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Al-Seykal I, Bose A, Chevli PA, Hashmath Z, Sharma N, Mishra AK, Laidlaw D. Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cryoballoon ablation outcomes for paroxysmal atrial fibrillation. World J Cardiol 2022; 14:537-545. [PMID: 36339889 PMCID: PMC9627355 DOI: 10.4330/wjc.v14.i10.537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/18/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cryoballoon ablation (CBA) is recommended for patients with paroxysmal atrial fibrillation (AF) refractory to antiarrhythmic drugs. However, only 80% of patients benefit from initial CBA. There is growing evidence that pretreatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decreases the recurrence of AF postablation, particularly in nonparoxysmal AF undergoing radiofrequency ablation. The role of ACEIs and ARBs in patients with paroxysmal AF in CBA remains unknown. We decided to investigate the role of ACEIs and ARBs in preventing the recurrence of atrial arrhythmia (AA) following CBA for paroxysmal AF. AIM To investigate the role of ACEIs and ARBs in preventing recurrence of AA following CBA for paroxysmal AF. METHODS We followed 103 patients (age 60.6 ± 9.1 years, 29% women) with paroxysmal AF undergoing CBA 1-year post procedure. Recurrence was assessed by documented AA on electrocardiogram or any form of long-term cardiac rhythm monitoring. A multivariable Cox proportional hazard model was used to assess if ACEI or ARB treatment predicted the risk of AA recurrence. RESULTS After a 1-year follow-up, 19 (18.4%) participants developed recurrence of AA. Use of ACEI or ARB therapy was noted in the study population. Patients on ACEI/ARB had a greater prevalence of hypertension and coronary artery disease. On a multivariate model adjusted for baseline demographics and risk factors for AF, ACEI or ARB therapy did not prevent recurrence of AA following CBA (P = 0.72). Similarly, on Kaplan-Meier analysis pretreatment with ACEI/ARB did not predict the time to first recurrence of AA (P = 0.2173). CONCLUSION In our study population, preablation treatment with an ACEI or ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.
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Affiliation(s)
- Ibragim Al-Seykal
- Department of Medicine, Division of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - Abhishek Bose
- Department of Medicine, Division of Cardiology, University of Massachusetts Chan School of Medicine, Worcester, MA 01608, United States
| | - Parag A Chevli
- Section on Hospital Medicine, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States
| | - Zeba Hashmath
- Department of Medicine, Division of Cardiology, East Carolina University, Greenville, NC 27858, United States
| | - Nitish Sharma
- Department of Medicine, Division of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States
| | - Ajay K Mishra
- Department of Medicine, Division of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States.
| | - Douglas Laidlaw
- Department of Medicine, Division of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, United States
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Guo Y, Zhang C, Chen X, Liu X, Ye T, Fo Y, Shi S, Qu C, Liang J, Shen B, Yang B. Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder. Psychopharmacology (Berl) 2021; 238:487-499. [PMID: 33140216 DOI: 10.1007/s00213-020-05697-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023]
Abstract
RATIONALE It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias. OBJECTIVE We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats. METHODS MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique. RESULTS Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (ICa-L) amplitudes. On the other hand, a trend of depolarization of Ito and hyperpolarization of ICa-L was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and ICa-L. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca2+ by hyperpolarizing the steady-state activation of ICa-L. All these effects were blocked by BD1047. CONCLUSION Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and ICa-L to possibly exert antiarrhythmic effects.
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Affiliation(s)
- Yan Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Cui Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Xiuhuan Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Xin Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Tianxin Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Yuhong Fo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Shaobo Shi
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Chuan Qu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Jinjun Liang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China
| | - Bo Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China.
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China.
| | - Bo Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
- Cardiovascular Research Institute, Wuhan University, Wuhan, People's Republic of China.
- Hubei Key Laboratory of Cardiology, Wuhan, People's Republic of China.
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Pierce JB, Rosenthal J, Stone NJ. Worth Remembering: Cardiac Memory Presenting as Deep Anterior T-Wave Inversions Explained by Intermittent Left Bundle Branch Block. Am J Cardiol 2020; 135:174-176. [PMID: 32866450 DOI: 10.1016/j.amjcard.2020.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 08/17/2020] [Accepted: 08/21/2020] [Indexed: 10/23/2022]
Abstract
Cardiac memory is a common cause of deep T-wave inversions (TWI) in the anterior precordial leads and can be difficult to distinguish from alternative causes of TWI such as myocardial ischemia. Cardiac memory is generally a benign condition except in the setting of prolonged QT when it can contribute to the precipitation of torsades de pointes. Herein, we describe the presentation and clinical course of a case of cardiac memory due to intermittent left bundle branch block (LBBB) that presented asymptomatically to our outpatient cardiology clinic with deep anterior TWI. We discuss common causes of and mechanisms underlying cardiac memory and how to distinguish it from alternative causes of TWI based on 12-lead electrocardiogram. In conclusion, intermittent LBBB is an under-recognized cause of cardiac memory that can present as deep anterior TWI mimicking cardiac ischemia, and awareness of this clinical entity may help prevent unnecessary invasive and expensive testing on otherwise healthy patients.
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Affiliation(s)
- Jacob B Pierce
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - James Rosenthal
- Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois
| | - Neil J Stone
- Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois.
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Vohra J. Editorial: Cardiac or T wave memory after radiofrequency ablation of right ventricular outflow tract ectopics. J Cardiovasc Electrophysiol 2019; 30:1557-1559. [PMID: 31165545 DOI: 10.1111/jce.14007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 05/27/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Jitendra Vohra
- Cardiology Department, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
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Tafoya C, Singh A. Cardiac Memory: A Case Report and Review of the Literature. J Emerg Med 2019; 57:85-93. [PMID: 31047746 DOI: 10.1016/j.jemermed.2019.02.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/16/2019] [Accepted: 02/18/2019] [Indexed: 11/24/2022]
Abstract
BACKGROUND A variety of clinical syndromes can cause T-wave inversion (TWI), ranging from life-threatening events to benign conditions. One benign cause of TWI is cardiac memory, which is characterized by the transient inversion of T-waves following abnormal activation of the ventricles, commonly due to intermittent left bundle branch block (LBBB), tachydysrhythmias, electrical pacing, or ventricular pre-excitation. CASE REPORT A 72-year-old man presented to the emergency department with chest pain, nausea, vomiting, and headache. Upon arrival, his electrocardiogram (ECG) showed new-onset LBBB with appropriate secondary ST-T wave changes. A subsequent ECG showed disappearance of LBBB and newly inverted T-waves in precordial leads V1-V5, followed by a repeat ECG that again showed LBBB. Serial troponin testing was unremarkable. During hospitalization, echocardiogram and nuclear perfusion stress test were normal. The transient TWIs in this patient were believed to be due to cardiac memory. We performed a literature review and identified 39 published cases of cardiac memory. The most common etiology for cardiac memory was after cardiac pacemaker placement, followed by intermittent LBBB (as was seen in our patient), and post-tachydysrhythmia. Patient ages ranged from 21 to 88 years, with an equal number of cases reported in men and women. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Cardiac memory is a poorly understood, rarely observed phenomenon that can occur in the setting of intermittent LBBB. Testing for acute cardiac ischemia and underlying coronary artery disease is still recommended, as the diagnosis of cardiac memory can only be made after negative workup.
