Isoprenaline Infusion Research Articles

Conflicting responses with simultaneous atrioventricular pacing. What is the mechanism?

A 60-year-old woman presented with recurrent episodes of palpitations, documented short RP, narrow QRS tachycardia and absence of preexcitation in the electrocardiogram during sinus rhythm. During an electrophysiology study, programmed stimulation induced a narrow QRS tachycardia with cycle length of 380 ms, VA interval of 164 ms and earliest atrial activation in the His region. Ventricular overdrive pacing failed to entrain the atrium even with isoprenaline infusion and atrial burst pacing repeatedly terminated the tachycardia. Difference in AH interval with pacing and SVT was 27 msec. Simultaneous atrial and ventricular pacing was done with atrial pacing from the high right atrium and showed a His signal as the first return electrogram suggestive of atrioventricular nodal reentrant tachycardia (AVNRT). The manoeuvre was repeated with atrial pacing from the proximal coronary sinus and showed an atrial signal as the first return electrogram suggestive of atrial tachycardia (AT). What is the explanation for the conflicting results of the two pacing maneuvers?

Circulating mitochondria promoted endothelial cGAS-derived neuroinflammation in subfornical organ to aggravate sympathetic overdrive in heart failure mice

BackgroundSympathoexcitation contributes to myocardial remodeling in heart failure (HF). Increased circulating pro-inflammatory mediators directly act on the Subfornical organ (SFO), the cardiovascular autonomic center, to increase sympathetic outflow. Circulating mitochondria (C-Mito) are the novel discovered mediators for inter-organ communication. Cyclic GMP–AMP synthase (cGAS) is the pro-inflammatory sensor of damaged mitochondria.ObjectivesThis study aimed to assess the sympathoexcitation effect of C-Mito in HF mice via promoting endothelial cGAS-derived neuroinflammation in the SFO.MethodsC-Mito were isolated from HF mice established by isoprenaline (0.0125 mg/kg) infusion via osmotic mini-pumps for 2 weeks. Structural and functional analyses of C-Mito were conducted. Pre-stained C-Mito were intravenously injected every day for 2 weeks. Specific cGAS knockdown (cGAS KD) in the SFO endothelial cells (ECs) was achieved via the administration of AAV9-TIE-shRNA (cGAS) into the SFO. The activation of cGAS in the SFO ECs was assessed. The expression of the mitochondrial redox regulator Dihydroorotate dehydrogenase (DHODH) and its interaction with cGAS were also explored. Neuroinflammation and neuronal activation in the SFO were evaluated. Sympathetic activity, myocardial remodeling, and cardiac systolic dysfunction were measured.ResultsC-Mito were successfully isolated, which showed typical structural characteristics of mitochondria with double-membrane and inner crista. Further analysis showed impaired respiratory complexes activities of C-Mito from HF mice (C-MitoHF) accompanied by oxidative damage. C-Mito entered ECs, instead of glial cells and neurons in the SFO of HF mice. C-MitoHF increased the level of ROS and cytosolic free double-strand DNA (dsDNA), and activated cGAS in cultured brain endothelial cells. Furthermore, C-MitoHF highly expressed DHODH, which interacted with cGAS to facilitate endothelial cGAS activation. C-MitoHF aggravated endothelial inflammation, microglial/astroglial activation, and neuronal sensitization in the SFO of HF mice, which could be ameliorated by cGAS KD in the ECs of the SFO. Further analysis showed C-MitoHF failed to exacerbate sympathoexcitation and myocardial sympathetic hyperinnervation in cGAS KD HF mice. C-MitoHF promoted myocardial fibrosis and hypertrophy, and cardiac systolic dysfunction in HF mice, which could be ameliorated by cGAS KD.ConclusionCollectively, we demonstrated that damaged C-MitoHF highly expressed DHODH, which promoted endothelial cGAS activation in the SFO, hence aggravating the sympathoexcitation and myocardial injury in HF mice, suggesting that C-Mito might be the novel therapeutic target for sympathoexcitation in HF.Graphic

OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes

Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI)-induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO-induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKG-SERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure.

Efficacy and Safety of Isoprenaline during Unstable Third-Degree Atrioventricular Block.

Unstable and symptomatic complete atrioventricular block represents a potentially fatal condition that requires prompt therapy while waiting for definitive pacemaker implantation. Although transcutaneous pacing is included in acute management, it could be a difficult approach due to its painfulness and the occasional failure of mechanical capture. Drug therapy is a feasible choice, and current guidelines encompass the use of atropine, dopamine, or epinephrine. Isoprenaline has never been investigated in this setting, and no specific indication of its use has been provided despite its potentially more favorable pharmacological profile. The study population included a consecutive series of patients who presented to the emergency department because of unstable third-degree atrioventricular block and were treated with either isoprenaline or dopamine infusion while waiting for definitive pacemaker implantation. Asymptomatic patients or those with reversible causes of complete atrioventricular block were excluded. The clinical response to the drug was deemed poor if, despite achieving a full drug dose, patients remained symptomatic and/or with hemodynamic instability, ventricular rate and rhythm did not improve or worsened, including if ventricular arrhythmias or asystolic pauses and/or irrepressible nausea/vomiting occurred. Isoprenaline infusion has proved to be safe and tolerated with no arrhythmia induction or hypotensive issues. Isoprenaline has also proven to be more satisfactory in achieving an effective clinical response in 84% of patients rather than dopamine (31%, p < 0.001), reducing the need for temporary artificial pacing. Our data point out the efficacy and safety of isoprenaline infusion and its greater tolerability over dopamine in the acute management of unstable third-degree AV block while waiting for definitive pacemaker implantation.

Ablation of left ventricle summit PVCs using guidewire and 2F octapolar microcatheter mapping

Abstract Funding Acknowledgements Type of funding sources: None. Background Ventricular arrhythmias originating in the left ventricular summit region are especially difficult to map and ablate. The development of microcatheters allows access to the septal coronary venous system, which facilitates its mapping. Purpose To describe the strategy for mapping and ablation of ventricular LV-Summit extrasystoles in the first 6 cases at our center, performed using a 2F octapolar microcatheter, as well as the results obtained. Methods 6 cases of left ventricular summit PVCs were recruited between January 2019 and October 2022. TTE and/or MRI were performed as well as initial Holter, evidencing a high density of PVCs. The studies were carried out with intracardiac echo and anatomical reconstruction with a navigator. The coronary sinus was cannulated with a 6F guide catheter for venography. Mapping of the septal coronary venous system was performed with a 4F vertebral catheter and angioplasty guidewire, connecting the guidewire to the polygraph where good precocity (up to -30 ms) was obtained with a QS pattern in the monopolar lead during PVCs. An octapolar catheter was advanced, obtaining maximum precocity and appreciating fragmented late potentials and local abnormal ventricular activities (LAVA) during sinus rhythm with greater precocity during extrasystole and achieving a topostimulation of 95% concordance with PVCs. Radiofrequency applications were made with an irrigated contact catheter in the areas facing the octapolar catheter until acute suppression of PVC was achieved and its absence was verified after infusion of isoprenaline. Results The mean age of the sample was 60 years, 3 of them women, with a mean LVEF of 51% and a daily average of PVCs of 17.28%. Three of the patients had previously studied cardiomyopathies. After ablation, antiarrhythmics were stopped in 80% of cases and beta-blockers in 40%. The percentage of PVCs was significantly reduced (mean after the procedure 4.4%, p = 0.04) with a single recurrence at follow-up. No complications were recorded. Conclusions The microcatheter-guided ablation of the septal coronary venous system is a safe and effective procedure for the removal of left ventricular summit PVCs.

P454 ARRHYTHMIC RISK AND REPOLARIZATION ALTERATIONS ON THE ECG UNCOVERED BY AN ISOPRENALINE TEST

Abstract A 62–year–old man came to our attention for a syncopal episode that occurred during a competitive race, without prodromes, lasting a few seconds, with total, spontaneous regression and without issues. On ECG sinus bradycardia, HR 46/min and QRS fragmented in V1. During monitoring were documented many polymorphic premature ventricular complex (PVC) and polymorphic nonsustained ventricular tachycardia (NSVT). Coronary angiography showed normal coronary arteries. The Isoprenaline test was performed (intravenous infusion of Isoprenaline 0.2 mg in 100 ml of physiological solution at variable speed until obtaining a HR increase of at least 20% compared to baseline). As HR increased, a clear epsilon wave in V1 became evident. Also documented numerous polymorphic PVC and polymorphic NSVT. Cardiac magnetic resonance (MRI) was performed with documentation of findings suggestive of primary cardiomyopathy with biventricular phenotypic expression with a clear left prevalence. All these elements placed the patient at high arrhythmic risk. An implantable cardiac defibrillator was then performed. The isoprenaline–induced increase in heart rate made the epsilon wave manifest, which is an expression of an extremely delayed depolarization caused by the fibroadipose replacement of portions of the myocardium (as documented by cardiac MRI). It was also possible to exclude a J–wave syndrome in which the alterations are of repolarization and are due to the epi–endocardial electrical gradient which increases and becomes more evident at lower heart rates. The test with isoprenaline has therefore allowed us to distinguish depolarization disorders from repolarization disorders and to direct us towards the former.

Right Ventricular Outflow Tract Stenting is a Safe and Effective Bridge to Definitive Repair in Symptomatic Infants With Tetralogy of Fallot1.

Right ventricular outflow tract (RVOT) stent angioplasty is a palliative procedure for neonates and infants with symptomatic tetralogy of Fallot prior to surgical repair. We review our institutional outcomes of RVOT stenting. Retrospective review of all infants with tetralogy of Fallot under 3 months of age who underwent primary native RVOT stent angioplasty at The Children's Hospital at Westmead, Sydney, Australia between January 2010 and December 2020. Demographics and echocardiographic pulmonary artery dimensions were collected pre-stent angioplasty and prior to surgical repair. Twenty (20) infants underwent primary RVOT stenting. Median age at stent was 14 days (interquartile range [IQR] 7-32) and median weight 2.7 kg (IQR 2.1-3.4). Three patients underwent hybrid per-ventricular procedures. Indication for RVOT stenting was recurrent hyper-cyanotic spells in 12 (60%) and duct-dependent pulmonary blood flow in 8 (40%). Saturations increased from a median of 80% (IQR 75-85) to 91% (IQR 90-95) post procedure (P<0.001). A single major complication occurred: transient complete atrioventricular dissociation requiring isoprenaline infusion for <24 hours. Twelve (12, 60%) required catheter re-intervention prior to definitive repair for further augmentation of pulmonary blood flow. There were two non-cardiac deaths distant from the stent procedure, but prior to surgical repair. Median right and left pulmonary artery Z-scores increased respectively from -2.06 (IQR -2.99 to -0.17) and -1.2 (IQR -2.59 to -0.14) prior to RVOT stent, to -0.74 (IQR [-1.21 to 0.26], P=0.01) and 0.06 (IQR [-1.87 to 1.15], P=0.006) by the time of definitive repair. Eighteen (18) patients achieved definitive repair at a median age of 6.1 months (IQR 4.7-7.3). Palliation with more than one RVOT stent was associated with an increased duration of cardiac bypass (P=0.035) and cross-clamp (P=0.044) time at definitive repair. In symptomatic neonates and infants with tetralogy of Fallot at high-risk of peri-operative complications, RVOT stent angioplasty can safely and effectively augment pulmonary blood flow prior to definitive repair.

594 HIDDEN CAUSES FOR UNEXPLAINED SINCOPE

Abstract Bicuspid aortic valve (BAV) is a congenital cardiac abnormality, affecting approximately 1%-2% of the general population (male &amp;gt; female). A 33-year-old man was admitted to emergency department (ED) for syncope during exertion. He had a history of cigarette smoking with a known previously discovered BAV with mild stenosis. TTE showed a severely calcified bicuspid aortic valve with severe stenosis and regurgitation. ECGs showed frequent asymptomatic complete hearth block (CHB), unresponsive to isoprenaline infusion. He underwent ministernotomy aortic valve replacement (AVR) with mechanical valve. During hospital stay, the 24h ECG telemetric monitoring did not show any A-V disturbance and TTE demonstrated normal prosthesis function. Pacemaker implantation was delayed, Follow-up was performed at 1, 6 and 10 months after surgery: 24h-ECG recordings were performed showing no A-V conduction disturbances. At 1 year, during routine medical screening, cardiac frequency of 38 bpm was detected (ECG revealed sinus rhythm with CHB and junctional escape rhythm of 38 bpm). ICCU echocardiogram showed good ventricular and prosthesis function. Therefore, a dual-chamber MRI compatible pacemaker was implanted. Few cases are reported in literature of young patients presenting with A-V block having a severely calcified aortic bicuspid valve. Their management is poorly explored, and therapies (medical therapy, aortic valve replacement and pacemaker implantation) are not fully evidence based. In literature, 3 cases of possible reversibility of conducting system disorders after severe stenotic aortic valve surgery are described. Noninvasive strategy was initially successful as demonstrated by both the post-operative absence of any AV conduction disturbance and/or symptoms and the close follow-up monitoring. Despite of previous evidence, our experience demonstrates that a complete heart block can recur following aortic valve surgery, even in young patients. Initial presentation of CHB was intermittent, suggesting that the structural damage to the conducting system could not be irreversible; thus, it could positively respond to valve surgery. Unfortunately, in CHB with calcific aortic stenosis patients should be considered for PM implantation at the time of aortic surgery. When a waiting strategy prevails, especially for young patients, close monitoring and follow-up must be warranted to early detect A-V disturbances recurrence.

Inferior Tricuspid Annular Atrial Tachycardia

A 60-year-old male with recurrent episodes of supraventricular tachycardia on regular medications had another episode. Was taken up for electrophysiological study and radiofrequency ablation (EPS and RFA) under 3-D electro-anatomical mapping (EAM). The challenges in the case were need for isoprenaline infusion for sustenance of tachycardia and relatively wider area of ablation requirement for success.

