Ischaemic stroke in women with atrial fibrillation: temporal trends and clinical implications.

BACKGROUND AND AIMS: Female sex has been linked with higher risk of ischaemic stroke (IS) in atrial fibrillation (AF), but no prior study has examined temporal trends in the IS risk associated with female sex. METHODS: The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) study included all patients with AF in Finland from 2007 to 2018. Ischaemic stroke rates and rate ratios were computed. RESULTS: Overall, 229 565 patients with new-onset AF were identified (50.0% women; mean age 72.7 years). The crude IS incidence was higher in women than in men across the entire study period (21.1 vs. 14.9 events per 1000 patient-years, P < .001), and the incidence decreased both in men and women. In 2007-08, female sex was independently associated with a 20%-30% higher IS rate in the adjusted analyses, but this association attenuated and became statistically non-significant by the end of the observation period. Similar trends were observed when time with and without oral anticoagulant (OAC) treatment was analysed, as well as when only time without OAC use was considered. The decrease in IS rate was driven by patients with high IS risk, whereas in patients with low or moderate IS risk, female sex was not associated with a higher IS rate. CONCLUSIONS: The association between female sex and IS rate has decreased and become non-significant over the course of the study period from 2007 to 2018, suggesting that female sex could be omitted as a factor when estimating expected IS rates and the need for OAC therapy in patients with AF.

Critical limb-threatening ischaemia and microvascular transformation: clinical implications.

BACKGROUND AND AIMS: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology. METHODS: Clinical high-resolution imaging of CLTI patients (n = 50) and muscle samples from amputated CLTI limbs (n = 40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischaemia model in rabbits (n = 24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome. RESULTS: Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P < .01) in CLTI muscles. Critical limb-threatening ischaemia muscle microvasculature also exhibited capillary enlargement (P < .001) and further arterialization along worsening of myofibre atrophy and detaching of capillaries from myofibres. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P < .05) and tissue outcome (P < .01) under chronic ischaemia in rabbits and in healthy, normal rabbit muscle. CONCLUSIONS: These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.

Ischemic Stroke Temporally Associated With New-Onset Atrial Fibrillation: A Population-Based Registry-Linkage Study.

BACKGROUND: Limited data exist on the temporal relationship between new-onset atrial fibrillation (AF) and ischemic stroke and its impact on patients' clinical characteristics and mortality. METHODS: A population-based registry-linkage database includes all patients with new-onset AF in Finland from 2007 to 2018. Ischemic stroke temporally associated with AF (ISTAF) was defined as an ischemic stroke occurring within ±30 days from the first AF diagnosis. Clinical factors associated with ISTAF were studied with logistic regression and 90-day survival with Cox proportional hazards analysis. RESULTS: Among 229 565 patients with new-onset AF (mean age, 72.7 years; 50% female), 204 774 (89.2%) experienced no ischemic stroke, 12 209 (5.3%) had past ischemic stroke >30 days before AF, and 12 582 (5.8%) had ISTAF. The annual proportion of ISTAF among patients with AF decreased from 6.0% to 4.8% from 2007 to 2018. Factors associated positively with ISTAF were higher age, lower education level, and alcohol use disorder, whereas vascular disease, heart failure, chronic kidney disease cancer, and psychiatric disorders were less probable with ISTAF. Compared with patients without ischemic stroke and those with past ischemic stroke, ISTAF was associated with ≈3-fold and 1.5-fold risks of death (adjusted hazard ratios, 2.90 [95% CI, 2.76-3.04] and 1.47 [95% CI, 1.39-1.57], respectively). The 90-day survival probability of patients with ISTAF increased from 0.79 (95% CI, 0.76-0.81) in 2007 to 0.89 (95% CI, 0.87-0.91) in 2018. CONCLUSIONS: ISTAF depicts the prominent temporal clustering of ischemic strokes surrounding AF diagnosis. Despite having fewer comorbidities, patients with ISTAF had worse, albeit improving, survival than patients with a history of or no ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04645537. URL: https://www.encepp.eu; Unique identifier: EUPAS29845.

