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1.
Eur J Cardiothorac Surg ; 51(suppl 1): i15-i19, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28108564

RESUMO

SummaryThe development of new devices to improve treatment and to explore new indications that have not yet been adequately addressed is a natural consequence of the clinical demand for solutions to as yet unmet needs. The frozen elephant trunk technique was one of the major steps within the last 15 years to improve on existing treatments as well as to explore new indications. The goal of this article is to provide technical details about advances in implantation techniques for the treatment of acute and chronic thoracic aortic pathological conditions.


Assuntos
Aorta Torácica/cirurgia , Doenças da Aorta/cirurgia , Implante de Prótese Vascular/métodos , Prótese Vascular , Anastomose Cirúrgica/métodos , Implante de Prótese Vascular/instrumentação , Cateterismo Cardíaco/métodos , Hemostasia Cirúrgica/métodos , Humanos , Monitorização Intraoperatória/métodos , Desenho de Prótese , Artéria Subclávia/cirurgia
2.
Interact Cardiovasc Thorac Surg ; 22(2): 228-30, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26541961

RESUMO

There is a growing number of devices used for thoracic endovascular aortic repair (TEVAR). The designs of stent grafts and their delivery systems differ substantially. The success of TEVAR is based on the correct use of stent graft delivery systems, the identification and understanding of radiopaque markers, and the stent graft's accurate placement. In this brief communication, we introduce the TEVAR App-a novel guide for thoracic endovascular aortic repair. It is a tool that provides key information that is quick to access and easy to understand on the thoracic aortic stent grafts currently available. It includes instructions for use, animations demonstrating the stent grafts' deployment, troubleshooting information, size tables, the locations of radiopaque markers, stent graft and delivery system photos, chest X-rays, and information on magnetic resonance safety and compatibility. Furthermore, it contains the TEVAR Calculator, which assists one in planning stent graft size according to individual aortic dimensions and oversizing factors. The TEVAR App is cost-free, and its development has not been supported financially by any industry. It is a non-profit project that aims to educate and help physicians performing TEVARs.


Assuntos
Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , Procedimentos Endovasculares/métodos , Software , Cirurgia Assistida por Computador/métodos , Procedimentos Cirúrgicos Torácicos/métodos , Humanos
3.
Dtsch Arztebl Int ; 112(48): 816-22, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26667980

RESUMO

BACKGROUND: Abdominal and thoracic aortic aneurysms are diagnosed in 40 and 10 to 15 out of 100 000 persons per year, respectively. Fenestrated (fEVAR) and branched (bEVAR) stent grafts have been developed for abdominal juxtarenal and thoracoabdominal aneurysms. We discuss the patency and complication rates of fEVAR and bEVAR procedures and compare them with the outcome of open surgery. METHODS: This review is based on pertinent publications from 2011 to 2014 that were retrieved by a selective literature search. The clinical outcomes of case series involving a total of more than 1500 patients are presented. The discussion takes account of recommendations contained in the literature and the authors' own experience. RESULTS: Open surgery and aortic stent grafting have not been compared in any randomized trial to date. We identified 7 clinical series that included a total of 1270 fEVAR patients and 5 with a total of 408 bEVAR patients. The perioperative mortality after fEVAR procedures was 0-4%. Spinal cord ischemia arose in 1% of cases. The stent patency rate in visceral vessels ranged from 93 to 98%. bEVAR procedures were associated with both higher mortality (4-7%) and more common spinal cord ischemia (4-13%). 5-8% of all patients needed dialysis perioperatively, and the stent patency rate in visceral vessels was 94-97%. Preoperative renal insufficiency was a risk factor for peri-interventional death. Impaired renal function after fEVAR/bEVAR procedures was mainly associated with intermittent lower limb ischemia. CONCLUSION: The results of fEVAR/bEVAR procedures in the last 5 years are similar to those of open surgery. The high postoperative rate of spinal cord ischemia remains a serious problem in the endovascular treatment of thoracoabdominal aortic aneurysms. The decision to implant a stent graft by an endovascular approach or to treat surgically should be made on a case-to-case basis in an interdisciplinary vascular conference.


Assuntos
Aneurisma Aórtico/mortalidade , Aneurisma Aórtico/terapia , Prótese Vascular/estatística & dados numéricos , Complicações Pós-Operatórias/mortalidade , Aneurisma Aórtico/diagnóstico , Humanos , Complicações Pós-Operatórias/prevenção & controle , Prevalência , Desenho de Prótese , Fatores de Risco , Stents/estatística & dados numéricos , Taxa de Sobrevida , Resultado do Tratamento
4.
Circulation ; 128(15): 1602-11, 2013 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-24025592

RESUMO

BACKGROUND: Cardiac surgery with cardiopulmonary bypass is associated with mechanical manipulation of the ascending aorta that occasionally leads to type A aortic dissection (AAD). METHODS AND RESULTS: One hundred three patients with surgical repair for AAD following nonaortic cardiac surgery were identified. With the use of logistic regression modeling, coronary artery bypass surgery (CABG), either isolated or combined with another procedure in the initial operation, was associated with significantly higher operative mortality in comparison with patients with non-CABG procedures at the time of AAD repair both for all patients (odds ratio, 2.90; 95% confidence interval, 1.09-7.72; P=0.033) and for patients with acute and chronic AAD≥30 days after the initial operation (odds ratio, 3.62; 95% confidence interval, 1.13-11.54; P=0.03). In patients who developed AAD late after the initial operation, operative mortality was highest in patients without preoperative coronary angiography and appropriate management of their native coronary artery disease and graft disease (odds ratio, 5.36; 95% confidence interval, 1.68-17.0; P=0.002). Nearly all the intimal dissection tears were located at sites of previous surgical trauma. Most of the ascending aortas that had dissected initially had a diameter≥40 mm with histological evidence of medial degeneration in resected tissue samples. CONCLUSIONS: In patients who have undergone previous cardiac surgery, preexisting aortic wall pathology contributes to AAD with typical intimal damage at sites of mechanical trauma. The operative mortality was the highest in patients with previous CABG in comparison with patients with non-CABG procedures. Preoperative coronary angiography and operative management of native coronary and graft disease were significantly associated with outcome in patients with previous CABG.


Assuntos
Aneurisma Aórtico/mortalidade , Dissecção Aórtica/mortalidade , Ponte de Artéria Coronária/efeitos adversos , Cardiopatias Congênitas/mortalidade , Doenças das Valvas Cardíacas/mortalidade , Complicações Pós-Operatórias/mortalidade , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Dissecção Aórtica/etiologia , Aorta , Aneurisma Aórtico/etiologia , Valva Aórtica , Doença da Válvula Aórtica Bicúspide , Ponte Cardiopulmonar , Doença Crônica , Feminino , Seguimentos , Cardiopatias Congênitas/etiologia , Doenças das Valvas Cardíacas/etiologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos
5.
Eur J Cardiothorac Surg ; 44(1): 156-62, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23321435

RESUMO

OBJECTIVES: To investigate mid-term outcome in patients undergoing thoracic endovascular aortic repair (TEVAR) for non-dissected aortic pathology with favourable and unfavourable landing zone and aortic anatomy. METHODS: Between 2000 and 2011, TEVAR was performed in 208 patients with descending thoracic aortic disease. Of 105 patients with non-dissected thoracic aortic pathology, 69 presented with unfavourable anatomy as defined by short length (<15 mm), large diameter (>42 mm), angulation of >60° of the proximal or distal landing zone or extreme aortic tortuosity. The endpoints perioperative mortality, 1-year survival, endoleak occurrence and incidence of secondary intervention were compared with the remaining 36 patients with favourable anatomy. RESULTS: Median follow-up was 18 months. TEVAR was performed emergently in 24 of 69 (35%) patients with unfavourable anatomy and in 11 of 36 (31%) of those with favourable anatomy (P = 0.68). No patients underwent conversion to open surgery, no periinterventional rupture was observed. Perioperative mortality did not differ between cohorts (1/69 vs 1/36, P = 0.78). Postoperative permanent spinal cord ischaemia occurred in patients with unfavourable anatomy only (2/69 vs 0/36, P = 0.78). Early endoleak and secondary intervention were more frequent in patients with unfavourable anatomy (19/69 vs 7/36 and 13/69 vs 1/36), but not statistically significant (P = 0.5 and P = 0.13, respectively). One-year aorta-related survival rates were similar in both groups (66/69 vs 33/36, P = 0.45). CONCLUSIONS: Mid-term outcome after TEVAR does not differ between patients with favourable and unfavourable landing zone anatomy in terms of aorta-related survival. However, the more frequent need for secondary intervention warrants a more rigorous follow-up after TEVAR in patients with unfavourable anatomy.


Assuntos
Aneurisma da Aorta Torácica , Procedimentos Endovasculares/mortalidade , Procedimentos Cirúrgicos Torácicos/mortalidade , Idoso , Idoso de 80 Anos ou mais , Aorta/patologia , Aorta/cirurgia , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Resultado do Tratamento
6.
Cardiovasc Intervent Radiol ; 35(4): 945-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21898166

RESUMO

Complex peripheral aneurysm anatomy with major artery branches in the immediate vicinity and mycotic aneurysm often impede endovascular management using covered stent grafts. The Cardiatis Multilayer Stent (Cardiatis, Isnes, Belgium) is a recently approved innovative stent system for peripheral aneurysm management. Its multilayer design aims at decreasing mean velocity and vorticity within the aneurysm sac to cause thrombus formation while maintaining patency of branching vessels due to laminar flow. We present a case of bilateral subclavian artery aneurysms and perivisceral aortic aneurysms in an AIDS patient successfully treated with the Cardiatis Multilayer Stent at 18 months' follow-up.


Assuntos
Aneurisma/terapia , Aneurisma da Aorta Abdominal/terapia , Procedimentos Endovasculares , Infecções por HIV/complicações , Stents , Artéria Subclávia , Aneurisma/diagnóstico por imagem , Angiografia Digital , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ultrassonografia
7.
PLoS One ; 5(10): e13608, 2010 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-21049052

RESUMO

BACKGROUND: Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo. METHODOLOGY: Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans. PRINCIPAL FINDINGS: In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10(-6) M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70(S6) kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group). CONCLUSIONS: Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target.


Assuntos
Aterosclerose/patologia , Músculo Liso Vascular/metabolismo , Profilinas/metabolismo , Animais , Sequência de Bases , Células Cultivadas , Primers do DNA , Humanos , Músculo Liso Vascular/patologia , Fosforilação , Reação em Cadeia da Polimerase , Profilinas/fisiologia , Ratos , Ratos Endogâmicos WKY , Transdução de Sinais
8.
Dtsch Arztebl Int ; 106(13): 224-33; quiz 234, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19471589

RESUMO

BACKGROUND: Surgery plays a central role in the management of acquired valvular heart disease. The optimal diagnostic evaluation, surgical treatment, and postoperative care of these patients are only possible through a cooperative effort of the primary care physician, the cardiologist, and the cardiac surgeon. METHODS: The literature was selectively searched for information on surgical indications, operative techniques, and postoperative care in acquired valvular heart disease. Evidence-based guidelines and treatment recommendations were also taken into account. RESULTS: A wide variety of techniques and implants are now available for the surgical treatment of acquired valvular heart disease. If they are used in evidence-based fashion, the perioperative mortality is low and the long-term outcome is favorable. CONCLUSIONS: The volume of surgery for acquired valvular heart disease in Germany has increased substantially in recent years, from 25,495 cases in 2002 (corresponding to 26.5% of all heart operations in that year) to 33,412 in 2007 (36.5% of all heart operations). The causes for this include both demographic changes and the availability of new, less invasive surgical techniques that yield better results in elderly and/or multimorbid patients. Because of these new techniques, the indications for surgery have widened, while the results have remained favorable.


Assuntos
Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/mortalidade , Implante de Prótese de Valva Cardíaca/métodos , Próteses Valvulares Cardíacas , Cuidados Pós-Operatórios/estatística & dados numéricos , Alemanha/epidemiologia , Humanos , Incidência
9.
Eur J Cardiothorac Surg ; 33(4): 554-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18282760

RESUMO

OBJECTIVE: The technically demanding full root aortic valve replacement necessitating coronary ostia reimplantation apparently leads to hesitation by some surgeons despite the superior hemodynamics and excellent long-term clinical performances of the stentless xenografts. Clinical data of stentless full root replacements was retrospectively analyzed in this perspective for validation. METHODS: From November 1999 to March 2007, 317 adult patients (male: 196, female, 121) underwent modified Bio-Bentall procedure using the Medtronic Freestyle xenograft as a full root replacement. Two hundred and three patients received an isolated root replacement or a root and ascending aortic replacement (ARR). In 114 patients a variety of concomitant procedures including coronary artery bypass grafting (n=32), mitral valve repair (n=11) and aortic arch replacement (n=36) were performed. (ARR+). RESULTS: Mean patient age was 70.3+/-10.2 years (range 17-94 years), 97 patients were 75 and older at time of procedure. Mean operative time for the ARR was 190+/-57 min with a clamp time of 88+/-27 min. Mean operative time for ARR+ group was 282+/-93 min with an average clamp time of 110+/-32 min. Overall operative mortality was 7.9% (25/317), for ARR it was 5.4% (11/203). Mean ICU stay was 4.9+/-8.1 days, mean hospital stay being 9.8+/-8.1 days. Necessity for bailout bypass surgery among patients with ARR was low at 1.5% (3/203) comparable to stented xenograft implantations. Echocardiography demonstrated excellent clinical results with low transvalvular gradients especially when a single suture inflow anastomosis technique was used. CONCLUSIONS: Full root stentless valve implantation preserving porcine root integrity is a valuable option in aortic valve/ascending aorta surgery. Though technically a more challenging operation, it does not lead to increased perioperative morbidity and mortality and can be beneficial mainly for elderly patients with small aortic roots with or without aortic root pathology.


Assuntos
Doenças da Aorta/cirurgia , Valva Aórtica/transplante , Implante de Prótese de Valva Cardíaca/métodos , Desenho de Prótese/normas , Transplante Heterólogo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/fisiopatologia , Feminino , Seguimentos , Implante de Prótese de Valva Cardíaca/normas , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
10.
J Interv Cardiol ; 19(2): 163-5, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16650246

RESUMO

Catheter interventional treatment of atrial septal defect (ASD) is widely accepted. The ASD occluder system (ASDOS) is no longer a widely used device nowadays. However, it is implanted in a substantial number of patients. We report a case of severe left-to-right shunt 8 years after catheter interventional closure of an ASD with an ASDOS device. The shunt was due to a membrane perforation, while the arms of the device were not dislocated. Microscopy, microbiology, and histology could not establish a proper explanation for the dysfunction; so long-term follow-up investigation may be required in patients with an implanted ASDOS device.


Assuntos
Comunicação Interatrial/cirurgia , Próteses e Implantes , Implantação de Prótese/efeitos adversos , Idoso , Diagnóstico Diferencial , Ecocardiografia Transesofagiana , Comunicação Interatrial/diagnóstico por imagem , Humanos , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/patologia , Falha de Prótese , Implantação de Prótese/instrumentação , Radiografia
11.
Circulation ; 111(4): 399-404, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15687126

RESUMO

BACKGROUND: The pacemaker current I(f) is present in atrial and ventricular myocytes. However, it remains controversial whether I(f) overexpression in diseased states might play a role for arrhythmogenesis, because first I(f) activation in whole-cell recordings hardly overlapped the diastolic voltage of working myocardium. METHODS AND RESULTS: To obtain further insight into I(HCN) and I(f) properties, we provide for the first time detailed single-channel analysis of heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) isoforms and native human I(f). HCN subtypes differed significantly in single-channel amplitude, conductance, and activation kinetics. Interestingly, threshold potentials of HCN isoforms were more positive than would have been expected from whole-cell measurements. Single-channel properties of cells cotransfected with HCN2 and HCN4 were distinct from cells expressing HCN2 or HCN4 alone, demonstrating that different HCN isoforms can influence current properties of a single HCN channel complex, thus providing direct functional evidence for HCN heteromerization. Pooled data of homomeric and heteromeric HCN channels and of native I(f) extrapolated from maximum likelihood fits indicated a multistate gating scheme comprising 5 closed- and 4 open-channel states. Single-channel characteristics of I(f) in human atrial myocytes closely resembled those of HCN4 or HCN2+HCN4, supporting the hypothesis that native I(f) channels in atrial myocardium are heteromeric complexes composed of HCN4 and/or HCN2. Most interestingly, half-maximal activation of single-channel atrial I(f) (-68.3+/-4.9 mV; k=-9.9+/-1.5; n=8) was well within the diastolic voltage range of human atrial myocardium. CONCLUSIONS: These observations support a potential contribution of HCN/I(f) to the arrhythmogenesis of working myocardium under pathological conditions.


Assuntos
Arritmias Cardíacas/fisiopatologia , Átrios do Coração/metabolismo , Ativação do Canal Iônico/fisiologia , Canais Iônicos/fisiologia , Proteínas Musculares/fisiologia , 4-Aminopiridina/farmacologia , Idoso , Animais , Arritmias Cardíacas/metabolismo , Apêndice Atrial/citologia , Células CHO/fisiologia , Células Cultivadas/fisiologia , Colforsina/farmacologia , Cricetinae , Cricetulus , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Feminino , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/química , Cinética , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/química , Proteínas do Tecido Nervoso , Técnicas de Patch-Clamp , Canais de Potássio , Isoformas de Proteínas/química , Isoformas de Proteínas/fisiologia , Multimerização Proteica , Proteínas Recombinantes de Fusão/fisiologia , Transfecção
12.
Basic Res Cardiol ; 100(1): 1-13, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15490203

RESUMO

Voltage-gated calcium channels are key components in cardiac electrophysiology. We demonstrate that Ca(v)2.3 is expressed in mouse and human heart and that mice lacking the Ca(v)2.3 voltage-gated calcium channel exhibit severe alterations in cardiac function. Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the expression of three different Ca(v)2.3 splice variants. The ablation of Ca(v)2.3 was found to be accompanied by a compensatory upregulation of the Ca(v)3.1 T-type calcium channel, while other voltage-gated calcium channels remained unaffected. Telemetric ECG recordings from Ca(v)2.3 deficient mice displayed subsidiary escape rhythm, altered atrial activation patterns, atrioventricular conduction disturbances and alteration in QRS-morphology. Furthermore, time domain analysis of heart rate variability (HRV) in Ca(v)2.3(-/-) mice exhibited a significant increase in heart rate as well as in the coefficient of variance (CV) compared to control mice. Administration of atropin/propranolol revealed that increased heart rate was due to enhanced sympathetic tonus and that partial decrease of CV in Ca(v)2.3(-/-) mice after autonomic block was in accordance with a complete abolishment of 2(nd) degree atrioventricular block. However, escape rhythms, atrial activation disturbances and QRS-dysmorphology remained unaffected, indicating that these are intrinsic cardiac features in Ca(v)2.3(-/-) mice. We conclude that the expression of Ca(v)2.3 is essential for normal impulse generation and conduction in murine heart.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Canais de Cálcio/fisiologia , Sistema Cardiovascular/fisiopatologia , Animais , Arritmias Cardíacas/etiologia , Bloqueio Nervoso Autônomo , Eletrocardiografia , Camundongos , Camundongos Endogâmicos C57BL
13.
AIDS ; 18(3): 403-11, 2004 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-15090791

RESUMO

OBJECTIVES: HIV protease inhibitors (PI) such as ritonavir have dramatically decreased HIV-related morbidity and mortality. However they exhibit significant side-effects such as hyperlipidemia, hyperglycemia with or without lipodystrophy, which may increase patients' risk for atherosclerosis. Direct effects of PI on the vascular wall have not been investigated. Platelet-derived growth factor (PDGF) is a major contributor to atherogenesis. DESIGN: In the present study the effects of ritonavir on PDGF-BB-induced responses of vascular smooth muscle cells (VSMCs) were evaluated. METHODS: PDGF-induced proliferation of VSMCs was measured by BrdU-incorporation, and chemotaxis was assessed by utilizing modified Boyden chambers. Cytotoxicity and apoptosis were quantified using LDH-release- and apoptosis-kits. Immunoprecipitation and Western blot analyses were performed to evaluate betaPDGF receptor (betaPDGFR) expression and phosphorylation, and to monitor intracellular signaling. RESULTS: Pretreatment of VSMCs with ritonavir resulted in a significant concentration-dependent inhibition of PDGF-BB-induced cellular responses. At a therapeutic concentration (10 microg/ml), ritonavir significantly reduced PDGF-induced DNA synthesis and chemotaxis by 46.8 +/- 5.5% and 37.2 +/- 3.3%, respectively (P < 0.05 each). In addition it significantly inhibited PDGF-dependent downstream signaling, such as Erk activation. These inhibitory effects were not due to cytotoxicity or apoptosis. Instead, ritonavir inhibited the ligand-induced tyrosine phosphorylation of the betaPDGFR, whereas it did not alter betaPDGFR expression. CONCLUSIONS: Ritonavir has direct effects on VSMCs at clinically relevant concentrations in vitro, as it inhibits betaPDGFR activation and PDGF-dependent proliferation and migration of VSMCs. Although ritonavir may increase the risk of vascular disease by its metabolic side effects, it may exhibit anti-atherogenic properties on the cellular level.


Assuntos
Inibidores da Protease de HIV/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Ritonavir/farmacologia , Animais , Apoptose/efeitos dos fármacos , Becaplermina , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Músculo Liso Vascular/citologia , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Proto-Oncogênicas c-sis , Ratos , Ratos Endogâmicos WKY , Receptores do Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo
14.
J Cardiovasc Pharmacol ; 41(5): 734-43, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12717104

RESUMO

Sildenafil (Viagra) has been proved effective in the therapy for erectile dysfunction. Cardiovascular adverse effects are a matter of continuous debate. The aim of the study was to investigate effects of sildenafil on isolated human cardiovascular tissue directly. Isometric force of contraction was determined in isolated, electrically stimulated (1 Hz, 37 degrees C) human right atrial and left ventricular muscle strips. Vascular tension was determined in rings of human internal mammaria arteries and saphenous veins. Sildenafil (0.0001-10 microM) neither in human atrium (n = 12) nor in failing (n = 8) or nonfailing (n = 5) ventricle exerted a significant inotropic response. Furthermore, no effect on isoprenaline-elicited arrhythmias was observed. Neither addition of isoprenaline (0.1 microM) nor addition of the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) (100 microM) affected myocardial contractility in the presence of sildenafil (10 microM). In precontracted arteries and veins, addition of sildenafil (0.1-10 microM) led to pronounced vasorelaxation (maximal 35.5 +/- 2.2% and 45.6 +/- 6.3%, respectively, in the presence of 10 microM sildenafil). In the presence of SNAP (0.03 microM), this effect was markedly increased in arteries (72.4 +/- 10.1%, n = 4, P < 0.02) as well as in veins (73.5 +/- 6.3%, n = 6, P < 0.02). Sildenafil exerts potent vasodilatory actions but has no direct influence on human myocardial contractility or proarrhythmic effects in vitro.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Artéria Torácica Interna/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Veia Safena/efeitos dos fármacos , 3',5'-GMP Cíclico Fosfodiesterases , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Estimulação Elétrica , Átrios do Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Humanos , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/fisiologia , Isoproterenol , Artéria Torácica Interna/fisiologia , Milrinona/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Contração Miocárdica/fisiologia , Doadores de Óxido Nítrico/farmacologia , Inibidores de Fosfodiesterase/efeitos adversos , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/efeitos adversos , Purinas , S-Nitroso-N-Acetilpenicilamina/farmacologia , Veia Safena/fisiologia , Citrato de Sildenafila , Sulfonas , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia
15.
J Mol Cell Cardiol ; 35(1): 71-80, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12623301

RESUMO

Lysophosphatidic acid (LPA) is a phospholipid messenger, which is released from activated platelets and leukocytes. This study examined the effects of LPA on myocardial contractility and characterized the signal transduction pathway involved in these effects. Functional effects of LPA were determined in isolated, electrically driven human myocardial preparations and rat cardiac myocytes. In human atrial and ventricular myocardial preparations, LPA (100 micromol/l) decreased isoprenaline (0.03 micromol/l) enhanced force of contraction by 17 +/- 2% and 28 +/- 3%, respectively. The effect of LPA was attenuated by suramin (1 mmol/l). In isolated rat cardiomyocytes, LPA (1-100 micromol/l) concentration dependently abolished isoprenaline (0.03 micromol/l) induced increase in cell shortening. This antiadrenergic effect was blunted after pretreatment with pertussis toxin (5 microg/ml, 12 h). Forskolin (10 micromol/l) stimulated adenylyl cyclase activity was inhibited by LPA in human myocardial membranes. PCR analysis of human atrial and ventricular cDNAs revealed the expression of two cognate LPA receptors: EDG-2 and EDG-7. Our results suggest that LPA exerts antiadrenergic effects on force of contraction in human and rodent myocardium via a Galpha(i/o) protein-mediated mechanism, most probably by LPA binding to the mammalian LPA receptors EDG-2 and/or EDG-7. This newly discovered action of LPA might be of pathophysiological importance in conditions like myocardial ischemia or inflammatory disorders when LPA release is enhanced.


Assuntos
Lisofosfolipídeos/metabolismo , Contração Miocárdica/fisiologia , Receptores Acoplados a Proteínas G , Adenilil Ciclases/metabolismo , Animais , Humanos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/metabolismo , Toxina Pertussis/farmacologia , Ratos , Receptores de Superfície Celular/metabolismo , Receptores de Lisofosfolipídeos , Suramina/farmacologia
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