risk of cardiovascular disease but to malignancy as well," said senior author Amir Lerman, MD, Mayo Clinic, Rochester, Minnesota. "This risk prediction appears to precede the development of disease by more than 5 years."

"The current study shows that microvascular endothelial dysfunction measured using RH-PAT acts as an indicator of risk for the future development of solid-tumor cancer, and could therefore be used to identify patients who require more aggressive screening," the authors state. 

"This in turn could allow for the detection of pre-malignant disease, or cancer in the early stages of its natural history, that may still be amenable to curative therapy, or potentially to identify individuals at risk in whom lifestyle interventions and therapeutic approaches targeting vascular health could be recommended," they add. "However, further studies are needed to clarify whether any therapy targeting endothelial dysfunction could reduce the risk of incident solid-tumor cancers."

But Lerman cautions that the study should be viewed as preliminary and the findings needs confirmation in other cohorts. 

"I would not recommend at this point that a patient who has been found to have endovascular dysfunction undergoes additional tests for cancer, or that this test is used to screen for early cancer detection. But maybe this could be the case in the future if our results are replicated by others," he told Medscape Medical News.  

"I think this endothelial dysfunction is a sign of systemic inflammation and oxidative stress in the body," he added. "And I think we can say from our results that detection of endovascular dysfunction is a sign of general poor health of the vessels and the body, and the patients need to look at their lifestyle in terms of diet, exercise, smoking, stress, etc."

Lerman said he and his colleagues conducted the study after new data was published linking inflammation to the development of cancer.

"This sparked our curiosity as inflammation is also a predictor of cardiovascular disease and can be measured by assessing endovascular dysfunction," he said. "We know endovascular dysfunction predicts the risk of future cardiovascular events and we decided to look at whether it could also predict the development of cancer."

The study involved 488 patients (mean age 53) who had undergone microvascular endothelial function testing at the Mayo Clinic for the assessment of chest pain and/or cardiovascular risk between 2006 and 2014.

The prevalence of a preexisting diagnosis of a solid-tumor cancer was not different between the groups at baseline. Patients with hematologic cancers at baseline were excluded. Tumor types of interest included breast, lung, prostate, colorectal, cervical, and skin cancers. 

Microvascular endothelial dysfunction was defined as an RH-PAT index of 2.0 or less and was present in 221 patients (45% of the cohort tested).

Over a follow up period of up to 12 years (median 6 years), 9.5% of those who had microvascular endothelial dysfunction were diagnosed with a solid-tumor cancer compared with 3.7% of patients who did not have endothelial dysfunction (P = .009).

The most common tumor types were skin cancers (n = 15), breast cancer (n = 6), and lung cancer (n = 5). The findings were consistent after adjusting for age, gender, coronary artery disease, and other factors.

The association between microvascular endothelial dysfunction and cancer was more prominent among men and in patients with hypertension, significant coronary artery disease, smoking, and obesity.

Microvascular endothelial dysfunction at baseline was also significantly associated with decreased solid-tumor cancer-free survival with the divergence in survival curves becoming apparent after 6 years.

"The current study supports the concept that microvascular endothelial dysfunction may predispose to the development of cancer and/or may act as a surrogate marker of risk for the development of cancer," the authors say.

What Is the Mechanism?

Lerman commented that the mechanism behind this relationship is not known, but it seems likely "that the substances causing inflammation in the blood vessel and oxidative stress may also contribute to the growth of cancers."

In the article, the authors write: "Evidence to date suggests that several proatherogenic stimuli trigger inflammation and reactive oxygen species production in endothelial cells, and that excess oxidative stress plays a crucial role in the pathologic manifestations of atherosclerosis. Meanwhile, inflammation and genotoxic stress induce apoptosis via reactive oxygen species production, and reactive oxygen species-induced DNA damage may play an essential role in the development of cancer."

Chronic inflammation and excess oxidative stress are among underlying biological processes for both atherosclerotic cardiovascular disease and cancer, the investigators add. "The fact that anti-inflammatory treatment targeting interleukin-1b reduced not only major cardiovascular events post-myocardial infarction but also lung cancer incidence and mortality in the CANTOS trial further supports this notion."

They also point out that endothelial dysfunction may impose a risk for chronic hypoxia to perfusing tissue, which could cause alteration of DNA damage-associated checkpoints and decreased DNA repair. Furthermore, it could cause a metabolic shift to anaerobic glycolysis, resulting in accumulation of various glycolytic metabolites used to synthesize hyaluronic acid, which has been linked to cancer development.

In addition, tissue hypoxia can stimulate angiogenesis, which is a common pathway in atherogenesis and carcinogenesis, the researchers note.

The authors received no financial support for the research, authorship, and/or publication of this article. Lerman declares consulting for Itamar Medical.

Eur J Prev Cardiol. Published online October 31, 2019. Full text

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