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The left axillary artery is an attractive alternative access route for transcatheter aortic valve replacement (TAVR) and may provide better outcomes compared to other alternatives. Nevertheless, there remain concerns about vascular complications, lack of compressibility, and thorax-related complications. Between March 2019 and March 2021, 13 patients underwent transaxillary TAVR for severe aortic stenosis at the University Hospital Bonn. The puncture was performed with a puncture at the distal segment of the axillary artery through the axilla, with additional femoral access for applying a safety wire inside the axillary artery. Device success was defined according to the VARC 2 criteria. The study participants were advanced in age (77 ± 9 years old), and 54% were female, with an intermediate risk for surgery (STS risk score 4.7 ± 2.0%). The average diameter of the distal segment of the axillary artery was 5.8 ± 1.0 mm (i.e., the puncture site) and 7.6 ± 0.9 mm for the proximal axillary artery. Device success was achieved in all patients. 30-day major adverse cardiac and cerebrovascular events were 0%. With complete percutaneous management, stent-graft implantation was performed at the puncture site in 38.5% of patients. Minor bleeding was successfully managed with manual compression. Moreover, no thorax-related complications, hematomas, or nerve injuries were observed. Percutaneous trans-axilla TAVR was found to be feasible and safe. This modified approach may mitigate the risk of bleeding and serious complications in the thorax and be less invasive than surgical alternatives.
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Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/complicaciones , Axila/cirugía , Femenino , Arteria Femoral/cirugía , Hemorragia/etiología , Humanos , Masculino , Factores de Riesgo , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del TratamientoRESUMEN
This study aimed to evaluate the diagnostic and prognostic value of cardiac magnetic resonance in acute peripartum cardiomyopathy (PPCM). A total of 17 patients with PPCM in the acute stage and 15 healthy controls were retrospectively analyzed regarding myocardial function, edema, late gadolinium enhancement (LGE), and T1 and T2 mappings (T1, T2). Echocardiographic follow-ups were performed. Functional recovery was defined as a left ventricular ejection fraction (LVEF) of ≥50%. Patients with PPCM displayed biventricular dysfunction with reduced myocardial strain parameters and left ventricular and atrial dilatation, as well as diffuse myocardial edema (T2 signal intensity ratio: 2.10 ± 0.34 vs. 1.58 ± 0.21, p < 0.001; T1: 1070 ± 51 ms vs. 980 ± 28 ms, p = 0.001; T2: 63 ± 5 ms vs. 53 ± 2 ms, p < 0.001). Visual myocardial edema was present in 10 patients (59%). LGE was positive in 2 patients (12%). A total of 13 patients (76%) showed full LVEF recovery. The absence of visual myocardial edema and impairment of strain parameters were associated with delayed LVEF recovery. Multivariable Cox regression analysis revealed global longitudinal strain as an independent prognostic factor for LVEF recovery. In conclusion, biventricular systolic dysfunction with diffuse myocardial edema seems to be present in acute PPCM. Myocardial edema and strain may have prognostic value for LVEF recovery.
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BACKGROUND: Myocardial toxicity is a common side effect of chemotherapy and is associated with adverse outcomes in cancer patients. Sufficient prediction of chemotherapy-induced myocardiotoxicity (CIMC) is desirable. Therefore, we sought to develop a feasible scoring system to predict CIMC in cancer patients undergoing non-anthracycline chemotherapy. METHODS: We determined a scoring system, the "Cardiotoxicitiy Score" (the CardTox-Score), by multivariable regression of the parameters considered relevant to the development of CIMC, based on previously published data and current guidelines. Variables of the risk model consist of clinical (age, presence of cardiovascular risk conditionsconditions), blood tests (NT-proBNP), and echocardiographic parameters (left ventricular (LV) ejection fraction, LV strain analysis). The CardTox-Score was examined in an internal validation cohort by use of ROC and regression analysis. RESULTS: We prospectively investigated 225 patients (58.21 ± 6.3 years, 52.8% female) who received non-anthracycline myocardiotoxic anticancer agent as a derivation cohort. All patients underwent echocardiography before, during and after anticancer therapy. The mean follow-up duration was 25 ± 4 months. We found the CardTox-Score (>6 points) to be a strong independent predictor (AUC: 0.983, OR: 6.38, 95% CI: 1.6 2.8, p < 0.001) for the development of CIMC with high sensitivity (100%) and specificity (84.2%) in the validation cohort (n = 30, 59.2 ± 6.5 years, 57% female). Moreover, the CardTox-Score appropriately predicted all-cause mortality with high specificity (93.7%) and sensitivity (92.9%) as well (OR: 4.85, AUC: 0.978, p = 0.01). CONCLUSION: The CardTox-Score offers a promising, feasible, and easy-to-handle scoring system for predicting CIMC in cancer patients undergoing non-anthracycline regimes, independent from the type of cancer.
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INTRODUCTION: 17ß-oestradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ mediates vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC). MATERIAL AND METHODS: Primary HCASMC were stimulated with E2 (10 nM), the selective oestrogen receptor α (ERα) agonist propylpyrazole triol (PPT) (50 nM) and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) (1 µM), respectively. Changes in PPARγ mRNA, protein expression, and DNA binding affinity were assessed. RESULTS: E2 significantly increased PPARγ expression in HCASMC (1.95 ±0.41-fold; n = 5; p = 0.0335). This effect was mimicked by ERα agonist PPT (1.63 ±0.27-fold; n = 7; p = 0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17 ±0.18-fold; n = 3; p vs. control > 0.05). PPARγ-DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94 ±0.11-fold; n = 4; p vs. control > 0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24 ±0.09-fold; n = 3; p vs. E2 = 0.0017). CONCLUSIONS: The present study identifies PPARγ as an important downstream mediator of E2-related atheroprotective effects in HCASMC. PPARγ agonism might be a promising therapeutic strategy to prevent neointimal hyperplasia and consecutive cardiovascular events in postmenopausal women with depleted E2 plasma levels.
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INTRODUCTION: The angiotensin II type 1 receptor (AT1R) and the peroxisome proliferator-activated receptor γ (PPARγ) have been implicated in the pathogenesis of atherosclerosis. A number of studies have reported that AT1R inhibition or genetic AT1R disruption and PPARγ activation inhibit vascular inflammation and improve glucose and lipid metabolism, underscoring a molecular interaction of AT1R and PPARγ. We here analyzed the hypothesis that vasculoprotective anti-inflammatory and metabolic effects of AT1R inhibition are mediated by PPARγ. MATERIAL AND METHODS: Female ApoE(-/-)/AT1R(-/-) mice were fedwith a high-fat and cholesterol-rich diet and received continuous treatment with the selective PPARγ antagonist GW9662 or vehicle at a rate of 700 ng/kg/min for 4 weeks using subcutaneously implanted osmotic mini-pumps. Additionally, one group of female ApoE(-/-) mice served as a control group. After treatment for 4 weeks mice were sacrificed and read-outs (plaque development, vascular inflammation and insulinsensitivity) were performed. RESULTS: Using AT1R deficient ApoE(-/-) mice (ApoE(-/-)/AT1R(-/-) mice) we found decreased cholesterol-induced endothelial dysfunction and atherogenesis compared to ApoE(-/-) mice. Inhibition of PPARγ by application of the specific PPARγ antagonist GW9662 significantly abolished the anti-atherogenic effects of AT1R deficiency in ApoE(-/-)/AT1R(-/-) mice (plaque area as % of control: ApoE(-/-): 39 ±5%; ApoE(-/-)/AT1R(-/-): 17 ±7%, p = 0.044 vs. ApoE(-/-); ApoE(-/-)/AT1R(-/-) + GW9662: 31 ±8%, p = 0.047 vs. ApoE(-/-)/AT1R(-/-)). Focusing on IL6 as a pro-inflammatory humoral marker we detected significantly increased IL-6 levels in GW9662-treated animals (IL-6 in pg/ml: ApoE(-/-): 230 ±16; ApoE(-/-)/AT1R(-/-): 117 ±20, p = 0.01 vs. ApoE(-/-); ApoE(-/-)/AT1R(-/-) + GW9662: 199 ±20, p = 0.01 vs. ApoE(-/-)/AT1R(-/-)), while the anti-inflammatory marker IL-10 was significantly reduced after PPARγ inhibition in GW9662 animals (IL-10 in pg/ml: ApoE(-/-): 18 ±4; ApoE(-/-)/AT1R(-/-): 55 ±12, p = 0.03 vs. ApoE(-/-); ApoE(-/-)/AT1R(-/-) + GW9662: 19 ±4, p = 0.03 vs. ApoE(-/-)/AT1R(-/-)). Metabolic parameters of glucose homeostasis (glucose and insulin tolerance test) were significantly deteriorated in ApoE(-/-)/AT1R(-/-) mice treated with GW9662 as compared to vehicle-treated ApoE(-/-)/AT1R(-/-) mice. Systolic blood pressure and plasma cholesterol levels were similar in all groups. CONCLUSIONS: Genetic disruption of the AT1R attenuates atherosclerosis and improves endothelial function in an ApoE(-/-) mouse model of hypercholesterolemia-induced atherosclerosis via PPARγ, indicating a significant role of PPARγ in reduced vascular inflammation, improvement of insulin sensitivity and atheroprotection of AT1R deficiency.
