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OBJECTIVE: To describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multicenter cohort, given that data supporting its use in pediatric PAH are sparse. STUDY DESIGN: We report a multicenter, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: before selexipag, 3-12 months after selexipag, and >12 months follow-up. RESULTS: Eighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. The median starting and final doses were 4.7 and 28.5 µg/kg/dose twice daily, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53; P = .034) with a lower average mean pulmonary artery pressure (46 vs 39 mm Hg; P = NS), and oxygen consumption (maximal oxygen consumption during cardiopulmonary exercise testing [VO2 max] 27.8 mL/kg/min vs 30.9 mL/kg/min; P = NS). Transition patients demonstrated stable mean pulmonary artery pressure (47 mm Hg vs 45 mm Hg; P = NS) and a lower mean indexed pulmonary vascular resistance (10.9 Wood units∗m2 vs 8.2 Wood units∗m2; P = NS) but late functional worsening in some with VO2 max decreased at follow-up (26.0 mL/kg/min vs 19.5 mL/kg/min). Side effects were noted in 40% of the cohort, but prompted discontinuation in only 2%. CONCLUSIONS: In a large, multicenter cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring.
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BACKGROUND: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes. METHODS: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia. RESULTS: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05). CONCLUSION: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD. IMPACT: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD.
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Arginina , Citrulina , Óxido Nítrico , Humanos , Arginina/análogos & derivados , Arginina/sangre , Arginina/metabolismo , Estudios Prospectivos , Masculino , Femenino , Lactante , Óxido Nítrico/metabolismo , Óxido Nítrico/sangre , Citrulina/sangre , Tiempo de Internación , Ventrículos Cardíacos/metabolismo , Hipoxia/sangre , Estudios de Casos y Controles , Recién Nacido , Cuidados Paliativos , Cardiopatías Congénitas/sangre , Cardiopatías Congénitas/metabolismo , Corazón Univentricular/cirugía , MorbilidadRESUMEN
We examined postnatal echocardiograms for 62 infants with congenital diaphragmatic hernia born from 2014 through 2020. Left and right ventricular dysfunction on D0 were sensitive, whereas persistent dysfunction on D2 was specific for extracorporeal membrane oxygenation requirement. Biventricular dysfunction had the strongest association with extracorporeal membrane oxygenation. Serial echocardiography may inform prognosis in congenital diaphragmatic hernia.
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Oxigenación por Membrana Extracorpórea , Hernias Diafragmáticas Congénitas , Recién Nacido , Lactante , Humanos , Hernias Diafragmáticas Congénitas/complicaciones , Hernias Diafragmáticas Congénitas/diagnóstico por imagen , Hernias Diafragmáticas Congénitas/terapia , Estudios Retrospectivos , Ecocardiografía , PronósticoRESUMEN
We examined the results of cardiac catheterization in infants with congenital diaphragmatic hernia (CDH) from 2009 to 2020. Catheterization confirmed pulmonary arterial hypertension in all cases (n = 17) and identified left ventricular (LV) diastolic dysfunction (LVDD) in 53%. LVDD was associated with greater respiratory morbidity. Preprocedural noninvasive assessment showed inconsistent agreement with catheterization results.
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Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Izquierda , Recién Nacido , Lactante , Humanos , Hernias Diafragmáticas Congénitas/complicaciones , Hipertensión Pulmonar/complicaciones , Estudios Retrospectivos , Disfunción Ventricular Izquierda/complicaciones , Hemodinámica , Cateterismo CardíacoRESUMEN
BACKGROUND: Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population. We explored the feasibility of GFI as a predictor of CAO in a pediatric PH population. METHODS: Two center retrospective chart review identified pediatric PH patients undergoing CMR from Jan 2005-June 2021. GFI, defined as the ratio of the stroke volume to the sum of mean ventricular cavity and myocardial volume, was calculated for each patient. CAO was defined as death, lung transplant, Potts shunt, or parenteral prostacyclin initiation after CMR. Cox proportional hazards regression was used to estimate associations and assess model performance between CMR parameters and CAO. RESULTS: The cohort comprised 89 patients (54% female, 84% World Health Organization (WHO) Group 1; 70% WHO-FC ≤ 2; and 27% on parenteral prostacyclin). Median age at CMR was 12 years (IQR 8.1-17). Twenty-one (24%) patients experienced CAO during median follow up of 1.5 years. CAO cohort had higher indexed RV volumes (end systolic-145 vs 99 mL/m2, p = 0.003; end diastolic-89 vs 46 mL/m2, p = 0.004) and mass (37 vs 24 gm/m2, p = 0.003), but lower ejection fraction (EF) (42 vs 51%, p < 0.001) and GFI (40 vs 52%, p < 0.001). Higher indexed RV volumes (hazard ratios [HR] 1.01, CI 1.01-1.02), lower RV EF (HR 1.09, CI 1.05-1.12) and lower RV GFI (HR 1.09, CI 1.05-1.11) were associated with increased risk of CAO. In survival analysis, patients with RV GFI < 43% demonstrated decreased event-free survival and increased hazard of CAO compared to those with RV GFI ≥ 43%. In multivariable models, inclusion of GFI provided improved prediction of CAO compared to models incorporating ventricular volumes, mass or EF. CONCLUSIONS: RV GFI was associated with CAO in this cohort, and inclusion in multivariable models had increased predictive value compared to RVEF. GFI uses readily available CMR data without additional post-processing and may provide additional prognostic value in pediatric PH patients beyond traditional CMR markers.
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Hipertensión Pulmonar , Disfunción Ventricular Derecha , Adulto , Humanos , Femenino , Niño , Adolescente , Masculino , Estudios Retrospectivos , Factores de Riesgo , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular DerechaRESUMEN
BACKGROUND: Developmental pulmonary vein pulmonary vein stenosis in the setting of prematurity is a rare and poorly understood condition. Diagnosis can be challenging in the setting of chronic lung disease of prematurity. High-resolution non-contrast chest computed tomography (CT) is the conventional method of evaluating neonates for potential structural changes contributing to severe lung dysfunction and pulmonary hypertension but may miss pulmonary venous stenosis due to the absence of contrast and potential overlap in findings between developmental pulmonary vein pulmonary vein stenosis and lung disease of prematurity. OBJECTIVE: To describe the parenchymal changes of pediatric patients with both prematurity and pulmonary vein stenosis, correlate them with venous disease and to describe the phenotypes associated with this disease. MATERIALS AND METHODS: A 5-year retrospective review of chest CT angiography (CTA) imaging in patients with catheterization-confirmed pulmonary vein stenosis was performed to identify pediatric patients (< 18 years) who had a history of prematurity (< 35 weeks gestation). Demographic and clinical data associated with each patient were collected, and the patients' CTAs were re-reviewed to evaluate pulmonary veins and parenchyma. Patients with post-operative pulmonary vein stenosis and those with congenital heart disease were excluded. Data was analyzed and correlated for descriptive purposes. RESULTS: A total of 17 patients met the inclusion criteria (12 female, 5 male). All had pulmonary hypertension. There was no correlation between mild, moderate, and severe grades of bronchopulmonary dysplasia and the degree of pulmonary vein stenosis. There was a median of 2 (range 1-4) diseased pulmonary veins per patient. In total, 41% of the diseased pulmonary veins were atretic. The right upper and left upper lobe pulmonary veins were the most frequently diseased (n = 13/17, 35%, n = 10/17, 27%, respectively). Focal ground glass opacification, interlobular septal thickening, and hilar soft tissue enlargement were always associated with the atresia of an ipsilateral vein. CONCLUSION: Recognition of the focal parenchymal changes that imply pulmonary vein stenosis, rather than chronic lung disease of prematurity changes, may improve the detection of a potentially treatable source of pulmonary hypertension, particularly where nonangiographic studies result in a limited direct venous assessment.
