RESUMO
Background: Endothelial dysfunction defines outcomes and serves as a surrogate parameter for the progression of cardiovascular disease. For symptomatic peripheral artery disease (PAD) endovascular treatment is the primary revascularization strategy, which affects endothelial function. Interventional mechanical atherothrombectomy (MATH) provides advantages when treating complex atherosclerotic and thrombotic lesions. We now aimed to determine the impact and mechanisms of MATH on endothelial function. Patients and methods: Endothelial function was determined using flow-mediated dilation (FMD) before and after lower limb intervention with a six-month follow-up in the target and control vessel in 15 PAD MATH+DCB treated patients and compared to 15 non-Math controls. In a further cohort of 20 patients the impact of MATH and DCB on vascular structure and virtual histology was assessed through intravascular ultrasound (IVUS) and compared to DCB treatment alone. Results: Improved endothelial function after 6 months was observed in both groups for the target and nontarget vessel. When comparing the changes from baseline endothelial function, treatment with MATH+DCB was superior to DCB treatment in the target vessel. IVUS revealed a greater improvement in luminal area and plaque burden reduction after MATH treatment. Virtual histology disclosed MATH-associated changes in plaque composition evidenced by alterations in fibrous volume and reductions in superficial calcium. Conclusions: We demonstrate an improved endothelial function after MATH treatment as compared to DCB treatment. The improved vessel function is evidenced by MATH-related plaque burden reduction, improved luminal gain and a decrease in superficial calcification. Clinicaltrials.gov: NCT04092972.
Assuntos
Doença Arterial Periférica , Placa Aterosclerótica , Humanos , Extremidade Inferior , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/cirurgia , Valor Preditivo dos Testes , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
OBJECTIVES: Among changes in demographics, aging is the most relevant cardiovascular risk factor. The prevalence of peripheral artery disease (PAD) is high in elderly patients and is associated with a worse prognosis. Despite optimal treatments, mortality in the high-risk population of octo- and nonagenarians with PAD remains excessive, and predictive factors need to be identified. The objective of this study was to investigate predictors of mortality in octo- and nonagenarians with PAD. METHODS: Cases of treated octo- and nonagenarians, including the clinical characteristics and markers of myocardial injury and heart failure, were studied retrospectively with respect to all-cause mortality. Hazard ratios [HR] were calculated and survival was analyzed by Kaplan-Meyer curves and receiver operating characteristic curved were assessed for troponin-ultra and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and chronic limb-threatening ischemia (CLTI). RESULTS: A total of 123 octo- and nonagenarians admitted for PAD were eligible. The troponin level was the major predictor of all-cause mortality (HR: 4.6, 95% confidence interval [CI]: 1.4-15.3), followed by the NT-proBNP level (HR: 3.9, 95% CI 1.8-8.8) and CLTI (HR: 3.1, 95% CI 1.6-5.9). Multivariate regression revealed that each increment of 1 standard deviation in log troponin and log NT-proBNP was associated with a 2.7-fold (95% CI 1.8-4.1) and a 1.9-fold (95% CI 1.2-2.9) increased risk of all-cause death. Receiver operating characteristic curve analysis using a combination of all predictors yielded an improved area under the curve of 0.888. In a control group of an equal number of younger individuals, only NT-proBNP (HR: 4.2, 95% CI 1.2-14.1) and CLTI (HR: 6.1, 95% CI 1.6-23.4) were predictive of mortality. CONCLUSION: Our study demonstrates that cardiovascular biomarkers and CLTI are the primary predictors of increased mortality in elderly PAD patients. Further risk stratification through biomarkers in this high-risk population of octo- and nonagenarians with PAD is necessary.
Assuntos
Envelhecimento , Isquemia/mortalidade , Doença Arterial Periférica/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Feminino , Humanos , Isquemia/sangue , Isquemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Troponina/sangueRESUMO
Background: Treatment of symptomatic peripheral artery disease (PAD) through endovascular interventions is the primary revascularization strategy. Interventions restore perfusion but may cause severe injury to the vascular endothelium, which regulates vascular tone. Endothelial dysfunction is involved in the progression of cardiovascular disease, with higher incidences of vascular events. We aimed to determine the impact of percutaneous interventions on change in endothelial function. Patients and methods: Endothelial function was determined using flow-mediated dilation (FMD) before, the day after lower limb intervention with paclitaxel-coated balloons or stent guided interventions and after a six-month follow-up in the target limb, control limb and the systemic circulation in 42 PAD patients aged 70.2±9 years and 66% men. Additionally, macro- and microvascular function were assessed. Results: In PAD patients aged 70.2±9 years and 66% men, we observed an immediate enhancement of macro-, microvascular and endothelial function after endovascular treatment (FMD of superficial femoral artery (SFA) 3.7±0.2% to 4.1±0.1%, n=42, p=0.02), a sustained long-term improvement after 6-months (FMD SFA 3.7±0.2% to 4.2±0.1%, n=42, p=0.01), and moreover an improved systemic endothelial function (FMD brachial artery 4.3±0.1% to 4.7±0.2, n=42, p=0.01) following peripheral interventions. Subgroup analysis however revealed that following paclitaxel-based percutaneous intervention, the paclitaxel dosage applied was inversely related to the chronic improvement in local endothelial function (r=-0.6, n=22, p=0.005) without evidence for systemic effects (r=-0.25, p=0.27). Conclusions: We demonstrate an improved local and systemic endothelial function after treatment of atherosclerotic peripheral disease with a distinguished response after endovascular intervention with higher dosage of applied paclitaxel restraining the benefits. Further studies have to determine the optimal interventional strategy with respect to different treatment modalities to maintain vessel functions.
Assuntos
Angioplastia com Balão , Doença Arterial Periférica , Angioplastia com Balão/efeitos adversos , Endotélio Vascular , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Masculino , Paclitaxel/efeitos adversos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Resultado do TratamentoRESUMO
Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E-deficient (ApoE-/- ) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7-like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti-atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1ß at the site of injection. In male mice, CFA-induced TSLP occurred in immigrated monocytes-and not epithelial cells-and was dependent on NLRP3 inflammasome activation and IL1ß-signalling. In females, CFA-induced TSLP was independent of IL1ß and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR-/- mice, with increased INFγ/IL4 ratio compared with wild-type controls. To test whether TSLP contributes to the anti-atherogenic effects of Freund's adjuvant, we treated ApoE-/- and ApoE-/- /TSLPR-/- mice with either CFA/IFA or PBS. ApoE-/- mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE-/- /TSLPR-/- mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune-modulating effects via TSLP induction. TSLP-TSLPR signalling is critical for CFA/IFA-mediated attenuation of atherosclerosis.
Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Citocinas/metabolismo , Imunomodulação , Animais , Citocinas/genética , Suscetibilidade a Doenças , Feminino , Adjuvante de Freund/imunologia , Expressão Gênica , Imunidade , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Transdução de Sinais , Pele/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Circulating sca1+/flk1+ cells are hypothesized to be endothelial progenitor cells (EPCs) in mice that contribute to atheroprotection by replacing dysfunctional endothelial cells. Decreased numbers of circulating sca1+/flk1+ cells correlate with increased atherosclerotic lesions and impaired reendothelialization upon electric injury of the common carotid artery. However, legitimate doubts remain about the identity of the putative EPCs and their contribution to endothelial restoration. Hence, our study aimed to establish a phenotype for sca1+/flk1+ cells to gain a better understanding of their role in atherosclerotic disease. In wild-type mice, sca1+/flk1+ cells were mobilized into the peripheral circulation by granulocyte-colony stimulating factor (G-CSF) treatment and this movement correlated with improved endothelial regeneration upon carotid artery injury. Multicolor flow cytometry analysis revealed that sca1+/flk1+ cells predominantly co-expressed surface markers of conventional B cells (B2 cells). In RAG2-deficient mice and upon B2 cell depletion, sca1+/flk1+ cells were fully depleted. In the absence of monocytes, sca1+/flk1+ cell levels were unchanged. A PCR array focused on cell surface markers and next-generation sequencing (NGS) of purified sca1+/flk1+ cells confirmed their phenotype to be predominantly that of B cells. Finally, the depletion of B2 cells, including sca1+/flk1+ cells, in G-CSF-treated wild-type mice partly abolished the endothelial regenerating effect of G-CSF, indicating an atheroprotective role for sca1+/flk1+ B2 cells. In summary, we characterized sca1+/flk1+ cells as a subset of predominantly B2 cells, which are apparently involved in endothelial regeneration.
Assuntos
Antígenos Ly/metabolismo , Aterosclerose/metabolismo , Subpopulações de Linfócitos B/metabolismo , Lesões das Artérias Carótidas/metabolismo , Artéria Carótida Primitiva/metabolismo , Proliferação de Células , Células Progenitoras Endoteliais/metabolismo , Proteínas de Membrana/metabolismo , Reepitelização , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Antígenos Ly/genética , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/imunologia , Lesões das Artérias Carótidas/patologia , Artéria Carótida Primitiva/imunologia , Artéria Carótida Primitiva/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Células Progenitoras Endoteliais/imunologia , Células Progenitoras Endoteliais/patologia , Feminino , Depleção Linfocítica , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Background: Pseudoxanthoma elasticum (PXE) is a heritable recessive disease characterized by calcification and fragmentation of soft connective tissue. Besides progressive loss of vision, alternations of the skin, and early-onset atherosclerosis different reports have suggested a microvascular manifestation of PXE and restrictive lung disease. Aim of this study was to elaborate a specific pattern of capillary alterations in PXE as well as to contemplate a possible connection to restrictive lung disease. Patients and methods: 53 consecutive patients with PXE and 26 controls were studied. All patients underwent nailfold capillaroscopy, body plethysmography, capillary blood gas analysis, and venous puncture to assess titer of autoantibodies. Results: PXE was associated with highly pathological alterations of capillaries compared to control. Atypical capillaries, such as ramifications and bushy forms, as well as dilatations varied at highest significance (p < .001). This effect was mirrored by perivascular edema, density and tortuous capillaries. Titer of anti-nuclear autoantibodies were not elevated in patients with PXE. Further analysis revealed negative correlation between vital capacity and presence of atypical capillaries. Conclusions: This study firstly describes the pattern of nailfold capillaries in PXE. Capillaries are highly pathological and consist of ramifications and bushy forms as well as dilatations. Frequently, tortuous capillaries, pericapillary edema and reduced denseness of capillary loops occur. Frequency of atypical capillaries is negatively correlated with vital capacity which can be interpreted as further lead on restrictive lung disease.
Assuntos
Pseudoxantoma Elástico , Humanos , Angioscopia Microscópica , PeleRESUMO
Background: The transradial artery approach is the preferred access for cardiac catheterization according to current guidelines. However, the most common complication is radial artery occlusion (RAO). Despite the rare indication for surgical reopening, the occluded radial artery is not available for further procedures or as a potential bypass graft. Still, treatment regimens for RAO are scarce. We now determined whether the addition of antithrombotic to antiplatelet therapy improves the rate of partial or complete regain of patency in RAO following transradial cardiac catheterization in a retrospective analysis. Patients and methods: In a two-center tertiary referral hospital retrospective analysis 4135 files of patients who had undergone transradial catheterization were screened for documented RAO. 141 patients were identified and 138 patients with complete information on the medical regimen and ultrasound examinations for a maximum of 3 months were included in the analysis, whereas 3 patients were excluded due to missing or incomplete follow-up information. Results: 3.3% of all patients that had undergone transradial catheterization featured an oligosymptomatic RAO, confirmed by color-coded duplex sonography. 21% of patients with additional anticoagulation regained full patency vs. 9% without additional anticoagulation (p = 0.07). 40% of patients with anticoagulation featured a partial or full regain of patency vs. 16% of patients without additional anticoagulation for a maximum of 3 months treatment (p = 0.006). No major bleedings were reported during the follow-up visits. Conclusions: RAO remains a rare complication of cardiac catheterization. The addition of antithrombotic therapy for 3 months appears to safely improve the partial or even full regain of radial patency in case of postinterventional RAO.
Assuntos
Arteriopatias Oclusivas , Cateterismo Cardíaco/efeitos adversos , Cateterismo Periférico , Humanos , Incidência , Artéria Radial/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Recent studies have highlighted the relevance of viral nucleic acid immunorecognition by pattern recognition receptors in atherogenesis. Melanoma differentiation associated gene 5 (MDA-5) belongs to the intracellular retinoic acid inducible gene-I like receptors and its activation promotes pro-inflammatory mechanisms. Here, we studied the effect of MDA-5 stimulation in vascular biology. To gain insights into MDA-5 dependent effects on endothelial function, cultured human coronary artery endothelial cells (HCAEC) were transfected with the synthetic MDA-5 agonist polyIC (long double-stranded RNA). Human coronary endothelial cell expressed MDA-5 and reacted with receptor up-regulation upon stimulation. Reactive oxygen species formation, apoptosis and the release of pro-inflammatory cytokines was enhanced, whereas migration was significantly reduced in response to MDA-5 stimulation. To test these effects in vivo, wild-type mice were transfected with 32.5 µg polyIC/JetPEI or polyA/JetPEI as control every other day for 7 days. In polyIC-treated wild-type mice, endothelium-dependent vasodilation and re-endothelialization was significantly impaired, vascular oxidative stress significantly increased and circulating endothelial microparticles and circulating endothelial progenitor cells significantly elevated compared to controls. Importantly, these effects could be abrogated by MDA-5 deficiency in vivo. Finally, chronic MDA-5 stimulation in Apolipoprotein E/toll-like receptor 3 (TLR3) double(-) deficient (ApoE(-/-) /TLR3(-/-) ) mice-enhanced atherosclerotic plaque formation. This study demonstrates that MDA-5 stimulation leads to endothelial dysfunction, and has the potential to aggravate atherosclerotic plaque burden in murine atherosclerosis. Thus, the spectrum of relevant innate immune receptors in vascular diseases and atherogenesis might not be restricted to TLRs but also encompasses the group of RLRs including MDA-5.
Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Células Endoteliais/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , RNA de Cadeia Dupla/farmacologia , Animais , Antígenos Ly/metabolismo , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Contagem de Células , Vasos Coronários/patologia , Citocinas/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Células Endoteliais/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Helicase IFIH1 Induzida por Interferon/deficiência , Espaço Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Poli I-C/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
BACKGROUND: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. METHODS AND RESULTS: OTII-transgenic mice that were treated with a single dose of 5 × 10(7) OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, "atherosclerosis-associated" antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E - deficient (ApoE-/-) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE-/- mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE-/- mice. CONCLUSION: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen-coupled splenocytes in its present form already impacts the immune responses and deserves further exploration.
Assuntos
Apolipoproteína B-100/imunologia , Apolipoproteínas E/deficiência , Aterosclerose/terapia , Lipoproteínas LDL/imunologia , Placa Aterosclerótica/terapia , Animais , Apolipoproteína B-100/química , Apolipoproteínas E/genética , Apolipoproteínas E/imunologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Carbodi-Imidas/química , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Injeções Intravenosas , Interferon gama/biossíntese , Interferon gama/metabolismo , Lipoproteínas LDL/química , Transfusão de Linfócitos , Linfócitos/química , Linfócitos/imunologia , Macrófagos/química , Macrófagos/imunologia , Macrófagos/transplante , Masculino , Camundongos , Camundongos Knockout , Monócitos/química , Monócitos/imunologia , Monócitos/transplante , Placa Aterosclerótica/genética , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Baço/citologia , Baço/imunologia , Células Th1/imunologia , Células Th1/patologia , Falha de TratamentoRESUMO
BACKGROUND: Statins have been shown to increase the level of circulating progenitor cells in peripheral blood supposedly due to a mobilization of progenitor cells from the bone marrow niche. Osteoclast/osteoblast interaction has been associated with progenitor cell mobilization. Here, we investigated the role of statins on progenitor cell mobilization with a focus on bone metabolism. METHODS AND RESULTS: FGF2(-/-) and wild type (wt) mice were treated with atorvastatin or placebo. In contrast to wt mice, the number of sca-1/flk-1 positive progenitor cells in peripheral blood (PB) of atorvastatin treated FGF2(-/-) mice did not increase, and was accompanied by a defective reendothelialization after perielectric injury of the common carotid artery. In wt, but not FGF2(-/-) mice, statin treatment was associated with increased levels of receptor activator of NF-κB ligand (RANKL) in bone marrow (BM) supernatant. Treatment with recombinant RANKL increased sca-1/flk-1 positive progenitors in FGF2(-/-) mice. Interestingly, osteoclast activation was not altered. To measure the egress of sca-1/flk-1 positive progenitor cells from the bone marrow, we performed in-situ perfusion experiments of isolated hind limbs. Mobilization was not significantly affected by atorvastatin in both wt and FGF2(-/-) mice. Furthermore, RANK - the specific receptor to RANKL - is expressed on progenitor cells, and RANKL stimulation increases cell proliferation in vitro and in vivo. CONCLUSIONS: Atorvastatin treatment increases RANKL levels with no measurable effect on bone metabolism and mobilization of progenitor cells from BM to PB. RANKL is essential for the statin-mediated increase of progenitor cell levels but predominantly due to a RANKL-induced stimulation of cell proliferation.
Assuntos
Medula Óssea/fisiologia , Proliferação de Células , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirróis/farmacologia , Ligante RANK/fisiologia , Células-Tronco/fisiologia , Animais , Antígenos Ly/metabolismo , Atorvastatina , Medula Óssea/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Membro Posterior/irrigação sanguínea , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica , Osteoprotegerina/metabolismo , Perfusão , Reepitelização , Células-Tronco/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
RATIONALE: Endothelial dysfunction and atherosclerosis are chronic inflammatory diseases characterized by activation of the innate and acquired immune system. Specialized protein receptors of the innate immune system recognize products of microorganisms and endogenous ligands such as nucleic acids. Toll-like receptor 3 (TLR3), for example, detects long double-stranded RNA and is abundantly expressed in endothelial cells. Whether innate immunity contributes to atherogenic mechanisms in endothelial cells is poorly understood. OBJECTIVE: We sought to determine the effects of TLR3 activation in endothelial cells. METHODS AND RESULTS: We first investigated whether stimulation of TLR3 influences endothelial biology in mice. Intravenous injection of polyinosine polycytidylic acid, a synthetic double-stranded RNA analog and TLR3 ligand, impaired endothelium-dependent vasodilation, increased vascular production of reactive oxygen species, and reduced reendothelialization after carotid artery injury in wild-type mice compared with controls but had no effect in TLR3(-/-) animals. TLR3 stimulation not only induced endothelial dysfunction but also enhanced the formation of atherosclerotic plaques in apolipoprotein E-deficient mice. In vitro incubation of endothelial cells with polyinosine polycytidylic acid induced production of the proinflammatory cytokines interleukin-8 and interferon-γ-induced protein 10, increased formation of reactive oxygen species, diminished proliferation, and increased apoptosis, which suggests that endothelial cells are able to directly detect and respond to TLR3 ligands. Neutralization of interleukin-8 and interferon-γ-induced protein 10 antagonizes the observed negative effects of polyinosine polycytidylic acid. We found elevated levels of circulating endothelial progenitor cells in polyinosine polycytidylic acid-treated mice, although they displayed increased endothelial dysfunction. Stimulation of TLR3 in cultured endothelial progenitor cells, however, led to increased formation of reactive oxygen species, increased apoptosis, and reduced migration. Injection of endothelial progenitor cells that had been incubated with polyinosine polycytidylic acid ex vivo hindered reendothelialization after carotid artery injury. Therefore, endothelial progenitor cell function was affected by TLR3 stimulation. Finally, apolipoprotein E-deficient/TLR3-deficient mice exhibited improved endothelial function compared with apolipoprotein E-deficient/TLR3(+/+) littermates. CONCLUSIONS: Immunorecognition of long double-stranded RNA by endothelial cells may be an important mechanism involved in endothelial cell activation and development of endothelial dysfunction.
Assuntos
Aterosclerose/metabolismo , Endotélio Vascular/metabolismo , RNA de Cadeia Dupla/metabolismo , Receptor 3 Toll-Like/metabolismo , Vasculite/metabolismo , Animais , Apolipoproteínas E/genética , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Imunidade Inata/fisiologia , Indutores de Interferon/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Poli I-C/farmacologia , RNA de Cadeia Dupla/imunologia , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Vasculite/imunologia , Vasculite/fisiopatologiaRESUMO
BACKGROUND: Lipid-lowering therapy (LLT) in patients with cardiovascular disease (CVD) is insufficient despite clear guideline recommendations. Lipid clinics have specialized in patients with dyslipidemia, but the magnitude and reduction of low-density lipoprotein cholesterol (LDL-C) in lipid clinics has not yet been studied in depth. OBJECTIVE: To assess LDL-C reduction in very high-risk CVD patients achieved in a lipid clinic through different forms of LLT in comparison to standard care without the initiation of PSCK9 inhibitors. METHODS: Data from 96 lipid clinic patients were analyzed retrospectively and compared to 84 standard care patients. Very high-risk patients were defined according to the European Society of Cardiology (ESC). Different combinations of LLT focusing on statins and ezetimibe were investigated. Achievement of LDL-C treatment goals according to ESC guidelines as well as LDL-C reduction were assessed. RESULTS: Baseline and follow-up data of 180 very high-risk CVD patients (mean age 67.7 (±9.8) y; 60.6% male) were used. Achievement of the LDL-C goal in lipid clinic patients increased significantly from 14.6% at baseline to 41.7% at the latest visit (p<0.001) while standard care patients improved from 21.4% to 33.3% (p=0.08). The largest relative LDL-C reduction via an adjustment in LLT was achieved by initiation of high-intensity statins (50.8 ± 4.9%, n = 5, p < 0.05). CONCLUSION: Treatment in a lipid clinic leads to a superior LDL-C goal achievement in very high-risk CVD patients as compared to standard care with the highest reduction under LLT with high-intensity statins and ezetimibe. Referral algorithms have to be established for high-risk patients.
Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Masculino , Idoso , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , LDL-Colesterol , Inibidores de PCSK9 , Pró-Proteína Convertase 9 , Estudos Retrospectivos , Universidades , Resultado do Tratamento , Ezetimiba/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Anticolesterolemiantes/uso terapêuticoRESUMO
Low-dose oral tetrahydrocannabinol (THC) reduces progression of atherosclerosis in mice. THC activates central cannabinoid-1 receptors (CB1) with subsequent psychoactive effects as well as peripheral cannabinoid-2 receptors (CB2). In order to dissect the underlying mechanisms, we performed experiments under selective CB2 stimulation as well as after genetic disruption of the CB2 receptor. Atherosclerosis prone apolipoprotein E-deficient mice were crossed with cannabinoid receptor-2 deficient mice to obtain ApoE -/- CB2 -/- double knockout mice. After 8weeks of a high-cholesterol diet, immunohistochemical stainings of the aortic root revealed that vascular leukocyte infiltration in atherosclerotic plaques was accelerated in ApoE -/- CB2 -/- mice compared with ApoE -/- mice. This was accompanied by increased release of reactive oxygen species as measured using L012-enhanced chemiluminescence, and by decreased endothelial function as assessed in isolated aortic rings in organ chamber experiments. ApoE -/- mice treated with the selective CB2 agonist JWH 133 during a high-cholesterol diet showed decreased atherosclerotic lesion formation, improved endothelial function and reduced levels of reactive oxygen species. To assess whether CB2 expression in circulating cells influences atherosclerosis, irradiated ApoE -/- mice were repopulated with bone marrow-derived cells from ApoE -/- and ApoE -/- CB2 -/- mice and were fed a high-cholesterol diet for 8weeks. CB2 deficiency in bone marrow-derived cells increased leukocyte infiltration into the vessel wall, but had no impact on plaque formation. Cell culture experiments revealed that CB2 activation diminishes ROS generation in vascular cells. Selective CB2 receptor stimulation modulates atherogenesis via impact on both circulating proinflammatory and vascular cells.
Assuntos
Aterosclerose/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Pressão Sanguínea , Transplante de Medula Óssea , Moduladores de Receptores de Canabinoides/metabolismo , Colesterol/sangue , Células Endoteliais/metabolismo , Endotélio/metabolismo , Frequência Cardíaca , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Receptor CB2 de Canabinoide/genéticaRESUMO
BACKGROUND Atherosclerosis and malignancies are leading causes of morbidity and mortality worldwide. In lower-extremity arterial disease (LEAD), progressing or ruptured atherosclerotic plaques are the main culprit for limb ischemia and may cause claudication, chronic wounds, or necrotic lesions. In those cases, standard of care includes revascularization in addition to best medical therapy. Other sources for acute or chronic limb ischemia different from atherosclerosis are often overlooked, especially once atherosclerotic plaques have been detected. CASE REPORT We report the rare case of a patient presenting with painful necrotic ulcerations of the lower extremity due critical essential thrombocythemia that was complicated by an atherosclerotic disease. Based on the clinical presentation, 4 major differential diagnoses were initially considered: Martorell's ulcer, pyoderma gangrenosum, LEAD, and recurrent thromboembolic occlusions due to a malignant disease. Following a thorough, holistic diagnostic work-up, we identified the first diagnosis of critical essential thrombocythemia, which was aggravated by LEAD. CONCLUSIONS This case report highlights the importance of taking malignancies into consideration as a differential diagnosis in patients with repetitive arterial occlusions. With a broad variety of differential diagnoses to be considered for the presented ulcerations, this case report highlights the crucial importance of a rapid interdisciplinary approach to treat and relieve symptoms and prevent further arterial thrombotic events. The learning objective is to give a clear diagnostic work-up to navigate through the most important differential diagnoses of non-atherosclerotic conditions aggravating LEAD.
Assuntos
Arteriopatias Oclusivas , Trombocitemia Essencial , Arteriopatias Oclusivas/diagnóstico , Arteriopatias Oclusivas/etiologia , Artérias , Humanos , Isquemia , Extremidade Inferior , Trombocitemia Essencial/complicações , Trombocitemia Essencial/diagnósticoRESUMO
As the percentage of overweight individuals in the population rises, diseases associated with excess weight resulting from poor nutrition are becoming more and more widespread. So far, the influence of weight or nutrition on bone health has shown conflicting results. In the literature, the existing studies disagree about the effect of diet on bones. Therefore, this study investigated the impact of a long-term, high-fat, and high-cholesterol diet on the spine in a mouse model. Wild-type mice were randomly separated into two groups; one group received a high-fat and high-cholesterol diet, and a control group was fed with a regular diet since birth for a duration of 8 months. The first to fifth thoracic vertebrae were extracted and investigated using histology and micro-CT. Samples were analyzed regarding different parameters: percentage of bone structure compared to the whole vertebra and the amount and thickness of the trabeculae. Both methods of the analysis showed similar results. Diet did not have a significant impact on the bone density of the vertebrae. The micro-CT examination showed that the average bone percentage of the examined vertebra was 6% (p = 0.2330) higher in the control group compared to the diet group. The same tendency was demonstrated in histology even though with a smaller difference of only 5%. The results of both methods were comparable and showed trends for the influence of different diets but not significant impacts. In summary, this study showed that a high-fat and high-cholesterol diet has a slightly negative impact on bone density. In order to further analyze the effects of different diets on bone composition, structure, and density, additional long-term studies should be carried out, and more parameters such as movement and genetic factors should be analyzed. Furthermore, other parameters such as exercise and genetic factors that could have a secondary influence on obesity should be investigated.
Assuntos
Densidade Óssea , Obesidade , Animais , Colesterol , Dieta , Camundongos , Coluna VertebralRESUMO
BACKGROUND: Peripheral artery disease (PAD) patients have high morbidity and mortality rates, demonstrating a need for improved treatment strategies. While underuse and undertreatment have been reported, there is no clear picture of patterns in population-level disease prevalence, prescription of guideline-recommended pharmacotherapy, or frequency of contact with dedicated specialists. We present population-level data on changes in prevalence, care and treatment of PAD from 2009 to 2018 in Germany. METHODS: We analyzed the ambulatory claims data for all statutorily insured patients comprising 70.1 million patients each year and 87% of the German population. Prevalence was assessed by documentation of PAD and stratified by age and sex within the 10-year study timeframe. In addition, current ambulatory care, stratified by vascular specialists (vascular surgeons or angiologists), internists, cardiologists and primary care physicians, were examined. FINDINGS: Prevalence increased from 1·85% in 2009 to 3·14% in 2018, affecting 2·3 million patients in 2018 and more males (55%) than females (45%). A low level of visits to vascular specialists, with 11·1% receiving care from vascular surgeons and 8·1% from angiologists, was shown. Moreover, analysis of guideline-recommended prescriptions revealed increasing, but still insufficient, prescription frequencies among PAD patients between 2009 and 2016, from 42·6% to 56% for statins and from 40·2% to 48·0% for antiplatelets. INTERPRETATION: Our results show that the prevalence of PAD in Germany, as assessed by outpatient PAD documentation, is increasing and PAD patients are underutilizing specialized vascular care; moreover, the prescription frequency of guideline-recommended therapies remains low. There is a clear need to improve the referral and treatment algorithms in the high-risk PAD population. FUNDING: None.
RESUMO
BACKGROUND: Mobile health interventions are intended to support complex health care needs in chronic diseases digitally, but they are mainly targeted at general health improvement and neglect disease-specific requirements. Therefore, we designed TrackPAD, a smartphone app to support supervised exercise training in patients with peripheral arterial disease. OBJECTIVE: This pilot study aimed to evaluate changes in the 6-minute walking distance (meters) as a primary outcome measure. The secondary outcome measures included changes in physical activity and assessing the patients' peripheral arterial disease-related quality of life. METHODS: This was a pilot two-arm, single-blinded, randomized controlled trial. Patients with symptomatic PAD (Fontaine stage IIa/b) and access to smartphones were eligible. Eligible participants were randomly assigned to the study, with the control group stratified by the distance covered in the 6-minute walking test using the TENALEA software. Participants randomized to the intervention group received usual care and the mobile intervention (TrackPAD) for the follow-up period of 3 months, whereas participants randomized to the control group received routine care only. TrackPAD records the frequency and duration of training sessions and pain levels using manual user input. Clinical outcome data were collected at the baseline and after 3 months via validated tools (the 6-minute walk test and self-reported quality of life). The usability and quality of the app were determined using the Mobile Application Rating Scale user version. RESULTS: The intervention group (n=19) increased their mean 6-minute walking distance (83 meters, SD 72.2), while the control group (n=20) decreased their mean distance after 3 months of follow-up (-38.8 meters, SD 53.7; P=.01). The peripheral arterial disease-related quality of life increased significantly in terms of "symptom perception" and "limitations in physical functioning." Users' feedback showed increased motivation and a changed attitude toward performing supervised exercise training. CONCLUSIONS: Besides the rating providing a valuable support tool for the user group, the mobile intervention TrackPAD was linked to a change in prognosis-relevant outcome measures combined with enhanced coping with the disease. The influence of mobile interventions on long-term prognosis must be evaluated in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04947228; https://clinicaltrials.gov/ct2/show/NCT04947228.
Assuntos
Doença Arterial Periférica , Telemedicina , Tecnologia Biomédica , Terapia por Exercício , Humanos , Doença Arterial Periférica/terapia , Projetos Piloto , Qualidade de VidaRESUMO
Background: The avoidance of prolonged hospital stay is a major goal in the management of transcatheter aortic valve implantation (TAVI) - medically and economically. Materials & methods: We compared the time range of the preprocedural length of stay in 2014/2015 with 2016/2017, after the implementation of the TAVI coordinator in 2016. This included restructured pathways for screening and pre-interventional diagnosis, performed examinations during the inpatient stay and major outcome variables. Results: After 2016, we observed a significant reduction in preprocedural length of stay (admission to procedure) compared with 2014/2015 (11.3 ± 7.9 vs 7.5 ± 5.6 days, p = 0.001). There was no difference in other major outcome variables. Conclusion: The introduction of the TAVI coordinator caused a shortening of preprocedural length of stay.
Assuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Fluoroscopia , Humanos , Tempo de Internação , Resultado do TratamentoRESUMO
Circulating endothelial progenitor cells (EPC) contribute to endothelial replenishment. Telmisartan is an angiotensin-receptor blocker with PPARgamma-agonistic properties. PPARgamma-agonists and HMG-CoA reductase inhibitors have been shown to enhance EPC number and function. We focused on the effects of telmisartan alone or in combination with simvastatin on EPC. EPC were isolated from healthy human volunteers, cultured and stimulated with telmisartan, simvastatin, or the combination of telmisartan and simvastatin. Telmisartan significantly increased the number of acLDL/lectin double-positive early EPC, the number of colony forming units (EC-CFU) as well as EPC migratory capacity, inhibited TNFalpha-induced EPC apoptosis and reduced glucose-induced oxidative stress. The telmisartan effect was dose-dependent and could be inhibited by GW9662, indicating a PPARgamma-dependent mechanism. The combination of telmisartan and simvastatin led to a significant additive increase in EPC count and function. In wild-type mice, systemic treatment with either telmisartan or simvastatin elevated the number of sca-1/flk-1-positive EPC in bone marrow and peripheral blood, spleen-derived acLDL/lectin double-positive EPC, EPC migration and EC-CFU. Consistent with the in vitro findings, the combination of telmisartan and simvastatin resulted in a further enhancement of EPC counts. Re-endothelialization after carotid injury was significantly enhanced by telmisartan, simvastatin and the combination. Telmisartan increases EPC number and function mediated by a PPARgamma-dependent mechanism. This effect is further enhanced by combination with simvastatin, suggesting a synergistic activation of potentially diverse intracellular pathways.
Assuntos
Benzimidazóis/farmacologia , Benzoatos/farmacologia , Células Endoteliais/citologia , Sinvastatina/farmacologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Adulto , Animais , Apoptose/efeitos dos fármacos , Contagem de Células , Movimento Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Humanos , Lectinas/metabolismo , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Baço/citologia , Células-Tronco/metabolismo , TelmisartanRESUMO
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.