RESUMEN
Electronic cigarette use has increased globally prompting calls for improved understanding of nicotine's cardiovascular health effects. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension and right ventricular (RV) remodeling in male mice, but not female mice, suggesting sex differences in nicotine-related pathology. Clinically, biological females develop pulmonary hypertension more often but have less severe disease than biological males, likely because of the cardiopulmonary protective effects of estrogen. Nicotine is also metabolized more rapidly in biological females because of differences in cytochrome-P450 activity, which are thought to be mediated by female sex hormones. These findings led us to hypothesize that female mice are protected against nicotine-induced pulmonary hypertension by an ovarian hormone-dependent mechanism. In this study, intact and ovariectomized (OVX) female mice were exposed to chronic, inhaled nicotine or room air for 12 h/day for 10-12 wk. We report no differences in serum cotinine levels between intact and OVX mice. In addition, we found no structural (RV or left ventricular dimensions and Fulton index) or functional (RV systolic pressure, pulmonary vascular resistance, cardiac output, ejection fraction, and fractional shortening) evidence of cardiopulmonary dysfunction in intact or OVX mice. We conclude that ovarian hormones do not mediate cardiopulmonary protection against nicotine-induced pulmonary hypertension. Due to profound sex differences in clinical pulmonary hypertension pathogenesis and nicotine metabolism, further studies are necessary to elucidate mechanisms underlying protection from nicotine-induced pathology in female mice.NEW & NOTEWORTHY The emergence of electronic cigarettes poses a threat to cardiovascular and pulmonary health, but the direct contribution of nicotine to these disease processes is largely unknown. Our laboratory has previously shown that chronic, inhaled nicotine induces pulmonary hypertension and right ventricular remodeling in male mice, but not female mice. This study using a bilateral ovariectomy model suggests that the cardiopulmonary protection observed in nicotine-exposed female mice may be independent of ovarian hormones.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Hipertensión Pulmonar , Disfunción Ventricular Derecha , Femenino , Masculino , Ratones , Animales , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/prevención & control , Remodelación Ventricular , Nicotina/farmacología , Función Ventricular Derecha , Cotinina/efectos adversos , Arteria Pulmonar , Estrógenos/farmacología , Hormonas Esteroides Gonadales , Citocromos/farmacología , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/prevención & controlRESUMEN
AIMS: While immune checkpoint inhibitor (ICI) therapy significantly improves survival rates in advanced melanoma, ICI can evoke severe immune-related cardiovascular adverse events. Right ventricular (RV) dysfunction negatively impacts the outcomes in cardiovascular diseases and may be an early sign for overall cardiotoxicity. We aimed to assess RV function in melanoma patients undergoing ICI therapy using conventional echocardiographic and strain imaging techniques. METHODS AND RESULTS: We retrospectively examined 30 patients (40% women, age 59 ± 13 years) with advanced melanoma (stage III/IV) before and 4 weeks after the start of ICI therapy (follow-up at 39 ± 15 days); n = 15 of the patients received nivolumab, and n = 15 received the combination therapy nivolumab/ipilimumab. Two-dimensional echocardiography with assessment of RV longitudinal strain of the free wall (RV-LSFW) and assessment of right atrial (RA) strain from speckle tracking was performed at baseline and after the start of ICI therapy. Short-term ICI therapy caused a reduction of RV-LSFW (-25.5 ± 6.4% vs. -22.4 ± 4.3%, P = 0.002) and of RA strain during contraction phase (-10.6 ± 3.5% vs. -7.7 ± 3.1%, P = 0.001). Conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and pulmonary artery systolic pressure were not different between the two time points (TAPSE 26 ± 5 vs. 25 ± 5 mm, P = 0.125; FAC 38 ± 13% vs. 38 ± 14%, P = 0.750; and pulmonary artery systolic pressure 27 ± 10 vs. 25 ± 8 mmHg, P = 0.268). CONCLUSIONS: Analysis of RV and RA strain shows alterations even in a short-term follow-up, while changes in RV function are not visible by conventional RV parameters. Alterations in RV and RA strain could be early signs of cardiotoxicity and therefore should be assessed in patients undergoing ICI therapy.
