Although the link between some chemotherapy agents and cardiac damage is well-known, new research published online September 28, 2015 in Heart, suggests that some cancers on their own may contribute to cardiac dysfunction.
A study of more than 500 cancer patients, none of whom had undergone prior cardiotoxic cancer therapy, showed that levels of high-sensitivity troponin T (hs-TnT) and five cardiovascular neurohormones were elevated at baseline and increased as tumor stage progressed.
In addition, hs-TnT, N-terminal pro B-type natriuretic peptide (NT-proBNP), midregional pro–atrial natriuretic peptide (MR-proANP), midregional pro–adrenomedullin (MR-proADM), C-terminal pro–endothelin-1 (CT-proET-1), and copeptin were all significant predictors of all-cause mortality within 25 months, the primary end point.
The results suggest “the presence of subclinical functional and morphological myocardial damage directly linked to disease progression,” write the researchers, led by Dr Noemi Pavo (Medical University of Vienna, Austria).
Coinvestigator Dr Martin Hülsmann (Medical University of Vienna) said that the most important finding for him was that the neurohormones were so predictive even after extensive adjustment. However, “I currently have no recommendations for clinicians because I think we have found more questions than answers,” said Hülsmann.
Revealing “Cross talk”
Past research has shown that malignant cancer cells can produce vasoactive peptides (such as ADM and ET-1) and cardiac hormones (such as ANP and BNP), note the investigators. However, an “underlying morphological cardiac substrate” has not been commonly found for the latter group. “Elevated levels of natriuretic peptides have been, therefore, considered to be false-positive findings,” they add.
Still, after results from some small animal studies suggested that CV neurohormones “are less innocent bystanders and equally that TnT should not be overlooked,” the researchers sought to conduct their own trial “to reveal the humoral cross talk between cancer and cardiac disease.”
They enrolled 555 consecutive cancer patients (60% women) at Vienna General Hospital between April 2011 and June 2013. Tumor existence and stage were measured at baseline and at follow-up (mean 25 months). In addition, blood samples were taken.
At follow-up, 34% of the study participants had died. Although the strongest predictor of all-cause mortality, as shown in univariate analysis, was NT-proBNP, all of the following were significant:
Adjusted* Hazard Ratio (HR) for All-Cause Mortality
|Variable||HR (95% CI)||P|
When the model was also adjusted for hs-TnT, there was still a significant association with mortality for all of the variables except for MR-proANP, “highlighting the independent impact of these hormones in cancer.”
In addition, patients at tumor stage 4 had significantly higher levels of the proinflammatory cytokine interleukin 6 (IL-6), the inflammatory marker C-reactive protein (CRP), haptoglobin, and serum amyloid A than those at stages 1 through 3 (all comparisons, P<0.05).
Finally, the following three hormones were significantly associated with IL-6 and CRP: NT-proBNP, MR-proANP, and MR-proADM; hs-TnT was associated with CRP only.
“Whether the effect on mortality is primarily due to a detrimental local influence on the tumor microenvironment or is induced by systemic cardiovascular dysregulation cannot be determined,” write the investigators.
Still, “the results provide intellectual support of heart-failure therapy in patients with cancer beyond the current focus on preventing therapy-related cardiotoxic side effects.”
Hülsmann noted that he is now interested to see what happens with the neurohormones in cancer patients over time. “Does [risk for CVD] steadily increase after diagnosis, and does it decrease if the patient is cured? We’re also very interested in what happens during therapy.”
“This is an important discovery that these peptides are elevated significantly on a routine basis in cancer patients,” Dr Steven Ewer (University of Wisconsin School of Medicine and Public Health, Madison) said. “And I think this reflects some complex interactions between the malignancy and cardiovascular disease in ways that are not yet fully understood but are probably important,” he added.
“There could be some preexisting subclinical cardiac disease in these patients. Whether that’s due to comorbidities or to age or to specific tumor-related vasoactive peptides is a little bit unclear,” he said. “But it was an important trial-design aspect that they didn’t have any cardiotoxic treatment before measurements.” Ewer, who was not involved with this research, established his university’s cardio-oncology clinic in 2009.
When asked if there are any clinical implications from the study, Ewer said there are potential systemic effects of the tumor-related peptides that deserve further exploration. “But whether that can be carried out in the clinical setting yet is doubtful.”
Limitations of the study that he cited included that it study looked only at all-cause mortality and did not distinguish between cancer death and CV death.
Still, “it’s important to realize these molecules are circulating in the bloodstream and could be having potential effects on the cardiovascular system and potentially even contributing to mortality. So I think this study is an important first step,” said Ewer.
Pavo N, Raderer M, Hülsmann M, et al. Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality. Heart 2015; DOI:10.1136/heartjnl-2015-307848. Article