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Displasia Broncopulmonar , Cardiopatías Congénitas , Hipertensión Pulmonar , Venas Pulmonares , Estenosis de Vena Pulmonar , Recién Nacido , Lactante , Humanos , Masculino , Niño , Femenino , Estenosis de Vena Pulmonar/diagnóstico por imagen , Estenosis de Vena Pulmonar/complicaciones , Recien Nacido Prematuro , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/anomalías , Cardiopatías Congénitas/complicaciones , Tomografía Computarizada por Rayos X , Pulmón/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
The Ross-Konno (RK) operation is a well-established surgical treatment for combined left ventricular outflow tract obstruction and aortic valve pathology in children. Prior study has demonstrated that mechanical and electrical dyssynchrony exist post-RK compared to normal controls. The purpose of this study was to evaluate myocardial function pre- and post-RK as defined by echocardiography. Patients undergoing the RK operation (n = 13; median age: 1.3 years; range: 0.5-13.3 years) were evaluated by echocardiography at defined timepoints: pre-RK, post-RK, 1-year post-RK, and 2 years post-RK. Defined parameters of left ventricular performance were analyzed: systolic mechanical dyssynchrony (M-Dys), global left ventricular circumferential strain (GCS), and diastolic relaxation fraction (DRF). Patients with post-operative atrioventricular block (n = 6) were analyzed separately. No pre- versus post-RK differences existed in M-Dys, GCS, or DRF in patients both with and without post-RK atrioventricular block. Further, 1- and 2-year follow-up post-RK demonstrated significant heterogeneity in evaluated parameters of function with no pre- and post-RK differences in M-Dys, GCS, or DRF. Mechanical dyssynchrony exists post-RK reconstruction in both short- and long-term follow-up yet these echocardiographic parameters of ventricular performance are independent of the RK operation. Further study is, therefore, warranted to define causal relationships for observed short- and long-term ventricular dysfunction post-RK as the findings of the present study suggest a deleterious mechanism apart from the technical RK reconstruction.
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Estenosis de la Válvula Aórtica , Bloqueo Atrioventricular , Procedimientos Quirúrgicos Cardíacos , Disfunción Ventricular Izquierda , Obstrucción del Flujo Ventricular Externo , Niño , Humanos , Lactante , Estenosis de la Válvula Aórtica/cirugía , Obstrucción del Flujo Ventricular Externo/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Estudios Retrospectivos , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Disfunción Ventricular Izquierda/diagnóstico por imagen , Resultado del TratamientoRESUMEN
Acute kidney injury (AKI) is a common cause of morbidity after congenital heart disease surgery. Progress on diagnosis and therapy remains limited, however, in part due to poor mechanistic understanding and a lack of relevant translational models. Metabolomic approaches could help identify novel mechanisms of injury and potential therapeutic targets. In the present study, we used a piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB/DHCA) and targeted metabolic profiling of kidney tissue, urine, and serum to evaluate metabolic changes specific to animals with histological acute kidney injury. CPB/DHCA animals with acute kidney injury were compared with those without acute kidney injury and mechanically ventilated controls. Acute kidney injury occurred in 10 of 20 CPB/DHCA animals 4 h after CPB/DHCA and 0 of 7 control animals. Injured kidneys showed a distinct tissue metabolic profile compared with uninjured kidneys (R2 = 0.93, Q2 = 0.53), with evidence of dysregulated tryptophan and purine metabolism. Nine urine metabolites differed significantly in animals with acute kidney injury with a pattern suggestive of increased aerobic glycolysis. Dysregulated metabolites in kidney tissue and urine did not overlap. CPB/DHCA strongly affected the serum metabolic profile, with only one metabolite that differed significantly with acute kidney injury (pyroglutamic acid, a marker of oxidative stress). In conclusion, based on these findings, kidney tryptophan and purine metabolism are candidates for further mechanistic and therapeutic investigation. Urine biomarkers of aerobic glycolysis could help diagnose early acute kidney injury after CPB/DHCA and warrant further evaluation. The serum metabolites measured at this early time point did not strongly differentiate based on acute kidney injury.NEW & NOTEWORTHY This project explored the metabolic underpinnings of postoperative acute kidney injury (AKI) following pediatric cardiac surgery in a translationally relevant large animal model of cardiopulmonary bypass with deep hypothermic circulatory arrest. Here, we present novel evidence for dysregulated tryptophan catabolism and purine catabolism in kidney tissue and increased urinary glycolysis intermediates in animals who developed histological AKI. These pathways represent potential diagnostic and therapeutic targets for postoperative AKI in this high-risk population.
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Lesión Renal Aguda , Procedimientos Quirúrgicos Cardíacos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Animales , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Paro Circulatorio Inducido por Hipotermia Profunda/efectos adversos , Humanos , Riñón , Purinas , Porcinos , TriptófanoRESUMEN
Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = -0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = -0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices.NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.