A case of unexpected intraoperative airway obstruction in a patient with an aneurysm of the ascending aorta and aortic arch.

Upper airway compression is one of the clinical manifestations of thoracic aortic aneurysm, which is associated with poor prognosis and high mortality. A 44-year-old patient with ascending aortic and arch aneurysm who was scheduled for Bentall surgery and total arch replacement under cardiopulmonary bypass suffered difficult ventilation after endotracheal intubation. The patient did not exhibit any positional dyspnoea or orthopnoea, did not show any difficulties in the supine position, and had no noteworthy medical history. However, we encountered unexpected hypoventilation after intubation. Isoprenaline infusion was effective while emergency cardiopulmonary bypass was established to deal with this crisis. Fibreoptic bronchoscopy revealed complete obstruction of the carina and confirmed the supracarinal position of the tube. Complete airway obstruction may occur even if there are no symptoms before surgery in patients with thoracic aortic aneurysm. Comprehensive preoperative assessment, a well-developed airway management plan, and responses to possible emergencies are essential to reduce unnecessary events or complications.

Provocation and localization of atrial ectopy in patients with atrial septal defects

BackgroundAtrial fibrillation (AF) is associated with atrial septal defects (ASDs), but the mechanism of arrhythmia in these patients is poorly understood. We hypothesised that right-sided atrial ectopy may predominate in this cohort. Here, we aimed to localise the origin of spontaneous and provoked atrial ectopy in ASD patients.MethodsFollowing invasive calibration of P-wave axes, 24-h Holter monitoring was used to determine the chamber of origin of spontaneous atrial ectopy. Simultaneous electrogram recording from multiple intra-cardiac catheters was used to determine the chamber of origin of isoprenaline-provoked ectopy. Comparison was made to a group of non-congenital heart disease AF patients.ResultsAmongst ASD patients, a right-sided origin for spontaneous atrial ectopy was significantly more prevalent than a left-sided origin (24/30 patients with right-sided ectopy vs. 14/30 with left-sided ectopy, P = 0.015). Amongst AF patients, there was no difference in the prevalence of spontaneous right vs. left-sided ectopy. For isoprenaline-provoked ectopy, there was no significant difference in the proportions of patients with right-sided or left-sided ectopy in either group.ConclusionsWhen spontaneous atrial ectopy occurs in ASD patients, it is significantly more prevalent from a right-sided than left-sided origin. Isoprenaline infusion did not reveal the predilection for right-sided ectopy during electrophysiology study.

P146 A CASE OF TYROSINE–KINASE INHIBITOR INDUCED CARDIOTOXICITY

Abstract This case is about a 69 years–old woman with no prior cardiovascular disease and a history of rheumatoid arthritis;in 2017 underwent right nephrectomy for renal cancer. A few weeks before admission, due to evidence of secondary bone lesions at a follow–up CT–scan, a single dose of the tyrosine kinase inhibitor (TKI) Nivolumab was administered. On the same evening she suffered from a severe reacutization of arthritic symptoms, that led her Oncologist to suspend treatment with nivolumab, and oral corticosteroid therapy was initiated. The following weeks remained though characterized by intense persistent asthenia, severe arthralgias, profuse diarrhea and a syncopal episode; no chest pain was reported. Given the persistence of symptoms, she went to the Emergency Room. Initial work–up revealed a complete heart block, with a previously unknown right bundle branch block (see Figure 1). At blood tests there was a significant increase of troponin I to 7616 ng/L (Normal&amp;lt;12ng/L), BNP 1113 pg/mL (NR &amp;lt; 100 pg/mL), creatinine 2.34 mg/dL (NR 0.55–1.02mg/dL), CPK 1681 U/L (NR 10–145 U/L) and D–dimer 17780 mcg/L (NR &amp;lt; 600). She was immediately transferred to our Cardiologic Intensive Care Unit, where an echocardiogram showed normally functioning ventricular chambers and no valvulopathies. Due to the ongoing acute kidney injury and the history of right nephrectomy, a coronary angiography was not immediately performed, considering the low probability of ACS (no typical symptoms, no regional wall motion abnormalities).Suspecting nivolumab–induced myocarditis, high–dose glucocorticoids were initiated. After a few days we observed persistence of bradycardia and complete AV block despite isoprenaline infusion, and due to signs of peripheral malperfusion (acute kidney injury, hypotension) a definitive leadless pace–maker Micra was implanted (this choice given the need of immunosuppressive therapy that could predispose her to device infections). After normalization of renal function, we performed a coronary angiography that showed normal coronary arteries. Despite the initial improvement of the clinical conditions, the patient suffered a fatal cardiac arrest due to electromechanical dissociation 3 weeks after admission. This case report is an important example showing the significant mortality of cardiotoxicity induced by tyrosine–kinase inhibitors, a side effect that every Cardiologist must be aware of in order to recognize it and immediately intervene with the appropriate therapy.

P13 COMPLETE ATRIOVENTRICULAR BLOCK IN A 52–YEAR–OLD MAN ASSOCIATED WITH LYMPHATIC CANCER WITH CARDIAC INVOLVEMENT

Abstract A 52–year–old man arrived at the local emergency room for worsening dyspnea and asthenia, present for about a month, but significantly worsening during the night of the access. The ECG (Figure 1) revealed complete AtrioVentricular Block (ABV) with a narrow–QRS junctional escape rhythm, with a heart rate of about 30 beats per minute (bpm). The other vital parameters were within the normal limits and no anomalies were detected on the physical examination. Medium–dose intravenous isoprenaline infusion was immediately started, with an increase in the junctional escape rate up to 50 bpm. The patient also underwent chest x–ray, which showed interstitial thickening in the pulmonary hilus, which was judged to be nonspecific. The blood chemistry was normal and the echocardiogram (Figure 2) did not show any abnormalities. Since there were no apparent reversible causes of the complete AV block, on the next day, a bicameral pacemaker was implanted via the left cephalic vein. The procedure was uneventful and the patient was discharged home two days later, in good general condition. Eight days after the discharge, surgical wound control and pacemaker control were performed, with completely normal parameters. About 15 days after the discharge the patient went back to the local emergency room for dyspnea and fever. Chest Computed Tomography (CT) without contrast medium was performed, which revealed the presence of widespread pathological mediastinal lymphadenopathy. Therefore, the patient was admitted to the internal medicine ward. An in–depth diagnostic was performed first with thoraco–abdominal angio–CT, then with Positron Emission Tomography (PET)–CT (see Figure 3), which revealed the presence of diffuse areas of fixation of the radio–drug (18F–Fluorodeoxyglucose –FDG–), at the ilo–mediastinal, hepatic, pulmonary, retrocrural, retrocaval, iliac, supra and subclavicular, and also cardiac area (activation of interatrial brown fat and between aortic root and the superior vena cava). The patient was therefore transferred to another hospital for diagnostic investigations and lymphoma therapy. In the light of the picture that emerged, the arrhythmological disease was considered to be referred to the cardiac involvement of the oncological disease; to date there are few similar cases described in the literature. Legend of the figures: Figure 1: ECG at the admission Figura 2: Echocardiogram at the admission Figura 3: PET / CT with myocardial areas of 18F–FDG fixation.

739 Atypical presentation of Takotsubo syndrome early after pacemaker implantation

Abstract Aims Takotsubo syndrome (TTS) is an acute stress-induced cardiomyopathy showing left ventricular (LV) dysfunction without obstructive coronary arteries disease. A sudden massive surge of circulatory catecholamines from an intense physical or emotional stress may play a central role in the pathogenesis of TTS. We report the case of an 87 years-old woman who developed TTS with uncommon presentation after permanent pacemaker (PM) implantation. Methods and results The patient was referred to our hospital for PM implantation because of advanced atrio-ventricular block (3:1). She suffered by rheumatoid arthritis (RA), arterial hypertension, and chronic kidney disease. Echocardiogram, performed before PM implantation, showed normal LV kinesis and normal ejection fraction (EF 60%). She was initially administered with infusion of Isoprenaline 2 mcg/min. The subsequent day, she underwent permanent dual-chamber pacemaker implantation without any complications. After 3 days, the patient complained severe asthenia and fever, together with increase of white blood cells and C reactive protein. Blood cultures were negative. We started antibiotic therapy and, suspecting a reactivation of RA, steroid therapy with infusion of methylprednisolone 40 mg/die. Electrocardiogram showed normal sinus rhythm and paced ventricular rhythm. PM interrogation showed normal function. Surprisingly, echocardiogram showed LV dysfunction with apical and medium segments akinesia, and severe EF reduction (35%). Coronary angiography documented absence of coronary obstructive lesions, assessing diagnosis of TTS. The patient was discharged 1 week after admission in good clinical condition. One week later, an echocardiogram showed apical akinesia, partial recovery of medium segments motility, and slight increase of EF (40%). The excess of catecholamines could lead to decreased cardiac muscular function and to spasm of coronary arteries: these events can lead to acute heart failure and decrease of LVEF. Furthermore, about 90% of patients with TTS are women, especially in postmenopausal period. Peculiarities of this case were the atypical symptoms of TTS and the combination of different predisposing stressors factors: female sex in postmenopausal period, anamnesis of chronic inflammatory disease, use of stress-inducing drugs (methylprednisolone and isoprenaline, the last associated with TTS after PM-implantation), atrio-ventricular block itself, and PM implantation procedure. Our findings remark that even a low-risk procedure could be a possible cause of TTS in patient with such risk factors. In our opinion, in this subset of patients, conscious sedation could be useful to reduce the stress load, together with an early procedure and consequently the minimal use of exogenous stress drugs like Isoprenaline, even if the patient is in a good clinical condition. Conclusions This case highlights TTS as a potential complication after PM implantation, especially in post-menopausal women with high pre-existing stress load.

179 ICD or not ICD? A difficult choice for a young patient presenting with palpitations in emergency department

Abstract A fit-and-well 52-year-old worker, with negative familiar story, was admitted to Emergency Department (ED) with haemodynamically unstable but well bore broad complex tachycardia of 180 b.p.m. (Figure 1). Twenty years before the patient had heart-surgery to repair atrial septal venous sinus defect with patch. The defect determined anomalous pulmonary venous return in right atrium with left to right shunt and moderate pulmonary hypertension. The surgery, 20 years before, was complicated by a single event of supraventricular tachycardia pharmacology resolved. Next follow-up was normal although at transthoracic echocardiography severe right ventricular (RV) dilation was reported. In the ED the patient had palpitation but not chest pain or dyspnoea. General clinical examination was normal but he was hypertensive (170/137 mmHg) and with heart rate of 180 b.p.m. Valsalva manoeuver was performed and adenosine (6 mg–12 mg–12 mg) was administered without benefit. Eventually, the patient was cardioverted to sinus rhythm with a single 100 J shock. His baseline ECG (Figure 2) showed sinus rhythm, normal axis, as well as right bundle branch block and T-wave inversion in leads V1–V4 and a waves with a small spike upward in lead V1 which represent characteristic epsilon waves. Successively patient was admitted to Cardiology Department where transthoracic echocardiography showed severe RV dilation and moderate hypokinesia with a tricuspid annular plane excursion of 15 mm, TAV 9.6 cm/s, fractional area change of 29%. The right atrium was moderate dilated (volume 70 ml, indexed volume 35.53 ml/m2). Left chambers were normal. No shunts were observed. An electrophysiology study with isoprenaline infusion was performed but no arrhythmias were induced. Cardiac magnetic resonance imaging (MRI) was normal save for global RV dilatation, increased RV end diastolic volume (156 ml/m2), and global RV systolic dysfunction (reduction of RV ejection fraction 31%). Arrhythmogenic cardiomyopathy was excluded as patient’s background suggested RV dilation was due the overload caused by the history of left–right shunt. Blood tests and personal history negative initially exclude myocarditis and cardiac MRI confirmed the absence of oedema. An accurate ECG analysis excluded Brugada syndrome. Following discussion between electrophysiologists, clinical cardiologists, and the patient who first need to be informed, trans-venous ICD was implanted. 179 Figure 1ECG in ED. Figure 2 Baseline ECG. Figure 3 Cardiac MRI.

567 Wolff–Parkinson–White syndrome and sport activity: a peculiar case in a young athlete

Abstract Aims Wolff–Parkinson–White (WPW) is a cardiac conduction system disorder characterized by abnormal accessory conduction pathways between the atria and the ventricles. Palpitations, presyncope, or syncope that result from supraventricular tachycardia represent classic symptoms; however, especially in young athletes, the syndrome can occur with sudden cardiac death. As result, the presence of an accessory pathway (AP) and tachycardia induced by physical activity contraindicates agonist physical activity and represents an indication to perform an electrophysiology (EP) study to stratify the arrhythmic risk, also allowing an eventual transcatheter ablation (TCA) of the AP. Methods and results An agonist football player, known since the age of 6 years for Wolff–Parkinson–White syndrome from an intermittent right midseptal parahissian AP, underwent a transesophageal EP study and subsequently ineffective TCA with radiofrequency when he was 13 years old. For evidence of intermittent ventricular preexcitation (VPE), at the age of 15 he underwent a further endocavitary EP study with documentation of poor conductive abilities of the AP. Subsequently, at the age of 17, he had a resumption of palpitation and lipotimie during effort; during another sport medical examination with an exercise stress test (EST), a persistent VPE with the start of an orthodromic atrioventricular reentrant tachycardia during the recovery phase was documented. A new EP study with isoprenaline infusion confermed the precence of the parahissian AP and the inducibility of an orthodromic atrioventricular reentrant tachycardia (Picture 1-2B); therefore, after mapping the arrhythmia, a cryoablation of AP was performed (Picture 1c-1d). Nevertheless, 12 h after the procedure, there was still evidence of intermittent VPE. The patient was then discharged and, after a month, he repeated the EST with documentation of persistent VPE which suddenly disappeared at the peak of the exercise and reappeared during the recovery phase. At the 1-year follow-up, no arrhythmic recurrence but persistence of VPE was reported and a successive EST confirmed abrupt interruption of VPE at the peak of the exercise. Due to the low arrhythmic risk, sport activity was not more restricted. Conclusions This represents an original clinical case, as it raises the question of what practical criteria should be defined as an effective TCA of AP in a competitive athlete with unfavorable anatomy. The current guidelines (Sport Cardiology and Exercise 2020) provide useful indications in linear and common cases, but may be a source of doubts in particular cases. Therefore, only the experience and the careful evaluation of the individual patient can provide the key to a correct management of the cases like this.

Ferulic Acid Alleviates Oxidative Stress-Induced Cardiomyocyte Injury by the Regulation of miR-499-5p/p21 Signal Cascade.

Objective To investigate the protective effects and regulatory mechanisms of ferulic acid on oxidative stress-induced cardiomyocyte injury. Methods We established a cardiomyocyte oxidative stress cell model by H2O2 treatment and a mouse heart injury model by isoprenaline infusion of male C57BL/6 mice. Ferulic acid was applied to treat oxidative stress-induced cardiomyocyte injury. DHE staining was used to detect ROS production. DNA fragmentation, TUNEL assay, and cleaved caspase-3 were used to analyze cell apoptosis. Real-time PCR and Western blotting were used to analyze miRNA and protein levels to investigate the regulatory mechanisms of ferulic acid on oxidative stress-induced cardiomyocyte injury. Results Ferulic acid pretreatment significantly inhibited H2O2- and isoprenaline-induced oxidative stress and cell apoptosis by promoting miR-499-5p expression and inhibiting p21 expression. MiR-499-5p inhibition reversed the protective effects of ferulic acid. Further study found that ferulic acid could also attenuate isoprenaline-induced mouse heart fibrosis and cell apoptosis by reducing oxidative stress, inflammation, and apoptosis in vivo. Conclusions We proved that ferulic acid protects cardiomyocytes from oxidative stress-induced injury by regulating the miR-499-5p/p21signaling pathway, which provides insight into the clinical application of ferulic acid in the treatment of cardiovascular diseases.

Evaluation of ventricular tachycardia inducibility after implementation of a standardized programmed ventricular stimulation protocol in patients with repaired Tetralogy of Fallot

Abstract Introduction The electrophysiologic (EP) evaluation with programmed electrical stimulation (PVS) is generally recommended in patients with repaired Tetralogy of Fallot and additional risk factors for sudden cardiac death. Nevertheless, different PVS protocols have been described. The aim of our study was to evaluate the differences in ventricular tachycardia (VT) inducibility of patients with TOF after the implementation of a standard PVS protocol in the EP laboratory of a Congenital Heart Disease reference center. Methods All patients with repaired TOF who underwent an EP study with PVS between January 2001 and October 2020 were included. The new standardized PVS protocol was performed in 2 ventricular sites (apex and outflow tract) with 3 drive trains (cycle lengths 400, 500 and 600ms) and up to 3 extrastimuli. In absence of VT induction, the protocol was repeated under isoprenaline infusion. This new protocol was implemented since January 2012. Non protocolized PVS studies before 2012 were defined as “Non-standardized”. Baseline clinical information about symptoms and previous arrhythmias was recorded as well as electrocardiogram, echocardiogram and cardiac MRI parameters. Finally, the follow-up events (ICD implantation, sudden cardiac death, global mortality, arrythmias and ICD therapies) were also retrospective recorded. Results A total of 154 EP studies with PVS were performed in 128 patients with repaired TOF. 31 of them were performed before the 1st January 2012 (non-standardized PVS) and 112 were performed with the new standardized protocol. The median follow-up was 6,5 years. Both groups had similar baseline characteristics except LVEF and RVEF, that were lower in the “Non-standardized PVS” group. There were no differences between the ventricular tachycardia inducibility of both protocols (22,3% vs 33,3%; p=0,162). The risk factors for VT inducibility were the QRS length (184,46ms vs 169,34 ms; p=0,038), the RVEF (36,25% vs 43,79; p=0,0007), the presence of ventricular ectopia (VE) (38,5% vs 20,0%; p=0,024) and previous VT (35,9% vs 13,9%; p=0,003). VT induction during EP study was related with ICD implantation (71,8% vs 21,7%, p≤0,001), VT (30,8% vs 20%, p&amp;lt;0,001) and all kind of arrythmias (VT, non-sustained VT, VE and auricular flutter) (41% vs 21,7%, p=0,005) during follow-up. A total of 6 deaths (1 in the group with induced VT and 5 in the group with non-induced VT) were recorded. Conclusions The implementation of a standardized and more complete PVS protocol in patients with repaired TOF has not shown differences in the experience of our center. The risk factors for VT inducibility were the QRS length, the RVEF, the presence of ventricular ectopia and previous VT, which have also been reported as risk factors for sudden cardiac death in previous studies. The presence of VT induction entailed more ICD implantation and more arrythmias at follow-up. Funding Acknowledgement Type of funding sources: None.

Phosphorylation at Serines 157 and 161 Is Necessary for Preserving Cardiac Expression Level and Functions of Sarcomeric Z-Disc Protein Telethonin.

Aims: In cardiac myocytes, the sarcomeric Z-disc protein telethonin is constitutively bis-phosphorylated at C-terminal residues S157 and S161; however, the functional significance of this phosphorylation is not known. We sought to assess the significance of telethonin phosphorylation in vivo, using a novel knock-in (KI) mouse model generated to express non-phosphorylatable telethonin (TcapS157/161A).Methods and Results:TcapS157/161A and wild-type (WT) littermates were characterized by echocardiography at baseline and after sustained β-adrenergic stimulation via isoprenaline infusion. Heart tissues were collected for gravimetric, biochemical, and histological analyses. At baseline, TcapS157/161A mice did not show any variances in cardiac structure or function compared with WT littermates and mutant telethonin remained localized to the Z-disc. Ablation of telethonin phosphorylation sites resulted in a gene-dosage dependent decrease in the cardiac telethonin protein expression level in mice carrying the S157/161A alleles, without any alteration in telethonin mRNA levels. The proteasome inhibitor MG132 significantly increased the expression level of S157/161A telethonin protein in myocytes from TcapS157/161A mice, but not telethonin protein in myocytes from WT mice, indicating a role for the ubiquitin–proteasome system in the regulation of telethonin protein expression level. TcapS157/161A mice challenged with sustained β-adrenergic stimulation via isoprenaline infusion developed cardiac hypertrophy accompanied by mild systolic dysfunction. Furthermore, the telethonin protein expression level was significantly increased in WT mice following isoprenaline stimulation but this response was blunted in TcapS157/161A mice.Conclusion: Overall, these data reveal that telethonin protein turnover in vivo is regulated in a novel phosphorylation-dependent manner and suggest that C-terminal phosphorylation may protect telethonin against proteasomal degradation and preserve cardiac function during hemodynamic stress. Given that human telethonin C-terminal mutations have been associated with cardiac and skeletal myopathies, further research on their potential impact on phosphorylation-dependent regulation of telethonin protein expression could provide valuable mechanistic insight into those myopathies.

Severe bradycardia in critically ill patients with COVID-19 – A cases report

IntroductionCardiac injury has been reported as an important manifestation of coronavirus disease 2019 (COVID-19) and arrhythmic events are common. Here, we report a case series of severe sinus bradycardia among patients hospitalized in intensive care units (ICU) with COVID-19.Objective and methodFrom January to May 2020, 113 patients were admitted in ICU for severe COVID-19. All these patients underwent continuous monitoring of their cardiac rhythm. Ten patients (9%) presented a bradycardia. A 24-hour Holter-ECG was subsequently performed for 7 patients.ResultsPatients had a median age of 63 years. Most of them were men and had severe acute respiratory distress syndrome. All episodes were due to sinus bradycardia with a median heart rate of 36 bpm. Bradycardia was sudden for four patients and required brief resuscitation maneuvers for one. Bradycardia was persistent for the six other patients and required transient continuous isoprenaline infusion for three. Patients had normal baseline ECG and echocardiography. A comprehensive review of patient's files ruled out bradycardia due to drug-drug interactions, myocarditis, hyperkalemia, hypoxia or vagal physical stimulation. Two patients had beta-blockers interrupted several days before bradycardia and one patient received Hydroxychloroquine discontinued 21 days before bradycardia. On the Holter-ECG, 3 recordings evoked vagal hyperactivity (low mean heart rate and elevated pNN50/RMSSD, Fig. 1, patient A), 3 others cardiac dysautonomia (SDNN < 100 ms, Fig. 1, patient B). Amongst these 10 patients, five returned home and five died from COVID-19 associated multiple-organ failure. None of them required temporary or permanent cardiac pacing (Fig. 1).ConclusionWe hypothesized that bradycardia may be due to an autonomic nervous system injury. The parallel course of COVID-19 and bradycardia suggest that these patients do not have intrinsic sinus node disease and that pacemaker implantation should not be recommended.