Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release.

Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile

Old and new intravenous inotropic agents in the treatment of advanced heart failure

Inotropic agents are administered to improve cardiac output and peripheral perfusion in patients with systolic dysfunction and low cardiac output. However, there is evidence of increased mortality and adverse effects associated with current inotropic agents. These adverse outcomes may be ascribed to patient selection, increased myocardial energy expenditure and oxygen consumption, or to specific mechanisms of action. Both sympathomimetic amines and type III phosphodiesterase inhibitors act through an increase in intracellular cyclic adenosine monophoshate and free calcium concentrations, mechanisms that increase oxygen consumption and favor arrhythmias. Concomitant peripheral vasodilation with some agents (phosphodiesterase inhibitors and levosimendan) may also lower coronary perfusion pressure and favor myocardial damage. New agents with different mechanisms of action might have a better benefit to risk ratio and allow an improvement in tissue and end-organ perfusion with less untoward effects. We have summarized the characteristics of the main inotropic agents for heart failure treatment, the data from randomized controlled trials, and future perspectives for this class of drugs

Treatment of heart failure in the elderly: never say it's too late

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Postdischarge assessment after a heart failure hospitalization: the next step forward.

Heart failure (HF) is the most frequent cause of hospitalization for patients >65 years of age. Mortality during the initial hospitalization ranges from 6% to 7% in Europe to 3% to 4% in the United States, depending on the length of hospital stay. Poor outcomes have universally been shown after discharge, with 60- to 90-day mortality rates of 5% to 15% and hospital readmission rates of 30%. Whereas the prognosis of patients with chronic HF has improved in recent years, there has been no change in the high risk of death or rehospitalization after an HF hospitalization. In addition to the lack of new therapies, incomplete relief from fluid overload, insufficient patient education, lack of implementation of evidence-based therapies, and poor postdischarge follow-up planning are among the main causes of these poor outcomes. A better assessment of the patient at the time of discharge and in the following weeks seems therefore as mandatory. This article outlines the main components of such a program. These include the personnel who should be involved, i.e. HF specialists and cardiologists versus non-specialists, the variables which should be assessed, i.e. those related with congestion and fluid overload, the times when they should be assessed, as the phase at highest risk is immediately after discharge from hospital, and, finally, the aims of such programs. We retain that an improvement of post-discharge follow-up will be able to significantly improve patients’ outcomes with a rate of success comparable, if not greater, to that which can be achieved by new therapies

Can we improve the treatment of congestion in heart failure?

INTRODUCTION: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes. AREAS COVERED: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed. EXPERT OPINION: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need

Applicazione di Reti Neurali Artificiali (ANN) sulla rilevazione del dolore postoperatorio in ambito ortopedico per l’individuazione di algoritmi di valutazione obbiettiva

Nel nostro reparto afferiscono circa 700 fratture di femore anno, mentre circa 400 risultano i ricoveri di protesica in elezione. Il trattamento del dolore riveste importanza in quanto condizionante il trattamento riabilitativo e l\u2019outcame, in relazione anche al controllo della risposta alla terapia per i soggetti meno responsivi. Abbiamo pensato di applicare strumenti di AI per individuare una risposta utile alle gestione del sintomo dolore. In questo contesto, sia gli algoritmi di machine learning (2), sia le reti neurali artificiali (1) possono rappresentare un supporto a: un'efficace intervento precoce; l\u2019identificazione di gruppi a rischio; l\u2019elaborazione della diagnosi (3); l\u2019ottimizzazione temporale ed economica delle azioni proattive e reattive (\u201cTecnologie cognitive e nuove strategie di realt\ue0 virtuale nel paziente anziano: diagnosi, prognosi e recupero funzionale\u201d Folgieri SIMFER2017). A seconda della dimensione e della complessit\ue0 dei dati, \ue8 possibile applicare differenti algoritmi di AI. In particolare, le Reti Neurali Artificiali (ANN) appaiono adatte allo studio per la peculiare capacit\ue0 di generalizzazione anche a fronte di dati incompleti, in una sorta di \u201cinsight\u201d, che le rende adatte all\u2019ambito considerato per la capacit\ue0 delle ANN di apprendere da esempi, in assenza di esplicita descrizione del problema. Dati gli input, le ANN possono determinare (relazione input-output) il peso dei criteri componenti la scala ricercata individuando il minimo sottoinsieme di parametri utili. Materiali e metodi Il campione analizzato consta di 65 pazienti di et\ue0 compresa tra i 45 e i 90 anni, di cui 30 di sesso maschile. Sono stati collezionati 45 parametri tra anamnesi, diagnosi, terapia, abitudini alimentari, stile di vita, stato neuropsicologico. I dati sono stati analizzati con una rete neurale artificiale (ANN) supervisionata con algoritmo di backpropagation. La rete presenta 44 neuroni di input, un hidden layer composto da cinque neuroni e un neurone di uscita. Il target error \ue8 risultato 0.01, mentre l\u2019average training error \ue8 stato di 0.0099. Una Rete Neurale \ue8 utilizzata per classificare un set di osservazioni composte da n differenti variabili. I neuroni (nodi), che rappresentano l\u2019unit\ue0 di base per processare i segnali, sono organizzati in strati (layer). Nello strato di input ogni neurone accetta un singolo e genera un valore di output che sar\ue0 usato quale input per i neuroni del livello successivo. Per il neurone j strato ricevente, il net input \ue8 calcolato mediante la formula: netj= 11_i\u2592\u3016WijIi \u3017 (1) Ii \ue8 il segnale dal neurone i dello strato che invia il segnale, netj \ue8 il segnale raccolto dal neurone ricevente j , e wi,j \ue8 il peso da sommare una volta moltiplicato per il corrispondente segnale ricevuto dal neruone di input. Il neurone ricevente crea l\u2019attivazione in risposta al segnale netj . Nel caso della rete neurale sviluppata, l\u2019attivazione avviene mediante la funzione sigmoidale: 1/(1+e^(-netj) ) (2) L\u2019attivazione diviene l\u2019input per lo strato successive. Le equazioni (1) e (2) possono essere usate per processare nuovamente il segnale. I processi di raccolta e attivazione continuano finch\ue9 i segnali finali raggiungono lo strato di output. Attraverso l\u2019algoritmo feedforward, la rete calcola i pesi per i nodi di input e per quelli nascosti verso i nodi di output. I pesi sono determinati tramite algoritmo di addestramento di back propagation (BP), l\u2019algoritmo si ferma quando il valore della funzione errore arriva alla soglia prevista. L\u2019algoritmo di back propagation seleziona i pesi iniziali in modo random e confronta l\u2019output ottenuto con il risultato atteso. La differenza tra questi valori \ue8 valutata mediante la mean squared error. Una volta che tutte le osservazioni sono state presentate alla rete, i pesi vengono modificati in accordo alla delta rule generalizzata, in modo che l\u2019errore totale sia distribuito tra i vari nodi della rete. Un sottoinsieme di dati di training viene utilizzato per ottenere i pesi ottimali iniziali. Discussione e risultati Il target error \ue8 stato impostato 0.01, e l\u2019average training error \ue8 risultato 0.0099. I risultati ottenuti, sebbene preliminari, sembrano consentire di individuare: i parametri significativi per misurazioni obiettive e meno soggettive; la graduazione del rischio, in relazione alla manifestazione di stati dolorosi acuti. Dai 45 parametri inizialmente utilizzati sono state selezionate tra le 9 e le 8 variabili realmente incidenti sull\u2019algoritmo di graduazione. Conclusioni A fronte di un ampliamento del campione analizzato, pensiamo di rivalutare il numero dei parametri mentre l\u2019ANN sviluppata potrebbe permettere di individuare: parametri significativi per l\u2019individuazione del rischio e l\u2019ottimizzazione della terapia graduazione obiettiva del trattamento del dolore Bibliografia Baxt, W. G. (1995). Application of artificial neural networks to clinical medicine. The lancet, 346(8983), 1135-1138. Kononenko, I. (2001). Machine learning for medical diagnosis: history, state of the art and perspective. Artificial Intelligence in medicine, 23(1), 89-109. Lucchiari, C., Folgieri, R., & Pravettoni, G. (2014). Fuzzy cognitive maps: a tool to improve diagnostic decisions. Diagnosis, 1(4), 289-293. Rojas R. (1996), Neural Networks, Springer-Verlag, Berlin. Buscema, M. (1998). Back propagation neural networks. Substance use & misuse, 33(2), 233-270. Kantardzic M. (2011), Data mining: concepts, models, methods, and algorithms, John Wiley & Son

Raised homocystein plasma concentration in patients with Heart Failure: clinical significance

Elevated plasma levels of homocysteine is associated with increased risk of thrombotic and atherosclerotic vascular disease. Several studies have demonstrated that hyperhomocysteinemia is an indipendent risk factor for vascular disease and is associated to heart failure. However there are no data regarding the association between homocysteine and various objective as well as subjective measures of heart failure. We hypothesized that plasma homocysteine is associated with clinical and echocardiographic signs of heart failure. On this ground we have analysed levels of homocysteine in patients with heart failure and possible correlation between these levels and clinical-functional pattern (NYHA class and ejection fraction). Methods: Plasma homocysteine levels were determined in 123 patients with dilated cardiomyopathy (59 males, 64 females, mean age 67±10 years, mean EF 31±11% and mean NYHA 2.4±0.9, 47 idiopatic and 76 postischemic cardiomyopathy) and 85 healthy control subjects (homogeneus group for sex and age). Patients with chronic renal failure, vitamin B12 and folate deficiency or factors affecting homocysteine plasma levels were escluded from this study. Homocysteine levels were determined in coded plasma samples by immunoenzimatic methods. Results: Patients with heart failure had a higher homocysteine level (mcg/L) than control subjects (21.72±10.28 vs 12.9±6.86, p<0,001) both postischemic (20.89±9.6 vs 12.9±6.86, p<0,001) and idiopatic cardiomiopathy (23.0±11.2 vs 12.9±6.86, p<0,001). A significant correlation was observed between homocysteine and NYHA functional class (p<0,001), age (p<0,001), creatinine (p<0,001), colesterol (p<0,05) while no correlations were observed with hemodynamic (HR, BP), functional (ejection fraction) and other metabolic parameters (triglycerides). Serum homocysteine was lowest in control and increased with increasing NYHA class. In idiopatic cardiomiopathy the correlation between homocysteine and NYHA functional class, creatinine (p<0,001), fibrinogen (p<0,05) was confirmed; in postischemic cardiomiopathy a significant correlation with creatinine and NYHA class (p<0,001) and with triglycerides (p<0,05) was also found. Conclusion: Plasma homocysteine was directly related to NYHA class. This observation may underline the strong relations of plasma homocysteine to congestive heart failure. Further research is indicated to evaluate a causal or noncausal mechanism for this association

Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis

Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells