Adenoviral Gene Therapy Vectors in Clinical Use-Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety.

Adenoviral vectors are commonly used in clinical gene therapy. Apart from oncolytic adenoviruses, vector replication is highly undesired as it may pose a safety risk for the treated patient. Thus, careful monitoring for the formation of replication-competent adenoviruses (RCA) during vector manufacturing is required. To render adenoviruses replication deficient, their genomic E1 region is deleted. However, it has been known for a long time that during their propagation, some viruses will regain their replication capability by recombination in production cells, most commonly HEK293. Recently developed RCA assays have revealed that many clinical batches contain more RCA than previously assumed and allowed by regulatory authorities. The clinical significance of the higher RCA content has yet to be thoroughly evaluated. In this review, we summarize the biology of adenovirus vectors, their manufacturing methods, and the origins of RCA formed during HEK293-based vector production. Lastly, we share our experience using minimally RCA-positive serotype 5 adenoviral vectors based on observations from our clinical cardiovascular gene therapy studies.

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study.

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3-10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36-2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Intramyocardial adenoviral vascular endothelial growth factor-D∆N∆C gene therapy does not induce ventricular arrhythmias.

BACKGROUND: The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-DΔNΔC (AdVEGF-D) gene therapy (GT) to alleviate symptoms in refractory angina (RA) patients. In KAT301, 30 patients with RA were randomized to AdVEGF-D or the control group in 4:1 ratio. The treatment was found to be feasible, increasing myocardial perfusion and reducing angina symptoms at 1-year follow-up. However, there is some evidence suggesting that the intramyocardial delivery route and overexpression of (vascular endothelial growth) VEGFs might induce ventricular arrhythmias. Thus, we investigated whether intramyocardial AdVEGF-D GT increases the risk of ventricular arrhythmias in patients treated for RA. METHODS: We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up. RESULTS: We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. CONCLUSIONS: In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.

Vernakalant for Cardioversion of Recent-Onset Atrial Fibrillation in the Emergency Department: The SPECTRUM Study.

INTRODUCTION: Intravenous vernakalant is a therapeutic option for symptomatic, recent-onset atrial fibrillation (AF). This secondary analysis from the large SPECTRUM study assessed the safety and effectiveness of vernakalant when used in the emergency department setting (ED group) or in an inpatient hospital setting (non-ED group). METHODS: This post hoc analysis of the international, observational, post-authorization SPECTRUM study included 1,289 and 720 recent-onset AF episodes in adults in the ED and non-ED groups, respectively. Safety endpoints included the evaluation of pre-defined health outcomes of interest (HOIs) and other serious adverse events (SAEs) during vernakalant treatment and during the first 24 h after the last infusion. Effectiveness endpoints comprised the rate of successful vernakalant cardioversion, the time from the start of the vernakalant infusion to cardioversion, and the length of hospital stay. Data were analysed using descriptive statistics. RESULTS: The safety profile of vernakalant was similar in the ED and non-ED groups. In the ED group, 12 pre-defined HOIs were reported in 11 patients (0.9%); all but one occurred within 2 h after start of the first infusion. These events comprised nine significant bradycardia cases, of which one was associated with transient hypotension and three with sinus arrest, and 2 cases of atrial flutter with 1:1 conduction. Five other SAEs were reported. All patients with vernakalant-related events recovered without sequelae. No Torsade de Pointes, ventricular fibrillation, or deaths occurred. Successful cardioversion was reported in 67.8% (95% confidence interval: 65.2-70.4) and 66.4% (62.5-70.1) of episodes, with a median time to conversion of 11.0 and 10.0 min in the ED and non-ED groups, respectively. Patients had a median length of hospital stay of 7.4 h and 17.1 h in the ED and non-ED groups, respectively. CONCLUSION: Intravenous vernakalant was well tolerated with similar cardioversion rates in patients treated in the ED or non-ED setting and does not require admission to a coronary care unit or intensive care unit. First-line treatment with vernakalant could allow an early discharge in patients with recent-onset AF treated in the ED.

Sequence of cardiovascular autonomic alterations after fingolimod initiation.

BACKGROUND: Homeostasis between heart rate and blood pressure is based on several interacting regulatory reflexes, which become influenced by fingolimod initiation. The aim of this study was to determine the sequence of changes in cardiovascular autonomic regulation after fingolimod initiation. METHODS: Twenty-seven patients with relapsing-remitting multiple sclerosis underwent continuous electrocardiogram recording during the first 6 hr after the first dose of fingolimod. In addition to the time interval between two consecutive R-peaks (RR interval), blood pressure and heart rate variability (HRV) were measured on hourly basis. Cardiac parasympathetic and sympathetic regulation were assessed by the different components of HRV. RESULTS: HRV demonstrated an enhancement in cardiac parasympathetic regulation starting 1 hr after the first dose of fingolimod. Blood pressure started to decrease 2 hr and sympathetic cardiac regulation 3 hr after fingolimod initiation. Recovery in RR interval, systolic and diastolic blood pressure, as well as in cardiac autonomic regulation started after 5 hr postdose, whereas pulse pressure (difference between systolic and diastolic blood pressure) continued to increase at the time of hospital discharge. CONCLUSIONS: RR interval, blood pressure, as well as the parasympathetic and sympathetic components of cardiac autonomic regulation alter sequentially in different temporal pattern after fingolimod initiation. These findings enhance the understanding of the effects of fingolimod initiation on cardiovascular autonomic regulation in real life.

Can we predict the failure of electrical cardioversion of acute atrial fibrillation? The FinCV study.

BACKGROUND: Data on predictors of failure of electrical cardioversion of acute atrial fibrillation are scarce. METHODS: We explored 6,906 electrical cardioversions of acute (<48 hours) atrial fibrillation in 2,868 patients in a retrospective multicenter study. RESULTS: The success rate of electrical cardioversion was 94.2%. In 26% of unsuccessful cardioversions, the cardioversion was performed successfully later. Antiarrhythmic drug therapy, short (<12 hours) duration of atrial fibrillation episode, advanced age, permanent pacemaker, history of atrial fibrillation episodes within 30 days before cardioversion, and ß-blockers were independent predictors of unsuccessful electrical cardioversion. In the subgroup of patients with cardioversion of the first atrial fibrillation episode (N = 1,411), the short duration of episode (odds ratio [OR] = 2.28; 95% confidence interval [CI] 1.34-3.90, P = 0.003) and advanced age (OR = 1.03; 95% CI 1.02-1.05, P < 0.001) were the only independent predictors of unsuccessful cardioversion. After successful cardioversion, the rate of early (<30 days) clinical recurrence of atrial fibrillation was 17.3%. The index cardioversion being performed due to the first atrial fibrillation episode was the only predictor of remaining in the sinus rhythm. CONCLUSION: A short (<12 hours) duration of acute atrial fibrillation is a significant predictor of unsuccessful cardioversion, especially during the first attack. First atrial fibrillation episode was the only predictor of remaining in the sinus rhythm.

Unintended Deformation of Stents During Bifurcation PCI: An OCTOBER Trial Substudy.

BACKGROUND: Unintended deformation of implanted coronary stents can lead to loss of coronary access, stent thrombosis and coronary events during follow-up. The incidence, mechanisms and clinical outcomes of unintended stent deformations (USD) during complex bifurcation stenting are not well characterized. OBJECTIVES: In a prespecified analysis of the OCTOBER (European Trial on Optical Coherence Tomography Optimized Bifurcation Event Reduction) trial, we aimed to: 1) determine the incidence and characterize mechanisms of USD identified by optical coherence tomography (OCT); and 2) evaluate physician's detection and correction of accidental abluminal rewiring and USD. METHODS: OCT scans were analyzed for accidental abluminal rewiring and USD. When USD was identified, the plausible mechanism was determined by analysis of all procedural OCT scans and the corresponding angiograms. RESULTS: USD was identified by the core lab in 9.3% (55/589) of OCT-guided cases. Accidental abluminal rewiring was the cause in 44% (24/55), and guide catheter collision was the cause in 40% (22/55) of cases. USD was found in 18.5% of all cases with left main bifurcation percutaneous coronary intervention. The total incidence of abluminal rewiring was 33 in 32 OCT-guided cases (5.4%) and was corrected by physicians in 18 of 33 appearances (54.5%). The 2-year major adverse cardiac event rate for patients with untreated USD (n = 30) was 23.3%, whereas patients with confirmed or possibly corrected USD (n = 25) had no events during follow-up. CONCLUSIONS: USD was associated with adverse procedural complications and cardiac events during follow-up when not identified and corrected. The predominant mechanisms were undetected abluminal rewiring and guide catheter collision. Left main bifurcation percutaneous coronary intervention was a particular risk with USD detected in 18.5% of cases.

Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease.

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.

Electromagnetic interference with cardiac pacemakers and implantable cardioverter-defibrillators from low-frequency electromagnetic fields in vivo.

AIMS: Electromagnetic interference (EMI) can pose a danger to workers with pacemakers and implantable cardioverter-defibrillators (ICDs). At some workplaces electromagnetic fields are high enough to potentially inflict EMI. The purpose of this in vivo study was to evaluate the susceptibility of pacemakers and ICDs to external electromagnetic fields. METHODS AND RESULTS: Eleven volunteers with a pacemaker and 13 with an ICD were exposed to sine, pulse, ramp, and square waveform magnetic fields with frequencies of 2-200 Hz using Helmholtz coil. The magnetic field flux densities varied to 300 µT. We also tested the occurrence of EMI from an electronic article surveillance (EAS) gate, an induction cooktop, and a metal inert gas (MIG) welding machine. All pacemakers were tested with bipolar settings and three of them also with unipolar sensing configurations. None of the bipolar pacemakers or ICDs tested experienced interference in any of the exposure situations. The three pacemakers with unipolar settings were affected by the highest fields of the Helmholtz coil, and one of them also by the EAS gate and the welding cable. The induction cooktop did not interfere with any of the unipolarly programmed pacemakers. CONCLUSION: Magnetic fields with intensities as high as those used in this study are rare even in industrial working environments. In most cases, employees can return to work after implantation of a bipolar pacemaker or an ICD, after an appropriate risk assessment. Pacemakers programmed to unipolar configurations can cause danger to their users in environments with high electromagnetic fields, and should be avoided, if possible.

Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study.

AIMS: To determine the incidence and risk factors of arrhythmic complications after electrical cardioversion of acute atrial fibrillation (AF). METHODS AND RESULTS: Our retrospective multicentre study collected data from 7660 cardioversions of acute (<48 h) AF in 3143 consecutive patients. Immediate arrhythmic complications were evaluated after 6906 (90.2%) electrical cardioversions performed in 2868 patients. We also assessed the predictors of arrhythmic complications and whether post-cardioversion bradycardia or asystole led to later a permanent pacemaker implantation. Altogether, 63 (0.9%) electrical cardioversions resulted in bradyarrhythmia in 54 patients. Asystole (>5 s) occurred immediately after 51 cardioversions leading to a short resuscitation in seven cases and two patients needed extrinsic pacing after the cardioversion. In nine cases, asystole was followed by bradycardia. Bradycardic ventricular rate (<40 b.p.m.) alone was seen after 12 procedures. No ventricular arrhythmias needing intervention were detected. Old age [odds ratio (OR) 1.1; 95% confidence interval (CI) 1.05-1.10, P < 0.0001], female sex (OR 2.5; 95% CI 1.4-4.8, P = 0.004), and unsuccessful cardioversion (OR 2.2; 95% CI 1.1-4.6, P = 0.03) were the independent predictors of bradycardic complications. Slow ventricular rate, use of digoxin, beta blocker, or antiarrhythmic medication did not increase the risk of bradycardic complications. Pacemaker was implanted in 24 (44.4%) patients after a median delay of 66 days. CONCLUSION: Bradycardic complications are rare and usually benign after cardioversion of acute AF. They seem to reflect sinus node dysfunction and often result in later implantation of a permanent pacemaker.

Novel Technologies in the Detection of Atrial Fibrillation: Review of Literature and Comparison of Different Novel Technologies for Screening of Atrial Fibrillation.

Atrial fibrillation (AF) is globally the most common arrhythmia associated with significant morbidity and mortality. It impairs the quality of the patient's life, imposing a remarkable burden on public health, and the healthcare budget. The detection of AF is important in the decision to initiate anticoagulation therapy to prevent thromboembolic events. Nonetheless, AF detection is still a major clinical challenge as AF is often paroxysmal and asymptomatic. AF screening recommendations include opportunistic or systematic screening in patients ≥65 years of age or in those individuals with other characteristics pointing to an increased risk of stroke. The popularities of well-being and taking personal responsibility for one's own health are reflected in the continuous development and growth of mobile health technologies. These novel mobile health technologies could provide a cost-effective solution for AF screening and an additional opportunity to detect AF, particularly its paroxysmal and asymptomatic forms.

Frequency of cardioversions as an additional risk factor for stroke in atrial fibrillation - the FinCV-4 study.

BACKGROUND: Patients with atrial fibrillation (AF) are selected for oral anticoagulation based on individual patient characteristics. There is little information on how clinical AF burden associates with the risk of ischaemic stroke or systemic embolism (SSE). The aim of this study was to explore the association of the frequency of cardioversions (CV) as a measure of clinical AF burden on the long-term SSE risk, with a focus on patients at intermediate stroke risk based on CHA2DS2-VASc score. For these patients, additional SSE risk stratification by assessing CV frequency may aid in the decision on whether to initiate oral anticoagulation. METHODS: This retrospective analysis of FinCV Study from years 2003-2010 included 2074 patients who were not using any oral anticoagulation (long term or temporary) after CVs and undergoing a total of 6534 CVs for AF from emergency departments of three hospitals. Two study groups were formed: high CV frequency (mean interval between CVs ≤12 months and low frequency (>12 months). RESULTS: A total of 107 SSEs occurred during a mean follow-up of 5.4 years. The event rates per 100 patient-years were 1.82 and 0.67 in high versus low CV frequency groups, respectively. After adjustment for CHA2DS2-VASc score, CV frequency independently predicted SSE (HR, 2.87 [95% CI, 1.47 to 5.64]; p = .002) at 3 years. Competing risk analysis also identified CV frequency (sHR, 2.70 [95% CI, 1.38-5.31]; p = .004) as an independent predictor for SSE. In patients with CHA2DS2-VASc score 1 and low CV frequency, the SSE risk was only 0.08 per 100 patient-years. CONCLUSIONS: Frequency of CVs for symptomatic AF episodes provides additional information on stroke risk in AF patients with CHA2DS2-VASc score 1.Key messagesThis retrospective study offers a unique opportunity to observe the natural course of AF patients with infrequent episodes of clinical arrhythmia when they were not using OAC (before introduction of CHA2DS2-VASc score).Stroke or systemic embolism rate was very low (0.08 per 100 patient-years) in patients with one CHA2DS2-VASc point who visited the emergency room for cardioversion less than once a year.Frequency of cardioversions can be used for additional risk stratification in patients at intermediate risk of stroke based on CHA2DS2-VASc score.

Late incidence and recurrence of new-onset atrial fibrillation after isolated surgical aortic valve replacement.

OBJECTIVES: Atrial fibrillation (AF) is a common complication after cardiac surgery. More knowledge is needed about long-term AF recurrence and adverse outcomes related to new-onset AF (NOAF) during the index hospitalization. METHODS: A total of 1073 patients underwent isolated surgical aortic valve replacement at the 4 participating hospitals (2002-2014). After the exclusion of patients with a history of any preoperative AF, the final study population included 529 patients in the bioprosthetic and 253 patients in the mechanical valve prosthesis cohort. Median follow-up time was 5.4 (interquartile range, 3.4-8.2) years in the combined cohort. RESULTS: Altogether 333 (42.6%) patients had in-hospital NOAF and 250 (32.0%) AF after hospital discharge. In the mechanical cohort, 64 (25.3%) experienced in-hospital NOAF and 74 (29.2%) AF after hospital discharge, whereas in the bioprosthetic cohort, 269 (50.9%) patients had in-hospital NOAF and 176 (33.3%) AF after hospital discharge. Patients with NOAF during the index hospital stay had a multifold risk of AF after hospital discharge in the combined cohort (hazard ratio [HR], 3.68; 95% confidence interval [CI], 2.82-4.81; P < .0001) as well as in both cohorts separately (bioprosthetic: HR, 4.35; 95% CI, 3.05-6.22; P < .001; mechanical: HR, 2.54; 95% CI, 1.59-4.03; P < .001). Patients with an in-hospital NOAF also had a significantly higher adjusted risk of death during the follow-up in the mechanical (HR, 2.05; 95% CI, 1.10-3.82; P = .025) and bioprosthetic (HR, 1.63; 95% CI, 1.17-2.28; P = .004) valve prosthesis cohorts. CONCLUSIONS: NOAF during the index hospitalization is associated with a 2- to 4-fold risk of later AF and 1.6- to 2.0-fold risk of all-cause mortality after mechanical and bioprosthetic surgical aortic valve replacement.

Continuous mHealth Patch Monitoring for the Algorithm-Based Detection of Atrial Fibrillation: Feasibility and Diagnostic Accuracy Study.

BACKGROUND: The detection of atrial fibrillation (AF) is a major clinical challenge as AF is often paroxysmal and asymptomatic. Novel mobile health (mHealth) technologies could provide a cost-effective and reliable solution for AF screening. However, many of these techniques have not been clinically validated. OBJECTIVE: The purpose of this study is to evaluate the feasibility and reliability of artificial intelligence (AI) arrhythmia analysis for AF detection with an mHealth patch device designed for personal well-being. METHODS: Patients (N=178) with an AF (n=79, 44%) or sinus rhythm (n=99, 56%) were recruited from the emergency care department. A single-lead, 24-hour, electrocardiogram-based heart rate variability (HRV) measurement was recorded with the mHealth patch device and analyzed with a novel AI arrhythmia analysis software. Simultaneously registered 3-lead electrocardiograms (Holter) served as the gold standard for the final rhythm diagnostics. RESULTS: Of the HRV data produced by the single-lead mHealth patch, 81.5% (3099/3802 hours) were interpretable, and the subject-based median for interpretable HRV data was 99% (25th percentile=77% and 75th percentile=100%). The AI arrhythmia detection algorithm detected AF correctly in all patients in the AF group and suggested the presence of AF in 5 patients in the control group, resulting in a subject-based AF detection accuracy of 97.2%, a sensitivity of 100%, and a specificity of 94.9%. The time-based AF detection accuracy, sensitivity, and specificity of the AI arrhythmia detection algorithm were 98.7%, 99.6%, and 98.0%, respectively. CONCLUSIONS: The 24-hour HRV monitoring by the mHealth patch device enabled accurate automatic AF detection. Thus, the wearable mHealth patch device with AI arrhythmia analysis is a novel method for AF screening. TRIAL REGISTRATION: ClinicalTrials.gov NCT03507335; https://clinicaltrials.gov/ct2/show/NCT03507335.

Inadequate oral anticoagulation with warfarin in women with cerebrovascular event and history of atrial fibrillation: the FibStroke study.

BACKGROUND: Women with atrial fibrillation (AF) may be treated less actively with oral anticoagulation (OAC) than men. PATIENTS AND METHODS: We assessed sex differences in the implementation of stroke risk stratification with CHADS2 and CHA2DS2-VASc scores and reasons not to use OAC in 1747 AF patients suffering their first cerebrovascular event after the AF diagnosis. RESULTS: Women were older and had more often a high stroke risk (CHADS2/CHA2DS2-VASc ≥2) than men (p < .001). On admission, 46.4% of women and 48.2% of men were on OAC with no sex difference (p = .437). However, of patients without OAC, 74.4% of women and 49.5% of men should have been on OAC based on CHADS2/CHA2DS2-VASc ≥2 (p < .001). Conversely, 34.8% of men and 17.5% of women on OAC had a low or moderate risk (CHADS2/CHA2DS2-VASc 0-1, p < .001). A valid reason to omit OAC was reported in 38.6% of patients and less often in women (p < .001). CONCLUSIONS: OAC was underused in high-risk AF patients, particularly women, but prescribed often in men with low or moderate stroke risk. Reasons for omitting OAC treatment were poorly reported, particularly for women. KEY MESSAGE Women were at higher stroke risk, but were less often treated with oral anticoagulation (OAC). Men were more often on OAC at low or moderate stroke risk. Reasons for omitting guideline based OAC were poorly reported, particularly for women.

Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-DΔNΔC Gene Therapy Containing Residual Replication-Competent Adenoviruses.

Biological bypass through induced angiogenesis by vascular endothelial growth factor D (VEGF-D) gene therapy (GT) is a new concept for the treatment of cardiac ischemia. Serotype 5 adenoviruses are used in the clinical trials for transferring the VEGF-D cDNA into the ischemic myocardium. However, the presence of replication-competent vectors in the adenovirus products is a widely recognized problem that may pose a potential safety risk to the treated patients. We compared three different VEGF-D GT production lots containing different levels of replication-competent adenoviruses (RCA) tested in 3 × 1010 viral particles (vp): <10 RCA (VEGF-D L-RCA1), 10-100 RCA (VEGF-D H-RCA2), and 100-200 RCA (VEGF-D H-RCA3), as measured by a novel droplet digital polymerase chain reaction (PCR) RCA assay in a preclinical rabbit model (n = 21). ß-galactosidase encoding nonclinical-grade preparation was used as a nonangiogenic control. Each preparation was injected into the right semimembranosus muscle using dose of 1 × 1011 vp. Efficacy of the products was tested by the combination of contrast pulse sequencing ultrasound and modified Miles assay as well as quantifying the total cross-sectional area of capillaries. Safety, immunogenicity, toxicity, biodistribution, and shedding were assessed by general histology, serial measurements of C-reactive protein, white blood cell count and body temperature as well as using quantitative real-time PCR with primers targeted to the VEGF-D and replication-permitting E1 sequences. We found no significant differences in the efficacy or safety between the study groups. Most importantly, no detectable presence of RCA-specific E1 sequence was found in any samples tested, indicating that no detectable vector replication took place in vivo. We conclude that relatively low levels of RCA in adenoviral GT products may not be as important major safety issue as previously anticipated.

Automatic Mobile Health Arrhythmia Monitoring for the Detection of Atrial Fibrillation: Prospective Feasibility, Accuracy, and User Experience Study.

BACKGROUND: Atrial fibrillation (AF) is the most common tachyarrhythmia and associated with a risk of stroke. The detection and diagnosis of AF represent a major clinical challenge due to AF's asymptomatic and intermittent nature. Novel consumer-grade mobile health (mHealth) products with automatic arrhythmia detection could be an option for long-term electrocardiogram (ECG)-based rhythm monitoring and AF detection. OBJECTIVE: We evaluated the feasibility and accuracy of a wearable automated mHealth arrhythmia monitoring system, including a consumer-grade, single-lead heart rate belt ECG device (heart belt), a mobile phone application, and a cloud service with an artificial intelligence (AI) arrhythmia detection algorithm for AF detection. The specific aim of this proof-of-concept study was to test the feasibility of the entire sequence of operations from ECG recording to AI arrhythmia analysis and ultimately to final AF detection. METHODS: Patients (n=159) with an AF (n=73) or sinus rhythm (n=86) were recruited from the emergency department. A single-lead heart belt ECG was recorded for 24 hours. Simultaneously registered 3-lead ECGs (Holter) served as the gold standard for the final rhythm diagnostics and as a reference device in a user experience survey with patients over 65 years of age (high-risk group). RESULTS: The heart belt provided a high-quality ECG recording for visual interpretation resulting in 100% accuracy, sensitivity, and specificity of AF detection. The accuracy of AF detection with the automatic AI arrhythmia detection from the heart belt ECG recording was also high (97.5%), and the sensitivity and specificity were 100% and 95.4%, respectively. The correlation between the automatic estimated AF burden and the true AF burden from Holter recording was >0.99 with a mean burden error of 0.05 (SD 0.26) hours. The heart belt demonstrated good user experience and did not significantly interfere with the patient's daily activities. The patients preferred the heart belt over Holter ECG for rhythm monitoring (85/110, 77% heart belt vs 77/109, 71% Holter, P=.049). CONCLUSIONS: A consumer-grade, single-lead ECG heart belt provided good-quality ECG for rhythm diagnosis. The mHealth arrhythmia monitoring system, consisting of heart-belt ECG, a mobile phone application, and an automated AF detection achieved AF detection with high accuracy, sensitivity, and specificity. In addition, the mHealth arrhythmia monitoring system showed good user experience. TRIAL REGISTRATION: ClinicalTrials.gov NCT03507335; https://clinicaltrials.gov/ct2/show/NCT03507335.

Continuous 24-h Photoplethysmogram Monitoring Enables Detection of Atrial Fibrillation.

Aim: Atrial fibrillation (AF) detection is challenging because it is often asymptomatic and paroxysmal. We evaluated continuous photoplethysmogram (PPG) for signal quality and detection of AF. Methods: PPGs were recorded using a wrist-band device in 173 patients (76 AF, 97 sinus rhythm, SR) for 24 h. Simultaneously recorded 3-lead ambulatory ECG served as control. The recordings were split into 10-, 20-, 30-, and 60-min time-frames. The sensitivity, specificity, and F1-score of AF detection were evaluated for each time-frame. AF alarms were generated to simulate continuous AF monitoring. Sensitivities, specificities, and positive predictive values (PPVs) of the alarms were evaluated. User experiences of PPG and ECG recordings were assessed. The study was registered in the Clinical Trials database (NCT03507335). Results: The quality of PPG signal was better during night-time than in daytime (67.3 ± 22.4% vs. 30.5 ± 19.4%, p < 0.001). The 30-min time-frame yielded the highest F1-score (0.9536), identifying AF correctly in 72/76 AF patients (sensitivity 94.7%), only 3/97 SR patients receiving a false AF diagnosis (specificity 96.9%). The sensitivity and PPV of the simulated AF alarms were 78.2 and 97.2% at night, and 49.3 and 97.0% during the daytime. 82% of patients were willing to use the device at home. Conclusion: PPG wrist-band provided reliable AF identification both during daytime and night-time. The PPG data's quality was better at night. The positive user experience suggests that wearable PPG devices could be feasible for continuous rhythm monitoring.

Wrist Band Photoplethysmography Autocorrelation Analysis Enables Detection of Atrial Fibrillation Without Pulse Detection.

Atrial fibrillation is often asymptomatic and intermittent making its detection challenging. A photoplethysmography (PPG) provides a promising option for atrial fibrillation detection. However, the shapes of pulse waves vary in atrial fibrillation decreasing pulse and atrial fibrillation detection accuracy. This study evaluated ten robust photoplethysmography features for detection of atrial fibrillation. The study was a national multi-center clinical study in Finland and the data were combined from two broader research projects (NCT03721601, URL: https://clinicaltrials.gov/ct2/show/NCT03721601 and NCT03753139, URL: https://clinicaltrials.gov/ct2/show/NCT03753139). A photoplethysmography signal was recorded with a wrist band. Five pulse interval variability, four amplitude features and a novel autocorrelation-based morphology feature were calculated and evaluated independently as predictors of atrial fibrillation. A multivariate predictor model including only the most significant features was established. The models were 10-fold cross-validated. 359 patients were included in the study (atrial fibrillation n = 169, sinus rhythm n = 190). The autocorrelation univariate predictor model detected atrial fibrillation with the highest area under receiver operating characteristic curve (AUC) value of 0.982 (sensitivity 95.1%, specificity 93.7%). Autocorrelation was also the most significant individual feature (p < 0.00001) in the multivariate predictor model, detecting atrial fibrillation with AUC of 0.993 (sensitivity 96.4%, specificity 96.3%). Our results demonstrated that the autocorrelation independently detects atrial fibrillation reliably without the need of pulse detection. Combining pulse wave morphology-based features such as autocorrelation with information from pulse-interval variability it is possible to detect atrial fibrillation with high accuracy with a commercial wrist band. Photoplethysmography wrist bands accompanied with atrial fibrillation detection algorithms utilizing autocorrelation could provide a computationally very effective and reliable wearable monitoring method in screening of atrial fibrillation.

Health-related quality of life after coronary artery bypass grafting: a review of randomized controlled trials.

Objective outcome measures (i.e., survival, mortality, morbidity, complication rate, symptom recurrence, and need for re-interventions) have long been used as benchmarks for successful cardiac surgery, including coronary artery bypass grafting (CABG). Along with these objectively measurable outcome indicators, acquired improvement by cardiac surgery in subjectively experienced health-related quality of life (HRQoL) has gained importance during the last decade in cardiac surgical research. If an increasing proportion of adult patients referred for CABG are elderly, octogenarians or even nonagenarians, the acquired HRQoL benefit from bypass surgery should be considered to be at least as important an outcome measure as potentially marginal improvement in life expectancy or longevity alone. To achieve the maximal HRQoL benefit and to optimize patient selection, a comprehensive analysis and understanding of contributors that affect pre- and postoperative self-perceived HRQoL is essential. These include patient-related characteristics (e.g., demographics and underlying comorbidities), surgical technique-related factors, and healthcare-related attributes. In this paper we review the randomized controlled trials published during the last ten years to analyze the effect of CABG on HRQoL. Specifically, we focus on the differences between the on-pump and off-pump (OPCAB) bypass techniques, investigate the factors that contribute to post-CABG HRQoL, and study post-CABG HRQoL in elderly patients.