RESUMEN
Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.
Asunto(s)
Hipertensión Pulmonar , Hipertrofia Ventricular Derecha , Monoaminooxidasa , Especies Reactivas de Oxígeno , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Ratones Noqueados , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Monoaminooxidasa/deficiencia , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Especies Reactivas de Oxígeno/metabolismo , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/patologíaRESUMEN
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Mitocondrias Cardíacas , Animales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Masculino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/genética , Proteómica , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/patología , Función Ventricular Derecha , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/patología , Ratas , Función Ventricular Izquierda , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/genética , Transcriptoma , Ratas Sprague-Dawley , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genéticaRESUMEN
PURPOSE: To investigate right ventricular (RV) volume and mass by cardiac magnetic resonance (CMR) and the added value of tissue tracking strain analysis as markers of RV dysfunction in pediatric patients with end-stage renal disease (ESRD) and preserved RV ejection fraction. MATERIALS AND METHODS: Twenty-five children with ESRD and preserved RVEF (>50%) and 10 healthy control children were enrolled. Tissue tracking CMR was used to assess Global Longitudinal, circumferential (GCS), and radial short and long axes (GRS SAX and GRS LAX) RV strains in the patients group compared with controls. Correlations between strain parameters and other CMR parameters and clinical biomarkers were assessed. Binary logistic regression was used to test the independence of cofounders and detect their significance. RESULTS: RV end-diastolic volume and mass (RVMi) were significantly higher in patients (97.2±19.3 mL/m 2 and 26.6±7gr/m 2 ) than control (71±7.8 mL/m 2 and 11.9±2 gr/m 2 , P values 0.000). All RV global strain parameters were significantly impaired in patients compared with control (all P values <0.05). RV Global Longitudinal was significantly correlated to LVEF (r=-0.416, P =0.039), LVEDVi (r=0.481, P =0.015), LVMi (r=0.562, P =0.004), and systolic blood pressure index (r=0.586, P =0.002). RV GRS (LAX) was significantly correlated to LV GCS (r=-0.462, P =0.020) and LV GRS (SAX) (r=0.454, P =0.023). GRS (SAX) and GCS demonstrated the highest diagnostic accuracy (area under curve: 0.82 and 0.81) to detect strain impairment. Univariate binary logistic regression with patients versus control as dependent variables identified LVMi, RV end-diastolic volume, RVMi, weight, body surface area, RV GCS, RV GRS (LAX), RV GRS (SAX), LV GCS, and LV GRS (SAX) as significantly correlated to patients with ESRD. When adjusted to other cofounders in the multivariable model, only RVMi remained as an independent significant cofounder (Odds ratio:0.395, P =0.046). CONCLUSION: RV global strain, volume, and mass by CMR are markers of RV dysfunction in ESRD pediatric patients with preserved RVEF.
Asunto(s)
Fallo Renal Crónico , Disfunción Ventricular Derecha , Humanos , Niño , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Magnética , Ventrículos Cardíacos , Volumen Sistólico , Fallo Renal Crónico/diagnóstico por imagen , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/patología , Función Ventricular IzquierdaRESUMEN
BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a pulmonary vasculature obstructive disease that leads to right heart failure and death. Maresin 1 is an endogenous lipid mediator known to promote inflammation resolution. However, the effect of Maresin 1 on PAH remains unclear. EXPERIMENTAL APPROACH: The serum Maresin 1 concentration was assessed using UPLC. A mouse model of PAH was established by combining the Sugen 5416 injection and hypoxia exposure. After treatment with Maresin 1, the right ventricular systolic pressure (RVSP) and right ventricular function were measured by haemodynamic measurement and echocardiography, respectively. Vascular remodelling was evaluated by histological staining. Confocal microscopy and western blot were used to test related protein expression. In vitro cell migration, proliferation and apoptosis assays were performed in primary rat pulmonary artery smooth muscle cells (PASMCs). Western blotting and siRNA transfection were used to clarify the mechanism of Maresin 1. KEY RESULTS: Endogenous serum Maresin 1 was decreased in PAH patients and mice. Maresin 1 treatment decreased RVSP and attenuated right ventricular dysfunction (RVD) in the murine PAH model. Maresin 1 reversed abnormal changes in pulmonary vascular remodelling, attenuating endothelial to mesenchymal transformation and enhancing apoptosis of α-SMA positive cells. Furthermore, Maresin 1 inhibited PASMC proliferation and promoted apoptosis by inhibiting STAT, AKT, ERK, and FoxO1 phosphorylation via LGR6. CONCLUSION AND IMPLICATIONS: Maresin 1 improved abnormal pulmonary vascular remodelling and right ventricular dysfunction in PAH mice, targeting aberrant PASMC proliferation. This suggests Maresin 1 may have a potent therapeutic effect in vascular disease.