Asunto(s)
Melanoma , Disfunción Ventricular Derecha , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Cardiotoxicidad , Nivolumab/efectos adversos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Melanoma/complicacionesRESUMEN
Pulmonary hypertension (PH) is a global health issue with a prevalence of 10% in ages >65 years. Right heart failure (RHF) is the main cause of death in PH. We have previously shown that monocrotaline (MCT)-induced PH and RHF are due to an increase in oxidative stress. In this study, probucol (PROB), a strong antioxidant with a lipid-lowering property, versus lovastatin (LOV), a strong lipid-lowering drug with some antioxidant effects, were evaluated for their effects on the MCT-induced RHF. Rats were treated (I.P.) with PROB (10 mg/kg ×12) or LOV (4 mg/kg ×12), daily 6 days before and 6 days after a single MCT injection (60 mg/kg). Serial echocardiography was performed and at 4-week post-MCT, lung wet-to-dry weight, hemodynamics, RV glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase, lipid peroxidation, and myocardial as well as plasma lipids were examined. MCT increased RV systolic and diastolic pressures, wall thickness, RV end diastolic diameter, mortality, and decreased ejection fraction as well as pulmonary artery acceleration time. These changes were mitigated by PROB while LOV had no effect. Furthermore, PROB prevented lipid peroxidation, lowered lipids, and increased GSHPx and SOD in RV myocardium. LOV did decrease the lipids but had no effect on antioxidants and lipid peroxidation. A reduction in oxidative stress and not the lipid-lowering effect of PROB may explain the prevention of MCT-induced PH, RHF, and mortality. Thus targeting of oxidative stress as an adjuvant therapy is suggested.
Asunto(s)
Anticolesterolemiantes/farmacología , Antioxidantes/farmacología , Insuficiencia Cardíaca/metabolismo , Corazón/efectos de los fármacos , Hipertensión Pulmonar/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lovastatina/farmacología , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Probucol/farmacología , Animales , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Ecocardiografía , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Pulmón/efectos de los fármacos , Monocrotalina/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Ratas , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling. Exploring new therapy target is urgent. The purpose of the present study is to investigate whether and how spliced x-box binding protein 1 (xbp1s), a key component of endoplasmic reticulum stress (ERS), contributes to the pathogenesis of PH. Forty male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), MCT+AAV-CTL (control), and MCT+AAV-xbp1s. The xbp1s protein levels were found to be elevated in lung tissues of the MCT group. Intratracheal injection of adeno-associated virus serotype 1 carrying xbp1s shRNA (AAV-xbp1s) to knock down the expression of xbp1s effectively ameliorated the MCT-induced elevation of right ventricular systolic pressure (RVSP), total pulmonary resistance (TPR), right ventricular hypertrophy and medial wall thickness of muscularized distal pulmonary arterioles. The abnormally increased positive staining rates of proliferating cell nuclear antigen (PCNA) and Ki67 and decreased positive staining rates of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) in pulmonary arterioles were also reversed in the MCT+AAV-xbp1s group. For mechanistic exploration, bioinformatics prediction of the protein network was performed on the STRING database, and further verification was performed by qRT-PCR, Western blots and co-immunoprecipitation (Co-IP). DNA damage-inducible transcript 3 (Ddit3) was identified as a downstream protein that interacted with xbp1s. Overexpression of Ddit3 restored the decreased proliferation, migration and cell viability caused by silencing of xbp1s. The protein level of Ddit3 was also highly consistent with xbp1s in the animal model. Taken together, our study demonstrated that xbp1s-Ddit3 may be a potential target to interfere with vascular remodeling in PH.
Asunto(s)
Presión Arterial , Hipertensión Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Factor de Transcripción CHOP/metabolismo , Remodelación Vascular , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Monocrotalina , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas Sprague-Dawley , Transducción de Señal , Factor de Transcripción CHOP/genética , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Proteína 1 de Unión a la X-Box/genéticaAsunto(s)
Estenosis de la Válvula Aórtica , Hipotensión , Reemplazo de la Válvula Aórtica Transcatéter , Disfunción Ventricular Derecha , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Humanos , Hipotensión/inducido químicamente , Hipotensión/diagnóstico , Protaminas/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del Tratamiento , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnósticoRESUMEN
Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure-volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.
Asunto(s)
Cardiotónicos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Fosfatos de Inositol/farmacología , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Cardiotónicos/administración & dosificación , Modelos Animales de Enfermedad , Hemoglobinas/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/inducido químicamente , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Monocrotalina/administración & dosificación , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Ratas , Ratas Wistar , Resultado del Tratamiento , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha/fisiologíaRESUMEN
Depressed right ventricular ejection fraction (RVEF) has clear prognostic significance in patients with pulmonary arterial hypertension (PAH). Accordingly, improvements in RVEF represent a desirable end-point in the development of PAH therapies. However, current methods for determination of RVEF require measurement of RV volume and are relatively complex and costly. Here, we validate a novel method for quantitative estimation of RVEF in rats based entirely upon analysis of readily available RV pressure waveforms that eliminates the need for simultaneous volume measurement and can be rapidly applied. Right ventricular pressure and volume (conductance catheter) measurements acquired from 15 rats (7 controls, 8 sugen/hypoxia PAH; 220-250 g) were used for the study. Over the same 10 beat interval, RVEF was directly measured from the volume signal and estimated from the pressure signal. Simultaneous measures were compared by linear regression and Bland-Altman analysis to define bias (accuracy) and precision. Measured RVEF ranged from 0.19 to 0.60 (mean 0.44 ± 0.10) and estimated from 0.19 to 0.52 (mean 0.42 ± 0.09). Across the dataset there was strong correlation (r2 = 0.813), with minimal bias (0.01) and an overall error of 20% consistent with acceptable accuracy and precision. Study results support the potential utility of a method based entirely upon analysis of the RV pressure waveform for assessing drug effects on RVEF in rat models of PAH.
Asunto(s)
Hipertensión Pulmonar , Disfunción Ventricular Derecha , Animales , Desarrollo de Medicamentos , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Ratas , Roedores , Volumen Sistólico , Disfunción Ventricular Derecha/inducido químicamente , Función Ventricular DerechaRESUMEN
BACKGROUND: Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. OBJECTIVE: We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. STUDY DESIGN: A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline (P=.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<.05). Nifedipine did not alter fetal left ventricular functional parameters or cardiac output. When normoxemia was restored, fetal right ventricular functional parameters and cardiac output returned to baseline level. CONCLUSION: In hypoxemic fetus, nifedipine impaired right ventricular function and reduced its cardiac output. The detrimental effects of nifedipine on fetal right ventricular function were abolished, when normoxemia was restored. Our findings suggest that in a hypoxemic environment nifedipine triggers detrimental effects on fetal right ventricular function.
Asunto(s)
Bloqueadores de los Canales de Calcio/efectos adversos , Gasto Cardíaco/efectos de los fármacos , Hipoxia Fetal/complicaciones , Nifedipino/efectos adversos , Disfunción Ventricular Derecha/inducido químicamente , Animales , Presión Arterial/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Diástole/efectos de los fármacos , Ecocardiografía Doppler de Pulso , Monitoreo Fetal , Modelos Animales , OvinosRESUMEN
To investigate whether 2D strain and 3D echocardiography could early identify the impaired right ventricular (RV) function after anthracycline exposure. Sixty-one patients with diffuse large B-cell lymphoma treated with anthracycline were studied. Echocardiography was conducted at baseline, after the third cycle of the chemotherapy, after the completion of the chemotherapy, and follow-up at 10 months after the initiation of chemotherapy. RV global longitudinal strain (RV GLS) and RV free wall longitudinal strain (RV FWLS) were calculated using speckle tracking echocardiography. RV ejection fraction (RVEF) was analyzed by 3D echocardiography. RV systolic dysfunction was defined by ≥ 2 RV parameters below the threshold value, and cardiotoxicity was defined as a reduction in left ventricular EF > 10 to < 53%. After the third cycle of chemotherapy, only RV GLS was significantly decreased, while after the completion of the chemotherapy, RV GLS, RV FWLS, and RVEF were all significantly decreased compared with baseline measurements. At the end of follow-up, 9 patients (14.8%) were diagnosed with RV systolic dysfunction, and 16 patients (26.2%) had at least 1 abnormal RV function parameter. The proportion of RV systolic dysfunction was significantly higher in patients with cardiotoxicity than in patients without cardiotoxicity, yielding an odds ratio of 5.143. A percentage decrease in RV FWLS and RVEF were independent predictors of RV systolic dysfunction. Two-dimensional strain and 3D echocardiography are valuable methods for evaluating anthracycline-related impairment of RV function in DLBCL patients receiving chemotherapy. RV FWLS and RVEF are reliable predictors of RV systolic dysfunction.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , Ecocardiografía Tridimensional , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnóstico por imagen , Función Ventricular Derecha/efectos de los fármacos , Adulto , Cardiotoxicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600 ppm for 45 min) and the survivors were sacrificed at 14 or 28 days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.
Asunto(s)
Bromo , Cardiomegalia/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Izquierda , Función Ventricular Derecha , Remodelación Ventricular , Animales , Proteínas de Unión al Calcio/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiotoxicidad , Diástole , Modelos Animales de Enfermedad , Fibrosis , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Miocardio/metabolismo , Miocardio/ultraestructura , NADPH Oxidasa 2/metabolismo , Péptido Natriurético Encefálico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Fosforilación , Proteína Fosfatasa 1/metabolismo , Ratas Sprague-Dawley , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Sístole , Factores de Tiempo , Troponina I/metabolismo , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.
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Antihipertensivos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Fenilpropionatos/farmacología , Piridazinas/farmacología , Tadalafilo/farmacología , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Ecocardiografía , Femenino , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/diagnóstico por imagen , Hipertrofia Ventricular Derecha/fisiopatología , Pulmón/diagnóstico por imagen , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Monocrotalina/administración & dosificación , Neumonectomía , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Remodelación Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Microtomografía por Rayos XRESUMEN
Background Cancer therapies inhibiting PI 3Kα (phosphoinositide 3-kinase-α)-dependent growth factor signaling, including trastuzumab inhibition of HER 2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI 3Kα is now in clinical trials, but the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI 3Kα inhibition and heart-specific genetic deletion of p110α, the catalytic subunit of PI 3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI 3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI 3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI 3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI 3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.
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Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Corazón/efectos de los fármacos , Miocardio/patología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Tiazoles/farmacología , Disfunción Ventricular Derecha/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Animales , Atrofia , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Corazón/fisiopatología , Ratones , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/patología , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Trastuzumab improves dramatically the prognosis of HER2-positive breast cancer patients, but it may lead to cardiotoxicity with left ventricular (LV) systolic dysfunction. Its effects on right ventricular (RV) function have not however been elucidated. We sought to assess LV and RV deformation mechanics during treatment with trastuzumab in breast cancer patients. METHODS AND RESULTS: We studied 101 consecutive women (mean age 54.3 ± 11.4 years) receiving trastuzumab for 12 months; 62 of them (61.4%) had previously received anthracyclines and 26 (25.7%) were receiving taxanes concurrently with trastuzumab. Comprehensive two-dimensional echocardiography with speckle tracking imaging of LV and RV global longitudinal strain (GLS) and RV free wall longitudinal strain (FWLS) analyses were performed at baseline and every 3 months up to treatment completion. Cardiotoxicity was defined as a decrease of baseline LV ejection fraction > 10 percentage units to a value < 50%. At 3 months, only LV GLS was significantly reduced (-19.5 ± 2.7 to -18.7 ± 2.8, P = 0.0410), while at 6 months, LV GLS, RV GLS and RV FWLS had significantly declined reaching their lowest values (-17.9 ± 6.1, P = 0.002, -19.6 ± 5.2, P = 0.003 and -19.7 ± 5.6, P = 0.004, respectively). Ten women (9.9%) developed cardiotoxicity. A RV GLS percent change of -14.8% predicted cardiotoxicity with 66.7% sensitivity and 70.8% specificity (area under the curve 0.68, 95% confidence interval 0.54-0.81), classifying correctly 90% of women with cardiotoxicity. This cut-off is quite similar to the 15% change of LV GLS previously suggested as predictive of cardiotoxicity. CONCLUSIONS: Deformation mechanics of both the left and right ventricle follow similar temporal pattern and degree of impairment during trastuzumab therapy, confirming the global and uniform effect of trastuzumab on myocardial function.
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Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Trastuzumab/efectos adversos , Adulto , Antraciclinas , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Fenómenos Biomecánicos , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/etiología , Ecocardiografía , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Taxoides , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Disfunción Ventricular Izquierda , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Izquierda , Función Ventricular Derecha/efectos de los fármacosRESUMEN
BACKGROUND: Recently, attention has been focused on the cardiovascular protective effects of beet juice (BJ) with high amounts of nitrate. In this study, we examined the effect of BJ supplementation in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). METHODS: MCT (60 mg/kg) was subcutaneously administered to rats, and BJ (prepared by dissolving BJ powder at a concentration of 1 g/l or 10 g/l in drinking water) supplementation was started from the day of, 1 week before, and 2 weeks after MCT injection. Saline-injected rats given drinking water were used as controls. RESULTS: Low-dose BJ supplementation starting from the day of MCT injection exerted protective effects on the MCT-induced elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arterial remodeling, without causing a significant increase in plasma nitrite plus nitrate (NOx) levels. On the other hand, such beneficial effects were not observed with high-dose BJ supplementation, although the NOx levels were slightly higher than those in the low-dose group. In addition, low-dose BJ supplementation starting from 1 week before MCT injection did not improve PH symptoms, as described above. Furthermore, low-dose BJ supplementation starting from 2 weeks after MCT injection was ineffective against functional and morphological alterations in pulmonary circulation associated with MCT-induced PH. CONCLUSIONS: Habitual ingestion of a suitable amount of BJ could be a potential option for preventing PH. However, beneficial effects cannot be expected when PH has developed to some degree.
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Presión Arterial , Beta vulgaris , Suplementos Dietéticos , Jugos de Frutas y Vegetales , Hipertensión Arterial Pulmonar/prevención & control , Arteria Pulmonar/fisiopatología , Animales , Modelos Animales de Enfermedad , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/prevención & control , Masculino , Monocrotalina , Óxido Nítrico/metabolismo , Raíces de Plantas , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Remodelación Vascular , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular DerechaRESUMEN
One of the leading causes of morbidity and mortality in patients with heart failure is right ventricular (RV) dysfunction, especially if it is due to pulmonary hypertension. For a better understanding and treatment of this disease, precise hemodynamic monitoring of left and right ventricular parameters is important. For this reason, it is essential to establish experimental pig models of cardiac hemodynamics and measurements for research purpose. This article shows the induction of ARDS by using oleic acid (OA) and consequent right ventricular dysfunction, as well as the instrumentation of the pigs and the data acquisition process that is needed to assess hemodynamic parameters. To achieve right ventricular dysfunction, we used oleic acid (OA) to cause ARDS and accompanied this with pulmonary artery hypertension (PAH). With this model of PAH and consecutive right ventricular dysfunction, many hemodynamic parameters can be measured, and right ventricular volume load can be detected. All vital parameters, including respiratory rate (RR), heart rate (HR) and body temperature were recorded throughout the whole experiment. Hemodynamic parameters including femoral artery pressure (FAP), aortic pressure (AP), right ventricular pressure (peak systolic, end systolic and end diastolic right ventricular pressure), central venous pressure (CVP), pulmonary artery pressure (PAP) and left arterial pressure (LAP) were measured as well as perfusion parameters including ascending aortic flow (AAF) and pulmonary artery flow (PAF). Hemodynamic measurements were performed using transcardiopulmonary thermodilution to provide cardiac output (CO). Furthermore, the PiCCO2 system (Pulse Contour Cardiac Output System 2) was used to receive parameters such as stroke volume variance (SVV), pulse pressure variance (PPV), as well as extravascular lung water (EVLW) and global end-diastolic volume (GEDV). Our monitoring procedure is suitable for detecting right ventricular dysfunction and monitoring hemodynamic findings before and after volume administration.
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Modelos Animales de Enfermedad , Monitorización Hemodinámica/métodos , Hemodinámica/fisiología , Arteria Pulmonar/fisiopatología , Síndrome de Dificultad Respiratoria/fisiopatología , Animales , Presión Sanguínea/fisiología , Gasto Cardíaco/efectos de los fármacos , Gasto Cardíaco/fisiología , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Masculino , Ácido Oléico/toxicidad , Arteria Pulmonar/efectos de los fármacos , Síndrome de Dificultad Respiratoria/inducido químicamente , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Porcinos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.
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Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fabaceae , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina , Miocardio , Aceites de Plantas/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Fármacos Cardiovasculares/aislamiento & purificación , Modelos Animales de Enfermedad , Fabaceae/química , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
We investigated the changes in expression profile and potential roles of long noncoding RNAs (lncRNAs) in right ventricle (RV) myocardium of pulmonary arterial hypertension (PAH) rats with RV failure induced by acute inflammation. Sprague-Dawley rats were given monocrotaline to establish a PAH model and acute heart failure was induced by an injection of lipopolysaccharide. The RV failure was confirmed by echocardiography data. The expression profiles of lncRNAs and messenger RNAs (mRNAs) in RV tissues were obtained by RNA sequencing. Bioinformatics analyses were performed, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and co-expression network analysis. We also conducted real-time quantitative polymerase chain reaction (qRT-PCR) to confirm the results of RNA sequencing. A total of 169 lncRNAs (101 upregulated and 68 down-regulated) and 898 mRNAs (623 upregulated and 275 down-regulated) were differently expressed in PAH rats with acute RV failure. The expression levels of lncRNA (TCONS_00052110, TCONS_00201718, TCONS_00094247, and TCONS_00296056) and mRNA (Cxcl-1 and Timp4) were verified through qRT-PCR, the results of which were consistent with RNA sequencing. lncRNA expression data in RV myocardium of PAH rats with acute RV failure will provide important insights about the contribution of lncRNAs to heart failure in PAH model.
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Insuficiencia Cardíaca/genética , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Disfunción Ventricular Derecha/genética , Animales , Biología Computacional , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Lipopolisacáridos , Masculino , Monocrotalina , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Transcriptoma , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular DerechaRESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. METHODS: Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 0.35 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). RESULTS: Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. CONCLUSIONS: Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.
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Complejo III de Transporte de Electrones/antagonistas & inhibidores , Complejo III de Transporte de Electrones/metabolismo , Glucólisis/fisiología , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Mitocondrias/metabolismo , Vasoconstricción/fisiología , Animales , Antimicina A/toxicidad , Femenino , Glucólisis/efectos de los fármacos , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Mitocondrias/efectos de los fármacos , Monocrotalina/toxicidad , Ratas , Ratas Sprague-Dawley , Vasoconstricción/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Paracetamol (acetaminophen or N-acetyl-p-aminophenol) is considered a safe analgesic and antipyretic nonsteroidal antiinflammatory drug commonly used during pediatric ages and during pregnancy. We report on a term neonate with closed ductus arteriosus, severe cardiomyopathy, right ventricular dysfunction, and functional stenosis of pulmonary arteries at birth after maternal self-medication with paracetamol and consumption of polyphenol-rich foods in late pregnancy. This drug, especially when associated with other vasoconstrictors (such as polyphenols), interferes with prostaglandin metabolism, which seriously accentuates the intrauterine ductus arteriosus constriction and leads to pharmacologic adverse events. We suggest maternal educational programs to avoid risky self-medications and provide training for the best diets.
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Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Cardiomiopatías/inducido químicamente , Conducto Arterial/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Disfunción Ventricular Derecha/inducido químicamente , Dieta Mediterránea/efectos adversos , Femenino , Soplos Cardíacos/inducido químicamente , Humanos , Recién Nacido , Polifenoles/efectos adversos , Embarazo , Estenosis de la Válvula Pulmonar/inducido químicamente , Automedicación , Vasoconstrictores/efectos adversosRESUMEN
INTRODUCTION: Mustard gas (MG) is a chemical warfare agent widely used in the Iran-Iraq War. Its catastrophic effects on the lungs, eyes, and skin have been well studied. However, it also affects the cardiovascular system. We aimed to evaluate the long-term effect of MG on right ventricular (RV) function. METHODS: All patients presenting to the university clinics between May 2014 and September 2015 were consecutively evaluated to enter the study based on the inclusion criteria (documented proof of chemical injury, no past or present cardiovascular disease, not a current smoker, and no history of sleep apnea). A comparable control group of veterans without MG exposure was randomly selected. All patients underwent echocardiographic measurement of RV size and function by a blinded cardiologist. RESULTS: We included 23 patients in the MG-exposed group and 19 subjects in the control group, with a mean age of 48.6 years. Mean chemical injury severity score was 29.7% and mean time from the MG exposure was 29.2 years. The main complaint of MG-exposed patients pertained to respiratory symptoms (91%). Pulmonary artery pressure was higher (32.83 vs. 28.95 mmHg) and RV strain was lower (-17.05% vs. -20.72%) in the MG-exposed than in the control group (P < .05). CONCLUSION: Our results present baseline RV values for MG-exposed patients and show mild but significant changes after 3 decades. Further cellular and molecular studies are needed to evaluate underlying mechanisms of MG cardiotoxicity.