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Hipertensión Pulmonar/fisiopatología , Metaloproteinasas de la Matriz/sangre , Inhibidores Tisulares de Metaloproteinasas/sangre , Rigidez Vascular/fisiología , Función Ventricular/fisiología , Adolescente , Presión Arterial/fisiología , Niño , Femenino , Hemodinámica/fisiología , Humanos , Hipertensión Pulmonar/sangre , Masculino , Arteria Pulmonar/fisiopatologíaRESUMEN
INTRODUCTION: Acute lung injury is common following cardiopulmonary bypass and deep hypothermic circulatory arrest for congenital heart surgery with the most severe injury in the dorsocaudal lung. Metabolomics offers promise in deducing mechanisms of disease states, providing risk stratification, and understanding therapeutic responses in regards to CPB/DHCA related organ injury. OBJECTIVES: Using an infant porcine model, we sought to determine the individual and additive effects of CPB/DHCA and lung region on the metabolic fingerprint, metabolic pathways, and individual metabolites in lung tissue. METHODS: Twenty-seven infant piglets were divided into two groups: mechanical ventilation + CPB/DHCA (n = 20) and mechanical ventilation only (n = 7). Lung tissue was obtained from dorsocaudal and ventral regions. Targeted analysis of 235 metabolites was performed using HPLC/MS-MS. Data was analyzed using Principal Component Analysis (PCA), Partial Least Square Discriminant Analysis (PLS-DA), ANOVA, and pathway analysis. RESULTS: Profound metabolic differences were found in dorsocaudal compared to ventral lung zones by PCA and PLS-DA (R2 = 0.7; Q2 = 0.59; p < 0.0005). While overshadowed by the regional differences, some differences by exposure to CPB/DHCA were seen as well. Seventy-four metabolites differed among groups and pathway analysis revealed 20 differential metabolic pathways. CONCLUSION: Our results demonstrate significant metabolic disturbances between dorsocaudal and ventral lung regions during supine mechanical ventilation with or without CPB/DHCA. CPB/DHCA also leads to metabolic differences and may have additive effects to the regional disturbances. Most pathways driving this pathology are involved in energy metabolism and the metabolism of amino acids, carbohydrates, and reduction-oxidation pathways.
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Puente Cardiopulmonar , Pulmón , Animales , Humanos , Metaboloma , Metabolómica , PorcinosRESUMEN
PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) causes high morbidity and mortality in children. In this review, we discuss advances in diagnosis and treatment of this disorder. RECENT FINDINGS: Proceedings published from the 2018 World Symposium updated the definition of pulmonary hypertension to include all adults and children with mean pulmonary artery pressure more than 20âmmHg. Targeted PAH therapy is increasingly used off-label, but in 2017, bosentan became the first Food and Drug Administration-targeted PAH therapy approved for use in children. SUMMARY: In recent years, advanced imaging and clinical monitoring have allowed improved risk stratification of pulmonary hypertension patients. New therapies, approved in adults and used off-label in pediatric patients, have led to improved outcomes for affected children.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Adulto , Antihipertensivos/uso terapéutico , Niño , Hipertensión Pulmonar Primaria Familiar , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
BACKGROUND: We sought to determine differences in the circulating metabolic profile of infants with or without acute kidney injury (AKI) following cardiothoracic surgery with cardiopulmonary bypass (CPB). METHODS: We performed a secondary analysis of preoperative and 24-h postoperative serum samples from infants ≤ 120 days old undergoing CPB. Metabolic profiling of the serum samples was performed by targeted analysis of 165 serum metabolites via tandem mass spectrometry. We then compared infants who did or did not develop AKI in the first 72 h postoperatively to determine global differences in the preoperative and 24-h metabolic profiles in addition to specific differences in individual metabolites. RESULTS: A total of 57 infants were included in the study. Six infants (11%) developed KDIGO stage 2/3 AKI and 13 (23%) developed stage 1 AKI. The preoperative metabolic profile did not differentiate between infants with or without AKI. Infants with severe AKI could be moderately distinguished from infants without AKI by their 24-h metabolic profile, while infants with stage 1 AKI segregated into two groups, overlapping with either the no AKI or severe AKI groups. Differences in these 24-h metabolic profiles were driven by 21 metabolites significant at an adjusted false discovery rate of < 0.05. Prominently altered pathways include purine, methionine, and kynurenine/nicotinamide metabolism. CONCLUSION: Moderate-to-severe AKI after infant cardiac surgery is associated with changes in the serum metabolome, including prominent changes to purine, methionine, and kynurenine/nicotinamide metabolism. A portion of infants with mild AKI demonstrated similar metabolic changes, suggesting a potential role for metabolic analysis in the evaluation of lower stage injury.
