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Background Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis.Case presentation A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date.Conclusion The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures. [ABSTRACT FROM AUTHOR]

BackgroundLeft ventricle (LV) and right ventricle (RV) are characterized by well-known physiological differences, mainly related to their different embryological origin, hemodynamic environment, function, structure, and cellular composition. Nevertheless, scarce information is available about cellular peculiarities between left and right ventricular chambers in physiological and pathological contexts. Cardiac mesenchymal stromal cells (C-MSC) are key cells affecting many functions of the heart. Differential features that distinguish LV from RV C-MSC are still underappreciated.AimTo analyze the physiological differential amount, function, and transcriptome of human C-MSC in LV versus (vs.) RV.MethodsHuman cardiac specimens of LV and RV from healthy donors were used for tissue analysis of C-MSC number, and for C-MSC isolation. Paired LV and RV C-MSC were compared as for surface marker expression, cell proliferation/death ratio, migration, differentiation capabilities, and transcriptome profile.ResultsHistological analysis showed a greater percentage of C-MSC in RV vs. LV tissue. Moreover, a higher C-MSC amount was obtained from RV than from LV after isolation procedures. LV and RV C-MSC are characterized by a similar proportion of surface markers. Functional studies revealed comparable cell growth curves in cells from both ventricles. Conversely, LV C-MSC displayed a higher apoptosis rate and RV C-MSC were characterized by a higher migration speed and collagen deposition. Consistently, transcriptome analysis showed that genes related to apoptosis regulation or extracellular matrix organization and integrins were over-expressed in LV and RV, respectively. Besides, we revealed additional pathways specifically associated with LV or RV C-MSC, including energy metabolism, inflammatory response, cardiac conduction, and pluripotency.ConclusionTaken together, these results contribute to the functional characterization of RV and LV C-MSC in physiological conditions. This information suggests a possible differential role of the stromal compartment in chamber-specific pathologic scenarios.

Background: Left ventricle (LV) and right ventricle (RV) are characterized by well-known physiological differences, mainly related to their different embryological origin, hemodynamic environment, function, structure, and cellular composition. Nevertheless, scarce information is available about cellular peculiarities between left and right ventricular chambers in physiological and pathological contexts. Cardiac mesenchymal stromal cells (C-MSC) are key cells affecting many functions of the heart. Differential features that distinguish LV from RV C-MSC are still underappreciated. Aim: To analyze the physiological differential amount, function, and transcriptome of human C-MSC in LV versus (vs.) RV. Methods: Human cardiac specimens of LV and RV from healthy donors were used for tissue analysis of C-MSC number, and for C-MSC isolation. Paired LV and RV C-MSC were compared as for surface marker expression, cell proliferation/death ratio, migration, differentiation capabilities, and transcriptome profile. Results: Histological analysis showed a greater percentage of C-MSC in RV vs. LV tissue. Moreover, a higher C-MSC amount was obtained from RV than from LV after isolation procedures. LV and RV C-MSC are characterized by a similar proportion of surface markers. Functional studies revealed comparable cell growth curves in cells from both ventricles. Conversely, LV C-MSC displayed a higher apoptosis rate and RV C-MSC were characterized by a higher migration speed and collagen deposition. Consistently, transcriptome analysis showed that genes related to apoptosis regulation or extracellular matrix organization and integrins were over-expressed in LV and RV, respectively. Besides, we revealed additional pathways specifically associated with LV or RV C-MSC, including energy metabolism, inflammatory response, cardiac conduction, and pluripotency. Conclusion: Taken together, these results contribute to the functional characterization of RV and LV C-MSC in physiological conditions. This information suggests a possible differential role of the stromal compartment in chamber-specific pathologic scenarios. [ABSTRACT FROM AUTHOR]

Background: In patients with left heart failure, micro-RNAs (miRNAs) have been shown to be of diagnostic and prognostic value. The present study aims to identify those miRNAs in patients with univentricular heart (UVH) disease that may be associated with overt heart failure. Methods: A large panel of human miRNA arrays were used to determine miRNA expression profiles in the blood of 48 UVH patients and 32 healthy controls. For further selection, the most abundantly expressed miRNA arrays were related to clinical measures of heart failure and selected miRNAs validated by polymerase chain reaction were used for the prediction of overt heart failure and all-cause mortality. Results: According to microarray analysis, 50 miRNAs were found to be significantly abundant in UVH patients of which miR-150-5p was best related to heart failure parameters. According to ROC analysis, NT-proBNP levels (AUC 0.940, 95% CI 0.873–1.000; p = 0.001), miR-150-5p (AUC 0.905, 95% CI 0.779–1.000; p = 0.001) and a higher NYHA class ≥ III (AUC 0.893, 95% CI 0.713–1.000; p = 0.002) were the 3 most significant predictors of overt heart failure. Using a combined biomarker model, AUC increased to 0.980 indicating an additive value of miR-150-5p. Moreover, in the multivariate analysis, a higher NYHA class ≥ III (p = 0.005) and miR-150-5p (p = 0.006) turned out to be independent predictors of overt heart failure. Conclusion: In patients with UVH, miR-150-5p is an independent predictor of overt heart failure and thus may be used in the risk assessment of these patients. [ABSTRACT FROM AUTHOR]

One hundred and twenty dogs were enrolled to value the effect of loading condition changes on left ventricular volumes before and 24-hours after the patent ductus arteriosus (PDA) occlusion by Amplatzer Canine Duct Occluder (ACDO) using standard echocardiography. The animals were divided in pure breed (n. 94) and mixed breed (n. 26); subsequently, the pure breed dogs were divided on the basis of the size of the breed of belonging in 3 groups (small size n. 36; medium size n. 8; large size n. 50). Moreover, the animals were divided in three classes based on their age: until 6 months; 6–12 months; over 12 months. A significant reduction of all the examined parameters (left ventricle internal diameter at end-diastole—LVIDd; left ventricle internal diameter at end-systole—LVIDs; end-diastolic volume—EDV; end-systolic volume—ESV; end-diastolic volume index—EDVI; end-systolic volume index—ESVI; fractional shortening—FS) was observed after ductal closure. Twenty-four hours after the closure, the evaluation of the relative percentage difference (RPD) of the echocardiographic parameters showed a significant reduction, higher in small size breed than in large size breed dogs. No significant difference related to breed size was observed only for RPD_FS variable. A significant interaction effect, between breed size and age classes, was observed only for RPD_EDVI (F = 3.39; p = 0.039). Until six months of age there was no significant difference in RPD_EDVI reduction, but over 6 months a significant reduction between small size and large size breed dogs at 24-hours from the occlusion was observed. In conclusion, our data seem to indicate that small breed dogs show a greater tolerance to congenital volume overload than large breed dogs, and this finding could be justify a delay of PDA closure in order to simplify the interventional procedure. [ABSTRACT FROM AUTHOR]

