RESUMEN
Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial 'Ischemia and No Obstructive Coronary Artery disease' (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction-achieved despite reduced capillary density-resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA.
Asunto(s)
Diabetes Mellitus Experimental/sangre , Hipercolesterolemia/sangre , Isquemia Miocárdica/sangre , Miocardio/metabolismo , Consumo de Oxígeno , Oxígeno/sangre , Insuficiencia Renal Crónica/sangre , Animales , Biomarcadores/sangre , Comorbilidad , Circulación Coronaria , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Modelos Animales de Enfermedad , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Hemodinámica , Hipercolesterolemia/complicaciones , Hipercolesterolemia/fisiopatología , Isquemia Miocárdica/etiología , Isquemia Miocárdica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Sus scrofa , Función Ventricular IzquierdaRESUMEN
KEY POINTS: Passive, isolated post-capillary pulmonary hypertension (PH) secondary to left heart disease may progress to combined pre- and post-capillary or 'active' PH This 'activation' of post-capillary PH significantly increases morbidity and mortality, and is still incompletely understood. In this study, pulmonary vein banding gradually produced post-capillary PH with structural and functional microvascular remodelling in swine. Ten weeks after banding, the pulmonary endothelin pathway was upregulated, likely contributing to pre-capillary aspects in the initially isolated post-capillary PH. Inhibition of the endothelin pathway could potentially stop the progression of early stage post-capillary PH. ABSTRACT: Passive, isolated post-capillary pulmonary hypertension (IpcPH) secondary to left heart disease may progress to combined pre- and post-capillary or 'active' PH (CpcPH) characterized by chronic pulmonary vascular constriction and remodelling. The mechanisms underlying this 'activation' of passive pulmonary hypertension (PH) remain incompletely understood. Here we investigated the role of the vasoconstrictor endothelin-1 (ET) in the progression from IpcPH to CpcPH in a swine model for post-capillary PH. Swine underwent pulmonary vein banding (PVB; n = 7) or sham-surgery (Sham; n = 6) and were chronically instrumented 4 weeks later. Haemodynamics were assessed for 8 weeks, at rest and during exercise, before and after administration of the ET receptor antagonist tezosentan. After sacrifice, the pulmonary vasculature was investigated by histology, RT-qPCR and myograph experiments. Pulmonary arterial pressure and resistance increased significantly over time. mRNA expression of prepro-endothelin-1 and endothelin converting enzyme-1 in the lung was increased, while ETA expression was unchanged and ETB expression was downregulated. This was associated with increased plasma ET levels from week 10 onward and a more pronounced vasodilatation to in vivo administration of tezosentan at rest and during exercise. Myograph experiments showed decreased endothelium-dependent vasodilatation to Substance P and increased vasoconstriction to KCl in PVB swine consistent with increased muscularization observed with histology. Moreover, maximal vasoconstriction to ET was increased whereas ET sensitivity was decreased. In conclusion, PVB swine gradually developed PH with structural and functional vascular remodelling. From week 10 onward, the pulmonary ET pathway was upregulated, likely contributing to pre-capillary activation of the initially isolated post-capillary PH. Inhibition of the ET pathway could thus potentially provide a pharmacotherapeutic target for early stage post-capillary PH.
Asunto(s)
Endotelinas/metabolismo , Hipertensión Pulmonar/metabolismo , Microvasos/metabolismo , Animales , Regulación hacia Abajo , Endotelinas/genética , Endotelio Vascular/metabolismo , Femenino , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Pulmón/irrigación sanguínea , Masculino , Microvasos/efectos de los fármacos , Microvasos/fisiopatología , Piridinas/farmacología , Porcinos , Tetrazoles/farmacología , Vasodilatadores/farmacología , Disfunción Ventricular Izquierda/complicacionesRESUMEN
Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O2) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O2 delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility (Ees and dP/dtmax) were higher in PH compared with control with preserved cardiac index and RV O2 delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/dtmax, and end-systolic elastance (Ees), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O2 delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O2 content was not significantly altered in PH. Moreover, RV O2 delivery reserve correlated with RV functional reserve, Δcardiac index (r2 = 0.85), ΔdP/dtmax (r2 = 0.49), and ΔEes (r2 = 0.70), all P < 0.05. The inability to sufficiently increase RV O2 supply to meet the increased O2 demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH.NEW & NOTEWORTHY Impaired right ventricular (RV) O2 delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O2 delivery.
