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1.
Europace ; 23(Supplement_2): ii34-ii39, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837756

RESUMO

The RACE trial was one of the first landmark trials to establish whether restoring and maintaining sinus rhythm could reduce morbidity and mortality in patients with atrial fibrillation (AF). Its neutral outcome shaped clinical decision-making for almost 20 years. However, there were two important treatment-related factors associated with mortality of rhythm control therapy at that time: One was safety of antiarrhythmic drug therapy, and the other one withdrawal of anticoagulation after restoration of sinus rhythm. Both concerns have been overcome, and, moreover, important knowledge considering the importance of time for the treatment of AF has been gained. These insights led to the concept of the EAST-AFNET 4 trial, and after more than two decades in the pursuit of ongoing therapeutic improvement, early rhythm control therapy has demonstrated to reduce a composite of cardiovascular death, stroke, and hospitalization for worsening of HF or acute coronary syndrome, by 21% (first primary outcome, absolute reduction 1.1 per 100 patient-years). For this entire period, Harry Crijns characterized the treatment of AF patients, and contributed decisively to realizing the benefit of rhythm control therapy. It is almost easier to list the clinical trials without Harry's involvement than to list those which he co-designed and led.

2.
Clin Res Cardiol ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33779809

RESUMO

AIMS: CMR feature tracking strain (CMR-FT) provides prognostic information. However, there is a paucity of data in hypertrophic cardiomyopathy (HCM). We sought to analyze global CMR-FT parameters in all four cardiac chambers and to assess associations with NT-proBNP and cardiac troponin T (hsTnT) in patients with HCM. METHODS: This retrospective study included 144 HCM patients and 16 healthy controls with CMR at 1.5 T. Analyses were performed on standard steady-state free precession cine (SSFP) CMR data using a commercially available software. Global left ventricular (LV) strain was assessed as longitudinal (LVLAX-GLS), circumferential (LVLAX-GCS) and radial strain (LVLAX-GRS) on long -axis (LAX) and as LVSAX-GCS and LVSAX-GRS on short- axis (SAX). Right ventricular (RV-GLS), left atrial (LA-GLS) and right atrial (RA-GLS) strain were assessed on LAX. RESULTS: We found LVLAX-GLS [- 18.9 (- 22.0, - 16.0), - 23.5 (- 25.5, - 22.0) %, p = 0.0001), LVSAX-GRS [86.8 (65.9-115.5), 119.6 (91.3-143.7) %, p = 0.001] and LALAX-GLS [LA2CH-GLS 29.2 (19.1-37.7), LA2CH-GLS 38.2 (34.3-47.1) %, p = 0.0036; LA4CH-GLS 22.4 (14.6-30.7) vs. LA4CH-GLS 33.4 (28.4-37.3) %, p = 0.0033] to be impaired in HCM compared to healthy controls despite normal LVEF. Furthermore, LV and LA strain parameters were impaired in HCM with elevated NT-proBNP and/or hsTnT, despite preserved LVEF compared to HCM with normal biomarker levels. There was a moderate correlation of LV and LA CMR-FT with levels of NT-proBNP and hsTnT. CONCLUSION: CMR-FT reveals LV and LA dysfunction in HCM despite normal LVEF. The association between impaired LV strain and elevated NT-proBNP and hsTnT indicates a link between unapparent functional abnormalities and disease severity in HCM. Typical CMR-FT findings in patients with hypertrophic cardiomyopathy.

3.
J Chin Med Assoc ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33742992

RESUMO

BACKGROUND: Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing. METHODS: We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing. RESULTS: A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥ 1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the non-recommended 60-mg dose. Compared with the recommended 60-mg group, the non-recommended 30-mg group had a higher proportion of patients aged ≥ 75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥ 75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group. CONCLUSION: The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label.

4.
Cell Signal ; 82: 109970, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33677066

RESUMO

BACKGROUND: There is ongoing interest in generating cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) to study human cardiac physiology and pathophysiology. Recently we found that norepinephrine-stimulated calcium currents (ICa) in hiPSC-cardiomyocytes were smaller in conventional monolayers (ML) than in engineered heart tissue (EHT). In order to elucidate culture specific regulation of ß1-adrenoceptor (ß1-AR) responses we investigated whether action of phosphodiesterases (PDEs) may limit norepinephrine effects on ICa and on cytosolic cAMP in hiPSC-cardiomyocytes. Results were compared to adult human atrial cardiomyocytes. METHODS: Adult human atrial cardiomyocytes were isolated from tissue samples obtained during open heart surgery. All patients were in sinus rhythm. HiPSC-cardiomyocytes were dissociated from ML and EHT. Förster-resonance energy transfer (FRET) was used to monitor cytosolic cAMP (Epac1-camps sensor, transfected by adenovirus). ICa was recorded by whole-cell patch clamp technique. Cilostamide (300 nM) and rolipram (10 µM) were used to inhibit PDE3 and PDE4, respectively. ß1-AR were stimulated with the physiological agonist norepinephrine (100 µM). RESULTS: In adult human atrial cardiomyocytes, norepinephrine increased cytosolic cAMP FRET ratio by +13.7 ± 1.5% (n = 10/9, mean ± SEM, number of cells/number patients) and ICa by +10.4 ± 1.5 pA/pF (n = 15/10). This effect was not further increased in the concomitant presence of rolipram, cilostamide and norepinephrine, indicating saturation by norepinephrine alone. In ML hiPSC-cardiomyocytes, norepinephrine exerted smaller increases in cytosolic cAMP and ICa (FRET +9.6 ± 0.5% n = 52/21, number of cells/number of ML or EHT, and ICa + 1.4 ± 0.2 pA/pF n = 34/7, p < 0.05 each) and both were augmented in the presence of the PDE4 inhibitor rolipram (FRET +16.7 ± 0.8% n = 94/26 and ICa + 5.6 ± 1.4 pA/pF n = 11/5, p < 0.05 each). Cilostamide increased the response to norepinephrine on FRET (+12.7 ± 0.5% n = 91/19, p < 0.05), but not on ICa. In EHT hiPSC-cardiomyocytes, norepinephrine responses on both, FRET and ICa, were larger than in ML (FRET +12.1 ± 0.3% n = 87/32 and ICa + 3.3 ± 0.2 pA/pF n = 13/5, p < 0.05 each). Rolipram augmented the norepinephrine effect on ICa (+6.2 ± 1.6 pA/pF; p < 0.05 vs. norepinephrine alone, n = 10/4), but not on FRET. CONCLUSION: Our results show culture-dependent differences in hiPSC-cardiomyocytes. In conventional ML but not in EHT, maximum norepinephrine effects on cytosolic cAMP depend on PDE3 and PDE4, suggesting immaturity when compared to the situation in adult human atrial cardiomyocytes. The smaller ICa responses to norepinephrine in ML and EHT vs. adult human atrial cardiomyocytes depend at least partially on a non-physiological large impact of PDE4 in hiPSC-cardiomyocytes.

5.
ESC Heart Fail ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33763997

RESUMO

AIMS: Differences between female and male patients in clinical presentation, causes and treatment of cardiogenic shock (CS) are poorly understood. We aimed to investigate sex differences in presentation with and treatment of CS. METHODS AND RESULTS: We analysed data of 978 patients presenting with CS to a tertiary care hospital between October 2009 and October 2017. Multivariable adjusted logistic/Cox regression models were fitted to investigate the association between sex and clinical presentation, use of treatments and 30 day mortality. Median age was 70 years (interquartile range 58-79 years), and 295 (30.2%) patients were female. After adjustment for multiple relevant confounders, female patients were more likely to be older [odds ratio (OR) 1.21, 95% confidence interval (CI) 1.02-1.42, P = 0.027], but other relevant presentation characteristics did not differ between both sexes. Despite the similar presentation, female patients were less likely to be treated with percutaneous left ventricular assist devices (OR 0.78, 95% CI 0.64-0.94, P = 0.010), but more likely to be treated with catecholamines (OR 1.21, 95% CI 1.02-1.44, P = 0.033) or vasopressors (OR 1.26, 95% CI 1.05-1.50, P = 0.012). A 30 day mortality risk in female patients was as high as in male patients (hazard ratio 1.08, 95% CI 1.00-1.18, P = 0.091). CONCLUSIONS: In this large, contemporary cohort, clinical presentation was comparable in female and male patients, and both sexes were associated with a comparably high mortality risk. Nevertheless, female patients received different treatment for CS and were most importantly less likely to be treated with percutaneous left ventricular assist devices.

6.
Artigo em Alemão | MEDLINE | ID: mdl-33783622

RESUMO

Atrial fibrillation (AF) can be a significant burden for patients as well as the health care system. Every third 55-year-old will develop AF. Despite improvements of disease management, a significant risk for cardiovascular events remains. The current AF guidelines of the European Society of Cardiology focus on an integrative therapy approach. The new algorithm "CC to ABC" comprises recommendations for diagnosis ("confirm" and "characterise") and treatment ("avoid stroke", "better symptom control", "comorbidities") of AF. Direct oral anticoagulants administered according to the CHA2DS2-VASc score remain the corner stones of stroke prevention. Besides the concept of heart rate control, rhythm control therapy like antiarrhythmic drugs or catheter ablation is recommended to relieve symptoms and in certain patient groups for the improvement of prognosis. Therapy of comorbidities and reduction of risk factors like hypertension, diabetes mellitus, obesity and obstructive sleep apnoea should be part of any comprehensive treatment approach. The results of the randomized, prospective EAST-AFNET 4 trial were published in August 2020. The trial shows that an early rhythm control therapy can lead to a reduction of cardiovascular mortality and incidence of stroke additionally to guideline-based AF management. Given the safety profile and potential positive effects of antiarrhythmic drugs and catheter ablation, early initiation of rhythm control therapy should be considered in every patient during the first months after diagnosis of AF.

7.
Heart Rhythm ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33737232

RESUMO

BACKGROUND: Although atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide. OBJECTIVE: The purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs. METHODS: The sodium channel blocking effects of propafenone (300 nM, 1 µM), flecainide (1 µM), and dronedarone (5 µM, 10 µM) were measured in human stem cell-derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c. RESULTS: A more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/- hearts, which have a more positive RMP compared to wild type. CONCLUSION: Atrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.

8.
Heart ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692093

RESUMO

OBJECTIVE: To improve the echocardiographic assessment of heart failure in patients with atrial fibrillation (AF) by comparing conventional averaging of consecutive beats with an index-beat approach, whereby measurements are taken after two cycles with similar R-R interval. METHODS: Transthoracic echocardiography was performed using a standardised and blinded protocol in patients enrolled in the RATE-AF (RAte control Therapy Evaluation in permanent Atrial Fibrillation) randomised trial. We compared reproducibility of the index-beat and conventional consecutive-beat methods to calculate left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and E/e' (mitral E wave max/average diastolic tissue Doppler velocity), and assessed intraoperator/interoperator variability, time efficiency and validity against natriuretic peptides. RESULTS: 160 patients were included, 46% of whom were women, with a median age of 75 years (IQR 69-82) and a median heart rate of 100 beats per minute (IQR 86-112). The index-beat had the lowest within-beat coefficient of variation for LVEF (32%, vs 51% for 5 consecutive beats and 53% for 10 consecutive beats), GLS (26%, vs 43% and 42%) and E/e' (25%, vs 41% and 41%). Intraoperator (n=50) and interoperator (n=18) reproducibility were both superior for index-beats and this method was quicker to perform (p<0.001): 35.4 s to measure E/e' (95% CI 33.1 to 37.8) compared with 44.7 s for 5-beat (95% CI 41.8 to 47.5) and 98.1 s for 10-beat (95% CI 91.7 to 104.4) analyses. Using a single index-beat did not compromise the association of LVEF, GLS or E/e' with natriuretic peptide levels. CONCLUSIONS: Compared with averaging of multiple beats in patients with AF, the index-beat approach improves reproducibility and saves time without a negative impact on validity, potentially improving the diagnosis and classification of heart failure in patients with AF.

9.
ESC Heart Fail ; 8(2): 1295-1303, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33605565

RESUMO

AIM: The management of cardiogenic shock remains a clinical challenge even in well-developed healthcare systems, best illustrated by its high mortality despite numerous innovative proposals for management. The aim of this study was to describe temporal trends in incidence, causes, use of mechanical circulatory support, and mortality in cardiogenic shock in Germany. METHODS AND RESULTS: Data on all cardiogenic shock patients treated in German hospitals between 2005 and 2017 were obtained from the Federal Bureau of Statistics. The data set comprised 441 696 patients with cardiogenic shock, mean age 71 (±13.8) years, 171 383 (39%) female patients. Incidence rates increased from 33.1/100 000 population in 2005 (27 246 cases) to 51.7/100 000 population in 2017 (42 779 cases). Acute myocardial infarction was the most common cause of cardiogenic shock in 2005-07 (43 422 of 82 037 cases, 52.9%), but the proportion of cases caused by it decreased until 2014-17 (73 274 of 165 873 cases, 44.2%). Over time, intra-aortic balloon pump (2005: 5104; 2017: 973 cases) was used less frequently, whereas use of extracorporeal-membrane-oxygenation (2007: 35; 2017: 2414 cases) and percutaneous left ventricular assist devices (2005: 27; 2017: 1323 cases) increased. Mortality remained high at around 60% without relevant temporal trends in patients without acute myocardial infarction and slightly decreased in patients with acute myocardial infarction. CONCLUSIONS: In this large, nation-wide study, annual incidence of cardiogenic shock was growing, its causes were changing, and mortality was high despite a shift towards use of novel mechanical circulatory support devices. This highlights the need to address the evidence gap in this field, in particular for cardiogenic shock caused by diseases other than acute myocardial infarction.

10.
PLoS Med ; 18(2): e1003405, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33534825

RESUMO

BACKGROUND: Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. METHODS AND FINDINGS: For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. CONCLUSIONS: Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. TRIAL REGISTRATION: Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom.

12.
J Clin Med ; 10(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546442

RESUMO

Non-vitamin K antagonist oral anticoagulants such as edoxaban are the standard of care for stroke prevention in patients with atrial fibrillation (AF). The Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program integrates prospective, observational, noninterventional regional studies from Europe, Japan, and other Asian countries, collecting data on patient characteristics and clinical outcomes in unselected patients treated with edoxaban for stroke prevention in AF. Overall, 26,823 patients completed a 1-year follow-up and were treated with edoxaban; either 60 or 30 mg once daily. The majority (82.6%) of patients received the recommended doses according to the local label. At baseline, the median (interquartile range) age was 75 (68, 80) years, the CHA2DS2-VASc score was 3.0 (2.0, 4.0), and the hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs, or alcohol (HAS-BLED) score was 2.0 (2.0, 3.0). At one year, there were 273 (1.12%/year) major bleeding events, including 75 (0.31%/year) intracranial hemorrhages and 140 (0.57%/year) major gastrointestinal (GI) bleeds. There were 214 ischemic strokes (0.87%/year). Mortality was 3.03%/year (745 deaths), and cardiovascular mortality accounted for 40% of all deaths (1.22%/year, 299 cardiovascular deaths). In conclusion, stroke, intracranial hemorrhage, and other major bleeding events were low in patients with AF treated with edoxaban in routine care. Even on anticoagulation, cardiovascular death remained common.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33580778

RESUMO

AIMS: Cardiogenic shock (CS) is associated with poor outcomes in older patients, but it remains unclear if this is due to higher shock severity. We sought to determine the associations between age and shock severity on mortality among patients with CS. METHODS AND RESULTS: Patients with a diagnosis of CS from Mayo Clinic (2007-15) and University Clinic Hamburg (2009-17) were subdivided by age. Shock severity was graded using the Society for Cardiovascular Angiography and Intervention (SCAI) shock stages. Predictors of 30-day survival were determined using Cox proportional-hazards analysis. We included 1749 patients (934 from Mayo Clinic and 815 from University Clinic Hamburg), with a mean age of 67.6 ± 14.6 years, including 33.6% females. Acute coronary syndrome was the cause of CS in 54.0%. The distribution of SCAI shock stages was 24.1%; C, 28.0%; D, 33.2%; and E, 14.8%. Older patients had similar overall shock severity, more co-morbidities, worse kidney function, and decreased use of mechanical circulatory support compared to younger patients. Overall 30-day survival was 53.3% and progressively decreased as age or SCAI shock stage increased, with a clear gradient towards lower 30-day survival as a function of increasing age and SCAI shock stage. Progressively older age groups had incrementally lower adjusted 30-day survival than patients aged <50 years. CONCLUSION: Older patients with CS have lower short-term survival, despite similar shock severity, with a high risk of death in older patients with more severe shock. Further research is needed to determine the optimal treatment strategies for older CS patients.

14.
Cardiovasc Res ; 117(2): 336-337, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33458743
15.
Europace ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33462602

RESUMO

AIMS: Genetically altered mice are powerful models to investigate mechanisms of atrial arrhythmias, but normal ranges for murine atrial electrophysiology have not been robustly characterized. METHODS AND RESULTS: We analyzed results from 221 electrophysiological (EP) studies in isolated, Langendorff-perfused hearts of wildtype mice (114 female, 107 male) from 2.5 to 17.7 months (mean 7 months) with different genetic backgrounds (C57BL/6, FVB/N, MF1, 129/Sv, Swiss agouti). Left atrial monophasic action potential duration (LA-APD), interatrial activation time (IA-AT), and atrial effective refractory period (ERP) were summarized at different pacing cycle lengths (PCLs). Factors influencing atrial electrophysiology including genetic background, sex, and age were determined. LA-APD70 was 18 ± 0.5 ms, atrial ERP was 27 ± 0.8 ms, and IA-AT was 17 ± 0.5 ms at 100 ms PCL. LA-APD was longer with longer PCL (+17% from 80 to 120 ms PCL for APD70), while IA-AT decreased (-7% from 80 to 120 ms PCL). Female sex was associated with longer ERP (+14% vs. males). Genetic background influenced atrial electrophysiology: LA-APD70 (-20% vs. average) and atrial ERP (-25% vs. average) were shorter in Swiss agouti background compared to others. LA-APD70 (+25% vs. average) and IA-AT (+44% vs. average) were longer in 129/Sv mice. Atrial ERP was longer in FVB/N (+34% vs. average) and in younger experimental groups below 6 months of age. CONCLUSION: This work defines normal ranges for murine atrial EP parameters. Genetic background has a profound effect on these parameters, at least of the magnitude as those of sex and age. These results can inform the experimental design and interpretation of murine atrial electrophysiology.

16.
Acta Cardiol ; : 1-9, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406996

RESUMO

BACKGROUND: Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS: With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 mL/min, weight ≤60 kg, and/or use of strong p-glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS: Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION: There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION: NCT02944019; Date of registration: October 24, 2016.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33278190

RESUMO

Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) provide a novel, human source to model cardiovascular diseases. Here we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling.After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 s twice a minute over three weeks and compared to transduced spontaneously beating isogenic aEHTs (1.95±0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138±15 V/s vs. 87±11 V/s, n=15-13/3; p=0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0±1.8 mV vs. 68.0±1.9 mV; p=0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07±0.01 vs. 0.03±0.004 s, n=15-13/3; p=0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 (Kir2.2, inward rectifier (IK1); 69±7 vs. 44±4, p=0.014) and NPPB (NT-proBNP; 39690±4834 vs. 23671±3691; p=0.024).Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation might clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation.

19.
JAMA ; 324(24): 2497-2508, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351042

RESUMO

Importance: There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure. Objective: To compare low-dose digoxin with bisoprolol (a ß-blocker). Design, Setting, and Participants: Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. Interventions: Digoxin (n = 80; dose range, 62.5-250 µg/d; mean dose, 161 µg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). Main Outcomes and Measures: The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting. Results: Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group. Conclusions and Relevance: Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points. Trial Registration: ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bisoprolol/uso terapêutico , Digoxina/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Qualidade de Vida , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Fibrilação Atrial/complicações , Fibrilação Atrial/fisiopatologia , Bisoprolol/efeitos adversos , Bisoprolol/farmacologia , Digoxina/efeitos adversos , Digoxina/farmacologia , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Volume Sistólico
20.
Circulation ; 142(22): 2095-2106, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33032450

RESUMO

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. METHODS: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort. RESULTS: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; P=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). CONCLUSIONS: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

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