RESUMO
The fetal myocardium is known to be sensitive to hemodynamic load, responding to systolic overload with cellular hypertrophy, proliferation, and accelerated maturation. However, the fetal cardiac growth response to primary volume overload is unknown. We hypothesized that increased venous return would stimulate fetal cardiomyocyte proliferation and terminal differentiation, particularly in the right ventricle (RV). Vascular catheters and pulmonary artery flow probes were implanted in 16 late-gestation fetal sheep: a right carotid artery-jugular vein (AV) fistula was surgically created in nine fetuses, and sham operations were performed on seven fetuses. Instrumented fetuses were studied for 1 wk before hearts were dissected for component analysis or cardiomyocyte dispersion for cellular measurements. Within 1 day of AV fistula creation, RV output was 20% higher in experimental than sham fetuses ( P < 0.0001). Circulating atrial natriuretic peptide levels were elevated fivefold in fetuses with an AV fistula ( P < 0.002). On the terminal day, RV-to-body weight ratios were 35% higher in the AV fistula group ( P < 0.05). Both left ventricular and RV cardiomyocytes grew longer in fetuses with an AV fistula ( P < 0.02). Cell cycle activity was depressed by >50% [significant in left ventricle ( P < 0.02), but not RV ( P < 0.054)]. Rates of terminal differentiation were unchanged. Based on these studies, we speculate that atrial natriuretic peptide suppressed fetal cardiomyocyte cell cycle activity. Unlike systolic overload, fetal diastolic load appears to drive myocyte enlargement, but not cardiomyocyte proliferation or maturation. These changes could predispose to RV dysfunction later in life. NEW & NOTEWORTHY Adaptation of the fetal heart to changes in cardiac load allows the fetus to maintain adequate blood flow to its systemic and placental circulations, which is necessary for the well-being of the fetus. Addition of arterial-venous fistula flow to existing venous return increased right ventricular stroke volume and output. The fetal heart compensated by cardiomyocyte elongation without accelerated cellular maturation, while cardiomyocyte proliferation decreased. Even transient volume overload in utero alters myocardial structure and cardiomyocyte endowment.
Assuntos
Coração Fetal/fisiopatologia , Hipertrofia Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita , Remodelação Ventricular , Animais , Derivação Arteriovenosa Cirúrgica , Fator Natriurético Atrial/sangue , Artérias Carótidas/cirurgia , Pontos de Checagem do Ciclo Celular , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Modelos Animais de Doenças , Feminino , Coração Fetal/metabolismo , Coração Fetal/patologia , Idade Gestacional , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Veias Jugulares/cirurgia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Gravidez , Carneiro Doméstico , Volume Sistólico , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/patologiaRESUMO
Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17ß-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s'). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s' were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s' in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.
Assuntos
Ecocardiografia , Estradiol/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/prevenção & controle , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Estradiol/sangue , Fibrose , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Monocrotalina , Peptídeo Natriurético Encefálico/sangue , Ratos Sprague-Dawley , Fatores de Tempo , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologiaRESUMO
BACKGROUND: Pulmonary hypertension (PH), caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV) dysfunction. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet. RESULTS: The majority (95.1%) of PH patients had 25(OH)D levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OH)D levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated. CONCLUSIONS: Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OH)D are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.