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Lesión Renal Aguda , Procedimientos Quirúrgicos Cardíacos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Humanos , Lactante , Quinurenina , Metaboloma , Metionina , Niacinamida , Complicaciones Posoperatorias/etiología , PurinasRESUMEN
Adverse ventricle-ventricle interaction and resultant left ventricular (LV) dysfunction are a recognized pathophysiological component of disease progression in pulmonary arterial hypertension (PAH) and can be associated with electrical and mechanical dyssynchrony. The purpose of this study was to investigate the clinical and mechanistic implications of LV electromechanical dyssynchrony in children with PAH by using novel systolic stretch and diastolic relaxation discoordination indexes derived noninvasively from cardiac MRI (CMR). In children with PAH referred for CMR (n = 64) and healthy controls (n = 20), we calculated two novel markers of ventricular discoordination, systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF and DRF were evaluated with respect to 1) electrical dyssynchrony, 2) functional status, and 3) composite clinical outcomes. SSF was increased in patients with PAH compared with controls (P = 0.004). There was no difference in DRF between PAH and control groups. There were no differences between groups in standard mechanical dyssynchrony and LV global circumferential strain. Increased SSF was associated with greater electrical dyssynchrony (QRS duration) as well as worse WHO functional class. SSF, DRF, mechanical dyssynchrony, and right ventricular (RV) volumes were prognostic for worse clinical outcomes. LV dyssynchrony indexes are altered in pediatric patients with PAH compared with controls in proportion with greater degrees of RV dilation. Patients with PAH with greater dyssynchrony have worse clinical outcomes. RV-induced increased LV electromechanical dyssynchrony therefore may be an important link in the causal pathway from PAH to clinically significant LV dysfunction. Since dyssynchrony could precede overt LV dysfunction, addition of ventricular synchrony analysis to CMR postprocessing protocols may be of clinical benefit.NEW & NOTEWORTHY We demonstrate that left ventricular discoordination indexes are altered in pediatric patients with pulmonary arterial hypertension compared with controls and pediatric patients with pulmonary arterial hypertension with greater dyssynchrony have worse clinical outcomes. Furthermore, there is evidence for the mechanism of right ventricular-induced left ventricular discoordination to include a combination of delayed early systolic electromechanical activation, late-systolic septal shift, and prolonged, postsystolic septal thickening.
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Pruebas de Función Cardíaca , Hipertensión Arterial Pulmonar/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Adolescente , Presión Sanguínea , Niño , Fenómenos Electrofisiológicos , Femenino , Hemodinámica , Humanos , Imagen por Resonancia Magnética , Masculino , Fenómenos Mecánicos , Contracción Miocárdica , Hipertensión Arterial Pulmonar/diagnóstico por imagen , Estudios Retrospectivos , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
The Fontan circulation is characterized as a nonpulsatile flow propagation without a pressure-generating ventricle. However, flow through the Fontan circulation still exhibits oscillatory waves as a result of pressure changes generated by the systemic single ventricle. Identification of discrete flow patterns through the Fontan circuit may be important to understand single ventricle performance. Ninety-seven patients with Fontan circulation underwent phase-contrast MRI of the right pulmonary artery, yielding subject-specific flow waveforms. Principal component (PC) analysis was performed on preprocessed flow waveforms. Principal components were then correlated with standard MRI indices of function, volume, and aortopulmonary collateral flow. The first principal component (PC) described systolic versus diastolic-dominant flow through the Fontan circulation, accounting for 31.3% of the variance in all waveforms. The first PC correlated with end-diastolic volume (R = 0.34, P = 0.001), and end-systolic volume (R = 0.30, P = 0.003), cardiac index (R = 0.51, P < 0.001), and the amount of aortopulmonary collateral flow (R = 0.25, P = 0.027)-lower ventricular volumes and a smaller volume of collateral flow-were associated with diastolic-dominant cavopulmonary flow. The second PC accounted for 19.5% of variance and described late diastolic acceleration versus deceleration and correlated with ejection fraction-diastolic deceleration was associated with higher ejection fraction. Principal components describing the diastolic flow variations in pulmonary arteries are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to preserved ventricular volume and function, respectively.NEW & NOTEWORTHY The exact physiological significance of flow oscillations of phasic and temporal flow variations in Fontan circulation is unknown. With the use of principal component analysis, we discovered that flow variations in the right pulmonary artery of Fontan patients are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to more ideal ventricular volume and systolic function, respectively.
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Procedimiento de Fontan/efectos adversos , Ventrículos Cardíacos/fisiopatología , Hemodinámica , Modelos Cardiovasculares , Complicaciones Posoperatorias/fisiopatología , Arteria Pulmonar/fisiopatología , Adolescente , Niño , Circulación Coronaria , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Contracción Miocárdica , Modelación Específica para el Paciente , Complicaciones Posoperatorias/diagnóstico por imagen , Análisis de Componente Principal , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/cirugíaRESUMEN
BACKGROUND: Serum kynurenic acid is associated with poor outcomes after infant cardiopulmonary bypass (CPB), but comprehensive mapping of the kynurenine pathway (KP) after CPB has yet to be performed. AIMS: To map changes in the KP induced by infant CPB. METHODS: Compared changes in serum KP metabolites through 48hrs post-op with liquid-chromatography-tandem mass spectrometry. RESULTS: Infant CPB results in marked increase in proximal, but not distal metabolites of the KP. CONCLUSIONS: Infant CPB leads to accumulation of circulating KP metabolites, which have important neurologic and immunologic activities. Thus, further exploration of the KP is warranted in these high-risk infants.
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Procedimientos Quirúrgicos Cardíacos/métodos , Puente Cardiopulmonar/métodos , Quinurenina/metabolismo , Triptófano/metabolismo , Preescolar , Cromatografía Liquida , Humanos , Lactante , Espectrometría de Masas , Metabolómica , Estudios Prospectivos , SerotoninaRESUMEN
OBJECTIVES: To assess whether better baseline pulmonary hemodynamics or positive acute vasoreactivity testing (AVT) during cardiac catheterization are associated with improved outcomes in infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). STUDY DESIGN: This retrospective, single-center study included 26 premature neonates with BPD who underwent catheterization to evaluate PH. AVT was assessed with exposure to 100% fractional inspired oxygen with or without inhaled nitric oxide. AVT was positive if the patient met the Barst criteria or increased shunt volume and decreased pulmonary vascular resistance index by >50%. RESULTS: At baseline, the median pulmonary artery mean pressure was 29 mm Hg (IQR, 24-35) and the pulmonary vascular resistance index was 5.3 units*m2 (IQR, 3.5-6.9). Nine patients (35%) had a positive AVT response, which was associated with a decreased risk of death or tracheostomy by 2-year follow-up (hazard ratio, 0.15; P = .02). Baseline pulmonary hemodynamics and the presence of left ventricular diastolic dysfunction were not associated with late outcomes in this cohort. CONCLUSIONS: We found that 35% of infants with BPD who underwent catheterization had positive AVT and that a positive response was associated with better long-term outcomes than nonresponders. AVT better distinguishes higher from lower risk PH in infants with BPD than baseline pulmonary hemodynamics. AVT may aid in the assessment of disease severity and management of BPD-associated PH.
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Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/terapia , Cateterismo Cardíaco , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/terapia , Enfermedades del Prematuro/terapia , Administración por Inhalación , Ecocardiografía , Hemodinámica , Humanos , Recién Nacido , Recien Nacido Prematuro , Pulmón/fisiopatología , Óxido Nítrico/metabolismo , Modelos de Riesgos Proporcionales , Arteria Pulmonar , Estudios Retrospectivos , Riesgo , Resultado del Tratamiento , Vasodilatadores/farmacologíaAsunto(s)
Hipertensión Pulmonar/complicaciones , Dolor , Escorbuto/complicaciones , Adolescente , Ácido Ascórbico/administración & dosificación , Dolor en el Pecho/complicaciones , Colecalciferol/administración & dosificación , Suplementos Dietéticos , Ecocardiografía , Encía/patología , Hemorragia/complicaciones , Humanos , Hierro/metabolismo , Pierna/patología , Masculino , Heridas y Lesiones/complicacionesAsunto(s)
Hemodinámica , Hipertensión Pulmonar/diagnóstico por imagen , Imagen por Resonancia Magnética , Anastomosis Quirúrgica , Velocidad del Flujo Sanguíneo , Niño , Cardiopatías Congénitas/cirugía , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Masculino , Oxígeno/metabolismo , Arteria Pulmonar/diagnóstico por imagenRESUMEN
Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins-increased MMP 7 and decreased MMP 8-was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD.