RESUMEN
The right ventricle and its stress response is perhaps the most important arbiter of survival in patients with pulmonary hypertension of many causes. The physiology of the cardiopulmonary unit and definition of right heart failure proposed in the 2018 World Symposium on Pulmonary Hypertension have proven useful constructs in subsequent years. Here, we review updated knowledge of basic mechanisms that drive right ventricular function in health and disease, and which may be useful for therapeutic intervention in the future. We further contextualise new knowledge on assessment of right ventricular function with a focus on metrics readily available to clinicians and updated understanding of the roles of the right atrium and tricuspid regurgitation. Typical right ventricular phenotypes in relevant forms of pulmonary vascular disease are reviewed and recent studies of pharmacological interventions on chronic right ventricular failure are discussed. Finally, unanswered questions and future directions are proposed.
RESUMEN
Rationale: Donor brain death-induced lung injury may compromise graft function after transplantation. Establishing strategies to attenuate lung damage remains a challenge because the underlying mechanisms remain uncertain. Objectives: The effects of tacrolimus pretreatment were evaluated in an experimental model of brain death-induced lung injury. Methods: Brain death was induced by slow intracranial infusion of blood in anesthetized pigs after randomization to tacrolimus (orally administered at 0.25 mg â kg-1 twice daily the day before the experiment and intravenously at 0.05 mg â kg-1 1 h before the experiment; n = 8) or placebo (n = 9) pretreatment. Hemodynamic measurements were performed 1, 3, 5, and 7 hours after brain death. After euthanasia of the animals, lung tissue was sampled for pathobiological and histological analysis, including lung injury score (LIS). Measurements and Main Results: Tacrolimus pretreatment prevented increases in pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary capillary pressure and decreases in systemic arterial pressure and thermodilution cardiac output associated with brain death. After brain death, the ratio of PaO2 to FiO2 decreased, which was prevented by tacrolimus. Tacrolimus pretreatment prevented increases in the ratio of IL-6 to IL-10, VCAM1 (vascular cell adhesion molecule 1), circulating concentrations of IL-1ß, and glycocalyx-derived molecules. Tacrolimus partially decreased apoptosis (Bax [Bcl2-associated X apoptosis regulator]-to-Bcl2 [B-cell lymphoma-2] ratio [P = 0.07] and number of apoptotic cells in the lungs [P < 0.05]) but failed to improve LIS. Conclusions: Immunomodulation through tacrolimus pretreatment prevented pulmonary capillary hypertension as well as the activation of inflammatory and apoptotic processes in the lungs after brain death; however, LIS did not improve.
Asunto(s)
Hipertensión Pulmonar , Lesión Pulmonar , Animales , Muerte Encefálica , Pulmón/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , Porcinos , Tacrolimus/farmacología , Tacrolimus/uso terapéuticoRESUMEN
Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Ventrículos Cardíacos , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar , Estudios Retrospectivos , Disfunción Ventricular Derecha/tratamiento farmacológico , Función Ventricular DerechaRESUMEN
PURPOSE OF THE REVIEW: Tricuspid regurgitation is associated with increased mortality in proportion to right ventricular adaptation to increased volume loading and pulmonary artery pressure. We here review recent progress in the understanding of right ventricular adaptation to pre- and after-loading conditions for improved recommendations of tricuspid valve repair. RECENT FINDINGS: Trans-catheter tricuspid valve repair has made the correction of tricuspid regurgitation more easily available, triggering a need of tighter indications. Several studies have shown the feasibility and relevance to the indications of tricuspid valve repair of imaging of right ventricular ejection fraction measured by magnetic resonance imaging or 3D-echocardiography, and the 2D-echocardiography of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio combined with invasively determined mean pulmonary artery pressure and pulmonary vascular resistance. Improved definitions of right ventricular failure and pulmonary hypertension may be considered in future recommendations on the treatment of tricuspid regurgitation.
Asunto(s)
Insuficiencia Cardíaca , Insuficiencia de la Válvula Tricúspide , Humanos , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Volumen Sistólico , Función Ventricular Derecha , EcocardiografíaRESUMEN
Pulmonary arterial hypertension (PAH) is a rare dyspnoea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodelling, lung function in PAH is generally well preserved, with hyperventilation and increased physiological dead space, but minimal changes in lung mechanics and only mild to moderate hypoxaemia and hypocapnia. Hypoxaemia is mainly caused by a low mixed venous oxygen tension from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure-flow relationships with a correction for haematocrit. Pulsatile pulmonary vascular pressure-flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency domain or in the time domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV-pulmonary artery coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Hipertensión Pulmonar Primaria Familiar , Insuficiencia Cardíaca/complicaciones , Humanos , Hipocapnia/complicaciones , Hipocapnia/patología , Hipoxia , Arteria Pulmonar , Función Ventricular DerechaRESUMEN
BACKGROUND: According to current guidelines, the diagnosis of pulmonary hypertension (PH) relies on echocardiographic probability followed by right heart catheterisation (RHC). How echocardiography predicts PH recently redefined by mean pulmonary arterial pressure (mPAP) >20â mmHg instead of ≥25â mmHg and pulmonary vascular disease defined by pulmonary vascular resistance (PVR) ≥3 or >2â WU has not been established. METHODS: A total of 278 patients referred for PH underwent comprehensive echocardiography followed by RHC. 15 patients (5.4%) were excluded because of insufficient quality echocardiography. RESULTS: With PH defined by mPAP >20â mmHg, 23 patients had no PH, 146 had pre-capillary PH and 94 had post-capillary PH. At univariate analysis, maximum tricuspid regurgitation velocity (TRV) 2.9-3.4 m·s-1, left ventricle (LV) eccentricity index >1.1, right ventricle outflow tract acceleration time (RVOT-AT) <105â ms or notching, RV/LV basal diameter >1 and pulmonary artery diameter predicted PH, whereas inferior vena cava diameter and right atrial area did not. At multivariable analysis, only TRV ≥2.9â m·s-1 independently predicted PH. Additional independent prediction of PVR ≥3â WU was offered by LV eccentricity index >1.1, and RVOT-AT <105â ms and/or notching, but with no improvement of optimal combination of specificity and sensitivity or positive prediction. CONCLUSIONS: Echocardiography as recommended in current guidelines can be used to assess the probability of redefined PH in a referral centre. However, the added value of indirect signs is modest and sufficient quality echocardiographic signals may not be recovered in some patients.
Asunto(s)
Hipertensión Pulmonar , Cateterismo Cardíaco , Ecocardiografía , Humanos , Probabilidad , Circulación Pulmonar , Resistencia VascularRESUMEN
Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
Asunto(s)
Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina/uso terapéutico , Hemodinámica/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Resistencia Vascular/efectos de los fármacos , Administración Oral , Anciano , Anciano de 80 o más Años , Combinación de Medicamentos , Antagonistas de los Receptores de Endotelina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Conducta de Reducción del Riesgo , Resultado del TratamientoRESUMEN
Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman's ρ: -0.518, P < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, P < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.
Asunto(s)
Hipertensión Pulmonar/patología , Volumen Sistólico , Sístole , Resistencia Vascular , Disfunción Ventricular Derecha/complicaciones , Presión Ventricular , Presión Sanguínea , Femenino , Humanos , Hipertensión Pulmonar/etiología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVE: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. METHODS: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. RESULTS: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. CONCLUSION: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.
Asunto(s)
Enfermedades del Tejido Conjuntivo/fisiopatología , Tolerancia al Ejercicio/fisiología , Microvasos/fisiopatología , Enfermedades del Tejido Conjuntivo/complicaciones , Disnea/etiología , Disnea/fisiopatología , Elasticidad , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/metabolismoRESUMEN
PURPOSE: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork. METHODS: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured. RESULTS: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%. CONCLUSIONS: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.
Asunto(s)
Ecocardiografía Doppler/normas , Ventrículos Cardíacos/diagnóstico por imagen , Circulación Pulmonar/fisiología , Volumen Sistólico/fisiología , Disfunción Ventricular Derecha/diagnóstico , Función Ventricular Derecha/fisiología , Anciano , Prueba de Esfuerzo , Femenino , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Curva ROC , Sístole , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Izquierda/fisiologíaRESUMEN
The functional relevance of right atrial (RA) function in pulmonary hypertension (PH) remains incompletely understood. The purpose of this study was to explore the correlation of cardiac magnetic resonance (CMR) feature tracking-derived RA phasic function with invasively measured pressure-volume (P-V) loop-derived right ventricular (RV) end-diastolic elastance (Eed) and RV-arterial coupling [ratio of end-systolic elastance to arterial elastance (Ees/Ea)]. In 54 patients with severe PH, CMR was performed within 24 h of diagnostic right heart catheterization and P-V measurements. RA phasic function was assessed by CMR imaging of RA reservoir, passive, and active strain. The association of RA phasic function with indexes of RV function was evaluated by Spearman's rank correlation and linear regression analyses. Median [interquartile range] RA reservoir strain, passive strain, and active strain were 19.5% [11.0-24.5], 7.0% [4.0-12.0], and 13.0% [7.0-18.5], respectively. Ees/Ea was 0.73 [0.48-1.08], and Eed was 0.14 mmHg/mL [0.05-0.22]. RV diastolic impairment [RV end-diastolic pressure (EDP) and Eed] was correlated with RA phasic function, but Ea and Ees were not. In addition, RA phasic function was correlated with inferior vena cava diameter. In multivariate linear regression analysis, adjusting for key P-V loop indexes, Eed and EDP remained significantly associated with RA phasic function. We conclude that RA phasic function is altered in relation to impaired diastolic function of the chronically overloaded right ventricle and contributes to backward venous flow and systemic congestion. These results call for more attention to RA function in the management of patients with PH.NEW & NOTEWORTHY There is growing awareness of the importance of the right atrial (RA)-right ventricular (RV) axis in pulmonary hypertension (PH). Our results uncover alterations in RA phasic function that are related to depressed RV lusitropic function and contribute to backward venous return and systemic congestion in chronic RV overload. Assessment of RA function should be part of the management and follow-up of patients with PH.
Asunto(s)
Función del Atrio Derecho , Cateterismo Cardíaco , Hipertensión Pulmonar/diagnóstico , Imagen por Resonancia Magnética , Disfunción Ventricular Derecha/diagnóstico , Función Ventricular Derecha , Adulto , Anciano , Femenino , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/fisiopatología , Presión VentricularRESUMEN
AIM: To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an Acute Respiratory Distress Syndrome (ARDS). METHODS: Ninety-four consecutive patients (mean age 64 years) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio RESULTS: The majority of patients needed ventilatory support, which was noninvasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62 ± 13 vs. 68 ± 12 years, p = 0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO2)/fraction of inspired O2 (FIO2) ratio (270 ± 104 vs. 117 ± 57 mmHg, p < 0.001). In the non-survivors, PASP was increased (42 ± 12 vs. 30 ± 7 mmHg, p < 0.001), while TAPSE was decreased (19 ± 4 vs. 25 ± 4 mm, p < 0.001). Accordingly, the TAPSE/PASP ratio was lower than in the survivors (0.51 ± 0.22 vs. 0.89 ± 0.29 mm/mmHg, p < 0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR: 0.026; 95%CI 0.01-0.579; p: 0.019) and PaO2/FIO2 (HR: 0.988; 95%CI 0.988-0.998; p: 0.018) ratios were the only independent predictors of mortality, with ROC-determined cutoff values of 159 mmHg and 0.635 mm/mmHg, respectively. CONCLUSIONS: COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO2/FIO2 in ARDS on COVID-19.
Asunto(s)
COVID-19/complicaciones , COVID-19/mortalidad , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/virología , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/virología , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/mortalidad , Anciano , COVID-19/epidemiología , Ecocardiografía , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Estudios Prospectivos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/fisiopatología , SARS-CoV-2 , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.
Asunto(s)
Endotelina-1/metabolismo , Miocitos del Músculo Liso/patología , Proteína-Lisina 6-Oxidasa/metabolismo , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno/metabolismo , Elastina/metabolismo , Epoprostenol/farmacología , Perfilación de la Expresión Génica , Humanos , Pulmón/irrigación sanguínea , Pulmón/cirugía , Trasplante de Pulmón , Neumonectomía , Cultivo Primario de Células , Hipertensión Arterial Pulmonar/cirugía , Arteria Pulmonar/citología , Trapidil/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: In metabolic disorders, myocardial fatty infiltration is critically associated with lipotoxic cardiomyopathy. METHODS: Twenty Psammomys obesus gerbils were randomly assigned to normal plant or high fat diet. Sixteen weeks later, myocardium was sampled for pathobiological evaluation. RESULTS: A sixteen-week high fat diet resulted in myocardial structure disorganization, with collagen deposits, lipid accumulation, cardiomyocyte apoptosis and inflammatory cell infiltration. Myocardial expressions of glucose transporter GLUT1 and pyruvate dehydrogenase (PDH) inhibitor, PDH kinase (PDK)4 increased, while insulin-regulated GLUT4 expression remained unchanged. Myocardial expressions of molecules regulating fatty acid transport, CD36 and fatty acid binding protein (FABP)3, were increased, while expression of rate-controlling fatty acid ß-oxidation, carnitine palmitoyl transferase (CPT)1B decreased. Myocardial expression of AMP-activated protein kinase (AMPK), decreased, while expression of peroxisome proliferator activated receptors (PPAR)-α and -γ did not change. CONCLUSION: In high fat diet fed Psammomys obesus, an original experimental model of nutritionally induced metabolic syndrome mixing genetic predisposition and environment interactions, a short period of high fat feeding was sufficient to induce myocardial structural alterations, associated with altered myocardial metabolic gene expression in favor of lipid accumulation.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/genética , Gerbillinae/genética , Miocardio/metabolismo , Animales , Carnitina O-Palmitoiltransferasa/genética , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Proteína 3 de Unión a Ácidos Grasos/genética , Regulación de la Expresión Génica/efectos de los fármacos , Gerbillinae/metabolismo , Transportador de Glucosa de Tipo 1/genética , Humanos , Insulina/genética , Insulina/metabolismo , Metaboloma/genética , Miocardio/patología , Oxidación-Reducción/efectos de los fármacos , PPAR alfa/genética , Proteínas Quinasas/genéticaAsunto(s)
Antihipertensivos , Quimioterapia Combinada , Ecocardiografía , Fenotipo , Hipertensión Arterial Pulmonar , Humanos , Femenino , Masculino , Italia , Persona de Mediana Edad , Ecocardiografía/métodos , Antihipertensivos/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Anciano , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/diagnóstico por imagen , Adulto , Administración OralAsunto(s)
Función Ventricular Derecha , Animales , Función Ventricular Derecha/fisiología , Ratas , Ratones , RoedoresRESUMEN
In exercising humans, cardiac output (CO) increases, with minor increases in pulmonary artery pressure (PAP). It is unknown if the CO is accommodated via distention of already perfused capillaries or via recruitment of nonconcomitantly perfused pulmonary capillaries. Ten subjects (9 female) performed symptom-limited exercise. Six had resting mean PAP (PAPm) <20 mmHg, and four had PAPm between 21 and 24 mmHg. The first-pass pulmonary circulatory metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) was measured at rest and at peak exercise, and functional capillary surface area (FCSA) was calculated. Data are means ± SD. Mean pulmonary arterial pressure rose from 18.8 ± 3.3 SD mmHg to 28.5 ± 4.6 SD mmHg, CO from 6.4 ± 1.6 to 13.4 ± 2.9 L/min, and pulmonary artery wedge pressure from 14 ± 3.3 to 19.5 ± 5 mmHg (all P ≤ 0.001). Percent BPAP metabolism fell from 74.7 ± 0.1% to 67.1 ± 0.1%, and FCSA/body surface area (BSA) rose from 2,939 ± 640 to 5,018 ± 1,032 mL·min-1·m-2 (all P < 0.001). In nine subjects, the FCSA/BSA-to-CO relationship suggested principally capillary recruitment and not distention. In subject 10, a marathon runner, resting CO and FCSA/BSA were high, and increases with exercise suggested distention. Exercising humans demonstrate pulmonary capillary recruitment and distention. At moderate resting CO, increasing blood flow causes principally recruitment while, based on one subject, when exercise begins at high CO, further increases appear to cause distention. Our findings clarify an important physiologic question. The technique may provide a means for further understanding exercise physiology, its limitation in pulmonary hypertension, and responses to therapy.
Asunto(s)
Capilares/metabolismo , Ejercicio Físico/fisiología , Hemodinámica/fisiología , Circulación Pulmonar/fisiología , Adulto , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Descanso/fisiologíaRESUMEN
The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.