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Introduzione: l'invecchiamento porta ad un aumento dei livelli di catecolamine circolante che contribuiscono alla disfunzione del recettore adrenergico cardiaco e alla sua desensibilizzazione. Nel cervello, i fattori neurotrofici, in particolare il brain-derived neurotrophic factor (BDNF), promuovono il benessere dei neuroni, quindi funzionano, incluso il riassorbimento dei neurotrasmettitori vitali per la comunicazione sinaptica. Scopo: In questo lavoro di tesi, abbiamo testato se nel cuore senile, una riduzione dell'innervazione autonomica, insieme alle neurotrofine associate, potesse comportare una perdita nel controllo autonomico della funzione miocardica e nello spillover delle catecolamine. Metodi: Abbiamo usato ratti Fisher giovani (3 mesi; n=10) e anziani (24 mesi; n=11) e cellule di neuroblastoma umano (SH-SY5Y). Risultati: Rispetto ai ratti giovani, quelli anziani mostrano una marcata riduzione della densità complessiva delle fibre nervose autonomiche, che colpisce sia i compartimenti simpatici che colinergici, secondo la colorazione immunoistochimica con dopamina β-idrossilasi (dβh) e del trasportatore di acetilcolina vescicolare (VaChT). L'analisi immunoblot eseguita nei lisati di ventricolo sinistro dei ratti anziani ha anche rivelato una pronunciata sottoregolazione dei fattori GAP-43 e di BDNF. Successivamente, abbiamo cercato di determinare se l'invecchiamento compromette la capacità autocrina delle fibre autonomiche. A tal fine, abbiamo stimolato le cellule SH-SY5Y in vitro con siero ottenuto da sangue periferico dei ratti giovani o degli anziani. Entrambi i sieri aumentavano la neuritogenesi delle SH-SY5Y (saggiata tramite saggio cristallo violetto); tuttavia, questo effetto risultava notevolmente ridotto in cellule coltivate con siero di ratti anziani; e in queste stesse cellule, è stato evidente un marcato calo sia dei livelli GAP- 43 che BDNF rispetto a quelli trattati con siero di ratto giovane. Conclusione: L'invecchiamento favorisce un depauperamento generale delle fibre autonomiche, e la mancanza di BDNF neuronale probabilmente contribuisce a questa perdita quantitativa e qualitativa.

The mineralocorticoid hormone aldosterone (Aldo) has been intensively studied for its ability to influence both the physiology and pathophysiology of the cardiovascular system. Indeed, although research on Aldo actions for decades has mainly focused on its effects in the kidney, several lines of evidence have now demonstrated that this hormone exerts disparate extrarenal adverse effects, especially in the circulatory system. Accordingly, in the last lusters, a number of studies in preclinical models (in vitro and in vivo) and in humans have established that Aldo, following the interaction with its receptor—the mineralocorticoid receptor (MR)—is able to activate specific intracellular genomic and nongenomic pathways, thus regulating the homeostasis of the cardiovascular system. Importantly, through this mechanism of action, this hormone becomes a crucial regulator of the function and growth of different types of cells, including fibroblasts, cardiomyocytes, and vascular cells. For this main reason, it is plausible that when Aldo is present at high levels in the blood, it profoundly modifies the physiology of these cells, therefore being at the foundation of several cardiovascular disorders, such as heart failure (HF). On these grounds, in this review, we will provide an updated account on the current knowledge concerning Aldo activity in the cardiovascular system and the most recent preclinical studies and clinical trials designed to test better approaches able to counter the hyperactivity of the Aldo/MR signaling pathway in the setting of cardiovascular diseases.

