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2.
Eur Heart J ; 40(26): 2142-2151, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31098611

RESUMO

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

4.
Commun Biol ; 1: 104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271984

RESUMO

Impaired activated protein C (aPC) generation is associated with atherosclerosis and diabetes mellitus. Diabetes-associated atherosclerosis is characterized by the hyperglycaemic memory, e.g., failure of disease improvement despite attenuation of hyperglycaemia. Therapies reversing the hyperglycaemic memory are lacking. Here we demonstrate that hyperglycaemia, but not hyperlipidaemia, induces the redox-regulator p66Shc and reactive oxygen species (ROS) in macrophages. p66Shc expression, ROS generation, and a pro-atherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of p66Shc abolishes this sustained pro-atherogenic phenotype, identifying p66Shc-dependent ROS in macrophages as a key mechanism conveying the hyperglycaemic memory. The p66Shc-associated hyperglycaemic memory can be reversed by aPC via protease-activated receptor-1 signalling. aPC reverses glucose-induced CpG hypomethylation within the p66Shc promoter by induction of the DNA methyltransferase-1 (DNMT1). Thus, epigenetically sustained p66Shc expression in plaque macrophages drives the hyperglycaemic memory, which-however-can be reversed by aPC. This establishes that reversal of the hyperglycaemic memory in diabetic atherosclerosis is feasible.

5.
J Am Coll Cardiol ; 72(8): 874-882, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30115226

RESUMO

BACKGROUND: Prognosis of Takotsubo syndrome (TTS) remains controversial due to scarcity of available data. Additionally, the effect of the triggering factors remains elusive. OBJECTIVES: This study compared prognosis between TTS and acute coronary syndrome (ACS) patients and investigated short- and long-term outcomes in TTS based on different triggers. METHODS: Patients with TTS were enrolled from the International Takotsubo Registry. Long-term mortality of patients with TTS was compared to an age- and sex-matched cohort of patients with ACS. In addition, short- and long-term outcomes were compared between different groups according to triggering conditions. RESULTS: Overall, TTS patients had a comparable long-term mortality risk with ACS patients. Of 1,613 TTS patients, an emotional trigger was detected in 485 patients (30%). Of 630 patients (39%) related to physical triggers, 98 patients (6%) had acute neurologic disorders, while in the other 532 patients (33%), physical activities, medical conditions, or procedures were the triggering conditions. The remaining 498 patients (31%) had no identifiable trigger. TTS patients related to physical stress showed higher mortality rates than ACS patients during long-term follow-up, whereas patients related to emotional stress had better outcomes compared with ACS patients. CONCLUSIONS: Overall, TTS patients had long-term outcomes comparable to age- and sex-matched ACS patients. Also, we demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor. We propose a new classification based on triggers, which can serve as a clinical tool to predict short- and long-term outcomes of TTS. (International Takotsubo Registry [InterTAK Registry]; NCT01947621).

6.
J Cardiol ; 72(2): 135-139, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29544658

RESUMO

BACKGROUND: Implantable cardioverter/defibrillator (ICD) shocks can cause myocardial injury, contributing to the progression of the underlying heart disease. The aim was to evaluate whether internal electrical cardioversion (int-CV) via the ICD or conventional external CV (ext-CV) of persistent atrial fibrillation (AF) in heart failure (HF) patients induces myocardial injury and initiates inflammation. METHODS AND RESULTS: A total of 115 HF patients with an ejection fraction between 20% and 45% were prospectively enrolled. Fifty-one patients were excluded due to failure of electrical CV at the first attempt as well as early relapse of AF within 8h after CV. The int-CV group consisted of 22 and the ext-CV group of 42 patients. Baseline values of high sensitive troponin T (hsTnT), interleukin (IL)-6, and C-reactive protein (CRP) did not differ significantly in both groups, whereas baseline N-terminal pro B-type natriuretic peptide (NT-pro BNP) was significantly lower in the ext-CV group. Eight hours after CV, the level of hsTnT increased significantly in the int-CV group, whereas no significant change was observed in the ext-CV group. Furthermore, CV significantly increased IL-6 and CRP in the int-CV group, whereas an insignificant increase could be documented in the ext-CV group. Due to electrical CV in both groups, the NT-pro BNP levels significantly declined in approximately the same content (int-CV 29% vs. ext-CV 36%). CONCLUSIONS: The significant increase in hsTnT, IL-6, and CRP in patients who underwent int-CV compared to those undergoing ext-CV may suggest that int-CV causes significant myocardial damage and induces systemic inflammation.

