Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Filtros adicionais











Tipo de estudo
País/Região como assunto
Intervalo de ano
1.
J Mol Cell Cardiol ; 131: 53-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005484

RESUMO

AIMS: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. METHODS AND RESULTS: Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. CONCLUSIONS: Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

2.
Basic Res Cardiol ; 114(3): 19, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887214

RESUMO

Heart failure is a consequence of various cardiovascular diseases and associated with poor prognosis. Despite progress in the treatment of heart failure in the past decades, prevalence and hospitalisation rates are still increasing. Heart failure is typically associated with cardiac remodelling. Here, inflammation and fibrosis are thought to play crucial roles. During cardiac inflammation, immune cells invade the cardiac tissue and modulate tissue-damaging responses. Cardiac fibrosis, however, is characterised by an increased amount and a disrupted composition of extracellular matrix proteins. As evidence exists that cardiac inflammation and fibrosis are potentially reversible in experimental and clinical set ups, they are interesting targets for innovative heart failure treatments. In this context, animal models are important as they mimic clinical conditions of heart failure patients. The advantages of mice in this respect are short generation times and genetic modifications. As numerous murine models of heart failure exist, the selection of a proper disease model for a distinct research question is demanding. To facilitate this selection, this review aims to provide an overview about the current understanding of the pathogenesis of cardiac inflammation and fibrosis in six frequently used murine models of heart failure. Hence, it compares the models of myocardial infarction with or without reperfusion, transverse aortic constriction, chronic subjection to angiotensin II or deoxycorticosterone acetate, and coxsackievirus B3-induced viral myocarditis in this context. It furthermore provides information about the clinical relevance and the limitations of each model, and, if applicable, about the recent advancements in their methodological proceedings.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Animais , Fibrose , Insuficiência Cardíaca/patologia , Camundongos , Miocardite/complicações , Miocárdio/patologia
3.
Resuscitation ; 136: 14-20, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30654013

RESUMO

BACKGROUND: Neuron-specific-enolase (NSE) is frequently used to predict the neurologic outcome in persistently unconscious patients after cardiopulmonary resuscitation (CPR). However, its predictive value is unclear in the setting of veno-arterial extracorporeal membrane oxygenation therapy (ECMO). Aim of this project is to evaluate the predictive value of NSE in ECMO patients. METHODS: NSE was measured after 24, 48, and 72 h in post-CPR ECMO patients. Neurologic status was evaluated using the best Cerebral Performance Categories Score (CPC) during the hospital stay. Patients who deceased within the first 24 h and patients who were awake during the first 24 h were excluded. ROC curves were calculated to assess the discriminative ability of single NSE measurements. Trajectories of serial NSE values were investigated using latent class mixed models. RESULTS: The derivation cohort consisted of 65 patients, 30-day all-cause mortality was 47.7% and a poor neurological outcome with a CPC score of 4-5 was seen 30.7%. NSE measurement after 48 h showed the best discrimination for poor neurological outcome (AUC of 0.87 in the ROC curve; cut-off value of 70 µg/L). Specificity was highest if using serial NSE measurements at all three time points. These results could be validated in an external cohort of 64 patients. CONCLUSION: In post-CPR patients on ECMO, NSE can be used to assess the neurologic outcome. Importantly, specificity was highest if using serial NSE measurements. Further research using prospective datasets is needed to verify these findings.

4.
Biomolecules ; 9(2)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678084

RESUMO

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto /paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.


Assuntos
Fibroblastos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Animais , Células Cultivadas , Fibroblastos/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais/genética
5.
JACC Heart Fail ; 6(12): 1035-1043, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30497643

RESUMO

OBJECTIVES: This report relates the authors' ongoing experience with percutaneous left ventricular (LV) unloading by using a transaortic LV assist device in combination with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and provides an in-depth analysis of the hemodynamic benefit of this approach. BACKGROUND: VA-ECMO is increasingly used in cases of severe cardiogenic shock. However, increase in afterload with subsequent LV overload is a major drawback of VA-ECMO. METHODS: Consecutive patients were treated with a transaortic LV assist device in addition to VA-ECMO for cardiogenic shock. The primary endpoint was 30-day all-cause mortality. Additional endpoints included weaning from VA-ECMO and safety endpoints. RESULTS: Between September 2013 and January 2018, 106 patients were treated with percutaneous LV unloading, using a transaortic LV assist device in combination with VA-ECMO. Successful weaning from VA-ECMO support was achieved in 51.9% of all patients. In the overall cohort, survival at day 30 was 35.8%, which was higher than predicted by the SAVE score (20%) or by the SAPS-II score (6.9%). Right heart catheterization indicated a marked decrease of PCWP after addition of the device to VA-ECMO. CONCLUSIONS: The strategy of percutaneous LV unloading using a transaortic LV assist device in combination with VA-ECMO improved outcome in an all-comers cohort compared to established risk scores. A prospective, randomized study is needed to further investigate this approach.

7.
Proc Natl Acad Sci U S A ; 115(37): E8727-E8736, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30166452

RESUMO

Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM1 receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation.


Assuntos
Adrenomedulina/genética , Inflamação/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Precursores de Proteínas/genética , Adrenomedulina/metabolismo , Adrenomedulina/farmacologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células Cultivadas , Citocinas/metabolismo , Feminino , Expressão Gênica/genética , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Precursores de Proteínas/metabolismo , Precursores de Proteínas/farmacologia
8.
Am J Physiol Heart Circ Physiol ; 315(3): H669-H680, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29727215

RESUMO

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 µg·kg-1·min-1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

9.
Heart Rhythm ; 15(9): 1328-1336, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29803020

RESUMO

BACKGROUND: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. OBJECTIVE: We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT. METHODS: Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed. RESULTS: DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; P < .05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the in vivo experiments associated with increased atrial size. CONCLUSION: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

10.
J Am Heart Assoc ; 7(6)2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29545259

RESUMO

BACKGROUND: Percutaneous mitral valve edge-to-edge repair (pMVR) with a MitraClip is beneficial for the clinical symptoms of patients irrespective of the ejection fraction (EF). Nevertheless, the consequences on hemodynamics are poorly understood. Therefore, we used data from noninvasive pressure-volume loops to investigate the left ventricular (LV) remodeling of patients after pMVR dependent on their baseline EF. METHODS AND RESULTS: In 130 patients with successful pMVR, the end-diastolic pressure-volume relationship (EDPVR) and end-systolic pressure-volume relationship were estimated noninvasively from echocardiographic data. We compared EDPVR and end-systolic pressure-volume relationship at discharge and follow-up between patients with a reduced EF (<40%) and patients with a mid-ranged or preserved EF (≥40%). Reduced EF was present in 71 patients (54%). Mean follow-up duration was 277±117 days. We observed a significant reduction in degree of mitral regurgitation and an improvement in functional status at follow-up irrespective of baseline EF. In patients with a mid-ranged or preserved EF, the EDPVR and end-systolic pressure-volume relationship were shifted leftwards, suggesting an improvement in LV function. In contrast, in patients with a reduced EF, EDPVR and end-systolic pressure-volume relationship remained stable, although comparison with the baseline data indicates a rightward shift of the EDPVR. This indicates that there is no improvement in LV function after pMVR in patients with reduced EF. CONCLUSIONS: The pMVR is associated with improved clinical symptoms in all patient subgroups. However, it leads to different hemodynamic responses. In patients with mid-ranged or preserved EF, we found reverse remodeling with reduced LV dilatation and increased contractility. In contrast, in patients with reduced EF, we observed no reverse remodeling and no improvement in LV function.

11.
J Cardiovasc Electrophysiol ; 28(9): 1058-1067, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28597532

RESUMO

BACKGROUND: Ablation of scar-related ventricular tachycardia (VT), especially in noninducible VT or hemodynamically unstable patients, can be challenging. Thus, we evaluated feasibility of an ultra high-density 3-D mapping approach to characterize the ventricular substrate and, if possible, to map VT. METHODS AND RESULTS: Twenty-two patients (67 ± 2 years, mean LV-EF 36 ± 3%) with both ischemic and nonischemic cardiomyopathy and documented VT underwent mapping and catheter ablation using a 64-electrode mini-basket catheter. Substrate characterization included ultra high-density voltage maps, identification of areas of slow conduction and late potentials. Whenever VT was inducible activation mapping was performed. In 13 of 22 patients, the presumed clinical VT (in 16 of 22 any VT) was inducible. A total of 50 maps were generated (22 substrate maps, 28 during VT), mapping time was 33 ± 4 minutes, number of points was 10,937 ± 1,923. Low voltage areas were related with the site of origin in all mapped VT. Isochronal maps indicated areas of slow conduction in 14 of 22 patients, all in border zone scar. In 95% of patients, late potentials were found. Mapping time during VT was 9 ± 2 minutes, number of points 6,740 ± 1,140. Covered cycle length was 82 ± 5% (16 re-entry, 10 focal, and two undetermined). During 4 months follow-up, 90% remained free from VT recurrence. CONCLUSION: Ultra high-density mapping in patients with scar-related VT is feasible, safe and enables detailed insight into tachycardia mechanisms. Critical sites can be identified (1) by precise substrate characterization when VT is not inducible or hemodynamically not tolerated and (2) during short lasting episodes of VT in order to guide catheter ablation.


Assuntos
Mapeamento Potencial de Superfície Corporal/métodos , Cardiomiopatias/complicações , Ablação por Cateter/métodos , Cicatriz/complicações , Frequência Cardíaca/fisiologia , Imagem Tridimensional/métodos , Taquicardia Ventricular/cirurgia , Idoso , Cardiomiopatias/diagnóstico , Cicatriz/diagnóstico , Eletrocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Curva ROC , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Resultado do Tratamento
12.
Minerva Cardioangiol ; 65(4): 331-335, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28146144

RESUMO

BACKGROUND: Aorto-ostial lesions as well as bifurcation lesions still provide challenges in percutaneous coronary intervention (PCI), as meticulous stent placement is needed. The Szabo-technique, which uses a second wire to anchor the stent at the ostium, may be helpful here. In this article, we will provide detailed information on the technique including video material as well as procedural and long-term follow-up data of a cohort of patients treated with this technique. METHODS: A retrospective single-centre study was performed in patients undergoing Szabo-PCI from 2014 to 2016 (N.=28). RESULTS: Indications for PCI were elective in 53% and urgent/emergent in 47%. Target vessel was the ostial right coronary artery in 43%, the ostial left main artery in 7%, the proximal left anterior descending artery in 29% and the proximal circumflex artery in 21% of the cases. Primary success rate was 86%. In the other 14%, delivery of the stent failed due to a high-grade calcification. There were no periprocedural complications. During the follow-up time (mean 308 days) there was one case of cardiovascular and one case of non-cardiovascular death without any stroke events. In one case target lesions revascularisation was necessary. CONCLUSIONS: The Szabo-technique offers a feasible and safe approach for PCI of ostial and bifurcation lesions. Calcified lesions seem to be a challenging aspect.


Assuntos
Doença da Artéria Coronariana/terapia , Intervenção Coronária Percutânea/métodos , Stents , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
13.
Pacing Clin Electrophysiol ; 40(2): 175-182, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27995637

RESUMO

BACKGROUND: Extensive and repeated substrate modification (SM) is frequently performed as an ablation strategy in persistent atrial fibrillation (persAF). The effect of these extended ablation strategies on atrial function has not been investigated sufficiently so far. The purpose was to assess atrial function by cardiac magnetic resonance (CMR) and its association with left atrial (LA) scar burden by electroanatomical voltage-mapping after multiple persAF ablation procedures. METHODS: We included 16 persAF patients who had ≥2 SM procedures and a control group (CG) of 21 persAF patients without prior ablation. CMR was performed in sinus rhythm at least 4 weeks after the last cardioversion. Active left and right (RA) atrial emptying fractions (AEF) as well as peak active left atrial appendage (LAA) emptying velocities were obtained by CMR flow measurements. Furthermore, LA scar burden was quantified on electroanatomical voltage maps by the portion of points with local voltage amplitude <0.2 mV. RESULTS: We found median LA-AEF to be lower (13 [9-22] vs 32 [26-36] %, P < 0.001) and median LA scar burden to be higher (40 [20-68] vs nine [3-18] %, P < 0.05) in the SM group compared with the CG. Furthermore, a significant correlation was found between mean LA voltage and LA-AEF (r2 = 0.62, P < 0.001). No significant differences were detected with respect to median RA-AEF (41 [28-48] vs 47 [35-50] %, P = 0.43) and median peak LAA emptying velocities (30 [16-40] vs 17 [13-28] cm/s, P = 0.07). CONCLUSIONS: Active LA function is preserved but significantly impaired and associated with ablation-related LA scar burden after multiple extensive persAF ablations.


Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Função Atrial , Remodelamento Atrial , Ablação por Cateter/efeitos adversos , Cicatriz/etiologia , Idoso , Fibrilação Atrial/diagnóstico , Doença Crônica , Cicatriz/patologia , Cicatriz/fisiopatologia , Feminino , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reoperação/efeitos adversos , Resultado do Tratamento
14.
Int J Cardiol ; 227: 272-277, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27838133

RESUMO

BACKGROUND: Heart failure (HF) incidence is rising worldwide and HF with preserved ejection fraction (HFpEF) represents nearly half of all cases. Treatment options are still limited in HFpEF in comparison to HF with reduced ejection fraction (HFrEF). METHODS: We analyzed biomarkers in the general population to characterize HFpEF and HFrEF and defined a biomarker index to differentiate HFpEF from HFrEF. Growth differentiation factor-15 (GDF-15), soluble source of tumorigenicity 2 (sST2), C-reactive protein (CRP) and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS). The median follow-up time for all-cause mortality was 7.3years with 213 events. RESULTS: Identification of subjects with HF was improved by GDF-15 (p<0.001) in addition to NT-proBNP with an odds ratio (OR) of 1.4 (95% confidence interval [CI]:1.1-1.7). Discrimination of subjects with and without HF was slightly higher for GDF-15 (area under the ROC curve [AUC]:0.79 [95%CI:0.75-0.83]) compared to NT-proBNP (AUC:0.77 [95% CI:0.72-0.82]). For subjects with HF, differentiating HFpEF from HFrEF was feasible with the index ((CRP+GDF-15+sST2)/NT-proBNP) with an OR of 3.7 (95% CI:1.9-8.5) (p<0.001). The best biomarkers predicting all-cause mortality were NT-proBNP and GDF-15 with a hazard ratio (HR) of 1.9 (95% CI:1.6-2.2) and 1.7 (95%CI:1.6-1.9) (both p<0.001), respectively. CONCLUSION: GDF-15 was useful to detect prevalent HF in addition to NT-proBNP and was elevated in HFrEF and HFpEF, whereas NT-proBNP was higher in HFrEF than in HFpEF. All biomarkers were useful to predict mortality in the general population. The index of ((CRP+GDF-15s+sST2)/NT-proBNP) was able to discriminate HFpEF from HFrEF.


Assuntos
Proteína C-Reativa/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Volume Sistólico
15.
Clin Res Cardiol ; 106(6): 401-410, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28004184

RESUMO

BACKGROUND: Obesity is a risk factor for heart failure (HF) and identification of symptomatic, and obese HF patients are challenging, because obesity can mimic HF symptoms. We aimed to evaluate novel biomarkers for HF in obese subjects of the general population. METHODS: Midregional proadrenomedullin (MR-proADM), growth differentiation factor-15 (GDF-15), midregional pro-atrial natriuretic peptide (MR-proANP), and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS), including 1204 obese individuals (BMI ≥ 30 kg/m2) and 107 individuals with HF. RESULTS: NT-proBNP and MR-proANP were lower in obese vs. non-obese HF individuals (p = 0.013 and p = 0.01, respectively), whereas GDF-15 was similar and MR-proADM was higher in obese vs. non-obese HF individuals. All biomarkers increased the odds ratio (OR) for prevalent HF. For NT-proBNP and MR-proANP, this increase was lower in obese vs. non-obese individuals, whereas it was comparable for MR-proADM and GDF-15. All biomarkers were associated with increased all-cause mortality (median follow-up 7.3 years, 211 events). Results were validated in 8373 individuals (n = 1734 with BMI ≥ 30 kg/m2) of the FINRISK study with a median follow-up of 13.8 years (1030 events). Using a dichotomized biomarker cutoff for HF, the best predictor for all-cause mortality in obese subjects was GDF-15 (p < 0.001). CONCLUSION: All biomarkers were associated with HF and higher risk for all-cause mortality in the general population. In contrast to the natriuretic peptides NT-proBNP and MR-proANP, the novel biomarkers MR-proADM and GDF-15 were not lower in obese HF individuals, indicating their potential to facilitate HF diagnosis and prognosis in an increasingly obese HF population.


Assuntos
Adrenomedulina/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Insuficiência Cardíaca/diagnóstico , Obesidade/complicações , Precursores de Proteínas/sangue , Idoso , Fator Natriurético Atrial/sangue , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Obesidade/sangue , Obesidade/mortalidade , Fragmentos de Peptídeos/sangue , Prognóstico , Estudos Prospectivos , Fatores de Risco
16.
Crit Care Med ; 44(12): e1258-e1259, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27858831
17.
Eur Heart J ; 37(23): 1807-14, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27055814

RESUMO

AIMS: Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure-volume relationship (EDPVR), which is different in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF patients and their association to risk factors and all-cause mortality in non-HF individuals. METHODS AND RESULTS: Based on clinical and echocardiographic data, participants were divided into 'No HF' (n = 14487), HFrEF (n = 215), and HFpEF (n = 79). We estimated the position of the EDPVR and its stiffness-coefficient ß from echocardiographic data using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with 'No HF', while the stiffness-coefficient ß was increased in both HFrEF and HFpEF. In 'No HF', a higher stiffness-coefficient ß was associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were associated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause mortality. CONCLUSION: In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with increased mortality.


Assuntos
Insuficiência Cardíaca/mortalidade , Disfunção Ventricular Esquerda/mortalidade , Adulto , Idoso , Volume Cardíaco/fisiologia , Causas de Morte , Ecocardiografia , Feminino , Alemanha/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Prognóstico , Estudos Prospectivos , Fatores de Risco , Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/fisiologia , Remodelação Ventricular/fisiologia
18.
J Electrocardiol ; 49(2): 124-31, 2016 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26803554

RESUMO

Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6weeks of rapid atrial pacing (RAP, 600bpm) using a custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose-response relationship between RAP duration and occurrence of sustained AF >60minutes. Left atrial (LA) dilatation was present already at 2weeks of RAP. There was no evidence of left ventricular heart failure after 6weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP+DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Marca-Passo Artificial , Próteses e Implantes , Telemetria/instrumentação , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Feminino , Suínos , Telemetria/métodos
19.
Crit Care Med ; 44(3): e158-67, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26474110

RESUMO

OBJECTIVES: The results from the recent Targeted Temperature Management trial raised the question whether cooling or merely the avoidance of fever mediates better neurologic outcome in resuscitated patients. As temperature per se is a major determinant of cardiac function, we characterized the effects of hyperthermia (40.5°C), normothermia (38.0°C), and mild hypothermia (33.0°C) on left ventricular contractile function in healthy pigs and compared them with dobutamine infusion. DESIGN: Animal study. SETTING: Large animal facility, Medical University of Graz, Graz, Austria. SUBJECTS: Nine anesthetized and mechanically ventilated closed-chest Landrace pigs (67 ± 2 kg). INTERVENTIONS: Core body temperature was controlled using an intravascular device. At each temperature step, IV dobutamine was titrated to double maximum left ventricular dP/dt (1.8 ± 0.1 µg/kg/min at normothermia). Left ventricular pressure-volume relationships were assessed during short aortic occlusions. Left ventricular contractility was assessed by the calculated left ventricular end-systolic volume at an end-systolic left ventricular pressure of 100 mm Hg. MEASUREMENTS AND MAIN RESULTS: Heart rate (98 ± 4 vs 89 ± 4 vs 65 ± 2 beats/min; all p < 0.05) and cardiac output (6.7 ± 0.3 vs 6.1 ± 0.3 vs 4.4 ± 0.2 L/min) decreased with cooling from hyperthermia to normothermia and mild hypothermia, whereas left ventricular contractility increased (left ventricular end-systolic volume at a pressure of 100 mm Hg: 74 ± 5 mL at hyperthermia, 52 ± 4 mL at normothermia, and 41 ± 3 mL at mild hypothermia; all p < 0.05). The effect of cooling on left ventricular end-systolic volume at a pressure of 100 mm Hg (hyperthermia to normothermia: -28% ± 3% and normothermia to mild hypothermia: -20% ± 5%) was of comparable effect size as dobutamine at a given temperature (hyperthermia: -28% ± 4%, normothermia: -27% ± 6%, and mild hypothermia: -27% ± 9%). CONCLUSIONS: Cooling from hyperthermia to normothermia and from normothermia to mild hypothermia increased left ventricular contractility to a similar degree as a significant dose of dobutamine in the normal porcine heart. These data indicate that cooling can reduce the need for positive inotropes and that lower rather than higher temperatures are appropriate for the resuscitated failing heart.


Assuntos
Dobutamina/farmacologia , Hipertermia Induzida , Hipotermia Induzida , Contração Miocárdica/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Gasometria , Débito Cardíaco , Frequência Cardíaca/efeitos dos fármacos , Hipertermia Induzida/métodos , Hipotermia Induzida/métodos , Contração Miocárdica/efeitos dos fármacos , Volume Sistólico , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacos
20.
Am J Physiol Heart Circ Physiol ; 309(9): H1407-18, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26342070

RESUMO

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.


Assuntos
Cardiomiopatias/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Miócitos Cardíacos/patologia , Volume Sistólico , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Conectina/metabolismo , Acetato de Desoxicorticosterona/toxicidade , Dieta Ocidental , Dilatação Patológica/etiologia , Dilatação Patológica/fisiopatologia , Modelos Animais de Doenças , Feminino , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/complicações , Hipertensão/induzido quimicamente , Hipertrofia/etiologia , Hipertrofia/patologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Mineralocorticoides/toxicidade , Miócitos Cardíacos/metabolismo , Óxido Nítrico Sintase/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Superóxidos/metabolismo , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA