SUMMARYWhat is known and objective: Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan. Methods: A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data. Results and discussion: Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries.

Rationale: Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations.Objective: Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization. Methods and Results:We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electron microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, whereas the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction. Conclusions:Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure. (Circ Res. 2012;110:688-700.) Key Words: cardiomyocyte Ⅲ extracellular matrix Ⅲ lateral membrane Ⅲ cardiac tissue Ⅲ architecture Ⅲ heart failure T he heart constitutes a particular compact organ relying on strong tissue architecture cohesion and tight cellular interactions that ensure both mechanical and electrochemical coupling. Thus, most cardiopathies are associated with cardiac tissue remodeling and with alterations in architecture involved in disease progression toward heart failure (HF).Despite considerable advances in the field and development of effective drugs, HF still remains a prevalent condition associated with high morbidity and mortality rates. This could be in part explained by still imperfect knowledge of molecular basis at the origin of HF. In fact, to date, most research has focused on cardiomyocyte (CM) contractile dysfunction Original received December 15, 2011; revision received January 16, 2012; accepted January 25, 2012. In December 2011, the average time from submission to first decision for all original research pape...

We report for the first time that increased peripheral chemoreflex sensitivity directly decreases sympathetic baroreflex function in CHF patients. This interaction contributes to sympathetic overactivity and blunted sympathetic baroreflex function of CHF patients and may explain how chemoreceptors contribute to the bad prognosis of CHF patients.

In this study, we aimed to provide an updated overview of drug data contained in the French health insurance database (SNIIRAM) and its associated national representative sample (EGB). This study identified most common problems concerning drug data: (i) change in level of coverage of drugs of interest (drug no more eligible for reimbursement or no more prescription-only), (ii) break in patients' eligibility (in connection with change of healthcare plan or patients' identifier), and (iii) technical and regulatory issues. We provide a brief checklist to enable a structured identification of these issues. The impact of gap in drug data availability on study validity will depend on the research question, drug, setting, and population of interest. The French health insurance database and associated sample are valuable resources for pharmacoepidemiological research. There is a need to pursue further methodological and validation studies to promote accurate and transparent use of French health insurance databases for pharmacoepidemiology.

Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE α2C-adrenergic receptor (α2C-AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α2C-AR–AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical Gs-cAMP–PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics.

Intracranial pressure (ICP) is the pressure within the cranium. ICP rise compresses brain vessels and reduces cerebral blood delivery. Massive ICP rise leads to cerebral ischemia, but it is also known to produce hypertension, bradycardia and respiratory irregularities due to a sympatho-adrenal mechanism termed Cushing response. One still unresolved question is whether the Cushing response is a non-synaptic acute brainstem ischemic mechanism or part of a larger physiological reflex for arterial blood pressure control and homeostasis regulation. We hypothesize that changes in ICP modulates sympathetic activity. Thus, modest ICP increase and decrease were achieved in mice and patients with respectively intra-ventricular and lumbar fluid infusion. Sympathetic activity was gauged directly by microneurography, recording renal sympathetic nerve activity in mice and muscle sympathetic nerve activity in patients, and gauged indirectly in both species by heart-rate variability analysis. In mice (n = 15), renal sympathetic activity increased from 29.9 ± 4.0 bursts.s−1 (baseline ICP 6.6 ± 0.7 mmHg) to 45.7 ± 6.4 bursts.s−1 (plateau ICP 38.6 ± 1.0 mmHg) and decreased to 34.8 ± 5.6 bursts.s−1 (post-infusion ICP 9.1 ± 0.8 mmHg). In patients (n = 10), muscle sympathetic activity increased from 51.2 ± 2.5 bursts.min−1 (baseline ICP 8.3 ± 1.0 mmHg) to 66.7 ± 2.9 bursts.min−1 (plateau ICP 25 ± 0.3 mmHg) and decreased to 58.8 ± 2.6 bursts.min−1 (post-infusion ICP 14.8 ± 0.9 mmHg). In patients 7 mmHg ICP rise significantly increases sympathetic activity by 17%. Heart-rate variability analysis demonstrated a significant vagal withdrawal during the ICP rise, in accordance with the microneurography findings. Mice and human results are alike. We demonstrate in animal and human that ICP is a reversible determinant of efferent sympathetic outflow, even at relatively low ICP levels. ICP is a biophysical stress related to the forces within the brain. But ICP has also to be considered as a physiological stressor, driving sympathetic activity. The results suggest a novel physiological ICP-mediated sympathetic modulation circuit and the existence of a possible intracranial (i.e., central) baroreflex. Modest ICP rise might participate to the pathophysiology of cardio-metabolic homeostasis imbalance with sympathetic over-activity, and to the pathogenesis of sympathetically-driven diseases.

We demonstrate that a single session of HIIE improves autonomic profile of CHF patients, leading to significant reductions of HR and arrhythmic events in a 24-h posttraining period. Cardioprotective effects of HIIE in CHF patients need to be confirmed in a larger study population and on a long-term basis.

BackgroundThe exact pathophysiology of Tako-Tsubo cardiomyopathy (TTC) remains unknown but a role for sympathetic hyperactivity has been suggested. Up to now, no direct evidence of sympathetic nerve hyperactivity has been established nor involvement of sympathetic baroreflex identified. The aim of our study was to determine, by direct sympathetic nerve activity (SNS) recording if sympathetic nervous system activity is increased and spontaneous baroreflex control of sympathetic activity reduced in patients with TTC.MethodsWe included 13 patients who presented with TTC and compared their SNS activity and spontaneous baroreflex control of sympathetic activity with that of 13 control patients with acutely decompensated chronic heart failure. SNS activity was evaluated by microneurography, a technique assessing muscle sympathetic nerve activity (MSNA). Spontaneous baroreflex control of sympathetic activity was evaluated as the absolute value of the slope of the regression line representing the relationship between spontaneous diastolic blood pressure values and concomitant SNS activity. Control patients were matched for age, sex, left ventricular ejection fraction and creatinine clearance.ResultsThe mean age of the patients with TTC was 80 years, all patients were women. There were no significant differences between the two groups of patients for blood pressure, heart rate or oxygen saturation level. TTC patients presented a significant increase in sympathetic nerve activity (MSNA median 63.3 bursts/min [interquartile range 61.3 to 66.0] vs median 55.7 bursts/min [interquartile range 51.0 to 61.7]; p = 0.0089) and a decrease in spontaneous baroreflex control of sympathetic activity compared to matched control patients (spontaneous baroreflex control of sympathetic activity median 0.7%burst/mmHg [interquartile range 0.4 to 1.9] vs median 2.4%burst/mmHg [interquartile range 1.8 to 2.9]; p = 0.005).ConclusionsWe report for the first time, through direct measurement of sympathetic nerve activity, that patients with TTC exhibit elevated SNS activity associated with a decrease in spontaneous baroreflex control of sympathetic activity. These data may explain the pathophysiology and clinical presentation of patient with TTC.