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2.
Circulation ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34648376

RESUMO

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Since mitochondrial function and ROS formation are regulated by excitation-contraction (EC) coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared to wild-type (WT) littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. EC coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. Results: Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, partly compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+ ATPase (SERCA). Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter (MCU) protein that prevented Ca2+-induced activation of the Krebs cycle during ß-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to ß-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export via the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Conclusions: Downregulation of MCU, increased myofilament Ca2+ affinity, and preactivated SERCA provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

3.
J Am Soc Nephrol ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588185

RESUMO

Background Coexistent chronic kidney diseases (CKD) and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 of monocytes in vitro In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

4.
Atherosclerosis ; 333: 116-123, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34399983

RESUMO

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is associated with high cardiovascular risk and underdiagnosed. Cutaneous manifestations are traditionally used as a major criterion of FH. They are included in the Dutch Lipid Clinic Network or Simon Broome registry criteria. The objective of this study was to evaluate cutaneous manifestations in contemporary FH patients. METHODS: We prospectively analysed the clinical presentation of FH patients referred to a University lipid clinic and validated these data in the German FH registry CaRe High. RESULTS: Physical examination revealed that only 14.4% of the FH patients in the lipid clinic cohort (n = 223) showed cutaneous manifestations. An arcus cornealis was present in 0.9%, xanthomata in 1.8%, and xanthelasmata in 12.1%. Xanthelasmata are not part of the clinical scores, but represented 84.4% of all cutaneous manifestations. In 42.6% (n = 95) of the patients, genetic analysis was available. A causal FH mutation was detected in 50.5%. Among carriers, 66.7% had no cutaneous manifestation, 8.3% exhibited an arcus cornealis or xanthomata, and 25.0% had xanthelasmata. In the CaRe High FH registry, data on cutaneous manifestations were available in n = 1274 patients. 3.5% had xanthomata, 5.7% an arcus cornealis, and 7.7% at least one of both; xanthelasmata were present in 10.3%. CONCLUSIONS: Cutaneous manifestations are only present in a minority of contemporary patients with FH including the subgroup with monogenic FH mutations. Although rare, the cutaneous signs have value in terms of specificity. However, the clinical characteristics shared by the majority of FH patients may be better suited for screening purposes.

5.
Circulation ; 144(11): 893-908, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34192892

RESUMO

BACKGROUND: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD. METHODS: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a-/- and Il1b-/- mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. RESULTS: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1ß, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice. CONCLUSIONS: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34273561

RESUMO

Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analysis were performed, which identified upregulation of Sam68-Like Mammalian Protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding and processing the mRNA of essential cardiac constituents such as titin.

7.
Sci Rep ; 11(1): 15156, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312415

RESUMO

Inflammation driven by intracellular activation of the NLRP3 inflammasome is involved in the pathogenesis of a variety of diseases including vascular pathologies. Inflammasome specks are released into the extracellular compartment from disrupting pyroptotic cells. The potential uptake and function of extracellular NLRP3 inflammasomes in human coronary artery smooth muscle cells (HCASMC) are unknown. Fluorescently labeled NLRP3 inflammasome particles were isolated from a mutant NLRP3-YFP cell line and used to treat primary HCASMC for 4 and 24 h. Fluorescent and expressional analyses showed that extracellular NLRP3-YFP particles are internalized into HCASMC, where they remain active and stimulate intracellular caspase-1 (1.9-fold) and IL-1ß (1.5-fold) activation without inducing pyroptotic cell death. Transcriptomic analysis revealed increased expression level of pro-inflammatory adhesion molecules (ICAM1, CADM1), NLRP3 and genes involved in cytoskleleton organization. The NLRP3-YFP particle-induced gene expression was not dependent on NLRP3 and caspase-1 activation. Instead, the effects were partly abrogated by blocking NFκB activation. Genes, upregulated by extracellular NLRP3 were validated in human carotid artery atheromatous plaques. Extracellular NLRP3-YFP inflammasome particles promoted the secretion of pro-atherogenic and inflammatory cytokines such as CCL2/MCP1, CXCL1 and IL-17E, and increased HCASMC migration (1.8-fold) and extracellular matrix production, such as fibronectin (5.8-fold) which was dependent on NFκB and NLRP3 activation. Extracellular NLRP3 inflammasome particles are internalized into human coronary artery smooth muscle cells where they induce pro-inflammatory and pro-atherogenic effects representing a novel mechanism of cell-cell communication and perpetuation of inflammation in atherosclerosis. Therefore, extracellular NLRP3 inflammasomes may be useful to improve the diagnosis of inflammatory diseases and the development of novel anti-inflammatory therapeutic strategies.

8.
Pharmacoepidemiol Drug Saf ; 30(11): 1493-1503, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34245078

RESUMO

PURPOSE: Conflicting information on potential benefits of drugs as well as reports on hypothetical harm of commonly used drugs in COVID-19 treatment have challenged clinicians and healthcare systems. We analyzed the change in ambulatory drug utilization before, during, and after the first wave of the pandemic in 2020. METHODS: We explored dispensing data of nearly 19 000 pharmacies at the expense of the statutory health insurance funds covering 88% of Germany's population. We analyzed utilization of publicly discussed drugs with conflicting information. Drug utilization as number of packages dispensed per week from January to June 2020, reflecting 314 million claims, was compared with 2019. RESULTS: Utilization of hydroxychloroquine increased +110% during March 2020 and then slightly decreased until week April 13-19. Renin-angiotensin-aldosterone system inhibitors and simvastatin/atorvastatin increased, +78% and +74%, respectively, and subsequently decreased below 2019 levels. Utilization of azithromycin and all systemic antibiotics decreased continuously from March 2-8 until June to levels considerably lower compared to 2019 (June 22-28: azithromycin: -55%, all systemic antibiotics: -27%). Pneumococcal vaccines utilization initially increased +373%, followed by supply shortages. Paracetamol utilization showed an initial increase of +111%, mainly caused by an increase of over-the-counter dispensings. CONCLUSIONS: Apart from the pandemic itself, the data suggest that dissemination of misinformation and unsound speculations as well as supply shortages influenced drug prescribing, utilization, and purchasing behavior. The findings can inform post-pandemic policy to prevent unfounded over- and underprescribing and off-label use as well as drug shortages during a public health crisis.

9.
ESC Heart Fail ; 8(5): 3566-3576, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34240570

RESUMO

AIMS: Patients with heart failure (HF) have poor outcomes, including poor quality of life, and high morbidity and mortality. In addition, they have a high medication burden due to the multiple drug therapies now recommended by guidelines. Previous reviews, including studies in hospital settings, provided evidence that pharmacist care improves outcomes in patients with HF. Because most HF is managed outside of hospitals, we aimed to synthesize the evidence for pharmacist care in outpatients with HF. METHODS AND RESULTS: We conducted a systematic literature search in PubMed of randomized controlled trials (RCTs) and integrated the evidence on patient outcomes in a meta-analysis. We found 24 RCTs performed in 10 countries, including 8029 patients. The data revealed consistent improvements in medication adherence (independent of the measuring instrument) and knowledge, physical function, and disease and medication management. Sixteen RCTs were included in meta-analyses. Differences in all-cause mortality (odds ratio (OR) = 0.97 [95% CI, 0.84-1.12], Q-statistic, P = 0.49, I2  = 0%), all-cause hospitalizations (OR = 0.86 [0.73-1.03], Q-statistic, P = 0.01, I2  = 45.5%), and HF hospitalizations (OR = 0.89 [0.77-1.02], Q-statistic, P = 0.11, I2  = 0%) were not statistically significant. We also observed an improvement in the standardized mean difference for generic quality of life of 0.75 ([0.49-1.01], P < 0.01), with no indication of heterogeneity (Q-statistic, P = 0.64; I2  = 0%). CONCLUSIONS: Results indicate that pharmacist care improves medication adherence and knowledge, symptom control, and some measures of quality of life in outpatients with HF. Given the increasing complexity of guideline-directed medical therapy, pharmacists' unique focus on medication management, titration, adherence, and patient teaching should be considered part of the management strategy for these vulnerable patients.

11.
Int J Lab Hematol ; 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097808

RESUMO

BACKGROUND: The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. OBJECTIVE: This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. METHODS: Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. RESULTS: The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. CONCLUSION: The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

12.
Clin Res Cardiol ; 110(7): 938-958, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34143285

RESUMO

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.

13.
PLoS One ; 16(6): e0252321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34115786

RESUMO

PURPOSE: Cardiovascular risk factors such as hypertension or dyslipidemia can influence the incidence and progression of diabetic retinopathy (DR) and diabetic macular edema (DME). The aim of this study is to describe the comorbidities in patients with DME. METHODS: Prospective, monocentric observational study. Patients presenting for the treatment of DME received laboratory and clinical examinations including 24-hour blood pressure measurement. RESULTS: Seventy-five consecutive patients were included in the study. The mean age was 61.0 ± 14.5 years, and 83% had type 2 diabetes. The mean body mass index (BMI) was 32.8 ± 6.0 kg/m2. Overweight (BMI ≥ 25 kg/m2) was present in 92% of all patients. HbA1c values were > 7.0% in 57%. Although 87% of the patients already received antihypertensive therapy, the blood pressure (BP) of 82% was still above the recommended target values of systolic < 140 mmHg and diastolic < 80 mmHg. An insufficient nocturnal fall of the systolic BP (< 10%, non-dipping or reverse dipping) was observed in 62%. In 83% of the patients the glomerular filtration rate was ≤ 90 ml/min/1.73m2. Despite 65% of the cohort already receiving lipid-lowering therapy, LDL cholesterol was above the target value of 1.4 mmol/l in 93%. All patients had at least one cardiovascular risk factor in addition to diabetes (overweight, hypertension, insufficient nocturnal BP fall, dyslipidemia, or renal dysfunction) and 86% had ≥ 3 risk factors. CONCLUSION: DME patients are characterized by highly prevalent cardiovascular risk factors that are poorly controlled. These comorbidities reduce the prognosis and negatively influence existing DR and DME. The data reveal an important opportunity for improving patient care by interaction of the ophthalmologist with the general practitioner and internal specialists for the detection and treatment of these conditions.

15.
ESC Heart Fail ; 8(4): 2448-2457, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33939295

RESUMO

AIMS: The study sought to investigate the long-term outcome after transcatheter mitral valve annuloplasty for secondary mitral regurgitation (MR). METHODS AND RESULTS: Consecutive patients with symptomatic secondary MR undergoing transcatheter mitral valve annuloplasty with the Carillon device at Leipzig University Hospital between 2012 and 2018 were studied prospectively. Left ventricular (LV) function and MR severity were quantified by standardized echocardiography. 33 patients were included. Mean age was 75 ± 10 years, and 20 patients were women. A Society of Thoracic Surgeons score of 8.1 ± 7.2% indicated high-risk status. In 24 patients, MR resulted from LV remodelling and dysfunction, eight suffered from left atrial dilatation, and one patient had MR due to combined primary and secondary aetiology. LV ejection fraction at baseline was (median) 38% [inter-quartile range (IQR) 30-49%]. During the mean follow-up time of 45 ± 20 months, 17 patients died, two patients withdraw consent, and four patients were lost. Of the remaining patients, four were hospitalized for decompensated heart failure. Two of these patients underwent additional transcatheter edge-to-edge mitral valve repair. At follow-up, New York Heart Association (NYHA) functional class improved from 95% in Class III/IV at baseline to 70% in Class I/II with no patients in NYHA Class IV (P < 0.0001). Mitral regurgitant volume was reduced from 27 mL (IQR 25-42 mL) to 8 mL (IQR 3-17 mL) (P = 0.018) and regurgitant fraction from 42% (IQR 34-54%) to 11% (IQR 8-24%) (P = 0.014). LV end-diastolic volume index [92 mL/m2 (IQR 74-107 mL/m2 ) vs. 67 mL/m2 (IQR 46-101 mL/m2 ), P = 0.065] and end-systolic volume index [50 mL/m2 (IQR 44-69 mL/m2 ) vs. 32 mL/m2 (IQR 20-53 mL/m2 ), P = 0.037] decreased. Total stroke volume remained unchanged [38 mL/m2 (IQR 33-43 mL/m2 ) vs. 33 mL/m2 (IQR 26-44 mL/m2 ), P = 0.695], while LV ejection fraction increased [43% (IQR 35-49%) vs. 54% (IQR 46-57%), P = 0.014]. Forward stroke volume, heart rate, and forward cardiac output were not significantly altered. CONCLUSIONS: Among high-risk patients undergoing transcatheter mitral valve annuloplasty for symptomatic secondary MR, mortality was ~50% at 4 years. In the surviving patients, reduced MR severity was associated with reduced NYHA functional class, reverse LV remodelling, and improved LV function.

16.
ESC Heart Fail ; 8(4): 2546-2555, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33949148

RESUMO

AIMS: Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences. METHODS AND RESULTS: We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF-related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF-related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; -29%), while the total number of HF-related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in-hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population). CONCLUSIONS: Heart failure remains the most common cause of hospitalization and in-hospital death throughout Germany. The increase in HF-related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.

17.
Lancet Neurol ; 20(6): 426-436, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34022169

RESUMO

BACKGROUND: Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months. METHODS: In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants. FINDINGS: Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9-1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0-2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8-1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5-0·9]). INTERPRETATION: Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention. FUNDING: Bayer Vital. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.


Assuntos
Fibrilação Atrial/fisiopatologia , Isquemia Encefálica/fisiopatologia , AVC Isquêmico/fisiopatologia , Monitorização Fisiológica/métodos , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Eletrocardiografia/métodos , Feminino , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
Heart ; 107(17): 1369-1375, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33795379

RESUMO

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.

19.
Br J Clin Pharmacol ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33792095

RESUMO

AIMS: The serum ratios of the brain-specific oxysterol 24S-hydroxycholesterol (24S-OHC) to cholesterol and to 27-OHC reflect brain cholesterol turnover. We studied the effect of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) that enhance low-density lipoprotein receptor activity on serum cholesterol and oxysterol concentrations. METHODS: Twenty-eight hypercholesterolaemic patients (15 males and 13 females) responding insufficiently to maximally tolerated statin and/or ezetimibe therapy were additionally subcutanously treated biweekly with either the PCSK9ab alirocumab (150 mg, n = 13) or evolocumab (140 mg, n = 15). Fasting serum cholesterol was measured by gas chromatography and the oxysterols 24S-OHC and 27-OHC using gas chromatography-mass spectrometry before, after 1-month (n = 28) and after 3-month (n = 13) treatment. RESULTS: As expected, PCSK9ab treatment lowered serum cholesterol and oxysterol levels after 1 month. The serum ratio of 24S-OHC to cholesterol increased after 1 month by 17 ± 28% (mean ± standard deviation; 95% confidence interval [CI]: 5.8 to 28%; P < .01) and 24S-OHC to 27-OHC by 15 ± 39% (95% CI: 0.2 to 30%; P < .01). Within 3 months, 24S-OHC to cholesterol increased by 2.8 µg g-1 mo-1 (95% CI: 2.1 to 3.6; P < .01) and 24S-OHC to 27-OHC by 0.019 mo-1 (95% CI: 0.007 to 0.032; P < .01). CONCLUSION: The serum ratios of 24S-OHC to cholesterol and to 27-OHC increased after treatment with PCSK9ab. We hypothesize that this is caused by a reduced entrance of 27-OHC into the brain, increased synthesis of brain cholesterol, increased production of 24S-OHC and its secretion across the blood-brain barrier.

20.
Int J Cardiovasc Imaging ; 37(8): 2369-2386, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33738612

RESUMO

2D speckle tracking echocardiography (2DSTE) is established to analyse left ventricular (LV) longitudinal function. The analysis of LV rotational deformation is challenging and requires standardization of image acquisition as well as postprocessing analysis. The aim of this study was to test the feasibility to analyse LV rotational deformation using 2DSTE by introducing a novel algorithm for the detection of artefacts. The study was performed in 20 healthy subjects serving as a control group and in 53 competitive sportsmen. Circumferential, radial strain (CS, RS) and LV rotation were analysed by 2DSTE in parasternal short axis views. The stepwise algorithm to exclude potential artefacts starts with the visual estimation of the image quality with respect to complete visualization of all myocardial segments during the entire cardiac cycle followed by the exclusion of data sets in participants with conduction abnormalities. The next step is the optimization of tracking areas and a cross-check of implausible strain waveforms in multiple acquired comparable cineloops. The last step is the exclusion of strain curves with persisting implausible waveforms if standardization failures and incorrect LV wall tracking are fixed. Plausible physiological strain curves were observed in 89% (n = 65/73) of all subjects. In controls all implausible waveforms could be verified as artefacts. The algorithm was applied in 53 professional athletes to test and confirm its feasibility. Abnormal CS waveforms were documented in 25 athletes, verified as artefacts due to tracking failures in 22 athletes and due to incorrect image acquisition in 3 athletes. CS artefacts were mostly located in the basal posterior and lateral LV segments. (endocardial: 6%, n = 4/70; p < 0.05) and basal posterior (endocardial: 8%, n = 5/70; p < 0.05) segments were highly susceptible to artefacts. 2DSTE of parasternal short axis views to analyse circumferential and radial deformation as well as LV rotation is feasible in athletes. The proposed algorithm helps to avoid artefacts and might contribute to standardization of this technique. 2DSTE might provide an interesting diagnostic tool for the detection of viral myocarditis, e.g. in athletes.

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