scholarly journals Impact of Chronic Fetal Hypoxia and Inflammation on Cardiac Pacemaker Cell Development

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 733 ◽  
Author(s):  
Martin G. Frasch ◽  
Dino A. Giussani
Keyword(s):  
Cardiovascular Disease ◽  
Cardiac Pacemaker ◽  
Current Evidence ◽  
Pacemaker Cell ◽  
Fetal Hypoxia ◽  
Pacemaker Cells ◽  
Adverse Conditions ◽  
Cardiac Myogenesis ◽  
Future Risk ◽  
Complicated Pregnancy

Chronic fetal hypoxia and infection are examples of adverse conditions during complicated pregnancy, which impact cardiac myogenesis and increase the lifetime risk of heart disease. However, the effects that chronic hypoxic or inflammatory environments exert on cardiac pacemaker cells are poorly understood. Here, we review the current evidence and novel avenues of bench-to-bed research in this field of perinatal cardiogenesis as well as its translational significance for early detection of future risk for cardiovascular disease.

scholarly journals Dynamics of PKA phosphorylation and gain of function in cardiac pacemaker cells: a computational model analysis

2016 ◽  
Vol 310 (9) ◽  
pp. H1259-H1266 ◽  
Author(s):  
Joachim Behar ◽  
Yael Yaniv
Keyword(s):  
Cycle Length ◽  
Cell Function ◽  
Membrane Surface ◽  
Cardiac Pacemaker ◽  
Neonatal Rat ◽  
Hek293 Cells ◽  
Pacemaker Cell ◽  
Pacemaker Cells ◽  
Clock System ◽  
Dominant Component

Cardiac pacemaker cell function is regulated by a coupled-clock system that integrates molecular cues on the cell-membrane surface (i.e., membrane clock) and on the sarcoplasmic reticulum (SR) (i.e., Ca2+ clock). A recent study has shown that cotransfection of spontaneous beating cells (HEK293 cells and neonatal rat myocytes) with R524Q-mutant human hyperpolarization-activated cyclic nucleotide-gated molecules (the dominant component of funny channels) increases the funny channel's sensitivity to cAMP and leads to a decrease in spontaneous action potential (AP) cycle length (i.e., tachycardia). We hypothesize that in rabbit pacemaker cells, the same behavior is expected, and because of the coupled-clock system, the resultant steady-state decrease in AP cycle length will embody contributions from both clocks: the initial decrease in the spontaneous AP beating interval, arising from increased sensitivity of the f-channel to cAMP, will be accompanied by an increase in the adenylyl cyclase (AC)-cAMP-PKA-dependent phosphorylation activity, which will further decrease this interval. To test our hypothesis, we used the recently developed Yaniv-Lakatta pacemaker cell numerical model. This model predicts the cAMP signaling dynamics, as well as the kinetics and magnitude of protein phosphorylation in both normal and mutant pacemaker cells. We found that R524Q-mutant pacemaker cells have a shorter AP firing rate than that of wild-type cells and that gain in pacemaker function is the net effect of the R514Q mutation on the functioning of the coupled-clock system. Specifically, our results directly support the hypothesis that changes in Ca2+-activated AC-cAMP-PKA signaling are involved in the development of tachycardia in R524Q-mutant pacemaker cells.

scholarly journals Transcriptional and Epigenetic Landscape of Cardiac Pacemaker Cells: Insights Into Cellular Specialization in the Sinoatrial Node

2021 ◽  
Vol 12 ◽  
Author(s):  
Ravi Mandla ◽  
Catherine Jung ◽  
Vasanth Vedantham
Keyword(s):  
Regulatory Networks ◽  
Sinus Node ◽  
Cardiac Pacemaker ◽  
Heart Rhythm ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Transcriptional Networks ◽  
Pacemaker Cell ◽  
Pacemaker Cells ◽  
Dna Regulatory Elements

Cardiac pacemaker cells differentiate and functionally specialize early in embryonic development through activation of critical gene regulatory networks. In general, cellular specification and differentiation require that combinations of cell type-specific transcriptional regulators activate expression of key effector genes by binding to DNA regulatory elements including enhancers and promoters. However, because genomic DNA is tightly packaged by histones that must be covalently modified in order to render DNA regulatory elements and promoters accessible for transcription, the process of development and differentiation is intimately connected to the epigenetic regulation of chromatin accessibility. Although the difficulty of obtaining sufficient quantities of pure populations of pacemaker cells has limited progress in this field, the advent of low-input genomic technologies has the potential to catalyze a rapid growth of knowledge in this important area. The goal of this review is to outline the key transcriptional networks that control pacemaker cell development, with particular attention to our emerging understanding of how chromatin accessibility is modified and regulated during pacemaker cell differentiation. In addition, we will discuss the relevance of these findings to adult sinus node function, sinus node diseases, and origins of genetic variation in heart rhythm. Lastly, we will outline the current challenges facing this field and promising directions for future investigation.

Salivary biomarkers in cardiovascular disease: An insight into the current evidence

FEBS Journal ◽  
2020 ◽  
Author(s):  
Eshak I. Bahbah ◽  
Christa Noehammer ◽  
Walter Pulverer ◽  
Martin Jung ◽  
Andreas Weinhäusel
Keyword(s):  
Cardiovascular Disease ◽  
Current Evidence ◽  
Salivary Biomarkers ◽  
Insight Into

Normal spontaneous firing of cardiac pacemaker cells is regulated by basal pkc delta activation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Vinogradova ◽  
K Tarasov ◽  
D Riordon ◽  
Y Tarasova ◽  
E Lakatta
Keyword(s):  
Protein Kinase ◽  
Cycle Length ◽  
Cardiac Pacemaker ◽  
Funding Source ◽  
Spontaneous Firing ◽  
Pacemaker Cells ◽  
Patch Clamp Technique ◽  
Sa Node ◽  
Pkc Delta ◽  
Pkc Isoforms

Abstract   The spontaneous beating rate of rabbit sinoatrial node cells (SANC) is regulated by local subsarcolemmal calcium releases (LCRs) from sarcoplasmic reticulum (SR). LCRs appear during diastolic depolarization (DD) and activate an inward sodium/calcium exchange current which increases DD rate and thus accelerates spontaneous SANC firing. High basal level of protein kinase A and calcium/calmodulin-dependent protein kinase II phosphorylation are required to sustain basal LCRs and normal spontaneous SANC firing. Recently we discovered that basal PKC activation is also obligatory for cardiac pacemaker function: inhibition of PKC activity by broad spectrum PKC inhibitors Bis I or calphostin C markedly suppressed SR calcium cycling and decreased or abolished spontaneous beating of freshly isolated rabbit SANC. Here we studied which PKC isoforms mediate PKC-dependent effects on cardiac pacemaker cell automaticity. The PKC superfamily consists of 3 major subgroups: conventional, novel and atypical. All PKC isoforms were detected at the RNA level (RT-qPCR) in the rabbit SA node and ventricle, and expression levels were comparable in both tissues. Expression of PKCβ, however, was markedly higher in the rabbit SA node, compared to other PKC isoenzymes in either tissue. We verified expression of conventional PKC (α, β) and novel PKC-delta at the protein level in SANC and ventricular myocytes (VM). Western blot confirmed RNA results, showing a 6-fold higher PKCβ protein abundance in SANC compared to VM. Expression of PKCα protein was similar in both cell types, while PKC-delta protein was more abundant in VM. To study whether PKCβ regulates spontaneous beating of SANC we employed selective inhibitor of conventional (α, β, gamma) PKC isoforms Go6976 (10 μmol/L), which had no effects on either LCR characteristics (confocal microscopy, calcium indicator Fluo-3AM) or spontaneous beating of freshly isolated rabbit SANC (perforated patch-clamp technique). Because selective PKC-delta inhibitors are not available, we explored effects of PKC-delta inhibition comparing effects of Go6976 (the inhibitor of conventional PKCs) and Go6983, which inhibits conventional PKCs and PKC-delta. In contrast to Go6976, Go6983 (5 μmol/L) markedly decreased the LCR size (from 7.1±0.4 to 4.5±0.3 μm) and number per each spontaneous cycle (from 1.3±0.1 to 0.8±0.1). It also markedly increased the LCR period (time from the prior AP-induced calcium transient to the subsequent LCR) which was paralleled by an increase in the spontaneous SANC cycle length. Rottlerin, another PKC-delta inhibitor, produced similar effects on LCR characteristics, and markedly and time-dependently decreased DD rate, leading to an increase in the spontaneous cycle length, and finally abrogated the spontaneous SANC firing. Thus, our data indicate that basal activity of PKC-delta, but not that of PKCβ, is essential for generation of LCRs and normal spontaneous firing of cardiac pacemaker cells. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Intramural Research Program, National Institute on Aging, National Institute of Health, USA

scholarly journals Mechanisms of Beat-to-Beat Regulation of Cardiac Pacemaker Cell Function by Ca2+ Cycling Dynamics

2013 ◽  
Vol 105 (7) ◽  
pp. 1551-1561 ◽  
Author(s):  
Yael Yaniv ◽  
Michael D. Stern ◽  
Edward G. Lakatta ◽  
Victor A. Maltsev
Keyword(s):  
Cell Function ◽  
Cardiac Pacemaker ◽  
Pacemaker Cell

scholarly journals Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model

2009 ◽  
Vol 296 (3) ◽  
pp. H594-H615 ◽  
Author(s):  
Victor A. Maltsev ◽  
Edward G. Lakatta
Keyword(s):  
Cell Model ◽  
Numerical Models ◽  
Experimental Studies ◽  
Cardiac Pacemaker ◽  
Critical Dimension ◽  
Pacemaker Cell ◽  
Pumping Rate ◽  
Rate Modulation ◽  
Wide Scale ◽  
Fail Safe

Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+ releases (Ca2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+ exchanger current ( INCX). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca2+ cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca2+ releases of sarcoplasmic reticulum (SR)-based Ca2+ clock ignite rhythmic action potentials via late DD INCX over much broader ranges of membrane clock parameters [e.g., L-type Ca2+ current ( ICaL) and/or hyperpolarization-activated (“funny”) current ( If) conductances]. The system Ca2+ clock includes SR and sarcolemmal Ca2+ fluxes, which optimize cell Ca2+ balance to increase amplitudes of both SR Ca2+ release and late DD INCX as SR Ca2+ pumping rate increases, resulting in a broad pacemaker rate modulation (1.8–4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca2+ clock is unchanged or lacking. When Ca2+ clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD INCX ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates.

Management of Cardiovascular Disease in Dialysis Patients

2017 ◽  
Author(s):  
John K. Roberts ◽  
John P. Middleton
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Acute Myocardial Infarction ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Volume Overload ◽  
Current Evidence ◽  
Dialysis Patients ◽  
Esrd Patients

Cardiovascular disease is a common cause of death and disease in patients with end-stage renal disease (ESRD). Registry data show that 41% of deaths in ESRD patients are due to a variety of cardiovascular causes, such as acute myocardial infarction, congestive heart failure, arrhythmia/sudden cardiac death, and stroke. In the general population, each of these disease entities in isolation can be effectively managed according to evidence from large clinical trials and evidence-based guidelines. However, many of these trials did not include patients with ESRD, limiting the transferability of this evidence to the care of patients on dialysis. To complicate matters, cardiovascular events in ESRD patients are likely augmented from a unique interplay of cardiac risk due to both reduced kidney function and the necessity for artificial renal replacement therapies. In this light, the patient on dialysis is subjected to a series of unique factors: the continued presence of the metabolic perturbations of uremia and the peculiar environment of the dialysis treatment itself. Since the ESRD heart is under a considerable amount of strain due to chronic volume overload, rapid electrolyte and fluid shifts, and accelerated vascular calcification, management can be complex and outcomes multifactorial. In this review, we summarize the current evidence regarding management of acute myocardial infarction, heart failure, sudden cardiac death, and atrial fibrillation. We also address modifiable risk factors related to the dialysis procedure itself and highlight recent randomized controlled trials that included dialysis patients and measured important cardiovascular outcomes. 

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