Aims High chromogranin-A (CgA) levels were observed in patients with heart failure but its source remained uncertain. We evaluated whether CgA is produced by myocardium and might affect myocardial function. Methods and results We measured plasma CgA levels and performed immunohistochemistry with anti-CgA antibodies on myocardial biopsies in 40 patients with dilated cardiomyopathy (DCM) and 20 patients with hypertrophic cardiomyopathy (HCM). Surgical myocardial specimens from DCM and HCM patients were used for PCR and ELISA. The presence of CgA-derived fragments in plasma was evaluated by gel-filtration HPLC and their effects on cardiac performance assessed in isolated perfused rat heart. All patients showed increased CgA plasma levels (DCM 153.7 ± 158.5 ng/mL; HCM 150.2 ± 86.7 ng/mL vs. 64.1 ± 17.9 ng/mL of controls) with a positive correlation between CgA and left ventricular end-diastolic pressure (DCM, R = 0.86; HCM, R = 0.83), and plasma brain natriuretic peptide (BNP) levels (DCM, R = 0.88; HCM, R = 0.85) ( P < 0.001). Immunohistochemistry showed cytoplasmic expression of CgA and co-localization with BNP in all patients, but not in controls. PCR detected CgA mRNA in both pathologic and normal myocardium, while ELISA showed a significant amount of CgA only in pathologic myocardium (>0.5 µg/g of tissue); gel-filtration HPLC of plasma samples identified immunoreactive N-terminal CgA fragments containing vasostatin-1. Administration of vasostatin-1 to perfused rat heart produced negative inotropic and lusitropic effects counteracting isoproterenol actions. Conclusion We demonstrate for the first time that CgA is produced by human myocardium and exerts negative inotropic and lusitropic effects on mammalian heart. CgA may represent a key player in neuroendocrine regulation of cardiac function and a potential therapeutic target in heart failure.

Circulating levels of catestatin (Cts; human chromogranin A_352–372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of β₂-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of β₂-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against β-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.

The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25HC, have been found to be elevated in hypercholesterolemic serum. Here, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25HC in breast and ovarian cancer cells. Moreover, 25HC exhibits the ERα-dependent ability like 17β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis. The estrogen action exerted by 25HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25HC elicited in the cardiovascular system may play a role against hypoxic environments.

Significance: Despite their serious side effects, anthracyclines (ANTs) are the most prescribed chemotherapeutic drugs because of their strong efficacy in both solid and hematological tumors. A major limitation to ANTs clinical application is the severe cardiotoxicity observed both acutely and chronically. The mechanism underlying cardiac dysfunction under chemotherapy is mainly dependent on the generation of oxidative stress and systemic inflammation, both of which lead to progressive cardiomyopathy and heart failure. Recent Advances: Over the years, the iatrogenic ANTs-induced cardiotoxicity was believed to be simply given by iron metabolism and reactive oxygen species production; however, several experimental data indicate that ANTs may use alternative damaging mechanisms, such as topoisomerase 2β inhibition, inflammation, pyroptosis, immunometabolism, and autophagy. Critical Issues: In this review, we aimed at discussing ANTs-induced cardiac injury from different points of view, updating and focusing on oxidative stress and inflammation, since these pathways are not exclusive or independent from each other but they together importantly contribute to the complexity of ANTs-induced multifactorial cardiotoxicity. Future Directions: A deeper understanding of the mechanistic signaling leading to ANTs side effects could reveal crucial targeting molecules, thus representing strategic knowledge to promote better therapeutic efficacy and lower cardiotoxicity during clinical application.