Cardiovascular Safety of Hydroxychloroquine-Azithromycin in 424 COVID-19 Patients.

Background and Objectives: Hydroxychloroquine (HCQ) combined with azithromycin (AZM) has been widely administered to patients with COVID-19 despite scientific controversies. In particular, the potential of prolong cardiac repolarization when using this combination has been discussed. Materials and Methods: We report a pragmatic and simple safety approach which we implemented among the first patients treated for COVID-19 in our center in early 2020. Treatment contraindications were the presence of severe structural or electrical heart disease, baseline corrected QT interval (QTc) > 500 ms, hypokalemia, or other drugs prolonging QTc that could not be interrupted. Electrocardiogram and QTc was evaluated at admission and re-evaluated after 48 h of the initial prescription. Results: Among the 424 consecutive adult patients (mean age 46.3 ± 16.1 years; 216 women), 21.5% patients were followed in conventional wards and 78.5% in a day-care unit. A total of 11 patients (2.6%) had contraindications to the HCQ-AZ combination. In the remaining 413 treated patients, there were no arrhythmic events in any patient during the 10-day treatment regimen. QTc was slightly but statistically significantly prolonged by 3.75 ± 25.4 ms after 2 days of treatment (p = 0.003). QTc prolongation was particularly observed in female outpatients <65 years old without cardiovascular disease. Ten patients (2.4%) developed QTc prolongation > 60 ms, and none had QTc > 500 ms. Conclusions: This report does not aim to contribute to knowledge of the efficacy of treating COVID-19 with HCQ-AZ. However, it shows that a simple initial assessment of patient medical history, electrocardiogram (ECG), and kalemia identifies contraindicated patients and enables the safe treatment of COVID-19 patients with HCQ-AZ. QT-prolonging anti-infective drugs can be used safely in acute life-threatening infections, provided that a strict protocol and close collaboration between infectious disease specialists and rhythmologists are applied.

Adenosine plasma level in patients with paroxysmal or persistent atrial fibrillation and normal heart during ablation procedure and/or cardioversion.

The mechanism of atrial fibrillation (AF) in patients with normal heart remains unclear. While exogenous adenosine can trigger AF, nothing is known about the behavior of endogenous adenosine plasma level (APL) at the onset of AF and during ablation procedure. Ninety-one patients (68 with paroxysmal AF: 40 males, 66 ± 16 years; 23 with persistent AF: 14 males, 69 ± 11 years) and 18 controls were included. Among paroxysmal patients: i) medical therapy alone was performed in 45 cases and ablation procedure in 23. AF was spontaneously resolutive in 6 cases; ii) 23 underwent ablation procedure and blood was collected simultaneously in a brachial vein and in the left atrium; 17 were spontaneously in sinus rhythm while 6 were in sinus rhythm after direct current cardioversion. Among persistent patients: i) in 17 patients, blood samples were collected in a brachial vein before and after direct current cardioversion; ii) in 6 patients, blood samples were collected simultaneously in a brachial vein and in left atrium before and after cardioversion during ablation procedure. CV-APL was higher in patients with persistent AF vs patients with paroxysmal AF (median [range]: 0.9[0.6-1.1] vs 0.7[0.4-1.1] µM; p < 0.001). In patients with paroxysmal AF, LA-APL increased during the AF episode (0.95[0.85-1.4] vs 2.7[1.5-7] µM; p = 0.03) and normalized in sinus rhythm after DCCV. In patients with persistent AF, LA-APL was higher than CV-APL (1.2[0.7-1.8] vs 0.9[0.6-1.1] µM; p < 0.001), and both normalized in sinus rhythm (CV-APL: 0.8[0.6-1.1] vs 0.75[0.4-1] µM; p = 0.03), (LA-APL: 1.95[1.3-3] vs 1[0.5-1.15] µM; p = 0.03). The occurrence of AF is associated with a strong increase of APL in the atrium. The cause of this increase needs further investigations.

Seasonal variations in cardiac implantable electronic device infections.

Infections of cardiac implantable electronic devices (CIEDs) have increased over the past decade. However, the impact of the climate on CIED infections is unknown. To determine whether there is a seasonal variation in CIED infections. In this single-center observational study, retrospective analysis of prospectively collected data was performed. Timone Hospital in Marseille (south-east France) is a tertiary care institution and the regional reference center for management of CIED infections. All consecutive patients with CIED extractions for infectious reasons were included over a 12-year period. We noted the mean temperature (°C), precipitation (mm) and the incidence of CIED infections over this period. Among 612 patients [mean (standard deviation) age, 72.4 (13.0) years; 74.0% male], 238 had endocarditis alone (38.9%), 249 had pocket infection alone (40.7%), and 125 had both (20.4%). We found bacterial documentation in 428 patients (70.0%), commensal in 245 (40.0%). The incidence of CIED infections was positively associated with high temperature (regression coefficient = 0.075; P = 0.01) and precipitation (regression coefficient = 0.022; P < 0.01). Seasonal variation was specific of pocket infections, whether they were associated with endocarditis or not. Subgroups with infection seasonality were: women, elderly people (> 75 years), late CIED infection and skin commensal bacterial infections. We found a seasonal variation in pocket infections, whether associated with endocarditis or not. Infections were associated with elevated temperatures and precipitation. Therefore, specific prevention strategy should be discussed in high-risk patients.

Device-Related Thrombus After Left Atrial Appendage Occlusion With the Amulet Device.

BACKGROUND: Left atrial appendage occlusion (LAAO) is increasingly used for stroke prevention in patients with atrial fibrillation who are considered unsuitable for a lifelong oral anticoagulant regimen. Recently, a single-centre study reported device-related thrombus formation in 16.7% of patients treated with the second-generation Amulet device (St. Jude Medical, St. Paul, MN, USA), presenting a potential major safety concern. As "real-world" data on device-related thrombus formation following LAAO with the Amulet occluder are scarce, we aimed to evaluate this outcome in a retrospective registry. METHODS: Clinical and tranosesophageal echocardiography data after LAAO with the Amulet in consecutive patients from three centres were collated. RESULTS: Among 38 patients (mean age 75.8 years), mean (standard deviation) CHA2DS2-VASc and HAS-BLED scores were 4.4 (1.2) and 3.4 (0.9), respectively. All patients underwent successful device placement without procedure-related adverse events. The antithrombotic regimen at discharge consisted of dual antiplatelet therapy (DAPT) in 27 patients (71.1%), single antiplatelet therapy in 10 patients (26.3%), and no antithrombotic therapy in one patient (2.6%). Device-related thrombus was observed in one patient (2.6%) despite DAPT regimen. The outcome of this patient was uncomplicated after adjustment of oral anticoagulant therapy. No patients presented with a thromboembolic event following LAAO during a mean (standard deviation) follow-up of 15 (5) months. CONCLUSIONS: In this retrospective study, device-related thrombus formation with the second-generation Amulet device was rare and occurred at a rate similar to that of the previous device. Importantly, no patient experienced a device-related thromboembolic event during follow-up. Larger real-life studies are required to confirm the safety profile of this increasingly used device.

Right ventricular and tricuspid valve function in patients chronically implanted with leadless pacemakers.

Aims: Leadless cardiac pacing has recently been proposed as alternative to conventional right ventricular (RV) pacing. With this approach, devices are directly screwed or fixed with tines in the RV wall, but the possible consequences on RV and tricuspid valve (TV) structure and function remain unknown. We thus conducted a study to evaluate this potential impact in chronically implanted patients. Methods and results: Repeated echocardiographic studies were performed prior to implantation, at discharge, and 2 months thereafter on all consecutive patients implanted with a leadless pacemaker at our centre between October 2014 and end-December 2015. Whenever possible, patients were evaluated in non-paced rhythm. Anatomical and functional parameters of RV, TV, and left cardiac structures were assessed. Overall, 23 patients (12 females, aged 85.2 ± 6.3 years) were included, with 14 implanted using Nanostim™ (Saint Jude Medical) and 9 with Micra™ (Medtronic). Indications for pacing were paroxysmal atrio-ventricular block in 12 patients, intermittent sinus bradycardia in 5, unexplained syncope in 3, and atrial fibrillation with slow ventricular rate in the remaining 3. The pacing percentage was 34 ± 42% at the last visit. Most devices were implanted in the septo-apical or mid-septal region. There were no significant changes in echocardiographic parameters observed. One patient developed significantly increased TV regurgitation, without abnormal leaflet motion or TV annulus size changes, suggesting it to be due to RV pressure changes. Conclusion: In patients chronically implanted with leadless pacemakers, there were no significant changes in heart structure and function observed, especially concerning the RV and TV.

Comparison of epicardial vs. endocardial reimplantation in pacemaker-dependent patients with device infection.

Aims: Reimplantation of cardiac implantable electronic devices (CIEDs) after extraction due to device infection is a major issue in pacemaker-dependent patients. We compared in-hospital and long-term outcomes with two techniques: epicardial reimplantation (EPI) before CIED extraction and temporary pacing (TP) with a view to delayed endocardial reimplantation. Methods and results: Two cohorts of consecutive pacemaker-dependent patients who underwent transvenous lead extraction at our tertiary centre were included in this retrospective cohort study. According to successive policies, either the EPI or the TP approach was used. In-hospital complications occurred at similar rates in the EPI (n = 59) and TP (n = 52) cohorts (37.3% vs. 32.7%, respectively; P = 0.61). Thirteen (25.0%) patients in the TP cohort eventually were reimplanted epicardially, mainly because of infection of the temporary lead. Finally, 65 patients were discharged with an epicardial device and 37 with an endocardial device. Median follow-up was 41.7 (interquartile range 34.1-51.5) months. No difference was observed in long-term mortality according to the reimplantation strategy, but use of TP was associated with a reduced risk of late endocarditis and device reintervention (hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.09-0.069, P = 0.01), whereas epicardial device reimplantation was associated with an increased risk (HR 3.62, 95% CI 1.07-12.21, P = 0.04). Conclusion: We observed similar in-hospital outcomes in our EPI and TP cohorts. Twenty-five percent of the patients initially paced by a TP strategy finally needed an epicardial device, mainly because of infection of their TP lead. Use of TP resulted in lower rates of late endocarditis and device reintervention.

Theophylline as an adjunct to control malignant ventricular arrhythmia associated with early repolarization.

Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward ICa,L current.

High-density mapping for catheter ablation of premature ventricular complexes originating from left ventricular papillary muscles: A case series.

PURPOSE: Ablation of premature ventricular complexes (PVCs) originating from left-sided papillary muscles is challenging. We tested a new approach by performing high-density mapping of PVC. METHODS AND RESULTS: We used a 20-pole deflectable spiral catheter during ablation procedures in four consecutive patients. Three presented with mitral valve prolapse, one with dilated cardiomyopathy. PVC burden was 24 ± 13%. The procedures lasted 182 ± 55.4 minutes, including 10 ± 3.2 minutes of radiofrequency. In all patients, mapping evidenced internal primary activation relative to the left ventricle shell (mean distance 21.3 ± 5.1 mm). Endocavitary prematurity was -38.3 ± 4.8 ms. Primary ablation success was achieved for all patients. CONCLUSIONS: High-density mapping of the papillary muscles in the left ventricle using a spiral catheter may be feasible. We identified the PVC foci away from the left ventricular shell. This consolidates the assumption for the origin of these ectopic beats at the junction between the chordae tendineae and the papillary muscles.

Ventricular Arrhythmia Occurrence and Compliance in Patients Treated With the Wearable Cardioverter Defibrillator Following Percutaneous Coronary Intervention.

BACKGROUND: The wearable cardioverter defibrillator (WCD) is a life-saving therapy in patients with high risk of arrhythmic death. We aimed to evaluate ventricular arrhythmia (VA) occurrence rate and compliance with the WCD during the first 90 days following myocardial revascularisation with percutaneous coronary intervention (PCI) in patients with left ventricular ejection fraction (LVEF) <30%. METHODS: From September 2015 to November 2016, clinical characteristics, WCD recordings and compliance data of the aforementioned subset of patients were prospectively collected. RESULTS: Twenty-four patients (men=20, 80%) were included in this analysis. Mean age was 56±10 years and mean LVEF at enrolment was 26.6±4.3%. During a mean wearing period of 3.0±1.3 months, two episodes of VA occurred in two patients (8.3%): one successfully treated with WCD shock and one with spontaneous termination. The mean and median daily use of the WCD was 21.5hours and 23.5hours a day, respectively. Eighteen patients (75%) wore the WCD more than 22hours a day. CONCLUSIONS: The rate of VA, during the WCD period use after myocardial revascularisation with PCI, was high in our study. Otherwise it underlined that patient compliance is critical during the WCD period use. Remote monitoring and patient education are keys to achieve good compliance.

Outcomes and costs associated with two different lead-extraction approaches: a single-centre study.

AIMS: We sought to compare outcomes and costs of a stepwise approach to transvenous lead extraction (TLE) involving laser-assisted sheaths or mechanical polypropylene sheaths, with/without crossover. METHODS AND RESULTS: We prospectively included patients who underwent TLE (between August 2013 and December 2014) as part of a stepwise approach involving simple traction, lead snaring, and sheath-assisted dissection; all of these patients underwent a first-line polypropylene-sheath-extraction approach (Group A). The comparison group (Group B) was consecutive patients who had undergone TLE before August 2013, during which laser-assisted sheath extraction was the first-line approach. The number of patients in Group B was adjusted to match the number who eventually needed sheaths in Group A. Procedural data, outcomes, and costs were compared between groups (comparison of approaches) and in patients who needed sheath-assisted extraction (comparison of techniques). Overall, 521 leads were extracted (131 patients in Group A, 104 in Group B). Radiological and clinical success rates were similar; crossover from polypropylene to laser sheaths was needed in 10 patients in Group A (vs. none in Group B). Radiological (P< 0.001) and clinical (P= 0.01) success rates were higher and were achieved with a lower radiation exposure (P= 0.03) with laser sheaths in patients (60 in each group) who needed sheath-assisted extraction. Complication rates were similar in both groups (P= 0.66) but two deaths occurred in Group B. The laser approach had higher material cost (P= 0.002). CONCLUSIONS: Although laser-assisted TLE was more effective than polypropylene sheath-assisted TLE, the latter was associated with fewer complications and was more cost-effective.

Spare Adenosine A2a Receptors Are Associated With Positive Exercise Stress Test In Coronary Artery Disease.

During exercise, cardiac oxygen-consumption increases and the resulting low oxygen level in myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A2A receptor (A2AR). According to the "spare receptor" pharmacological model, a strong A2AR-mediated response can occur in the context of a large number of receptors remaining unoccupied, activation of only a weak fraction of A2AR (evaluated using KD) resulting in maximal cAMP production (evaluated using EC50), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A2AR are present in CAD patients to correct ischemia. Seventeen patients with angiographically-documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A2AR-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A2AR was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients, and in none of the controls. Adenosine plasma-concentration increased by 60% at peak exercise in patients only (p<0.01). Most patients (65%), and none of the controls, had spare A2AR (identified when EC50/KD≤0.1) and a low A2AR-expression (mean: -37% vs controls; p<0.01). All patients with spare A2AR had a positive EST whereas the subjects without spare A2AR had a negative EST (p<0.05). Spare A2AR are therefore associated with positive EST in CAD patients and their detection may be used as a diagnostic marker.

Ischaemia-modified albumin during experimental apnoea.

Ischaemia-modified albumin (IMA) is a marker of the release of reactive oxygen species (ROS) during hypoxaemia. In elite divers, breath-hold induces ROS production. Our aim was to evaluate the kinetics of IMA serum levels during apnea. Twenty breath-hold divers were instructed to perform a submaximal static breath-hold. Twenty non-diver subjects served as controls. Blood samples were collected at rest, every minute, at the end of breath-hold, and 10 min after recovery. The IMA level increased after 1 min of breath-hold (p < 0.003) and remained high until recovery. Divers were separated into 2 groups: subjects who held their breath for less than 4 min (G-4) and those who held it for more than 4 min (G+4). After 3 min of apnoea, the increase of IMA was higher in the G-4 group than in the G+4 group (p < 0.008). However, at the end of apnoea, the IMA level did not differ between groups. If IMA level was globally correlated with the apnoea duration, it is interesting to note that the higher IMA level was not found in the best divers. Similarly, if arterial blood oxygen saturation (SpO2) was globally inversely correlated with apnoea duration, the lowest SpO2 at the end of breath-hold was not found in the divers that performed the best apnoea. We concluded that these divers save their oxygen. The IMA level provides a useful measure of resistance to hypoxaemia.

Diaphragm movement sensor for phrenic nerve monitoring during cryoballoon procedures: the first clinical evaluation.

Background and aims: Right phrenic nerve palsy is the most frequent complication of cryoballoon procedures. The SMARTFREEZE™ console (Boston Scientific, St. Paul, MN, USA) has integrated a new tool for diaphragm monitoring-the Diaphragm Movement Sensor; however, it has not been evaluated in clinical practice. We aimed to assess the diagnostic performance of the Diaphragm Movement Sensor based on compound motor action potential data recorded simultaneously. Methods: Thirty consecutive patients (mean age 63.2 ± 10.2 years) were included. We simultaneously recorded the compound motor action potential and the Diaphragm Movement Sensor during cryoapplications in the right pulmonary veins. The right phrenic nerve was paced at 60 per minute, 12 V and 2.9 ms. Compound motor action potential monitoring with a 30% decrease cutoff for the diagnosis of phrenic nerve threatening was considered the gold standard. The Diaphragm Movement Sensor decrease threshold was also set at 30%. Results: Considering compound motor action potential monitoring, phrenic nerve threatening occurred 11 times (in seven patients) among 84 cryoapplications (13.1%) at the right pulmonary veins. The sensitivity and specificity of the Diaphragm Movement Sensor were, respectively, 33% (95% CI: 7%-70%) and 49% (95% CI: 38%-61%; P < 0.001). The predictive positive and negative values for the Diaphragm Movement Sensor were, respectively, 7% (95% CI: 2%-20%) and 86% (95% CI: 72%-95%). The Diaphragm Movement Sensor gave an erroneous diagnosis in 44/84 cryoapplications (52.4%). Conclusions: The diagnostic performance of the Diaphragm Movement Sensor is low, and the relevance of its use in clinical practice may be debated.

Fall in oxygen tension of culture medium stimulates the adenosinergic signalling of a human T cell line.

We examined the short-course expression of various parameters involved in the adenosinergic signalling of a human T cell line during in vitro decrease of the medium culture oxygen tension mimicking in vivo hypoxia. Fall of 92 mmHg in oxygen tension of culture medium induced in CEM, a CD4+ human T cell line, a continuous production of hypoxia-inducing factor-1α with a plateau value at 9 h, a rapid increase in adenosine production peaking at 3 h and a decrease in adenosine deaminase peaking at 6 h. The adenosine A(2A) receptor (A(2A)R) protein level of CEM cells was enhanced with a peak at 6 h. Intracellular 3',5'-cyclic adenosine monophosphate accumulated in CEM cells with a maximal level at 9 h. These results show that a human-cultured T cells line can upregulate its own adenosine production and A(2A)R expression during exposure to acute hypoxia. Hypoxia-increased stimulation of the adenosinergic signalling of T cells may have immunosuppressive properties and, consequently, A(2A)R agonists may have therapeutic relevance.

Histopathological effects and evolution of transvenous ß-radiation applications in right and left atria: an animal study.

AIMS: ß-radiation is a novel potential energy source for the creation of myocardial lesions. While the feasibility of delivering ß-radiation via a deflectable transvenous catheter has been described, dose effects and the time course of histopathological changes have not been previously assessed. The purpose of this study was to characterize pathological aspects of cardiac lesions induced by ß-radiation in an animal model at various stages of evolution and in response to different dose exposures. METHODS AND RESULTS: Nine dogs and one pig were studied. The cavotricuspid isthmus, antrum of pulmonary veins (PVs), and mitral isthmus were irradiated (25, 50, 75, or 100 Gy) with strontium-yttrium-90, delivered via a deflectable catheter (cavotricuspid isthmus and mitral isthmus) or a double-loop catheter (antrum of PVs). Eighteen lesions were created. Animals were sacrificed at 2 weeks, 1 month, 3 months, or 6 months. Lesions were processed for morphometric histopathological analyses. Over the first month, lesions were characterized by inflammation, haemorrhage, and myocyte necrosis. Thereafter, fibrotic replacement was predominant. Transmurality of lesions was observed in 50% of cases, with no dose-response effect (P = 0.976). Surface fibrin thrombus was present in 50% of cases and was essentially limited to lesions assessed within the first month. No neighbouring injury or pulmonary venous stenosis was observed. CONCLUSIONS: Atrial lesions created by ß-radiation are characterized by an inflammatory phase with surface fibrin thrombosis during the first month and replacement fibrosis thereafter. No appreciable dose-response effect was noted within the 25-100 Gy range tested.

Characteristics of recurrent clockwise atrial flutter after previous radiofrequency catheter ablation for counterclockwise isthmus-dependent atrial flutter.

AIMS: Isthmus-dependent (ID) clockwise (CW) atrial flutters (AFl) are rare in comparison with counterclockwise (CCW) AFl. Little is known about clinical and electrophysiological characteristics of CW AFl occurring after previous radiofrequency (RF) catheter ablation of CCW AFl. We sought to compare CW AFl de novo vs. CW AFl occurring after previous CCW AFl RF ablation. METHODS AND RESULTS: A total of 246 procedures of RF catheter ablation for AFl from January 2009 to January 2011 were reviewed. Clinical and electrophysiological data were analysed. Patients were excluded if they were in sinus rhythm at the beginning of the procedure, if they had concomitant/previous atrial fibrillation ablation, or if AFl was not ID. Twenty-seven patients presented CW AFl (10.9% of all ID AFl), including 10 CW AFl occurring after a previous RF catheter ablation for CCW AFl. Mean time for recurrence after the previous procedure of CCW AFl RF ablation was 3.5 years. They were younger (61.6 ± 11 years) than patients with CW AFl de novo (74.0 ± 7.2 years; P = 0.005). Bidirectional isthmus block was obtained in all patients. There was a significant difference in terms of double potential separation after ablation (155 ± 31 ms for CW AFl de novo vs. 111 ± 7 ms for recurrent CW AFl; P = 0.028). No differences were observed concerning CHADS score, AFl cycle length, and electrocardiogram typical pattern for CW AFl between the two groups. CONCLUSION: Patients with CW AFl occurrence after CCW AFl RF catheter ablation are younger than patients with CW AFl de novo. They also have a smaller interspike interval after block completion.