Assuntos
Hipertensão Pulmonar/dietoterapia , Hipertrofia Ventricular Direita/dietoterapia , Vitamina D/análogos & derivados , Vitamina D/administração & dosagem , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Artéria Pulmonar , Ratos , Remodelação Ventricular/efeitos dos fármacos , Vitamina D/sangueRESUMO
BACKGROUND: Previous echocardiographic studies have revealed an association between enlarged cardiac chamber volumes and elevated troponin concentrations. An automatic 4-chamber volumetric analysis tool was adopted to investigate this association in patients who underwent cardiac-gated computed tomography angiography (CCTA). HYPOTHESIS: We hypothesized that troponin concentration within the normal range correlates with cardiac chambers' volumes. METHODS: Serum troponin was obtained from 157 ambulatory patients before undergoing CCTA for nonacute coronary artery evaluation. Volumes of the cardiac chambers and the left ventricular mass were automatically analyzed and indexed to body surface area. Patients with a troponin concentrations within the upper quartile (>0.007 ng/mL, n = 39) were compared to patients with a troponin concentrations within the 3 lower quartiles of troponin concentrations (≤0.007 ng/mL, n = 118). RESULTS: None of the patients had a troponin concentration >0.05 ng/mL (the 99th percentile of the general population). There were no significant differences in baseline characteristics between the groups. There were significant correlations between troponin and ventricular volumes after adjustments for age and gender. In an analysis that included 107 patients without any known heart diseases, including those pathological findings in the current CCTA, there were significant correlations between troponin and the left and right ventricular volumes after adjustments for age, gender, and baseline characteristics (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, P = 0.002 and OR: 1.11, 95% CI: 1.04-1.19, P = 0.002; respectively). CONCLUSIONS: Using the technology of automatic volumetric analysis in individuals undergoing CCTA, an association between larger right and left cardiac chambers and higher levels of troponin concentration was shown.
Assuntos
Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico , Tomografia Computadorizada Multidetectores , Troponina/sangue , Biomarcadores/sangue , Técnicas de Imagem de Sincronização Cardíaca , Vasos Coronários/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de RegistrosRESUMO
OBJECTIVES: Drag-reducing polymers (DRPs) are blood-soluble macromolecules which may increase blood flow and reduce vascular resistance. The purpose of the present study was to observe the effect of DRPs on monocrotaline-induced pulmonary hypertension (PH) in the rat model. METHODS: A total of 64 male Wistar rats were randomly divided into four groups: Group I (pulmonary hypertension model + DRP treatment); Group II (pulmonary hypertension model + saline treatment); Group III (control + DRP treatment); Group IV (control + saline treatment). After five weeks, comparisons were made of the following indices: survival rate, body weight, blood pressure, right ventricular systolic pressure, right ventricular hypertrophy, wall thickness of pulmonary arteries, the internal diameter of small pulmonary arteries, plasma IL-1ß and IL-6. RESULTS: The survival rate after 5 weeks varied significantly across all groups (P=0.013), but the survival rates of Groups I and II were not statistically significantly different. Administration of DRP (intravenous injection twice weekly) attenuated the PH-induced increase in right ventricular systolic pressure and suppressed the increases in right ventricular (RV) weight and the ratio of right ventricular weight to left ventricle plus septum weight (RV/LV + S). DRP treatment also significantly decreased the wall thickness of pulmonary arteries, augmented the internal diameter of small pulmonary arteries, and suppressed increases in the plasma levels of IL-1ß and IL-6. CONCLUSIONS: DRP treatment with intravenous injection effectively inhibited the development of monocrotaline-induced pulmonary hypertension in the rat model. DRPs may have potential application for the treatment of pulmonary hypertension.
Assuntos
Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/prevenção & controle , Monocrotalina/toxicidade , Polietilenoglicóis/farmacologia , Polímeros/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Hemodinâmica , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/patologia , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Wistar , Tensoativos/farmacologiaRESUMO
The response of the right ventricle (RV) to pulmonary arterial hypertension (PAH) involves changes in contractile function, chamber size, hypertrophy, and extracellular matrix (ECM). Galectin-3 (Gal-3) is a mediator of myocardial ECM metabolism and biomarker for left heart remodeling, yet its ability to reflect RV remodeling is unknown. We hypothesized that serum Gal-3 levels correlate with RV morphology and function in PAH, and that Gal-3 is associated with circulating markers of ECM. Fifteen subjects with PAH and 10 age-matched controls underwent same-day echocardiography, cardiac magnetic resonance (CMR) imaging, and phlebotomy for Gal-3 and ECM biomarkers including N-terminal propeptide of type III collagen type (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA). RV ejection fraction, end diastolic volume index, end systolic volume index, and mass index were calculated using CMR. Echocardiography was used to estimate RV systolic pressure and measure RV strain. Serum Gal-3, TIMP-1, and HA levels were all significantly increased in PAH subjects when compared to controls. Gal-3 correlated with RV ejection fraction (ρ -0.44, p 0.03), end diastolic volume index (ρ 0.42, p 0.03), end systolic volume index (ρ 0.44, p 0.027), mass index (ρ 0.47, p 0.016), systolic pressure (ρ 0.55, p < 0.001), and strain (ρ 0.43, p 0.03). Gal-3 levels positively correlated with the ECM markers TIMP-1 and HA but not with PIIINP. In conclusion, Gal-3 levels are associated with multiple indices of RV function and morphology. Gal-3 may represent a novel biomarker for RV remodeling and associated ECM turnover in PAH.