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Affiliation(s)
- Chelsea Tafoya
- Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland, California
| | - Amandeep Singh
- Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland, California
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Nguyên UC, Verzaal NJ, van Nieuwenhoven FA, Vernooy K, Prinzen FW. Pathobiology of cardiac dyssynchrony and resynchronization therapy. Europace 2018; 20:1898-1909. [DOI: 10.1093/europace/euy035] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 02/16/2018] [Indexed: 02/04/2023] Open
Affiliation(s)
- Uyên Châu Nguyên
- Department of Physiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
| | - Nienke J Verzaal
- Department of Physiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
| | - Frans A van Nieuwenhoven
- Department of Physiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
| | - Kevin Vernooy
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
| | - Frits W Prinzen
- Department of Physiology, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, ER Maastricht, The Netherlands
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Abstract
Objective: Atrial fibrillation (AF) is the most common rapid cardiac arrhythmia associated with high morbidity and mortality. Stimulation of the sympathetic nerve is involved in AF occurrence. The gap junction protein connexin 43 (Cx43) plays a key role in electrical conduction velocity in cardiac tissues, and under expression of Cx43 was linked with AF. The aim of this study was to investigate whether Cx43 was involved in sympathetic AF. Methods: Fifteen dogs were randomly divided into 3 groups (5 in each group). Sympathetic AF was induced in dogs and isolated canine atrial myocytes by isoproterenol (ISO) perfusion and rapid atrium pacing (RAP). The expression levels of nerve growth factor (NGF) and tyrosine hydroxylase (TH) in the atrial tissues were detected using immunohistochemical staining. The transcription and protein expression of Cx43 in the AF cell model was measured. Subsequently, Cx43 was blocked by short interfering (si) RNA in atrial myocytes and the gap junctional inter-cellular communication was detected using the scrape-loading and dye transfer assay. Results: Sympathetic AF was successfully induced by a combination of ISO perfusion and RAP. The expression levels of NGF and TH were increased in the RAP group, and further increased in the RAP + ISO group. Tissue samples from the AF dogs had a lower Cx43 level than those of the control group (p<0.05). The expressions of mRNA and protein of Cx43 in sympathetic AF cell model decreased by 26% and 28%, respectively, when compared with the control group, with p<0.05. Silencing Cx43 in cells by siRNA could also efficiently reduce Cx43 expression. The relative levels of Cx45 mRNA were decreased by 73% compared with unaffected cells. The scrape-loading and dye transfer assay showed that gap junctional intercellular communication was hampered in the sympathetic AF cell model and silencing Cx43 could impede channel conduction. Conclusion: The results suggested that low expression of Cx43 was involved in sympathetic AF by influencing intercellular channel conduction. Intervention of Cx43 expression might be an appealing therapy to sympathetic AF.
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Cui C, Geng L, Shi J, Zhu Y, Yang G, Wang Z, Wang J, Chen M. Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes. Stem Cell Res Ther 2017; 8:109. [PMID: 28490375 PMCID: PMC5426064 DOI: 10.1186/s13287-017-0566-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/16/2017] [Accepted: 04/26/2017] [Indexed: 01/15/2023] Open
Abstract
Background Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro. Methods Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing. Results Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs. Conclusions The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0566-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chang Cui
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Le Geng
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jiaojiao Shi
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yue Zhu
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Gang Yang
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zidun Wang
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jiaxian Wang
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Minglong Chen
- Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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9
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Speerschneider T, Grubb S, Olesen SP, Calloe K, Thomsen MB. Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice. Acta Physiol (Oxf) 2017; 219:660-668. [PMID: 27459728 DOI: 10.1111/apha.12761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 04/13/2016] [Accepted: 07/22/2016] [Indexed: 11/29/2022]
Abstract
AIM In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+ -channel-interacting protein 2 (KChIP2-/- and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia. METHODS Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT + APD) were measured in isolated hearts using floating microelectrodes. RESULTS Proarrhythmia in WT and KChIP2-/- was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2-/- hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KChIP2-/- mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2-/- mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. CONCLUSION Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and the amplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability.
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Affiliation(s)
- T. Speerschneider
- Department of Biomedical Sciences; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - S. Grubb
- Department of Veterinary Clinical and Animal Science; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - S. P. Olesen
- Department of Biomedical Sciences; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - K. Calloe
- Department of Veterinary Clinical and Animal Science; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - M. B. Thomsen
- Department of Biomedical Sciences; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
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Herweg B, Marcus MB, Barold SS. Diagnosis of myocardial infarction and ischemia in the setting of bundle branch block and cardiac pacing. Herzschrittmacherther Elektrophysiol 2016; 27:307-322. [PMID: 27402134 DOI: 10.1007/s00399-016-0439-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The diagnosis of myocardial infarction (MI) in the presence of left bundle branch block (LBBB) or during ventricular pacing (VP) is challenging because of inherent changes in the sequence of ventricular depolarization and repolarization associated with both conditions. Although LBBB and right ventricular (RV) pacing may both produce abnormalities in the ECG, it is often possible to diagnose an acute MI (AMI) or an old MI based on selected morphologic changes. Primary ST-segment changes scoring 3 points or greater according to the Sgarbossa criteria are highly predictive of an AMI in patients with LBBB or RV pacing. The modified Sgarbossa criteria are useful for the diagnosis of AMI in patients with LBBB; however, these criteria have not yet been studied in the setting of RV pacing. Although changes of the QRS complex are not particularly sensitive for the diagnosis of an old MI in the setting of LBBB or RV pacing, the qR complex and Cabrera sign are highly specific for the presence of an old infarct. Diagnosing AMI in the setting of biventricular (BiV) pacing is challenging. To date there is minimal evidence suggesting that the traditional electrocardiographic criteria for diagnosis of AMI in bundle branch block may be applicable to patients with BiV pacing and positive QRS complexes on their ECG in lead V1. This report is a careful review of the electrocardiographic criteria facilitating the diagnosis of acute and remote MI in patients with LBBB and/or VP.
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Affiliation(s)
- B Herweg
- Department of Cardiovascular Disease, University of South Florida Morsani College of Medicine, South Tampa Campus (5th floor), Two Tampa General Circle, FL 33606, Tampa, FL, USA.
| | - M B Marcus
- Department of Cardiovascular Disease, University of South Florida Morsani College of Medicine, South Tampa Campus (5th floor), Two Tampa General Circle, FL 33606, Tampa, FL, USA.
| | - S S Barold
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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Cardiac memory: The slippery slope twixt normalcy and pathology. Trends Cardiovasc Med 2015; 25:687-96. [DOI: 10.1016/j.tcm.2015.02.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/17/2015] [Accepted: 02/18/2015] [Indexed: 12/19/2022]
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Perrotta L, Ricciardi G, Pieragnoli P, Nesti M, Pontecorboli G, Fantini F, Padeletti L. Cardiac memory in cardiac resynchronization therapy: A vectorcardiographic comparison of biventricular and left ventricular pacing. J Electrocardiol 2015; 48:571-7. [PMID: 25987410 DOI: 10.1016/j.jelectrocard.2015.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Indexed: 11/26/2022]
Abstract
INTRODUCTION "Cardiac memory" (CM) refers to a change in repolarization induced by an altered pathway of activation, manifested after resumption of spontaneous ventricular activation (SVA). AIMS To investigate for the first time in humans the effects of left ventricular (LV) pacing on CM development through vectorcardiography (VCG). METHODS We studied 28 patients with heart failure (HF) and left bundle branch block (LBBB) treated with cardiac resynchronization therapy (CRT). Fourteen patients underwent biventricular (BIV) stimulation; the other 14 underwent LV stimulation only. VCG was acquired during SVA at baseline and during AAI and DDD pacing immediately after and 7 and 90 days after the implant. RESULTS At baseline, in both groups, the QRS and T vectors angles were those specific of LBBB pattern. During DDD pacing, QRS vector angle changed to the right and upward in BIV patients while no significant differences were observed in LV patients. During AAI pacing, T vector angle changed significantly in BIV patients, following the direction of the paced QRS and amplitude significantly increased. In LV patients no significant differences in T vector angles were observed. Only T vector amplitude significantly increased at 7 days (p=0.03) and at 90 days (p=0.008 vs baseline). CONCLUSION In patients with LBBB, BIV pacing induces cardiac memory development as a significant change in T vector magnitude and angle, while LV pacing doesn't induce significant modifications in QRS and T vector angles and CM is manifested only as a significant T vector amplitude change.
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Josephson ME, Wellens HJ. A tachycardia showing marked T-wave changes after its termination. Heart Rhythm 2015; 12:458-60. [DOI: 10.1016/j.hrthm.2014.08.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Indexed: 11/25/2022]
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Song B, Wang BN, Chen DN, Luo ZG. Myocardial remodeling and bioelectric changes in tachycardia-induced heart failure in dogs. Braz J Med Biol Res 2014; 46:797-802. [PMID: 24036911 PMCID: PMC3854429 DOI: 10.1590/1414-431x20132694] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 04/01/2013] [Indexed: 11/24/2022] Open
Abstract
In this study, electrical and structural remodeling of ventricles was examined in
tachycardia-induced heart failure (HF). We studied two groups of weight-matched
adult male mongrel dogs: a sham-operated control group (n=5) and a pacing group
(n=5) that underwent ventricular pacing at 230 bpm for 3 weeks. Clinical
symptoms of congestive HF were observed in both groups. Their hemodynamic
parameters were determined and the severity of the HF was evaluated by M-mode
echocardiography. Changes in heart morphology were observed by scanning electron
and light microscopy. Ventricular action potential duration (APD), as well as
the 50 and 90% APD were measured in both groups. All dogs exhibited clinical
symptoms of congestive HF after rapid right ventricular pacing for 3 weeks.
These data indicate that rapid, right ventricular pacing produces a useful
experimental model of low-output HF in dogs, characterized by biventricular pump
dysfunction, biventricular cardiac dilation, and non-ischemic impairment of left
ventricular contractility. Electrical and structural myocardial remodeling play
an essential role in congestive HF progression, and should thus be
prevented.
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Kershaw MA, Rogers FJ. Intermittent left bundle branch block: an overlooked cause of electrocardiographic changes that mimic high-grade stenosis of the left anterior descending coronary artery. J Osteopath Med 2014; 114:868-73. [PMID: 25352408 DOI: 10.7556/jaoa.2014.174] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
CONTEXT The electrocardiographic (ECG) pattern of high-grade stenosis of the left anterior descending coronary artery (LAD) is important clinically because of the high risk of myocardial infarction and cardiac death if the pattern is not recognized. Although the recognition of this pattern is currently widespread, false-positive ECG changes that mimic this pattern are infrequently reported. OBJECTIVE To demonstrate that ECG changes from intermittent left bundle branch block (LBBB) and cardiac memory can mimic anterior ischemia. METHODS Medical record review of cardiology patients in whom ECG tracings showed intermittent LBBB and anterior T-wave changes during normal QRS conduction. Patients were included if ECG changes suggestive of high-grade LAD stenosis in leads V2 and V3 met the following criteria: (1) the QRS conduction was essentially normal during periods of absent LBBB; (2) the ST segment took off from an isoelectric point or only slightly elevated from baseline; and (3) the ST segment sloped up gradually with an abrupt and sharp down stroke leading to terminal T-wave inversion. Additional criteria were little or no ST segment elevation, no loss of precordial R waves, and ECG changes suggestive of high-grade LAD stenosis demonstrated in precordial leads V2 and V3. All patients demonstrated intermittent LBBB, and patients were excluded if a ventricular pacemaker was present. The case series began in 2003 and continued until 2011. RESULTS Sixteen patients (3 male) with intermittent LBBB were identified with ST- and T-wave changes during normal ventricular conduction that matched the pattern described by Hein J.J. Wellens, MD. Of these patients, none had evidence of clinically substantial coronary artery disease. Eleven patients had stress testing with myocardial perfusion imaging, and 5 patients underwent cardiac catheterization. In 1 patient whose ECG pattern showed high-grade LAD stenosis but normal coronary arteries at catheterization, a stress test was later performed, which provoked LBBB. All other patients had spontaneous, intermittent periods of LBBB and normal conduction. CONCLUSION The ECG pattern of high-grade LAD stenosis has proven to be an important marker of high-risk patients with chest pain. This pattern may also be seen in patients with a right ventricular pacemaker on resumption of native QRS conduction. Intermittent LBBB is a less obvious cause of a similar ECG pattern that may mimic anterior ischemia due to high-grade stenosis.
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Affiliation(s)
- Melissa A Kershaw
- From the Department of Cardiology at Oakwood Southshore Medical Center in Trenton, Michigan
| | - Felix J Rogers
- From the Department of Cardiology at Oakwood Southshore Medical Center in Trenton, Michigan
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Chiale PA, Etcheverry D, Pastori JD, Fernandez PA, Garro HA, González MD, Elizari MV. The multiple electrocardiographic manifestations of ventricular repolarization memory. Curr Cardiol Rev 2014; 10:190-201. [PMID: 24827802 PMCID: PMC4040871 DOI: 10.2174/1573403x10666140514102021] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 05/28/2013] [Accepted: 01/28/2014] [Indexed: 11/22/2022] Open
Abstract
T wave “memory” is a peculiar variety of cardiac remodeling caused by a transient change in the course of ventricular depolarization (due to ventricular pacing, rate-dependent intraventricular block, ventricular preexcitation or tachyarrhythmias with wide QRS complexes). It is usually manifested by inverted T waves that appears when normal ventricular activation is restored. This phenomenon is cumulative and occurs earlier if the ventricular myocardium has previously been exposed to the same conditioning stimuli. In this article the different conditions giving rise to “classical” T wave memory development are reviewed and also “another” type of T wave memory is described. It is also shown that cardiac memory may induce not only negative (pseudo-primary) T waves but also a reversal of primary and pseudo-primary T waves leading to “normalization” of ventricular repolarization. The knowledge of these dissimilar consequences of T wave memory is essential to assess the characteristics of ventricular repolarization.
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Affiliation(s)
| | | | | | | | | | | | - Marcelo V Elizari
- Centro de Arritmias Cardíacas de la Ciudad Autónoma de Buenos Aires. Cardiology Division. Hospital J.M. Ramos Mejía. Buenos Aires. Argentina.
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Kuijpers NHL, Hermeling E, Lumens J, ten Eikelder HMM, Delhaas T, Prinzen FW. Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT. Am J Physiol Heart Circ Physiol 2014; 306:H1644-59. [DOI: 10.1152/ajpheart.00689.2013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca2+ current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventricular stroke work and increased end-diastolic volume. During sustained LBBB, MEC reduced intraventricular dispersion of mechanical workload and repolarization. However, MEC-induced reduction in contractility in late-activated regions was larger than the contractility increase in early-activated regions, resulting in further decrease of stroke work and increase of end-diastolic volume. Upon the start of CRT, stroke work increased despite a wider dispersion of mechanical workload. During sustained CRT, MEC-induced reduction in dispersion of workload and repolarization coincided with a further reduction in end-diastolic volume. In conclusion, MEC may represent a useful framework for better understanding the long-term changes in cardiac electrophysiology and contraction following LBBB as well as CRT.
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Affiliation(s)
- Nico H. L. Kuijpers
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Evelien Hermeling
- Department of Radiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Joost Lumens
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Huub M. M. ten Eikelder
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Tammo Delhaas
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Frits W. Prinzen
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Chiale PA, Etcheverry D, Pastori JD, Garro HA, Fernández PA, González MD, Elizari MV. Clinical Evaluation of Losartan and Diltiazem on the Development of T-Wave Memory by Right Apical Ventricular Pacing. J Am Coll Cardiol 2014; 63:1929-31. [DOI: 10.1016/j.jacc.2014.02.524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 01/30/2014] [Accepted: 02/04/2014] [Indexed: 11/27/2022]
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Žižek D, Cvijić M, Ležaić L, Salobir BG, Zupan I. Impact of myocardial viability assessed by myocardial perfusion imaging on ventricular tachyarrhythmias in cardiac resynchronization therapy. J Nucl Cardiol 2013; 20:1049-59. [PMID: 24136364 DOI: 10.1007/s12350-013-9795-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 09/24/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND The presence of myocardial fibrosis is associated with ventricular tachyarrhythmia (VT) occurrence irrespective of cardiomyopathy etiology. The aim of our study was to evaluate the impact of global and regional viability on VTs in patients undergoing cardiac resynchronization therapy (CRT). METHODS Fifty-seven patients with advanced heart failure (age 62.3 ± 10.2; 38 men; 24 ischemic etiology) were evaluated using single-photon emission computed tomography myocardial perfusion imaging before CRT defibrillator device implantation. Global myocardial viability was determined by the number of viable segments in a 20-segment model. Regional viability was calculated as the mean tracer activity in the corresponding segments at left ventricular (LV) lead position. LV lead segments were determined at implant venography using 2 projections (left anterior oblique 30 and right anterior oblique 30) of coronary sinus tributaries. Patients were followed 30 (24-34) months for the occurrence of VTs. RESULTS VTs were registered in 18 patients (31.6%). Patients without VTs had significantly more viable segments (17.6 ± 2.35 vs 14.2 ± 4.0; P = .002) and higher regional myocardial viability at LV lead position (66.1% ± 10.3% vs 54.8% ± 11.4% of tracer activity; P = .001) than those with VTs. In multivariate logistic regression models, the number of viable segments (OR = 0.66; 95% confidence interval (CI) 0.53-0.85; P = .001) and regional viability (OR = 0.90; 95% CI 0.85-0.97; P = .003) were the only independent predictors of VT occurrence. CONCLUSION Global and regional myocardial viability are independently related to the occurrence of VTs in patients after CRT.
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Affiliation(s)
- David Žižek
- Department of Cardiology, University Medical Centre Ljubljana, Zaloška 7, 1000, Ljubljana, Slovenia,
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Chen Z, Hanson B, Sohal M, Sammut E, Child N, Shetty A, Boucher R, Bostock J, Gill J, Carr-White G, Rinaldi CA, Taggart P. Left Ventricular Epicardial Electrograms Show Divergent Changes in Action Potential Duration in Responders and Nonresponders to Cardiac Resynchronization Therapy. Circ Arrhythm Electrophysiol 2013; 6:265-71. [DOI: 10.1161/circep.112.000148] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Zhong Chen
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Ben Hanson
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Manav Sohal
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Eva Sammut
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Nick Child
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Anoop Shetty
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Ryan Boucher
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Julian Bostock
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Jaswinder Gill
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Gerald Carr-White
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - C. Aldo Rinaldi
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
| | - Peter Taggart
- From the Kings College London, London, United kingdom (Z.C., M.S., E.S., N.C., A.S., J.B., J.G., G.C.-W., C.A.R.); University College London, London, United Kingdom (B.H., P.T.); and St. Jude Medical, Stratford Upon Avon, United Kingdom (R.B.)
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Hermeling E, Delhaas T, Prinzen FW, Kuijpers NHL. Mechano-electrical feedback explains T-wave morphology and optimizes cardiac pump function: insight from a multi-scale model. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2012; 110:359-71. [PMID: 22835663 DOI: 10.1016/j.pbiomolbio.2012.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 07/16/2012] [Indexed: 11/17/2022]
Abstract
In the ECG, T- and R-wave are concordant during normal sinus rhythm (SR), but discordant after a period of ventricular pacing (VP). Experiments showed that the latter phenomenon, called T-wave memory, is mediated by a mechanical stimulus. By means of a mathematical model, we investigated the hypothesis that slow acting mechano-electrical feedback (MEF) explains T-wave memory. In our model, electromechanical behavior of the left ventricle (LV) was simulated using a series of mechanically and electrically coupled segments. Each segment comprised ionic membrane currents, calcium handling, and excitation-contraction coupling. MEF was incorporated by locally adjusting conductivity of L-type calcium current (g(CaL)) to local external work. In our set-up, g(CaL) could vary up to 25%, 50%, 100% or unlimited amount around its default value. Four consecutive simulations were performed: normal SR (with MEF), acute VP, sustained VP (with MEF), and acutely restored SR. MEF led to T-wave concordance in normal SR and to discordant T-waves acutely after restoring SR. Simulated ECGs with a maximum of 25-50% adaptation closely resembled those during T-wave memory experiments in vivo and also provided the best compromise between optimal systolic and diastolic function. In conclusion, these simulation results indicate that slow acting MEF in the LV can explain a) the relatively small differences in systolic shortening and mechanical work during SR, b) the small dispersion in repolarization time, c) the concordant T-wave during SR, and d) T-wave memory. The physiological distribution in electrophysiological properties, reflected by the concordant T-wave, may serve to optimize cardiac pump function.
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Affiliation(s)
- Evelien Hermeling
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
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22
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Özgen N, Lu Z, Boink GJJ, Lau DH, Shlapakova IN, Bobkov Y, Danilo P, Cohen IS, Rosen MR. Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing. Heart Rhythm 2012; 9:1865-72. [PMID: 22820054 DOI: 10.1016/j.hrthm.2012.07.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Indexed: 01/09/2023]
Abstract
BACKGROUND Left ventricular pacing (LVP) in canine heart alters ventricular activation, leading to reduced transient outward potassium current (I(to)), loss of the epicardial action potential notch, and T-wave vector displacement. These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to I(to), are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in I(to) as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex. OBJECTIVE To test the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R, and I(to) are prevented by blocking subunit trafficking. METHODS We used standard electrophysiological, biophysical, and biochemical methods to study 4 groups of dogs: (1) Sham, (2) 2h LVP, (3) LVP + colchicine (microtubule-disrupting agent), and (4) LVP + losartan (AT1R blocker). RESULTS The T-wave vector displacement was significantly greater in LVP than in Sham and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in KChIP2 and AT1R proteins in the membrane fraction after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes, AngII-induced I(to) reduction and loss of action potential notch were blocked by colchicine. CONCLUSIONS LVP-induced reduction of KChIP2 in plasma light membranes depends on an AngII-mediated pathway and intact microtubular status. Loss of I(to) and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits.
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Affiliation(s)
- Nazira Özgen
- Department of Pharmacology, Columbia University, New York, New York 10032, USA
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Grubb S, Calloe K, Thomsen MB. Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure. Front Physiol 2012; 3:118. [PMID: 22586403 PMCID: PMC3343377 DOI: 10.3389/fphys.2012.00118] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Accepted: 04/11/2012] [Indexed: 01/16/2023] Open
Abstract
Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current (Ito) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a KV4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac Ito, including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2. The interplay between Ito and myocardial calcium handling is pivotal in the development of heart failure, and is further strengthened by the dual role of KChIP2 as a functional subunit on both KV4 and CaV1.2. Moreover, the potential arrhythmogenic consequence of reduced Ito may contribute to the high relative incidence of sudden death in the early phases of human heart failure. With this review, we offer an overview of the insights into the physiological and pathological roles of KChIP2 and we discuss the limitations of translating the molecular basis of electrophysiological remodeling from animal models of heart failure to the clinical setting.
