How progressive cancer endangers the heart: an intriguing and underestimated problem

Abstract

Since it came into being as a discipline, cardio-oncology has focused on the prevention and treatment of cardiotoxicity induced by antitumor chemotherapy and radiotherapy. Over time, it has been proved that even more detrimental is the direct effect generated by cancer cells that release pro-cachectic factors in the bloodstream. Secreted molecules target different organs at a distance, including the heart. Inflammatory and neuronal modulators released by the tumor bulk, either as free molecules or through exosomes, contribute to the pathogenesis of cardiac disease. Progressive cancer causes cachexia and severe cardiac muscle wasting accompanied by cardiomyocyte atrophy, tissue fibrosis, and several functional impairments up to heart failure. The molecular mechanisms responsible for such a cardiac muscle wasting have been partially elucidated in animal models, but minimally investigated in humans, although severe cardiac dysfunction exacerbates global cachexia and hampers efficient anti-cancer treatments. This review provides an overview of cancer-induced structural cardiac and functional damage, drawing on both clinical and scientific research. We start by looking at the pathophysiological mechanisms and evolving epidemiology and go on to discuss prevention, diagnosis, and a multimodal policy of intervention aimed at providing overall prognosis and global care for patients. Despite much interest in the cardiotoxicity of cancer therapies, the direct tumor effect on the heart remains poorly explored. There is still a lack of diagnostic criteria for the identification of the early stages of cardiac disease in cancer patients, while the possibilities that there are for effective prevention are largely underestimated. Research on innovative therapies has claimed considerable advances in preclinical studies, but none of the molecular targets suitable for clinical application has been approved for therapy. These issues are critically discussed here.

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…[3][4][5][6] Further, given the severe metabolic dysregulation and hypercatabolism that persists with cachexia, it is no surprise that clinical and experimental investigations have identified perturbations in several tissues besides skeletal muscle, including fat, bone, and heart. 3,[7][8][9][10] Unfortunately, viable treatment options to counteract cachexia, especially in the most advanced stages of cancer, remain elusive.…”

Cancer Cachexia and Related Metabolic Dysfunction

“…In addition, muscle wasting is not an exclusive feature of skeletal muscle involved in locomotion, it has also been shown to affect respiratory muscles and even myocardium in patients with chronic disease-associated wasting [36][37][38]. Additionally, the progression of tumor cells, as well as cardiotoxicity induced by cancer treatment, may lead to a condition called "cardiac cachexia" that is characterized by cardiac atrophy, fibrosis, and myocardial dysfunction [39].…”

Development of Cancer in Patients With Heart Failure: How Systemic Inflammation Can Lay the Groundwork

“…Clinical and experimental studies have demonstrated that cancer patients develop cardiac disease not only as a consequence of cardiotoxicity induced by chemotherapies, but also because tumor cells release soluble factors that affect various organs at a distance, including the heart (1, 2). Cancer-derived pro-inflammatory molecules cause cardiomyocyte atrophy and tissue remodeling, which can degenerate to cachexia and HF (3)(4)(5).…”