The risk of early radiation-induced lung toxicity (RILT) limits the dose and efficacy of radiation therapy of thoracic tumors. In addition to lung dose, coirradiation of the heart is a known risk ...factor in the development RILT. The aim of this study was to identify the underlying physiology of the interaction between lung and heart in thoracic irradiation.
Rat hearts, lungs, or both were irradiated to 20 Gy using high-precision proton beams. Cardiopulmonary performance was assessed using breathing rate measurements and F18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scans biweekly and left- and right-sided cardiac hemodynamic measurements and histopathology analysis at 8 weeks postirradiation.
Two to 12 weeks after heart irradiation, a pronounced defect in the uptake of 18F-FDG in the left ventricle (LV) was observed. At 8 weeks postirradiation, this coincided with LV perivascular fibrosis, an increase in LV end-diastolic pressure, and pulmonary edema in the shielded lungs. Lung irradiation alone not only increased pulmonary artery pressure and perivascular edema but also induced an increased LV relaxation time. Combined irradiation of lung and heart induced pronounced increases in LV end-diastolic pressure and relaxation time, in addition to an increase in right ventricle end-diastolic pressure, indicative of biventricular diastolic dysfunction. Moreover, enhanced pulmonary edema, inflammation and fibrosis were also observed.
Both lung and heart irradiation cause cardiac and pulmonary toxicity via different mechanisms. Thus, when combined, the loss of cardiopulmonary performance is intensified further, explaining the deleterious effects of heart and lung coirradiation. Our findings show for the first time the physiological mechanism underlying the development of a multiorgan complication, RILT. Reduction of dose to either of these organs offers new opportunities to improve radiation therapy treatment of thoracic tumors, potentially facilitating increased treatment doses and tumor control.
Pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) can be reversed by early shunt closure, but this potential is lost beyond a certain point of no return. Therefore, it is ...crucial to accurately assess the reversibility of this progressive pulmonary arteriopathy in an early stage. Reversibility assessment is currently based on a combination of clinical symptoms and haemodynamic variables such as pulmonary vascular resistance. These measures, however, are of limited predictive value and leave many patients in the grey zone. This review provides a concise overview of the mechanisms involved in flow-dependent progression of PAH in CHD and evaluates existing and future alternatives to more directly investigate the stage of the pulmonary arteriopathy. Structural quantification of the pulmonary arterial tree using fractal branching algorithms, functional imaging with intravascular ultrasound, nuclear imaging, putative new blood biomarkers, genetic testing and the potential for transcriptomic analysis of circulating endothelial cells and educated platelets are being reviewed.
The right ventricle has long been perceived as the “low pressure bystander” of the left ventricle. Although the structure consists of, at first glance, the same cardiomyocytes as the left ventricle, ...it is in fact derived from a different set of precursor cells and has a complex three-dimensional anatomy and a very distinct contraction pattern. Mechanisms of right ventricular failure, its detection and follow-up, and more specific different responses to pressure versus volume overload are still incompletely understood. In order to fully comprehend right ventricular form and function, evolutionary biological entities that have led to the specifics of right ventricular physiology and morphology need to be addressed. Processes responsible for cardiac formation are based on very ancient cardiac lineages and within the first few weeks of fetal life, the human heart seems to repeat cardiac evolution. Furthermore, it appears that most cardiogenic signal pathways (if not all) act in combination with tissue-specific transcriptional cofactors to exert inductive responses reflecting an important expansion of ancestral regulatory genes throughout evolution and eventually cardiac complexity. Such molecular entities result in specific biomechanics of the RV that differs from that of the left ventricle. It is clear that sole descriptions of right ventricular contraction patterns (and LV contraction patterns for that matter) are futile and need to be addressed into a bigger multilayer three-dimensional picture. Therefore, we aim to present a complete picture from evolution, formation, and clinical presentation of right ventricular (mal)adaptation and failure on a molecular, cellular, biomechanical, and (patho)anatomical basis.
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis ...and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.
Bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and often complicated by pulmonary hypertension (PH), leading to substantial morbidity and mortality. Sildenafil is ...often used to treat PH and improve symptoms in this condition, even though evidence of safety and effectiveness is scarce. The aim of this study was to perform a systematic review and meta-analysis about the effectiveness and safety of chronic use of sildenafil in preterm infants with BPD-associated PH. Data sources were PubMed, EMBASE, and Medline. Studies reporting the effectiveness of sildenafil therapy in BPD-associated PH in newborns and infants were included. All-cause mortality, improvement in PH, improvement in respiratory scores, and adverse events were extracted. Five studies were included, yielding a total of 101 patients with 94.2 patient-years of total follow-up. The pooled mortality rate was 29.7%/year (95% confidence interval CI = 6.8–52.7). Estimated pulmonary arterial pressure improved > 20% in 69.3% (95% CI = 56.8–81.8) of patients within 1–6 months. Respiratory scores improved in 15.0% (95% CI = 0.0–30.4) of patients within 2–7 days. There were no serious adverse events during sildenafil therapy. This systematic review shows that in the treatment of BPD-associated PH in preterm infants, sildenafil may be associated with improvement in PAP and respiratory scores. However, there is no clear evidence of its effect on mortality rates. Considering BPD as a complex disease with variable expression patterns, these results support the need for a prospective registry and standardized approach.
Background Right ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by ...diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta-analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease. Methods and Results Medline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat-models, inducing pressure load by hypoxia, Sugen-hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta-analysis revealed increased Hedges' g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochondrial respiratory capacity and fatty acid uptake varied considerably between studies, yet there was a model effect in carbohydrate respiratory capacity in MCT-rats. Conclusions This systematic review and meta-analysis on metabolic remodeling in the pressure-loaded RV showed a consistent increase in glucose uptake and glycolysis, strongly suggest a downregulation of beta-oxidation, and showed divergent and model-specific changes regarding fatty acid uptake and oxidative metabolism. To translate metabolic results from animal models to human disease, more extensive characterization, including function, and uniformity in methodology and studied variables, will be required.
Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a ...young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT-proBNP (N-terminal pro-B-type natriuretic peptide), GDF-15 (growth differentiation factor 15), Gal-3 (galectin-3), ST2 (suppression of tumorigenicity 2), DLK-1 (protein delta homolog 1), FABP-4 (fatty acid-binding protein 4), IGFBP-1 (insulin-like growth factor-binding protein 1), IGFBP-7, MMP-2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1-12.1) years after Fontan completion. After this baseline study measurement, follow-up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4-15.9) years, median age at Fontan 3.2 (2.5-3.9) years. After a median follow-up of 6.2 (4.9-6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT-proBNP was associated with (all) events during follow-up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32-2.68). The severe event-free survival was better in patients with low levels of GDF-15 (
=0.005) and vWF (
=0.008) and high levels of DLK-1 (
=0.041). There was a positive correlation (β=0.33,
=0.003) between DLK-1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT-proBNP, GDF-15, vWF, DLK-1, ST-2 FABP-4, and IGFBP-7 levels relate to long-term outcome in young patients who have undergone the Fontan procedure.
Right ventricular (RV) function is an important determinant of prognosis in congenital heart diseases, pulmonary hypertension, and heart failure. Preventive sildenafil treatment has been shown to ...enhance systolic RV function and improve exercise capacity in a model of fixed RV pressure load. However, it is unknown whether sildenafil has beneficial effects when treatment is started in established RV dysfunction, which is clinically more relevant. Our aim was to assess the effects of sildenafil treatment on RV function and fibrosis in a model of established RV dysfunction due to fixed afterload. Rats were subjected to pulmonary artery banding (PAB), which induced RV dysfunction after 4 wk, characterized by reduced exercise capacity, decreased tricuspid annular plane systolic excursion, and RV dilatation. From week 4 onward, 50% of rats were treated with sildenafil (100 mg·kg(-1)·day(-1), n = 9; PAB-SIL group) or vehicle (n = 9; PAB-VEH group). At 8 wk, exercise capacity was assessed using cage wheels, and RV function was assessed using invasive RV pressure-volume measurements under anesthesia. Sildenafil treatment, compared with vehicle, improved RV ejection fraction (44 ± 2% vs. 34 ± 2%, P < 0.05, PAB-SIL vs. PAB-VEH groups), reduced RV end-diastolic pressure (2.3 ± 0.5 vs. 5.1 ± 0.9 mmHg, P < 0.05), and RV dilatation (end-systolic volume: 468 ± 45 vs. 643 ± 71 μl, P = 0.05). Sildenafil treatment also attenuated RV fibrosis (30 ± 6 vs. 17 ± 3‰, P < 0.05) but did not affect end-systolic elastance, exercise capacity, or PKG or PKA activity. In conclusion, sildenafil improves RV diastolic function and attenuates interstitial fibrosis in rats with established RV dysfunction, independent from afterload. These results indicate that sildenafil treatment has therapeutic potential for established RV dysfunction.
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