Assuntos
Galectina 3/sangue , Hipertensão Pulmonar/sangue , Hipertrofia Ventricular Direita/sangue , Disfunção Ventricular Direita/sangue , Função Ventricular Direita , Remodelação Ventricular , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas , Ecocardiografia Doppler de Pulso , Fibrose , Galectinas , Humanos , Ácido Hialurônico/sangue , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/diagnóstico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Imagem Cinética por Ressonância Magnética , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Fragmentos de Peptídeos/sangue , Projetos Piloto , Valor Preditivo dos Testes , Pró-Colágeno/sangue , Estudos Prospectivos , Inibidor Tecidual de Metaloproteinase-1/sangue , Regulação para Cima , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Pressão VentricularRESUMO
RATIONALE: Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival. OBJECTIVES: We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy. METHODS AND RESULTS: Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron, and ferritin), reduced erythropoiesis, and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodeling with prominent muscularization, medial hypertrophy, and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of hypoxia-induced factor-1α and hypoxia-induced factor-2α, nuclear factor of activated T cells and survivin, and signal transducers and activators of transcription-3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, glucose transporter 1, and glycolytic genes, hk1 and pdk1, lung fluorine-18-labeled 2-fluoro-2-deoxyglucose ligand uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodeling were reversed by iron replacement (ferric carboxymaltose, 75 mg/kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, 2 putative treatments explored for pulmonary arterial hypertension that target aerobic glycolysis and proliferation, respectively. CONCLUSIONS: These data suggest a major role for iron in pulmonary vascular homeostasis and support the clinical evaluation of iron replacement in patients with pulmonary hypertension.
Assuntos
Pressão Arterial , Deficiências Nutricionais/complicações , Hipertensão Pulmonar/etiologia , Deficiências de Ferro , Artéria Pulmonar/fisiopatologia , Remodelação Vascular , Animais , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Benzamidas/farmacologia , Proliferação de Células , Deficiências Nutricionais/sangue , Deficiências Nutricionais/tratamento farmacológico , Ácido Dicloroacético/farmacologia , Modelos Animais de Doenças , Eritropoese , Compostos Férricos/farmacologia , Ferritinas/sangue , Glicólise , Hematínicos/farmacologia , Homeostase , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Mesilato de Imatinib , Ferro/sangue , Fígado/metabolismo , Masculino , Maltose/análogos & derivados , Maltose/farmacologia , Piperazinas/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Pirimidinas/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Transferrina/metabolismo , Remodelação Vascular/efeitos dos fármacosRESUMO
OBJECTIVES: The aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents. BACKGROUND: Obesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics. METHODS: We prospectively recruited 61 obese (13.5 ± 2.7 years of age, 46% male sex, SD score body mass index, 2.52 ± 0.60) and 40 nonobese (14.1 ± 2.8 years of age, 50% male sex, SD score body mass index, -0.33 ± 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children. RESULTS: Compared with nonobese children, blood pressure, low-density lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly lower. Compared with nonobese children, obese children were characterized by enlarged left- and right-sided cardiac chambers, thicker left ventricular walls, and, consequently, increased left ventricular mass. Despite a comparable left ventricular ejection fraction, decreased tissue Doppler-derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking-derived longitudinal (-18.2 ± 2.0 vs. -20.5 ± 2.3, p < 0.001) and circumferential (-17.0 ± 2.7 vs. -19.5 ± 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both longitudinal strain and circumferential strain were independently associated with obesity. CONCLUSIONS: The results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium.
Assuntos
Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Direita/etiologia , Obesidade Infantil/complicações , Adolescente , Biomarcadores/sangue , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , LDL-Colesterol/sangue , Ecocardiografia Doppler , Feminino , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/etnologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico , Hipertrofia Ventricular Direita/etnologia , Hipertrofia Ventricular Direita/fisiopatologia , Modelos Lineares , Masculino , Análise Multivariada , Variações Dependentes do Observador , Obesidade Infantil/sangue , Obesidade Infantil/diagnóstico , Obesidade Infantil/etnologia , Obesidade Infantil/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Volume Sistólico , Função Ventricular Esquerda , População Branca , Adulto JovemRESUMO
BACKGROUND: Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels. METHODS: Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart. RESULTS: When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 ± 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern. CONCLUSIONS: Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association.
Assuntos
Anemia Falciforme/complicações , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Direita/diagnóstico , Fígado/metabolismo , Imageamento por Ressonância Magnética , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Direita/diagnóstico , Função Ventricular Esquerda , Função Ventricular Direita , Adulto , Anemia Falciforme/sangue , Estudos de Casos e Controles , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Valor Preditivo dos Testes , Estudos Prospectivos , Volume Sistólico , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Adulto JovemRESUMO
The central pathway for oxygen-dependent control of red cell mass is the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. PHD site specifically prolyl hydroxylates the transcription factor HIF-α, thereby targeting the latter for degradation. Under hypoxia, this modification is attenuated, allowing stabilized HIF-α to activate target genes, including that for erythropoietin (EPO). Studies employing genetically modified mice point to Hif-2α, one of two main Hif-α isoforms, as being the critical regulator of Epo in the adult mouse. More recently, erythrocytosis patients with heterozygous point mutations in the HIF2A gene have been identified; whether these mutations were polymorphisms unrelated to the phenotype could not be ruled out. In the present report, we characterize a mouse line bearing a G536W missense mutation in the Hif2a gene that corresponds to the first such human mutation identified (G537W). We obtained mice bearing both heterozygous and homozygous mutations at this locus. We find that these mice display, in a mutation dose-dependent manner, erythrocytosis and pulmonary hypertension with a high degree of penetrance. These findings firmly establish missense mutations in HIF-2α as a cause of erythrocytosis, highlight the importance of this HIF-α isoform in erythropoiesis, and point to physiologic consequences of HIF-2α dysregulation.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipertensão Pulmonar/genética , Mutação de Sentido Incorreto , Policitemia/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Gasometria , Células Cultivadas , Modelos Animais de Doenças , Endotelina-1/genética , Endotelina-1/metabolismo , Eritropoese , Eritropoetina/sangue , Eritropoetina/genética , Expressão Gênica , Técnicas de Introdução de Genes , Estudos de Associação Genética , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/fisiopatologia , Rim/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese , Policitemia/sangue , Policitemia/fisiopatologia , Proteínas Proto-Oncogênicas c-sis/genética , Proteínas Proto-Oncogênicas c-sis/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Taxa Respiratória , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Improved medical techniques have allowed most women with repaired tetralogy of Fallot (TOF) to reach childbearing age. The predictors of adverse events and the effects of pregnancy on cardiac function have not been clearly described in these patients. METHODS AND RESULTS: In the present study we retrospectively reviewed 40 deliveries in 25 patients with repaired TOF. There were 23 patients in New York Heart Association (NYHA) class I, and 2 in classes II-III before pregnancy. The mean age at delivery was 29.1 years and the mean gestational period was 37.8 weeks. Seven pregnancies (17.5%) in 7 patients were complicated with cardiac events such as a decline in NYHA class and arrhythmia. History of ablation and the baseline cardiothoracic ratio on chest radiography were predictors of adverse events. Peak plasma brain natriuretic peptide (BNP) level after the second trimester was higher in patients with cardiac events. Left ventricular size and contraction did not change from before to after pregnancy, but the right ventricle was enlarged at 6 months after delivery. CONCLUSIONS: Many of the pregnancies in women with repaired TOF were successful. However, careful management is required for some patients and the BNP level may be a useful marker to identify these patients. Because the right heart tended to be enlarged in the late postpartum period, pregnancy may also affect the long-term prognosis of patients with repaired TOF.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Hipertrofia Ventricular Direita/etiologia , Complicações Cardiovasculares na Gravidez/etiologia , Resultado da Gravidez , Tetralogia de Fallot/cirurgia , Adulto , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Feminino , Idade Gestacional , Humanos , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico , Hipertrofia Ventricular Direita/fisiopatologia , Japão , Peptídeo Natriurético Encefálico/sangue , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Early prediction of infarct size and of the subsequent development of congestive heart failure (CHF) and pulmonary hypertension (PH) would be useful in therapeutic trials using the rat myocardial infarction (MI) model. METHODS: A total of 194 rats were subjected to MI or sham surgery, and plasma cardiac troponin T (cTnT) was measured 24 h after surgery in rats. Echocardiography was performed after 2 and 5 weeks. Hemodynamic and morphometric parameters were evaluated 5 weeks after MI. RESULTS: cTnT had strong positive correlations with left ventricular (LV) wall motion abnormalities at 2 and 5 weeks (R=.85 and .89; P<.0001), and with histological infarct size (R=.87, P<.0001). cTnT ≥5.1 µg/l predicted LV wall motion abnormalities ≥ 30% with a sensitivity of 90.9% and specificity of 84.0%. Rats with cTnT≥5.1 µg/l developed PH [right ventricular (RV) systolic pressure 37 ± 3 vs. 23 ± 0.6 mmHg], RV hypertrophy (RV/LV+septum weight 42 ± 4% vs. 24 ± 0.5%), and lung structural remodeling (all P<.01). CONCLUSION: Early single cTnT measurement correlates with infarct size in rats, and a cutoff value of 5.1 µg/l provides good sensitivity and specificity to predict CHF with secondary PH. cTnT could be used for treatment allocations in therapeutic trials of secondary pulmonary hypertension using this model.
Assuntos
Insuficiência Cardíaca/etiologia , Hipertensão Pulmonar/etiologia , Infarto do Miocárdio/sangue , Miocárdio/patologia , Troponina T/sangue , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/etiologia , Contração Miocárdica , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Valor Preditivo dos Testes , Ratos , Sensibilidade e Especificidade , Fatores de Tempo , Ultrassonografia , Função Ventricular Esquerda , Função Ventricular Direita , Pressão VentricularRESUMO
OBJECTIVE: The traditionally accepted mechanism for ventricular adaptation to obesity suggests that cavity dilatation in response to increased blood volume and elevated filling pressure results in ventricular hypertrophy as a compensatory mechanism. Our hypothesis was that, instead, initiation of ventricular hypertrophy in obesity may be explained by changes in hormonal milieu and not by cavity dilatation. RESEARCH DESIGN AND METHODS: 88 female subjects without identifiable cardiovascular risk factors, covering a wide range of body mass indices (BMI), from normal (21.2 ± 1.6 kg/m(2)) to severely obese (45.0 ± 4.6 kg/m(2)), underwent cardiovascular MRI to determine left ventricular (LV) and right ventricular (RV) mass and volumes. RESULTS: BMI correlated positively with LV and RV mass and end-diastolic volumes (EDV). However overweight is associated with a significant LV and RV hypertrophy (LV: 78 ± 11 g vs 103 ± 16 g, p<0.01; RV: 26 ± 7 g vs 40 ± 11 g, p<0.01) was observed in the absence of differences in LV and RV volumes (LV: EDV 119 ± 15 vs 121 ± 21 ml, p>0.99, RV: 131 ± 17 vs 130 ± 24 ml; p>0.99). Furthermore, significant increases of serum leptin occurred at this pre-obese stage (15.6 ± 19 vs 36.5 ± 22 ng/ml; p=0.013). CONCLUSION: In a cohort of healthy female subjects with a wide range of BMIs, ventricular hypertrophy occurs without associated cavity dilatation in overweight individuals, while in manifest obesity, both cavity dilatation and ventricular hypertrophy occur. Elevated leptin levels may have a role in this effect on ventricular mass.
Assuntos
Índice de Massa Corporal , Cardiomegalia/etiologia , Obesidade/complicações , Adulto , Cardiomegalia/sangue , Cardiomegalia/patologia , Estudos de Coortes , Feminino , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/patologia , Insulina/sangue , Resistência à Insulina/fisiologia , Leptina/sangue , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , Função Ventricular Esquerda/fisiologia , Função Ventricular Direita/fisiologiaRESUMO
BACKGROUND: Plasma B-type natriuretic peptide (BNP) levels are closely related to symptoms in left ventricle (LV) systolic heart failure, although marked regarding heterogeneity levels among subjects are reported. AIMS: To assess the influence of right ventricle on plasma BNP in the patients with different grades of its overload secondary to severe mitral valve stenosis (MVS). METHODS: Plasma BNP was evaluated in MVS patients (n = 27) before valve replacement and during follow-up (FUV) 401 ± 42 days after operation. RESULTS: Initial examination showed severe MVS (0.9 ± 0.2 cm²), left atrial enlargement (LAI 30 ± 4.5 mm m⻲), right ventricle diastolic dilatation (RVDI 16 ± 3.6 mm m⻲), normal LV size/function and elevated BNP levels (166 ± 137 pg ml⻹). FUV examination revealed a significant reduction in LAI (27 ± 2.2 mm m⻲), RVDI (14 ± 1.6 mm m⻲) and BNP levels (80 ± 35 pg ml⻹). The regression analysis of the initial parameters found RVDI to be the strongest predictor (R² = 0.61; P<0.0001) for BNP level, whereas RVDI reduction was the strongest factor for BNP decrease (R² = 0.65; P<0.0001) during FUV. CONCLUSIONS: Right ventricle should be taken into account as a potential important source of plasma BNP owing to the fact that LV size and function are well preserved in MVS patients. RVDI determines BNP plasma levels whereas after MVS removal, the RVDI reduction predicts BNP level decrease.
Assuntos
Insuficiência Cardíaca/etiologia , Implante de Prótese de Valva Cardíaca , Hipertrofia Ventricular Direita/etiologia , Estenose da Valva Mitral/cirurgia , Peptídeo Natriurético Encefálico/sangue , Cardiopatia Reumática/cirurgia , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Humanos , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estenose da Valva Mitral/sangue , Estenose da Valva Mitral/complicações , Estenose da Valva Mitral/diagnóstico por imagem , Estenose da Valva Mitral/fisiopatologia , Polônia , Análise de Regressão , Cardiopatia Reumática/sangue , Cardiopatia Reumática/complicações , Cardiopatia Reumática/diagnóstico por imagem , Cardiopatia Reumática/fisiopatologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Função Ventricular Esquerda , Função Ventricular DireitaRESUMO
Normotensive patients with acute pulmonary embolism (PE) who have increased troponin levels and right ventricular (RV) dysfunction are thought to be at high risk of death, but the level of risk is unclear. We retrospectively evaluated outcome in 1,273 stable patients with PE who had echocardiographic evaluations of RV size and/or measurement of cardiac troponin I (cTnI). In-hospital all-cause mortality was higher in those with RV enlargement (8.0%, 19 of 237, vs 3.3%, 22 of 663, p = 0.003). With an increased cTnI, irrespective of RV enlargement, all-cause mortality was 8.0% (28 of 330) versus 1.9% (15 of 835) in patients with a normal cTnI (p <0.0001). In patients with an increased cTnI combined with an enlarged right ventricle, all-cause mortality was 10.2% (12 of 118) compared to 1.9% (8 of 421) in patients who had neither (p <0.0001). These data show that increased levels of cTnI and RV enlargement are associated with an adverse outcome in stable patients with acute PE. In conclusion, increased levels of cTnI in combination with RV enlargement might indicate a group who would benefit from intense monitoring and aggressive treatment if subsequently indicated. The outcomes, however, were not extreme enough to warrant routine thrombolytic therapy.
Assuntos
Hipertrofia Ventricular Direita/fisiopatologia , Embolia Pulmonar/mortalidade , Embolia Pulmonar/fisiopatologia , Troponina I/sangue , Disfunção Ventricular Direita/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Mortalidade Hospitalar , Humanos , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/mortalidade , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/sangue , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento , Ultrassonografia , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/mortalidadeRESUMO
RATIONALE: In animal models of pulmonary hypertension, simvastatin has been shown to reduce pulmonary artery pressure and induce regression of associated right ventricular (RV) hypertrophy. OBJECTIVES: To assess the therapeutic value of simvastatin in patients with pulmonary arterial hypertension (PAH). METHODS: Forty-two patients with PAH were randomized to receive either simvastatin (80 mg/d) or placebo in addition to current care for 6 months, and thereafter offered open-label simvastatin. The primary outcome was change in RV mass, assessed by cardiac magnetic resonance (CMR). MEASUREMENTS AND MAIN RESULTS: At 6 months, RV mass decreased by 5.2 +/- 11 g in the statin group (P = 0.045) and increased 3.9 +/- 14 g in the placebo group. The treatment effect was -9.1 g (P = 0.028). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased significantly in the statin group (-75 +/- 167 fmol/ml; P = 0.02) but not the placebo group (49 +/- 224 fmol/ml; P = 0.43; overall treatment effect -124 fmol/ml; P = 0.041). There were no significant changes in other outcome measures (including 6-minute walk test, cardiac index, and circulating cytokines). From 6 to 12 months, both RV mass and NT-proBNP increased toward baseline values in 16 patients on active treatment who continued with simvastatin but remained stable in 18 patients who switched from placebo to simvastatin. Two patients required a reduction in dose but not cessation of simvastatin. CONCLUSIONS: Simvastatin added to conventional therapy produces a small and transient early reduction in RV mass and NT-proBNP levels in patients with PAH, but this is not sustained over 12 months.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Sinvastatina/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/patologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Ultrassonografia , Adulto JovemRESUMO
Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure (PAP), pulmonary vascular remodeling and right ventricular hypertrophy, which are mainly due to endothelial dysfunction. Electro-acupuncture has shown beneficial effects on cardiovascular homeostasis, but little evidence has been obtained on pulmonary effects. The goal of the present study was to investigate whether electro-acupuncture on bladder-13 and -15 points can protect against chronic hypoxia-induced PH by regulating endothelium-derived endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). Male Wistar rats were exposed to hypoxia to induce PH. Hemodynamic analysis revealed that mean PAP was similar under normoxic conditions. Chronic hypoxia increased mean PAP to 37 +/- 3 mmHg, and electro-acupuncture attenuated it to 29 +/- 3 mmHg. Absolute right ventricular weight was ameliorated by electro-acupuncture from 0.288 +/- 0.048 g to 0.228 +/- 0.029 g under hypoxic conditions. Hypoxia-induced right ventricular hypertrophy index decreased from 0.477 +/- 0.069 to 0.378 +/- 0.053 with electro-acupuncture treatment. Histological examination revealed that hypoxic rats showed increased medial pulmonary artery wall thickness as well as muscularization. However, these alternations by chronic hypoxia were attenuated by electro-acupuncture. There was no difference in eNOS or ET-1 between groups under normoxic conditions. Electro-acupuncture treatment significantly improved the circulating eNOS concentration (365.36 +/- 31.51 pg/mL) compared with only hypoxia exposure (247.60 +/- 30.64 pg/mL). In lung homogenate, levels of eNOS under hypoxia increased from 684.96 +/- 117.90 to 869.86 +/- 197.61 pg/mg by electro-acupuncture treatment. Levels of ET-1 changed oppositely to eNOS in response to electro-acupuncture (ET-1 in plasma, 29.44 +/- 2.09 versus 20.70 +/- 2.37 pg/mL; ET-1 in lung homogenate, 120.51 +/- 3.03 versus 110.60 +/- 4.04 pg/mg). In conclusion, these results indicated that treatment with electro-acupuncture can protect against hypoxia-induced PH, possibly by regulating the balance of endothelium-derived vasoconstrictors and vasodilators.
Assuntos
Eletroacupuntura , Endotelina-1/sangue , Endotélio/metabolismo , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Óxido Nítrico Sintase Tipo III/sangue , Animais , Hemodinâmica , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/enzimologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/sangue , Pulmão/enzimologia , Pulmão/patologia , Pulmão/fisiopatologia , Ratos , Ratos Wistar , Extratos de TecidosRESUMO
AIMS: Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression. METHODS AND RESULTS: Right ventricular heart failure was induced in male Wistar rats by intraperitoneal injection of monocrotaline (MCT). Two groups were studied: MCT-treated rats (MCT-rats), and age-matched controls (CON-rats). Serial echocardiography and in vivo 67-Gallium ((67)Ga) scintigraphy were performed. Local inflammation in the RV was assessed by (i) ex vivo semi-quantitative (67)Ga autoradiography, (ii) immunohistochemistry of myeloperoxidase (MPO), a marker of neutrophil activity, and (iii) mRNA assays of tumour necrosis factor-alpha (TNF-alpha). In MCT-rats, (67)Ga scintigraphy showed increased myocardial uptake which started during the early stages of RV disease. (67)Ga autoradiography revealed that this increased (67)Ga uptake occurred in the RV and inter-ventricular septum, but not in the LV. The stage-dependent increases of in vivo (67)Ga RV myocardial uptake were paralleled by increases in mRNA gene expression for TNF-alpha in RV, and increased MPO staining in RV. CONCLUSION: Development and progression of RV heart failure is associated with an early increase in RV inflammation. (67)Ga scintigraphy may be used for the serial assessment of inflammation and monitoring of disease progression in RV heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Inflamação/etiologia , Animais , Autorradiografia , Modelos Animais de Doenças , Progressão da Doença , Radioisótopos de Gálio , Perfilação da Expressão Gênica , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Hipertrofia Ventricular Direita/sangue , Imunoquímica , Masculino , Monocrotalina/efeitos adversos , Miocárdio/metabolismo , Ativação de Neutrófilo/fisiologia , Peroxidase/metabolismo , Cintilografia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/análise , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/complicações , Disfunção Ventricular Direita/diagnóstico por imagemRESUMO
Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure, and death. Endothelial dysfunction and inflammation were implicated in the pathogenesis of PAH. Epoxyeicosatrienoic acids (EETs), products of the cytochrome P450 epoxygenase metabolism of arachidonic acid, are potent vasodilators that possess anti-inflammatory and other protective properties in endothelial cells. We investigated whether gene delivery with the human cytochrome P450 epoxygenase 2J2 (CYP2J2) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Significant pulmonary hypertension developed 3 weeks after the administration of MCT, but gene therapy with CYP2J2 significantly attenuated the development of pulmonary hypertension and pulmonary vascular remodeling, without causing changes in systemic arterial pressure or heart rate. These effects were associated with increased pulmonary endothelial NO synthase (eNOS) expression and its activity, inhibition of inflammation in the lungs, and transforming growth factor (TGF)-ß/type II bone morphogenetic protein receptor (BMPRII)-drosophila mothers against decapentaplegic proteins (Smads) signaling. Collectively, these data suggest that gene therapy with CYP2J2 may have potential as a novel therapeutic approach to this progressive and oftentimes lethal disorder.