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Trends in Cardiovascular Medicine
Volume 14, Issue 2,
, Pages 61-66
Ventricular tachycardia in nonischemic heart failure (HF) initiates by a nonreentrant mechanism that appears to be due to triggered activity primarily from delayed afterdepolarizations that arise from altered cellular Ca handling and ionic currents. In HF, factors that conspire to enhance triggered arrhythmias include upregulated Na/Ca exchange, preserved β-adrenergic responsiveness, and decreased IK1. Overall, the further delineation of key factors that underlie triggered arrhythmias in HF will provide the basis for new therapeutic strategies directed toward novel targets that can reduce the high incidence of sudden death in patients with HF.
Electrophysiologic Alterations in HF
In animal models of ventricular hypertrophy and HF, action potential duration (APD) is prolonged, and resting membrane potential (Em) and action potential (AP) rate of rise (phase 0 Vmax) are often reduced (see Vermeulen 1998). Myocytes from patients with end-stage HF also exhibit prolonged APDs, which may be due to decreased outward K currents such as Ito or IK1 (Vermeulen 1998). Slow conduction and heterogeneous repolarization, which has been demonstrated in experimental models of nonischemic
Nonreentrant Initiation of VT
Delineating reentrant versus nonreentrant (or triggered) mechanisms of VT in HF requires a mechanistic arrhythmia assessment in vivo, and an animal model of HF that is arrhythmogenic. Pogwizd (1995) used computerized three-dimensional (3-D) cardiac mapping to record bipolar electrograms from several hundred intramural sites throughout the hearts in an arrhythmogenic rabbit HF model (combined pressure and volume overload, Figure 1A). These HF rabbits exhibit moderate to severe LV dysfunction,
Nature of Nonreentrant Mechanism in HF
The nonreentrant mechanism in HF likely involves triggered activity from either DADs or EADs (Figure 1B). DADs occur at high intracellular Ca load and are due to spontaneous sarcoplasmic reticulum (SR) Ca release and activation of a transient inward current (Iti) that is mediated by either Na/Ca exchange (NCX), a nonspecific cationic current (INS), or a Ca-activated chloride current (ICl (Ca)) although NCX is favored Pogwizd et al., 2001, Wit & Rosen, 1992. DADs tend to occur with rapid
Altered Myocyte Ca Handling in HF
Myocyte Ca transients (and contractions) are depressed in HF (Figure 2), and this is associated with comparable reductions in SR Ca content in human HF and in rabbit and canine HF models Hobai & O'Rourke, 2001, Piacentino et al., 2003, Pogwizd et al., 2001. ICa density is typically unchanged, and these studies all suggest that there is no intrinsic alteration of the excitation-contraction coupling (ECC) mechanism itself (i.e., fractional release is not depressed), although Gómez et al. (2001)
Preserved β-AR Responsiveness
If SR Ca load is reduced in HF, how might DADs and triggered APs arise? One possibility is that a lower threshold SR Ca load might cause spontaneous SR Ca release. We measured this threshold directly in voltage-clamped rabbit HF cells using protocols to drive increasing amounts of Ca into the cell, and measuring the occurrence of aftercontractions and Iti (at measured SR Ca loads). The threshold SR Ca load for triggering Iti was unchanged in HF (Pogwizd et al. 2001). Therefore, if SR Ca load is
NCX Current Underlies Iti and DADs
In myocytes from both rabbit and human HF, we used rapid application of caffeine to produce controlled SR Ca releases and Ca-dependent afterdepolarizations (or cDADs) and Iti (Figure 3A) (Bers et al., 2002, Pogwizd et al., 2001; see also Köster et al. 1999). These cDADs and Itis were almost 100% blocked when NCX was prevented (but when both INS and ICl(Ca) should be functional). Blocking ICl(Ca) with niflumic acid had little effect on either cDADs or Iti. These results demonstrate that
Enhanced NCX and Decreased IK1 Increase DADs in HF
Once a spontaneous SR Ca release event occurs in HF, we would expect a larger Iti (where functional NCX expression is elevated) and a consequently larger DAD. We analyzed this hypothesis quantitatively, using controlled SR Ca releases of different amplitudes (cDADs as above at different SR Ca loads) in voltage-clamped rabbit myocytes. Indeed in HF, a given Δ[Ca]i produced a greater depolarization (vs. control). Moreover, the mean Δ[Ca]i threshold for a triggered AP was decreased by ~50% in HF
New Paradigm for Arrhythmogenesis in HF and Implications
The above data support a novel paradigm in which changes in NCX, IK1, and retained β-adrenergic responsiveness combine to greatly enhance the propensity for triggered arrhythmias in HF (Figure 4). An important implication of this paradigm is the enhanced safety margin evident in control cardiac myocytes. Thus, in control hearts, even when a spontaneous SR Ca release occurs, there is low enough NCX to limit the Iti amplitude and enough IK1 to keep that Iti from depolarizing the cell to the
NCX Is a Difficult Therapeutic Target
Although upregulated NCX plays a dual role in contributing to contractile dysfunction and arrhythmogenesis (by mediating enhanced Iti), it represents a difficult therapeutic target. Inhibiting NCX would limit Ca efflux and enhance SR Ca load (as with glycoside inotropy) and reduce Iti. However, this could also impair relaxation, cause diastolic Ca overload, and increase DAD incidence. On the positive side, Hobai and O'Rourke (2002) showed that modest (~30%) NCX inhibition with intracellular
β-AR Blockade Reduces Sudden Death in HF
The β-AR is already recognized as a therapeutic target in HF, and there are data from several clinical trials showing reduction in SCD (sudden cardiac death) in HF with β-AR blockade (e.g., MERIT-HF Study Group 1999; Poole-Wilson et al. 2003). It should also help in limiting the occasional and potentially regional SR Ca overload that is arrhythmogenic in our paradigm. Whether the arrhythmogenic effects of β-adrenergic stimulation are due to β1- and/or β2-ARs remains to be determined.
IK1 and SR Ca Transport as Potential Therapeutic Targets
Until recently, little attention has been given to modulating IK1. Gene transfer to enhance IK1 may stabilize the resting Em, but it may also reduce APD and consequently reduce Ca entry, SR Ca load, and contractile function (Nuss et al. 1996). However, recent approaches by Ennis et al. (2002), with combined Kir2.1 (which encodes IK1) plus SERCA1 (the skeletal muscle form of SR Ca ATPase), showed important proof of principle that this combined approach could be contractile function neutral.
- PA Poole-Wilson et al.Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised control trial
- PH Pak et al.Repolarization abnormalities, arrhythmias and sudden death in canine tachycardia-induced cardiomyopathy
J Am Coll Cardiol
- SO Marx et al.PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts
- K Davia et al.SERCA2 overexpression decreases the incidence of aftercontractions in adult rabbit ventricular myocytes
J Mol Cell Cardiol
- DW Baker et al.Mortality trends for 23,505 Medicare patients hospitalized with heart failure in Northeast Ohio, 1991–1997
Am Heart J
- FG Akar et al.
Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure
- RA Altschuld et al.
Response of failing canine and human heart cells to beta-2 adrenergic stimulation
- KP Anderson et al.
Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy
J Clin Invest
- DM Bers et al.
Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure
Basic Res Cardiol
- DM Bers et al.
Sarcoplasmic reticulum Ca2+ and heart failure. Roles of diastolic leak and Ca2+ transport
Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts
N Engl J Med
Type I phosphatase, a negative regulator of cardiac function
Mol Cell Biol
Intracellular Na+ concentration is elevated in heart failure, but Na/K pump function is unchanged
Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility
J Clin Invest
Cellular electrophysiologic abnormalities of diseased human ventricular myocardium
Am J Cardiol
Heart failure after myocardial infarction: altered excitation-contraction coupling
Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing myocardium
Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure
Restoration of Ca handling by Na/Ca exchange blockade in canine pacing-induced heart failure [abst]
Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current
Activation of beta-2 adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure
Characterization of a [Ca2+]i-dependent current in human atrial and ventricular cardiomyocytes in the absence of Na+ and K+
- Klotho relieves inflammation and exerts a cardioprotective effect during renal ischemia/reperfusion-induced cardiorenal syndrome
2022, Biomedicine and Pharmacotherapy
Renal ischemia and reperfusion injury (IRI) is the main cause of acute kidney injury (AKI). AKI induces the development of cardiac hypertrophy (CH) during cardiorenal syndrome (CRS), and cardiomyocyte calcium mishandling though systemic inflammation after 8 days of renal IRI. Klotho has recently been described as an anti-inflammatory component. Given this, Klotho treatment could prevent or attenuate the inflammation, thereby also preventing electrical cardiac outcomes incurred by CRS. The aim of this study was to investigate the therapeutic role of Klotho in CRS after unilateral renal IRI through its anti-inflammatory action.
We examined renal tissue structure and function, intracellular Ca2+ dynamics in adult ventricular cardiomyocytes and serum cytokine levels from C57BL/6 mice that suffered unilateral renal IRI by occluding the left pedicle for 60min and reperfusion for 8 days. The animals were treated with recombinant Klotho protein starting from the day of the surgery, then daily for 8 days.
After Klotho treatment for 8 days, the left renal tissue remained damaged, however the renal function was restored due to the right kidney tissue preservation. In parallel, Klotho also prevented an increase in serum interleukin (IL-) 6, IL-1β, and tumor necrosis factor alpha (TNF-α) levels. CH and low cell contraction were also prevented, as well as a decrease in systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transient decay, an increase in spontaneous Ca2+ release and the incidence of pro-arrhythmic events.
The Klotho treatment showed promise, playing an important role in the pathophysiology of CRS. We were unable to observe a total renoprotective role of the compound in the model; in turn, a cardioprotective role of Klotho was demonstrated through the prevention of hypertrophy and normalization of the Ca2+ cycle dysfunction of cardiomyocytes. We propose that Klotho acts in the cardiorenal syndrome by systematically preventing inflammation and increased FGF23, alleviating cardiac outcomes.
- Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of G<inf>i/o</inf> signaling
2022, Journal of Molecular and Cellular Cardiology
Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause G protein dysregulation, contributing to modest blood pressure elevation and exaggerated cardiac hypertrophic response to pressure-overload. Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is unknown. Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac structure and function.
We found that Rgs2/5 dbKO mice showed left ventricular dilatation at baseline by echocardiography. Cardiac contractile response to dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice had 75% mortality within 72–96 h after surgery, accompanied by elevated baseline blood pressure and decreased cardiac contractile function. At the cellular level, cardiomyocytes (CM) from Rgs2/5 dbKO mice showed augmented Ca2+ transients and increased incidence of arrhythmia without augmented contractile response to electrical field stimulation (EFS) and activation of β-adrenergic receptors (βAR) with isoproterenol. Dual loss of Rgs2 and 5 suppressed forskolin-induced cAMP production, which was restored by Gi/o inactivation with pertussis toxin that also reduced arrhythmogenesis during EFS or βAR stimulation. Cardiomyocyte NCX and PMCA mRNA expression was unaffected in Rgs2/5 dbKO male mice. However, there was an exaggerated elevation of EFS-induced cytoplasmic Ca2+ in the presence of SERCA blockade with thapsigargin.
We conclude that RGS2 and 5 promote normal ventricular rhythm by coordinating their regulatory activity towards Gi/o signaling and facilitating cardiomyocyte calcium handling.
- Mechanisms of Lian-Gui-Ning-Xin-Tang in the treatment of arrhythmia: Integrated pharmacology and in vivo pharmacological assessment
Lian-Gui-Ning-Xin-Tang (LGNXT), a classical traditional Chinese medicine (TCM) formula, has been widely used in clinical practice and has shown satisfactory efficacy in the treatment of arrhythmias. However, its mechanism of action in the treatment of arrhythmias is still unknown. Moreover, the complex chemical composition and therapeutic targets of LGNXT pose a challenge in pharmacological research.
To analyze the active compounds and action mechanisms of LGNXT for the treatment of arrhythmias.
Here, we used an integrated pharmacology approach to identify the potential active compounds and mechanisms of action of LGNXT in treating arrhythmias. Potential active compounds in LGNXT were identified using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and the potential related targets of these compounds were predicted using an integrated in silico approach. The obtained targets were mapped onto relevant databases to identify their corresponding pathways, following the experiments that were conducted to confirm whether the presumptive results of systemic pharmacology were correct.
Eighty-three components were identified in herbal materials and in animal plasma using UPLC-Q-TOF/MS and were considered the potential active components of LGNXT. Thirty key targets and 57 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified as possible targets and pathways involved in LGNXT-mediated treatment using network pharmacology, with the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/Ca2+ system pathway being the most significantly affected. This finding was validated using an adrenaline (Adr)-induced rat model of arrhythmias. Pretreatment with LGNXT delayed the occurrence, shortened the duration, and reduced the severity of arrhythmias. LGNXT exerted antiarrhythmic effects by inhibiting cAMP, PKA, CACNA1C, and RyR2.
The findings of this study revealed that preventing intracellular Ca2+ overload and maintaining intracellular Ca2+ homeostasis may be the primary mechanisms of LGNXT in alleviating arrhythmias. Thus, we suggest that the β-adrenergic receptor (AR)/cAMP/PKA/Ca2+ system signaling hub may constitute a promising molecular target for the development of novel antiarrhythmic therapeutic interventions. Additionally, we believe that the approach of investigation of the biological effects of a multi-herbal formula by the combination of metabolomics and network pharmacology, as used in this study, could serve as a systematic model for TCM research.(Video) Arrhythmias | Types, Pathophysiology, Diagnosis, Treatment
- Phosphoproteomics reveals NMDA receptor-mediated excitotoxicity as a key signaling pathway in the toxicity of gelsenicine
2021, Food and Chemical Toxicology
Gelsenicine is one of the most toxic compounds in the genus Gelsemium, but the mechanism of toxicity is not clear. In this paper, tandem mass tag quantitative phosphoproteomics was used to study the changes in protein phosphorylation in different brain regions at different time points after gelsenicine poisoning in mice. The correlation between neurotransmitter receptors and the toxicity of gelsenicine was analyzed by molecular docking and rescue experiments. Parallel reaction monitoring (PRM) was used to verify the related proteins. A total of 17877 unique phosphosites were quantified and mapped to 4170 brain proteins to understand the signaling pathways. Phosphoproteomics revealed gelsenicine poisoning mainly affected protein phosphorylation levels in the hippocampus, and through bioinformatics analysis, it was found gelsenicine poisoning significantly affected neurotransmitter synaptic pathway. The molecular docking results showed that gelsenicine could bind to the N-methyl-D-aspartic acid receptor (NMDAR). In addition, we found that NMDA was effective in improving the survival rate of the animals tested, and this effect was associated with reduced protein phosphorylation by PRM validation. The results revealed that gelsenicine affects neurotransmitter release and receptor function. This is the first demonstration that NMDA receptor-mediated excitotoxicity is a key signaling pathway in the toxicity of gelsenicine.
- Blockade of sodium‑calcium exchanger via ORM-10962 attenuates cardiac alternans
2021, Journal of Molecular and Cellular Cardiology
Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium‑calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug's mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodium‑calcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans.
- The role of pacing rate in the modulation of mechano-induced immediate and delayed changes in the force and Ca-transient of cardiac muscle
2021, Progress in Biophysics and Molecular Biology
Myocardial function is tuned by dynamic changes in length and load via mechano-calcium feedback. This regulation may be significantly affected by heart rhythm. We evaluated the mechano-induced modulation of contractility and Ca-transient (CaT) in the rat myocardium subjected to twitch-by-twitch shortening–re-lengthening (↓–↑) trains of different lengths (N=1 … 720 cycles) at low (1Hz) and near-physiological (3.5Hz) pacing rates. Force/CaT characteristics were evaluated in the first post-train isometric twitch (immediate effect) and during slow changes (delayed maximal elevation/decrease) and compared with those of the pre-train twitch. The immediate inotropic effect was positive for N=30 … 720 and negative for N=1 … 20, while the delayed effect was always positive. The immediate and delayed inotropic effects were significantly higher at 3.5-Hz vs 1-Hz (P<0.05). The prominent inotropism was accompanied by much smaller changes in the CaT diastolic level/amplitude. The shortening–re-lengthening train induced oscillations of the slow change in force at 3.5-Hz (always) and at 1-Hz (∼50% of muscles), which were dependent of the train length and independent of the pacing rate. We suggest that twitch-by-twitch shortening–re-lengthening of cardiac muscle decreases Ca2+ buffering by troponin C and elevates Ca2+ loading of the sarcoplasmic reticulum (SR); the latter cumulatively depends on the train length. A high pacing rate intensifies the cumulative transient shift in the SR Ca2+ loading, augmenting the post-train inotropic response and prolonging its recovery to the pre-train level. The pacing-dependent mechano-induced inotropic effects remain to be elucidated in the myocardium with impaired Ca handling.
Research articleClinical PET Myocardial Perfusion Imaging and Flow Quantification
Cardiology Clinics, Volume 34, Issue 1, 2016, pp. 69-85
Research articleSystems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline
Progress in Biophysics and Molecular Biology, Volume 115, Issues 2–3, 2014, pp. 162-172
We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of invivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats.
We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate.(Video) Cardiac Arrhythmias
Echocardiography was used to estimate increased wall stress in failure, invivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.
Research articleCharacterisation of ivermectin and multi-drug resistance in two field isolates of Teladorsagia circumcincta from Irish sheep flocks
Veterinary Parasitology: Regional Studies and Reports, Volumes 1–2, 2015, pp. 3-9
Ivermectin resistant Teladorsagia circumcincta were isolated from two Irish sheep farms. Parasite naïve lambs were artificially challenged with the isolates in order to test their sensitivity to benzimidazole (BZ), levamisole (LEV) and ivermectin (IVM) by means of a faecal egg count reduction test (FECRT). Both isolates were found to be resistant to all three anthelmintics with reductions of 47% (C.I. 10–68), 92% (C.I. 74–97) and 50% (C.I. 24–68) for the Farm A isolate and of 85% (C.I. 59–94), 89% (C.I. 69–96) and 73% (C.I. 49–86) for the Farm B isolate for BZ, LEV and IVM, respectively. A controlled efficacy test (CET) was undertaken to confirm resistance to IVM and to determine the efficacy of moxidectin (MOX). In agreement with the FECRT, IVM resistance was confirmed for both isolates, with reductions in worm burden of 78% (C.I. 67–85) and 80% (C.I. 45–93) for the Farm A and B isolates respectively. Both isolates were found to be MOX susceptible, with reductions in worm burden of 97% (C.I. 91–99) and 100% for the Farm A and B isolates respectively. Additionally, in vitro tests confirmed the results of the FECRT; results from the larval development assay (LDA) confirmed that both isolates were resistant to BZ and LEV with development observed at the discriminating dose for each drug, while the larval migration inhibition assay (LMIA) confirmed IVM resistance and indicated MOX susceptibility in both isolates. These results represent the first confirmed cases of IVM resistance on Irish sheep farms as well as the first report of multiple anthelmintic resistant gastrointestinal nematodes in Ireland.
Research articleTriggered activity in atrial myocytes is influenced by Na+/Ca2+ exchanger activity in genetically altered mice
Journal of Molecular and Cellular Cardiology, Volume 101, 2016, pp. 106-115
In atrial fibrillation, increased function of the Na+/Ca2+-exchanger (NCX) is one among several electrical remodeling mechanisms.
Using the patch-clamp- and Ca2+ imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WTOE; WTKO). NCX mediated Ca2+ extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WTOE and KO vs. WTKO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WTOE (ratio sAP/DAD: OE:0.18±0.05; WTOE:0.02±0.02; p<0.001). Using the same protocol, a DAD triggered an sAP by tendency less often in KO vs. WTKO (p=0.06) and significantly less often under a more aggressive proarrhythmic protocol (ratio sAP/DAD: KO:0.01±0.003; WT KO: 0.12±0.05; p=0.007). The DAD amplitude was increased in OE vs. WTOE and decreased in KO vs. WTKO. There were no differences in SR-Ca2+-load, the number of spontaneous Ca2+-release-events or IKACh/IK1.
Atrial myocytes with increased NCX expression exhibited increased vulnerability towards sAPs while atriomyocytes with reduced NCX expression were protected. The underlying mechanism consists of a modification of the DAD-amplitude by the level of NCX-activity. Thus, although the number of spontaneous Ca2+-releases and therefore DADs is unaltered, the higher DAD-amplitude in OE made a transgression of the voltage-threshold of an sAP more likely. These findings indicate that the level of NCX activity could influence triggered activity in atrial myocytes independent of possible remodeling processes.
Research articleHow cardiomyocyte excitation, calcium release and contraction become altered with age
Journal of Molecular and Cellular Cardiology, Volume 83, 2015, pp. 62-72
Cardiovascular disease is the main cause of death globally, accounting for over 17 million deaths each year. As the incidence of cardiovascular disease rises markedly with age, the overall risk of cardiovascular disease is expected to increase dramatically with the aging of the population such that by 2030 it could account for over 23 million deaths per year. It is therefore vitally important to understand how the heart remodels in response to normal aging for at least two reasons: i) to understand why the aged heart is increasingly susceptible to disease; and ii) since it may be possible to modify treatment of disease in older adults if the underlying substrate upon which the disease first develops is fully understood. It is well known that age modulates cardiac function at the level of the individual cardiomyocyte. Generally, in males, aging reduces cell shortening, which is associated with a decrease in the amplitude of the systolic Ca2+ transient. This may arise due to a decrease in peak L-type Ca2+ current. Sarcoplasmic reticulum (SR) Ca2+ load appears to be maintained during normal aging but evidence suggests that SR function is disrupted, such that the rate of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)-mediated Ca2+ removal is reduced and the properties of SR Ca2+ release in terms of Ca2+ sparks are altered. Interestingly, Ca2+ handling is modulated by age to a lesser degree in females. Here we review how cellular contraction is altered as a result of the aging process by considering expression levels and functional properties of key proteins involved in controlling intracellular Ca2+. We consider how changes in both electrical properties and intracellular Ca2+ handling may interact to modulate cardiomyocyte contraction. We also reflect on why cardiovascular risk may differ between the sexes by highlighting sex-specific variation in the age-associated remodeling process. This article is part of a Special Issue entitled CV Aging.
Research articleMutation-linked, excessively tight interaction between the calmodulin binding domain and the C-terminal domain of the cardiac ryanodine receptor as a novel cause of catecholaminergic polymorphic ventricular tachycardia
Heart Rhythm, Volume 15, Issue 6, 2018, pp. 905-914
Ryanodine receptor (RyR2) is known to be a causal gene of catecholaminergic polymorphic ventricular tachycardia (CPVT), an important inherited disease. Some of the human CPVT-associated mutations have been found in a domain (4026-4172) that has EF hand motifs, the so-called calmodulin (CaM)-like domain (CaMLD).
The purpose of this study was to investigate the underlying mechanism by which CPVT is induced by a mutation at CaMLD.
A new N4103K/+ knock-in (KI) mice model was generated.
Sustained ventricular tachycardia was frequently observed after infusion of caffeine plus epinephrine in KI mice. Endogenous CaM bound to RyR2 decreased even at baseline in isolated KI cardiomyocytes. Ca2+ spark frequency (CaSpF) was much higher in KI cells than in wild-type cells. Addition of GSH-CaM (higher affinity CaM to RyR2) significantly decreased CaSpF. In response to isoproterenol, spontaneous Ca2+ transient (SCaT) was frequently observed in intact KI cells. Incorporation of GSH-CaM into intact KI cells using a protein delivery kit decreased SCaT significantly. An assay using a quartz crystal microbalance technique revealed that mutated CaMLD peptide showed higher binding affinity to CaM binding domain (CaMBD) peptide.See Also20 Team Building Activities for College Students for 2021101 Ideas - Your Bucket List for Summer 2022 - With Printable PDFBehavior Intervention: Definition, Strategies, and Resources | Regis College Online46 Social Distancing Activities to Try During Coronavirus
In the N4103K mutant, CaM binding affinity to RyR2 was significantly reduced regardless of beta-adrenergic stimulation. We found that this was caused by an abnormally tight interaction between CaMBD and mutated CaM-like domain (N4103K-CaMBD). Thus, CaMBD–CaMLD interaction may be a novel therapeutic target for treatment of lethal arrhythmia.
Copyright © 2004 Elsevier Inc. All rights reserved.