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Introduction: B-blockers are regarded as beneficial pharmacologic agents in cardiac care, but their role in the acute setting remains ambiguous. Increasing evidence supports the important role of landiolol in critical care, a highly cardioselective intravenous b-blocker with rapid onset of action and short elimination time. Among its most valuable properties, which may aid to overcome special reservations related to b-blocker therapy in the acute setting, landiolol has a potent negative chronotropic effect while at the same time it exhibits a mild negative inotropic effect., Areas Covered: This expert opinion review aims to present basic pharmacologic aspects of landiolol and provide current clinical research focused on its efficacy and safety., Expert Opinion: Landiolol is a valuable and safe pharmacologic agent in acute cardiac care. Japanese and European guidelines have incorporated its use for the management of atrial tachyarrhythmia in patients with cardiac dysfunction. Although emerging clinical trials have experimented its use in patients with sustained ventricular tachycardia/fibrillation, acute myocardial infarction undergoing primary percutaneous intervention and in patients with septic cardiomyopathy, more studies are needed in order to establish its value in such cardiac conditions.

Sacubitril/valsartan is a novel, first-in-class drug, which combines a neprilysin inhibitor with an angiotensin receptor blocker. Sacubitril inhibits neprilysin endopeptidase, blocking the catabolism of natriuretic peptides (NP), thereby increasing their bioavailability. Valsartan counterbalances the increase of angiotensin II that results from neprilysin inhibition, exerting also the beneficial effects of angiotensin receptor blockers seen in previous HF trials. PARADIGM-HF trial has proved the superiority of sacubitril/valsartan (LCZ696) over ACE inhibitor enalapril to reduce mortality and morbidity of symptomatic HF patients with reduced ejection fraction (HFrEF), setting the grounds for the replacement of ACE inhibitors by sacubitril/valsartan in the management of HFrEF. Sacubitril/valsartan is currently being tested in a phase III trial (PARAGON-HF) in patients with HF with preserved EF. PARAGON-HF is also expected to provide further data regarding the long-term safety of sacubitril/valsartan, hopefully to alleviate concerns regarding the effects of neprilysin inhibition on cognitive function.

Background: Acute decompensated heart failure (ADHF) is associated with increased hospitalization rates and high in-hospital mortality, and has emerged as a major public health problem over the past decade. In recent years, several new drugs and therapeutic approaches have failed to reduce short- and long-term morbidity and mortality in ADHF patients. New agents and strategies are under investigation in order to effectively reduce the mortality and morbidity in these patients., Objective: To review the recent experimental and clinical evidence on existing therapeutic algorithms and investigational drugs used for the treatment of ADHF., Methods: A systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1995 to January 2009. The results of unpublished trials were obtained from presentations at national and international meetings., Results: Renal dysfunction and low systolic blood pressure (SBP) remain the main predictors of adverse clinical outcomes in ADHF patients. Thus, therapy should be tailored according to the level of SBP at admission, renal function and fluid retention. ADHF due to hypertensive disease should be treated with intravenous vasodilators and diuretics at low doses, while patients with low output syndrome need mainly inotropic support. However, few agents currently employed in the treatment of ADHF have been shown in large prospective randomized clinical trials to improve clinical outcomes. The calcium sensitizer levosimendan is superior than traditional inotropes in improving central hemodynamics and neurohormonal response in ADHF patients, without increasing their long-term survival. Vasopressin antagonists also seem to be promising and safe drugs in the treatment of ADHF patients, facilitating diuresis on top of standard-care therapy. Encouraging novel therapies include adenosine receptor antagonists, ularitide, istaroxime, cardiac myosin activators and relaxin., Conclusions: Clinical scenarios based on SBP are essential determinants of therapeutic approaches used for the management of ADHF. Traditional drugs (diuretics, dobutamine and milrinone) have several limitations in real clinical practice, and increase mortality rates. Investigational drugs targeting to novel pathophysiologic concepts are promising treatment approaches and ongoing trials will define their clinical efficacy and safety.