7.
Int J Cardiol ; 268: 156-161, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29548538

RESUMO

BACKGROUND: Right ventricular (RV) dysfunction is recognized as a cardinal prognostic marker in systolic heart failure patients. Conflicting data exist on the interaction of RV function and left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT). This prospective monocentric trial was set up to assess the predictive value of baseline RV function and corresponding RV-pulmonary artery (PA) coupling on LV reverse remodeling after CRT. METHODS: 110 patients with a CRT indication were prospectively enrolled. RV function and RV-PA interaction were analyzed at baseline using echocardiographic and invasive pressure-volume loop catheter approach. The primary endpoint was reverse LV remodeling (CRT-responder) defined as a reduction in LV end-systolic volume of ≥15% at 6 months. RESULTS: Responders had higher RV-PA coupling ratios (single-beat end-systolic elastance/PA elastance: Ees/Ea) at baseline, which corresponded to smaller RVs with better ejection fraction and lower afterload. After multivariate adjustment, the baseline Ees/Ea remained an independent predictor for LV response (OR 14.0 [1.5-130.8], p = 0.021). Normal coupling (Ees/Ea ≥ 1) was associated with higher responder rates (RR) (86%). Progressive uncoupling was associated with lower LV-RR (Ees/Ea ≤ 1-0.5: 57%, and Ees/Ea < 0.5: 32%, p < 0.001), corresponded with higher degrees of LV impairment and severity of mitral regurgitation, and was independently associated with an adverse outcome. CONCLUSIONS: A higher baseline RV-PA coupling, reflecting a lower degree of LV-induced pulmonary hypertension and secondary RV-dysfunction, is associated with an improved LV-reverse remodeling and is independently associated with better prognosis. The value of RV-PA ratio as potential guide for CRT patient selection warrants further investigation. Clinical Trial Registration - URL: http://www.drks.de. Unique Identifier: DRKS00011133.

8.
J Vis Exp ; (126)2017 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-28872119

RESUMO

The therapeutic goal for peripheral arterial disease and ischemic heart disease is to increase blood flow to ischemic areas caused by hemodynamic stenosis. Vascular surgery is a viable option in selected cases, but for patients without indications for surgery such as progression to rest pain, critical limb ischemia, or major disruptions to life or work, there are few possibilities for mitigating their disease. Cell therapy via monocyte-enhanced perfusion through the stimulation of collateral formation is one of a few non-invasive options. Our group examines arteriogenesis after monocyte transplantation into mice using the hindlimb ischemia model. Previously, we have demonstrated improvement in hindlimb perfusion using tetanus-stimulated syngeneic monocyte transplantation. In addition to the effects on the collateral formation, tumor growth could be affected by this therapy as well. To investigate these effects, we use a basement membrane-like matrix mouse model by injecting the extracellular matrix of the Engelbreth-Holm-Swarm sarcoma into the flank of the mouse, after occlusion of the femoral artery. After the artificial tumor studies, we use intravital microscopy to study in vivo tumor-angiogenesis and monocyte homing within collateral arteries. Previous studies have described the histological examination of animal models, which presupposes subsequent analysis to post-mortem artifacts. Our approach visualizes monocyte homing to areas of collateralization in real time sequences, is easy to perform, and investigates the process of arteriogenesis and tumor angiogenesis in vivo.


Assuntos
Microscopia Intravital/métodos , Monócitos/patologia , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Neovascularização Fisiológica
9.
Blood ; 130(24): 2664-2677, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-28882883

RESUMO

Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.


Assuntos
Inflamassomos/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína C/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Animais Recém-Nascidos , Anticoagulantes/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Immunoblotting , Inflamassomos/metabolismo , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Substâncias Protetoras/farmacologia , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Traumatismo por Reperfusão/metabolismo
10.
Medicine (Baltimore) ; 96(34): e7692, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28834872

RESUMO

Elevated blood pressure (BP) is frequently diagnosed in very elderly hospitalized patients. Accurate diagnosis of hypertension is challenging in the hospital environment, due to the "white coat effect," and both overtreatment and undertreatment can adversely affect clinical outcome. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has the potential to avoid the "white coat effect" and accurately guide the management of hypertension. However, effects of the hospital environment on ABPM are unknown in the very elderly. We set out to enroll 45 patients, age ≥70 years, with elevated conventional BP during hospitalization in this observational study. It was prespecified by protocol to assess initially the difference between 24-hour BP during hospital-admission and home follow-up. Subsequent analysis should investigate the change in anxiety (Hospital Anxiety and Depression Scale-A [HADS-A]) after discharge, the correlation with change in 24-hour BP after discharge, and the prevalence of orthostatic hypertension. Thirty-one patients were included in the final analysis (age 83.5 ±â€Š4.4 years; 71% female). Twenty-four-hour BP decreased significantly after hospital discharge (systolic from 133.5 ±â€Š15.6 to 126.2 ±â€Š14.4 mm Hg [millimeter of mercury], P = .008; diastolic from 71.0 ±â€Š9.0 to 68.3 ±â€Š8.6 mm Hg, P = .046). Anxiety level (HADS-A) decreased significantly after discharge, from 7.5 (interquartile range [IQR]: 4.0-13.8) to 5.0 (IQR: 4.0-8.0, P = .012). The change in anxiety was a predictor of change in systolic BP after discharge (F[1,20] = 5.9, P = .025). Sixty-one percent of the patients had significant orthostatic hypotension during hospital stay. In conclusion, 24-hour BP in very elderly patients is lower in the home environment than during hospitalization. This phenomenon seems to be directly linked to a lower anxiety-level at home. Reassessing hypertension at home may decrease the need for (intensified) antihypertensive medical therapy in a substantial number of patients. This is particularly important in the very elderly, who have a high prevalence of symptomatic and asymptomatic orthostatic hypotension, making them prone to hazardous effects of antihypertensive therapy.


Assuntos
Monitorização Ambulatorial da Pressão Arterial/estatística & dados numéricos , Pressão Sanguínea , Hospitalização/estatística & dados numéricos , Hipertensão/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Ansiedade/epidemiologia , Ansiedade/fisiopatologia , Depressão/epidemiologia , Depressão/fisiopatologia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipotensão Ortostática/epidemiologia , Masculino , Dor/epidemiologia , Dor/fisiopatologia
11.
Am J Transl Res ; 9(6): 3084-3095, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28670395

RESUMO

BACKGROUND: Investigations in factor VII activating protease (FSAP)-/- mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. METHODS AND RESULTS: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP-/- mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP-/- mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP-/- mice. CONCLUSIONS: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP.

12.
SLAS Discov ; 22(7): 837-847, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28346101

RESUMO

Automatization in microscopy, cell culture, and the ease of digital imagery allow obtainment of more information from single samples and upscaling of image-based analysis to high-content approaches. Simple segmentation algorithms of biological imagery are nowadays widely spread in biomedical research, but processing of complex sample structures, for example, variable sample compositions, cell shapes, and sizes, and rare events remains a difficult task. As there is no perfect method for image segmentation and fully automatic image analysis of complex content, we aimed to succeed by identification of unique and reliable features within the sample. Through exemplary use of a coculture of vascular smooth muscle cells (VSMCs) and macrophages (MPs), we demonstrate how rare interactions within this highly variable sample type can be analyzed. Because of limitations in immunocytochemistry in our specific setup, we developed a semiautomatic approach to examine the interaction of lipid-laden MPs with VSMCs under hypoxic conditions based on nuclei morphology by high-content analysis using the open-source software CellProfiler ( www.cellprofiler.org ). We provide evidence that, in comparison with fully automatic analysis, a low threshold within the analysis workflow and subsequent manual control save time, while providing more objective and reliable results.

13.
Cell Death Differ ; 24(2): 371-383, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28009354

RESUMO

Deregulated proliferation is key to tumor progression. Although unrestricted proliferation of solid tumor cells correlates with the cold-shock protein Y-box (YB)-binding protein-1 accumulation in the nuclei, little is known about its expression and function in hematopoietic malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL). Here we show that YB-1 protein is highly enriched in the nuclei of activated T cells and malignant human T-ALL cell lines but not in resting T cells. YB-1 S102 mutations that either mimic (S102D) or prevent phosphorylation (S102N) led to accumulation of YB-1 in the nucleus of T cells or strictly excluded it, respectively. Inactivation of ribosomal S6 kinase (RSK) was sufficient to abrogate T-cell and T-ALL cell proliferation, suggesting that RSK mediates cell-cycle progression, possibly dependent on YB-1-phosphorylation. Indeed, phosphomimetic YB-1S102D enhanced proliferation implying that S102 phosphorylation is a prerequisite for malignant T-cell proliferation. At initial diagnosis of T-ALL, YB-1 localization was significantly altered in the nuclei of tumor blasts derived from bone marrow or peripheral blood. Our data show deregulated YB-1 in the nucleus as a yet unreported characteristic of T-ALL blasts and may refine strategies to restrict progression of hematopoietic tumors.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Adolescente , Adulto , Idoso , Benzopiranos/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Enterotoxinas/toxicidade , Feminino , Humanos , Células Jurkat , Masculino , Pessoa de Meia-Idade , Monossacarídeos/farmacologia , Mutagênese Sítio-Dirigida , Fosforilação/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/genética , Adulto Jovem
14.
Sci Rep ; 6: 38553, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27929056

RESUMO

The NF-κB signaling pathway is central for the innate immune response and its deregulation is found in multiple disorders such as autoimmune, chronic inflammatory and metabolic diseases. IKKγ/NEMO is essential for NF-κB activation and NEMO dysfunction in humans has been linked to so-called progeria syndromes, which are characterized by advanced ageing due to age-dependent inflammatory diseases. It has been suggested that glycogen synthase kinase-3ß (GSK-3ß) participates in NF-κB regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3ß substrate that is phosphorylated at serine 8, 17, 31 and 43 located within its N-terminal domain. The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3ß binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKKα and IKKß. Even IκBα was found degraded. Still, TNFα-stimulated NF-κB activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3ß is critically important for ordered NF-κB signalling through modulation of NEMO phosphorylation.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , NF-kappa B/metabolismo , Animais , Células HEK293 , Humanos , Quinase I-kappa B/metabolismo , Células MCF-7 , Camundongos , Proteínas Mutantes/metabolismo , Células NIH 3T3 , Fosforilação , Ligação Proteica , Estabilidade Proteica
16.
Curr Cardiol Rev ; 12(4): 297-303, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26864096

RESUMO

We performed a comparative literature review, to elucidate the major features of the Takotsubo (stress) cardiomyopathy (TCM) collected in last 25 years. TCM is characterized by left- or biventricular apical ballooning with a clinical presentation, electrocardiographic abnormalities, and biomarker profils similar to those seen in acute myocardial infarction. Epidemiological studies have shown that TCM is more common in postmenopausal women; however exact figures are not available. The underlying aetiology is still largely undetermined. Elevated catecholamine levels, lack of estrogen, disturbed myocardial fatty acid metabolism and plaque rupture with spontaneous thrombolysis are potentially discussed mechanisms responsible for inducing a prolonged stunned myocardium. Strong emotional or physical stress is the most frequently described trigger in the literature. Therapy recommendations include appropriate antiplatelet treatment, ß-blockers and ACE inhibitors. The abnormal kinetics usually resolve or improve within a month and carry a favorable prognosis in most cases. However, all the suspected complications of an acute myocardial infarction, including cardiogenic shock or lethal arrhythmias, may still occur.


Assuntos
Cardiomiopatia de Takotsubo , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Arritmias Cardíacas/complicações , Feminino , Humanos , Masculino , Menopausa , Infarto do Miocárdio/metabolismo , Prognóstico , Fatores Sexuais , Cardiomiopatia de Takotsubo/diagnóstico , Cardiomiopatia de Takotsubo/etiologia , Cardiomiopatia de Takotsubo/fisiopatologia , Cardiomiopatia de Takotsubo/terapia , Fatores de Tempo
17.
N Engl J Med ; 373(10): 929-38, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26332547

RESUMO

BACKGROUND: The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS: The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS: Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS: Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).


Assuntos
Cardiomiopatia de Takotsubo , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/diagnóstico por imagem , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ecocardiografia , Eletrocardiografia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Cardiomiopatia de Takotsubo/complicações , Cardiomiopatia de Takotsubo/tratamento farmacológico , Cardiomiopatia de Takotsubo/mortalidade , Cardiomiopatia de Takotsubo/fisiopatologia , Função Ventricular Esquerda
18.
Cardiology ; 131(3): 165-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25967848

RESUMO

OBJECTIVE: Despite the advanced therapy with statins, antithrombotics, and antihypertensive agents, the medical treatment of atherosclerotic disease is less than optimal. Therefore, additional therapeutic antiatherosclerotic options are desirable. This pilot study was performed to assess the potential antiatherogenic effect of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in nondiabetic patients. METHODS: A total of 54 nondiabetic patients were observed in a prospective, double-blind, placebo-controlled study. Patients were randomized to pioglitazone or placebo. The following efficacy parameters were determined by serial analyses: artery pulse wave analysis and carotid-femoral pulse wave velocity (PWV), static and dynamic retinal vessel function, and the common carotid intima-media thickness (IMT). The main secondary endpoint was the change in different biochemical markers. RESULTS: After 9 months, no relevant differences could be determined in the two treatment groups in PWV (pioglitazone 14.3 ± 4.4 m/s vs. placebo 14.2 ± 4.2 m/s), retinal arterial diameter (pioglitazone 112.1 ± 23.3 µm vs. placebo 117.9 ± 21.5 µm) or IMT (pioglitazone 0.85 ± 0.30 mm vs. placebo 0.79 ± 0.15 mm). Additionally, there were no differences in the change in biochemical markers like cholesteryl ester transfer protein, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein or white blood cell count. CONCLUSIONS: Treatment with a peroxisome proliferator-activated receptor-γ agonist in nondiabetic patients did not improve the function of large and small peripheral vessels (PPP Trial, clinicaltrialsregister.eu: 2006-000186-11).


Assuntos
Biomarcadores , Glicemia/metabolismo , Doença das Coronárias/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , PPAR gama/uso terapêutico , Tiazolidinedionas/uso terapêutico , Idoso , Proteína C-Reativa/metabolismo , Espessura Intima-Media Carotídea , Proteínas de Transferência de Ésteres de Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Contagem de Leucócitos , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pioglitazona , Estudos Prospectivos , Análise de Onda de Pulso
19.
Cardiovasc Res ; 106(3): 488-97, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25852083

RESUMO

AIMS: Being central part of the DNA repair machinery, DNA-dependent protein kinase (DNA-PK) seems to be involved in other signalling processes, as well. NOR1 is a member of the NR4A subfamily of nuclear receptors, which plays a central role in vascular smooth muscle cell (SMC) proliferation and in vascular proliferative processes. We determined putative phosphorylation sites of NDA-PK in NOR1 and hypothesized that the enzyme is able to modulate NOR1 signalling and, this way, proliferation of SMC. METHODS AND RESULTS: Cultured human aortic SMC were treated with the specific DNA-PK inhibitor NU7026 (or siRNA), which resulted in a 70% inhibition of FCS-induced proliferation as measured by BrdU incorporation. Furthermore, FCS-stimulated up-regulation of NOR1 protein as well as the cell-cycle promoting proteins proliferating cell nuclear antigen (PCNA), cyclin D1, and hyperphosphorylation of the retinoblastoma protein were prevented by DNA-PK inhibition. Co-immunoprecipitation studies from VSM cell lysates demonstrated that DNA-PK forms a complex with NOR1. Mutational analysis and kinase assays demonstrated that NOR1 is a substrate of DNA-PK and is phosphorylated in the N-terminal domain. Phosphorylation resulted in post-transcriptional stabilization of the protein through prevention of its ubiquitination. Active DNA-PK and NOR1 were found predominantly expressed within the neointima of human atherosclerotic tissue specimens. In mice, inhibition of DNA-PK significantly attenuated neointimal lesion size 3 weeks after wire-injury. CONCLUSION: DNA-PK directly phosphorylates NOR-1 and, this way, modulates SMC proliferation. These data add to our understanding of vascular remodelling processes and opens new avenues for treatment of vascular proliferative diseases.


Assuntos
Aterosclerose/enzimologia , Proliferação de Células , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Proteínas Nucleares/metabolismo , Remodelação Vascular , Animais , Aterosclerose/genética , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclina D1/metabolismo , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/enzimologia , Artéria Femoral/lesões , Artéria Femoral/patologia , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Neointima , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Fosforilação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Estabilidade Proteica , Proteólise , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Ubiquitinação , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/patologia
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