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Affiliation(s)
- Søren Grubb
- Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen Copenhagen, Denmark
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24
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Kuijpers NHL, Hermeling E, Bovendeerd PHM, Delhaas T, Prinzen FW. Modeling cardiac electromechanics and mechanoelectrical coupling in dyssynchronous and failing hearts: insight from adaptive computer models. J Cardiovasc Transl Res 2012; 5:159-69. [PMID: 22271009 PMCID: PMC3294221 DOI: 10.1007/s12265-012-9346-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2011] [Accepted: 01/04/2012] [Indexed: 12/13/2022]
Abstract
Computer models have become more and more a research tool to obtain mechanistic insight in the effects of dyssynchrony and heart failure. Increasing computational power in combination with increasing amounts of experimental and clinical data enables the development of mathematical models that describe electrical and mechanical behavior of the heart. By combining models based on data at the molecular and cellular level with models that describe organ function, so-called multi-scale models are created that describe heart function at different length and time scales. In this review, we describe basic modules that can be identified in multi-scale models of cardiac electromechanics. These modules simulate ionic membrane currents, calcium handling, excitation-contraction coupling, action potential propagation, and cardiac mechanics and hemodynamics. In addition, we discuss adaptive modeling approaches that aim to address long-term effects of diseases and therapy on growth, changes in fiber orientation, ionic membrane currents, and calcium handling. Finally, we discuss the first developments in patient-specific modeling. While current models still have shortcomings, well-chosen applications show promising results on some ultimate goals: understanding mechanisms of dyssynchronous heart failure and tuning pacing strategy to a particular patient, even before starting the therapy.
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Affiliation(s)
- Nico H. L. Kuijpers
- Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands
| | - Evelien Hermeling
- Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands
| | - Peter H. M. Bovendeerd
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Tammo Delhaas
- Department of Biomedical Engineering, Maastricht University, Maastricht, The Netherlands
| | - Frits W. Prinzen
- Department of Physiology, Maastricht University, Maastricht, The Netherlands
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25
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Electrical Remodeling in Dyssynchrony and Resynchronization. J Cardiovasc Transl Res 2012; 5:170-9. [DOI: 10.1007/s12265-012-9348-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Accepted: 01/10/2012] [Indexed: 12/31/2022]
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Bovendeerd PHM. Modeling of cardiac growth and remodeling of myofiber orientation. J Biomech 2011; 45:872-81. [PMID: 22169149 DOI: 10.1016/j.jbiomech.2011.11.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2011] [Indexed: 11/26/2022]
Abstract
The heart has the ability to respond to long-term changes in its environment through changes in mass (growth), shape (morphogenesis) and tissue properties (remodeling). For improved quantitative understanding of cardiac growth and remodeling (G&R) experimental studies need to be complemented by mathematical models. This paper reviews models for cardiac growth and remodeling of myofiber orientation, as induced by mechanical stimuli. A distinction is made between optimization models, that focus on the end stage of G&R, and adaptation models, that aim to more closely describe the mechanistic relation between stimulus and effect. While many models demonstrate qualitatively promising results, a lot of questions remain, e.g. with respect to the choice of the stimulus for G&R or the long-term stability of the outcome of the model. A continued effort combining information on mechanotransduction at the cellular level, experimental observations on G&R at organ level, and testing of hypotheses on stimulus-effect relations in mathematical models is needed to answer these questions on cardiac G&R. Ultimately, models of cardiac G&R seem indispensable for patient-specific modeling, both to reconstruct the actual state of the heart and to assess the long-term effect of potential interventions.
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Affiliation(s)
- Peter H M Bovendeerd
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
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Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications. J Hum Hypertens 2011; 26:563-9. [PMID: 22129612 DOI: 10.1038/jhh.2011.105] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Hypertension is one of the most important risk factors associated with atrial fibrillation (AF) and increased the risk of cardiovascular events in patients with AF. However, the pathophysiological link between hypertension and AF is unclear. Nevertheless, this can be explained by the hemodynamic changes of the left atrium secondary to long standing hypertension, resulting in elevated left atrium pressure and subsequently left atrial enlargement. Moreover, the activation of renin-angiotensin-aldosterone system (RAAS) activation in patients with hypertension induces left atrial fibrosis and conduction block in the left atrium, resulting in the development of AF. Accordingly, recent studies have shown that effective blockage of RAAS by angiotensin converting enzyme inhibitors or angiotensin receptor antagonist may be effective in both primary and secondary prevention of AF in patients with hypertension, although with controversies. In addition, optimal antithrombotic therapy, blood pressure control as well as rate control for AF are key to the management of patients with AF.
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Satin J, Schroder EA, Crump SM. L-type calcium channel auto-regulation of transcription. Cell Calcium 2011; 49:306-13. [PMID: 21295347 PMCID: PMC3097264 DOI: 10.1016/j.ceca.2011.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 01/06/2011] [Accepted: 01/07/2011] [Indexed: 01/24/2023]
Abstract
L-type calcium channels (LTCC) impact the function of nearly all excitable cells. The classical LTCC function is to mediate trans-sarcolemmal Ca(2+) flux. This review focuses on the contribution of a mobile segment of the LTCC that regulates ion channel function, and also serves as a regulator of transcription in the nucleus. Specifically we highlight recent work demonstrating an auto-feedback regulatory pathway whereby the LTCC transcription factor regulates the LTCC. Also discussed is acute and long-term regulation of function by the LTCC-transcription regulator.
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Affiliation(s)
- Jonathan Satin
- Department of Physiology, MS-508, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0298, USA.
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Van de Heyning CM, Moerenhout CM, Vrints CJ. Case report: Chest pain, intermittent left bundle branch block and negative T waves. Int J Cardiol 2011; 147:302-4. [PMID: 21215481 DOI: 10.1016/j.ijcard.2010.12.059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 12/09/2010] [Indexed: 10/18/2022]
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Cutler MJ, Jeyaraj D, Rosenbaum DS. Cardiac electrical remodeling in health and disease. Trends Pharmacol Sci 2011; 32:174-80. [PMID: 21316769 PMCID: PMC3073587 DOI: 10.1016/j.tips.2010.12.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Revised: 11/25/2010] [Accepted: 12/01/2010] [Indexed: 01/12/2023]
Abstract
Electrical remodeling of the heart takes place in response to both functional (altered electrical activation) and structural (including heart failure and myocardial infarction) stressors. These electrophysiological changes produce a substrate that is prone to malignant ventricular arrhythmias. Understanding the cellular and molecular mechanisms of electrical remodeling is important in elucidating potential therapeutic targets designed to alter maladaptive electrical remodeling. For example, altered patterns of electrical activation lead primarily to electrical remodeling, without significant structural remodeling. By contrast, secondary remodeling arises in response to a structural insult. In this article we review cardiac electrical remodeling (predominantly in the ventricle) with an emphasis on the mechanisms causing these adaptations. These mechanisms suggest novel therapeutic targets for the management or prevention of the most devastating manifestation of heart disease, sudden cardiac death (SCD).
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Affiliation(s)
- Michael J Cutler
- The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA
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Kobrinsky E, Duong SQ, Sheydina A, Soldatov NM. Microdomain organization and frequency-dependence of CREB-dependent transcriptional signaling in heart cells. FASEB J 2011; 25:1544-55. [PMID: 21248242 DOI: 10.1096/fj.10-176198] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Voltage-gated Ca(v)1.2 calcium channels couple membrane depolarization to cAMP response-element-binding protein (CREB)-dependent transcriptional activation. To investigate the spatial and temporal organization of CREB-dependent transcriptional nuclear microdomains, we combined perforated patch-clamp technique and FRET microscopy for monitoring CREB and CREB-binding protein interaction in the nuclei of live cells. The experimental approach to the quantitative assessment of CREB-dependent transcriptional signaling evoked by cAMP- and Ca(v)1.2-dependent mechanisms was devised in COS1 cells expressing recombinant Ca(v)1.2 calcium channels. Using continuous 2-dimensional wavelet transform and time series analyses, we found that nuclear CREB-dependent transcriptional signaling is organized differentially in spatially and temporally separated microdomains of 4 distinct types. In rat neonatal cardiomyocytes, CREB-dependent transcription is mediated by the cAMP-initiated CaMKII-sensitive and Ca(v)1.2-initiated CaMKII-insensitive mechanisms. The latter microdomains show a tendency to exhibit periodic behavior correlated with spontaneous contraction of myocytes suggestive of frequency-dependent CREB-dependent transcriptional regulation in the heart.
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Affiliation(s)
- Evgeny Kobrinsky
- National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
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Ozgen N, Lau DH, Shlapakova IN, Sherman W, Feinmark SJ, Danilo P, Rosen MR. Determinants of CREB degradation and KChIP2 gene transcription in cardiac memory. Heart Rhythm 2010; 7:964-70. [PMID: 20346417 PMCID: PMC2904822 DOI: 10.1016/j.hrthm.2010.03.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Accepted: 03/19/2010] [Indexed: 01/12/2023]
Abstract
BACKGROUND Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to) channel accessory subunit, KChIP2. The KChIP2 decrease is attributed to a decrease in its transcription factor, cyclic adenosine monophosphate response element binding protein (CREB). OBJECTIVE This study sought to determine the mechanisms responsible for the CREB decrease that is initiated by LVP. METHODS CM was quantified as T-wave vector displacement in 18 LVP dogs. In 5 dogs, angiotensin II receptor blocker, saralasin, was infused before and during pacing. In 3 dogs, proteasomal inhibitor, lactacystin, was injected into the left anterior descending artery before LVP. Epicardial biopsy samples were taken before and after LVP. Neonatal rat cardiomyocytes (NRCM) were incubated with H(2)O(2) (50 micromol/l) for 1 hour with or without lactacystin. RESULTS LVP significantly displaced the T-wave vector and was associated with increased lipid peroxidation and increased tissue angiotensin II levels. Saralasin prevented T-vector displacement and lipid peroxidation. CREB was significantly decreased after 2 hours of LVP and was comparably decreased in H(2)O(2)-treated NRCM. Lactacystin inhibited the CREB decrease in LVP dogs and H(2)O(2)-treated NRCM. LVP and H(2)O(2) both induced CREB ubiquitination, and the H(2)O(2)-induced CREB decrease was prevented by knocking down ubiquitin. CONCLUSION LVP initiates myocardial angiotensin II production and reactive oxygen species synthesis, leading to CREB ubiquitination and its proteasomal degradation. This sequence of events would explain the pacing-induced reduction in KChIP2, and contribute to altered repolarization and the T-wave changes of cardiac memory.
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Affiliation(s)
- Nazira Ozgen
- Department of Pharmacology, Columbia University, New York, New York 10032, USA.
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Yue-Chun L, Li-Sha G, Xue-Qiang G, Peng C, Lian-Pin W, Peng-Lin Y, Ji-Fei T, Jia-Feng L. Establishment of a canine model of cardiac memory using endocardial pacing via internal jugular vein. BMC Cardiovasc Disord 2010; 10:30. [PMID: 20569432 PMCID: PMC2906410 DOI: 10.1186/1471-2261-10-30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2010] [Accepted: 06/22/2010] [Indexed: 11/20/2022] Open
Abstract
Background Development of experimental animal models has played an important role in understanding the mechanisms of cardiac memory. The purpose of this study was to evaluate a new canine model of cardiac memory using endocardial ventricular pacing via internal jugular vein. Methods Twelve Beagle dogs underwent placement of a permanent ventricular pacemaker mimicking the use of pacemakers in humans and induction of cardiac memory by endocardial ventricular pacing. Results Cardiac memory was achieved in 11 of 12 attempts overall. Procedural mortality due to cardiac tamponade (n = 1) occurred in the first attempt. The T-wave memory persisted for 96 ± 17 minutes and 31 ± 6 days in the short-term and long-term cardiac memory groups, respectively. There were no significant differences in the heart rate, blood pressure and echocardiographic parameters in the animals between before and after ventricular pacing in the short-term and long-term cardiac memory groups. No significant pathologic changes with the light microscopy were found in the present study in all dogs. Conclusion The model does require surgery but is not as invasive as an open-chest model. This canine model can serve as a useful tool for studying mechanisms of cardiac memory.
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Affiliation(s)
- Li Yue-Chun
- Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China.
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Bierhuizen MFA, Vos MA. The molecular labyrinth of electrical remodeling: making sense of cardiac memory. Heart Rhythm 2010; 7:971-2. [PMID: 20382268 DOI: 10.1016/j.hrthm.2010.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Indexed: 12/28/2022]
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Abstract
PURPOSE OF REVIEW We focus on the molecular and cellular basis of excitability, conduction and electrical remodeling in heart failure with dyssynchronous left ventricular contraction (DHF) and its restoration by cardiac resynchronization therapy (CRT) using a canine tachy-pacing heart failure model. RECENT FINDINGS The electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. In human studies and a number of animal models of heart failure, functional downregulation of K currents and alterations in depolarizing Na and Ca currents and transporters are demonstrated. Alterations in intercellular ion channels and extracellular matrix contribute to heterogeneity of APD and conduction slowing. The changes in cellular and tissue function are regionally heterogeneous, particularly in the DHF. Furthermore, beta-adrenergic signaling and modulation of ionic currents is blunted in heart failure. CRT partially reverses the DHF-induced downregulation of K current and improves Na channel gating. CRT significantly improves Ca homeostasis, especially in lateral myocytes, and restores the DHF-induced blunted beta-adrenergic receptor responsiveness. CRT abbreviates DHF-induced prolongation of APD in the lateral myocytes, reduces the left ventricular regional gradient of APD and suppresses development of early afterdepolarizations. SUMMARY CRT partially restores DHF-induced electrophysiological remodeling, abnormal Ca homeostasis, blunted beta-adrenergic responsiveness, and regional heterogeneity of APD, and thus may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improving mechanical performance of the heart.
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Sachdeva G, Kalyanasundaram K, Krishnan J, Chakravarthy VS. Bistable dynamics of cardiac cell models coupled by dynamic gap junctions linked to cardiac memory. BIOLOGICAL CYBERNETICS 2010; 102:109-121. [PMID: 20012545 DOI: 10.1007/s00422-009-0352-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Accepted: 11/16/2009] [Indexed: 05/28/2023]
Abstract
In an earlier study, we suggested that adaptive gap junctions (GJs) might be a basis of cardiac memory, a phenomenon which refers to persistent electrophysiological response of the heart to external pacing. Later, it was also shown that the proposed mechanism of adaptation of GJs is consistent with known electrophysiology of GJs. In the present article, we show that a pair of cardiac cell models coupled by dynamic, voltage-sensitive GJs exhibits bistable behavior under certain conditions. Three kinds of cell pairs are considered: (1) a Noble-Noble cell pair that represents adjacent cells in Purkinje network, (2) a pair of DiFranceso-Noble cells that represents adjacent SA nodal cells, and (3) a model of Noble cell coupled to Luo-Rudy cell model, which represents an interacting pair of a Purkinje fiber and a ventricular myocyte. Bistability is demonstrated in all the three cases. We suggest that this bistability might be an underlying factor behind cardiac memory. Focused analysis of a pair of Noble cell models showed that bistability is obtained only when the properties of GJs "match" with the properties of the pair of cells that is coupled by the GJs. This novel notion of match between GJs and cardiac cell types might give an insight into specialized distributions of various connexin proteins in cardiac tissue.
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Affiliation(s)
- Gairik Sachdeva
- Department of Biotechnology, Indian Institute of Technology, Chennai, India
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Abstract
The following article is a personal reflection on my study of a subject which has long interested me. The subject is the T wave, and especially the T wave changes occurring as a marker of cardiac memory. My interest evolved over coffees that Mauricio Rosenbaum and I used to share at the Hotel Algonquin during his frequent trips from Buenos Aires to New York. There is something about the Algonquin, whose scarred wooden tabletops carry the imprints of Robert Benchley, Dorothy Parker, and the 1920's New York literati, and there was something about Mauricio-clinician-scientist, friend, and raconteur extraordinaire-that made his repeated challenges to me to "look at cardiac memory before you begin losing your own" irresistible. So began my personal voyage into trying to understand the T wave. My guideposts were the experiments of Wilson and Finch,(1) the astute observations of a host of investigators who followed, and Mauricio's iconoclastic insights. The story is far from over...I doubt I'll see the end of it in my lifetime. But if the beauty of discovery is in the voyage, then it has been - for me - a memorable trip.
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Affiliation(s)
- Michael R Rosen
- Department of Pharmacology, Center for Molecular Therapeutics, and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
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Aiba T, Tomaselli GF, Shimizu W. Electrophysiological Remodeling in Heart Failure Dyssynchrony vs. Resynchronization. J Arrhythm 2010. [DOI: 10.1016/s1880-4276(10)80011-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Jeyaraj D, Ashwath M, Rosenbaum DS. Pathophysiology and clinical implications of cardiac memory. PACING AND CLINICAL ELECTROPHYSIOLOGY: PACE 2009; 33:346-52. [PMID: 20025710 DOI: 10.1111/j.1540-8159.2009.02630.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Altering the pattern of activation of the ventricle causes remodeling of the mechanical and electrical properties of the myocardium. The electrical remodeling is evident on the surface electrocardiogram as significant change in T-wave polarity following altered activation; this phenomenon is ascribed to as "T-wave memory" or "cardiac memory." The electrophysiological remodeling following altered activation is characterized by distinct changes in regions proximal (early-activated) versus distal (late-activated) to the site of altered activation. The early-activated region exhibits marked attenuation of epicardial phase 1 notch due to reduced expression of the transient outward potassium current (I(to)). This is attributed to electrotonic changes during altered activation, and angiotensin-mediated regulation of Kv4.3 (the pore-forming alpha subunit responsible for I(to)). The late-activated region exhibits the most significant action potential prolongation due to markedly increased mechanical strain through a mechano-electrical feedback mechanism. Consequently, regionally heterogeneous action potential remodeling occurs following altered activation. This enhances regional repolarization gradients that underlie the electrophysiological basis for T-wave memory. Further, recent clinical studies highlight detrimental consequences of altered activation including worsening mechanical function and increased susceptibility to arrhythmias. Future studies to identify molecular mechanisms that link electrotonic and mechanical strain-induced changes to cellular electrophysiology will provide important insights into the role of altered activation in regulating cardiac repolarization and arrhythmogenesis.
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Affiliation(s)
- Darwin Jeyaraj
- Heart and Vascular Research Center, The Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, USA
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Abstract
l-Type calcium channels (LTCCs) are major contributors to electrical and contractile function of the heart. They regulate action potential duration, enable calcium entry into cardiac myocytes for contraction, and regulate growth-related signaling in the heart. In cardiac development and in mature heart disease, LTCCs are regulated at levels of acute function and transcription. In addition, LTCCs are clinically relevant therapeutic targets for antihypertensive medications. In this review, we discuss LTCC homeostasis whereby cardiac myocytes maintain LTCC expression via a novel transcriptionally regulated pathway that includes a segment of the LTCC that moves between surface membrane and nucleus.
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Affiliation(s)
- Jonathan Satin
- Department of Physiology, MS508 University of Kentucky College of Medicine, Lexington, KY 40536-0298, USA.
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van Deursen C, van Geldorp IE, Rademakers LM, van Hunnik A, Kuiper M, Klersy C, Auricchio A, Prinzen FW. Left Ventricular Endocardial Pacing Improves Resynchronization Therapy in Canine Left Bundle-Branch Hearts. Circ Arrhythm Electrophysiol 2009; 2:580-7. [DOI: 10.1161/circep.108.846022] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Caroline van Deursen
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Irene E. van Geldorp
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Leonard M. Rademakers
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Arne van Hunnik
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Marion Kuiper
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Catherine Klersy
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Angelo Auricchio
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
| | - Frits W. Prinzen
- From the Departments of Physiology and Cardiothoracic Surgery (C.v.D., I.E.v.G., L.M.R., A.H., M.K., F.W.P.), Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands; Biometry and Clinical Epidemiology (C.K.), Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; and Fondazione Cardiocentro Ticino (A.A.), Lugano, Switzerland
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Kooshkabadi M, Whalen P, Yoo D, Langberg J. Stretch-activated receptors mediate cardiac memory. PACING AND CLINICAL ELECTROPHYSIOLOGY: PACE 2009; 32:330-5. [PMID: 19272062 DOI: 10.1111/j.1540-8159.2008.02240.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Cardiac memory refers to long-lasting T-wave changes that follow an episode of altered ventricular activation sequence. Memory-induced alterations in repolarizing ion channel activity have been characterized. However, the mechanism by which changes in activation sequence produce these effects is unknown. We hypothesized that cardiac memory is mediated by the response of stretch-activated receptors (SARs) to a change in mechanical activation sequence. METHODS In anesthetized, closed-chest dogs, coronary sinus leads were used to pace the posterolateral left ventricle (LV) continuously for 1 hour at a rate of 120 bpm. The surface vectorcardiogram was used to quantify cardiac memory by measuring T-wave displacement after pacing. Streptomycin, which has been shown to block SARs, was given at a dose of 4 g intramuscularly 1 hour before experimental LV pacing sessions. T-wave displacement after control sessions of LV pacing in the absence of drug (n = 12) was compared to that produced by pacing after streptomycin administration (n = 10 sessions). RESULTS There was a distinct and consistent cardiac memory seen after 1 hour of LV pacing under control conditions, with T-wave displacement of 1.28 +/- 0.43 mV (P < 0.001 vs baseline). Pretreatment with streptomycin had no direct effect on the electrocardiogram or hemodynamics, but decreased pacing-induced T-wave displacement to 0.50 +/- 0.28 mV (P < 0.001 vs control sessions). CONCLUSIONS Streptomycin, a SAR blocker, dramatically attenuated the development of cardiac memory following epicardial pacing. These data suggest that SARs are a critical link between mechanical sequence of activation and regional modulation of action potential duration that is responsible for cardiac memory.
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Affiliation(s)
- Mohammad Kooshkabadi
- Section of Cardiac Electrophysiology, Emory University, 1342 Clifton Road, Atlanta, GA 30322, USA.
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Shvilkin A, Bojovic B, Vajdic B, Gussak I, Zimetbaum P, Josephson ME. Vectorcardiographic determinants of cardiac memory during normal ventricular activation and continuous ventricular pacing. Heart Rhythm 2009; 6:943-8. [PMID: 19560083 DOI: 10.1016/j.hrthm.2009.03.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2009] [Accepted: 03/13/2009] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cardiac memory (CM) refers to persistent T-wave changes on resumption of normal conduction after a period of abnormal ventricular activation. Traditionally, to observe CM, normal ventricular activation had to be restored, limiting the exploration of this phenomenon in clinical practice. OBJECTIVE This study sought to prove that CM can be detected during continuous aberrant activation and to establish factors affecting its magnitude using a vectorcardiographic technique. METHODS Sixteen nonpacemaker-dependent patients (11 male, age 72 +/- 8 years, mean +/- SD) undergoing pacemaker/internal cardioverter-defibrillator implantation were paced in DDD mode with a short atrioventricular (AV) delay for 7 days to induce CM. Electrocardiograms were acquired during AAI and DDD pacing at a constant rate before and after CM induction. Dower transform-derived vectorcardiograms were reconstructed and analyzed. RESULTS T vector during AAI pacing changed in both magnitude (baseline, 0.26 +/- 0.10 mV; Day 7, 0.39 +/- 0.13 mV, P < .01) and direction aligning with the paced QRS vector (baseline DDD QRS - AAI T angle 125 degrees +/- 36 degrees; Day 7, 39 degrees +/- 21 degrees, P < .01). During DDD pacing, there was no change in T-vector direction, but T amplitude decreased (baseline, 1.06 +/- 0.32 mV; Day 7, 0.71 +/- 0.26 mV, P < .01). CM measured as T-vector peak displacement (TPD) was identical in AAI and DDD mode (TPD 0.46 +/- .0.17 mV and 0.46 +/- 0.17 mV, respectively). Individual CM magnitude correlated with QRS/T-vector amplitude ratio during DDD pacing at baseline (r = 0.90). CONCLUSION CM can be reliably shown during continuous ventricular pacing, expanding its application to situations in which abnormal ventricular activation persists. Its magnitude is determined by the QRS/T-amplitude ratio of the ventricular paced beat.
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Affiliation(s)
- Alexei Shvilkin
- Department of Medicine/Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
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Aiba T, Hesketh GG, Barth AS, Liu T, Daya S, Chakir K, Dimaano VL, Abraham TP, O'Rourke B, Akar FG, Kass DA, Tomaselli GF. Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy. Circulation 2009; 119:1220-30. [PMID: 19237662 PMCID: PMC2703676 DOI: 10.1161/circulationaha.108.794834] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. METHODS AND RESULTS Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K(+) current (I(K1)), delayed rectifier K(+) current (I(K)), and transient outward K(+) current (I(to)) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I(K1) and I(K) but not I(to), consistent with trends in the changes in steady state K(+) channel mRNA and protein levels. DHF reduced the peak inward Ca(2+) current (I(Ca)) density and slowed I(Ca) decay in lateral compared with anterior cells, whereas CRT restored peak I(Ca) amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca(V)1.2 (alpha1C) mRNA or protein expression, but reduced Ca(V)beta2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca(2+) ATPase and increased Na(+)-Ca(2+) exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca(2+) ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. CONCLUSIONS CRT partially restores DHF-induced ion channel remodeling and abnormal Ca(2+) homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.
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Affiliation(s)
- Takeshi Aiba
- Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Abstract
Cardiac memory is a form of electrophysiological remodeling generally considered benign, although it shares transduction pathways with factors that may be pathological, such as angiotensin II and reactive oxygen species. When induced by electrical pacing, memory provides a window into the mechanisms engaged during cardiac device therapy. Emphasis is placed on the complexity of signaling processes occurring downstream to the simple intervention of cardiac pacing and the relationship of resultant ion channel changes to their expression in action potentials and body surface recordings.
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Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study. Ann Biomed Eng 2008; 36:1816-35. [DOI: 10.1007/s10439-008-9559-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Accepted: 08/27/2008] [Indexed: 12/20/2022]
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Xiao L, Coutu P, Villeneuve LR, Tadevosyan A, Maguy A, Le Bouter S, Allen BG, Nattel S. Mechanisms underlying rate-dependent remodeling of transient outward potassium current in canine ventricular myocytes. Circ Res 2008; 103:733-42. [PMID: 18723449 DOI: 10.1161/circresaha.108.171157] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Transient outward K+ current (I to) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiac I(to) and underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37 degrees C) were paced continuously at 1 or 3 Hz for 24 hours. I to was recorded with whole-cell patch clamp. The 3-Hz pacing reduced I to by 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by approximately 30% and approximately 40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca2+ loading with nimodipine or calmodulin inhibition with W-7, A-7, or W-13 eliminated 3-Hz pacing-induced I to downregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II with KN93, or calcineurin with cyclosporin A, also prevented I to downregulation. CaMKII-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced CaMKII activity, with functional significance suggested by acceleration of the Ca2+i transient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na+/Ca2+ exchange and sarcoplasmic reticulum Ca2+-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT prevented I to reduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing. CaMKII inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulates I to expression, with the Ca2+/calmodulin-dependent CaMKII and calcineurin/NFAT systems playing key Ca2+-sensing and signal-transducing roles in rate-dependent I to control.
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Affiliation(s)
- Ling Xiao
- Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
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Sosunov EA, Anyukhovsky EP, Rosen MR. Altered ventricular stretch contributes to initiation of cardiac memory. Heart Rhythm 2008; 5:106-13. [DOI: 10.1016/j.hrthm.2007.09.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Accepted: 09/07/2007] [Indexed: 11/24/2022]
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Lee KT, Chu CS, Lin TH, Yen HW, Voon WC, Sheu SH, Lai WT. Effect of sodium and calcium channel blockers on short-term cardiac memory in humans. Int J Cardiol 2008; 123:94-101. [PMID: 17320222 DOI: 10.1016/j.ijcard.2006.11.151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Revised: 11/10/2006] [Accepted: 11/13/2006] [Indexed: 11/15/2022]
Abstract
BACKGROUND Cardiac memory (CM) can be induced by both short and long period of pacing from the right ventricle. Although several mechanisms have been proposed in animal studies, mechanisms of CM in humans are not well studied. METHODS A total of 46 patients (20 females; mean age 46+/-13 years) with paroxysmal supraventricular tachycardia referred for catheter ablation were enrolled. After catheter ablation, CM was induced by 20 min of pacing from right ventricular apex (RVA). The CM was quantified as the difference of T wave area in each lead between baseline and after RVA pacing. After complete recovery from the induced CM, verapamil (1.5 mg/kg; 0.005 mg/kg/min), lidocaine (1 mg/kg; 2 mg/min), procainamide (10 mg/kg; 4 mg/min), and nitroglycerine (0.6 mg sublingually; 5 microg/min), were given in 14, 10, 12, and 10 patients respectively. The pacing procedure was repeated and the degrees of CM were compared before and after each drug administered. RESULTS The short-term CM was demonstrated by changes in T wave area after RVA pacing in all patients. The degrees of CM were suppressed in patients after verapamil and lidocaine. In contrast, procainamide and nitroglycerin had no significant effect on the degrees of CM expression. CONCLUSIONS The expression of short-term CM can be suppressed by verapamil and lidocaine but not by procainamide and nitroglycerin. The results may suggest that short-term CM in humans can be modulated by calcium dependent process and the functional alternations of sodium and potassium channels.
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Affiliation(s)
- Kun-Tai Lee
- Department of Internal Medicine, College of Medicine, Kaohsiung Medicine University, Kaohsiung, Taiwan
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Darbar D, Hardin B, Harris P, Roden DM. A rate-independent method of assessing QT-RR slope following conversion of atrial fibrillation. J Cardiovasc Electrophysiol 2007; 18:636-41. [PMID: 17488270 DOI: 10.1111/j.1540-8167.2007.00817.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Following conversion of atrial fibrillation (AF), QT interval transiently and variably prolongs and can trigger torsades de pointes (TdP). However, quantitative analysis of risk in this setting is difficult because cycle length variability during AF makes rate-corrected QT impossible to calculate. In this study, a newly developed method to study heart rate dependence of the QT interval during AF was applied to assess the QT-RR relationships prior to and following cardioversion in patients with AF. METHODS AND RESULTS Cardiac rhythm was digitized for > or = 30 minutes prior to and following elective cardioversion to sinus rhythm (SR) in 12 patients. Each QT interval was placed in a "bin" (50 ms), according to the preceding RR interval. All QT intervals within a bin were averaged and RR bin-specific QT values were derived. The slope of the QT-RR relationship was much flatter in AF (0.058 +/- 0.02) compared with that predicted by conventionally used QT rate corrections (0.130 [Bazett], 0.096 [Fridericia]) and much steeper after cardioversion (0.238 +/- 0.14, P < 0.01 compared with AF). The method also allowed us to establish that QT at any given RR interval prolonged when SR was restored (e.g., at RR interval 800 ms: QT = 0.38 +/- 0.03 second [AF] vs 0.46 +/- 0.05 second [SR], P < 0.01). The longest QT values were in patients receiving sotalol or quinidine. CONCLUSIONS The results of this study demonstrate that QT interval can be reliably measured in AF using a method that is independent of heart rate. We also showed that cardioversion of AF acutely increases the QT interval and the steepness of the QT-RR slope.
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Affiliation(s)
- Dawood Darbar
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenneessee 37323-6602, USA.
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