Background: Calcium sensitizers belong to a new class of cardiac enhancers that stimulate cardiac contractility without causing intracellular calcium overload or increasing myocardial oxygen demand. Levosimendan, the most well-studied calcium sensitizer in the real clinical practice, produces greater hemodynamic and symptomatic improvement in patients with acute heart failure than traditional inotropes., Objective: To review the recent experimental and clinical evidence on novel biologic mechanisms explaining the pleiotropic effects of levosimendan on the failing heart., Methods: A systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1995 to December 2007. The results of unpublished trials were obtained from presentations at national and international meetings., Results: Levosimendan has a unique dual mechanism of action by enhancing cardiac contractility and causing peripheral vasodilatation. Immunomodulatory and antiapoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in acute heart failure, leads to cardioprotection, and beneficially intervenes in the progression of syndrome. Experimental data show that levosimendan exerts its cardioprotective effects through its antioxidant properties and seems to be a potent inhibitor of H2O2-induced cardiomyocyte apoptotic cell death. Clinical data demonstrate that levosimendan does not increase markers of oxidative and nitrosative stress, in contrast to placebo treatment, in advanced chronic heart failure patients. Levosimendan has also been shown to activate mitoK(ATP) channels which are important mediators of ischemic preconditioning. Pharmacological modulation of K(ATP) channels may prove beneficial in patients at risk of myocardial ischemia, particularly those requiring inotropic support., Conclusion: Pleiotropic effects of levosimendan appear to have important clinical and prognostic implications in acute heart failure syndromes and ischemic heart disease.

Depression is four to five times as common in chronic heart failure (CHF) patients as in the general population, may confer a higher risk of developing CHF in susceptible populations, and is significantly related to higher hospital readmission rates and increased mortality in established CHF. This effect may be mediated via the pathophysiological mechanisms that are shared between CHF and depression, including increased hypothalamic-pituitary-adrenal function, sympathoadrenal hyperactivity, diminished heart-rate variability and excessive pro-inflammatory cytokine activation. Each of these pathways of linkage represents a potential therapeutic target to improve outcome in CHF. This paper reviews the recent investigational observations that clarify the direct effects of antidepressants on immune functions, as well as the indirect effects of anticytokine pharmacological agents on depressive symptoms in CHF. With recent evidence suggesting that selective serotonin re-uptake inhibitors improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this comorbidity may beneficially affect the functional capacity and prognosis of CHF patients.

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that produces left ventricular dysfunction and a negative inotropic effect in cardiac tissue when overexpressed in human subjects. Previous studies have shown that levels of circulating TNF-alpha are elevated in patients with advanced congestive heart failure (CHF) and especially in those with cardiac cachexia. To clarify the potential role of TNF-alpha in the unstable state of decompensated advanced CHF, we investigated the TNF-alpha serum activity in 25 cachectic and 22 non-cachectic CHF patients (New York Heart Association, NYHA functional classes III or IV), who were treated with intravenous diuretics and positive inotropic agents for acute decompensation of the disease, during a 5-day hospitalization period, as well as in 15 age-matched healthy control subjects. Cachectic CHF patients needed higher dosages of inotropic agents than non-cachectic patients and the determination of TNF-alpha serum concentrations in this patient group showed high levels of TNF-alpha at hospital admission (18.3 +/- 3.2 pg/ml) and a transient increase in circulating TNF-alpha during the treatment period with the highest levels on the 2nd day of hospitalization (32.5 +/- 7.1 pg/ml). The TNF-alpha serum levels were low in non-cachectic CHF patients and healthy controls on the 1st day (4.0 +/- 0.9 and 3.7 +/- 0.6 pg/ml, respectively) and did not change substantially during the course of the study. The present results show that TNF-alpha serum activity is transiently increased during the treatment of decompensated cachectic CHF patients only and may be related to the clinical instability and the consequent therapeutic interventions in this category of CHF patients.