Ventricular Electrophysiological Properties Research Articles

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapytargeting LMCG represented a promising strategy for the treatment of AMI.

Endurance training increases ventricular refractoriness and wavelength of the cardiac impulse without participation of parasympathetic postganglionic neurons. A study in isolated rabbit heart

Abstract Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p<0.05). Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

Regional modulation of action potential duration and arrhythmias by ß1- and ß2-adrenergic receptor stimulation in the porcine right ventricle

The right ventricular outflow tract (RVOT) is the main origin of idiopathic ventricular tachycardia (IVTs). Sympathetic stimulation is involved in IVTs but mechanisms underlying this preferential origin remain unknown. To determine the role of ß1- and ß2-adrenergic receptors (ß1-AR, ß2-AR) in the regional modulation of right ventricular (RV) electrophysiological properties and arrhythmias. Porcine RVs were isolated and perfused via both right and left coronary arteries. Epicardial (EPI) electrical activity was optically mapped (di-4-ANEPPS 20 μM) and APD measured at 80% repolarization (APD80) in the RVOT and posterior RV free wall region (RVFW). Regional mRNA and protein expression for ß1-AR and ß2-AR was determined respectively by RT-PCR and Western-Blot. Combined ß1- and ß2-AR stimulation (50 nM isoprenaline, ISO) shortened APD80 EPI with a larger effect in the RVFW than the RVOT. Interestingly, isolated ß2-AR stimulation (10–25 μM salbutamol, SALBU with 4 μM metoprolol, METO) only decreased APD80 significantly in the RVOT EPI ( P < 0.05). ß2-AR stimulation did not affect APD80 in the RVOT endocardium leading to a larger transmural APD gradient in this region ( P < 0.01). ß1-AR expression was lower in the RVOT than in the RVFW EPI at the mRNA and protein levels. Conversely, ß2-AR protein expression was greater in the RVOT EPI ( P < 0.05). ISO (1.8 nM–1 μM) led to a significant increase in spontaneous arrhythmias while isolated ß2-AR did not (SALBU 10–50 μM). At higher concentrations (500nM-1 μM) ISO triggered VT episodes that originated from the RVOT or the anterior RV. ß2-AR blockade (ICI 118,551 100 nM) accelerated while ß1-AR blocker METO (4 μM) slowed or abolished VT. Conlcusion These results suggest a ß2-AR specific regulation of RVOT electrophysiology but its role in the triggering of arrhythmias in this region requires further studies.

Identification of IRX5 transcription factor regulatory mechanisms in human cardiomyocyte function

In the heart, several transcription factors (TF) are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles of TF in physiological functions. Several studies on animal models have shown that the Iroquois homeobox (Irx) TFs are key patterning and differentiation regulators that confer cell type-specific properties to specialized cardiac lineages. Importantly, studies in mice have shown that IRX5 is expressed very early during cardiogenesis and maintained in adult heart where it regulates ventricular electrophysiological properties, the repolarizing gradient. It has also been shown that IRX5 target-genes regulation occurs through recruitment of histone modifiers. In order to study IRX5 in human, we used cardiomyocytes differentiated from induced pluripotent stem cells (hiPS-CMs) generated from patients carrying loss of function mutations in IRX5 (IRX5Mut) and control individuals. As we detected IRX5 protein as early as in the pluripotent state, we also analyzed cells at hiPS stage in our experiments. High-throughput transcriptomic and epigenetic analyses were performed to obtain a global understanding of IRX5 function. The transcriptomic experiments allowed us to determine the entire set of differentially expressed genes in hiPS and hiPS-CMs IRX5Mut cells as compared to control cells. The epigenetic experiments, performed by ChIPseq, suggested that IRX5 binds to already open chromatin, and preferentially, to enhancer rich regions rather than proximal promoters. Combining these high-throughput experiments, we found direct target genes of IRX5 at hiPS-CM stage, and some of them are relevant to cardiac function. Notably, we showed that this TF regulates the expression of several actors of electrical conduction, such as SCN5A, at hiPS-CM stage. IRX5 seems to be an important factor for the regulation of human cardiac function, and more specifically of its electrical function.