Asunto(s)
Tolerancia al Ejercicio , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/fisiopatología , Consumo de Oxígeno , Oxígeno/sangre , Esfuerzo Físico , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Factores de Edad , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/sangre , Masculino , Sus scrofa , Disfunción Ventricular Derecha/sangre , Presión VentricularRESUMEN
Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor Nω-nitro-l-arginine methyl ester until 2 wk before the end of study. Swine were subjected to exercise, and the pulmonary vasculature was investigated by hemodynamic, histological, quantitative PCR, and myograph experiments. In swine with CTEPH, the increased right-ventricular afterload, decreased cardiac index, and mild ventilation-perfusion-mismatch were exacerbated during exercise. Pulmonary microvascular remodeling was evidenced by increased muscularization, which was accompanied by an increased maximal vasoconstriction. Although ET-1-induced vasoconstriction was increased in CTEPH pulmonary small arteries, the ET-1 sensitivity was decreased. Moreover, the contribution of the ETA receptor to ET-1 vasoconstriction was increased, whereas the contribution of the ETB receptor was decreased and the contribution of Rho-kinase was lost. A reduction in endogenous NO production was compensated in part by a decreased phosphodiesterase 5 (PDE5) activity resulting in an apparent increased NO sensitivity in CTEPH pulmonary small arteries. These findings suggest that pulmonary microvascular remodeling with a reduced activity of PDE5 and Rho-kinase may contribute to the lack of therapeutic efficacy of PDE5 inhibitors and Rho-kinase inhibitors in CTEPH.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Pulmón/fisiopatología , Microvasos/fisiopatología , Embolia Pulmonar/fisiopatología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Endotelina-1/metabolismo , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Microvasos/metabolismo , Óxido Nítrico/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/fisiología , Embolia Pulmonar/metabolismo , Porcinos , Vasoconstricción/fisiología , Quinasas Asociadas a rho/metabolismoRESUMEN
Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be beneficial for PH secondary to MI. Nitric oxide (NO) is an important activator of cGMP synthesis and can be enhanced in early PH and decreased in severe PH. In the present study, we investigated if PDE5 inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential. The PDE5 inhibitor EMD360527 was administered in awake, chronically instrumented swine with or without MI. At rest, PDE5 inhibition produced pulmonary vasodilation as evidenced by a decrease in pulmonary vascular resistance, which was more pronounced in MI ( n = 5) compared with normal swine ( n = 10, P ≤ 0.01) and was accompanied by an increase in stroke volume in MI swine. Both pulmonary vasodilation and increased stroke volume were maintained during exercise, suggesting that this therapy may improve exercise capacity in patients with PH secondary to MI. Interestingly, prior inhibition of NO significantly enhanced ( P ≤ 0.01) pulmonary vasodilation by PDE5 inhibition in both normal ( n = 8) and MI swine ( n = 5, P ≤ 0.05 vs. normal). This suggests that the increased vasodilator responses to PDE5 inhibition after MI were not due to an increase in NO-induced cGMP production. These observations indicate that PDE5 inhibition represents an interesting pharmacotherapeutic approach in early PH after a recent MI to prevent overt PH. NEW & NOTEWORTHY This research article is the first to describe that pulmonary vasodilation to phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in resting and exercising swine with pulmonary hypertension as a result of myocardial infarction. This suggests that phosphodiesterase 5 inhibition can normalize pulmonary hemodynamics in postcapillary pulmonary hypertension after a recent myocardial infarction and may improve exercise capacity.
Asunto(s)
Antihipertensivos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Óxido Nítrico/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Arteria Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Presión Arterial/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Masculino , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Arteria Pulmonar/enzimología , Arteria Pulmonar/fisiopatología , Transducción de Señal/efectos de los fármacos , Sus scrofa , Resistencia Vascular/efectos de los fármacosRESUMEN
Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of patients after pulmonary embolism and is accompanied by an impaired exercise tolerance, which is ascribed to the increased right ventricular (RV) afterload in combination with a ventilation/perfusion (V/Q) mismatch in the lungs. The present study aimed to investigate changes in arterial Po2 and hemodynamics in response to graded treadmill exercise during development and progression of CTEPH in a novel swine model. Swine were chronically instrumented and received multiple pulmonary embolisms by 1) microsphere infusion (Spheres) over 5 wk, 2) endothelial dysfunction by administration of the endothelial nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) for 7 wk, 3) combined pulmonary embolisms and endothelial dysfunction (L-NAME + Spheres), or 4) served as sham-operated controls (sham). After a 9 wk followup, embolization combined with endothelial dysfunction resulted in CTEPH, as evidenced by mean pulmonary artery pressures of 39.5 ± 5.1 vs. 19.1 ± 1.5 mmHg (Spheres, P < 0.001), 22.7 ± 2.0 mmHg (L-NAME, P < 0.001), and 20.1 ± 1.5 mmHg (sham, P < 0.001), and a decrease in arterial Po2 that was exacerbated during exercise, indicating V/Q mismatch. RV dysfunction was present after 5 wk of embolization, both at rest (trend toward increased RV end-systolic lumen area, P = 0.085, and decreased stroke volume index, P = 0.042) and during exercise (decreased stroke volume index vs. control, P = 0.040). With sustained pulmonary hypertension, RV hypertrophy (Fulton index P = 0.022) improved RV function at rest and during exercise, but this improvement was insufficient in CTEPH swine to result in an exercise-induced increase in cardiac index. In conclusion, embolization in combination with endothelial dysfunction results in CTEPH in swine. Exercise increased RV afterload, exacerbated the V/Q mismatch, and unmasked RV dysfunction. NEW & NOTEWORTHY Here, we present the first double-hit chronic thromboembolic pulmonary hypertension swine model. We show that embolization as well as endothelial dysfunction is required to induce sustained pulmonary hypertension, which is accompanied by altered exercise hemodynamics and an exacerbated ventilation/perfusion mismatch during exercise.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/fisiopatología , Esfuerzo Físico , Arteria Pulmonar/fisiopatología , Embolia Pulmonar/fisiopatología , Remodelación Vascular , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Remodelación Ventricular , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Masculino , Arteria Pulmonar/metabolismo , Embolia Pulmonar/complicaciones , Embolia Pulmonar/metabolismo , Sus scrofa , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismoRESUMEN
Pulmonary vascular disease (PVD) represents an underestimated and increasing clinical burden not only in the neonatal period but also later in life, when exercise tolerance is decreased. Animal models performing long-term followup after a perinatal insult are lacking. This study aimed to develop and characterize a neonatal swine model with hypoxia-induced PVD during long-term followup after reexposure to normoxia and to investigate the exercise response in this model. Piglets were exposed to a normoxic ( n = 10) or hypoxic environment ( n = 9) for 4 wk. Neonatal hypoxia exposure resulted in pulmonary hypertension. Mean pulmonary artery pressure was elevated 1 day after reexposure to normoxia (30.2 ± 3.3 vs. 14.3 ± 0.9 mmHg) and remained significantly higher in the second week (32.8 ± 3.8 vs. 21.4 ± 1.2 mmHg), accompanied by decreased exercise tolerance. Exercise resulted in a trend toward an exaggerated increase of pulmonary artery pressure in hypoxia-exposed animals ( week 6, P = 0.086). Although pulmonary hypertension was transient, thickening of pulmonary arterioles was found at the end of followup. Furthermore, right ventricular dilation, lower right ventricular fractional area change ( week 8, 40.0 ± 2.7% vs. 29.5 ± 4.7%), and tricuspid annular plane systolic excursion ( week 8, 27.0 ± 2.5 vs. 22.9 ± 2.1 mm) persisted during followup. Male animals showed more severe PVD than female animals. In conclusion, we developed a neonatal swine model that allows examination of the long-term sequelae of damage to the developing neonatal lung, the course of the disease and the effect of therapy on long-term outcome. NEW & NOTEWORTHY The swine model of neonatal pulmonary vascular disease developed in the present study is the first that allows exercise testing and examination of long-term sequelae of a perinatal hypoxic insult, the course of the disease, and the effect of therapy on long-term outcome.
Asunto(s)
Presión Arterial , Hiperoxia/complicaciones , Hipertensión Pulmonar/etiología , Arteria Pulmonar/fisiopatología , Remodelación Vascular , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ecocardiografía , Tolerancia al Ejercicio , Femenino , Hiperoxia/patología , Hiperoxia/fisiopatología , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/patología , Factores Sexuales , Sus scrofa , Factores de Tiempo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular DerechaRESUMEN
Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (â¼300-µm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/l) compared with HFD (5.1 ± 0.4 mmol/l) and Normal (5.8 ± 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/l) and HFD (18.1 ± 2.6 mmol/l) compared with Normal (2.1 ± 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ETB receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ETB receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Diabetes Mellitus Experimental/fisiopatología , Hipercolesterolemia/fisiopatología , Microvasos/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Bradiquinina/farmacología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa , Endotelina-1/farmacología , Hipercolesterolemia/complicaciones , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Masculino , Microvasos/metabolismo , Microvasos/patología , Microvasos/fisiopatología , Óxido Nítrico/metabolismo , Placa Aterosclerótica/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , S-Nitroso-N-Acetilpenicilamina/farmacología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Sus scrofa , Porcinos , Vasoconstricción/fisiología , Vasodilatación/fisiologíaRESUMEN
Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-µm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.
Asunto(s)
Citocinas/sangre , Microesferas , Infarto del Miocardio/tratamiento farmacológico , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Función Ventricular , Animales , Células Cultivadas , Femenino , Humanos , Masculino , Microvasos/fisiología , Poliésteres/química , Polietilenglicoles/química , Porcinos , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/efectos adversos , Factor A de Crecimiento Endotelial Vascular/farmacocinéticaRESUMEN
The objective of this study was to compare heart-specific fatty acid binding protein (hFABP) and high-sensitivity troponin I (hsTnI) via serial measurements to identify early time points to accurately quantify infarct size and no-reflow in a preclinical swine model of ST-elevated myocardial infarction (STEMI). Myocardial necrosis, usually confirmed by hsTnI or TnT, takes several hours of ischemia before plasma levels rise in the absence of reperfusion. We evaluated the fast marker hFABP compared with hsTnI to estimate infarct size and no-reflow upon reperfused (2 h occlusion) and nonreperfused (8 h occlusion) STEMI in swine. In STEMI (n = 4) and STEMI + reperfusion (n = 8) induced in swine, serial blood samples were taken for hFABP and hsTnI and compared with triphenyl tetrazolium chloride and thioflavin-S staining for infarct size and no-reflow at the time of euthanasia. hFABP increased faster than hsTnI upon occlusion (82 ± 29 vs. 180 ± 73 min, P < 0.05) and increased immediately upon reperfusion while hsTnI release was delayed 16 ± 3 min (P < 0.05). Peak hFABP and hsTnI reperfusion values were reached at 30 ± 5 and 139 ± 21 min, respectively (P < 0.05). Infarct size (containing 84 ± 0.6% no-reflow) correlated well with area under the curve for hFABP (r(2) = 0.92) but less for hsTnI (r(2) = 0.53). At 50 and 60 min reperfusion, hFABP correlated best with infarct size (r(2) = 0.94 and 0.93) and no-reflow (r(2) = 0.96 and 0.94) and showed high sensitivity for myocardial necrosis (2.3 ± 0.6 and 0.4 ± 0.6 g). hFABP rises faster and correlates better with infarct size and no-reflow than hsTnI in STEMI + reperfusion when measured early after reperfusion. The highest sensitivity detecting myocardial necrosis, 0.4 ± 0.6 g at 60 min postreperfusion, provides an accurate and early measurement of infarct size and no-reflow.
Asunto(s)
Circulación Coronaria , Proteínas de Unión a Ácidos Grasos/sangre , Infarto del Miocardio/terapia , Reperfusión Miocárdica/efectos adversos , Miocardio/metabolismo , Fenómeno de no Reflujo/etiología , Troponina I/sangre , Animales , Benzotiazoles , Biomarcadores/sangre , Modelos Animales de Enfermedad , Femenino , Hemodinámica , Masculino , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Necrosis , Fenómeno de no Reflujo/sangre , Fenómeno de no Reflujo/patología , Fenómeno de no Reflujo/fisiopatología , Valor Predictivo de las Pruebas , Factores de Riesgo , Coloración y Etiquetado/métodos , Porcinos , Sales de Tetrazolio , Tiazoles , Factores de Tiempo , Regulación hacia ArribaRESUMEN
The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitroso-redox balance, increased superoxide production-principally due to endothelial nitric oxide synthase (eNOS) uncoupling-reduced nitric oxide (NO) production, alterations in myocardial gene-expression-particularly genes related to glucose and fatty acid metabolism-and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e'. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction. These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetD-induced myocardial changes to prevent the development of overt cardiac failure.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Diástole , Mitocondrias/patología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Animales , Respiración de la Célula , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Hemodinámica , PorcinosRESUMEN
Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature.
RESUMEN
BACKGROUND: We studied the effect of bioresorbable vascular scaffold (BVS) implantation on distal coronary endothelial function, in swine on a high fat diet without (HFD) or with diabetes (DM+HFD). METHODS: Five DM+HFD and five HFD swine underwent BVS implantation on top of coronary plaques, and were studied six months later. Conduit artery segments >5mm proximal and distal to the scaffold and corresponding segments of non-scaffolded coronary arteries, and segments of small arteries within the flow-territory of scaffolded and non-scaffolded arteries were harvested for in vitro vasoreactivity studies. RESULTS: Conduit segments proximal and distal of the BVS edges showed reduced endothelium-dependent vasodilation as compared to control vessels (p≤0.01), with distal segments being most prominently affected(p≤0.01). Endothelial dysfunction was only observed in DM±HFD swine and was principally due to a loss of NO. Endothelium-independent vasodilation and vasoconstriction were unaffected. Surprisingly, segments from the microcirculation distal to the BVS showed enhanced endothelium-dependent vasodilation (p<0.01), whereas endothelium-independent vasodilation and vasoconstriction were unaltered. This enhanced vasorelaxation was only observed in DM+HFD swine, and did not appear to be either NO- or EDHF-mediated. CONCLUSIONS: Six months of BVS implantation in DM+HFD swine causes NO-mediated endothelial dysfunction in nearby coronary segments, which is accompanied by a, possibly compensatory, increase in endothelial function of the distal microcirculation. Endothelial dysfunction extending into coronary conduit segments beyond the implantation-site, is in agreement with recent reports expressing concern for late scaffold thrombosis and of early BVS failure in diabetic patients.
Asunto(s)
Implantes Absorbibles , Vasos Coronarios/cirugía , Diabetes Mellitus/cirugía , Endotelio Vascular/cirugía , Andamios del Tejido , Animales , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Diabetes Mellitus/etiología , Diabetes Mellitus/patología , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Masculino , Porcinos , Resultado del Tratamiento , Vasodilatadores/farmacologíaRESUMEN
Aims: More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results: DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions: The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.
Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Circulación Coronaria , Vasos Coronarios/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Hipercolesterolemia/complicaciones , Hipertensión Renovascular/complicaciones , Microcirculación , Miocardio/metabolismo , Disfunción Ventricular Izquierda/etiología , Función Ventricular Izquierda , Animales , Comorbilidad , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diástole , Femenino , Fibrosis , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatología , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Miocardio/patología , Estrés Oxidativo , Factores de Riesgo , Volumen Sistólico , Sus scrofa , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
It is increasingly recognized that obesity is a risk factor for microvascular disease, involving both structural and functional changes in the microvasculature. This review aims to describe how obesity impacts the microvasculature of a variety of tissues, including visceral adipose tissue, skeletal muscle, heart, brain, kidneys, and lungs. These changes involve endothelial dysfunction, which in turn (i) impacts control of vascular tone, (ii) contributes to development of microvascular insulin resistance, (iii) alters secretion of paracrine factors like nitric oxide and endothelin, but (iv) also influences vascular structure and perivascular inflammation. In concert, these changes impair organ perfusion and organ function thereby contributing to altered release and clearance of neurohumoral factors, such as adipokines and inflammatory cytokines. Global microvascular dysfunction in obese subjects is therefore a common pathway that not only explains exercise-intolerance but also predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and pulmonary hypertension.
Asunto(s)
Tejido Adiposo/irrigación sanguínea , Encéfalo/irrigación sanguínea , Enfermedades Cardiovasculares/fisiopatología , Vasos Coronarios/fisiopatología , Hemodinámica , Riñón/irrigación sanguínea , Pulmón/fisiopatología , Microcirculación , Microvasos/fisiopatología , Músculo Esquelético/irrigación sanguínea , Obesidad/fisiopatología , Adiposidad , Animales , Enfermedades Cardiovasculares/metabolismo , Circulación Cerebrovascular , Circulación Coronaria , Vasos Coronarios/metabolismo , Metabolismo Energético , Humanos , Microvasos/metabolismo , Obesidad/metabolismo , Circulación Pulmonar , Circulación Renal , Transducción de SeñalRESUMEN
BACKGROUND: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. AIM: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. METHODS: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. RESULTS: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. CONCLUSION: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.
Asunto(s)
Implantes Absorbibles/efectos adversos , Aterosclerosis/etiología , Aterosclerosis/patología , Diabetes Mellitus/patología , Neointima/patología , Andamios del Tejido/efectos adversos , Animales , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/metabolismo , Biomarcadores , Biopsia , Colágeno/metabolismo , Vasos Coronarios/patología , Diabetes Mellitus/metabolismo , Modelos Animales de Enfermedad , Masculino , Neointima/metabolismo , Porcinos , Tomografía de Coherencia ÓpticaRESUMEN
This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early cardiopulmonary dysfunction is difficult to diagnose, particularly in animal models, as cardiopulmonary function is often measured invasively, requiring anesthesia. As many anesthetic agents are cardiodepressive, subtle changes in cardiovascular function may be masked. In contrast, chronic instrumentation allows for measurement of cardiopulmonary function in the awake state, so that measurements can be obtained under quiet resting conditions, without the effects of anesthesia and acute surgical trauma. Furthermore, when animals are properly trained, measurements can also be obtained during graded treadmill exercise. Flow probes are placed around the aorta or pulmonary artery for measurement of cardiac output and around the left anterior descending coronary artery for measurement of coronary blood flow. Fluid-filled catheters are implanted in the aorta, pulmonary artery, left atrium, left ventricle and right ventricle for pressure measurement and blood sampling. In addition, a 20 G catheter is positioned in the anterior interventricular vein to allow coronary venous blood sampling. After a week of recovery, swine are placed on a motor-driven treadmill, the catheters are connected to pressure and flow meters, and swine are subjected to a five-stage progressive exercise protocol, with each stage lasting 3 min. Hemodynamic signals are continuously recorded and blood samples are taken during the last 30 sec of each exercise stage. The major advantage of studying chronically instrumented animals is that it allows serial assessment of cardiopulmonary function, not only at rest but also during physical stress such as exercise. Moreover, cardiopulmonary function can be assessed repeatedly during disease development and during chronic treatment, thereby increasing statistical power and hence limiting the number of animals required for a study.