scholarly journals Impaired Right Ventricular Calcium Cycling Is an Early Risk Factor in R14del-Phospholamban Arrhythmias

2021 ◽  
Vol 11 (6) ◽  
pp. 502
Author(s):  
Kobra Haghighi ◽  
George Gardner ◽  
Elizabeth Vafiadaki ◽  
Mohit Kumar ◽  
Lisa C. Green ◽  
...  
Keyword(s):  
Ventricular Tachyarrhythmia ◽  
Regulatory Protein ◽  
Altered Expression ◽  
Endogenous Gene ◽  
Improve Risk Stratification ◽  
Ventricular Activation ◽  
The Right ◽  
Malignant Ventricular Arrhythmia ◽  
Early Risk Factor ◽  
Human Wild Type

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset.

scholarly journals Comparing Ventricular Synchrony in Left Bundle Branch and Left Ventricular Septal Pacing in Pacemaker Patients

2021 ◽  
Vol 10 (4) ◽  
pp. 822
Author(s):  
Luuk I.B. Heckman ◽  
Justin G.L.M. Luermans ◽  
Karol Curila ◽  
Antonius M.W. Van Stipdonk ◽  
Sjoerd Westra ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Activation Time ◽  
Ventricular Synchrony ◽  
Septal Pacing ◽  
Ventricular Activation ◽  
Qrs Morphology ◽  
Conversion Matrix ◽  
Qrs Duration ◽  
The Right ◽  
Electrophysiological Effects

Background: Left bundle branch area pacing (LBBAP) has recently been introduced as a novel physiological pacing strategy. Within LBBAP, distinction is made between left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP, no left bundle capture). Objective: To investigate acute electrophysiological effects of LBBP and LVSP as compared to intrinsic ventricular conduction. Methods: Fifty patients with normal cardiac function and pacemaker indication for bradycardia underwent LBBAP. Electrocardiography (ECG) characteristics were evaluated during pacing at various depths within the septum: starting at the right ventricular (RV) side of the septum: the last position with QS morphology, the first position with r’ morphology, LVSP and—in patients where left bundle branch (LBB) capture was achieved—LBBP. From the ECG’s QRS duration and QRS morphology in lead V1, the stimulus- left ventricular activation time left ventricular activation time (LVAT) interval were measured. After conversion of the ECG into vectorcardiogram (VCG) (Kors conversion matrix), QRS area and QRS vector in transverse plane (Azimuth) were determined. Results: QRS area significantly decreased from 82 ± 29 µVs during RV septal pacing (RVSP) to 46 ± 12 µVs during LVSP. In the subgroup where LBB capture was achieved (n = 31), QRS area significantly decreased from 46 ± 17 µVs during LVSP to 38 ± 15 µVs during LBBP, while LVAT was not significantly different between LVSP and LBBP. In patients with normal ventricular activation and narrow QRS, QRS area during LBBP was not significantly different from that during intrinsic activation (37 ± 16 vs. 35 ± 19 µVs, respectively). The Azimuth significantly changed from RVSP (−46 ± 33°) to LVSP (19 ± 16°) and LBBP (−22 ± 14°). The Azimuth during both LVSP and LBBP were not significantly different from normal ventricular activation. QRS area and LVAT correlated moderately (Spearman’s R = 0.58). Conclusions: ECG and VCG indices demonstrate that both LVSP and LBBP improve ventricular dyssynchrony considerably as compared to RVSP, to values close to normal ventricular activation. LBBP seems to result in a small, but significant, improvement in ventricular synchrony as compared to LVSP.

scholarly journals Glia maturation factor-γ regulates murine macrophage iron metabolism and M2 polarization through mitochondrial ROS

2019 ◽  
Vol 3 (8) ◽  
pp. 1211-1225 ◽  
Author(s):  
Wulin Aerbajinai ◽  
Manik C. Ghosh ◽  
Jie Liu ◽  
Chutima Kumkhaek ◽  
Jianqing Zhu ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Mitochondrial Function ◽  
Regulatory Protein ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Glia Maturation Factor ◽  
Altered Expression ◽  
Murine Macrophages ◽  
Cellular Iron ◽  
Maturation Factor

Abstract In macrophages, cellular iron metabolism status is tightly integrated with macrophage phenotype and associated with mitochondrial function. However, how molecular events regulate mitochondrial activity to integrate regulation of iron metabolism and macrophage phenotype remains unclear. Here, we explored the important role of the actin-regulatory protein glia maturation factor-γ (GMFG) in the regulation of cellular iron metabolism and macrophage phenotype. We found that GMFG was downregulated in murine macrophages by exposure to iron and hydrogen peroxide. GMFG knockdown altered the expression of iron metabolism proteins and increased iron levels in murine macrophages and concomitantly promoted their polarization toward an anti-inflammatory M2 phenotype. GMFG-knockdown macrophages exhibited moderately increased levels of mitochondrial reactive oxygen species (mtROS), which were accompanied by decreased expression of some mitochondrial respiration chain components, including the iron-sulfur cluster assembly scaffold protein ISCU as well as the antioxidant enzymes SOD1 and SOD2. Importantly, treatment of GMFG-knockdown macrophages with the antioxidant N-acetylcysteine reversed the altered expression of iron metabolism proteins and significantly inhibited the enhanced gene expression of M2 macrophage markers, suggesting that mtROS is mechanistically linked to cellular iron metabolism and macrophage phenotype. Finally, GMFG interacted with the mitochondrial membrane ATPase ATAD3A, suggesting that GMFG knockdown–induced mtROS production might be attributed to alteration of mitochondrial function in macrophages. Our findings suggest that GMFG is an important regulator in cellular iron metabolism and macrophage phenotype and could be a novel therapeutic target for modulating macrophage function in immune and metabolic disorders.

Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control

2021 ◽  
Author(s):  
Joseph Hadaya ◽  
Una Buckley ◽  
Nil Z. Gurel ◽  
Christopher A. Chan ◽  
Mohammed A Swid ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Therapeutic Potential ◽  
Distal Portion ◽  
Left Ventricular ◽  
Sympathetic Chain ◽  
Strong Correlations ◽  
Norepinephrine Release ◽  
Ventricular Activation ◽  
Current Block ◽  
The Right

Maladaptation of the sympathetic nervous system contributes to the progression of cardiovascular disease and risk for sudden cardiac death, the leading cause of mortality worldwide. Axonal modulation therapy (AMT) directed at the paravertebral chain blocks sympathetic efferent outflow to the heart, and may be a promising strategy to mitigate excess disease-associated sympathoexcitation. The present work evaluates AMT, directed at the sympathetic chain, in blocking sympathoexcitation using a porcine model. In anesthetized porcine (n=14), we applied AMT to the right T1-T2 paravertebral chain and performed electrical stimulation of the distal portion of the right sympathetic chain (RSS). RSS-evoked changes in heart rate, contractility, ventricular activation recovery interval (ARI), and norepinephrine release were examined with and without kilohertz frequency alternating current block (KHFAC). To evaluate efficacy of AMT in the setting of sympathectomy, evaluations were performed in the intact state and repeated after left and bilateral sympathectomy. We found strong correlations between AMT intensity and block of sympathetic stimulation-evoked changes in cardiac electrical and mechanical indices (r=0.83-0.96, effect size d=1.9-5.7), as well as evidence of sustainability and memory. AMT significantly reduced RSS-evoked left ventricular interstitial norepinephrine release, as well as coronary sinus norepinephrine levels. Moreover, AMT remained efficacious following removal of the left sympathetic chain, with similar mitigation of evoked cardiac changes and reduction of catecholamine release. With growth of neuromodulation, an on-demand or reactionary system for reversible AMT may have therapeutic potential for cardiovascular disease-associated sympathoexcitation.

scholarly journals Stretch–excitation correlation in the toad heart

2020 ◽  
Vol 223 (23) ◽  
pp. jeb228882
Author(s):  
Vladimir A. Vityazev ◽  
Jan E. Azarov
Keyword(s):  
Bolus Injection ◽  
Ventricular Myocardium ◽  
Bufo Bufo ◽  
Interquartile Range ◽  
Video Recordings ◽  
Ventricular Activation ◽  
Potential Mapping ◽  
Activation Times ◽  
The Right ◽  
Activation Sequence

ABSTRACTThe activation sequence of the ventricular myocardium in ectotherms is a matter of debate. We studied the correlation between the ventricular activation sequence and the pattern of local stretches in 13 toads (Bufo bufo). Epicardial potential mapping was done with a 56-lead sock array. Activation times were determined as dV/dt (min) in each lead. Initial epicardial foci of activation were found on the left side of the ventricular base, whereas regions on the apex and the right side of the base demonstrated late activation. Video recordings (50 frames s−1) showed that the median presystolic stretch in left-side ventricular regions was greater than that in right-side regions [4.70% (interquartile range 3.25–8.85%) versus 1.45% (interquartile range 0.38–3.05%), P=0.028, respectively]. Intracardiac bolus injection elicited ventricular activation with a similar sequence and duration. Thus, ventricular areas of earliest activation were associated with greater presystolic stretch, implying the existence of a stretch–excitation relationship in ectotherm hearts.

Ventricular activation process and genesis of QRS complex in the goat

1961 ◽  
Vol 200 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Robert L. Hamlin ◽  
Allen M. Scher
Keyword(s):  
Interventricular Septum ◽  
Left Ventricular ◽  
Left Ventricular Cavity ◽  
Activation Process ◽  
Qrs Complex ◽  
Complex Activity ◽  
Single Burst ◽  
Ventricular Activation ◽  
The Right ◽  
Apical Area

The pathways of ventricular excitation in the interventricular septum and the free walls of the ventricles were determined in the goat. During the first 5 msec. of the QRS complex, activity occurs in a cup-shaped zone formed around the apex of the left ventricular cavity, consisting of the left endocardial portions of the septum and the endocardium of the free wall. Within the next 10 msec. of the QRS, the apical third of the septum is excited, simultaneously, from both the left and the right ventricular endocardial surfaces. Also, all of the ventricles, except the bases and a small epicardial apical area of the left ventricle, are excited with almost a single burst of depolarization. During the next 3–5 msec. the ventricular bases and the small apical epicardial area are excited along with the middle third of the interventricular septum. The final 15 msec. of the QRS and approximately 3 msec. of the following isoelectric period are inscribed during activation of the basilar third of the septum.

scholarly journals MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension

2013 ◽  
Vol 304 (2) ◽  
pp. H269-H281 ◽  
Author(s):  
R. Dale Brown ◽  
S. Kelly Ambler ◽  
Min Li ◽  
Timothy M. Sullivan ◽  
Lauren N. Henry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Cardiac Myocyte ◽  
Chronic Hypoxia ◽  
Regulatory Protein ◽  
Right Heart Failure ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
The Right

Pulmonary hypertension (PH) results in pressure overload of the right ventricle (RV) of the heart, initiating pathological RV remodeling and ultimately leading to right heart failure. Substantial research indicates that signaling through the MAPK superfamily mediates pathological cardiac remodeling. These considerations led us to test the hypothesis that the regulatory protein MAPKKK-2 (MEKK2) contributes to RV hypertrophy in hypoxia-induced PH. Transgenic mice with global knockout of MEKK2 (MEKK2−/− mice) and age-matched wild-type (WT) mice were exposed to chronic hypobaric hypoxia (10% O2, 6 wk) and compared with animals under normoxia. Exposure to chronic hypoxia induced PH in WT and MEKK2−/− mice. In response to PH, WT mice showed RV hypertrophy, demonstrated as increased ratio of RV weight to body weight, increased RV wall thickness at diastole, and increased cardiac myocyte size compared with normoxic control animals. In contrast, each of these measures of RV hypertrophy seen in WT mice after chronic hypoxia was attenuated in MEKK2−/− mice. Furthermore, chronic hypoxia elicited altered programs of hypertrophic and inflammatory gene expression consistent with pathological RV remodeling in WT mice; MEKK2 deletion selectively inhibited inflammatory gene expression compared with WT mice. The actions of MEKK2 were mediated in part through regulation of the abundance and phosphorylation of its effector, ERK5. In conclusion, signaling by MEKK2 contributes to RV hypertrophy and altered myocardial inflammatory gene expression in response to hypoxia-induced PH. Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathological remodeling in human PH.

Brief vagal stimuli and AV conduction in dogs: effects on retrograde exceed antegrade

1989 ◽  
Vol 257 (3) ◽  
pp. H812-H817
Author(s):  
P. J. Martin
Keyword(s):  
Right Atrium ◽  
Cardiac Cycle ◽  
Peak Amplitude ◽  
Pentobarbital Sodium ◽  
Av Conduction ◽  
Ventricular Activation ◽  
Computer Controlled ◽  
Atrial Activation ◽  
The Right ◽  
Composite Data

We opened the chests of 20 mongrel dogs (16–28 kg) that were anesthetized with pentobarbital sodium (22 mg/kg), given propranolol (1 mg/kg), and bipolar catheters placed into the right atrium and ventricle. We crushed the sinoatrial (SA) node and paced the heart to produce either an antegrade (A-V) or a retrograde (V-A) conduction (where A is atrial activation and V is ventricular activation). Both cervical vagosympathetic trunks were ligated and connected to electrodes that were driven by a computer-controlled, isolated stimulators. Three brief vagal stimulus bursts (at the same intensity but at different times in the cardiac cycle) were given at least 1 min apart, the pacing site was changed, and the identical three-stimulus bursts were again applied. This procedure was continued until the phase of the stimulus had scanned the entire cardiac cycle. Forty-four sets of vagal effect curves were generated. The composite data indicate that brief vagal stimuli have about twice the effect on the peak amplitude of the change in retrograde than in antegrade AV nodal conduction in the dog. Unexpectedly, the duration of the parasympathetic effect is also considerably greater (approximately 40%) and the decay is slower (approximately 48%) for retrograde than for antegrade conduction, even when the vagal effect curves have been normalized to the same amplitude. This latter result suggests that some factor other than diffusion and inactivation of ACh determines the duration of the A-V conduction response to a brief vagal stimulus.

scholarly journals Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia

2013 ◽  
Vol 305 (7) ◽  
pp. H1020-H1030 ◽  
Author(s):  
Marmar Vaseghi ◽  
Kentaro Yamakawa ◽  
Arjun Sinha ◽  
Eileen L. So ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Wave Vector ◽  
Ventricular Tachyarrhythmia ◽  
Stellate Ganglion ◽  
Posterior Wall ◽  
Left Ventricular ◽  
T Wave ◽  
Dispersion Of Repolarization ◽  
Stellate Ganglia ◽  
The Right ◽  
Vector Shift

Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals ( R2 = 0.92 LSGS; and R2 = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall ( P < 0.01) and on the apex versus base ( P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls ( P < 0.01) and on base versus apex ( P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.

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