RESUMEN
OBJECTIVES: In patients at risk of developing right ventricular failure after cardiac surgery, right ventricular support with a ventricular assist device may be a promising strategy to reduce mortality. We present our experience with intraoperative right ventricular assist device implantation as a prevention strategy of right ventricular failure after cardiac surgery. METHODS: Between 2016 and 2022, we implanted four right ventricular assist devices prophylactically in a series of patients with surgical indication for valvular heart disease and high risk of postoperative right ventricular failure. Indications for the right ventricular assist device were suprasystemic pulmonary hypertension or severe right ventricular dysfunction. RESULTS: Externalization of the device cannulas through intercostal spaces was performed in three patients, allowing early mobilization and withdrawal without resternotomy. Removal of the device ocurred on the eighth postoperative day. ICU and hospital length of stay was 12 (±1.6) and 23 days (±4.2) respectively. Hospital mortality was null. No patient died during follow-up, mean follow-up was 32.5 months [1-72]. Patients improved their NYHA functional class up to grade II during follow-up. CONCLUSIONS: Acute right ventricular failure after cardiac surgery remains a significant cause of morbidity and mortality. Prophylactic strategies to prevent postoperative right ventricular dysfunction may decrease the incidence of refractory postoperative right ventricular failure. We propose a novel approach to prevent right failure after cardiac surgery with prophylactic intraoperative ventricular assist device implantation.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Insuficiencia Cardíaca , Corazón Auxiliar , Disfunción Ventricular Derecha , Humanos , Corazón Auxiliar/efectos adversos , Implantación de Prótesis/efectos adversos , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Resultado del Tratamiento , Estudios Retrospectivos , Insuficiencia Cardíaca/prevención & control , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/etiología , Procedimientos Quirúrgicos Cardíacos/efectos adversosRESUMEN
Right ventricular (RV) function is the strongest predictor of survival in age-related heart failure as well as other clinical contexts in which aging populations suffer significant morbidity and mortality. However, despite the significance of maintaining RV function with age and disease, mechanisms of RV failure remain poorly understood and no RV-directed therapies exist. The antidiabetic drug and AMP-activated protein kinase (AMPK) activator metformin protects against left ventricular dysfunction, suggesting cardioprotective properties may translate to the RV. Here, we aimed to understand the impact of advanced age on pulmonary hypertension (PH)-induced right ventricular dysfunction. We further aimed to test whether metformin is cardioprotective in the RV and whether the protection afforded by metformin requires cardiac AMPK. We used a murine model of PH by exposing adult (4-6 mo) and aged (18 mo) male and female mice to hypobaric hypoxia (HH) for 4 wk. Cardiopulmonary remodeling was exacerbated in aged mice compared with adult mice as evidenced by elevated RV weight and impaired RV systolic function. Metformin attenuated HH-induced RV dysfunction but only in adult male mice. Metformin still protected the adult male RV even in the absence of cardiac AMPK. Together, we suggest that aging exacerbates PH-induced RV remodeling and that metformin may represent a therapeutic option for this disease in a sex- and age-dependent manner, but in an AMPK-independent manner. Ongoing efforts are aimed at elucidating the molecular basis for RV remodeling as well as delineating the mechanisms of cardioprotection provided by metformin in the absence of cardiac AMPK.NEW & NOTEWORTHY Right ventricular (RV) function predicts survival in age-related disease, yet mechanisms of RV failure are unclear. We show that aged mice undergo exacerbated RV remodeling compared with young. We tested the AMPK activator metformin to improve RV function and show that metformin attenuates RV remodeling only in adult male mice via a mechanism that does not require cardiac AMPK. Metformin is therapeutic for RV dysfunction in an age- and sex-specific manner independent of cardiac AMPK.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Metformina , Disfunción Ventricular Derecha , Masculino , Ratones , Femenino , Animales , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/prevención & control , Metformina/farmacología , Proteínas Quinasas Activadas por AMP , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Disfunción Ventricular Derecha/tratamiento farmacológico , Función Ventricular Derecha , Remodelación Ventricular , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Right ventricle (RV) dysfunction after a coronary artery bypass grafting procedure is a challenge that adversely affects RV filling pressure and contraction. This study sought to determine whether additional bypass of an RV branch would lessen RV dysfunction. METHODS: Patients with severe right coronary artery (RCA) stenosis were divided into 2 groups. Group 1 patients (n = 50) had a single distal bypass on the RCA. Group 2 patients (n = 50) had both distal RCA and additional bypass on the RV branch of the RCA. Right ventricular function was examined by echocardiogram by measuring transannular plane systolic excursion, fractional area change, tissue Doppler S-wave velocity, and inferior vena cava diameter. RESULTS: Transannular plane systolic excursion and fractional area change measurements rapidly decreased below the cutoff in both groups, but group 2 patient values reached normal limits at 90 days. Tissue Doppler S-wave velocity reached the normal limit in 7 days. Inotropic agents were required in 11 patients in group 1 and 2 patients in group 2 (P = .013). The mean (SD) intensive care unit stay was 2.11 (1.12) days and 1.45 (0.71) days (P = .033), and the hospital stay was 7.32 (1.44) days and 6.22 (0.45) days in groups 1 and 2, respectively (P = .027). CONCLUSION: The data in this study suggest that an additional graft on the RV branch of the RCA (eg, conus, marginal, any good runoff vessels on the RV) prevents severe RV dysfunction and allows for rapid recovery of RV dysfunction after off-pump coronary surgery.
Asunto(s)
Cardiomiopatías , Estenosis Coronaria , Disfunción Ventricular Derecha , Humanos , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Vasos Coronarios , Función Ventricular Derecha , Puente de Arteria Coronaria/efectos adversosRESUMEN
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
BACKGROUND: Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. METHODS: Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. RESULTS: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. CONCLUSION: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Arritmias Cardíacas , Compuestos de Bencidrilo , Calcio/metabolismo , Conexina 43/metabolismo , Modelos Animales de Enfermedad , Fura-2 , Glucosa , Glucósidos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Monocrotalina/toxicidad , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/complicaciones , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Ratas , Sodio , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Remodelación VentricularRESUMEN
OBJECTIVES: Given the anatomical variations of tetralogy of Fallot (TOF), different surgical techniques can be used to achieve correction. Transannular patches (TAPs) are the most commonly used technique; they are associated with right ventricular dysfunction, the incidence of which can be reduced through pulmonary valve preservation. METHODS: Between January 2010 and July 2019, we performed 274 surgical corrections of tetralogy of Fallot at Fundación Cardioinfantil; 63 patients (23%) underwent repair with a TAP in addition to a pulmonary neovalve (Group I), 66 patients (24.1%) received a TAP without a pulmonary valve (Group II) and 145 patients (52.9%) had a repair with valve preservation (Group III). We analysed patient's characteristics before, during and after surgery at a 30-day follow-up. RESULTS: We found that patients in Group III were older (P = 0.04). Group II had the lowest level of O2 saturation before surgery (82%, P = 0.001). Cardiopulmonary bypass and aortic cross-clamp times were longer in Group I (P < 0.001). Right ventricular dysfunction was less frequent in Group III (15.9%, P = 0.011). Severe residual pulmonary regurgitation was more common in Group II (21.9%, P = 0.001). CONCLUSIONS: Preservation of the pulmonary valve is an important factor for immediate postoperative management of tetralogy of Fallot. Patients who were repaired with a TAP with or without a pulmonary neovalve had a higher incidence of right ventricular dysfunction than those with pulmonary valve preservation.
Asunto(s)
Insuficiencia de la Válvula Pulmonar , Válvula Pulmonar , Tetralogía de Fallot , Disfunción Ventricular Derecha , Estudios de Seguimiento , Humanos , Lactante , Válvula Pulmonar/diagnóstico por imagen , Válvula Pulmonar/cirugía , Insuficiencia de la Válvula Pulmonar/diagnóstico por imagen , Insuficiencia de la Válvula Pulmonar/etiología , Insuficiencia de la Válvula Pulmonar/cirugía , Estudios Retrospectivos , Tetralogía de Fallot/complicaciones , Resultado del Tratamiento , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & controlRESUMEN
PURPOSE: Nrf2 is a nuclear transcription factor and plays an important role in the regulation of oxidative stress and inflammation. We recently demonstrated that sulforaphane (SFN) protected mice from developing pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction by elevating cardiac Nrf2 expression and function. Here we further investigate Nrf2 dependence for SFN-mediated prevention of PAH and RV dysfunction in an Nrf2 knockout mouse model. METHODS: We used male global Nrf2-knockout mice and male C57/6 J wild type mice in the following groups: Control group received room air and vehicle control; SuHx group received SU5416 and 10% hypoxia for 4 weeks to induce PAH; SuHx+SFN group received both SuHx and sulforaphane, a Nrf2 activator, for 4 weeks. Transthoracic echocardiography was performed to quantify RV function and estimate pulmonary vascular resistance over 4 weeks. PAH was confirmed using invasive RV systolic pressure measurement at 4 weeks. RESULTS: All Nrf2 knockout mice survived the 4-week SuHx induction of PAH. SuHx caused progressive RV diastolic/systolic dysfunction and increased RV systolic pressure. The development of RV diastolic dysfunction occurred earlier in the Nrf2 knockout PAH mice when compared with the wide type PAH mice. SFN partially or completely reversed SuHx-induced RV diastolic/systolic dysfunction and increased RV systolic pressure in wild-type mice, but not in Nrf2 knockout mice. CONCLUSION: Our findings demonstrated the essential role of Nrf2 in SFN-mediated prevention of RV dysfunction and PAH, and increasing Nrf2 activity in patients with PAH may have therapeutic potential.
Asunto(s)
Hipertensión Pulmonar , Factor 2 Relacionado con NF-E2 , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/prevención & control , Isotiocianatos , Masculino , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Arteria Pulmonar , Sulfóxidos , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/prevención & controlRESUMEN
OBJECTIVES: Right ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood. METHODS: We induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development. RESULTS: PL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P = .04 and 8 weeks: 0.00%/0.00%; P = .484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P = .468 and 8 weeks: 3.57/1.44; P = .024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P = .003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P = .009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P = .009/.078) in RV PL rats during childhood. CONCLUSIONS: RV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Derecha , Ratas , Animales , Hipertrofia Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Disfunción Ventricular Derecha/metabolismo , Presión Ventricular/fisiología , Neurregulina-1/genética , Neurregulina-1/metabolismo , Neurregulina-1/farmacología , Función Ventricular Derecha , Miocitos Cardíacos/metabolismo , Fibrosis , Insuficiencia Cardíaca/metabolismo , Ciclo Celular , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Perioperative right ventricular function is a significant predictor of patient outcomes after cardiac surgery. This prospective study aimed to identify perioperative factors associated with reduced intraoperative right ventricular function. METHODS: Right ventricular function was assessed at the beginning and end of surgery by standardized transesophageal echocardiographic measurements, including tricuspid annular plane systolic excursion, peak systolic longitudinal right ventricular strain, and fractional area change, in 109 adult patients undergoing cardiac surgery at Cleveland Clinic. Associations between right ventricular function and 33 patient characteristics and perioperative factors were analyzed by random forest machine learning. The relative importance of each variable in predicting right ventricular function at the end of surgery was determined. RESULTS: Longer aortic clamp duration and lower baseline right ventricular function were highly important variables for predicting worse right ventricular function measured by tricuspid annular plane systolic excursion, right ventricular strain, and fractional area change at the end of surgery. For example, right ventricular function after longer aortic clamp times of 100-120 minutes was worse (median [Q1, Q3] tricuspid annular plane systolic excursion 1.0 [0.9, 1.1] cm) compared with right ventricular function after shorter aortic clamp times of 50 to 70 minutes (tricuspid annular plane systolic excursion 1.5 [1.3, 1.7]; P = .001). Right ventricular strain at the end of surgery was reduced in patients with worse baseline right ventricular function compared with those with higher baseline right ventricular function (end of surgery right ventricular strain in lowest quartile -13.7 [-16.6, -12.4]% vs highest quartile -17.7 [-18.6, -15.3]% of baseline right ventricular function; P = .043). CONCLUSIONS: Intraoperative decline in right ventricular function is associated with longer aortic clamp time and worse baseline right ventricular function. Efforts to optimize these factors, including better myocardial protection strategies, may improve perioperative right ventricular function.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Disfunción Ventricular Derecha , Adulto , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Ecocardiografía Transesofágica , Ventrículos Cardíacos , Humanos , Estudios Prospectivos , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular DerechaRESUMEN
BACKGROUND: In this study, we evaluated the prevalence of tricuspid regurgitation (TR) worsening in patients with left ventricular assist devices (LVADs) and its impact on late right ventricular (RV) failure. METHODS: We enrolled 147 patients of the 184 patients who underwent continuous-flow LVAD implantations from 2005 to March 2018. The prevalence of postoperative TR worsening and late RV failure were retrospectively evaluated. RESULTS: Concomitant tricuspid annuloplasty (TAP) was performed in 28 of 41 patients (68%) with preoperative TR greater than or equal to moderate (TR group) and in 23 of 106 patients (22%) with preoperative TR less than or equal to mild (non-TR group). Regarding the TR-free rates, despite receiving or not receiving concomitant TAP, there was no significant difference between the 2 groups (TR group: p = 0.37; non-TR group: p = 0.42). Of the 9 patients with postoperative TR greater than or equal to moderate, late RV failure developed in 3 patients, with TR worsening after RV failure in each case. During follow-up, 16 patients (11%) had late RV failure. As for the late RV failure-free rates, despite receiving or not receiving concomitant TAP, there was no significant difference between the 2 groups (TR group: p = 0.37; non-TR group: p = 0.96). CONCLUSIONS: TR prognosis was preferable regardless of a patient receiving concomitant TAP; however, the presence of postoperative TR seemed to unrelated to late RV failure. Prophylactic TAP might not be necessary to prevent late RV failure.
Asunto(s)
Anuloplastia de la Válvula Cardíaca , Insuficiencia Cardíaca/etiología , Corazón Auxiliar , Complicaciones Posoperatorias , Insuficiencia de la Válvula Tricúspide/etiología , Disfunción Ventricular Derecha/etiología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/prevención & control , Insuficiencia Cardíaca/cirugía , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/terapia , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Insuficiencia de la Válvula Tricúspide/diagnóstico , Insuficiencia de la Válvula Tricúspide/epidemiología , Insuficiencia de la Válvula Tricúspide/prevención & control , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/epidemiología , Disfunción Ventricular Derecha/prevención & controlRESUMEN
The soluble guanylate cyclase (sGC)/GMPc pathway plays an important role in controlling pulmonary arterial hypertension (PAH). We investigated whether the novel sGC stimulator trans-4-methoxy-ß-nitrostyrene (T4MN), ameliorates monocrotaline (MCT)-induced PAH. At Day 0, rats were injected with MCT (60 mg/kg, s. c.). Control (CNT) rats received an equal volume of monocrotaline vehicle only (s.c.). Four weeks later, MCT-treated rats were orally treated for 14 days with T4MN (75 mg/kg/day) (MCT-T4MN group) or its vehicle (MCT-V group), and with sildenafil (SIL; 50 mg/kg) (MCT-SIL group). Compared to the CNT group, MCT treatment induced a significant increase in both the Fulton index and RV systolic pressure but significantly reduced the maximum relaxation induced by acetylcholine. Indeed, MCT treatment increased the wall thickness of small and larger pulmonary arterioles. Oral treatment with T4MN and SIL reduced the Fulton index and RV systolic pressure compared to the MCT-V group. Maximum relaxation induced by acetylcholine was significantly enhanced in MCT-SIL group. Both T4MN and SIL significantly reduced the enhanced wall thickness of small and larger pulmonary arterioles. Treatment with T4MN has a beneficial effect on PAH by reducing RV systolic pressure and consequently right ventricular hypertrophy, and by reducing pulmonary artery remodeling. T4MN may represent a new therapeutic or complementary approach for the treatment of PAH.
Asunto(s)
Arteriolas/efectos de los fármacos , Activadores de Enzimas/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Pulmón/irrigación sanguínea , Guanilil Ciclasa Soluble/metabolismo , Estirenos/farmacología , Remodelación Vascular/efectos de los fármacos , Animales , Arteriolas/enzimología , Arteriolas/fisiopatología , Modelos Animales de Enfermedad , Activación Enzimática , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/prevención & control , Monocrotalina , Transducción de Señal , Vasodilatación/efectos de los fármacos , Disfunción Ventricular Derecha/enzimología , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
Right ventricular dysfunction is a predictor for worse outcomes in patients with congenital heart disease. Myocardial ischemia is primarily associated with right ventricular dysfunction in patients with congenital heart disease and may be a therapeutic target for right ventricular dysfunction. Previously, autologous skeletal myoblast patch therapy showed an angiogenic effect for left ventricular dysfunction through cytokine paracrine effects; however, its efficacy in right ventricular dysfunction has not been evaluated. Thus, this study aimed to evaluate the angiogenic effect of autologous skeletal myoblast patch therapy and amelioration of metabolic and functional dysfunction, in a pressure-overloaded right heart porcine model. Pulmonary artery stenosis was induced by a vascular occluder in minipigs; after two months, autologous skeletal myoblast patch implantation on the right ventricular free wall was performed (n = 6). The control minipigs underwent a sham operation (n = 6). The autologous skeletal myoblast patch therapy alleviated right ventricular dilatation and ameliorated right ventricular systolic and diastolic dysfunction. 11C-acetate kinetic analysis using positron emission tomography showed improvement in myocardial oxidative metabolism and myocardial flow reserve after cell patch implantation. On histopathology, a higher capillary density and vascular maturity with reduction of myocardial ischemia were observed after patch implantation. Furthermore, analysis of mRNA expression revealed that the angiogenic markers were upregulated, and ischemic markers were downregulated after patch implantation. Thus, autologous skeletal myoblast patch therapy ameliorated metabolic and functional dysfunction in a pressure-overloaded right heart porcine model, by alleviating myocardial ischemia through angiogenesis.
Asunto(s)
Mioblastos Esqueléticos/trasplante , Isquemia Miocárdica/prevención & control , Estenosis de Arteria Pulmonar/terapia , Disfunción Ventricular Derecha/prevención & control , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Tomografía Computarizada Multidetector , Isquemia Miocárdica/etiología , Isquemia Miocárdica/metabolismo , Neovascularización Fisiológica , Estrés Oxidativo , Estenosis de Arteria Pulmonar/etiología , Estenosis de Arteria Pulmonar/metabolismo , Porcinos , Porcinos Enanos , Trasplante Autólogo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismoRESUMEN
Left ventricular assist device (LVAD) implantation results in superior survival rates compared with optimal medical therapy in patients with end-stage heart failure. However, a potential complication of LVAD implantation is right heart failure (RHF), which can be devastating. Therefore, identifying preoperative risk factors for RHF and optimal management for these patients are critical for ensuring favorable postoperative outcomes. This review focuses on methods of assessing the risk factors for RHF before surgery, including evaluation of biomarkers, echocardiography, hemodynamics, risk-scoring systems, and existing conditions of right heart dysfunction. In addition, the review also explores the perioperative strategic approaches to reducing the likelihood of RHF.
Asunto(s)
Insuficiencia Cardíaca , Corazón Auxiliar , Disfunción Ventricular Derecha , Ecocardiografía , Insuficiencia Cardíaca/terapia , Corazón Auxiliar/efectos adversos , Humanos , Estudios Retrospectivos , Medición de Riesgo , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & controlRESUMEN
ABSTRACT: Pulmonary artery hypertension (PAH) imposes right heart and lung detrimental remodeling which impairs cardiac contractility, physical effort tolerance, and survival. The effects of an early moderate-intensity continuous aerobic exercise training on the right ventricle and lung structure, and on contractility and the calcium (Ca2+) transient in isolated myocytes from rats with severe PAH induced by monocrotaline were analyzed. Rats were divided into control sedentary (CS), control exercise (CE), monocrotaline sedentary (MS), and monocrotaline exercise (ME) groups. Animals from control exercise and ME groups underwent a moderate-intensity aerobic exercise on a treadmill (60 min/d; 60% intensity) for 32 days, after a monocrotaline (60 mg/kg body weight i.p.) or saline injection. The pulmonary artery resistance was higher in MS than in control sedentary (1.36-fold) and was reduced by 39.39% in ME compared with MS. Compared with MS, the ME group presented reduced alveolus (17%) and blood vessel (46%) wall, fibrosis (25.37%) and type I collagen content (55.78%), and increased alveolus (52.96%) and blood vessel (146.97%) lumen. In the right ventricle, the ME group exhibited diminished hypertrophy index (25.53%) and type I collagen content (40.42%) and improved myocyte contraction [ie, reduced times to peak (29.27%) and to 50% relax (13.79%)] and intracellular Ca2+ transient [ie, decreased times to peak (16.06%) and to 50% decay (7.41%)] compared with MS. Thus, early moderate-intensity continuous aerobic exercise prevents detrimental remodeling in the right heart and lung increases in the pulmonary artery resistance and dysfunction in single myocyte contraction and Ca2+ cycling in this model.
Asunto(s)
Señalización del Calcio , Terapia por Ejercicio , Hipertrofia Ventricular Derecha/prevención & control , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Hipertensión Arterial Pulmonar/terapia , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha , Remodelación Ventricular , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Presión Arterial , Modelos Animales de Enfermedad , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Miocitos Cardíacos/patología , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Ratas Wistar , Resistencia Vascular , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
AIMS: Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. METHODS AND RESULTS: Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1ß, TGFß3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. CONCLUSION: The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.
Asunto(s)
Antiarrítmicos/farmacología , Antiinflamatorios/farmacología , Fibrilación Atrial/prevención & control , Ácidos Docosahexaenoicos/farmacología , Atrios Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/prevención & control , Mediadores de Inflamación/metabolismo , Disfunción Ventricular Derecha/prevención & control , Potenciales de Acción/efectos de los fármacos , Animales , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Remodelación Atrial/efectos de los fármacos , Modelos Animales de Enfermedad , Fibrosis , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Fenotipo , Ratas Wistar , Transducción de Señal , Transcriptoma , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.
Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Hipertrofia Ventricular Derecha/prevención & control , Miocardio/metabolismo , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha , Remodelación Ventricular , Animales , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Colágenos Fibrilares/metabolismo , Fibrosis , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Mutación , Miocardio/patología , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas Mutantes , Ratas Sprague-Dawley , Factores Sexuales , Transducción de Señal , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
BackgroundPulmonary hypertension (PH) results in increased right ventricular (RV) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor-neprilysin inhibition using sac/val attenuates RV remodeling in PH.Methods and ResultsRV pressure overload was induced in Sprague-Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo-treated PH, and sac/val-treated PH were studied in a 21-day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH. Sac/val treatment decreased RV maximum pressures (29% improvement, P=0.002), improved RV contractile (30%, P=0.012) and relaxation (29%, P=0.043) functions, reduced RV afterload (35% improvement, P=0.016), and prevented RV-pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P=0.006) and prevented transmural reorientation of RV collagen and myofibers (P=0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P=0.032).ConclusionsSac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.
Asunto(s)
Aminobutiratos/farmacología , Antagonistas de Receptores de Angiotensina/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Inhibidores de Proteasas/farmacología , Tetrazoles/farmacología , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Compuestos de Bifenilo , Colágeno/metabolismo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Miocardio/metabolismo , Miocardio/patología , Neprilisina/antagonistas & inhibidores , Ratas Sprague-Dawley , Valsartán , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies.NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Isotiocianatos/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Remodelación Vascular , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Hipertensión Pulmonar/complicaciones , Isotiocianatos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Arteria Pulmonar/patología , Sulfóxidos , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & controlRESUMEN
AIMS: Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. METHODS AND RESULTS: HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-ß), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation. CONCLUSIONS: PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-ß, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.
Asunto(s)
Acetatos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/prevención & control , Pulmón/efectos de los fármacos , Fibrosis Pulmonar/prevención & control , Disfunción Ventricular Derecha/prevención & control , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Endotelina-1/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Fosforilación , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/fisiopatología , Ratas Wistar , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
BACKGROUND: Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling. METHODS: PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON-normoxic animals with placebo (n=18); PH-Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16). RESULTS: In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone. CONCLUSIONS: Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.