Rationale: It has been reported that epicardial adipose tissue (EAT) may affect myocardial autonomic function. Objective: The aim of this study was to explore the relationship between EAT and cardiac sympathetic nerve activity in patients with heart failure. Methods and Results: In 110 patients with systolic heart failure, we evaluated the correlation between echocardiographic EAT thickness and cardiac adrenergic nerve activity assessed by 123 I-metaiodobenzylguanidine ( 123 I-MIBG). The predictive value of EAT thickness on cardiac sympathetic denervation ( 123 I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score) was tested in a multivariate analysis. Furthermore, catecholamine levels, catecholamine biosynthetic enzymes, and sympathetic nerve fibers were measured in EAT and subcutaneous adipose tissue biopsies obtained from patients with heart failure who underwent cardiac surgery. EAT thickness correlated with 123 I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score, but not with left ventricular ejection fraction. Moreover, EAT resulted as an independent predictor of 123 I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score and showed a significant additive predictive value on 123 I-MIBG planar and single-photon emission computed tomography results over demographic and clinical data. Although no differences were found in sympathetic innervation between EAT and subcutaneous adipose tissue, EAT showed an enhanced adrenergic activity demonstrated by the increased catecholamine levels and expression of catecholamine biosynthetic enzymes. Conclusions: This study provides the first evidence of a direct correlation between increased EAT thickness and cardiac sympathetic denervation in heart failure.

Background: Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional β-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and β-adrenergic receptor responsiveness in a rat model of postischemic HF. Methods and Results: Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1-year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac β-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet. Conclusions: We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and β-adrenergic receptor levels in failing myocardium.

The mineralocorticoid hormone aldosterone (Aldo) has been intensively studied for its ability to influence both the physiology and pathophysiology of the cardiovascular system. Indeed, although research on Aldo actions for decades has mainly focused on its effects in the kidney, several lines of evidence have now demonstrated that this hormone exerts disparate extrarenal adverse effects, especially in the circulatory system. Accordingly, in the last lusters, a number of studies in preclinical models (in vitroandin vivo) and in humans have established that Aldo, following the interaction with its receptor—the mineralocorticoid receptor (MR)—is able to activate specific intracellular genomic and nongenomic pathways, thus regulating the homeostasis of the cardiovascular system. Importantly, through this mechanism of action, this hormone becomes a crucial regulator of the function and growth of different types of cells, including fibroblasts, cardiomyocytes, and vascular cells. For this main reason, it is plausible that when Aldo is present at high levels in the blood, it profoundly modifies the physiology of these cells, therefore being at the foundation of several cardiovascular disorders, such as heart failure (HF). On these grounds, in this review, we will provide an updated account on the current knowledge concerning Aldo activity in the cardiovascular system and the most recent preclinical studies and clinical trials designed to test better approaches able to counter the hyperactivity of the Aldo/MR signaling pathway in the setting of cardiovascular diseases.

The sphingosine kinases 1 and 2 (SphK1 and 2) catalyze the phosphorylation of the lipid, sphingosine, generating the signal transmitter, sphingosine 1-phosphate (S1P). The activation of such kinases and the subsequent S1P generation and secretion in the blood serum of mammals represent a major checkpoint in many cellular signaling cascades. In fact, activating the SphK/S1P system is critical for cell motility and proliferation, cytoskeletal organization, cell growth, survival and response to stress. In the cardiovascular system, the physiological effects of S1P intervene through the binding and activation of a family of five highly-selective G protein-coupled receptors (GPCRs), called S1PR1–5. Importantly, SphK/S1P signal is present on both vascular and myocardial cells. S1P is a well-recognized survival factor in many tissues. Therefore, it is not surprising that the last two decades have seen a flourishing of interest and investigative efforts directed to obtain additional mechanistic insights into the signaling, as well as the biological activity of this phospholipid, and of its receptors, especially in the cardiovascular system. Here, we will provide an up-to-date account on the structure and function of sphingosine kinases, discussing the generation, release, and function of S1P. Keeping the bull's eye on the cardiovascular system, we will review the structure and signaling cascades and biological actions emanating from the stimulation of different S1P receptors. We will end this article with a summary of the most recent, experimental and clinical observations targeting S1PRs and SphKs as possible new therapeutic avenues for cardiovascular disorders, such as heart failure.