Hyperpolarization-activated Cyclic nucleotide-gated Channel and Cardiac Biological Pacemaker： Part Ⅰ

Hyperpolarization-activated cyclic-nucleotide-gated （HCN） channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current （ named If, Ib, or Iq ）. Recent studies have unveiled the molecular identity of HCN （HCN1-4） channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ib and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models, local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.     

Hyperpolarization-activated Cyclic nucleotide-gated Channel and Cardiac Biological Pacemaker:Part Ⅱ

Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unveiled the molecular identity of HCN (HCN 1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in the development of biological pacemakers.     

Pacemaker or ICD and MRI: is MRI safety the new standard?

Recently new models of cardiac pacemakers have been commercialised. Some of these models have the particularity to be compatible with MRI (they are called MRI safe). The safety of the MRI for the patients implanted depends on the device it self and the lead(s). These review article focuses on the benefits and limits of these new devices. A practical guideline is proposed for patients implanted by a pacemaker or ICD and undergoing MRI.     

Glucagon and Cyclic AMP: Time to Turn the Page?

It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K- dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca 2+ (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes.     

Cardiac remodelling and myocardial recovery: lost in translation?

The insight that decreases in left ventricular (LV) volume and mass occur secondary to the recovery of the myocardium at the cellular and molecular level has engendered a wider appreciation of the importance of LV remodelling as a mechanism for worsening heart failure. Despite these recent insights into the recognition of the importance of LV reverse remodelling in heart failure, many clinicians do not consider simple measurements of LV structure (i.e. LV volume) in their routine clinical decision‐making process, preferring instead to rely on measurements of LV function [e.g. ejection fraction (EF)] when making decisions about medical and surgical treatment options. Although there are probably multiple reasons of why the use of LV volumes has not gained wider acceptance in day‐to‐day clinical management of heart failure patients, the most likely reason is that clinicians remain extremely comfortable using the LVEF to assess their heart failure patients. Importantly, LV volumes predict outcome more reliably than does the EF. Moreover, knowledge regarding LV volumes is extremely useful in optimizing patient selection for surgical and device therapies. Based on the foregoing arguments, we suggest that it is time to begin developing individualized clinical strategies based upon a consideration of the important role that LV remodelling plays in the pathogenesis of heart failure, and that we begin to incorporate measurements of LV volume and mass into the clinical decision‐making process.     

Diabetes and stroke: Part one—Risk factors and pathophysiology

Diabetes is a major risk factor for stroke and is associated with an increase in overall stroke mortality. The metabolic syndrome associated with insulin resistance is also a significant risk factor for stroke. The etiology of stroke in diabetics is frequently microvascular disease from fibrinoid necrosis, which causes small subcortical infarcts designated as lacunar strokes. Diabetics also have an increased incidence of large vessel intracranial vascular disease. Although strict control of blood sugar has not been shown to reduce the overall incidence of stroke in diabetics, careful management of other associated risk factors, particularly hypercholesterolemia and hypertension, are imperative for the prevention of stroke in diabetic patients.     

Induction Therapy in Cardiac Transplantation: When and Why?

Induction therapy has continued to be a subject of controversy in heart transplantation for more than 20 years. It is an example of a therapy that is logical, and ought to be better than "doing without." However, a careful review of the evidence suggests otherwise. Except for patients where the benefits clearly outweigh the short and long-term risks, the use of induction therapy should be avoided. In immunosuppression, as in life, there is no "free lunch." Clinicians need to be certain they fully understand what they are ordering when asking for induction therapy to be administered to their patients.     

Cardiac and vascular effects of cannabinoids: toward a therapeutic use?

Interest in cannabinoid pharmacology developed rapidly since the discovery of cannabinoids receptors and endocannabinoids. Modulation of this system is becoming a hot topic in cardiovascular pharmacology mainly at the light of recent findings. Among them, cardiac effects of cannabinoids were described with respect to their probable participation to the well-studied preconditioning phenomenon. Beneficial effects of post-infarction cannabinoids administration against ischemia-reperfusion injury were also reported. Concerning their vascular effects the situation is more complex some studies reporting pressor effects while others depressor ones. It was also proposed that the endothelium-derived hyperpolarizing factor released by various vasodilators may be an endocannabinoid an hypothesis still discussed. Finally, pathological situations concerning the cardiovascular system and including brain ischemia, hemorrhagic and endotoxic shocks were reported to be linked with endocannabinoids. However, the clinical use of cannabinoid receptors agonists or antagonists will depend on the development of non psychoactive compounds.     

Carotid Artery Cut-Down in Pediatric Cardiac Catheterization: When and How?

Background: Vascular access used for pediatric cardiac catheterization is one of the most important factors that affects the success of the procedure. We aimed to compare the effect, success, and complications of cardiac catheterizations performed by carotid cut-down or femoral puncture in newborns or young infants. Methods: We included who underwent catheterization in our department between 28 January 2017 and 15 April 2021. These patients underwent balloon aortic valvuloplasty, balloon coarctation angioplasty, ductal stenting, diagnostic procedures for aortic arch pathologies, and modified Blalock-Taussig in-shunt intervention. Patients were divided into two groups: femoral puncture (group = 1) and carotid cut-down (CC, group = 2). Results: Seventy-two catheterization procedures were performed in 64 patients; 32 (44.4%) were performed via the femoral approach and 40 (55.6%) were performed via the carotid approach. Sixteen (22.2%) procedures were diagnostic and 56 (77.8%) procedures were interventional. CC was performed in 13 (32.5%) patients with failed femoral intervention. Patients in the CC group had shorter durations of procedure, vascular access, and anesthesia, compared with the femoral access group (80.9 and 116.2 min, p = 0.001; 12.9 and 22.5 min, p = 0.001; 140.9 and 166.6 min, p = 0.001, respectively). Patients who underwent CC had fewer complications than did patients in the femoral access group (2.5% and 21.8%, respectively; p = 0.01); larger sheats were used in CC patients (p = 0.028). Conclusion: The carotid artery can be successfully used as a primary catheterization route, particularly in patients with small body weight and patients who require rapid vascular access, or stenting of the vertical duct.