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1.
Artigo em Inglês | MEDLINE | ID: mdl-31481236

RESUMO

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

2.
Stud Health Technol Inform ; 267: 101-109, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31483261

RESUMO

One of the major obstacles for research on German medical reports is the lack of de-identified medical corpora. Previous de-identification tasks focused on non-German medical texts, which raised the demand for an in-depth evaluation of de-identification methods on German medical texts. Because of remarkable advancements in natural language processing using supervised machine learning methods on limited training data, we evaluated them for the first time on German medical reports using our annotated data set consisting of 113 medical reports from the cardiology domain. We applied state-of-the-art deep learning methods using pre-trained models as input to a bidirectional LSTM network and well-established conditional random fields for de-identification of German medical reports. We performed an extensive evaluation for de-identification and multiclass named entity recognition. Using rule based and out of domain machine learning methods as a baseline, the conditional random field improved F2-score from 70 to 93% for de-identification, the neural approach reached 96% in F2-score while keeping balanced precision and recall rates. These results show, that state-of-the-art machine learning methods can play a crucial role in de-identification of German medical reports.

3.
N Engl J Med ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475799

RESUMO

BACKGROUND: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. METHODS: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding. RESULTS: A total of 4018 patients underwent randomization. A primary-end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). CONCLUSIONS: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).

4.
Heart Fail Rev ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31364027

RESUMO

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)-related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

5.
Artigo em Alemão | MEDLINE | ID: mdl-31463582

RESUMO

Patients with oncological diseases frequently show cardiac arrhythmias. This is explained by an increased risk in this specific patient cohort and is frequently associated with specific oncological therapies. So far, it is unclear how to deal with the occurrence of arrhythmias diagnostically and therapeutically, since the current clinical data do not provide satisfying answers to these questions. Clinical care of high-risk patients in specialized teams with a focus on cardio-oncology is recommended. Based on the current clinical studies and the position papers of the European Society of Cardiology (ESC), we give a brief overview of arrhythmias in malignant diseases and their therapies.

6.
J Cardiovasc Magn Reson ; 21(1): 53, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31434577

RESUMO

BACKGROUND: The differentiated assessment of functional parameters besides morphological changes is essential for the evaluation of prognosis in systemic immunoglobulin light chain (AL) amyloidosis. METHODS: Seventy-four subjects with AL amyloidosis and presence of late gadolinium enhancement (LGE) pattern typical for cardiac amyloidosis were analyzed. Long axis strain (LAS) and myocardial contraction fraction (MCF), as well as morphological and functional markers, were measured. The primary endpoint was death, while death and heart transplantation served as a composite secondary endpoint. RESULTS: After a median follow-up of 41 months, 29 out of 74 patients died and 10 received a heart transplant. Left ventricular (LV) functional parameters were reduced in patients, who met the composite endpoint (LV ejection fraction 51% vs. 61%, LAS - 6.9% vs - 10%, GLS - 12% vs - 15% and MCF 42% vs. 69%; p <  0.001 for all). In unadjusted univariate analysis, LAS (HR = 1.05, p <  0.001) and MCF (HR = 0.96, p <  0.001) were associated with reduced transplant-free survival. Kaplan-Meier analyses showed a significantly lower event-free survival in patients with reduced MCF. MCF and LAS performed best to identify high risk patients for secondary endpoint (Log-rank test p <  0.001) in a combined model. Using sequential Cox regression analysis, the addition of LAS and MCF to LV ejection fraction led to a significant increase in the predictive power of the model (χ2 (df = 1) = 28.2, p <  0.001). CONCLUSIONS: LAS and MCF as routinely available and robust CMR-derived parameters predict outcome in LGE positive AL amyloidosis. Patients with impaired LV function in combination with reduced LAS and MCF are at the highest risk for death and heart transplantation.

7.
Clin Res Cardiol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401672

RESUMO

AIMS: In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. METHODS AND RESULTS: In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect-infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect-upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect-upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67-0.92). CONCLUSION: Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

8.
EMBO Mol Med ; : e10018, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31468715

RESUMO

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end-stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti-hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co-factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.

9.
Eur Heart J Acute Cardiovasc Care ; : 2048872619861911, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298551

RESUMO

BACKGROUND: Although the value of fast diagnostic protocols in suspected acute coronary syndrome has been validated, there is insufficient real world evidence including patients with lower pre-test probability, atypical symptoms and confounding comorbidities. The feasibility, efficacy and safety of European Society of Cardiology (ESC) 0/1 and 0/3-hour algorithms using high-sensitivity troponin T were evaluated in a consecutive cohort with suspected acute coronary syndrome. METHODS: During 12 months, 2525 eligible patients were enrolled. In a pre-implementation period of 6 months, the prevalence of protocols, disposition, lengths of emergency department stay and treatments were registered. Implementation of the 0/1-hour protocol was monitored for another 6 months. Primary endpoints comprised the change of diagnostic protocols and 30-day mortality after direct discharge from the emergency department. RESULTS: Use of the ESC 0/1-hour algorithm increased by 270% at the cost of the standard 0/3-hour protocol. After rule-out (1588 patients), 1309 patients (76.1%) were discharged directly from the emergency department, with an all-cause mortality of 0.08% at 30 days (one death due to lung cancer). Median lengths of stay were 2.9 (1.9-3.8) and 3.2 (2.7-4.4) hours using a single high-sensitivity troponin T below the limit of detection (5 ng/L) at presentation and the ESC 0/1-hour algorithm, respectively, as compared to 5.3 (4.7-6.5) hours using the ESC 0/3-hour rule-out protocol (P<0.001). Discharge rates increased from 53.9% to 62.8% (P<0.001), without excessive use of diagnostic resources within 30 days. CONCLUSION: Implementation of the ESC 0/1-hour algorithm is feasible and safe, is associated with shorter emergency department stay than the ESC 0/3-hour protocol, and an increase in discharge rates. TRIAL REGISTRATION: ClinicalTrials.gov , Unique identifier: NCT03111862.

10.
Acta Cardiol ; : 1-8, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311434

RESUMO

Background: Reduced ejection fraction (EF) in chronic moderate aortic regurgitation (AR) could be either due to a late remodelling response after longstanding moderate AR, or could represent a specific phenotype of cardiomyopathy (CMP) with concomitant AR. The aim of this study was to analyse progression of left ventricular (LV) impairment in moderate AR. Methods: All patients in our echocardiography database between 2005 and 2016 were screened to identify pure chronic moderate AR, excluding significant coronary artery disease (CAD) or concomitant valve disease. Remaining 152 patients were divided into three groups: (a) preserved systolic LV function; (b) reduced LV EF and prediagnosed concomitant cardiomyopathy (CMP); (c) reduced LV EF without prediagnosed CMP. Results: The majority patients (group A = 66%) had preserved systolic LV function, remaining oligosymptomatic with stable LVEDD at follow-up. Non-CMP patients with reduced EF at baseline (group C = 18%) were significantly older (group C: 74 vs. group A: 61 years, p < .001) whereas left ventricular end-diastolic diameter (LVEDD) significantly increased over time (p = .046). Development of renal insufficiency, atrial fibrillation and NYHA > II were significant risk factors linked to the worsening of LV function in patients with moderate AR. Conclusion: Preserved LV EF and LVEDD remain stable over a long lasting period in the majority of patients. However, these data suggest that some patients develop reduced LV EF, even without progression of AR to severe, especially if renal insufficiency or atrial fibrillation are present.

11.
Diagnosis (Berl) ; 6(3): 189-201, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31271552

RESUMO

Skeletal myopathies have been suggested as a non-cardiac cause of elevations of cardiac troponin (cTn), particularly cardiac troponin T (cTnT). This is of major clinical relevance and concern as cTn plays a major role in the early diagnosis of myocardial infarction (MI). While both the incidence as well as the true pathophysiology (cardiac versus non-cardiac) underlying elevations in cTn in skeletal myopathies remain largely unknown, re-expression of cTnT in regenerating adult skeletal muscle has been suggested as a possible contributor. However, unequivocal protein characterization in skeletal muscle and quantification of the relative amounts of this possible signal versus the cTn signal derived from true cardiomyocyte injury remains elusive. Alternatively, minor cross-reactivity of the cTnT (and possibly at times also cTnI) detection and capture antibodies used in current monoclonal immunoassays with the skeletal troponin T or I isoform may be considered. Both would represent "false positive" elevations from a clinical perspective and would need to be reliably differentiated from "true positive elevations" from subclinical cardiomyocyte injury not detectable by currently available imaging techniques such as echocardiography and contrast enhanced magnetic resonance imaging (MRI), which have at least a 5 times lower sensitivity for cardiomyocyte injury. This review aims to explore the currently available data, its methodological limitations and provide guidance to clinicians to avoid misinterpretation of cTn concentrations.

12.
Life Sci ; 232: 116620, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291594

RESUMO

AIMS: Cell-based biological pacemakers aim to overcome limitations and side effects of electronic pacemaker devices. We here developed and tested different approaches to achieve nodal-type differentiation using human adipose- and bone marrow-derived mesenchymal stem cells (haMSC, hbMSC). MAIN METHODS: haMSC and hbMSC were differentiated using customized protocols. Quantitative RT-PCR was applied for transcriptional pacemaker-gene profiling. Protein membrane expression was analyzed by immunocytochemistry. Pacemaker current (If) was studied in haMSC with and without lentiviral HCN4-transduction using patch clamp recordings. Functional characteristics were evaluated by co-culturing with neonatal rat ventricular myocytes (NRVM). KEY FINDINGS: Culture media-based differentiation for two weeks generated cells with abundant transcription of ion channel genes (Cav1.2, NCX1), transcription factors (TBX3, TBX18, SHOX2) and connexins (Cx31.9 and Cx45) characteristic for cardiac pacemaker tissue, but lack adequate HCN transcription. haMSC-derived cells revealed transcript levels, which were closer related to sinoatrial nodal cells than hbMSC-derived cells. To substitute for the lack of If, we performed lentiviral HCN4-transduction of haMSC resulting in stable If. Co-culturing with NRVM demonstrated that differentiated haMSC expressing HCN4 showed earlier onset of spontaneous contractions and higher beating regularity, synchrony and rate compared to co-cultures with non-HCN4-transduced haMSC or HCN4-transduced, non-differentiated haMSC. Confocal imaging indicated increased membrane expression of cardiac gap junctional proteins in differentiated haMSC. SIGNIFICANCE: By differentiation haMSC, rather than hbMSC attain properties favorable for cardiac pacemaking. In combination with lentiviral HCN4-transduction, a cellular phenotype was generated that sustainably controls and stabilizes rate in co-culture with NRVM.

13.
Circ Res ; 125(4): 431-448, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31284834

RESUMO

RATIONALE: Gene expression profiles have been mainly determined by analysis of transcript abundance. However, these analyses cannot capture posttranscriptional gene expression control at the level of translation, which is a key step in the regulation of gene expression, as evidenced by the fact that transcript levels often poorly correlate with protein levels. Furthermore, genome-wide transcript profiling of distinct cell types is challenging due to the fact that lysates from tissues always represent a mixture of cells. OBJECTIVES: This study aimed to develop a new experimental method that overcomes both limitations and to apply this method to perform a genome-wide analysis of gene expression on the translational level in response to pressure overload. METHODS AND RESULTS: By combining ribosome profiling (Ribo-seq) with a ribosome-tagging approach (Ribo-tag), it was possible to determine the translated transcriptome in specific cell types from the heart. After pressure overload, we monitored the cardiac myocyte translatome by purifying tagged cardiac myocyte ribosomes from cardiac lysates and subjecting the ribosome-protected mRNA fragments to deep sequencing. We identified subsets of mRNAs that are regulated at the translational level and found that translational control determines early changes in gene expression in response to cardiac stress in cardiac myocytes. Translationally controlled transcripts are associated with specific biological processes related to translation, protein quality control, and metabolism. Mechanistically, Ribo-seq allowed for the identification of upstream open reading frames in transcripts, which we predict to be important regulators of translation. CONCLUSIONS: This method has the potential to (1) provide a new tool for studying cell-specific gene expression at the level of translation in tissues, (2) reveal new therapeutic targets to prevent cellular remodeling, and (3) trigger follow-up studies that address both, the molecular mechanisms involved in the posttranscriptional control of gene expression in cardiac cells, and the protective functions of proteins expressed in response to cellular stress.

14.
Nat Commun ; 10(1): 3295, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337768

RESUMO

HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards 'reverse mode' leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy.

16.
Clin Res Cardiol ; 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31325044

RESUMO

BACKGROUND: Patients with unstable angina (UA) are regarded to be at low risk for future coronary events. Guidelines discourage routine coronary angiography and recommend early discharge after individualized risk stratification. The relative value of clinical risk indicators as compared to cardiac troponin (cTn) alone is unsettled in the era of high-sensitivity cardiac troponin (hsTn) assays. We aimed to investigate the clinical characteristics, therapies, and outcomes of UA patients with different hsTnT concentrations. METHODS: During 12 months, 2525 patients were enrolled. UA was defined as unstable symptoms and either undetectable (< 5 ng/L), normal (5-14 ng/L) or stable elevated hsTnT (15-51 ng/L). Follow-up for 1-year mortality was available in 98.7%. RESULTS: A total of 280 patients (11.1%) received a diagnosis of UA. Mortality rates at 12 months were 0%, 1.9% and 6.9% in presence of undetectable, normal and stable elevated hsTnT. Elevated hsTnT > 99th percentile but not unstable symptoms carried an independent 3.25-fold (1.78-5.93) higher risk for all-cause death after adjustment for other clinical risk indicators or the GRACE score. Utilization of guideline-recommended therapies was high albeit lower than for non-ST-elevation myocardial infarction (NSTEMI). Significantly fewer patients with UA received dual antiplatelet therapy (DAPT, odds ratio (OR) 0.51 [95% CI 0.44-0.59], P < 0.0001), coronary angiography (CA, OR 0.79, [95% CI 0.74-0.87], P < 0.0001), and percutaneous coronary intervention (PCI, OR 0.50, [95% CI 0.40-0.61], P < 0.0001), compared to NSTEMI. However, prevalence of significant obstructive coronary artery disease requiring PCI was 31.8%, even in patients with undetectable hsTnT, indicating the need for stress testing. CONCLUSIONS: The current dichotomization of patients into UA and NSTEMI is no longer appropriate. Additional risk stratification seems warranted including the presence and magnitude of hsTn concentration and additional risk indicators. Clinical Trials Identifier: NCT03111862.

17.
ESC Heart Fail ; 6(4): 640-648, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31259484

RESUMO

AIMS: Co-morbid atrial fibrillation (AF) increases both mortality and N-terminal pro brain natriuretic peptide (NT-proBNP) concentrations in patients with chronic heart failure (CHF). It is unclear whether AF worsens prognosis independently from NT-proBNP concentrations. If AF was an independent risk factor, NT-proBNP levels for outcome prediction would need to be adjusted in patients with AF. We aimed to analyse the influence of AF on the prognostic value of NT-proBNP in patients with CHF. METHODS AND RESULTS: A total of 2541 consecutive CHF patients with sinus rhythm (SR) or AF were identified in the outpatients' CHF registry of the University of Heidelberg, Germany. Of these, 250 patients with SR were individually matched to 250 patients with AF with respect to NT-proBNP, New York Heart Association functional class, sex, age, and aetiology of CHF. In the general sample, both AF and NT-proBNP were associated with all-cause mortality [hazard ratio (HR) = 1.96, 95% confidence interval (CI) 1.61-2.39, P < 0.001; and HR = 1.03 per 1000 ng/L increase, 95% CI 1.02 to 1.04, P < 0.001, respectively]. After matching, NT-proBNP retained its prognostic power (HR = 1.13 per 1000 ng/L increase, 95% CI 1.10 to 1.16, P < 0.001), but AF did not (HR = 0.91, 95% CI 0.66 to 1.25, P = 0.56). Despite similar prognosis, matched patients with SR were in more advanced CHF than were AF patients as indicated by a lower left ventricular ejection fraction (30 ± 13% vs. 34 ± 14%, P < 0.001). CONCLUSIONS: The prognostic value of NT-proBNP in CHF is not influenced by concomitant AF. AF, in return, might be a surrogate of a worse cardiac condition rather than an independent risk factor.

18.
ESC Heart Fail ; 6(4): 824-829, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31278857

RESUMO

AIMS: Our aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18 F-FDG positron emission tomography-computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism. METHODS AND RESULTS: In a retrospective cohort study, we analysed cardiac and skeletal muscle 18 F-FDG uptake in onco-positron emission tomography-computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non-Hodgkin's lymphoma, and non-lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18 F-FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step-down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non-Hodgkin's lymphoma (n = 57), and non-lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval-CI], P < 0.0001, and 0.52 [0.33, 0.82, 95% CI], P < 0.005, respectively). Hodgkin's lymphoma was associated with an increase in cardiac uptake (OR 2.4 [1.3, 4.5, 95% CI], P < 0.005). Decreased skeletal muscle 18 F-FDG uptake was noted in elderly and obese patients. In our multivariate analysis, Hodgkin's lymphoma patients showed higher cardiac 18 F-FDG uptake, while non-Hodgkin's lymphoma patients did not differ significantly from non-lymphatic cancer patients (OR 1.6 [0.7, 3.3, 95% CI], P = 0.24). High serum glucose levels and prior chemotherapy were both associated with a significantly decreased cardiac 18 F-FDG uptake (OR 0.40 [0.24, 0.65, 95% CI], P < 0.0005, and 0.50 [0.27, 0.90, 95% CI], P < 0.05, respectively). Notably, prior chemotherapy did not influence FDG uptake in skeletal muscle to the same extent. Obesity and older age were both significantly associated with decreased gluteal 18 F-FDG uptake (OR 0.49 [0.27, 0.89, 95% CI], P < 0.05, and 0.47 [0.25, 0.87, 95% CI], P < 0.05). CONCLUSIONS: Our data provide evidence for metabolic alterations in patients with Hodgkin's lymphoma related to cardiac glucose uptake in humans. This effect was independent from skeletal muscle metabolism.

19.
Prog Biophys Mol Biol ; 144: 128-138, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31182191

RESUMO

Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 µM), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 µM), and lidocaine (-59%; 100 µM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm.

20.
Nat Rev Dis Primers ; 5(1): 39, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171787

RESUMO

ST-segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease and is associated with great morbidity and mortality. A complete thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of post-STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve the occluding thrombus. The initiation of networks to provide around-the-clock cardiac catheterization availability and the generation of standard operating procedures within hospital systems have helped to reduce the time to reperfusion therapy. Together with new advances in antithrombotic therapy and preventive measures, these developments have resulted in a decrease in mortality from STEMI. However, a substantial amount of patients still experience recurrent cardiovascular events after STEMI. New insights have been gained regarding the pathophysiology of STEMI and feed into the development of new treatment strategies.

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