In the last decade, cardiologists and oncologists have provided clinical and experimental evidence that cancer, and not only chemotherapeutic agents, can cause detrimental effects on heart structure and function, a consequence that has serious clinical implications for patient management. In parallel, the intriguing idea that heart failure (HF) may be an oncogenic condition has also received growing attention. A number of epidemiological and clinical studies have reported that patients with HF have a higher risk of developing cancer. Chronic low-grade systemic inflammation has been proposed as a major pathophysiological process linking the failing heart to the multi-step process of carcinogenesis. According to this view, pro-inflammatory mediators secreted by the damaged heart generate a favorable milieu that promotes tumor development and accelerates malignant transformation. HF-associated inflammation synergizes with tumor-associated inflammation, so that over time it is no longer possible to distinguish the effects of one or the other. Experimental studies have just begun to search for the molecular effectors of this process, with the ultimate goal that of identifying mechanisms suitable for anti-cancer target therapy to reduce the risk of incident cancer in patients already affected by HF. In this review we critically discuss strengths and limitations of clinical and experimental studies that support a causal relationship between HF and cancer, and focus on HF-associated inflammation, cardiokines and their endocrine functions linking one and the other disease.

Familial hypertrophic cardiomyopathy (FHCM), an autosomal dominant disease, is caused by mutations in genes encoding cardiac sarcomeric proteins. E22K, a mutation in the myosin regulatory light chain sarcomere gene, is associated with the development of FHCM. However, the molecular mechanisms by which E22K mutation promotes septal hypertrophy are still elusive. The hypertrophic markers, including beta-myosin heavy chain, atrial natriuretic peptide and B-type natriuretic peptide, were upregulated, as detected by fluorescence quantitative PCR. The gene expression profiles were greatly altered in the left ventricle of E22K mutant mice. Among these genes, nuclear factor of activated T cells (NFAT) and protein kinase C-alpha (PKC-α) were upregulated, and their protein expression levels were also verified to be elevated. The fibrosis markers, such as phosphorylated Smad and transforming growth factor beta receptor, were also elevated in transgenic E22K mice. After receiving 6 weeks of procedural exercise training, the expression levels of PKC-α and NFAT were reversed in E22K mouse hearts. In addition, the expression levels of several fibrosis-related genes such as transforming growth factor beta receptor 1, Smad4, and alpha smooth muscle actin in E22K mouse hearts were also reversed. Genes that associated with cardiac remodeling such as myocyte enhancer factor 2C, extracellular matrix protein 2 and fibroblast growth factor 12 were reduced after exercising. Taken together, our results indicate that exercise can improve hypertrophy and fibrosis-related indices in transgenic E22K mice via PKC-α/NFAT pathway, which provide new insight into the prevention and treatment of familial hypertrophic cardiomyopathy.

Heart failure is a serious threat to human health, with morbidity and mortality rates increasing despite the existence of multiple treatment options. Therefore, it is necessary to identify new therapeutic targets for this disease. Sacubitril/valsartan is a supramolecular sodium salt complex of the enkephalinase inhibitor prodrug sacubitril and the angiotensin receptor blocker valsartan. Its combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects. Clinical evidence suggests that sacubitril/valsartan is superior to conventional renin-angiotensin-aldosterone inhibitor therapy for patients with reduced ejection fraction heart failure who can tolerate angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The therapy reduces the risk of heart failure hospitalization, cardiovascular mortality, and all-cause mortality and has a better safety and tolerability record. This review describes the potential pathophysiological mechanisms of cardiomyocyte injury amelioration by sacubitril/valsartan. We explore the protective effects of sacubitril/valsartan and outline the therapeutic value in patients with heart failure by summarizing the results of recent large clinical trials. Furthermore, a preliminary outlook shows that sacubitril/valsartan may be effective at treating other diseases, and provides some exploratory observations that lay the foundation for future studies on this drug.