Isoproterenol Infusion Research Articles

Segmental analysis by speckle-tracking echocardiography of the left ventricle response to isoproterenol in male and female mice

We studied by conventional and speckle-tracking echocardiography, the response of the left ventricle (LV) to a three-week continuous infusion of isoproterenol (Iso), a non-specific beta-adrenergic receptor agonist in male and female C57Bl6/J mice. Before and after Iso (30 mg/kg/day), we characterized LV morphology and function as well as global and segmental strain. We observed that Iso reduced LV ejection in both male (−8.7%) and female (−14.7%) mice. Several diastolic function parameters were negatively regulated in males and females such as E/A, E/E′, isovolumetric relaxation time. Global longitudinal (GLS) and circumferential (GCS) strains were reduced by Iso in both sexes, GLS by 31% and GCS by about 20%. For the segmental LV analysis, we measured strain, strain rate, reverse strain rate, peak speckle displacement and peak speckle velocity in the parasternal long axis. We observed that radial strain of the LV posterior segments were more severely modulated by Iso than those of the anterior wall in males. In females, on the other hand, both posterior and anterior wall segments were negatively impacted by Iso. Longitudinal strain showed similar results to the radial strain for both sexes. Strain rate, on the other hand, was only moderately changed by Iso. Reverse strain rate measurements (an index of diastolic function) showed that posterior LV segments were negatively regulated by Iso. We then studied the animals 5 and 17 weeks after Iso treatment. Compared to control mice, LV dilation was still present in males. Ejection fraction was decreased in mice of both sex compared to control animals. Diastolic function parameters, on the other hand, were back to normal. Taken together, our study indicates that segmental strain analysis can identify LV regions that are more negatively affected by a cardiotoxic agent such as Iso. In addition, cessation of Iso was not accompanied with a complete restoration of cardiac function after four months.

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.

A Randomized, Double-Blind, Placebo-Controlled Trial of Intravenous Alcohol to Assess Changes in AtrialElectrophysiology.

This study sought to identify acute changes in human atrial electrophysiology during alcohol exposure. The mechanism by which a discrete episode of atrial fibrillation (AF) occurs remains unknown. Alcohol appears to increase the risk for AF, providing an opportunity to study electrophysiologic effects that may render the heart prone to arrhythmia. In this randomized, double-blinded, placebo-controlled trial, intravenous alcohol titrated to 0.08% blood alcohol concentration was compared with a volume and osmolarity-matched, masked, placebo in patients undergoing AF ablation procedures. Right, left, and pulmonary vein atrial effective refractory periods (AERPs) and conduction times were measured pre- and post-infusion. Isoproterenol infusions and burst atrial pacing were used to assess AF inducibility. Of 100 participants (50 in each group), placebo recipients were more likely to be diabetic (22% vs. 4%; p=0.007) and to have undergone a prior AF ablation (36% vs. 22%; p=0.005). Pulmonary vein AERPs decreased an average of 12ms (95% confidence interval: 1 to 22ms; p=0.026) in the alcohol group, with no change in the placebo group (p=0.98). Whereas no statistically significant differences in continuously assessed AERPs were observed, the proportion of AERP sites tested that decreased with alcohol (median: 0.5; interquartile range: 0.6 to 0.6) was larger than with placebo (median: 0.4; interquartile range: 0.2 to 0.6; p=0.0043). No statistically significant differences in conduction times or in the proportion with inducible AF were observed. Acute exposure to alcohol reduces AERP, particularly in the pulmonary veins. These data demonstrate a direct mechanistic link between alcohol, a common lifestyle exposure, and immediate proarrhythmic effects in human atria. (How Alcohol Induces Atrial Tachyarrhythmias Study [HOLIDAY]; NCT01996943).

Presence of non-pulmonary vein foci in patients with atrial fibrillation undergoing standard ablation of pulmonary vein isolation: Clinical characteristics and long-term ablation outcome.

BackgroundThe clinical characteristics of atrial fibrillation (AF) resulting from non-pulmonary vein (PV) triggers remain unknown. This study aimed to evaluate the clinical characteristics of patients with AF caused by non-PV triggers, localization of non-PV foci, clinical differences, and clinical outcomes after catheter ablation in each AF focus.MethodsA total of 2967 patients who underwent initial catheter ablation for paroxysmal or persistent AF were examined. After PV isolation, all patients underwent high-dose isoproterenol infusion to assess the existence of non-PV foci.ResultsNon-PV foci were identified in 564 patients (19.2%). The localization of successfully ablated non-PV foci in 514 patients were the superior vena cava (SVC: 213 cases), interatrial septum (IAS: 125 cases), coronary sinus (CS: 98 cases), right atrium (RA: 125 cases), left atrium (LA: 114 cases), and unmappable (50 cases). Multivariate analysis revealed that female gender, low body mass index (BMI), non-paroxysmal AF (PAF), and sick sinus syndrome were independent and significant indicators of non-PV foci. In the multivariate analysis of each AF focus, female gender, low BMI, and non-PAF were significant predictors of IAS and CS foci, RA and IAS foci, and CS foci, respectively. In addition, dilatation of the LA was significantly associated with LA foci, whereas RA, LA, IAS, and CS foci were associated with AF recurrence.ConclusionThese findings could help to identify patients at a higher risk of AF caused by non-PV triggers and clarify the clinical difference according to the localization of non-PV foci.

Predictors of adequate intraprocedural premature ventricular complex (PVC) frequency during idiopathic PVC ablation

The aim of the present study was to determine the predictors of adequate intraprocedural premature ventricular complex (PVC) frequency for successful mapping and ablation of idiopathic PVCs. Atotal of 101consecutive patients (45men; age: 47.9 ± 14.2years) who had undergone idiopathic PVC ablation between 01November2018 and 24June2020 constituted our study population. Clinical and demographic data, procedural details and 24 h rhythm recordings that had been recorded before the procedure were retrospectively evaluated. Total PVC burden and diurnal variability assessed by the ratio of night time (22:00-06:00) over day time (06:00-22:00) PVC burden was calculated. The relationship between hourly PVC number and heart rate was also evaluated for each patient. Clinical characteristics and Holter parameters were compared between groups with and without adequate intraprocedural frequency of PVCs that permitted activation mapping. In all, 27patients (26.7%) had infrequent intraprocedural PVCs which necessitated isoproterenol infusion or cancellation of ablation procedure due to inability of activation mapping. PVC burden was significantly higher in the group with frequent intraprocedural PVCs (26.1 ± 9.4% vs 21.2 ± 10.3%; p: 0.026). There were no significant differences between groups regarding the relationship between hourly PVC number and heart rate or the ratio of night/day PVC burden. Binary logistic regression analysis revealed the 24 h Holter PVC burden as the sole parameter that is significant predictor of frequent intraprocedural PVCs permitting activation mapping. The 24 h PVC burden was the only predictor of adequate intraprocedural PVC frequency permitting activation mapping during idiopathic PVC ablation.

Predictive Value of Blood Pressure, Heart Rate, and Blood Pressure/Heart Rate Ratio in a Chinese Subpopulation with Vasovagal Syncope

Objective: The head-up tilt test (HUTT) is widely used but is time-consuming and not cost-effective to evaluate patients with vasovagal syncope (VVS). The present study aims to verify the hypothesis that ambulatory blood pressure (BP) monitoring (ABPM) and the simplistic tilt test may be potential alternatives to the HUTT. Methods: The study consecutively enrolled 360 patients who underwent the HUTT to evaluate VVS. BP), heart rate (HR), and BP/HR ratios derived from ABPM and the simplistic tilt test were evaluated to predict the presence, pattern, and stage of syncope during the HUTT. Results: Mixed response was the commonest pattern, and syncope occurred frequently with infusion of isoproterenol at a rate of 3 μg/min. During the simplistic tilt test, the cardioinhibitory group had higher tilted BP/HR ratios than the vasodepressor group, while the vasodepressor group had a faster tilted HR and a larger HR difference than the cardioinhibitory group. The higher the BP/HR ratio in the tilted position, the higher the isoproterenol dosage needed to induce a positive response. During ABPM, BP/HR ratios were significantly higher in the cardioinhibitory group than in the vasodepressor group. The higher the ABPM-derived BP, the higher the dosage of isoproterenol needed to induce syncope. There were significant correlations in BP/HR ratios between ABPM and the supine position in the vasodepressor group, while significant correlation was found only for the diastolic BP/HR ratio between ABPM and the tilted position in the cardioinhibitory group. The mixed pattern shared correlative features of the other two patterns. Conclusion: ABPM and the simplistic tilt test might be used as promising alternatives to the HUTT in VVS evaluation in clinical settings.

Outcomes of deep sedation for catheter ablation of paroxysmal supraventricular tachycardia, with adaptive servo ventilation.

BackgroundCatheter ablation for paroxysmal supraventricular tachycardia (PSVT) is an established treatment, but the effect of deep sedation on PSVT inducibility remains unclear.AimWe sought to examine PSVT inducibility and outcomes of catheter ablation under deep sedation using adaptive servo ventilation (ASV).MethodsWe retrospectively evaluated consecutive patients who underwent catheter ablation for PSVT under deep sedation (Propofol + Dexmedetomidine) with use of ASV. Anesthetic depth was controlled with BIS™ monitoring, and phenylephrine was administered to prevent anesthesia‐induced hypotension. PSVT induction was attempted in all patients using extrastimuli at baseline, and after isoproterenol (ISP) infusion when necessary.ResultsPSVT was successfully induced in 145 of 147 patients, although ISP infusion was required in the majority (89%). The PSVT was atrioventricular nodal reentrant tachycardia (AVNRT) in 77 (53%), atrioventricular reciprocating tachycardia (AVRT) in 51 (35%), and atrial tachycardia (AT) in 17 (12%). A higher ISP dose was required for AT compared to other PSVT (AVNRT: 0.06 (IQR 0.03‐0.06) vs AVRT: 0.03 (0.02‐0.06) vs AT: 0.06 (0.03‐0.12) mg/h, P = .013). More than half (51%) of the patients developed hypotension requiring phenylephrine; these patients were older. Acute success was obtained in 99% (patients with AVNRT had endpoints with single echo on ISP in 46%). Long‐term success rate was 136 of 144 (94%) (AVNRT 96%, AVRT 92%, and AT 93%). There were no complications related to deep sedation.ConclusionsDeep sedation with use of ASV is a feasible anesthesia strategy for catheter ablation of PSVT with good long‐term outcome. PSVT remains inducible if ISP is used.

Abstract 15059: Prevalence of Recovery of Conduction in the Left Atrial Appendage Following Electrical Isolation of the Appendage in Patients With Atrial Fibrillation

Background: Electrical isolation of the left atrial appendage (LAAEI) is considered in patients presenting with recurrence following effective PV isolation. Objective: We evaluated the prevalence of LAA reconnection following LAAEI in patients undergoing repeat procedure for AF recurrence. Methods: Consecutive AF patients undergoing repeat ablation for arrhythmia recurrence following LAAEI were included in this analysis. Transesophageal echocardiogram (TEE) was performed in all at baseline to evaluate LAA function. Isoproterenol infusion up to 30 μg/min for 10 to 15 min was administered to detect LAA triggers. Re-isolation of the LAA was performed if triggers were detected. Off-drug success rate was assessed in all. Results: A total of 594 post-LAAEI patients with recurrent AF were included in the analysis. At the redo, PVs were found to be electrically silent in all. LAA reconnection was detected in 214 (36%) patients. Baseline TEE revealed normal LAA contractility and flow-velocity in all. Re-isolation of the LAA was performed in these 214 patients. In patients with no LAA reconnection (n=380), non-PV triggers from other sites were targeted for ablation. There was no difference in the clinical characteristics of patients with vs. without LAA reconnection (Table). At 2 years after the repeat procedure, 201 (94%) patients with and 351 (92.3%) without LAA reconnection were arrhythmia-free off-drugs (p=0.47). Conclusion: In this series, LAA reconnection rate was 36% after single LAAEI procedure and re-isolation of the appendage led to high success rate. Additionally, normal LAA functions detected by TEE correctly predicted recovery of conduction in the LAA.

Abstract 16592: Excessive MCU-Mediated Mitochondrial Calcium Uptake During Chronic Stress Impairs Cardiac Contractility

Calcium (Ca 2+ ) uptake into the mitochondrial matrix occurs via the mitochondrial Ca 2+ uniporter channel (mtCU) and tunes mitochondrial metabolism to meet acute changes in cellular ATP demand. However, the role of mtCU-dependent mitochondrial Ca 2+ ( m Ca 2+ ) uptake in regulating homeostatic heart function and adaptation to chronic increases in workload remain controversial. We subjected mice with tamoxifen-inducible, cardiomyocyte-specific gain (flox-stop-MCU x αMHC-MCM, MCU-Tg) or loss ( Mcu fl/fl x αMHC-MCM , Mcu- cKO) of MCU function to 2wk isoproterenol (iso) infusion to test the hypothesis that m Ca 2+ uptake through MCU contributes to functional adaptation to sustained catecholamine signaling. Neither gain nor loss of MCU function altered baseline cardiac structure or function. Fractional shortening was increased after 2d of iso infusion in MCM control mice, but loss of MCU blocked this effect. In contrast, fractional shortening declined significantly after 7-14d of iso in MCU-Tg mice. MCU-Tg mice also exhibited increased LV dilation, heart mass, and lung edema compared to controls after 14d of iso. Acute treatment of MCU-Tg cardiomyocytes in vitro with the Ca 2+ ionophore ionomycin revealed increased ROS production and a trend towards increased sensitivity to Ca 2+ -induced cell death. In agreement, Evans blue dye exclusion assays revealed increased cardiomyocyte necrosis in MCU-Tg hearts following iso. Therefore, we deleted the mPTP regulator cyclophilin D (CypD) in MCU-Tg mice to test whether cardiomyocyte dropout due to m Ca 2+ overload-induced mPTP contributed to iso-induced contractile dysfunction. Unexpectedly, CypD deletion failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased rather than attenuated iso-induced cardiomyocyte death in MCU-Tg mice. We conclude that while MCU-dependent m Ca 2+ uptake is required for the heart’s initial contractile response to catecholaminergic stress, under prolonged stimulation augmented m Ca 2+ uptake becomes deleterious and predisposes to cardiomyocyte death and heart failure. Our findings support the notion that the detrimental effects of sustained MCU-dependent m Ca 2+ uptake are mediated by mechanisms distinct from mitochondrial permeability transition.

Signaling via the Interleukin-10 Receptor Attenuates Cardiac Hypertrophy in Mice During Pressure Overload, but not Isoproterenol Infusion.

Inflammation plays a key role during cardiac hypertrophy and the development of heart failure. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that is expressed in the heart and may play a crucial role in cardiac remodeling. Based on the evidence that IL-10 potentially reduces pathological hypertrophy, it was hypothesized that signaling via the IL-10 receptor (IL10R) in the heart produces a protective role in reducing cardiac hypertrophy. The aim of this study was to investigate the effects of the ablation of Il-10-r1 gene during pathological cardiac hypertrophy in mice. We found that IL-10R1 gene silencing in cultured cardiomyocytes diminished the anti-hypertrophic effect of Il-10 in TNF-α induced hypertrophy model. We then analyzed mice deficient in the Il-10-r1 gene (IL-10R1-/- mice) and subjected them to transverse aortic constriction or isoproterenol infusion to induce pathological hypertrophy. In response to transverse aortic constriction for 2 weeks, IL-10R1-/- mice displayed a significant increase in the hypertrophic response as indicated by heart weight/body weight ratio, which was accompanied by significant increases in cardiomyocyte surface area and interstitial fibrosis. In contrast, there was no difference in hypertrophic response to isoproterenol infusion (10 days) between the knockout and control groups. Analysis of cardiac function using echocardiography and invasive hemodynamic studies did not show any difference between the WT and IL-10R1-/- groups, most likely due to the short term nature of the models. In conclusion, our data shows that signaling via the IL-10 receptor may produce protective effects against pressure overload-induced hypertrophy but not against β-adrenergic stimuli in the heart. Our data supports previous evidence that signaling modulated by IL-10 and its receptor may become a potential target to control pathological cardiac hypertrophy.

A multiscale model of cardiac concentric hypertrophy incorporating both mechanical and hormonal drivers of growth.

Growth and remodeling in the heart is driven by a combination of mechanical and hormonal signals that produce different patterns of growth in response to exercise, pregnancy, and various pathologies. In particular, increases in afterload lead to concentric hypertrophy, a thickening of the walls that increases the contractile ability of the heart while reducing wall stress. In the current study, we constructed a multiscale model of cardiac hypertrophy that connects a finite-element model representing the mechanics of the growing left ventricle to a cell-level network model of hypertrophic signaling pathways that accounts for changes in both mechanics and hormones. We first tuned our model to capture published in vivo growth trends for isoproterenol infusion, which stimulates β-adrenergic signaling pathways without altering mechanics, and for transverse aortic constriction (TAC), which involves both elevated mechanics and altered hormone levels. We then predicted the attenuation of TAC-induced hypertrophy by two distinct genetic interventions (transgenic Gq-coupled receptor inhibitor overexpression and norepinephrine knock-out) and by two pharmacologic interventions (angiotensin receptor blocker losartan and β-blocker propranolol) and compared our predictions to published in vivo data for each intervention. Our multiscale model captured the experimental data trends reasonably well for all conditions simulated. We also found that when prescribing realistic changes in mechanics and hormones associated with TAC, the hormonal inputs were responsible for the majority of the growth predicted by the multiscale model and were necessary in order to capture the effect of the interventions for TAC.

Abstract 506: Enhanced Mitochondrial Calcium Uptake During Chronic β-adrenergic Stimulation Causes Maladaptive Remodeling and Impaired Left Ventricular Function Independent of Cyclophilin D-mediated Mitochondrial Permeability Transition

The mitochondrial calcium uniporter (MCU) forms the pore of the mitochondrial calcium uniporter channel (mtCU) and is required for rapid mitochondrial Ca 2+ ( m Ca 2+ ) uptake. MCU is necessary to increase cardiac energetics to fuel an increase in cardiac contractility during acute sympathetic stimulation. However, little is known about how MCU-dependent Ca 2+ flux may contribute to the heart’s adaptations to chronic stress. We therefore compared mice with adult cardiomyocyte (ACM)-specific loss ( Mcu fl/fl ; Mcu-cKO) or gain (CAG-CAT-MCU; MCU-Tg) of MCU function to examine the role of MCU-dependent m Ca 2+ uptake in a model of chronic catecholamine overload. In vitro characterization of ACMs confirmed that MCU overexpression enhanced and Mcu deletion inhibited acute m Ca 2+ uptake. Neither loss nor gain of MCU function altered baseline contractile function in vivo . In αMHC-MCM control mice, fractional shortening was transiently increased after 2 days of isoproterenol infusion. This initial increase in contractility was attenuated in MCU-cKO mice. In contrast, MCU-Tg mice exhibited decreased fractional shortening at 7 and 14 days of isoproterenol infusion. This detrimental effect on contractile function was associated with increased LV dilation, HW/BW ratio, and lung edema. MCU-Tg cardiomyocytes in vitro exhibited increased ROS production and a trend towards increased cell death upon elevation of cytosolic Ca 2+ with ionomycin. These data prompted us to test the hypothesis that isoproterenol-induced contractile dysfunction in MCU-Tg hearts is caused by cardiomyocyte dropout due to m Ca 2+ overload and mitochondrial permeability transition. However, genetic deletion of the mPTP component cyclophilin D did not prevent the decline in contractile function, diminish cardiomyocyte death, or attenuate LV remodeling in MCU-Tg animals during chronic isoproterenol infusion. We conclude that although mtCU-dependent m Ca 2+ uptake is essential for early energetic adaptations to high adrenergic load, under conditions of chronic adrenergic stress it is maladaptive and predisposes to heart failure. Our data suggest that this maladaptive response occurs via mechanisms independent of cyclophilin D-mediated permeability transition.

The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients.

Heart failure (HF) impairs diaphragm function. Animal models realistically mimicking HF should feature both the cardiac alterations and the diaphragmatic dysfunction characterizing this disease. The isoproterenol-induced HF model is widely used, but whether it presents diaphragmatic dysfunction is unknown. However, indirect data from research in other fields suggest that isoproterenol could increase diaphragm function. The aim of this study was to test the hypothesis that the widespread rodent model of isoproterenol-induced HF results in increased diaphragmatic contractility. Forty C57BL/6J male mice were randomized into 2 groups: HF and healthy controls. After 30 days of isoproterenol infusion to establish HF, in vivo diaphragmatic excursion and ex vivo isolated diaphragm contractibility were measured. As compared with healthy controls, mice with isoproterenol-induced HF showed the expected changes in structural and functional echocardiographic parameters and lung edema. isoproterenol-induced HF increased in vivo diaphragm excursion (by ≈30%, p<0.01) and increased by ≈50% both ex vivo peak specific force (p<0.05) and tetanic force (p<0.05) at almost all 10–100 Hz frequencies (p<0.05), with reduced fatigue resistance (p<0.01) when compared with healthy controls. Expression of myosin genes encoding the main muscle fiber types revealed that Myh4 was higher in isoproterenol-induced HF than in healthy controls (p<0.05), suggesting greater distribution of type IIb fibers. These results show that the conventional isoproterenol-induced HF model increases diaphragm contraction, a finding contrary to what is observed in patients with HF. Therefore, this specific model seems limited for translational an integrative HF research, especially when cardio-respiratory interactions are investigated.

Transcriptional signatures regulated by TRPC1/C4-mediated Background Ca2+ entry after pressure-overload induced cardiac remodelling

AimsAfter summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling. Methods and resultsMn2+-quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (−51.4%) or after one week of transverse aortic constriction (TAC; −73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts. ConclusionsDeletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies.

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.

Oral caffeine intake amplifies the effect of isoproterenol in patients with frequent premature ventricular contractions.

Infrequent appearance and failed induction of premature ventricular contractions (PVCs) at catheter ablation make their localization difficult and are associated with a poor procedural outcome. This study aimed to assess the effect of preprocedural oral caffeine intake on induction of PVCs during catheter ablation. Seventy patients (age: 54 ± 14 years, 37 men) undergoing catheter ablation for monofocal PVCs were randomized to receive oral caffeine (5 mg/kg) or placebo. Before ablation, PVC counts for 5 min were performed at baseline and during isoproterenol infusion and the isoproterenol washout period. PVC count fluctuation was defined as the difference between the highest and lowest 5-min count among the three-time periods. The 5-min PVC counts during baseline and isoproterenol infusion were equivalent between the groups. However, those during the isoproterenol washout period and PVC count fluctuation were significantly higher in the caffeine group than the control group (73.1 ± 73.2 vs. 38.9 ± 28.9 beats/5 min, P = 0.012 and 69.3 ± 61.3 vs. 37.7 ± 30.9 beats/5 min, P = 0.008, respectively). The procedure and ablation times were significantly shorter in the caffeine group than the control group (105.0 ± 23.4 vs. 136.9 ± 43.2 min, P < 0.01 and 219.1 ± 104.7 vs. 283.5 ± 136.0 sec, P < 0.01, respectively). Oral caffeine intake amplified the effect of isoproterenol infusion on PVC induction during catheter ablation. The combined use of oral caffeine intake and isoproterenol infusion can be an option to increase intraprocedural PVCs.

Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure.In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

JMJD1A Represses the Development of Cardiomyocyte Hypertrophy by Regulating the Expression of Catalase.

The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA-mediated JMJD1A knockdown facilitated ISO or angiotensin II-induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO-induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N-acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA-mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO-induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS-dependent manner.

Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019

Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019

Üç Boyutlu Elektroanatomik Haritalama Sistemi İle Sağ Atriyal Apendiks Taşikardisinin Ablasyonu: Nadir Bir Vaka

Atrial tachycardias (AT) originating from right atrial appendage (RAA) are quite rare among focal atrial tachycardias. A 38-year-old female patient presented to the emergency room complaining of palpitations and dizziness. Electrocardiography (ECG) showed regular narrow QRS complex tachycardia with a ventricular rate of 150 bpm. The patient had frequent episodes of palpitations for 5 years. Considering the ensuing tachycardiomyopathy under medical treatment, electrophysiological study (EPS) and ablation procedure was planned after having informed consent. During isoproterenol infusion (1-4 mcg/min), a sustained tachycardia with narrow QRS complex was induced. Diagnostic electrophysiological findings were consistent with AT. During tachycardia, by using a three-dimensional (3D) electroanatomic mapping system, simultaneous anatomical and activation mapping was performed with a quadripolar 3.5mm cooled-tip Thermocool Smarttouch bi-directional navigation catheter. Activation mapping demonstrated that the earliest endocardial activation site was basal portion of the RAA where the local electrogram was 104 msn prior to the Cs reference signal during tachycardia which is spreading in a centrifugal fashion. Impedance-controlled radiofrequency ablation (RF) ablation (35 W, 42° C, 5-10 g of contact force) was performed at the earliest site and tachycardia terminated in 10 seconds. No AT observed during the waiting period of 30 min after RF ablation.