Long-term continuous monitoring of arrhythmias in pigs with insertable cardiac monitors.

Arrhythmia detection is essential when assessing the safety of novel drugs and therapies in preclinical studies. Many short-term arrhythmia monitoring methods exist, including non-invasive ECG and Holter. However, there are no reliable, long-term, non-invasive, or minimally invasive methods for cardiac arrhythmia follow-up in large animals that allows free movement with littermates. A long follow-up time is needed when estimating the impact of long-lasting drugs or therapies, such as gene therapy. We evaluated the feasibility and performance of insertable cardiac monitors (ICMs) in pigs for minimally invasive, long-term monitoring of cardiac arrhythmias that allows free movement and species-specific behavior. Multiple implantation sites were tested to assess signal quality. ICMs recognized reliably many different arrhythmias but failed to detect single extrasystoles. They also over-diagnosed T-waves, resulting in oversensing. Muscle activity and natural startles of the animals caused noise, leading to a heterogeneous signal requiring post-recording evaluation. In spite of these shortcomings, the ICMs showed to be very useful for minimally invasive long-term monitoring of cardiac rhythm in pigs.

Temporal trends of gender disparities in oral anticoagulant use in patients with atrial fibrillation.

AIMS: To investigate sex-specific temporal trends in the initiation of oral anticoagulant (OAC) therapy among patients diagnosed with atrial fibrillation (AF) in Finland between 2007 and 2018. METHODS: The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) Study included all patients with incident AF in Finland from 2007 to 2018. The primary outcome was the initiation of any OAC therapy. RESULTS: We identified 229,565 patients with new-onset AF (50.0% women; mean age 72.7 years). The initiation of OAC therapy increased continuously during the observation period. While women were more likely to receive OAC therapy overall, after adjusting for age, stroke risk factors and other confounding factors, female sex was associated with a marginally lower initiation of OACs (unadjusted and adjusted hazard ratios comparing women to men: 1.08 (1.07-1.10) and 0.97 (0.96-0.98), respectively). Importantly, the gender disparities in OAC use attenuated and reached parity by the end of the observation period. Furthermore, when only patients eligible for OAC therapy according to the contemporary guidelines were included in the analyses, the gender inequalities in OAC initiation appeared minimal. Implementation of direct OACs for stroke prevention was slightly slower among women. CONCLUSION: This nationwide retrospective cohort study covering all patients with incident AF in Finland from 2007 to 2018 observed that although female sex was initially associated with a lower initiation of OAC therapy, the sex-related disparities resolved over the course of the study period.

Thromboembolic and bleeding complications after elective cardioversion of atrial fibrillation: a nationwide cohort study.

AIMS: Elective cardioversion (ECV) is routinely used in atrial fibrillation (AF) to restore sinus rhythm. However, it includes a risk of thromboembolism even during adequate oral anticoagulation treatment. The aim of this study was to evaluate the risk of thromboembolic and bleeding complications after ECV in a real-life setting utilizing data from a large AF population. METHODS AND RESULTS: This nationwide register-based study included all (n = 9625) Finnish AF patients undergoing their first-ever ECV between 2012 and 2018. The thromboembolic and bleeding complications within 30 days after ECV were analysed. The mean age of the patients was 67.7 ± 9.9 years, 61.2% were men, and the mean CHA2DS2-VASc score was 2.6 ± 1.6. Warfarin was used in 6245 (64.9%) and non-vitamin K oral anticoagulants (NOACs) in 3380 (35.1%) cardioversions. Fifty-two (0.5%) thromboembolic complications occurred, of which 62% were ischaemic strokes, 25% transient ischaemic attacks, and 13% other systemic embolisms. Thromboembolic events occurred in 14 (0.4%) NOAC-treated patients and in 38 (0.6%) warfarin-treated patients (odds ratio 0.77; confidence interval: 0.42-1.39). The median time from ECV to the thromboembolic event was 2 days, and 78% of the events occurred within 10 days. Age and alcohol abuse were significant predictors of thromboembolic events. Among warfarin users, thromboembolic complications were more common with international normalized ratio (INR) <2.5 than INR ≥2.5 (0.9% vs. 0.4%, P = 0.026). Overall, 27 (0.3%) bleeding events occurred. CONCLUSION: The rate of thromboembolic and bleeding complications related to ECV was low without significant difference between NOAC- and warfarin-treated patients. With warfarin, INR ≥2.5 at the time of cardioversion reduced the risk of thromboembolic complications.

Elective Cardiac Procedure Patients Have Low Preoperative Cardiorespiratory Fitness.

Preoperative cardiorespiratory fitness may influence the recovery after cardiac procedure. The aim of this study was to investigate the cardiorespiratory fitness of patients scheduled for elective cardiac procedures, using a six-minute walk test, and compare the results with a population-based sample of Finnish adults. Patients (n=234) awaiting percutaneous coronary intervention or coronary angiography, coronary artery bypass grafting, aortic valve replacement or mitral valve surgery performed the six-minute walk test. VO2max was calculated based on the walk test. The patients were compared to a population-based sample of 60-69-year-old Finnish adults from the FinFit2017 study. The mean six-minute walk test distances (meters) and VO2max (ml/kg/min) of the patient groups were: 452±73 and 24.3±6.9 (coronary artery bypass grafting), 499±84 and 27.6±7.2 (aortic valve replacement), 496±85 and 27.4±7.3 (mitral valve surgery), and 519±90 and 27.3±6.9 (percutaneous coronary intervention or coronary angiography). The population-based sample had significantly greater walk test distance (623±81) and VO2max (31.7±6.1) than the four patient groups (all p-values<0.001). All patient groups had lower cardiorespiratory fitness than the reference population of 60-69-year-old Finnish adults. Particularly the coronary artery bypass grafting group had a low cardiorespiratory fitness, and therefore might be prone to complications and challenging rehabilitation after the operation.

Association of income and educational levels on initiation of oral anticoagulant therapy in patients with incident atrial fibrillation: A Finnish nationwide cohort study.

AIMS: Socioeconomic disparities have been reported in the outcomes of patients with atrial fibrillation (AF). We assessed the hypothesis that AF patients with higher income or educational level are more frequently initiated with oral anticoagulant (OAC) therapy for stroke prevention. METHODS: The nationwide registry-based Finnish AntiCoagulation in Atrial Fibrillation cohort covers all patients with AF from all levels of care in Finland. Patients were divided into income quartiles according to their highest annual income during 2004-2018 and into three categories based on educational attainment. The outcome was the first redeemed OAC prescription. RESULTS: We identified 239 222 patients (mean age 72.7 ± 13.2 years, 49.8% female) with incident AF during 2007-2018. Higher income was associated with higher OAC initiation rate: compared to the lowest income quartile the adjusted SHRs (95% CI) for OAC initiation were 1.09 (1.07-1.10), 1.13 (1.11-1.14) and 1.13 (1.12-1.15) in the second, third and fourth income quartiles, respectively. Patients in the highest educational category had a slightly lower OAC initiation rate than patients in the lowest educational category (adjusted SHR 0.92 [95% CI 0.90-0.93]). Income-related disparities were larger and education-related disparities only marginal among patients at high risk of ischemic stroke. The socioeconomic disparities in OAC initiation within 1-year follow-up decreased from 2007 to 2018. The adoption of direct OACs as the initial anticoagulant was faster among patients with higher income or educational levels. CONCLUSION: These findings highlight potential missed opportunities in stroke prevention, especially among AF patients with low income, whereas the education-related disparities in OAC initiation appear controversial.

Atrial septal defect patients have an elevated risk for infective endocarditis.

Background. It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort. Methods. We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry. Results. Altogether, 8322 patients with ASD and 39,237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact. In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the patients with ASD and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20-29.46) in patients with ASD compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11). Conclusions. The incidence of IE in patients with ASD was higher than in the general population. Mortality associated with IE was higher in patients with ASD compared to controls.

Plasma N-terminal pro-B-type natriuretic peptide in the detection of aortic valve stenosis.

BACKGROUND: Systolic murmur suggestive of aortic valve origin is a common accidental finding, particularly in the elderly. Usually, it is due to aortic stenosis (AS) or aortic sclerosis (ASc). Currently, echocardiography is used to differentiate AS from ASc. Plasma N-terminal (NT)-prohormone BNP (NT-proBNP) is known to correlate with the severity of AS. We assessed whether NT-proBNP separates AS from ASc. METHODS: The study population consisted of three groups: AS (n = 87, age 77 ± 7 years), ASc (n = 76, age 72 ± 10 years), and healthy controls (n = 101, age 55 ± 10 years). All subjects underwent transthoracic echocardiography and measurement of plasma NT-proBNP. Patients with diseases known to increase NT-proBNP were excluded. RESULTS: The crude plasma NT-proBNP (median; IQR) in AS patients (413; 165-1055 ng/l) was significantly higher compared to ASc patients (96; 53-237 ng/l, p < 0.001) and healthy controls (50; 29-76 ng/l, p < 0.001). After adjusting for the confounding factors (age, coronary artery disease, renal function and diastolic blood pressure), plasma NT-proBNP remained significantly higher in AS patients as compared to ASc (p < 0.002) and controls (p < 0.0001). In the receiver-operating characteristic curve for NT-proBNP to identify AS from ASc and controls, the area under the curve was 0.878 with optimal cutoff of 115 ng/l. In addition, using 115 ng/l to separate AS from ASc yielded sensitivity of 0.885, and negative predictive value of 0.808. CONCLUSIONS: NT-proBNP was sensitive to identify AS and useful to rule out AS in patients with systolic murmur in the left ventricular outflow tract provided the patient does not have coexisting disease known to impact NT-proBNP.

Rural-urban and geographical differences in prognosis of atrial fibrillation in Finland: a nationwide cohort study.

AIMS: Rural-urban disparities have been reported in the outcomes of cardiovascular diseases. We assessed whether rural-urban or other geographical disparities exist in the risk of ischemic stroke (IS) and death in patients with atrial fibrillation (AF) in Finland. METHODS: The registry-based FinACAF cohort study covers all patients with AF from all levels of care in Finland from 2007 to 2018. Patients were divided into rural-urban categories and into hospital districts (HDs) based on their municipality of residence. RESULTS: We identified 222,051 patients (50.1% female; mean age 72.8 years; mean follow-up 3.9 years) with new-onset AF, of whom 15,567 (7.0%) patients suffered IS and 72,565 (32.7%) died during follow-up. The crude IS rate was similar between rural and urban areas, whereas the mortality rate was lower in urban areas (incidence rate ratios (IRRs) with 95% confidence intervals (CIs) 0.97 (0.93-1.00) and 0.92 (0.91-0.93), respectively). However, after adjustments, urban residence was associated with slightly higher IS and mortality rates (IRRs with 95% CIs 1.05 (1.01-1.08) and 1.06 (1.04-1.07), respectively). The highest crude IS rate was in the East Savo HD and the lowest in Åland, whereas the highest crude mortality rate was in the Länsi-Pohja HD and the lowest in the North Ostrobothnia HD (IRRs with 95% CIs compared to Helsinki and Uusimaa HD for IS 1.46 (1.28-1.67) and 0.79 (0.62-1.01), and mortality 1.24 (1.16-1.32) and 0.97 (0.93-1.00), respectively. CONCLUSIONS: Rural-urban differences in prognosis of AF in Finland appear minimal, whereas considerable disparities exist between HDs.

Impact of minimal invasive extracorporeal circulation on perioperative intravenous fluid management in coronary artery bypass surgery.

OBJECTIVE: Compare the use of blood products and intravenous fluid management in patients scheduled for coronary artery bypass surgery and randomized to minimal invasive extracorporeal circulation (MiECC) and conventional extracorporeal circulation (CECC). METHODS: A total of 240 patients who were scheduled for their first on-pump CABG, were randomized to MiECC or CECC groups. The study period was the first 84 hours after surgery. Hemoglobin <80 g/l was used as transfusion trigger. RESULTS: Red blood cell transfusions intraoperatively were given less often in the MiECC group (23.3% vs 9.2%, p = 0.005) and the total intravenous fluid intake was significantly lower in the MiECC group (3300 ml [2950-4000] vs 4800 ml [4000-5500], p < 0.001). Hemoglobin drop also was lower in the MiECC group (35.5 ± 8.9 g/l vs 50.7 ± 9 g/l, p < 0.001) as was hemoglobin drop percent (25.3 ± 6% vs 35.3 ± 5.9%, p < 0.001). Chest tube drainage output was higher in the MiECC group (645 ml [500-917.5] vs 550 ml [412.5-750], p = 0.001). Particularly, chest tube drainage in up to 600 ml category, was in benefit of CECC group (59.1% vs 40.8%, p = 0.003). ROC curve analysis showed that patients with hemoglobin level below 95 g/l upon arrival to intensive care unit was associated with increased risk of developing postoperative atrial fibrillation (POAF) (p = 0.002, auc = 0.61, cutoff <95, sensitivity = 0.47, positive predictive value = 0.64). CONCLUSION: MiECC reduced the intraoperative need for RBC transfusion and intravenous fluids compared to the CECC group, also reducing hemoglobin drop compared to the CECC group in CABG surgery patients. Postoperative hemoglobin drop was a predictor of POAF.

Impact of perfusion method on perioperative red blood cell transfusions and new-onset postoperative atrial fibrillation in mitral valve surgery patients.

INTRODUCTION: Red blood cell (RBC) transfusions are common in cardiac surgery and reportedly associated with increased mortality and morbidity, including increased risk of postoperative new-onset atrial fibrillation (NOAF). The aim of this study was to compare minimal invasive extracorporeal circulation (MiECC) and conventional extracorporeal circulation (CECC) in terms of RBC transfusions and the incidence of NOAF in mitral valve surgery. METHODS: The study population consisted of 89 MiECC and 169 CECC patients undergoing mitral valve surgery as an isolated procedure (80.6% of the patients) or in combination with coronary artery bypass grafting (19.4% of patients). 79.4% of the patients were male and the mean age was 62.1 years. RESULTS: 30.0% of patients aged < 65 years and 48.1% of patients aged ≥ 65 years needed RBC transfusion. The overall need for RBC transfusions did not differ between the treatment groups. Among patients < 65 years of age transfusions of ≥ 3 units were less frequent in MiECC than in CECC patients (OR 0.31, 95% CI 0.10-0.98, p = 0.045). The overall incidence of NOAF was 41.8% with no significant difference between MiECC and CECC groups. Red blood cell transfusions were associated with an increased risk of NOAF in an unadjusted analysis but not after adjustment for age and sex (OR 1.25, 95% CI 0.64-2.43, p = 0.515). CONCLUSIONS: In mitral valve surgery MiECC compared to CECC was associated with less need of RBC units and platelets, particularly in patients aged < 65 years. Use of RBC transfusions was associated with increased risk of NOAF significantly only in unadjusted analysis.

Perceived health among percutaneous coronary intervention patients over a six-year follow-up period.

AIMS AND OBJECTIVES: The study was conducted to describe long-term perceived health among patients after a percutaneous coronary intervention as well as clarify the associations between perceived health and various factors. BACKGROUND: Perceived health is an important outcome for coronary heart disease patients who have undergone percutaneous coronary intervention. Poor perceived health predicts low adherence to treatment, morbidity and mortality. DESIGN: An explanatory and descriptive survey with a six-year follow-up (STROBE Statement: File S1). METHODS: Baseline data (n = 416) were collected in 2013, with follow-up data collected from the same study group in 2019 (n = 154) at two university hospitals and three central hospitals in Finland. The employed self-reported questionnaire was based on the EuroQoL visual analogue scale and EuroQol five-dimensional scale. Data were analysed using descriptive statistics and multivariate methods. RESULTS: Perceived health did not significantly differ four months or six years after percutaneous coronary intervention. The respondents most commonly reported pain and discomfort (62.1%), problems in mobility (50.3%), issues with usual activities (27.5%), and anxiety and depression (24.0%). Managing self-care (8.5%) was least likely to be an issue for the respondents. A majority of the reported problems were of a mild nature. The consumption of an adequate amount of vegetables, lower systolic blood pressure, regular follow-up treatment, lack of prior invasive procedures, and younger age predicted better scores for both perceived health and its separate dimensions. CONCLUSION: Regular follow-up is important to ensure after percutaneous coronary intervention to identify patients with pain and discomfort, mobility problems, depression and anxiety. Healthcare professionals should pay particular attention to elderly patients, who have undergone severe invasive procedures. RELEVANCE TO CLINICAL PRACTICE: This study confirms the importance of regular follow-ups for post-percutaneous coronary intervention patients. PATIENT OR PUBLIC CONTRIBUTION: Patients have completed a self-reported questionnaire based on informed consent.

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.

Use of paclitaxel-coated balloons in clinical setting is not associated with increased mortality compared with plain balloon angioplasty in femoropopliteal lesions.

OBJECTIVE: To investigate mortality and causes of death associated with the use of paclitaxel-coated balloon (PCB) compared with plain balloon (PB) angioplasty in the treatment of femoropopliteal artery lesions in real-world clinical setting. METHODS: This retrospective, single-center study included patients who underwent percutaneous femoropopliteal artery angioplasty without stenting between years 2014 and 2020. Patients were stratified into PCB and PB groups according to the index procedure. Those who had undergone any prior or subsequent intervention using drug-eluting technology were excluded from the PB group. Long-term survival was estimated up to 5 years using the Kaplan-Meier method, and risk factors for all-cause mortality were assessed in a multivariable analysis. Causes of death were retrieved from a national registry. RESULTS: The study included 139 patients treated with PB and 190 with PCB. Patients treated with PCB had a higher prevalence of chronic pulmonary disease (27% vs 17%; P = .02) and were less often on anticoagulant therapy (34% vs 48%; P = .01) compared with patients in the PB group. Those treated with PB were more likely to have chronic limb-threatening ischemia (CLTI; 82% vs 72%; P = .04). Ipsilateral perioperative amputation rate was significantly higher in the PB group (7% vs 1%; P = .01). There were no major differences in other 30-day outcomes between the groups and no differences in the rates of reinterventions and ipsilateral amputations during a mean follow-up time of 2.7 ± 1.9 years. Survival at 1 year in the PCB group was 83% ± 3% compared with 73% ± 4% in the PB group (P = .0001). The 5-year survival estimates were 56% ± 5% and 37% ± 5%, respectively. PCB use was independently associated with decreased risk of mortality (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.50-0.97). Independent risk factors for increased mortality were age (HR, 1.04 per year; 95% CI, 1.02-1.06), cardiac insufficiency (HR, 1.60; 95% CI, 1.12-2.27), chronic renal insufficiency (HR, 2.04; 95% CI, 1.47-2.85), anticoagulation therapy (HR, 1.65, 95% CI, 1.16-2.34), and CLTI (HR, 2.85; 95% CI, 1.51-5.39). In the PCB group, 63% of deaths were due to cardiovascular causes compared with 42% in the PB group (P < .01). CONCLUSIONS: The use of PCB is safe, and there is no concern of increased mortality after the procedure based on the 5-year survival estimates.

Mental health conditions and risk of first-ever ischaemic stroke and death in patients with incident atrial fibrillation: A nationwide cohort study.

BACKGROUND: Atrial fibrillation (AF) patients with mental health conditions (MHCs) have higher incidence of ischaemic stroke (IS) than patients without MHC, but whether this results from direct impact of MHCs or relates to higher prevalence of comorbidities and differences in the use of oral anticoagulant (OAC) therapy is unclear. We assessed the hypothesis that MHCs independently increase the risk of IS in patients with incident AF. METHODS: The nationwide FinACAF cohort covered all 203,154 patients diagnosed with incident AF without previous IS or transient ischaemic attack in Finland during 2007-2018. MHCs of interest were depression, bipolar disorder, anxiety disorder, schizophrenia and any MHC. The outcomes were first-ever IS and all-cause death. RESULTS: The patients' (mean age 73.0 ± 13.5 years, 49.0% female) mean follow-up time was 4.3 (SD 3.3) years and 16,272 (8.0%) experienced first-ever IS and 63,420 (31.2%) died during follow-up. After propensity score matching and adjusting for OAC use, no MHC group was associated with increased IS risk (adjusted SHRs (95% CI): depression 0.961 (0.857-1.077), bipolar disorder 1.398 (0.947-2.006), anxiety disorder 0.878 (0.718-1.034), schizophrenia 0.803 (0.594-1.085) and any MHC 1.033 (0.985-1.085)). Lower rate of OAC use partly explained the observed higher crude IS incidence in patients with any MHC. Depression, schizophrenia and any MHC were associated with higher all-cause mortality (adjusted HRs [95% CI]: 1.208 [1.136-1.283], 1.543 [1.352-1.761] and 1.149 [1.116-1.175], respectively). CONCLUSIONS: In this nationwide retrospective cohort study, MHCs were not associated with the incidence of first-ever IS in patients with AF.

Discontinuing low-dose acetylsalicylic acid after gastrointestinal bleeding is associated with increased mortality.

BACKGROUND: Gastrointestinal bleeding is a common clinical problem in patients using low-dose acetylsalicylic acid (ASA). It is uncertain whether aspirin should continue to be used in patients who develop acute gastrointestinal bleeding during low-dose ASA therapy. AIMS: To assess whether ASA should be continued in patients who develop GI bleeding during low-dose ASA. METHODS: All patients admitted to an academic hospital for acute gastrointestinal bleeding between 2009 and 2011 were reviewed retrospectively. Clinical characteristics, comorbidities, medications and treatments were recorded from the patient records. Patients were divided into two groups based on continuing or discontinuing ASA after discharge. RESULTS: A total of 548 patients were included. ASA was continued in 282 (51.5%) (ASAc group) and discontinued in 266 (48.5%) patients (ASAd group). ASAc patients had more often coronary artery disease (57.8% vs. 42.5%, p < .001) and peripheral artery disease (17.4% vs. 9.0%, p = .004) than ASAd patients, whereas no differences were found in other comorbidities. There was no difference in 30-day all-cause mortality between ASAd and ASAc groups. However, after adjustment for age, gender and comorbidities, one-year all-cause mortality was double in the ASAd group (hazard ratio 2.16, 95% confidence interval 1.39-3.35). ASAd and ASAc groups did not differ with respect to cardiovascular mortality (4.9% vs. 5.3%, p = .811, respectively) or re-bleeding (10.2% vs. 9.2%, p = .713, respectively). CONCLUSION: Continuing low-dose ASA after gastrointestinal bleeding was associated with lower all-cause mortality during the first year without increasing the risk of re-bleeding.