The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts

BackgroundIt is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. ObjectiveThis study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. Methods24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. ResultsCompared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. ConclusionIL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability.

Transcutaneous stimulation of the auricular branch of the vagus nerve (AB-VNS) is a potentially noninvasive, inexpensive, and safe approach for vagus nerve stimulation that suppresses the induction and duration of atrial fibrillation and reduces sympathetic nerve outflow in healthy humans. Researchers have not determined whether AB-VNS affects ventricular arrhythmias. To evaluate the antiarrhythmic effects of noninvasive AB-VNS on ventricular arrhythmias induced by myocardial infarction (MI). Twelve beagle dogs were randomly divided into the following two groups: a AB-VNS group (coronary artery occlusion and noninvasive AB-VNS) and a control group (coronary artery occlusion but without AB-VNS). We examined spontaneous ventricular arrhythmias, ventricular electrophysiological properties, and cardiac function in conscious dogs. Morphology, fibrosis, and ultrastructures were also assessed. AB-VNS significantly reduced the occurrence of spontaneous ventricular arrhythmias, including isolated premature ventricular complexes, ventricular couplets, ventricular bigeminy, ventricular trigeminy, and ventricular tachycardia. AB-VNS effectively increased ventricular electrical stability, including significantly prolonged ventricular effective refractory periods, decreased the dispersion of effective refractory period, enhanced the ventricular fibrillation threshold, and decreased the maximum slope of the monophasic action potential duration restitution curve. AB-VNS treatments alleviate ventricular interstitial fibrosis after MI. However, cardiac function was not improved, and MI-induced ultrastructural changes in the myocardium were not reversed by 4weeks of AB-VNS. In addition, AB-VNS for 4weeks resulted in mild mitochondrial swelling within the neuronal axons of the auricular vagus fiber. Noninvasive AB-VNS reduces the occurrence of spontaneous ventricular arrhythmias in conscious dogs with MI. AB-VNS increases ventricular electrical stability and alleviates ventricular interstitial fibrosis induced by MI.

The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart.

A large body of work has established the prominent roles of the atrial M2R-IKACh signaling pathway, and the negative regulatory protein RGS6, in modulating critical aspects of parasympathetic influence on cardiac function, including pace-making, heart rate (HR) variability (HRV), and atrial arrhythmogenesis. Despite increasing evidence of its innervation of the ventricles, and the expression of M2R, IKACh channel subunits, and RGS6 in ventricle, the effects of parasympathetic modulation on ventricular electrophysiology are less clear. The main objective of our study was to investigate the contribution of M2R-IKACh signaling pathway elements in murine ventricular electrophysiology, using in-vivo ECG measurements, isolated whole-heart optical mapping and constitutive knockout mice lacking IKACh (Girk4–/–) or RGS6 (Rgs6-/-). Consistent with previous findings, mice lacking GIRK4 exhibited diminished HR and HRV responses to the cholinergic agonist carbachol (CCh), and resistance to CCh-induced arrhythmic episodes. In line with its role as a negative regulator of atrial M2R-IKACh signaling, loss of RGS6 correlated with a mild resting bradycardia, enhanced HR and HRV responses to CCh, and increased propensity for arrhythmic episodes. Interestingly, ventricles from mice lacking GIRK4 or RGS6 both exhibited increased action potential duration (APD) at baseline, and APD was prolonged by CCh across all genotypes. Similarly, CCh significantly increased the slope of APD restitution in all genotypes. There was no impact of genotype or CCh on either conduction velocity or heterogeneity. Our data suggests that altered parasympathetic signaling through the M2R-IKACh pathway can affect ventricular electrophysiological properties distinct from its influence on atrial physiology.

Antifibrillatory effects of renal denervation on ventricular fibrillation in a canine model of pacing-induced heart failure.

What is the central question of this study? In the present study, we investigated the effects of renal denervation on the vulnerability to ventricular fibrillation and the ventricular electrical properties in a rapid pacing-induced heart failure canine model. What is the main finding and its importance? Renal denervation significantly attenuated the process of heart failure and improved left ventricular systolic dysfunction, stabilized ventricular electrophysiological properties and decreased the vulnerability of the heart to ventricular fibrillation during heart failure. Thus, renal denervation can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action in a pacing-induced heart failure canine model. In this study, we investigated the effects of renal denervation (RDN) on the vulnerability to ventricular fibrillation (VF) and the ventricular electrical properties in a canine model of pacing-induced heart failure (HF). Eighteen beagles were divided into the following three groups: control (n=6), HF (n=6) and HF+RDN (n=6). Heart failure was induced by rapid right ventricular pacing. Renal denervation was performed simultaneously with the pacemaker implantation in the HF+RDN group. A 64-unipolar basket catheter was used to perform global endocardial mapping of the left ventricle. The restitution properties and dispersion of refractoriness were estimated from the activation recovery intervals (ARIs) by a pacing protocol. The VF threshold (VFT) was defined as the maximal pacing cycle length required to induce VF using a specific pacing protocol. The defibrillation threshold (DFT) was measured by an up-down algorithm. Renal denervation partly restored left ventricular systolic function and attenuated the process of HF. Compared with the control group, the VFT in the HF group was decreased by 27% (106±8.0 versus 135±10ms, P<0.01). However, RDN increased the VFT by 13% (135±10 versus 118±7.5ms, P<0.05) and decreased the DFT by 27% (30±6.3 versus 21.8±4.7J, P<0.05) in the treated hearts compared with the failing hearts. Renal denervation significantly flattened the ventricular ARI restitution curve by 15% (1.48±0.2 versus 1.26±0.11, P<0.05) and decreased the dispersion of ARI by 25% (0.08±0.02 versus 0.06±0.01, P<0.01) in the treated group compared with the HF group. The findings of this study suggest that RDN can attenuate ventricular electrical remodelling and exert a potential antifibrillatory action on VF in a canine model of pacing-induced HF.

GW28-e0744 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in normal canine heart

GW28-e0744 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in normal canine heart

GW28-e0744 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in normal canine heart

GW28-e0744 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in normal canine heart

GW27-e0356 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in acute myocardial ischemia-reperfusion injury canines

GW27-e0356 Effects of low-level vagus nerve stimulation on ventricular electrophysiological properties in acute myocardial ischemia-reperfusion injury canines

Sympathetic denervation of heart and kidney induces similar effects on ventricular electrophysiological properties.

We aimed to investigate whether sympathetic denervation of the heart and kidney had similar effects on ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties in a canine model. Twenty-four anaesthetised open-chest dogs (17-20 kg) were assigned to a sham operation group (n=8), a cardiac sympathetic denervation group (CSD, n=8) or a renal sympathetic denervation group (RSD, n=8). CSD was performed by ablating the caudal half of the LSG and T2-T4 thoracic sympathetic ganglia, while RSD was performed by ablating four sites on the adventitial surface of each renal artery. The ventricular electrophysiological properties were determined at four time points: baseline, 0 min, 30 min, and 60 min after interventions. The results showed that, when compared to the control group at the time point of 60 min after interventions, both CSD and RSD significantly reduced heart rate, prolonged the QT interval and ventricular ERP and APD, decreased the ERP dispersion and the slopes of APD restitution curves, and suppressed the APD alternans without affecting blood pressure and corrected QT interval. However, there were no significant differences in these parameters between CSD and RSD groups at the same time point. This study showed that sympathetic denervation of the heart and kidney induced similar electrophysiological effects in ventricles.

Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

: Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone.

Renal sympathetic denervation modulates ventricular electrophysiology and has a protective effect on ischaemia-induced ventricular arrhythmia.

Recently, a beneficial effect of renal sympathetic denervation (RSD) has been seen in patients with ventricular electrical storm. However, the effect of RSD on ventricular electrophysiology remains unclear. Thirty-three mongrel dogs were included in the present study. Renal sympathetic denervation was performed by radiofrequency ablation of the adventitial surface of the renal artery. In group1 (n=8), programmed stimulation was performed before and after RSD to determine the ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties. The same parameters were measured in five other animals that underwent sham RSD to serve as controls. In group2 (n=10), acute myocardial ischaemia (AMI) was induced by ligating the proximal left anterior descending coronary artery after the performance of RSD, and the incidence of ventricular arrhythmia (VA) was calculated during 1h of recording. In another 10 dogs (group3), AMI was induced and VA was measured with sham RSD. In group1, RSD significantly prolonged ventricular ERP and APD, reduced the maximal slope (Smax) of the restitution curve and suppressed APD alternans at each site. Renal sympathetic denervation also significantly decreased the spatial dispersion of ERP, APD and Smax. In the five control animals, no significant electrophysiological change was detected after sham RSD. The occurrence of spontaneous VA during 1h of AMI in group2 was significantly lower than that in group3. These data suggest that RSD stabilizes ventricular electrophysiological properties in normal hearts and reduces the occurrence of VA in hearts experiencing AMI.

Mesenchymal Stem Cells Enhanced Cardiac Nerve Sprouting via Nerve Growth Factor in a Rat Model of Myocardial Infarction

Transplantation of mesenchymal stem cells (MSCs) alters the ventricular electrophysiologic properties after myocardial infarction (MI) in rats. However, it is unclear whether MSCs transplantation enhances the secretion of nerve growth factor (NGF) and affects cardiac sympathetic remodeling. MI was induced in 35 male Sprague-Dawley rats. Two weeks later, the animals were randomized to MSCs or phosphate buffer solution (PBS) injections into the infarcted myocardium. Six weeks thereafter, the expressions of NGF, growth associated protein 43 (GAP43) and tyrosine hydroxylase (TH) were measured and the density of GAP43 and TH positive nerves was calculated in the borderzone. NGF levels were detected in different culture conditions with neonatal rat ventricular myocytes (NRVMs, 2 × 10(5)/well) and MSCs (2 × 10(5)/well). Compared with PBS, mRNA expression and protein levels of NGF, GAP43 and TH increased in the border zone after MSCs injection. Immunohistochemistry showed more GAP43- and TH-positive nerves in the MSCs than in the PBS group. Compared to monocultured MSCs, mono-cultured NRVMs secreted more NGF in vitro. The expression of NGF increased after MSCs transplantation, which may affect sympathetic remodeling and the electrophysiological properties after MI. Paracrine factors secreted by MSC-CM may be involved in this process.

Effects of low-intensity atrial ganglionated plexi stimulation on ventricular electrophysiology and arrhythmogenesis

Atrial ganglionated plexi (GP) have been shown to modulate sinus rate, atrioventricular conduction and atrial electrophysiology. The aim of this study was to investigate the effect of low-intensity GP stimulation (GPS) on ventricular electrophysiological properties in normal heart and on ventricular arrhythmogenesis after acute myocardial ischemia (AMI) in canine. Thirty-nine dogs were assigned into the normal heart group (n=12) and the acute myocardial ischemia (AMI) group (n=27, 12 in control and 15 in low-intensity GPS). In the normal heart group, ventricular effective refractory period (ERP), dynamic restitution and electrical alternans were measured at baseline and after 6-hour low-intensity GPS. In the AMI group, the incidence of ventricular arrhythmias was determined during 1-hour recording after AMI was induced. In the normal heart, 6-hour low-intensity GPS significantly prolonged ventricular ERP and action potential duration (APD) at each site (all P<0.05) but did not change their spatial dispersions when compared with baseline. Low-intensity GPS also caused an upward shift of ventricular restitution curves in each site but did not change the slope of restitution curves. APD alternans after low-intensity GPS occurred at longer pacing cycle length at each site when compared with baseline (all P<0.05). In the AMI heart, the incidence of ventricular arrhythmias in low-intensity GPS group was significantly lower than that in control group (P<0.05). Low-intensity GPS induces no increase in the risk of ventricular arrhythmias in the normal heart as well as protects against ventricular arrhythmogenesis during AMI.

Effects of ganglionated plexi ablation on ventricular electrophysiological properties in normal hearts and after acute myocardial ischemia

BackgroundGanglionated plexi (GP) ablation has been shown to play an important role in atrial fibrillation (AF) initiation and maintenance. Also, GP ablation increases chances for prevention of AF recurrence. This study investigated the effects of GP ablation on ventricular electrophysiological properties in normal dog hearts and after acute myocardial ischemia (AMI). MethodsFifty anesthetized dogs were assigned into normal heart group (n=16) and AMI heart group (n=34). Ventricular dynamic restitution, effective refractory period (ERP), electrical alternans and ventricular fibrillation threshold (VFT) were measured before and after GP ablation in the normal heart group. In the AMI heart group, the incidence of ventricular arrhythmias and VFT were determined. ResultsIn the normal heart group, GP ablation significantly prolonged ERP, facilitated electrical alternans but did not increase ERP dispersion, the slope of restitution curves and its spatial dispersion. Also, GP ablation did not cause significant change of VFT. In the AMI heart group, the incidence of ventricular arrhythmias after GP ablation was significantly higher than that in the control group or the GP plus stellate ganglion (SG) ablation group (P<0.05). Spontaneous VF occurred in 8/12, 1/10 and 2/12 dogs in the GP ablation group, the GP plus SG ablation group and the control group, respectively (P<0.05). VFT in the GP ablation group showed a decreased trend though a significant difference was not achieved compared with the control or the GP plus SG ablation group. ConclusionsGP ablation increases the risk of ventricular arrhythmias in the AMI heart compared to the normal heart.

Cardiac conduction disturbances and differential effects on atrial and ventricular electrophysiological properties in desmin deficient mice

Desmin mutations in humans cause desmin-related cardiomyopathy, resulting in heart failure, atrial and ventricular arrhythmias, and sudden cardiac death. The intermediate filament desmin is strongly expressed in striated muscle cells and in Purkinje fibers of the ventricular conduction system. The aim of the present study was to characterize electrophysiological cardiac properties in a desmin-deficient mouse model. The impact of desmin deficiency on cardiac electrophysiological characteristics was examined in the present study. In vivo electrophysiological studies were carried out in 29 adult desmin deficient (Des-/-) and 19 wild-type (Des+/+) mice. Additionally, epicardial activation mapping was performed in Langendorff-perfused hearts. Intracardiac electrograms showed no significant differences in AV, AH, and HV intervals. Functional testing revealed equal AV-nodal refractory periods, sinus-node recovery times, and Wenckebach points. However, compared to the wild-type situation, Des-/- mice were found to have a significantly reduced atrial (23.6+/-10.3 ms vs. 31.8+/-12.5 ms; p=0.045), but prolonged ventricular refractory period (33.0+/-8.7 ms vs. 26.7+/-6.5 ms; p=0.009). The probability of induction of atrial fibrillation was significantly higher in Des-/- mice (Des-/-: 38% vs. Des+/+: 27%; p=0.0255), while ventricular tachycardias significantly were reduced (Des-/-: 7% vs. Des+/+: 21%; p<0.0001). Epicardial activation mapping showed slowing of conduction in the ventricles of Des-/- mice. Des-/- mice exhibit reduced atrial but prolonged ventricular refractory periods and ventricular conduction slowing, accompanied by enhanced inducibility of atrial fibrillation and diminished susceptibility to ventricular arrhythmias. Desmin deficiency does not result in electrophysiological changes present in human desminopathies, suggesting that functional alterations rather than loss of desmin cause the cardiac alterations in these patients.

Abstract 322: Role of T-Type Calcium Current in Cardiac Remodeling Probed with Genetically Engineered Knockout Mice

Background: Previous studies suggested that T-type Ca 2+ -current (I CaT ) blockers suppress disease-related cardiac remodeling, but all available I CaT -blockers have non-specific actions on other currents and/or functions. To obtain a clearer sense of the role of I CaT in cardiac remodeling, we studied mice with the principal cardiac I CaT subunit (Cav3.1) knocked out. Methods: Adult male Cav3.1 knockout mice (KO) were compared with wild type (WT). LAD-ligation was performed to create anterior-wall myocardial infarction (MI). Echocardiography was used to evaluate cardiac performance at baseline, 2-w and 4-w post-MI. Intracardiac programmed stimulation was performed 4-w post-MI. Standard pacing protocols were used to determine atrial and ventricular electrophysiological properties and to induce arrhythmias. Results: Surface ECG parameters were examined in 10 KO and 10 WT mice prior to LAD ligation. At baseline, PQ interval was significantly longer in KO mice than in WT animals (44 ± 1 ms vs 40 ± 1 ms, respectively; p &lt; 0.05); no significant differences were observed in RR, QRS or QTc intervals. At 10 minutes post-MI, WT (but not KO) mice showed increased heart rate (p = 0.002). Baseline echocardiography showed smaller LV fractional shortening (FS) and ejection fraction (EF) in KO mice compared with WT (34 ± 1% KO vs 42 ± 3% WT; 69 ± 2% KO vs 77 ± 3% WT; respectively, p &lt; 0.05). At 4-w post-MI, FS and EF of KO mice were still smaller than WT mice (15.5 ± 1.6% vs 21.0 ± 1.5%; 37.4 ± 3.2% vs 48.1 ± 2.8%, respectively; p &lt; 0.05). At baseline and 4-w post-MI, the contractility index (pressure-volume curves) was decreased in KO mice (p &lt; 0.05). Intracardiac electrophysiological recordings revealed no differences in atrial and ventricular ERP or sinus node recovery time for WT vs KO. At 4-w post-MI, extrastimuli induced sustained atrial fibrillation (&gt; 2 s) in 60% (6/10) KO mice, versus 17% (1/6) in WT (p = 0.05) and ventricular tachyarrhythmias in 82% (9/11) of KO mice versus 17% (1/6) of WT (p &lt; 0.01). Conclusion: Contrary to previous studies with (imperfectly selective) pharmacological agents having T-type Ca 2+ channel blocking actions, our findings suggests that reductions in I CaT do not favorably alter post-MI remodeling and may negatively affect cardiac function and arrhythmias.

Gender Differences in Electrophysiologic Effects of Mental Stress and Autonomic Tone Inhibition:

Gender differences exist in electrophysiologic properties and the occurrence of certain arrhythmias. Mental stress may trigger serious arrhythmias, including ventricular tachycardias and ventricular fibrillation. This study investigates gender differences in the electrophysiologic effects on different levels of the cardiac conduction system elicited by mental stress and autonomic tone inhibition. Twenty-three healthy volunteers (11 male and 12 female) participated in the study. Electrophysiologic and hemodynamic variables were measured at baseline, during mental stress produced by Stroop's color word conflict test (CWT), and after autonomic tone inhibition (ATI) with propranolol (0.15 mg/kg) and atropine (0.02 mg/kg). During CWT, men showed shorter QT and JT durations, whereas women had shorter refractoriness in the atrial tissue and AV node. After ATI, no gender differences in sinus nodal properties were noted, whereas AV nodal refractoriness and conduction time became shorter in women, and QT and JT duration and the refractory period of the right ventricle were shorter in men. In women, mental stress produces a pronounced effect on the AV node and on the sinus node. Men react with a more pronounced effect on ventricular electrophysiologic properties. Certain gender differences in cardiac electrophysiologic properties seem to be intrinsic. After ATI, women have a higher heart rate and shorter AV nodal refractoriness but longer QT and JT intervals and longer effective refractory periods in the right ventricle. These differences may partly explain why certain arrhythmias occur more often in women than in men.