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BACKGROUND: Endothelial cell recovery requires replenishment of primary cells from the endothelial lineage. However, recent evidence suggests that cells of the innate immune system enhance endothelial regeneration. METHODS AND RESULTS: Focusing on mature CD11b+-monocytes, we analyzed the fate and the effect of transfused CD11b+-monocytes after endothelial injury in vivo. CD11b-diphtheria-toxin-receptor-mice--a mouse model in which administration of diphtheria toxin selectively eliminates endogenous monocytes and macrophages--were treated with WT-derived CD11b+-monocytes from age-matched mice. CD11b+-monocytes improved endothelium-dependent vasoreactivity after 7 days while transfusion of WT-derived CD11b--cells had no beneficial effect on endothelial function. In ApoE-/--CD11b-DTR-mice with a hypercholesterolemia-induced chronic endothelial injury transfusion of WT-derived CD11b+-monocytes stimulated by interferon-γ (IFNγ) decreased endothelial function, whereas interleukin-4-stimulated (IL4) monocytes had no detectable effect on vascular function. Bioluminescent imaging revealed restriction of transfused CD11b+-monocytes to the endothelial injury site in CD11b-DTR-mice depleted of endogenous monocytes. In vitro co-culture experiments revealed significantly enhanced regeneration properties of human endothelial outgrowth cells (EOCs) when cultured with preconditioned-media (PCM) or monocytes of IL4-stimulated-subsets compared to the effects of IFNγ-stimulated monocytes. CONCLUSION: CD11b+-monocytes play an important role in endothelial cell recovery after endothelial injury by homing to the site of vascular injury, enhancing reendothelialization and improving endothelial function. In vitro experiments suggest that IL4-stimulated monocytes enhance EOC regeneration properties most likely by paracrine induction of proliferation and cellular promotion of differentiation. These results underline novel insights in the biology of endothelial regeneration and provide additional information for the treatment of vascular dysfunction.
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Antígeno CD11b/fisiología , Traumatismos de las Arterias Carótidas/terapia , Células Endoteliales/fisiología , Monocitos/fisiología , Monocitos/trasplante , Animales , Traumatismos de las Arterias Carótidas/patología , Proliferación Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de ÓrganosAsunto(s)
Bioprótesis/efectos adversos , Diagnóstico por Imagen/métodos , Endocarditis Bacteriana/etiología , Endocarditis Bacteriana/cirugía , Prótesis Valvulares Cardíacas/efectos adversos , Infecciones Relacionadas con Prótesis/diagnóstico , Adulto , Ecocardiografía Transesofágica/métodos , Endocarditis Bacteriana/diagnóstico , Femenino , Estudios de Seguimiento , Implantación de Prótesis de Válvulas Cardíacas/métodos , Humanos , Válvula Mitral/fisiopatología , Válvula Mitral/cirugía , Tomografía de Emisión de Positrones/métodos , Diseño de Prótesis , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/cirugía , Reoperación/métodos , Índice de Severidad de la Enfermedad , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/etiología , Infecciones Estafilocócicas/cirugía , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
OBJECTIVE: Peroxisome-proliferator-activated-receptor-γ (PPARγ) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPARγ suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPARγ-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis. METHODS AND RESULTS: ApoE-/- and ApoE-/-/AT1R-/--mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE-/--mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPARγ antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE-/-/AT1R-/--mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE-/- and diabetic ApoE-/-/AT1-/--mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE-/--mice showed the lowest fasting blood glucose levels. Diabetic ApoE-/--mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE-/-/AT1R-/- and telmisartan-treated ApoE-/--mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE-/- and ApoE-/-/AT1R-/--mice with the selective PPARγ antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism. CONCLUSION: Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE-/--mice via the PPARγ pathway.
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Aterosclerosis/fisiopatología , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Endotelio Vascular/efectos de los fármacos , PPAR gamma/fisiología , Receptor de Angiotensina Tipo 1/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Anilidas/farmacología , Animales , Apolipoproteínas E/genética , Bencimidazoles/farmacología , Benzoatos/farmacología , Femenino , Ratones , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacos , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , Receptor de Angiotensina Tipo 1/genética , Transducción de Señal , TelmisartánRESUMEN
INTRODUCTION: Cardiogenic shock (CS) remains the leading cause of death in patients hospitalized for myocardial infarction (MI). Systemic inflammation with inappropriate vasodilatation is observed in many patients with CS and may contribute to an excess mortality rate. The purpose of this study was to determine the predictive role of serial measurements of Nt-proBNP, interleukin-6 (IL-6), and procalcitonin (PCT) for 30-day mortality in patients with CS due to MI. METHODS: The present study is a prospective single-center study including 87 patients with MI complicated by CS treated with acute revascularization and intraaortic balloon counterpulsation (IABP) support. Predictive values of plasma levels at admission (T0), after 24 hours (T1), and after 72 hours (T2) were examined according to 30-day mortality. RESULTS: Significant differences between survivors (n = 59) and nonsurvivors (n = 28) were seen for Nt-proBNP at T0, for IL-6 at T0 and T1, and for PCT at T1 and T2. According to ROC analyses, the highest accuracy predicting 30-day mortality was seen at T0 for IL-6, at T1 for PCT, and at T2 for PCT. In univariate analysis, significant values were found for Nt-proBNP at T1, and for IL-6 and PCT at all points in time. Within the multivariate analysis, age, creatinine, and IL-6 were significant determinants of 30-day mortality, in which IL-6 showed the highest level of significance. CONCLUSIONS: In patients with MI complicated by CS, IL-6 represented a reliable independent early prognostic marker of 30-day mortality. PCT revealed a significant value at later points in time, whereas Nt-proBNP seemed to be of lower relevance.
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Calcitonina/sangre , Mortalidad Hospitalaria , Interleucina-6/sangre , Infarto del Miocardio/complicaciones , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Precursores de Proteínas/sangre , Choque Cardiogénico/sangre , Choque Cardiogénico/mortalidad , Lesión Renal Aguda/complicaciones , Anciano , Análisis de Varianza , Biomarcadores/sangre , Péptido Relacionado con Gen de Calcitonina , Creatinina/sangre , Femenino , Hemodinámica , Humanos , Unidades de Cuidados Intensivos , Contrapulsador Intraaórtico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/cirugía , Revascularización Miocárdica , Estudios Prospectivos , Sensibilidad y Especificidad , Choque Cardiogénico/etiología , Choque Cardiogénico/cirugíaRESUMEN
The exact mechanism of estrogen in cardiovascular disease is not fully understood. As estrogen receptors (ERs), the peroxisome-proliferator-activated-receptor-γ (PPARγ) belongs to the family of ligand activated nuclear receptors regulating atheroprotective genes. The aim of this project was to investigate whether vascular effects of estrogen are mediated via PPARγ-regulation in the vascular compartment. Estrogen deficient ovariectomized wildtype-mice (OVX) displayed significant reduction of PPARγ-expression in aortic tissue compared to wildtype-mice with intact ovarian function (Sham). Hormone replacement with subdermal 17ß-estradiol pellets significantly increased vascular PPARγ-expression in ovariectomized female wildtype-mice (OVX/E2). Analogous to wildtype-mice, estrogen-deficient OVX ApoE(-/-)-mice had low vascular PPARγ-expression associated with ROS generation, endothelial dysfunction and atherogenesis. Estrogen replacement (OVX/E2) rescued vascular PPARγ-expression, reduced ROS generation, monocyte recruitment, atherosclerotic lesion formation and improved endothelial function. Inhibition of PPARγ by GW9662, a specific PPARγ-antagonist reduced 17ß-estradiol mediated vascular effects (OVX/E2+GW9662). Finally, despite estrogen deficiency treatment with pioglitazone (OVX+pioglitazone), a selective PPARγ-agonist, compensates deterioration of vascular morphology and function. 17ß-estradiol regulates vascular PPARγ-expression in wildtype- and ApoE(-/-)-mice. The presented data demonstrate the fundamental relevance of PPARγ as downstream target of 17ß-estradiol-related anti-inflammatory and atheroprotective effects within the vascular wall independent of its cardiovascular risk factor modifications.
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PPAR gamma/metabolismo , Anilidas/farmacología , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Presión Sanguínea/efectos de los fármacos , Western Blotting , Peso Corporal/efectos de los fármacos , Estradiol/farmacología , Estrógenos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Inmunohistoquímica , Ratones , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , Pioglitazona , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Superóxidos/metabolismo , Tiazolidinedionas/farmacologíaRESUMEN
AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A(-/-)). ApoE(-/-) mice and ApoE(-/-)/AT1A(-/-) mice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE(-/-) mice, but were markedly reduced in ApoE(-/-)/AT1A(-/-) mice. Concomitant treatment of ApoE(-/-)/AT1A(-/-) mice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE(-/-)/AT1A(-/-) mice compared to untreated ApoE(-/-)/AT1A(-/-) mice whereas pharmacological AT1 receptor inhibition with telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE(-/-)/AT1A(-/-) mice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE(-/-)/AT1A(-/-) mice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology.
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Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/agonistas , Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/patología , Presión Sanguínea , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Expresión Génica , Técnicas In Vitro , Mediadores de Inflamación/metabolismo , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Receptor de Angiotensina Tipo 1/deficiencia , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
UNLABELLED: Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C(4) (LTC(4)) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC(4). We investigated whether release of LTC(4)via the multidrug resistance related protein 1 (MRP1) induces apoptosis in cardiomyocytes in vitro and in vivo. METHODS AND RESULTS: Incubation of cultured embryonic cardiomyocytes (eCM) with recombined LTC(4) caused enhanced rates of reactive oxygen species (ROS) release measured via L012-luminescence method and apoptosis. Pharmacologic LTC(4) receptor blockade antagonized this effect in vitro. To evaluate the relevance of MRP1 mediated LTC(4) release after myocardial injury in vivo, MRP1(-/-) mice and FVB wildtype mice (WT) received cryoinjury of the left ventricle. Fourteen days after injury, left-ventricular ejection fraction (EF), end-diastolic volume (EDV), and akinetic myocardial mass (AMM) were quantified via echocardiography. MRP1(-/-) mice demonstrated increased EF (MRP1(-/-): 39 ± 3%, WT: 29 ± 4%) and reduced AMM (MRP1(-/-): 13 ± 2% WT: 16 ± 4%), indicating reduced post-infarction remodeling. Mechanistically, LTC(4) serum concentrations and levels of cellular apoptosis were increased in myocardial cryosections of FVB WT mice as compared to MRP1(-/-) mice. To identify key targets for pharmacological inhibition of LTC(4) actions, WT mice were treated with the specific Cys-LT1-receptor blocker Montelukast or the MRP1-Inhibitor MK571. Treatment of WT mice resulted in significant increase of EF (WT(Montelukast): 40 ± 5%, WT(MK571): 39 ± 3%, WT(vehicle): 33 ± 3% and decrease of AMM (WT(Montelukast): 12 ± 1%, WT(MK571): 10 ± 3%, WT(vehicle): 15 ± 5%) compared to untreated WT mice. CONCLUSION: Inhibition of leukotriene C(4) reduces levels of oxidative stress and apoptosis and demonstrates beneficial effects on myocardial remodeling after left ventricular injury.
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Apoptosis/fisiología , Leucotrieno C4/antagonistas & inhibidores , Isquemia Miocárdica/patología , Miocitos Cardíacos/patología , Estrés Oxidativo/fisiología , Remodelación Ventricular/fisiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Acetatos/farmacología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Ciclopropanos , Ecocardiografía/métodos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Leucotrieno C4/metabolismo , Leucotrieno C4/farmacología , Masculino , Ratones , Ratones Transgénicos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Quinolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sulfuros , Remodelación Ventricular/efectos de los fármacosRESUMEN
The renin-angiotensin-aldosterone system (RAAS) is part of the blood pressure regulating system. Its main effector peptide is angiotensin II (Ang II). Although it may induce hypertension, the proinflammatory, profibrotic, and prothrombotic effects are mainly mediated by effects of Ang II on the cellular and molecular level that are independent of blood pressure. Therefore, pharmacotherapeutic intervention within the RAAS is an important treatment modality for patients suffering from cardiovascular diseases, even those who are not hypertensive. In addition to the blood pressure lowering and vasculoprotective (pleiotropic) effects of angiotensin II type 1 (AT(1)) receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors, regenerative progenitor cell therapy emerges as an auxiliary therapy to improve regeneration of the vascular endothelium. This review focuses on the growing knowledge about regenerating vascular cells, their response to RAAS effectors, and RAAS-modulating pharmacotherapy in the context of endothelial cell damage and regeneration.
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Angiotensina II/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina II/antagonistas & inhibidores , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Endotelio Vascular/patología , Humanos , Hipertensión/patología , Especies Reactivas de Oxígeno , Renina/antagonistas & inhibidores , Renina/efectos de los fármacos , Factores de Riesgo , Células MadreRESUMEN
Cardiac diseases are the leading cause of death and reach epidemic proportions with aging. Advanced heart disease results from an abrupt or progressive loss of contractile cardiomyocytes. Following percutaneous coronary intervention and revascularization regenerative medicine aims at effectively repair damaged tissue and replacement of lost cardiomyocytes. However, mixed results were obtained from trials using bone marrow-derived stem cells. Benefits were rather attributed to paracrine effects leading to inhibition or reverse of negative remodeling processes than to regeneration of viable cardiomyocytes. Thus the aim of regenerative medicine, in particular stem cell research, to generate viable cardiac muscle has so far not been achieved in humans, reflecting our incomplete understanding of underlying biological mechanisms. Moreover, there is growing evidence that substantial person-to-person differences in the outcome of stem cell therapy exists. We here review our present knowledge in evolving stem cell based cardiovascular medicine and highlight personalized aspects of stem cell interventions.
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The multidrug resistance related protein-1 (MRP1) is a member of the ATP binding cassette (ABC) of cell surface transport proteins expressed in multiple cell lines and tissues including endothelial cells and haematopoietic stem cells. MRP1 blockade has been shown to prevent endothelial cell apoptosis and improve endothelial function. Besides mature endothelial cells vascular homing of endothelial progenitor cells (EPC) contributes to endothelial regeneration after vascular damage. Thus, we hypothesized that MRP1 influences number and function of EPCs and mechanisms of vascular repair. To test this, we investigated the effects of MRP1 inhibition in vitro and in vivo. MRP1 is abundantly expressed in cultured human early outgrowth EPCs. Pharmacological inhibition of MRP1 by MK571 increased intracellular glutathione levels and reduced intracellular reactive oxygen species levels. This stabilization of the intracellular redox homeostasis via inhibition of MRP1 prevented angiotensin II-induced apoptosis and increased the number of early outgrowth EPCs and colony forming units in vitro. To extend the observed cytoprotective effect of MRP1 blockade in EPCs to an in vivo situation, MRP1(-/-) knockout mice were investigated. MRP1(-/-) knockout mice showed significantly increased numbers of EPCs circulating in the peripheral blood and residing in the bone marrow. Consistently, colony forming unit formation was enhanced and rate of apoptosis reduced in early outgrowth EPCs derived from MRP1(-/-) knockout mice. In addition, MRP1(-/-) knockout mice showed improved reendothelialization after carotid artery injury, and transfusion of MNCs derived from MRP1(-/-) knockout mice into wild-type mice accelerated reendothelialization compared to transfusion of wild-type cells. These findings indicate that the enhanced function and survival of EPCs in MRP1(-/-) knockout mice resulted in improved reendothelialization. In conclusion, MRP1 negatively influences EPC function and survival via perturbation of the intracellular redox homeostasis which finally leads to increased cellular apoptosis. These results reveal novel mechanistic insights and may identify MRP1 as therapeutic target to improve reendothelialization after vascular damage.
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Traumatismos de las Arterias Carótidas/metabolismo , Endotelio Vascular/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/fisiología , Neovascularización Fisiológica , Células Madre/metabolismo , Animales , Apoptosis , Broncodilatadores/farmacología , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/patología , Supervivencia Celular/fisiología , Células Cultivadas , Endotelio Vascular/citología , Citometría de Flujo , Glutatión/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Propionatos/farmacología , Quinolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células Madre/citologíaRESUMEN
Enhanced proliferation of vascular smooth muscle cells (VSMCs) is one of the key features of the pathogenesis of atherosclerosis. The helix-loop-helix protein Inhibitor of DNA binding 3 (Id3) contributes to regulation of VSMC proliferation in a redox-sensitive manner. We investigated the role of Id3 and its interaction with other redox-sensitive genes, the transcription factor Gut-enriched Krüppel-like factor (GKLF, KLF4) and the tumor suppressor gene p53 in the regulation of VSMC proliferation. Cultured rat aortic VSMCs were transfected with Id3 sense and antisense constructs. Overexpression of Id3 significantly enhanced VSMC proliferation. Id3 antisense transfection inhibited VSMC proliferation induced by the physiological stimuli insulin and platelet-derived growth factor (PDGF). Because p53 is essential for the regulation of proliferation processes, the effect of Id3 on p53 expression was investigated. Id3 overexpression led to decreased p53 protein expression. Co-transfection of p53 sense constructs inhibited the enhanced VSMC mitogenicity induced by Id3 sense transfection. GKLF overexpression, which causes growth arrest in VSMCs, reduced Id3 promoter activity and led to decreased Id3 expression. Id3-induced VSMC proliferation was abolished by GKLF sense co-transfection. Finally, strong Id3 expression was found in the neointima of human coronary artery atherosclerotic plaques but not in healthy coronary arteries. These findings reveal a relevant interaction of GKLF, Id3, and p53 for VSMC proliferation which might constitute a general mechanism of growth control in vascular cells.
Asunto(s)
Proliferación Celular , Proteínas Inhibidoras de la Diferenciación/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Músculo Liso Vascular/citología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Aterosclerosis , Células Cultivadas , Vasos Coronarios/química , Proteínas Inhibidoras de la Diferenciación/fisiología , Factor 4 Similar a Kruppel , Masculino , Miocitos del Músculo Liso/citología , Ratas , Ratas Sprague-DawleyRESUMEN
Enrichment and terminal differentiation of mammalian striated muscle cells is severely hampered by fibroblast overgrowth, de-differentiation and/or lack of functional differentiation. Herein we report a new, reproducible and simple method to enrich and terminally differentiate muscle stem cells and progenitors from mice and humans. We show that a single gamma irradiation of muscle cells induces their massive differentiation into structurally and functionally intact myotubes and cardiomyocytes and that these cells can be kept in culture for many weeks. Similar results are also obtained when treating skeletal muscle-derived stem cells and progenitors with Mitomycin C.
Asunto(s)
Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de la radiación , Músculo Estriado/citología , Células Madre/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Células Cultivadas , Rayos gamma , Humanos , Masculino , Ratones , Mitomicina/farmacología , Músculo Estriado/efectos de los fármacos , Músculo Estriado/fisiología , Músculo Estriado/efectos de la radiación , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/efectos de la radiaciónRESUMEN
Targeting of viral vectors is a major challenge for in vivo gene delivery, especially after intravascular application. In addition, targeting of the endothelium itself would be of importance for gene-based therapies of vascular disease. Here, we used magnetic nanoparticles (MNPs) to combine cell transduction and positioning in the vascular system under clinically relevant, nonpermissive conditions, including hydrodynamic forces and hypothermia. The use of MNPs enhanced transduction efficiency of endothelial cells and enabled direct endothelial targeting of lentiviral vectors (LVs) by magnetic force, even in perfused vessels. In addition, application of external magnetic fields to mice significantly changed LV/MNP biodistribution in vivo. LV/MNP-transduced cells exhibited superparamagnetic behavior as measured by magnetorelaxometry, and they were efficiently retained by magnetic fields. The magnetic interactions were strong enough to position MNP-containing endothelial cells at the intima of vessels under physiological flow conditions. Importantly, magnetic positioning of MNP-labeled cells was also achieved in vivo in an injury model of the mouse carotid artery. Intravascular gene targeting can be combined with positioning of the transduced cells via nanomagnetic particles, thereby combining gene- and cell-based therapies.
Asunto(s)
Vectores Genéticos/farmacocinética , Magnetismo , Nanopartículas/administración & dosificación , Transducción Genética , Animales , Sistemas de Liberación de Medicamentos , Endotelio Vascular , Lentivirus/genética , Ratones , Nanopartículas/químicaRESUMEN
Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.