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Background: The challenge with the stentless strategy is that the method of optimal predilatation, and predictors of success remain unknown. Studies involving the stentless strategy prior to predilatation are limited. This study aimed to evaluate the long-term efficacy and safety of a new stentless strategy for treating acute coronary syndrome (ACS) using gradual, prolonged predilation with a perfusion balloon combined with a drug-coated balloon (DCB). Methods: This was a single-center, prospective, single-arm study. A total of 30 patients with ACS underwent gradual, prolonged predilation using a perfusion balloon for 10 minutes, followed by additional dilation using a DCB. The primary end point was target vessel failure at 24 months. Secondary end points were a composite of acute end points, including stentless strategy success rate, procedural complications, final grade of coronary dissection, acute coronary occlusion, in-hospital major adverse cardiac events, and a chronic end point of target vessel failure at 24 months. Results: A successful stentless strategy was achieved in 24 patients (80%), and 2 (8.3%) patients required ischemic-driven target lesion revascularization in the chronic phase. Six (20%) patients required stent placement due to type C dissection or acute recoil. No acute occlusion and in-hospital major adverse cardiac events were reported. Conclusions: A novel stentless strategy using predilation with a perfusion balloon and DCB may be helpful for the revascularization of patients with ACS.
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Acute coronary syndrome (ACS) is associated with a high incidence of unstable plaques beyond the culprit lesion, leading to early recurrence of cardiovascular events. Coronary computed tomography angiography (CCTA) can be used to noninvasively observe plaques throughout the coronary arteries. To evaluate the impact of intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy on quantitative changes in coronary plaque, assessed using CCTA in a study population with ACS. In total, 81 consecutive patients with ACS who underwent CCTA at discharge and at 1-year follow-up from April 2018 to March 2020 were analyzed. The patients were divided into 2 groups: those who achieved LDL-C <70 mg/100 ml and those who did not. Changes in plaque morphology within and between the 2 groups were compared using CCTA. A total of 198 vessels were analyzed. The calcified plaque volume was significantly increased in the LDL-C <70 group (65.8 ± 80.1 mm3 to 73.6 ± 83.7 mm3, p = 0.007), whereas no significant change was observed in the LDL-C ≥70 group (106.9 ± 161.7 mm3 to 105.7 ± 137.5 mm3, p = 0.552). Percent change in low-attenuation plaque volume in the LDL <70 group was significantly lower than in the LDL-C ≥70 group (17.2 ± 90.9% vs 84.4 ± 162.6%, p = 0.020). Receiver operating characteristic curve analysis demonstrated that the target LDL-C level for low-attenuation plaque volume regression was 64 mg/100 ml. In conclusion, noninvasive CCTA demonstrated that intensive LDL-C lowering in high-risk patients with ACS could potentially lead to plaque stabilization.
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Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Humanos , LDL-Colesterol , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Síndrome Coronario Agudo/tratamiento farmacológico , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Angiografía por Tomografía Computarizada/métodos , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Angiografía Coronaria/métodosRESUMEN
BACKGROUND: The efficacy of catheter ablation from the noncoronary aortic cusp (NCC) of verapamil-sensitive atrial tachycardia arising near the atrioventricular node (AVN-AT) has yet to be fully clarified. OBJECTIVE: We elucidated the determinant of an effective AVN-AT ablation from the NCC. METHODS: After identifying the earliest atrial activation site (EAAS) during tachycardia, the direction of the slow conduction zone (SCZ) of the reentry circuit was identified by demonstrating manifest entrainment in 26 patients with AVN-AT. Catheter ablation was initially performed from the NCC irrespective of the local activation time. If NCC ablation was ineffective, catheter ablation was performed targeting the SCZ entrance. Then the anatomical relationship between the SCZ and the successful ablation site was elucidated. RESULTS: NCC catheter ablation terminated AVN-AT in 14 patients (NCC group) but not in 12 (non-NCC group). Catheter ablation targeting the SCZ entrance terminated all non-NCC group ATs. The local activation time at the NCC relative to the EAAS did not differ between the NCC and non-NCC groups (10.1 ± 6.5 ms vs 11.2 ± 4.8 ms; P = .6333). The direction of the SCZ was posterior to the EAAS in all NCC group patients; however, it was posterolateral (n = 5) and lateral (n = 7) to the EAAS in the non-NCC group, suggesting that the SCZ existed in the direction of the NCC in the NCC group but was away from the NCC in the non-NCC group. CONCLUSION: A close proximity between the NCC and the SCZ of the reentry circuit, but not the local activation time at the NCC, determined the efficacy of NCC catheter ablation in AVN-ATs.
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Ablación por Catéter , Taquicardia Supraventricular , Nodo Atrioventricular , Electrocardiografía , Humanos , Taquicardia , Verapamilo/farmacología , Verapamilo/uso terapéuticoRESUMEN
To compare the diagnostic performance of on-site workstation-based computed tomography-derived fractional flow reserve (CT-FFR)Few data of CT-FFR were reported regarding the diagnostic performance for detecting hemodynamically significant coronary artery disease (CAD). This retrospective single-center analysis included 132 vessels in 77 patients who underwent CT angiography, myocardial perfusion imaging (MPI), and invasive FFR. The correlation coefficient between CT-FFR and invasive FFR and optimal cut-off value for CT-FFR to identify invasive FFR ≤ 0.8 were evaluated. The diagnostic accuracies of CT- FFR, and MPI were evaluated using an area under the receiver-operating characteristic curve (AUC) with invasive FFR as a reference standard. Diagnostic performance of CT-FFR was also evaluated concerning lesion characteristics, including intermediate lesions, left main lesions, tandem lesions, and/or diffuse lesions, and coronary calcium (Agatston score over 400). The Receiver Operating Characteristic curve analysis showed that the optimal cut-off value of CT-FFR for detecting invasive FFR ≤ 0.80 was 0.80 [AUC = 0.83, 95%CI: 0.76-0.90). Diagnostic sensitivity, specificity, positive and negative predictive value, and accuracy of CT-FFR when compared with those of MPI regarding per-patient analysis were 93% vs. 63%, 48% vs. 61%, 81% vs. 79%, 73% vs. 41%, and 79% vs. 62%, respectively, and for per-vessel analysis were 89% vs. 24%, 66% vs. 82%, 75% vs. 61%, 83% vs. 48%, and 78% vs. 51%, respectively. The AUC of the CT-FFR was significantly higher than MPI (0.83 vs. 0.57, p < 0.0001) regarding the per-vessel analysis. No differences in the diagnostic performance of CT-FFR were noted in the presence of intermediate lesions, left main lesions, tandem lesions, and/or diffuse lesions, and severe coronary calcium. On-site CT-FFR delivered a higher diagnostic performance than MPI for detecting CAD with invasive FFR ≤ 0.8, indicating the potential of CT-FFR as the gatekeeper of invasive coronary angiogram as well as percutaneous coronary intervention.
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Reserva del Flujo Fraccional Miocárdico , Imagen de Perfusión Miocárdica , Calcio , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Humanos , Miocardio , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Background: The optimal site for measuring computed tomography (CT)-derived fractional flow reserve (FFRCT) to detect significant coronary artery disease (CAD) remains unknown. We investigated how diagnostic performance changes with FFRCT measurement site. MethodsâandâResults: The diagnostic performance of FFRCT, measured 1-2 cm distal to the stenosis vs. a far-distal site, in detecting significant CAD with invasive fractional flow reserve ≤0.8 was evaluated in 254 diseased vessels from 146 patients with stable or suspected CAD diagnosed by coronary CT angiography. Receiver operating characteristic curve analysis revealed a significantly larger area under the curve for FFRCT measured 1-2 cm distal to the stenosis than at a far-distal site (0.829 vs. 0.791, respectively; P=0.0305). The rate of reclassification of positive FFRCT was 19% for measurements made 1-2 cm distal to the stenosis, and diagnostic accuracy for FFRCT 0.71-0.80 improved from 36% to 58% (P=0.0052). Vessel-based diagnostic accuracy of FFRCT 1-2 cm distal to the stenosis and at a far-distal site was 75% and 65%, respectively (P<0.0001), with corresponding sensitivity of 87% and 94% (P=0.0039), specificity of 60% and 29% (P<0.0001), a positive predictive value of 73% and 62% (P=0.028), and a negative predictive value of 78% and 79% (P=0.958). Conclusions: Our data suggest measuring FFRCT 1-2 cm distal to the stenosis has better diagnostic performance for detecting physiologically significant CAD.
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Fraction flow reserve (FFR) derived from computed tomography (FFRCT) has been proposed to be an effective gatekeeper for invasive angiographic referral. The purpose of the present study is to examine the real-world diagnostic performance of FFRCT and myocardial perfusion imaging as well as to assess the utility of FFRCT as a gatekeeper for invasive coronary angiography in patients suspected of having obstructive coronary artery disease. Total of 146 consecutive patients underwent both single-photon emission computed tomography (SPECT) and invasive FFR were evaluated. An FFRCT value 1 to 2 cm distal to a stenosis ≤0.80 was defined as positive for ischemia and a summed stress score ≥2 or transient ischemic dilatation ≥1.2 were positive for ischemia with the invasive FFR value of <0.80 serving as the gold standard. The patient-based sensitivity of FFRCT was significantly higher than SPECT (91 vs 52%, p <0.001) and exhibited similar positive predictive value (82 vs 82%, p = 0.91). These trends were observed even in patients with multivessel and left main trunk disease and those with severe coronary calcification. In conclusion, our data suggest that FFRCT has higher diagnostic performance characteristics than SPECT and details the superior FFRCT analysis in detecting patients with hemodynamically significant coronary artery disease. Our results support the clinical utility of FFRCT analysis as a gatekeeper for invasive coronary angiography in clinical practice.
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Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Reserva del Flujo Fraccional Miocárdico , Imagen de Perfusión Miocárdica , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Verapamil-sensitive atrial tachycardia originating from the atrioventricular node vicinity (AVN-AT) can be eliminated with radiofrequency energy (RF) deliveries targeting either the entrance or exit of its reentry circuit. However, the outcome of these different approaches has not been clarified well. Thus, we compared the catheter ablation outcome targeting the entrance of reentry circuit, identified by the entrainment method (Ent-Group; 21 patients) with that targeting the earliest atrial activation site (EAAS) during AT (Exit-Group; 16 patients). There was no significant difference in the tachycardia cycle length (441.4 ± 87.4 vs. 392.8 ± 64.8 ms, p = 0.0704) or distance from the His bundle (HB) site to the EAAS (6.5 ± 2.0 vs. 7.6 ± 1.8 mm, p = 0.0822) between the Ent- and Exit-Groups. However, distance from the successful ablation site to the HB site in the Ent-Group was significantly longer than that in the Exit-Group (13.4 ± 3.1 vs. 7.6 ± 1.8 mm, p < 0.0001), resulting in more frequent transient atrioventricular block episodes in the Exit-Group than Ent-Group (31.3 vs. 0%, p < 0.01). Initial ATs (AT1s) were terminated in all patients in both Groups. However, ATs accompanied by shifting in the EAAS (AT2) were induced more frequently in the Exit-Group than Ent-Group (50.0 vs. 14.3%, p < 0.02) after eliminating AT1. RF deliveries to the EAAS eliminated all AT2s. The number of RF deliveries was greater in the Exit-Group than Ent-Group (6.9 ± 3.3 vs. 3.9 ± 1.6, p < 0.001). In conclusion, RF ablation targeting the entrance sites can avoid AVN injury and is superior in reducing the number of RF deliveries and occurrence of different ATs than targeting the exit sites in the AVN-AT.
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Ablación por Catéter , Taquicardia por Reentrada en el Nodo Atrioventricular , Taquicardia Supraventricular , Nodo Atrioventricular/cirugía , Electrocardiografía , Humanos , Taquicardia , Taquicardia por Reentrada en el Nodo Atrioventricular/cirugía , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/cirugía , Verapamilo/uso terapéuticoRESUMEN
Fractional flow reserve (FFR) has become an increasingly important index for decision making concerning coronary revascularization. It is commonly accepted that significant improvement in FFR following percutaneous coronary intervention (PCI) is associated with better symptomatic relief and a lower event rate. However, in lesions with insufficient FFR improvement, PCI may not improve prognosis. Leading to the observation that the clinical and angiographic characteristics associated with insufficient FFR improvement have not been fully explored. The purpose of this study was to investigate the factors associated with insufficient improvement in FFR. Using our own PCI database, established between January 2014 and December 2018, we identified 220 stable coronary artery lesions, which had been evaluated for both pre- and post-PCI FFR values. All 220 of these lesions were included in this study. The improvement in FFR (ΔFFR) was calculated in each lesion with the lowest quartile of ΔFFR being defined as the lowest ΔFFR group, and the other quartiles being defined as the intermediate-high ΔFFR group. The mean ΔFFR in the lowest and intermediate-high ΔFFR groups was 0.07 ± 0.02 and 0.21 ± 0.11, respectively. In multivariate logistic regression analysis, a short total stent length (10 mm increase: OR 0.67, 95% CI 0.47-0.96, P = 0.030), higher pre-PCI FFR (0.1 increase: OR 4.07, 95% CI 1.83-9.06, P = 0.001), in-stent restenosis (ISR) (OR 8.02, 95% CI 1.26-51.09, P = 0.028), myocardial infarction (MI) in the target vessel (OR 6.87, 95% CI 1.19-39.69, P = 0.031) and non-use of intravascular imaging (OR 0.35, 95% CI 0.12-0.99, P = 0.048) were significantly associated with the lowest ΔFFR group. The use of short stents, higher pre-PCI FFR values, ISR, MI in the target vessel, and non-use of intravascular imaging were significantly associated with insufficient FFR improvement. It was conversely suggested that full coverage and adequate dilatation of the lesions under an intravascular imaging guidance might contribute to an improvement in FFR.
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Enfermedad de la Arteria Coronaria/terapia , Reserva del Flujo Fraccional Miocárdico , Intervención Coronaria Percutánea , Anciano , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Bases de Datos Factuales , Stents Liberadores de Fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Recuperación de la Función , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
The clinical benefits of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still controversial. The purpose of this study is to assess the quantitative therapeutic benefits of successful PCI for CTO from the clinical data acquired by myocardial perfusion imaging (MPI). Consecutive 42 patients, who were successfully revascularized of CTO between August 2013 and March 2018, were examined. A stress MPI was performed before CTO PCI and at follow-up, and the changes in quantitative gated and perfusion single photon emission computed tomography parameters were examined. The follow-up interval was 18 ± 9 (median 14) months, during which 36 patients were maintained patency (patent CTO), while 6 were re-occluded (R/O CTO). The reduction in the % myocardial ischemia and the improvement in the ejection fraction were significantly higher in the patent CTO group than those in the R/O CTO group (67.5 ± 37.0% vs. - 56.4 ± 84.9%, p < 0.0001, 20.7 ± 49.8% vs. - 9.2 ± 20.6%, p = 0.0247, respectively). Interestingly, the improvements we observed were predominantly in the patients with LAD CTO rather than those with RCA or LCx CTO. Successful CTO PCI was able to reduce myocardial ischemia and improve the cardiac function when the patency after CTO PCI was maintained, with the most notable significance in the patients with LAD CTO.
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Circulación Coronaria , Oclusión Coronaria/terapia , Imagen de Perfusión Miocárdica , Intervención Coronaria Percutánea , Tomografía Computarizada de Emisión de Fotón Único , Adenosina/administración & dosificación , Anciano , Enfermedad Crónica , Oclusión Coronaria/diagnóstico por imagen , Oclusión Coronaria/fisiopatología , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recuperación de la Función , Recurrencia , Sistema de Registros , Estudios Retrospectivos , Volumen Sistólico , Resultado del Tratamiento , Grado de Desobstrucción Vascular , Vasodilatadores/administración & dosificación , Función Ventricular IzquierdaRESUMEN
Patients with ischemic heart disease are administered a dual antiplatelet therapy after percutaneous coronary intervention. This consists of aspirin and thienopyridine, which can be switched from prasugrel to clopidogrel. However, the impact of switching is unknown. This study aimed to determine the efficacy and safety of switching from prasugrel to clopidogrel in Japanese patients. One-hundred and thirty-six patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention and patients with coronary artery disease requiring elective coronary stenting were enrolled. Patients were randomly assigned into the following groups: prasugrel for 6 weeks at loading/maintenance doses of 20/3.75 mg (Continued Group; n = 68) or prasugrel at 20/3.75 mg for 2 weeks followed by clopidogrel at 75 mg for 4 weeks (Switched Group; n = 68). Aspirin (loading dose/maintenance dose 324/81-100 mg/day) was coadministered in both groups. The primary endpoint was the mean P2Y12 reaction unit (PRU) at week 6 and the secondary endpoint was the PRU in groups subdivided based on the presence of CYP2C19 gene polymorphisms. At week 6, the PRU was significantly lower in the Continued Group relative to the Switched Group (140.7 and 183.0, respectively; P < 0.001), which was also evident after correction with the baseline values (144.1 vs. 176.6, respectively; P = 0.005). Extensive and poor metabolizers in the Switched Group, based on CYP2C19 gene polymorphisms, had significantly higher PRU values than those in the Continued Group. Thus, switching treatments from prasugrel to clopidogrel significantly increased the PRU in patients receiving antiplatelet therapy subsequent to percutaneous coronary intervention. Clinical Trial Registration UMIN ID, UMIN000015122.
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Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/cirugía , Inhibidores de Agregación Plaquetaria/administración & dosificación , Clorhidrato de Prasugrel/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Ticlopidina/análogos & derivados , Anciano , Aspirina/administración & dosificación , Clopidogrel , Citocromo P-450 CYP2C19/genética , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Polimorfismo Genético , Implantación de Prótesis , Receptores Purinérgicos/efectos de los fármacos , Stents , Ticlopidina/administración & dosificaciónRESUMEN
Access site problems often cause serious complications in endovascular treatment. The aim of this study is to investigate whether a sheath-less nitinol stenting technique leads to reduce access site complications. This study was a single-center retrospective analysis of a prospectively maintained database. The study enrolled consecutive 98 patients with 111 lesions undergoing provisional stenting for de novo iliac artery or femoro-popliteal artery stenosis between August 2010 and November 2011. The patients were divided into two groups, a conventional procedure group and a sheath-less procedure group. The outcomes of this study were peri-procedural access site complications, initial success rate, procedure time, hemostatic time and bed-rest time. Forty-four lesions in 39 patients that treated using the sheath-less nitinol stent delivery technique were compared with 67 lesions in 59 patients treated using the conventional procedure. All procedures were successful. The incidence of pseudoaneurysm was significantly lower in the sheath-less procedure group than in the conventional procedure group (p = 0.043). However, there were no significant differences in any other complications. No significant difference was observed in the procedural time (p = 0.309). However, hemostatic time and bed-rest time were significantly shorter in the sheath-less procedure than in the conventional procedure (p < 0.0001). A sheath-less stenting technique reduced the access site incidence of pseudoaneurysm and did not increase other access site complications. Besides, this technique shortened hemostatic time and bed-rest time. The sheath-less stenting technique is considered to be a useful method for endovascular treatment.
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Aleaciones , Angioplastia de Balón/instrumentación , Arteria Femoral , Arteria Ilíaca , Enfermedad Arterial Periférica/terapia , Arteria Poplítea , Stents , Anciano , Anciano de 80 o más Años , Procedimientos Endovasculares , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Platypnea-orthodeoxia syndrome (POS) is a rare clinical condition defined by the presence of dyspnea and deoxygenation accompanying changing from a supine to an upright position. We experienced the case of a 75-year-old woman who developed severe acute dyspnea after a car accident. Detailed history taking and a physical examination offered important clues that helped to make an accurate diagnosis of POS. The mechanism of onset is unique and rare; however, it is important for clinical cardiologists to keep this possibility in mind when making a differential diagnosis.
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Accidentes de Tránsito , Disnea/diagnóstico , Foramen Oval Permeable/diagnóstico , Hipoxia/diagnóstico , Fracturas de la Columna Vertebral/diagnóstico , Vértebras Torácicas/lesiones , Anciano , Disnea/etiología , Femenino , Foramen Oval Permeable/complicaciones , Humanos , Hipoxia/etiología , Postura/fisiología , Fracturas de la Columna Vertebral/complicaciones , SíndromeRESUMEN
AIM: It has been shown that the calcium antagonist nifedipine upregulates superoxide dismutase (SOD). Although the peroxisome proliferator-activated receptor (PPAR) response element is located in the promoter region of Cu/ZnSOD, it remains unclear whether nifedipine upregulates PPARs and inhibits vascular remodeling. We hypothesthized that nifedipine activates PPARgamma, inhibits vascular remodeling, and improves vascular function in hypertension. METHODS: Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with vehicle, nifedipine, and PPARgamma selective antagonist GW9662 with nifedipine. RESULTS: Systolic blood pressure in the three SHRSP groups was higher (p <0.01), and the left ventricular weight/body weight ratio was greater (p <0.01) than in the Wistar-Kyoto rat (WKY) group with no differences observed among the three SHRSP groups. In the SHRSP heart, nifedipine significantly inhibited intramyocardial arterial remodeling and perivascular fibrosis, and reduced oxidative stress, while it significantly restored adiponectin and the smooth muscle cell (SMC) phenotype, and selectively restored PPARgamma and Cu/ZnSOD expression/activities to their levels in the WKY rat heart. Furthermore, nifedipine induced a dose-dependent increase in PPARgamma expression in cultured vascular SMCs. These effects of nifedipine were completely abolished by the co-administration of GW9662 with nifedipine. Nifedipine treatment significantly improved acetylcholine-induced relaxation by 27% compared with the vehicle SHRSP group, but it was still significantly impaired by 20% compared with the WKY group. CONCLUSIONS: Nifedipine may inhibit vascular remodeling and improve vascular function by selective activation of PPARgamma through the activation of Cu/ZnSOD in hypertension.
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Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Nifedipino/uso terapéutico , PPAR gamma/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Superóxido Dismutasa/metabolismo , Anilidas/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/metabolismo , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión/metabolismo , Hipertensión/patología , Immunoblotting , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Estrés Oxidativo , PPAR gamma/antagonistas & inhibidores , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Superóxidos/metabolismoRESUMEN
Reactive oxygen species-scavenging enzyme Cu/Zn superoxide dismutase (SOD) regulated by peroxisome proliferator-activated receptors (PPARs) plays an important role in vascular responsiveness. However, it remains unknown whether statin restores vascular dysfunction through the activation of reactive oxygen species-scavenging enzymes in vivo. We hypothesized that pitavastatin restores vascular function by modulating oxidative stress through the activation of Cu/ZnSOD and PPAR-gamma in hypercholesterolemia. New Zealand White male rabbits were fed either normal chow or a 1% cholesterol (CHO) diet for 14 wk. After the first 7 wk, the CHO-fed rabbits were further divided into three groups: those fed with CHO feed only (HC), those additionally given pitavastatin, and those additionally given an antioxidant, probucol. The extent of atherosclerosis was assessed by examining aortic stiffness. When compared with the HC group, both the pitavastatin and probucol groups showed improved aortic stiffness by reducing aortic levels of reactive oxidative stress, nitrotyrosine, and collagen, without affecting serum cholesterol or blood pressure levels. Pitavastatin restored both Cu/ZnSOD activity (P < 0.005) and PPAR-gamma expression and activity (P < 0.01) and inhibited NAD(P)H oxidase activity (P < 0.0001) in the aorta, whereas probucol inhibited NAD(P)H oxidase activity more than did pitavastatin (P < 0.0005) without affecting Cu/ZnSOD activity or PPAR-gamma expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR-gamma activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR-gamma may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.
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Hipercolesterolemia , Estrés Oxidativo/fisiología , PPAR gamma/metabolismo , Probucol/farmacología , Quinolinas/farmacología , Superóxido Dismutasa/metabolismo , Animales , Anticolesterolemiantes/farmacología , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Elasticidad/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Inmunohistoquímica , Masculino , Estrés Oxidativo/efectos de los fármacos , ConejosRESUMEN
Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.
Asunto(s)
Amlodipino/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Enalapril/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Antihipertensivos/farmacología , Aorta Torácica/citología , Diferenciación Celular , Masculino , Miocitos del Músculo Liso/citología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cilazapril/farmacología , Hipertensión/tratamiento farmacológico , Imidazoles/farmacología , Piridinas/farmacología , Superóxido Dismutasa/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/metabolismo , Masculino , Miocardio/enzimología , Estrés Oxidativo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Accidente Cerebrovascular/metabolismoRESUMEN
Recent studies have shown that angiotensin II type 1 (AT1) receptor-mediated Akt activation induces vascular smooth muscle cell (VSMC) dedifferentiation in vitro. However, the critical signal transductions affecting the VSMC phenotype remain unclear in vivo. We examined whether signal transduction through AT1 receptor-mediated reactive oxygen species (ROS) could regulate the VSMC phenotype in stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs were randomized and treated for 6 weeks with a vehicle, an ACE inhibitor cilazapril, or an AT1 receptor antagonist E4177. The 2 drugs showed equipotent effects on the blood pressure, aortic morphology, and collagen deposition. Both drugs also significantly reduced aortic NAD(P)H oxidase activity and p38MAPK and ERK expression, whereas p-Akt, eNOS, and SM2 were significantly increased in SHRSP aortas. Furthermore, E4177 was more effective than cilazapril at inducing VSMC differentiation by reducing NAD(P)H oxidase activity, and up-regulating p-Akt, eNOS, and SM2. Thus, an ACE inhibitor and an AT1 receptor antagonist inhibited VSMC dedifferentiation through inhibition of NAD(P)H oxidase activity and up-regulation of eNOS and Akt in SHRSP aortas, suggesting that in contrast to the in vitro experiments, AT1 receptor-mediated NAD(P)H oxidase-generated ROS, eNOS, and Akt might be crucial determinants for the VSMC phenotype in hypertension in vivo.
Asunto(s)
Diferenciación Celular/fisiología , Hipertensión/metabolismo , Músculo Liso Vascular/citología , Óxido Nítrico Sintasa/biosíntesis , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Animales , Masculino , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintasa/fisiología , Óxido Nítrico Sintasa de Tipo III , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Regulación hacia Arriba/fisiologíaRESUMEN
Recent studies have suggested that the calcium antagonists have an antiatherogenic antioxidant property. The effects of the calcium antagonists on reactive oxygen species (ROS)-related enzymes, however, remain unknown. We hypothesized that the calcium antagonists inhibit oxidative stress in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) through the ROS-scavenging enzymes known as superoxide dismutases (SODs). Male 12-week-old Wister-Kyoto rats (WKY) and SHRSP were used for the study. SHRSP were randomized and treated for 6 weeks with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). NAD(P)H oxidase activity was measured by a luminescence assay, and SOD activity was measured spectrophotometrically. Protein expressions were analyzed by immunoblots. Both drugs showed equipotent effects on systolic blood pressure, left ventricular hypertrophy and fibrosis, the wall-to-lumen ratio, the manganese SOD activity, ROS, and the endothelial NO synthase expression in the SHRSP hearts. Furthermore, amlodipine significantly restored copper/zinc-containing SOD (Cu/ZnSOD) expression and its activity in SHRSP hearts to a level equal to that of WKY more effectively than did enalapril (p <0.05), whereas enalapril downregulated NAD(P)H oxidase activity more than did amlodipine (p <0.05) in the SHRSP hearts. Furthermore, amlodipine restored Cu/ZnSOD expression and its activity in SHRSP hearts to a level equal to that in WKY hearts, and this restoration was significantly more effective than that by enalapril (p <0.05); on the other hand, enalapril induced a greater downregulation of NAD(P)H oxidase activity in SHRSP hearts than did amlodipine (p <0.05). Thus, amlodipine may inhibit vascular remodeling and oxidative stress in the SHRSP heart by efficiently upregulating Cu/ZnSOD, suggesting that the calcium antagonist may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension.