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Mild hypothermia (MH) and retroperfusion are 2 techniques proposed to reduce infarct size due to myocardial infarction. The authors evaluated the effects of focal MH combined with selective coronary venous autoretroperfusion (SARP) as an acute cardioprotective modality before percutaneous coronary intervention (PCI) in a swine model of left ventricular myocardial infarction. Significant reduction in infarct size with preservation of cardiac function and cardiomyocyte viability were achieved. The authors propose that SARP alone or in combination with MH may provide a clinically relevant percutaneous short-term option of cardiac support to high-risk patients undergoing PCI.
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BACKGROUND: Proper vessel sizing during endovascular interventions is crucial to avoid adverse procedural and clinical outcomes. LumenRECON (LR) is a novel, nonimaging, 0.035-inch wire-based technology that uses the physics-based principle of Ohm's law to provide a simple, real-time luminal size while also providing a platform for therapy delivery. This study evaluated the accuracy, reliability, and safety of the LR system in patients presenting for a femoropopliteal artery intervention. METHODS AND RESULTS: This multicenter, prospective pilot study of 24 patients presenting for peripheral intervention compared LR measurements of femoropopliteal artery size to angiographic visual estimation, duplex ultrasound, quantitative angiography, and intravascular ultrasound. The primary effectiveness and safety end point was comparison against core laboratory adjudicated intravascular ultrasound values and major adverse events, respectively. Additional preclinical studies were also performed in vitro and in vivo in swine to determine the accuracy of the LR guidewire system. No intra- or postprocedure device-related adverse events occurred. A balloon or stent was successfully delivered in 12 patients (50%) over the LR wire. Differences in repeatability between successive LR measurements was 2.5±0.40% (R2=0.96) with no significant bias. Differences in measurements of LR to other modalities were 0.5±1.7%, 5.0±1.8%, -1.5±2.0%, and 6.8±3.4% for intravascular ultrasound core laboratory, quantitative angiography, angiographic, and duplex ultrasound, respectively. CONCLUSIONS: This study demonstrates that through a physics-based principle, LR provides a real-time, safe, reproducible, and accurate vessel size of the femoropopliteal artery during intervention and can additionally serve as a conduit for therapy delivery over its wire-based platform.
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Cateterismo Periférico/instrumentación , Procedimientos Endovasculares/instrumentación , Arteria Femoral/cirugía , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/cirugía , Arteria Poplítea/cirugía , Dispositivos de Acceso Vascular , Anciano , Angiografía , Animales , Toma de Decisiones Clínicas , Impedancia Eléctrica , Diseño de Equipo , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Modelos Animales , Selección de Paciente , Enfermedad Arterial Periférica/fisiopatología , Proyectos Piloto , Arteria Poplítea/diagnóstico por imagen , Arteria Poplítea/fisiopatología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Sus scrofa , Ultrasonografía Doppler Dúplex , Ultrasonografía Intervencional , Estados UnidosRESUMEN
Although the clinical range of interventions for coronary arteries is about 2 to 5 mm, the range of diameters of peripheral vasculature is significantly larger (about 10 mm for human iliac artery). When the vessel diameter is increased, the spacing between excitation electrodes on a conductance sizing device must also increase to accommodate the greater range of vessel diameters. The increase in the excitation electrodes distance, however, causes higher parallel conductance or current losses outside of artery lumen. We have previously shown that the conductance catheter/guidewire excitation electrode distances affects the measurement accuracy for the peripheral artery lumen sizing. Here, we propose a simple solution that varies the detection electrode distances to compensate for parallel conductance losses. Computational models were constructed to simulate the conductance guidewire with various electrodes spacing combinations over a range of peripheral artery lumen diameters and surrounding tissue electrical conductivities. The results demonstrate that the measurement accuracy may be significantly improved by increased detection spacing. Specifically, an optimally configured detection/excitation spacing (i.e., 5-5-5 or an equidistant electrode interval with a detection-to-excitation spacing ratio of 0.3) was shown to accurately predict the lumen diameter (i.e., -10% < error < 10%) over a broad range of peripheral artery dimensions (4 mm < diameter < 10 mm). The computational results were substantiated with both ex-vivo and in-vivo measurements of peripheral arteries. The present results support the accuracy of the conductance technique for measurement of peripheral reference vessel diameter.
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Vasos Sanguíneos/anatomía & histología , Catéteres , Vasos Coronarios/anatomía & histología , Animales , Aterosclerosis , Cateterismo/instrumentación , Simulación por Computador , Conductividad Eléctrica , Electrodos , Diseño de Equipo , Humanos , Arteria Ilíaca , Masculino , Modelos Cardiovasculares , Modelos Teóricos , Enfermedad Arterial Periférica/terapia , Reproducibilidad de los Resultados , PorcinosRESUMEN
BACKGROUND: Efforts to treat chronic venous insufficiency have focused on the development of prosthetic venous valves. The role of prosthetic valve-to-vessel size matching has not been determined. The purpose of this investigation was to assess the effect of size mismatching on venous valve function and to establish a mismatch limit that affects valve hemodynamic performance and venous wall stress to improve future valve designs and implants. METHODS: Flow dynamics of prosthetic venous valves were studied in vitro using a pulse duplicator flow loop. Valve performance based on flow rate and pressure measurements was determined at oversizing ratios ranging from 4.2% to 25%. Valve open area ratios at different size mismatching ratios were investigated by image analysis. Finally, a wall stress analysis was used to determine the magnitude of circumferential (hoop) stress in the venous wall at various degrees of oversizing. RESULTS: Our findings indicate that valve regurgitate volume, closing time, and pressure difference across the valve are significantly elevated at mismatch ratios greater than â¼15%. This is supported by increases in regurgitate velocity and open area relative to valves tested at near-nominal diameters. At this degree of size mismatch, the wall stress is increased by a factor of two to three times relative to physiologic pressures. CONCLUSIONS: These findings establish a relationship between valve size matching and valve hemodynamic performance, including vessel wall stress, which should be considered in future valve implants. The size of the prosthetic valve should be within 15% of maximum vein size to optimize venous valve hemodynamic performance and to minimize the hoop wall stress.
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Prótesis Vascular , Insuficiencia Venosa/cirugía , Válvulas Venosas/cirugía , Velocidad del Flujo Sanguíneo/fisiología , Humanos , Ensayo de Materiales/métodos , Diseño de Prótesis , Ajuste de Prótesis , Flujo Pulsátil/fisiología , Estrés Mecánico , Venas/patología , Venas/fisiopatología , Venas/cirugía , Insuficiencia Venosa/fisiopatología , Presión Venosa/fisiología , Válvulas Venosas/patología , Válvulas Venosas/fisiopatologíaRESUMEN
AIMS: Percutaneous structural heart therapies, such as mitral value repair, require site-specific transseptal access (TSA). This can be challenging for interventional cardiologists. We describe a TSA catheter (TSAC) that utilises suction for enhanced control and puncture accuracy. Here, we aim to evaluate the safety and efficacy of the device. METHODS AND RESULTS: Ex vivo interatrial septum preparations were dissected from swine (n=8) and diseased human hearts (n=6) to quantify TSAC suction and needle puncture force. TSAC suction was 6.5-fold greater than the opposing needle puncture force, and thus provides sufficient stabilisation for punctures. The safety and efficacy of TSAC was evaluated in a chronic mitral regurgitation swine model (n=10) and compared to a conventional TSA device. MR was induced by disrupting one to three mitral chordae tendineae, and the progression of heart disease was followed for three weeks. During device testing, procedure time and fluoroscopy exposure were not statistically different between devices. TSAC reduced septal displacement from 8.7±0.30 mm to 3.60±0.19 mm (p<0.05) and improved puncture accuracy 1.75-fold. CONCLUSIONS: TSAC provides controlled TSA and improves puncture accuracy, while maintaining procedure time and workflow. These findings provide a strong rationale for a first-in-man study to demonstrate the clinical utility of the device.
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Tabique Interatrial/cirugía , Diseño de Equipo , Tabiques Cardíacos/cirugía , Punciones , Succión , Animales , Cateterismo Cardíaco/instrumentación , Ablación por Catéter/instrumentación , Femenino , Humanos , Masculino , Punciones/métodos , Succión/métodos , PorcinosRESUMEN
There is a significant need for fixed biological tissues with desired structural and material constituents for tissue engineering applications. Here, we introduce the lung ligament as a fixed biological material that may have clinical utility for tissue engineering. To characterize the lung tissue for potential clinical applications, we studied glutaraldehyde-treated porcine pulmonary ligament (n = 11) with multiphoton microscopy (MPM) and conducted biaxial planar experiments to characterize the mechanical property of the tissue. The MPM imaging revealed that there are generally two families of collagen fibers distributed in two distinct layers: The first family largely aligns along the longitudinal direction with a mean angle of θ = 10.7 ± 9.3 deg, while the second one exhibits a random distribution with a mean θ = 36.6 ± 27.4. Elastin fibers appear in some intermediate sublayers with a random orientation distribution with a mean θ = 39.6 ± 23 deg. Based on the microstructural observation, a microstructure-based constitutive law was proposed to model the elastic property of the tissue. The material parameters were identified by fitting the model to the biaxial stress-strain data of specimens, and good fitting quality was achieved. The parameter e0 (which denotes the strain beyond which the collagen can withstand tension) of glutaraldehyde-treated tissues demonstrated low variability implying a relatively consistent collagen undulation in different samples, while the stiffness parameters for elastin and collagen fibers showed relatively greater variability. The fixed tissues presented a smaller e0 than that of fresh specimen, confirming that glutaraldehyde crosslinking increases the mechanical strength of collagen-based biomaterials. The present study sheds light on the biomechanics of glutaraldehyde-treated porcine pulmonary ligament that may be a candidate for tissue engineering.
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Glutaral/farmacología , Ligamentos/efectos de los fármacos , Ligamentos/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Fenómenos Mecánicos/efectos de los fármacos , Porcinos , Animales , Fenómenos Biomecánicos/efectos de los fármacos , Colágeno/metabolismo , Elastina/metabolismo , Ligamentos/fisiología , Pulmón/fisiología , Estrés Mecánico , Ingeniería de Tejidos , Soporte de PesoRESUMEN
Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.
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Circulación Coronaria/fisiología , Vasos Coronarios/metabolismo , Canales de Potasio KCNQ/genética , Comunicación Paracrina/fisiología , Adventicia/metabolismo , Aminopiridinas/farmacología , Animales , Western Blotting , Bradiquinina/farmacología , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/metabolismo , Indoles/farmacología , Canales de Potasio KCNQ/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ3/genética , Bloqueadores de los Canales de Potasio/farmacología , Piridinas/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Porcinos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
OBJECTIVE: The passive properties of the venous wall are important for the compliance function of the venous system. The objective of this study was to quantify the passive biomechanical response and structural growth and remodeling of veins subjected to chronic venous reflux and hypertension. METHODS: To investigate the effects of venous reflux on venous mechanics, the tricuspid valve was injured in a canine model by disrupting the chordae tendineae. The conventional inflation-extension protocol in conjunction with intravascular ultrasound was used to investigate the passive biomechanical response of both control common iliac veins (n = 9 dogs) and common iliac veins subjected to 8 weeks of venous reflux and hypertension (n = 9 dogs). The changes in vein wall thickness and constituent composition were quantified by multiphoton microscopy and histologic evaluation. RESULTS: Biomechanical results indicate that the veins became less compliant when exposed to 8 weeks of chronic venous reflux and hypertension. The mechanical stiffening was found to be associated with a significant increase in wall thickness (P < .05) and collagen-to-elastin ratio (P < .05). After 8 weeks of chronic reflux and hypertension, the circumferential vein wall stress was significantly reduced (P < .05) because of wall thickening, although it was not restored to control levels. CONCLUSIONS: The growth and remodeling of the venous wall reduces the wall stress, but the stress remains higher than at baseline at 8 weeks. The compliance of the veins also decreases because of the increase in wall thickness and remodeling of the microstructure of the venous wall. These findings provide insight into potential adaptations of the venous system in reflux and hypertension.
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Hipertensión , Vena Ilíaca/patología , Insuficiencia Venosa , Animales , Colágeno , Adaptabilidad , Modelos Animales de Enfermedad , Perros , Elastina , Vena Femoral , Estrés MecánicoRESUMEN
BACKGROUND: There is significant interest in a venous prosthesis to replace insufficient valves. The aim of the current study was to select the patients with hemodynamic conditions most likely to benefit from a valve implant. The hypothesis is that the venous valve prosthesis is most suitable for patients with significant reflux, such as in chronic venous insufficiency (CVI), right heart hypertrophy (RHH), and right heart failure (RHF). Conversely, a prosthetic valve is likely to be of least benefit for deep venous thrombosis (DVT) patients with low flow. METHODS: To address this hypothesis, fully coupled fluid and solid mechanics computational models were developed and validated in five acute canine implants. The animal-validated simulations were then carried out for the CVI, RHH, RHF, and DVT patients based on literature hemodynamic data. A mechanical stress ratio of leaflet wall stress to fluid wall shear stress was defined to combine the effects of both fluid mechanics and solid mechanics on leaflet function, for which a lower stress ratio is hemodynamically desirable. RESULTS: The simulation results of mean valve flow velocity and percentage valve opening were found to be within 10% of the measurements in canines. The simulations show that the patients in the CVI classes 4 to 6, RHH patients, and RHF patients may have a significant reduction in stress ratio with virtual implant of a prosthetic valve. The DVT patient simulations demonstrate a minimal reduction in the stress ratio. After thrombus removal where flow is restored, however, the prosthetic valve may be helpful for post-thrombotic patients. CONCLUSIONS: For patient selections of the venous valve prosthesis, the most suitable patients are the CVI classes 4 to 6, RHH, and RHF patients. The least suitable patients are the DVT patients because a valve is not effective under low-flow conditions. The present study demonstrates a physics-based approach to patient selection that can be tested in future clinical trials.
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Modelos Cardiovasculares , Selección de Paciente , Válvulas Venosas , Animales , Velocidad del Flujo Sanguíneo , Perros , Humanos , Estrés MecánicoAsunto(s)
Angioplastia Coronaria con Balón/instrumentación , Cateterismo Cardíaco/instrumentación , Catéteres Cardíacos , Vasos Coronarios , Animales , Cineangiografía , Angiografía Coronaria , Vasos Coronarios/diagnóstico por imagen , Conductividad Eléctrica , Electrodos , Diseño de Equipo , Modelos Animales , Fantasmas de Imagen , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Stents , Sus scrofa , Ultrasonografía IntervencionalRESUMEN
BACKGROUND: Inaccurate aortic valve sizing and selection is linked to paravalvular leakage in transcatheter aortic valve replacement (TAVR). Here, a novel sizing valvuloplasty conductance balloon (SVCB) catheter is shown to be accurate, reproducible, unbiased, and provides real-time tool for aortic valve sizing that fits within the standard valvuloplasty procedure. METHODS AND RESULTS: The SVCB catheter is a valvuloplasty device that uses real-time electrical conductance measurements based on Ohm's Law to size the balloon opposed against the aortic valve at any given inflation pressure. Accuracy and repeatability of the SVCB catheter was performed on the bench in phantoms of known dimension and ex vivo in three domestic swine aortic annuli with comparison to computed tomography (CT) and dilator measurements. Procedural workflow and safety was demonstrated in vivo in three additional domestic swine. SVCB catheter measurements had negligible bias or error for bench accuracy considered as the gold standard (Bias: -0.11 ± 0.26 mm; Error: 1.2%), but greater disagreement in ex vivo versus dilators (Bias: -0.3 ± 1.1 mm; Error: 4.5%), and ex vivo versus CT (Bias: -1.0 ± 1.6 mm; Error: 8.7%). The dilator versus CT accuracy showed similar agreement (Bias: -0.9 ± 1.5 mm; Error: 7.3%). Repeatability was excellent on the bench (Bias: 0.02 ± 0.12 mm; Error: 0.5%) and ex vivo (Bias: -0.4 ± 0.9 mm; Error: 4.6%). In animal studies, the device fit well within the procedural workflow with no adverse events or complications. CONCLUSIONS: Due to the clinical relevance of this accurate, repeatable, unbiased, and real-time sizing measurement, the SVCB catheter may provide a useful tool prior to TAVR. These findings merit a future human study.
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Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Valvuloplastia con Balón/instrumentación , Prótesis Valvulares Cardíacas , Animales , Estenosis de la Válvula Aórtica/diagnóstico , Modelos Animales de Enfermedad , Ecocardiografía Transesofágica , Diseño de Equipo , Diseño de Prótesis , Porcinos , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Determine the influence of passage through the body wall on the properties of lithotripter shock waves (SWs) and the characteristics of the acoustic field of an electromagnetic lithotripter. METHODS: Full-thickness ex vivo segments of pig abdominal wall were secured against the acoustic window of a test tank coupled to the lithotripter. A fiber-optic probe hydrophone was used to measure SW pressures, determine shock rise time, and map the acoustic field in the focal plane. RESULTS: Peak positive pressure on axis was attenuated roughly proportional to tissue thickness-approximately 6% per cm. Irregularities in the tissue path affected the symmetry of SW focusing, shifting the maximum peak positive pressure laterally by as much as â¼2 mm. Within the time resolution of the hydrophone (7-15 ns), shock rise time was unchanged, measuring â¼17-21 ns with and without tissue present. Mapping of the field showed no effect of the body wall on focal width, regardless of thickness of the body wall. CONCLUSIONS: Passage through the body wall has minimal effect on the characteristics of lithotripter SWs. Other than reducing pulse amplitude and having the potential to affect the symmetry of the focused wave, the body wall has little influence on the acoustic field. These findings help to validate laboratory assessment of lithotripter acoustic field and suggest that the properties of SWs in the body are much the same as have been measured in vitro.
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Pared Abdominal/fisiología , Fenómenos Electromagnéticos , Litotricia/métodos , Pared Abdominal/anatomía & histología , Acústica , Animales , Litotricia/instrumentación , Presión , Sus scrofa , PorcinosRESUMEN
OBJECTIVE: This study examined the mechanisms by which H2 S modulates coronary microvascular resistance and myocardial perfusion at rest and in response to cardiac ischemia. METHODS: Experiments were conducted in isolated coronary arteries and in open-chest anesthetized dogs. RESULTS: We found that the H2 S substrate l-cysteine (1-10 mM) did not alter coronary tone of isolated arteries in vitro or coronary blood flow in vivo. In contrast, intracoronary (ic) H2 S (0.1-3 mM) increased coronary flow from 0.49 ± 0.08 to 2.65 ± 0.13 mL/min/g (p < 0.001). This increase in flow was unaffected by inhibition of Kv channels with 4-aminopyridine (p = 0.127) but was attenuated (0.23 ± 0.02-1.13 ± 0.13 mL/min/g) by the KATP channel antagonist glibenclamide (p < 0.001). Inhibition of NO synthesis (l-NAME) did not attenuate coronary responses to H2 S. Immunohistochemistry revealed expression of CSE, an endogenous H2 S enzyme, in myocardium. Inhibition of CSE with ß-cyano-l-alanine (10 µM) had no effect on baseline coronary flow or responses to a 15-second coronary occlusion (p = 0.82). CONCLUSIONS: These findings demonstrate that exogenous H2 S induces potent, endothelial-independent dilation of the coronary microcirculation predominantly through the activation of KATP channels, however, our data do not support a functional role for endogenous H2 S in the regulation of coronary microvascular resistance.
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Circulación Coronaria/efectos de los fármacos , Gasotransmisores/farmacología , Sulfuro de Hidrógeno/farmacología , Microcirculación/efectos de los fármacos , Isquemia Miocárdica , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Perros , Femenino , Masculino , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Miocardio/metabolismoRESUMEN
BACKGROUND: In vivo studies have shown that valves in veins are paired in an orthogonal configuration. The aim of this study is to characterize the flow interaction of paired valves under controlled in vitro bench conditions. METHODS: A bench top in vitro experiment was set up at physiological flow conditions to simulate the flow inside a venous valve. Two bicuspid bioprosthetic valves paired in 0° and 90° orientations were tested in a 12-mm-diameter tube, and the two-dimensional velocity fields around the valve were measured by particle image velocimetry. The distance between the two valves was varied from 3 to 5 cm, and the corresponding velocities and vorticities were determined. RESULTS: Velocity field shows the flow exit from the orthogonal valve-pairing configurations forced the main jet stream to turn to the outer region of the tube. Flow patterns between the valves show significantly less stagnation region from the 90° valve pairing over a 0° valve pairing case. The variation in valves distance shows that the coupling effect of the two valves extends to a range beyond four times of the tube diameter, albeit the ability to alter the flow decreases at larger distances. CONCLUSIONS: The findings suggest that the 90° valve pairing configuration regulates the flow between the valves, and the separation distance affects the hemodynamic efficiency of the two valves by reducing the total reverse flow volume.
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Previous investigations indicate that diminished functional expression of voltage-dependent K(+) (KV) channels impairs control of coronary blood flow in obesity/metabolic syndrome. The goal of this investigation was to test the hypothesis that KV channels are electromechanically coupled to CaV1.2 channels and that coronary microvascular dysfunction in obesity is related to subsequent increases in CaV1.2 channel activity. Initial studies revealed that inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM) increased intracellular [Ca(2+)], contracted isolated coronary arterioles and decreased coronary reactive hyperemia. These effects were reversed by blockade of CaV1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of CaV1.2 channels with nifedipine (10 µg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, inhibition of CaV1.2 channels significantly increased coronary blood flow, conductance, and the balance between coronary flow and metabolism in obese swine (P < 0.05). These changes were associated with a ~50 % increase in inward CaV1.2 current and elevations in expression of the pore-forming subunit (α1c) of CaV1.2 channels in coronary smooth muscle cells from obese swine. Taken together, these findings indicate that electromechanical coupling between KV and CaV1.2 channels is involved in the regulation of coronary vasomotor tone and that increases in CaV1.2 channel activity contribute to coronary microvascular dysfunction in the setting of obesity.
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Canales de Calcio Tipo L/metabolismo , Circulación Coronaria/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Canales de Potasio/metabolismo , Animales , Hemodinámica/fisiología , PorcinosRESUMEN
Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.
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Diabetes Mellitus Tipo 2/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Péptido 1 Similar al Glucagón/uso terapéutico , Glucosa/metabolismo , Incretinas/farmacología , Incretinas/uso terapéutico , Miocardio/metabolismo , Obesidad/metabolismo , Adulto , Animales , Comorbilidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Modelos Animales de Enfermedad , Femenino , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Condicionamiento Físico Animal/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Descanso/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Porcinos , Resultado del Tratamiento , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: This investigation examined the mechanisms by which coronary perivascular adipose tissue (PVAT)-derived factors influence vasomotor tone and the PVAT proteome in lean versus obese swine. METHODS AND RESULTS: Coronary arteries from Ossabaw swine were isolated for isometric tension studies. We found that coronary (P=0.03) and mesenteric (P=0.04) but not subcutaneous adipose tissue augmented coronary contractions to KCl (20 mmol/L). Inhibition of CaV1.2 channels with nifedipine (0.1 µmol/L) or diltiazem (10 µmol/L) abolished this effect. Coronary PVAT increased baseline tension and potentiated constriction of isolated arteries to prostaglandin F2α in proportion to the amount of PVAT present (0.1-1.0 g). These effects were elevated in tissues obtained from obese swine and were observed in intact and endothelium denuded arteries. Coronary PVAT also diminished H2O2-mediated vasodilation in lean and, to a lesser extent, in obese arteries. These effects were associated with alterations in the obese coronary PVAT proteome (detected 186 alterations) and elevated voltage-dependent increases in intracellular [Ca(2+)] in obese smooth muscle cells. Further studies revealed that the Rho-kinase inhibitor fasudil (1 µmol/L) significantly blunted artery contractions to KCl and PVAT in lean but not obese swine. Calpastatin (10 µmol/L) also augmented contractions to levels similar to that observed in the presence of PVAT. CONCLUSIONS: Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (eg, calpastatin), Rho-dependent signaling, and the functional contribution of K(+) and CaV1.2 channels to smooth muscle tone.
Asunto(s)
Enfermedad de la Arteria Coronaria/fisiopatología , Grasa Intraabdominal/fisiopatología , Músculo Liso Vascular/fisiopatología , Obesidad/fisiopatología , Vasoconstricción/fisiología , Animales , Peso Corporal/fisiología , Proteínas de Unión al Calcio/farmacología , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/fisiopatología , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Grasa Intraabdominal/patología , Contracción Isométrica/efectos de los fármacos , Contracción Isométrica/fisiología , Arterias Mesentéricas/fisiopatología , Músculo Liso Vascular/patología , Obesidad/patología , Proteómica , Grasa Subcutánea/patología , Grasa Subcutánea/fisiopatología , Sus scrofa , Vasoconstricción/efectos de los fármacosRESUMEN
Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 ± 5 and 105 ± 9 µm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 ± 3 and 31 ± 3 µm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 ± 2 and 30 ± 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 × 10(6) ± 0.7 × 10(6) and 1.1 × 10(6) ± 0.2 × 10(6) dyn/cm(2) in Lean and MetS, respectively, P < 0.001; BSI: 10.3 ± 0.4 and 7.3 ± 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS.
Asunto(s)
Circulación Coronaria/fisiología , Vasos Coronarios/fisiopatología , Síndrome Metabólico/fisiopatología , Microvasos/fisiopatología , Obesidad/fisiopatología , Animales , Velocidad del Flujo Sanguíneo/fisiología , Colágeno/metabolismo , Vasos Coronarios/metabolismo , Elastina/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Microvasos/metabolismo , Obesidad/metabolismo , PorcinosRESUMEN
Large conductance, Ca(2+)/voltage-sensitive K(+) channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Iberiotoxin is considered the "gold standard" antagonist, but cost and membrane-impermeability limit its usefulness. Economical and membrane-permeable alternatives could facilitate the study of BK channels. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascular function in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo α or α + ß1 were blocked >95% by penitrem A (IC(50) 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K(+) currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K(+) currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent K(ATP) current. Penitrem A enhanced the sensitivity to K(+)-induced contraction in canine coronary arteries by 23 ± 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 ± 11% (p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro) studies as well as anesthetized animal (in vivo) experiments.
Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/antagonistas & inhibidores , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Micotoxinas/farmacología , Miocitos del Músculo Liso/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Línea Celular Transformada , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiología , Perros , Células HEK293 , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Péptidos/farmacología , Fenilefrina/farmacología , Potasio/metabolismo , Porcinos , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K(+) (K(V)) and Ca(2+) (Ca(V)1.2) channels play a critical role in coronary pressure-flow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of K(V) channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 µg/min, ic). 4AP significantly decreased vasodilatory responses to H(2)O(2) (0.3-10 µM, ic) and coronary flow at CPPs = 60-140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 ± 0.11 control vs. 0.46 ± 0.06 4-AP). In contrast, inhibition of Ca(V)1.2 channels progressively increased coronary blood flow at CPPs > 80 mmHg and substantially diminished coronary Gc to -0.20 ± 0.11 (P < 0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) K(V) channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of Ca(V)1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.