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https://www.readbyqxmd.com/read/29539403/positive-feedback-mechanisms-among-local-ca-releases-ncx-and-i-cal-ignite-pacemaker-action-potentials
#1
Alexey E Lyashkov, Joachim Behar, Edward G Lakatta, Yael Yaniv, Victor A Maltsev
Recent data suggest that cardiac pacemaker cell function is determined by numerous time-, voltage-, and Ca-dependent interactions of cell membrane electrogenic proteins (M-clock) and intracellular Ca cycling proteins (Ca-clock), forming a coupled-clock system. Many aspects of the coupled-clock system, however, remain underexplored. The key players of the system are Ca release channels (ryanodine receptors), generating local Ca releases (LCRs) from sarcoplasmic reticulum, electrogenic Na/Ca exchanger (NCX) current, and L-type Ca current (ICaL )...
March 13, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29239349/influences-of-ivabradine-treatment-on-serum-levels-of-cardiac-biomarkers-sst2-gdf-15-supar-and-h-fabp-in-patients-with-chronic-heart-failure
#2
Peter Jirak, Dzeneta Fejzic, Vera Paar, Bernhard Wernly, Rudin Pistulli, Ilonka Rohm, Christian Jung, Uta C Hoppe, P Christian Schulze, Michael Lichtenauer, Atilla Yilmaz, Daniel Kretzschmar
Chronic heart failure (CHF) represents a major cause of hospitalization and death. Recent evidence shows that novel biomarkers such as soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) are correlated with inflammatory and ischemic responses in CHF patients. In this study we examined the effects of Ivabradine that inhibited the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel, also called funny current If ), thereby leading to selective heart rate reduction and improved myocardial oxygen supply on the cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in 50 CHF patients at the University Hospital of Jena...
December 14, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29225577/-i-f-channel-as-an-emerging-therapeutic-target-for-cardiovascular-diseases-a-review-of-current-evidence-and-controversies
#3
REVIEW
Hayelom G Mengesha, Tadesse B Tafesse, Mohammed H Bule
In 2015, non-communicable diseases accounted for 39.5 million (70%) of the total 56.4 million deaths that occurred globally, of which 17.7 million (45%) were due to cardiovascular diseases. An elevated heart rate is considered to be one of the independent predictors and markers of future cardiovascular diseases. A variety of experimental and epidemiological studies have found that atherosclerosis, heart failure, coronary artery disease, stroke, and arrhythmia are linked to elevated heart rate. Although there are established drugs to reduce the heart rate, these drugs have undesirable side effects...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29197941/heterogeneous-functional-expression-of-the-sustained-inward-na-current-in-guinea-pig-sinoatrial-node-cells
#4
Futoshi Toyoda, Ding Wei-Guang, Hiroshi Matsuura
The sustained inward Na+ current (Ist ) identified in the sinoatrial node (SAN) cell has been suggested to play a pivotal role in cardiac pacemaking. However, the composition of cells in the SAN is heterogeneous and cell-to-cell variability in the magnitude of Ist remains to be fully characterized. The present study investigated the current density of Ist in morphologically different types of pacemaker cells dissociated from guinea pig SAN. Ist was preferentially detected in spontaneously active spindle or spider-shaped cells, but was less well expressed in larger-sized elongated spindle-type cells and practically absent in clearly striated atrial-like cells, despite clear expression of the funny current (If )...
March 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29115193/personality-modulates-amygdala-and-insula-connectivity-during-humor-appreciation-an-event-related-fmri-study
#5
Philipp Berger, Florian Bitsch, Arne Nagels, Benjamin Straube, Irina Falkenberg
Previous research and theory implicate that personality traits, such as extraversion and neuroticism, influence the processing of humor, as indicated by alterations in the activation of fronto-temporal and mesocorticolimbic brain regions during humor processing. In the current study, we sought to complement these findings by testing whether inter-individual differences in functional connectivity of humor-related brain regions are modulated by stable personality characteristics during humor processing. Using fMRI techniques, we studied 19 healthy subjects during the processing of standardized humorous and neutral cartoons...
November 8, 2017: Social Neuroscience
https://www.readbyqxmd.com/read/28958335/the-clinical-use-of-ivabradine
#6
REVIEW
Jacob S Koruth, Anuradha Lala, Sean Pinney, Vivek Y Reddy, Srinivas R Dukkipati
The clinical use of ivabradine has and continues to evolve along channels that are predicated on its mechanism of action. It selectively inhibits the funny current (If ) in sinoatrial nodal tissue, resulting in a decrease in the rate of diastolic depolarization and, consequently, the heart rate, a mechanism that is distinct from those of other negative chronotropic agents. Thus, it has been evaluated and is used in select patients with systolic heart failure and chronic stable angina without clinically significant adverse effects...
October 3, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28930912/reducing-elevated-heart-rates-in-patients-with-multiple-organ-dysfunction-syndrome-with-the-if-funny-channel-current-inhibitor-ivabradine
#7
Sebastian Nuding, Jochen Schröder, Peter Presek, Andreas Wienke, Ursula Müller-Werdan, Henning Ebelt, Karl Werdan
INTRODUCTION: A heart rate higher than 90 beats/min indicates an unfavorable prognosis for patients with multiple organ dysfunction syndrome (MODS). We sought to investigate the effect of the pacemaker current (If) inhibitor ivabradine on heart rate, hemodynamics, and disease severity among patients with MODS. PATIENTS AND METHODS: In this prospective, controlled, randomized, open-label, two-arm phase II trial, 70 patients with MODS, a sinus rhythm of at least 90 beats/min, and contraindications to β-blocker therapy were randomly assigned to receive the standard treatment ± ivabradine (5 mg twice daily) for 96 h via the enteral route...
April 2018: Shock
https://www.readbyqxmd.com/read/28868308/phosphodiesterases-3-and-4-differentially-regulate-the-funny-current-if-in-mouse-sinoatrial-node-myocytes
#8
Joshua R St Clair, Eric D Larson, Emily J Sharpe, Zhandi Liao, Catherine Proenza
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3',5'-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them...
September 2017: Journal of Cardiovascular Development and Disease
https://www.readbyqxmd.com/read/28855177/small-functional-i-f-current-in-sinoatrial-pacemaker-cells-of-the-brown-trout-salmo-trutta-fario-heart-despite-strong-expression-of-hcn-channel-transcripts
#9
Minna Hassinen, Jaakko Haverinen, Matti Vornanen
Funny current ( I f ), formed by hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), is supposed to be crucial for the membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout ( Salmo trutta fario ) sinoatrial (SA) pacemaker cells and their putative role in heart rate ( f H ) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3, and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4...
December 1, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28623610/a-singular-role-of-i-k1-promoting-the-development-of-cardiac-automaticity-during-cardiomyocyte-differentiation-by-i-k1-induced-activation-of-pacemaker-current
#10
Yu Sun, Valeriy Timofeyev, Adrienne Dennis, Emre Bektik, Xiaoping Wan, Kenneth R Laurita, Isabelle Deschênes, Ronald A Li, Ji-Dong Fu
The inward rectifier potassium current (IK1 ) is generally thought to suppress cardiac automaticity by hyperpolarizing membrane potential (MP). We recently observed that IK1 could promote the spontaneously-firing automaticity induced by upregulation of pacemaker funny current (If ) in adult ventricular cardiomyocytes (CMs). However, the intriguing ability of IK1 to activate If and thereby promote automaticity has not been explored. In this study, we combined mathematical and experimental assays and found that only IK1 and If , at a proper-ratio of densities, were sufficient to generate rhythmic MP-oscillations even in unexcitable cells (i...
October 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/28454527/effect-of-ivabradine-on-cardiovascular-outcomes-in-patients-with-stable-angina-meta-analysis-of-randomized-clinical-trials
#11
REVIEW
Hayelom Gebrekirstos Mengesha, Berhe Weldearegawi, Pammala Petrucka, Tadese Bekele, Mala George Otieno, Abraha Hailu
BACKGROUND: Although there are established drugs for treatment of cardiovascular diseases, due to adverse effects these drugs may not be clinically applicable to all patients. Recent trends have seen the emergence of drugs which act on funny current channels to induce selective heart rate reduction. Ivabradine is one such drug developed for coronary artery disease and heart failure. There is inconsistent evidence about the effect of this selective inhibitor in reduction of cardiovascular related mortality and morbidity...
April 28, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28422759/ryr2r420q-catecholaminergic-polymorphic-ventricular-tachycardia-mutation-induces-bradycardia-by-disturbing-the-coupled-clock-pacemaker-mechanism
#12
Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova, Olivier Villejoubert, Pilar D'Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E Mangoni, Jean-Pierre Benitah, Ana María Gómez
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (If )...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28371247/ivabradine-current-and-future-treatment-of-heart-failure
#13
REVIEW
Lene Thorup, Ulf Simonsen, Daniela Grimm, Elise R Hedegaard
In heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end-diastolic pressure. Current treatments for HF with reduced ejection fraction (HFrEF) include angiotensin-converting enzyme (ACE) inhibitors, angiotension receptor type 1 (AT1 ) antagonists, β-adrenoceptor antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT1 receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate (HR) above 70 bpm...
August 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28352365/heart-failure-modulates-electropharmacological-characteristics-of-sinoatrial-nodes
#14
Shih-Lin Chang, Hui-Lun Chuang, Yao-Chang Chen, Yu-Hsun Kao, Yung-Kuo Lin, Yung-Hsin Yeh, Shih-Ann Chen, Yi-Jen Chen
The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0...
February 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28256323/ivabradine-in-acute-coronary-syndromes-protection-beyond-heart-rate-lowering
#15
REVIEW
Giampaolo Niccoli, Josip Anđelo Borovac, Vincenzo Vetrugno, Paolo G Camici, Filippo Crea
Ivabradine is a heart rate reducing agent that exhibits anti-ischemic effects through the inhibition of funny electrical current in the sinus node resulting in heart rate reduction, thus enabling longer diastolic perfusion time, and reduced myocardial oxygen consumption without detrimental changes in arterial blood pressure, coronary vasomotion, and ventricular contractility. The current guideline-based clinical use of Ivabradine is reserved for patients with stable angina pectoris who cannot tolerate or whose symptoms are inadequately controlled with beta blockers...
June 1, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28217366/crizotinib-inhibits-hyperpolarization-activated-cyclic-nucleotide-gated-channel-4-activity
#16
Zhushan Zhang, Tai-Qin Huang, Igor Nepliouev, Hengtao Zhang, Adam S Barnett, Paul B Rosenberg, Sai-Hong I Ou, Jonathan A Stiber
BACKGROUND: Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects. METHODS: The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If , in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4...
2017: Cardio-Oncology
https://www.readbyqxmd.com/read/28185290/computational-analysis-of-the-human-sinus-node-action-potential-model-development-and-effects-of-mutations
#17
Alan Fabbri, Matteo Fantini, Ronald Wilders, Stefano Severi
KEY POINTS: We constructed a comprehensive mathematical model of the spontaneous electrical activity of a human sinoatrial node (SAN) pacemaker cell, starting from the recent Severi-DiFrancesco model of rabbit SAN cells. Our model is based on electrophysiological data from isolated human SAN pacemaker cells and closely matches the action potentials and calcium transient that were recorded experimentally. Simulated ion channelopathies explain the clinically observed changes in heart rate in corresponding mutation carriers, providing an independent qualitative validation of the model...
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28057842/cyclic-amp-reverses-the-effects-of-aging-on-pacemaker-activity-and-if-in-sinoatrial-node-myocytes
#18
Emily J Sharpe, Eric D Larson, Catherine Proenza
Aerobic capacity decreases with age, in part because of an age-dependent decline in maximum heart rate (mHR) and a reduction in the intrinsic pacemaker activity of the sinoatrial node of the heart. Isolated sinoatrial node myocytes (SAMs) from aged mice have slower spontaneous action potential (AP) firing rates and a hyperpolarizing shift in the voltage dependence of activation of the "funny current," If Cyclic AMP (cAMP) is a critical modulator of both AP firing rate and If  in SAMs. Here, we test the ability of endogenous and exogenous cAMP to overcome age-dependent changes in acutely isolated murine SAMs...
February 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/27895488/advances-in-the-management-of-heart-failure-the-role-of-ivabradine
#19
REVIEW
Ursula Müller-Werdan, Georg Stöckl, Karl Werdan
A high resting heart rate (≥70-75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect...
2016: Vascular Health and Risk Management
https://www.readbyqxmd.com/read/27803673/electrophysiological-mechanisms-of-brugada-syndrome-insights-from-pre-clinical-and-clinical-studies
#20
REVIEW
Gary Tse, Tong Liu, Ka H C Li, Victoria Laxton, Yin W F Chan, Wendy Keung, Ronald A Li, Bryan P Yan
Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na(+) channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na(+), K(+), Ca(2+), and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge...
2016: Frontiers in Physiology
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