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Proliferación Celular , Ácidos Docosahexaenoicos/farmacología , Ratones , Miocitos del Músculo Liso , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar , ARN Interferente Pequeño/farmacología , Ratas , Remodelación Vascular , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre to postpuberty. Rat pups (n = 57, 3 wk old, 30-45 g) were subjected to PAB or sham surgery. Animals were euthanized either before or after puberty (4 and 8 wk postsurgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 wk, whereas females did not. After 8 wk, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 wk in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared with males (P = 0.055). Histology showed significantly less RV myocardial fibrosis in female compared with male PAB rats 8 wk after surgery. Myosin heavy chain 7-to-6 ratio switch and calcineurin signaling were less pronounced in female PAB rats compared with males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure compared with males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones.NEW & NOTEWORTHY In this study, we describe sex differences in our unique weanling rat model of increased RV pressure load by pulmonary artery banding. We are the first to assess temporal sex-related differences in RV adaptation during pubertal development. Female rats show superior RV function and less diastolic dysfunction and fibrosis compared with male rats. These differences are already present before puberty, indicating that the differences in RV adaptation are not only determined by sex hormones.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Derecha , Animales , Femenino , Fibrosis , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos , Masculino , Ratas , Disfunción Ventricular Derecha/patología , Función Ventricular Derecha , Presión VentricularRESUMEN
OBJECTIVE: Acute pulmonary embolism (PE) is a life-threatening disease with a high mortality. Computed tomographic pulmonary angiography (CTPA) is used in clinical routine for diagnosis of PE. Many pulmonary obstruction scores were proposed to aid in stratifying clinical course of PE. The purpose of the present study was to compare common pulmonary obstruction scores in PE in regard of time efficiency and interreader agreement based upon a representative patient sample. METHODS: Overall, 50 patients with acute PE were included in this single center, retrospective analysis. Two readers scored the CT images blinded to each other and assessed the scores proposed by Mastora et al., Qanadli et al., Ghanima et al. and Kirchner et al. The required time was assessed of each reading for scoring. RESULTS: For reader 1, Mastora score took the longest time duration, followed by Kirchner score, Qanadli score and finally Ghanima score (every test, p<0.0001). The interreader variability was excellent for all scores with no significant differences between them. In the Spearman's correlation analysis strong correlations were identified between the scores of Mastora, Qanadli and Kirchner, whereas Ghanima score was only moderately correlated with the other scores. There was a weak correlation between time duration and Mastora score (r = 0.35, p = 0.014). For the Ghanima score, a significant inverse correlation was found (r = -0.67, p<0.0001). CONCLUSION: For the investigated obstruction scores, there are significant differences in regard of time consumption with no relevant differences in regard of interreader variability in patients with acute pulmonary embolism. Mastora score requires the most time effort, whereas the score by Ghanima the least time.
Asunto(s)
Angiografía por Tomografía Computarizada/métodos , Embolia Pulmonar/patología , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Disfunción Ventricular Derecha/patología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Embolia Pulmonar/diagnóstico por imagen , Estudios Retrospectivos , Disfunción Ventricular Derecha/diagnóstico por imagen , Adulto JovenRESUMEN
Although pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening.NEW & NOTEWORTHY Using a novel combination of hemodynamic and morphological measurements over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we found that compensated systolic function was almost entirely explained by RV hypertrophy, but subsequently altered RV end-diastolic mechanics were primarily explained by passive myocardial stiffening that was not associated with significant collagen extracellular matrix accumulation.
Asunto(s)
Ventrículos Cardíacos/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertensión Arterial Pulmonar/complicaciones , Disfunción Ventricular Derecha/etiología , Función Ventricular Derecha , Remodelación Ventricular , Animales , Fenómenos Biomecánicos , Diástole , Modelos Animales de Enfermedad , Fibrosis , Ventrículos Cardíacos/patología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Modelos Cardiovasculares , Miocardio/patología , Hipertensión Arterial Pulmonar/fisiopatología , Ratas Sprague-Dawley , Sístole , Factores de Tiempo , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
The EUROMACS Right-Sided Heart Failure Risk Score was developed to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. The predictive ability of the EUROMACS score has not been tested in other cohorts. We performed a single center analysis of a continuous-flow (CF) LVAD cohort (n = 254) where we calculated EUROMACS risk scores and assessed for right ventricular heart failure after LVAD implantation. Thirty-nine percent of patients (100/254) had post-operative RVF, of which 9% (23/254) required prolonged inotropic support and 5% (12/254) required RVAD placement. For patients who developed RVF after LVAD implantation, there was a 45% increase in the hazards of death on LVAD support (HR 1.45, 95% CI 0.98-2.2, p = 0.066). Two variables in the EUROMACS score (Hemoglobin and Right Atrial Pressure to Pulmonary Capillary Wedge Pressure ratio) were not predictive of RVF in our cohort. Overall, the EUROMACS score had poor external discrimination in our cohort with area under the curve of 58% (95% CI 52-66%). Further work is necessary to enhance our ability to predict RVF after LVAD implantation.
Asunto(s)
Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/patología , Disfunción Ventricular Derecha/patología , Anciano , Estudios de Cohortes , Femenino , Corazón Auxiliar , Humanos , Masculino , Persona de Mediana Edad , Implantación de Prótesis/métodos , Presión Esfenoidal Pulmonar/fisiología , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
OBJECTIVE: To assess coronary artery calcification (CAC) in patients with acute pulmonary embolism and determine whether this correlates with right ventricular dilation (RVD) and mortality. METHODS: Computed tomography pulmonary angiography scans of 330 patients were used to perform retrospective assessment of the pulmonary artery computed tomography obstruction index (PACTOI), the right/left ventricle diameter ratio, the diameter of the pulmonary trunk, and the ordinal CAC score. RESULTS: Age (P < 0.001), urea level (P < 0.001), D-dimer level (P = 0.006), diameter of the pulmonary trunk (P < 0.001), and PACTOI (P < 0.001) were significantly higher in the RVD-positive patient group. We found a significant relation between increased CAC score and increased mortality (P = 0.038). Left-sided CAC was detected much more often in RVD-positive patients (P = 0.008). CONCLUSIONS: Coronary artery calcification is common in patients with acute pulmonary embolism, especially when those patients are also RVD-positive. A significant relation was found between RVD and left-sided CAC.
Asunto(s)
Angiografía por Tomografía Computarizada/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Embolia Pulmonar/diagnóstico por imagen , Calcificación Vascular/diagnóstico por imagen , Disfunción Ventricular Derecha/complicaciones , Enfermedad Aguda , Anciano , Enfermedad de la Arteria Coronaria/complicaciones , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Femenino , Ventrículos Cardíacos/patología , Humanos , Masculino , Persona de Mediana Edad , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/patología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/patología , Estudios Retrospectivos , Calcificación Vascular/complicaciones , Calcificación Vascular/patología , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/patologíaRESUMEN
BACKGROUND: Heart failure is an inexorably progressive disease with a high mortality, for which heart transplantation (HTx) remains the gold standard treatment. Currently, donor hearts are primarily derived from patients following brain stem death (BSD). BSD causes activation of the sympathetic nervous system, increases endothelin levels, and triggers significant inflammation that together with potential myocardial injury associated with the transplant procedure, may affect contractility of the donor heart. We examined peri-transplant myocardial catecholamine sensitivity and cardiac contractility post-BSD and transplantation in a clinically relevant ovine model. METHODS: Donor sheep underwent BSD (BSD, n = 5) or sham (no BSD) procedures (SHAM, n = 4) and were monitored for 24h prior to heart procurement. Orthotopic HTx was performed on a separate group of donor animals following 24h of BSD (BSD-Tx, n = 6) or SHAM injury (SH-Tx, n = 5). The healthy recipient heart was used as a control (HC, n = 11). A cumulative concentration-effect curve to (-)-noradrenaline (NA) was established using left (LV) and right ventricular (RV) trabeculae to determine ß1-adrenoceptor mediated potency (-logEC50 [(-)-noradrenaline] M) and maximal contractility (Emax). RESULTS: Our data showed reduced basal and maximal (-)-noradrenaline induced contractility of the RV (but not LV) following BSD as well as HTx, regardless of whether the donor heart was exposed to BSD or SHAM. The potency of (-)-noradrenaline was lower in left and right ventricles for BSD-Tx and SH-Tx compared to HC. CONCLUSION: These studies show that the combination of BSD and transplantation are likely to impair contractility of the donor heart, particularly for the RV. For the donor heart, this contractile dysfunction appears to be independent of changes to ß1-adrenoceptor sensitivity. However, altered ß1-adrenoceptor signalling is likely to be involved in post-HTx contractile dysfunction.
Asunto(s)
Muerte Encefálica/patología , Tronco Encefálico/patología , Trasplante de Corazón/efectos adversos , Disfunción Ventricular Derecha/etiología , Animales , Modelos Animales de Enfermedad , Femenino , Contracción Miocárdica , Ovinos , Disfunción Ventricular Derecha/patologíaRESUMEN
Pulmonary arterial hypertension (PAH) affects more women than men, although affected females tend to survive longer than affected males. This sex disparity in PAH is postulated to stem from the diverse roles of sex hormones in disease etiology. In animal models, estrogens appear to be implicated not only in pathologic remodeling of pulmonary arteries, but also in protection against right ventricular (RV) hypertrophy. In contrast, the male sex hormone testosterone is associated with reduced survival in male animals, where it is associated with increased RV mass, volume, and fibrosis. However, it also has a vasodilatory effect on pulmonary arteries. Furthermore, patients of both sexes show varying degrees of response to current therapies for PAH. As such, there are many gaps and contradictions regarding PAH development, progression, and therapeutic interventions in male versus female patients. Many of these questions remain unanswered, which may be due in part to lack of effective experimental models that can consistently reproduce PAH pulmonary microenvironments in their sex-specific forms. This review article summarizes the roles of estrogens and related sex hormones, immunological and genetical differences, and the benefits and limitations of existing experimental tools to fill in gaps in our understanding of the sex-based variation in PAH development and progression. Finally, we highlight the potential of a new tissue chip-based model mimicking PAH-afflicted male and female pulmonary arteries to study the sex-based differences in PAH and to develop personalized therapies based on patient sex and responsiveness to existing and new drugs.
Asunto(s)
Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Caracteres Sexuales , Disfunción Ventricular Derecha/fisiopatología , Animales , Hormonas Esteroides Gonadales/farmacología , Humanos , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Disfunción Ventricular Derecha/patologíaRESUMEN
Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients.
Asunto(s)
Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Calcio/metabolismo , Insuficiencia Cardíaca , Ventrículos Cardíacos , Miocitos Cardíacos , Disfunción Ventricular Derecha , Animales , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
Cardiac disease is the primary cause of death in sickle cell disease (SCD). Cardiac abnormalities begin in childhood and progress throughout life. Right and left ventricular (RV, LV) myocardial strain are early markers of systolic dysfunction but are not well investigated among individuals with SCD. The objectives of this review were to (1) identify all published studies that have evaluated ventricular myocardial strain, (2) summarize their values, and (3) compare findings with those obtained from controls. From search results of four electronic databases-Medline, Embase, Scopus, and Web of Science-42 potential articles were identified, of which 18 articles and 17 studies met eligibility criteria for inclusion. The evaluated studies demonstrate that RV and LV myocardial strain are generally abnormal in individuals with SCD compared with controls, despite having normal ejection/shortening fraction. Myocardial strain has been inconsistently evaluated in this population and should be considered any time an echocardiogram is performed.
Asunto(s)
Anemia de Células Falciformes/patología , Cardiomiopatías/patología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Derecha/patología , Adulto , Niño , Ecocardiografía , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/patología , Humanos , Lactante , Persona de Mediana Edad , Volumen Sistólico/fisiologíaRESUMEN
BACKGROUND: Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH. METHODS: We performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5). RESULTS: We identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated cellular communication network factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV. CONCLUSIONS: Transcriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of cellular communication network factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure.
Asunto(s)
Transición Epitelial-Mesenquimal/genética , Insuficiencia Cardíaca/genética , Hipertensión Arterial Pulmonar/genética , Disfunción Ventricular Derecha/genética , Remodelación Ventricular/genética , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/toxicidad , Animales , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Hipoxia , Indoles/toxicidad , Masculino , Persona de Mediana Edad , Monocrotalina/toxicidad , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Pirroles/toxicidad , RNA-Seq , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
OBJECTIVE: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. CONCLUSIONS: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.
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Basigina/antagonistas & inhibidores , Ciclofilina A/antagonistas & inhibidores , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Triterpenos/uso terapéutico , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Antihipertensivos/uso terapéutico , Basigina/genética , Basigina/metabolismo , Ciclofilina A/metabolismo , Modelos Animales de Enfermedad , Humanos , Hipoxia/complicaciones , Indoles/toxicidad , Ratones , Ratones Transgénicos , Miocitos Cardíacos/metabolismo , Triterpenos Pentacíclicos , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Pirroles/toxicidad , Ratas , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Microcirculation disturbance is a crucial pathological basis of heart damage; however, microcirculation alterations induced by hypoxic pulmonary hypertension (HPH) remain unknown, and the left ventricle (LV) in HPH is conventionally ignored. Herein, we investigated the changes in the cardiac structure, function and microcirculation after HPH and further compared the differences between the right ventricle (RV) and LV. Using a neonatal rat model of HPH, we found RV myocardial hypertrophy, dysfunction and poor myocardial perfusion in HPH rats. Additionally, RV microcirculation disturbance manifested as the abnormal expression of endothelin-1/eNOS and increased expression of intercellular cell adhesion molecule-1 (ICAM-1) or E-selectin 3 days after hypoxia, followed by vascular inflammation, coronary arterial remodeling and microvascular sparseness. Impairment in LV vasodilation was detected in rats after 3 days of hypoxia; however, no obvious microvascular rarefaction or inflammatory reaction was observed in the LV. In conclusion, our results suggest that HPH mainly triggers RV microcirculation disturbances, causing low myocardial perfusion damage and cardiac dysfunction. Despite the differences in the RV and LV, their impaired microvascular function, mediated by endothelial cells, occurs almost simultaneously after HPH, earlier than cardiac functional or structural abnormalities.
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Circulación Coronaria , Vasos Coronarios/fisiopatología , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Microcirculación , Microvasos/fisiopatología , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Derecha/etiología , Animales , Animales Recién Nacidos , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Microvasos/metabolismo , Microvasos/patología , Ratas Wistar , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Izquierda , Función Ventricular Derecha , Remodelación VentricularRESUMEN
Right ventricular (RV) dysfunction induced type II cardiorenal syndrome (CRS) has a high mortality rate, but little attention has been paid to this disease, and its unique molecular characteristics remain unclear. This study aims to investigate the transcriptomic expression profile in this disease and identify key RNA pairs that regulate related molecular signaling networks. We established an RV dysfunction-induced type II CRS mouse model by pulmonary artery constriction (PAC). PAC mice developed severe RV hypertrophy and fibrosis; renal atrophy and dysfunction with elevated creatinine were subsequently observed. Expression profiles in RV and kidney tissues were obtained by whole transcriptome sequencing, revealing a total of 741 and 86 differentially expressed (DE) mRNAs, 159 and 29 DEmiRNAs and 233 and 104 DEcircRNAs between RV and kidney tissue, respectively. Competing endogenous RNA (ceRNA) networks were established. A significant alteration in proliferative, fibrotic and metabolic pathways was found based on GO and KEGG analyses, and the network revealed key ceRNA pairs, such as novel_circ_002631/miR-181a-5p/Creb1 and novel_circ_002631/miR-33-y/Kpan6. These findings indicate that significantly dysregulated pathways in RV dysfunction induced type II CRS include Ras, PI3K/Akt, cGMP-PKG pathways, and thyroid metabolic pathways. These ceRNA pairs can be considered potential targets for the treatment of type II CRS.
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Síndrome Cardiorrenal/genética , MicroARNs/metabolismo , ARN Circular/metabolismo , ARN Mensajero/metabolismo , Insuficiencia Renal/genética , Disfunción Ventricular Derecha/genética , Animales , Síndrome Cardiorrenal/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Expresión Génica , Perfilación de la Expresión Génica , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Riñón/metabolismo , Riñón/patología , Ratones , Miocardio/patología , Arteria Pulmonar/cirugía , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
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.
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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
Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline-induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor ß1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase-c-Jun N-terminal kinase-Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH.
Asunto(s)
Apolipoproteína A-V/genética , Hipertensión Pulmonar/genética , Factor de Crecimiento Transformador beta1/genética , Disfunción Ventricular Derecha/genética , Remodelación Ventricular/genética , Animales , Ecocardiografía , Matriz Extracelular/genética , Femenino , Fibrosis/sangre , Fibrosis/genética , Fibrosis/patología , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/patología , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/patología , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Masculino , Persona de Mediana Edad , Ratas , Proteína smad3/genética , Triglicéridos/sangre , Disfunción Ventricular Derecha/sangre , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/patologíaRESUMEN
Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600 ppm for 45 min) and the survivors were sacrificed at 14 or 28 days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.