Collapse of the lateral cerebral ventricles after ventriculo-peritoneal drainage is a fatal complication in dogs with internal hydrocephalus. It occurs due to excessive outflow of cerebrospinal fluid into the peritoneal cavity (overshunting). In most shunt systems, one-way valves with different pressure settings regulate flow into the distal catheter to avoid overshunting. The rationale for the choice of an appropriate opening pressure is a setting at the upper limit of normal intracranial pressure in dogs. However, physiological intraventricular pressure in normal dogs vary between 5 and 12 mm Hg. Furthermore, we hypothesise that intraventricular pressure in hydrocephalic dogs might differ from pressure in normal dogs and we also consider that normotensive hydrocephalus exists in dogs, as in humans. In order to evaluate intraventricular pressure in hydrocephalic dogs, twenty-three client owned dogs with newly diagnosed communicating internal hydrocephalus were examined before implantation of a ventriculo-peritoneal shunt using a single use piezo-resistive strain-gauge sensor (MicroSensor ICP probe). Ventricular volume and brain volume were measured before surgery, based on magnetic resonance images. Total ventricular volume was calculated and expressed in relation to the total volume of the brain, including the cerebrum, cerebellum, and brainstem (ventricle-brain index). Multiple logistic regression analysis was performed to assess the influence of the covariates “age”, “gender”, “duration of clinical signs”, “body weight”, and “ventricle-brain index” on intraventricular pressure. The mean cerebrospinal fluid pressure in the hydrocephalic dogs was 8.8 mm Hg (standard deviation 4.22), ranging from 3–18 mm Hg. The covariates “age”, (P = 0.782), “gender” (P = 0.162), “body weight”, (P = 0.065), or ventricle-brain index (P = 0.27)” were not correlated with intraventricular pressure. The duration of clinical signs before surgery, however, was correlated with intraventricular pressure (P< 0.0001). Dogs with internal hydrocephalus do not necessarily have increased intraventricular pressure. Normotensive communicating hydrocephalus exists in dogs. [ABSTRACT FROM AUTHOR]

The maturation of photon-counting detector (PCD) technology promises to enhance routine CT imaging applications with high-fidelity spectral information. In this paper, we demonstrate the power of this synergy and our complementary reconstruction techniques, performing 4D, cardiac PCD-CT data acquisition and reconstruction in a mouse model of atherosclerosis, including calcified plaque. Specifically, in vivo cardiac micro-CT scans were performed in four ApoE knockout mice, following their development of calcified plaques. The scans were performed with a prototype PCD (DECTRIS, Ltd.) with 4 energy thresholds. Projections were sampled every 10 ms with a 10 ms exposure, allowing the reconstruction of 10 cardiac phases at each of 4 energies (40 total 3D volumes per mouse scan). Reconstruction was performed iteratively using the split Bregman method with constraints on spectral rank and spatio-temporal gradient sparsity. The reconstructed images represent the first in vivo, 4D PCD-CT data in a mouse model of atherosclerosis. Robust regularization during iterative reconstruction yields high-fidelity results: an 8-fold reduction in noise standard deviation for the highest energy threshold (relative to unregularized algebraic reconstruction), while absolute spectral bias measurements remain below 13 Hounsfield units across all energy thresholds and scans. Qualitatively, image domain material decomposition results show clear separation of iodinated contrast and soft tissue from calcified plaque in the in vivo data. Quantitatively, spatial, spectral, and temporal fidelity are verified through a water phantom scan and a realistic MOBY phantom simulation experiment: spatial resolution is robustly preserved by iterative reconstruction (10% MTF: 2.8–3.0 lp/mm), left-ventricle, cardiac functional metrics can be measured from iodine map segmentations with ~1% error, and small calcifications (615 μm) can be detected during slow moving phases of the cardiac cycle. Given these preliminary results, we believe that PCD technology will enhance dynamic CT imaging applications with high-fidelity spectral and material information. [ABSTRACT FROM AUTHOR]

Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research. [ABSTRACT FROM AUTHOR]

Background: Impaired myocardial deformation has been sporadically described in cardiac asymptomatic systemic sclerosis (SSc). We aimed to study myocardial deformation indices in cardiac asymptomatic SSc patients using cardiac magnetic resonance feature tracking (CMR-FT) and correlate these findings to the phenotypic and autoimmune background. Methods: Fifty-four cardiac asymptomatic SSc patients (44 females, 56±13 years), with normal routine cardiac assessment and CMR evaluation, including cine and late gadolinium enhancement (LGE) images, were included. SSc patients were compared to 21 sex- and age- matched healthy controls (17 females; 54±19 years). For CMR-FT analysis, a mid-ventricular slice for LV peak systolic radial and circumferential strain and a 4-chamber view for LV/RV peak systolic longitudinal strain were used. Results: Twenty-four patients had diffuse cutaneous SSc and 30 limited cutaneous SSc. Thirteen patients had digital ulcers. Median disease duration was 3.6 years. LV ejection fraction was higher in SSc patients compared to controls (62±6% vs. 59±5%, p = 0.01). Four patients had no LGE examination; in the remaining patients LGE was absent in 74%, while 18% had RV insertion fibrosis and 8% evidence of subendocardial infarction. LV longitudinal strain differed in those with insertion fibrosis (-18.0%) and infarction (-16.7%) compared to no fibrosis (-20.3%, p = 0.04). Patients with SSc had lower RV longitudinal strain and strain rate compared to controls (p<0.001 and p = 0.01, respectively). All other strain and strain rate measurements were non-significant between patients and controls. Conclusions: In cardiac asymptomatic SSc patients with normal routine functional indices, CMR-FT identifies subclinical presence of insertion fibrosis and/or myocardial infarction by impaired LV longitudinal strain. RV derived longitudinal indices were impaired in the patient group. CMR FT indices did not correlate to the patients’ phenotypic and autoimmune features. [ABSTRACT FROM AUTHOR]

Patient-specific in vivo ventricle mechanical wall stress and strain conditions are important for cardiovascular investigations and should be calculated from correct zero-load ventricle morphologies. Cardiac magnetic resonance (CMR) data were obtained from 6 healthy volunteers and 12 Tetralogy of Fallot (TOF) patients with consent obtained. 3D patient-specific CMR-based ventricle models with different zero-load diastole and systole geometries due to myocardium contraction and relaxation were constructed to qualify right ventricle (RV) diastole and systole stress and strain values at begin-filling, end-filling, begin-ejection, and end-ejection, respectively. Our new models (called 2G models) can provide end-diastole and end-systole stress/strain values which models with one zero-load geometries (called 1G models) could not provide. 2G mean end-ejection stress value from the 18 participants was 321.4% higher than that from 1G models (p = 0.0002). 2G mean strain values was 230% higher than that of 1G models (p = 0.0002). TOF group (TG) end-ejection mean stress value was 105.4% higher than that of healthy group (HG) (17.54±7.42kPa vs. 8.54±0.92kPa, p = 0.0245). Worse outcome group (WG, n = 6) post pulmonary valve replacement (PVR) begin-ejection mean stress was 57.4% higher than that of better outcome group (BG, 86.94±26.29 vs. 52.93±22.86 kPa; p = 0.041). Among 7 selected parameters, End-filling stress was the best predictor to differentiate BG patients from WG patients with prediction accuracy = 0.8208 and area under receiver operating characteristic curve (AUC) value at 0.8135 (EE stress). Large scale studies are needed to further validate our findings. [ABSTRACT FROM AUTHOR]

In Ebstein’s anomaly, maximal expansion in the atrialized right ventricle (RV) occurs during early diastole, whereas that of the functional RV occurs in late diastole, resulting in diastolic dyssynchronous expansion (DSE). We quantitatively assessed DSE and identified preoperative factors correlated with persistent DSE after surgery. Seventeen patients diagnosed with Ebstein’s anomaly in whom transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) images available were retrospectively analyzed for quantitative DSE assessment and 10 patients who underwent surgery and postoperative TTE available were additionally analyzed for postoperative DSE. Severity of DSE was assessed by the time difference of maximal expansion between the atrialized and functional RV divided by the cardiac cycle length × 100 (“DSE index”). Relations between DSE and, clinical, electrophysiologic parameters and the severity of tricuspid valve (TV) tethering (the RV length / tethering height during diastole: “Tethering index”) were assessed. In total patients, median DSE index and tethering index were 30.3 and 2.1 respectively, and the DSE index was correlated with tethering index (rs = 0.664, P = 0.004). In 10 patients who underwent surgery, this association remained after surgery and at 2-year follow up. Tethering index ≥2.5 separated patients with and without persistent DSE. In conclusion, DSE exists in Ebstein’s anomaly. DSE index is related to the tethering index and DSE persists postoperatively if tethering index ≥ 2.5. As the persistent DSE might possibly impede the optimal recovery of RV function after surgery, severity of TV tethering should take into account in considering surgery. [ABSTRACT FROM AUTHOR]

Simvastatin reduces pulmonary arterial pressure and right ventricular hypertrophy in animal models of pulmonary arterial hypertension (PAH) and is thought to restore endothelial dysfunction. In vivo effects of drugs are complicated by several factors and little is known of the direct effects of statins on pulmonary arteries. This study investigated the direct effects of simvastatin on pulmonary arteries isolated from rats with or without monocrotaline-induced PAH. Simvastatin suppressed contractions evoked by the thromboxane A2 receptor agonist U46619 (30 nM), the α1–adrenergic agonist phenylephrine (5 μM) and KCl (50 mM) by ~50% in healthy and diseased arteries, but did not reduce contraction evoked by sarco/endoplasmic reticulum ATPase blockers. It relaxed hypertensive arteries in the absence of stimulation. Removing the endothelium or inhibiting eNOS did not prevent the inhibition by simvastatin. Inhibiting RhoA/rho kinase (ROCK) with Y27632 (10 μM) suppressed contractions to U46619 and phenylephrine by ~80% and prevented their inhibition by simvastatin. Y27632 reduced KCl-induced contraction by ~30%, but did not prevent simvastatin inhibition. Simvastatin suppressed Ca2+ entry into smooth muscle cells, as detected by Mn2+ quench of fura-2 fluorescence. The calcium antagonist, nifedipine (1 μM), almost abolished K+-induced contraction with less effect against U46619 and phenylephrine. We conclude that simvastatin relaxes pulmonary arteries by acting on smooth muscle to interfere with signalling through G-protein coupled receptors and voltage-dependent Ca2+ entry. Its actions likely include inhibition of ROCK-dependent Ca2+ sensitisation and voltage-gated Ca2+ channels. These are likely to contribute to the beneficial effects of simvastatin in animal models of PAH. [ABSTRACT FROM AUTHOR]

Direct cardiac compression (DCC) holds enormous potential as a safe and effective means to treat heart failure patients who require long-term, or even permanent, biventricular support. However, devices developed to date are not tuned to meet the individual compression requirements of the left and right ventricles, which can differ substantially. In this paper, a systematic study examining the relationship, range, and effect of independent pressures on the left and right epicardial surfaces of a passive human heart model was performed as a means to optimize cardiac output via DCC support. Hemodynamic and tissue deformation effects produced by varying epicardial compressions were examined using finite element analysis. Results indicate that 1) designing a direct cardiac compression pump that applies separate pressures to the left and right ventricles is critical to maintain equivalent stroke volume for both ventricles, and 2) left and right ventricular epicardial pressures of 340 mmHg and 44 mmHg, respectively, are required to induce normal ejection fractions in a passive heart. This pilot study provides fundamental insights and guidance towards the design of improved direct cardiac compression devices for long-term circulatory support. [ABSTRACT FROM AUTHOR]

Cardiac fibroblasts (CF) play a critical role in post-infarction remodeling which can ultimately lead to pathological fibrosis and heart failure. Recent evidence demonstrates that remote (non-infarct) territory fibrosis is a major mechanism for ventricular dysfunction and arrhythmogenesis. β-arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein independent fashion. Recent work has provided evidence that β-arrestin signaling in the heart may be beneficial, however, these studies have primarily focused on cardiac myocytes and their role in adult CF biology has not been well studied. In this study, we show that β-arrestins can regulate CF biology and contribute to pathological fibrosis. Adult male rats underwent LAD ligation to induce infarction and were studied by echocardiography. There was a significant decline in LV function at 2–12 weeks post-MI with increased infarct and remote territory fibrosis by histology consistent with maladaptive remodeling. Collagen synthesis was upregulated 2.9-fold in CF isolated at 8 and 12 weeks post-MI and β-arrestin expression was significantly increased. β-adrenergic signaling was uncoupled in the post-MI CF and β-agonist-mediated inhibition of collagen synthesis was lost. Knockdown of β-arrestin1 or 2 in the post-MI CF inhibited transformation to myofibroblasts as well as basal and TGF-β-stimulated collagen synthesis. These data suggest that β-arrestins can regulate CF biology and that targeted inhibition of these signaling molecules may represent a novel approach to prevent post-infarction pathological fibrosis and the transition to HF. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is a fetal condition that affects up to 10% of all pregnancies and is associated with cardiovascular structural and functional remodelling that persists postnatally. Some studies have reported an increase in myocardial coronary blood flow in severe IUGR fetuses which has been directly associated to the dilatation of the coronary arteries. However, a direct measurement of the coronaries’ lumen diameter in IUGR has not been reported before. The aim of this paper is to perform, for the first time, a quantitative analysis of the effects of IUGR in cardiac geometry and coronary vessel size in a well-known rabbit model of IUGR using synchrotron-based X-ray Phase Contrast Tomography Imaging (X-PCI). Eight rabbit fetal hearts were imaged non-destructively with X-PCI. 3D reconstructions of the coronary arterial tree were obtained after semi-automatic image segmentation. Different morphometric features including vessel lumen diameter of the three main coronaries were automatically quantified. IUGR fetuses had more globular hearts and dilated coronary arteries as compared to controls. We have quantitatively shown that IUGR leads to structural coronary vascular tree remodelling and enlargement as an adaptation mechanism in response to an adverse environment of restricted oxygen and nutrients and increased perfusion pressure. [ABSTRACT FROM AUTHOR]

Purpose: HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing. Methods: Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death. Results: We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020). Conclusions: We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM. [ABSTRACT FROM AUTHOR]

The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels. [ABSTRACT FROM AUTHOR]

Background: AXL is a receptor tyrosine kinase that has been related to kidney and vascular disorders. Heart failure patients with reduced ejection fraction have higher AXL in serum than controls. No information about Axl expression with HF progression is available. Methods: Thoracic transverse aortic constriction (TAC) was successfully performed on male Wistar rats (n = 25) with different constriction levels. Controls underwent sham surgery (n = 12). Echocardiography measurements were performed 4–8 weeks after surgery. Collagen deposition was measured with picrosirius red staining. Axl mRNA levels in left ventricle (LV), left kidney (LK) and ascending aorta (aAo) and the LV expression of cardiac remodeling and fibrogenic factors were quantified with real-time PCR. AXL LV protein levels were quantified with western blot and localization was analyzed by immunohistochemistry. Soluble AXL levels in plasma were assayed with ELISA. Results: Successful TAC rats were classified into LV hypertrophy (LVH) or heart failure (HF), modeling the progressive cardiac changes after pressure overload. Collagen deposition was increased only in the HF group. LV Axl mRNA levels were higher in LVH and HF than in Sham rats, and correlated with LVHi, and hypertrophic and fibrogenic mediators. However, no association was found with LV systolic function. AXL was expressed in LV myocytes and other cell types. Concentration of circulating sAXL in plasma was increased in the LVH group compared to Sham and HF rats. Axl mRNA levels were similar in all groups in the LK and aAo. Conclusions: Axl expression pattern suggests a role in the early progression of LV remodeling in HF but not in the later systolic dysfunction. The higher levels of circulating AXL found in HF patients most probably shed from the heart. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the relationship between the thickness of epicardial adipose tissue (EAT) and perivascular adipose tissue (PVAT) and the adipokine-cytokine profile of patients with coronary heart disease, which can be of significant importance for predicting the course of cardiovascular disease (CVD). Eighty-four patients with CVD were assessed and divided into two groups based on the presence of visceral obesity (VO). In patients with VO, the thickness of the epicardial deposits of the left and right ventricles were 1.75 and 1.43 times greater, respectively, than in patients without VO. For patients with VO, the prevalence of the volume of the left anterior descending artery was 10% higher, and the middle third of the envelope artery was 28% higher, when compared to patients without VO. When evaluating inflammatory status, it was established that the concentration of tumor necrosis factor-α, interleukin (IL)-1β, and leptin in the blood serum of patients with VO exceeded the values of patients without VO. The level of anti-inflammatory IL-10 was 2-times lower in patients with VO. The findings of this study show that increased EAT and PVAT are independent risk factors of CVD, as well as a possible model for the assessment of drug effectiveness for CVD. [ABSTRACT FROM AUTHOR]

Purpose: We previously reported that inhibitory G protein (Gi) exerts intrinsic receptor-independent inhibitory activity upon adenylyl cyclase (AC) that regulates contractile force in rat ventricle. The two major subtypes of AC in the heart are AC5 and AC6. The aim of this study was to determine if this intrinsic Gi inhibition regulating contractile force is AC subtype selective. Methods: Wild-type (WT), AC5 knockout (AC5KO) and AC6 knockout (AC6KO) mice were injected with pertussis toxin (PTX) to inactivate Gi or saline (control).Three days after injection, we evaluated the effect of simultaneous inhibition of phosphodiesterases (PDE) 3 and 4 with cilostamide and rolipram respectively upon in vivo and ex vivo left ventricular (LV) contractile function. Also, changes in the level of cAMP were measured in left ventricular homogenates and at the membrane surface in cardiomyocytes obtained from the same mouse strains expressing the cAMP sensor pmEPAC1 using fluorescence resonance energy transfer (FRET). Results: Simultaneous PDE3 and PDE4 inhibition increased in vivo and ex vivo rate of LV contractility only in PTX-treated WT and AC5KO mice but not in saline-treated controls. Likewise, Simultaneous PDE3 and PDE4 inhibition elevated total cAMP levels in PTX-treated WT and AC5KO mice compared to saline-treated controls. In contrast, simultaneous PDE3 and PDE4 inhibition did not increase in vivo or ex vivo rate of LV contractility or cAMP levels in PTX-treated AC6KO mice compared to saline-treated controls. Using FRET analysis, an increase of cAMP level was detected at the membrane of cardiomyocytes after simultaneous PDE3 and PDE4 inhibition in WT and AC5KO but not AC6KO. These FRET data are consistent with the functional data indicating that AC6 activity and PTX inhibition of Gi is necessary for simultaneous inhibition of PDE3 and PDE4 to elicit an increase in contractility. Conclusions: Together, these data suggest that AC6 is tightly regulated by intrinsic receptor-independent Gi activity, thus providing a mechanism for maintaining low basal cAMP levels in the functional compartment that regulates contractility. [ABSTRACT FROM AUTHOR]

Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), were known to cause outflow tract (OFT) defects in both human and mouse, but the underlying molecular mechanism was not clear. In this study, Gata4 haploinsufficiency in mice was found to result in OFT defects including double outlet right ventricle (DORV) and ventricular septum defects (VSDs). Gata4 was shown to be required for Hedgehog (Hh)-receiving progenitors within the second heart field (SHF) for normal OFT alignment. Restored cell proliferation in the SHF by knocking-down Pten failed to rescue OFT defects, suggesting that additional cell events under Gata4 regulation is important. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion, which is associated with abnormal EMT and cell proliferation in Gata4 haploinsufficiency. The genetic interaction of Hh signaling and Gata4 is further demonstrated to be important for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA). Restoration of Hedgehog signaling renormalized SHF cell proliferation and migration, and rescued OFT defects in Gata4 haploinsufficiency. In addition, there was enhanced Gata6 expression in the SHF of the Gata4 heterozygotes. The Gata4-responsive repressive sites were identified within 1kbp upstream of the transcription start site of Gata6 by both ChIP-qPCR and luciferase reporter assay. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development. [ABSTRACT FROM AUTHOR]

Coordinated transcriptional and epigenetic mechanisms that direct development of the later differentiating second heart field (SHF) progenitors remain largely unknown. Here, we show that a novel zebrafish histone deacetylase 1 (hdac1) mutant allele cardiac really gone (crg) has a deficit of ventricular CMs and smooth muscle within the outflow tract (OFT) due to both cell and non-cell autonomous loss in SHF progenitor proliferation. Cyp26-deficient embryos, which have increased retinoic acid (RA) levels, have similar defects in SHF-derived OFT development. We found that nkx2.5+ progenitors from Hdac1 and Cyp26-deficient embryos have ectopic expression of ripply3, a transcriptional co-repressor of T-box transcription factors that is normally restricted to the posterior pharyngeal endoderm. Furthermore, the ripply3 expression domain is expanded anteriorly into the posterior nkx2.5+ progenitor domain in crg mutants. Importantly, excess ripply3 is sufficient to repress VC development, while genetic depletion of Ripply3 and Tbx1 in crg mutants can partially restore VC number. We find that the epigenetic signature at RA response elements (RAREs) that can associate with Hdac1 and RA receptors (RARs) becomes indicative of transcriptional activation in crg mutants. Our study highlights that transcriptional repression via the epigenetic regulator Hdac1 facilitates OFT development through directly preventing expression of the RA-responsive gene ripply3 within SHF progenitors. [ABSTRACT FROM AUTHOR]

Introduction: Teaching cardiac ultrasound (CU) image acquisition requires hands-on practice under qualified instructors supervision. We assessed the efficacy of teaching medical students by their previously trained classmates (teaching assistants [TAs]) compared to teaching by expert trainers (cardiologists or diagnostic medical sonographers. Methods: Sixty-six students received 8-hour CU training: 4-hour lectures on ultrasound anatomy and imaging techniques of 6 main CU views (parasternal long [PLAV] and short axis [PSAV]; apical 4-chamber [4ch], 2-chamber [2ch], and 3-chamber [3ch]; and sub costal [SC]) followed by 4 hours of hands-on exercise in groups of ≤5 students under direct supervision of a TA (group A: 44 students) or a qualified trainer (group B: 22 students). Students’ proficiency was evaluated on a 6-minute test in which they were required to demonstrate 32 predetermined anatomic landmarks spread across the 6 views and ranked on a 0–100 scale according to a predetermined key. Results: The 6-minute test final grade displayed superiority of group A over group B (54±17 vs. 39±21, respectively [p = 0.001]). This trend was continuous across all 6 main views: PLAV (69±18 vs. 54±23, respectively), PSAV (65±33 vs. 41±32, respectively), 4ch (57±19 vs. 43±26, respectively), 2ch (37±29 vs. 33±27, respectively), 3ch (48±23 vs. 35±25, respectively), and SC (36±27 vs. 24±28, respectively). Conclusions: Teaching medical students CU imaging acquisition by qualified classmates is feasible. Moreover, students instructors were superior to senior instructors when comparing their students' capabilities in a practical test. Replacing experienced instructors with TAs could help medical schools teach ultrasound techniques with minimal dependence on highly qualified trainers. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate and quantify the effect of improved attenuation correction (AC) including bone segmentation and truncation correction on 18F-Fluordesoxyglucose cardiac positron emission tomography/magnetic resonance (PET/MR) imaging. Methods: PET data of 32 cardiac PET/MR datasets were reconstructed with three different AC-maps (1. Dixon-VIBE only, 2. HUGE truncation correction and bone segmentation, 3. MLAA). The Dixon-VIBE AC-maps served as reference of reconstructed PET data. 17-segment short-axis polar plots of the left ventricle were analyzed regarding the impact of each of the three AC methods on PET quantification in cardiac PET/MR imaging. Non-AC PET images were segmented to specify the amount of truncation in the Dixon-VIBE AC-map serving as a reference. All AC-maps were evaluated for artifacts. Results: Using HUGE + bone AC results in a homogeneous gain of ca. 6% and for MLAA 8% of PET signal distribution across the myocardium of the left ventricle over all patients compared to Dixon-VIBE AC only. Maximal relative differences up to 18% were observed in segment 17 (apex). The body volume truncation of -12.7 ± 7.1% compared to the segmented non-AC PET images using the Dixon-VIBE AC method was reduced to -1.9 ± 3.9% using HUGE and 7.8 ± 8.3% using MLAA. In each patient, a systematic overestimation in AC-map volume was observed when applying MLAA. Quantitative impact of artifacts showed regional differences up to 6% within single segments of the myocardium. Conclusions: Improved AC including bone segmentation and truncation correction in cardiac PET/MR imaging is important to ensure best possible diagnostic quality and PET quantification. The results exhibited an overestimation of AC-map volume using MLAA, while HUGE resulted in a more realistic body contouring. Incorporation of bone segmentation into the Dixon-VIBE AC-map resulted in homogeneous gain in PET signal distribution across the myocardium. The majority of observed AC-map artifacts did not significantly affect the quantitative assessment of the myocardium. [ABSTRACT FROM AUTHOR]

Purpose of this work was to assess feasibility of cardiac diffusion tensor imaging (cDTI) at 7 T in a set of healthy, unfixed, porcine hearts using various parallel imaging acceleration factors and to compare SNR and derived cDTI metrics to a reference measured at 3 T. Magnetic resonance imaging was performed on 7T and 3T whole body systems using a spin echo diffusion encoding sequence with echo planar imaging readout. Five reference (b = 0 s/mm2) images and 30 diffusion directions (b = 700 s/mm2) were acquired at both 7 T and 3 T using a GRAPPA acceleration factor R = 1. Scans at 7 T were repeated using R = 2, R = 3, and R = 4. SNR evaluation was based on 30 reference (b = 0 s/mm2) images of 30 slices of the left ventricle and cardiac DTI metrics were compared within AHA segmentation. The number of hearts scanned at 7 T and 3 T was n = 11. No statistically significant differences were found for evaluated helix angle, secondary eigenvector angle, fractional anisotropy and apparent diffusion coefficient at the different field strengths, given sufficiently high SNR and geometrically undistorted images. R≥3 was needed to reduce susceptibility induced geometric distortions to an acceptable amount. On average SNR in myocardium of the left ventricle was increased from 29±3 to 44±6 in the reference image (b = 0 s/mm2) when switching from 3 T to 7 T. Our study demonstrates that high resolution, ex vivo cDTI is feasible at 7 T using commercial hardware. [ABSTRACT FROM AUTHOR]

The homeodomain transcription factor NKX2-5 is known to be essential for both normal heart development and for heart function. But little is yet known about the identities of its downstream effectors or their function during differentiation of cardiac progenitor cells (CPCs). We have used transgenic analysis and CRISPR-mediated ablation to identify a cardiac enhancer of the Furin gene. The Furin gene, encoding a proprotein convertase, is directly repressed by NKX2-5. Deletion of Furin in CPCs is embryonic lethal, with mutant hearts showing a range of abnormalities in the outflow tract. Those defects are associated with a reduction in proliferation and premature differentiation of the CPCs. Deletion of Furin in differentiated cardiomyocytes results in viable adult mutant mice showing an elongation of the PR interval, a phenotype that is consistent with the phenotype of mice and human mutant for Nkx2-5. Our results show that Furin mediate some aspects of Nkx2-5 function in the heart. [ABSTRACT FROM AUTHOR]

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease. [ABSTRACT FROM AUTHOR]

Purpose: Dynamic contrast enhanced MRI of the heart typically acquires 2–4 short-axis (SA) slices to detect and characterize coronary artery disease. This acquisition scheme is limited by incomplete coverage of the left ventricle. We studied the feasibility of using radial simultaneous multi-slice (SMS) technique to achieve SA, 2-chamber and/or 4-chamber long-axis (2CH LA and/or 4CH LA) coverage with and without electrocardiography (ECG) gating using a motion-robust reconstruction framework. Methods: 12 subjects were scanned at rest and/or stress, free breathing, with or without ECG gating. Multiple sets of radial SMS k-space were acquired within each cardiac cycle, and each SMS set sampled 3 parallel slices that were either SA, 2CH LA, or 4CH LA slices. The radial data was interpolated onto Cartesian space using an SMS GRAPPA operator gridding method. Self-gating and respiratory states binning of the data were done. The binning information as well as a pixel tracking spatiotemporal constrained reconstruction method were applied to obtain motion-robust image reconstructions. Reconstructions with and without the pixel tracking method were compared for signal-to-noise ratio and contrast-to-noise ratio. Results: Full coverage of the heart (at least 3 SA and 3 LA slices) during the first pass of contrast at every heartbeat was achieved by using the radial SMS acquisition. The proposed pixel tracking reconstruction improves the average SNR and CNR by 21% and 30% respectively, and reduces temporal blurring for both gated and ungated acquisitions. Conclusion: Acquiring simultaneous multi-slice SA, 2CH LA and/or 4CH LA myocardial perfusion images in every heartbeat is feasible in both gated and ungated acquisitions. This can add confidence when detecting and characterizing coronary artery disease by revealing ischemia in different views, and by providing apical coverage that is improved relative to SA slices alone. The proposed pixel tracking framework improves the reconstruction while adding little computational cost. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular magnetic resonance feature tracking (CMR-FT) is increasingly used for myocardial deformation assessment including ventricular strain, showing prognostic value beyond established risk markers if used in experienced centres. Little is known about the impact of appropriate training on CMR-FT performance. Consequently, this study aimed to evaluate the impact of training on observer variance using different commercially available CMR-FT software. Methods: Intra- and inter-observer reproducibility was assessed prior to and after dedicated one-hour observer training. Employed FT software included 3 different commercially available platforms (TomTec, Medis, Circle). Left (LV) and right (RV) ventricular global longitudinal as well as LV circumferential and radial strains (GLS, GCS and GRS) were studied in 12 heart failure patients and 12 healthy volunteers. Results: Training improved intra- and inter-observer reproducibility. GCS and LV GLS showed the highest reproducibility before (ICC >0.86 and >0.81) and after training (ICC >0.91 and >0.92). RV GLS and GRS were more susceptible to tracking inaccuracies and reproducibility was lower. Inter-observer reproducibility was lower than intra-observer reproducibility prior to training with more pronounced improvements after training. Before training, LV strain reproducibility was lower in healthy volunteers as compared to patients with no differences after training. Whilst LV strain reproducibility was sufficient within individual software solutions inter-software comparisons revealed considerable software related variance. Conclusion: Observer experience is an important source of variance in CMR-FT derived strain assessment. Dedicated observer training significantly improves reproducibility with most profound benefits in states of high myocardial contractility and potential to facilitate widespread clinical implementation due to optimized robustness and diagnostic performance. [ABSTRACT FROM AUTHOR]

Background: The aim of our study was to evaluate the feasibility of exercise cardiac magnetic resonance (CMR) in patients with repaired tetralogy of Fallot (RTOF) and to assess right and left ventricular adaptation and aortic wall response to exercise in comparison with volunteers. Methods: 11 RTOF and 11 volunteers underwent prospective CMR at rest and during exercise. A supine bicycle ergometer was employed to reach twice the resting heart rate during continuous exercise, blood pressure and heart rate were recorded. Bi-ventricular parameters and aortic stiffness were assessed using accelerated cine sequences and flow-encoding CMR. A t-test was used to compare values between groups. A Mann Whitney test was used to compare values within groups. Results: In RTOF both ventricles showed an impaired contractile reserve (RVEF rest 36.2±8.3%, +1.3±3.9% increase after exercise; LVEF rest 53.8±6.1%, +5.7±6.4% increase after exercise) compared to volunteers (RVEF rest 50.5±5.0%, +10.4±7.1% increase after exercise, p = 0.039; LVEF rest 61.9±3.1%, +12.2±4.7% increase after exercise, p = 0.014). RTOF showed a reduced distensibility of the ascending aorta during exercise compared to volunteers (RTOF: 3.4±1.9 10-3.mmHg-1 vs volunteers: 5.1±1.4 10-3.mmHg-1; p = 0.027). Ascending aorta distensibility was correlated to cardiac work in the volunteers but not in RTOF. Conclusion: RTOF showed an impaired contractile reserve for both ventricles. The exercise unmasked a reduced distensibility of the ascending aorta in RTOF, which may be an early sign of increased aortic rigidity. [ABSTRACT FROM AUTHOR]

During vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used mouse genetics to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results show that mice with Tnnt2-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with Tnnt2-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function. [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. We investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2). Methods: The study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imaging (TDI) signals were recorded at the mitral annulus for measurement of s`and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s`and e`. Results: All the regional LV s`and e`, and both RV s`and RV e`, were lower in individuals with FRDA compared to controls (p<0.001 for all). On multivariate analysis, which included LV septal wall thickness (SWT), RV s`and RV e`were both inversely correlated with GAA1 (β = -0.32 & -0.33, respectively, p = 0.01), but not with GAA2, whereas anterior and lateral s`were both inversely correlated with GAA2 (β = -0.25 and β = -0.28, p = 0.02) but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s`and e`, whereas age was a consistent inverse correlate of e`but not of s`. Conclusion: There are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the FXN gene. [ABSTRACT FROM AUTHOR]

Objective: There is no consensus on the embryonic components or morphogenetic processes involved in mature ventricular outflow tract development. Our goal was to use in vivo labelling to investigate the prospective fate of the myocardium of each conal wall. The conal and atrioventricular cushion mesenchyme changes during transformation into mature structures and their role in apoptosis were also investigated. Methods: Plastic labels were placed at the cephalic and caudal conal limits of chicken embryo hearts (stage 22HH) and traced up to stage 36HH. Histological analyses, scanning electron microscopy and apoptotic detection using Lysotracker-Red were performed. The conal longitudinal length and medial displacement were registered. Muscle myosin was identified by immunofluorescence. Results: Labels positioned in the myocardium of each conal wall moved to the right ventricle (RV), shifting from the arterial subvalvular myocardial zone to the apex. No labels were found in the aortic vestibule. At stage 22HH, the conus was a tubular structure composed of myocardium and endocardium with scarce mesenchyme. The dorso-left conal myocardial wall gradually lost continuity and the free ends separated, while the myocardium was distributed to the RV free wall (24HH-28HH). At stage 22HH, conal crests were not observed, but they were apparent at the dorsal zone of the conus at stage 26HH; towards stage 30HH, they fused to form the supraventricular crest, and the pulmonary infundibulum was evident. The ventro-superior cushion of the AV canal was reorganized into the fibrous and muscular structures lined the aortic vestibule. Conclusions: The posterior conus is an erroneous concept. The conal myocardium is reorganized in the free wall of the RV. Internally, the conal lumen is transformed into the pulmonary infundibulum. The aortic vestibule is formed from the ventro-superior cushion of the AV canal. Thus, the ventricular outflow tracts have different embryonic origins. [ABSTRACT FROM AUTHOR]

Rotors are functional reentry sources identified in clinically relevant cardiac arrhythmias, such as ventricular and atrial fibrillation. Ablation targeting rotor sites has resulted in arrhythmia termination. Recent clinical, experimental and modelling studies demonstrate that rotors are often anchored around fibrotic scars or regions with increased fibrosis. However the mechanisms leading to abundance of rotors at these locations are not clear. The current study explores the hypothesis whether fibrotic scars just serve as anchoring sites for the rotors or whether there are other active processes which drive the rotors to these fibrotic regions. Rotors were induced at different distances from fibrotic scars of various sizes and degree of fibrosis. Simulations were performed in a 2D model of human ventricular tissue and in a patient-specific model of the left ventricle of a patient with remote myocardial infarction. In both the 2D and the patient-specific model we found that without fibrotic scars, the rotors were stable at the site of their initiation. However, in the presence of a scar, rotors were eventually dynamically anchored from large distances by the fibrotic scar via a process of dynamical reorganization of the excitation pattern. This process coalesces with a change from polymorphic to monomorphic ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the combined 17β-estradiol (E2) and exercise training on cardiac pro-survival and anti-apoptotic pathways in ovariectomized rats. Methods: Fifty-six female Sprague–Dawley rats were divided into a sham-operated (Sham), a bilaterally ovariectomized (OVX), an OVX treated with E2 (OVX-E2; 10μg/kg/day), and an OVX with E2 and treadmill exercise training (OVX-E2-EX; 60 min/day, 5 days/week) for 10 weeks. Following 10 weeks of exercise training, rat hearts were isolated for the evaluation of Histopathological analysis, TUNEL assay, and Western blotting. Results: The protein levels of estrogen receptor α (ERα), estrogen receptor β (ERβ), insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-phosphatidylinositol 3-kinase (p-PI3K) (estrogen receptors/IGF-1-related survival pathway) were significantly increased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. The protein levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL) and phosphorylated-Bad (p-Bad) (Bcl-2 family survival pathway) were significantly increased in the OVX-E2-EX group when compared with the OVX group. Only the p-Bad was significantly increased in the OVX-E2 group when compared with the OVX group. The protein levels of truncation of Bid (t-Bid), Bcl-2-associated death promotor (Bad), Bcl-2-associated X protein (Bax), Cytochrome c, caspases-9, and caspases-3 (mitochondria-dependent apoptotic pathway), as well as the protein levels of tumor necrosis factor-α (TNF-α), Fas ligand, Fas receptors, Fas-associated death domain (FADD), activated caspase-8 and activated caspase-3 (Fas receptor–dependent apoptotic pathway) were significantly decreased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. Furthermore, when compared with the OVX-E2 group, the protein levels of ERβ, IGF-1, IGF-1R, Bcl-2 and Bcl-xL were further enhanced in the OVX-E2-EX group as well as the protein levels of Cytochrome c, Fas receptors, FADD, activated caspase-8, activated caspase-9 and activated caspase-3 were further decreased in the OVX-EX-E2 group. Conclusions: Combined E2 and exercise training exhibited a positive effect of protection on ovariectomy-induced cardiac apoptosis by enhancing ERβ-related survival pathways, which might provide a more effective therapeutic effect on cardiac protection in bilaterally oophorectomized or menopausal women than E2 treatment only. [ABSTRACT FROM AUTHOR]

The alpha regulator subunit B'' of protein phosphatase 2 (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), was reported to present a special subcellular localization in cardiomyocytes and elevate in non-ischemia failing hearts. PPP2R3A has two transcriptions PR72 and PR130. PR72 acts as a negative regulator of the Wnt signaling cascade, while the Wnt signaling cascade plays a pivotal role in cardiac development. And PR130 was found to be involved in cardiac development of zebrafish in our previous study. Thus, to investigate the function of PR72 in heart, two stable pr72 knockout (KO) zebrafish lines were generated using Transcription Activator-Like Effector Nuclease (TALEN) technology. Homozygous pr72 KO fish struggled to survive to adulthood and exhibited cardiac developmental defects, including enlarged ventricular chambers, reduced cardiomyocytes and decreased cardiac function. And the defective sarcomere ultrastructure that affected mitochondria, I bands, Z lines, and intercalated disks was also observed. Furthermore, the abnormal heart looping was detected in mutants which could be rescued by injection with wild type pr72 mRNA. Additionally, it was found that Wnt effectors were elevated in mutants. Those indicated that deletion of pr72 in zebrafish interrupted cardiac development, probably through activation of the Wnt pathway. [ABSTRACT FROM AUTHOR]

Objectives: To assess the safety and efficacy of percutaneous closure of perimembranous ventricular septal defect (PmVSD) using patent ductus arteriosus (PDA) occluders. Background: Widespread use of conventional PmVSD closure devices has been limited by unacceptable high rate of complete heart block (CHB). The elegant design of PDA occluders is supposed to ease implantation, increase closure rate and minimize damage to adjacent structures. Thus, PDA occluders may reduce complications, especially the CHB, and offer a good alternative for PmVSD closure. Method: From September 2008 to October 2015, patients who underwent attempted percutaneous VSD closure using PDA occluders were included in the study. Patient demographics, echocardiography measurements, procedure details and follow-up data until October 2017 were collected. Results: In total, 321 patients with a mean age of 15.5±12.6 years and mean a weight of 33.3±20.5 kg were included in this study. The mean defect size was 4.8±2.1 mm. Implantation was successful in 307 (95.6%) patients. The median follow-up time was 63 months (24 to 108 months). The closure rates were 89.5%, 91.5%, and 99.3% after the procedure 24 hours, 6 months and 2 years, respectively. Major complications occurred in 5 (1.7%) patients during the procedure and follow-up, including persistent CHB in 2 (0.7%) patients and device embolization in 3 (1.0%) patients. No death, disability, or other major complication was detected. Conclusion: Percutaneous closure of PmVSD using PDA occluders is feasible, safe and efficacious in selected patients. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate the expression and localisation of thymosin β4 (Tβ4) in the developing human heart. Tβ4 is a cardioprotective protein which may have therapeutic potential. While Tβ4 is an endogenously produced protein with known importance during development, its role within the developing human heart is not fully understood. Elucidating the localisation of Tβ4 within the developing heart will help in understanding its role during cardiac development and is crucial for understanding its potential for cardioprotection and repair in the adult heart. Methods: Expression of Tβ4 mRNA in the early fetal human heart was assessed by PCR using both ventricular and atrial tissue. Fluorescence immunohistochemistry was used to assess the localisation of Tβ4 in sections of early fetal human heart. Co-staining with CD31, an endothelial cell marker, and with myosin heavy chain, a cardiomyocyte marker, was used to determine whether Tβ4 is localised to these cell types within the early fetal human heart. Results: Tβ4 mRNA was found to be expressed in both the atria and the ventricles of the early fetal human heart. Tβ4 protein was found to be primarily localised to CD31-expressing endothelial cells and the endocardium as well as being present in the epicardium. Tβ4-associated fluorescence was greater in the compact layer of the myocardial wall and the interventricular septum than in the trabecular layer of the myocardium. Conclusions: The data presented illustrates expression of Tβ4 in the developing human heart and demonstrates for the first time that Tβ4 in the human heart is primarily localised to endothelial cells of the cardiac microvasculature and coronary vessels as-well as to the endothelial-like cells of the endocardium and to the epicardium. [ABSTRACT FROM AUTHOR]

Purpose: Chordae rupture is one of the main lesions observed in traumatic heart events that might lead to severe tricuspid valve (TV) regurgitation. TV regurgitation following chordae rupture is often well tolerated with few or no symptoms for most patients. However, early repair of the TV is of great importance, as it might prevent further exacerbation of the regurgitation due to remodeling responses. To understand how TV regurgitation develops following this acute event, we investigated the changes on TV geometry, mechanics, and function of ex-vivo porcine hearts following chordae rupture. Methods: Sonomicrometry techniques were employed in an ex-vivo heart apparatus to identify how the annulus geometry alters throughout the cardiac cycle after chordae rupture, leading to the development of TV regurgitation. Results: We observed that the TV annulus significantly dilated (~9% in area) immediately after chordae rupture. The annulus area and circumference ranged from 11.4 ± 2.8 to 13.3 ± 2.9 cm2 and from 12.5 ± 1.5 to 13.5 ± 1.3 cm, respectively, during the cardiac cycle for the intact heart. After chordae rupture, the annulus area and circumference were larger and ranged from 12.3 ± 3.0 to 14.4 ± 2.9 cm2 and from 13.0 ± 1.5 to 14.0 ± 1.2 cm, respectively. Conclusions: In our ex-vivo study, we showed for the first time that the TV annulus dilates immediately after chordae rupture. Consequently, secondary TV regurgitation may be developed because of such changes in the annulus geometry. In addition, the TV leaflet and the right ventricle myocardium are subjected to a different mechanical environment, potentially causing further negative remodeling responses and exacerbating the detrimental outcomes of chordae rupture. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to evaluate CMR myocardial first-pass perfusion in the injured region as well as the non-infarcted area in ST-elevation myocardial infarction (STEMI) patients few days after successful primary percutaneous coronary intervention (PCI). Materials and methods: 220 patients with first time STEMI successfully treated with PCI (with or without postconditioning) were recruited from the Postconditioning in STEMI study. Contrast enhanced CMR was performed at a 1.5 T scanner 2 (1–5) days after PCI. On myocardial first-pass perfusion imaging signal intensity (SI) was measured in the injured area and in the remote myocardium and maximum contrast enhancement index (MCE) was calculated. MCE = (peak SI after contrast—SI at baseline) / SI at baseline x 100. Results: There were no significant differences in first-pass perfusion between patients treated with standard PCI and patients treated with additional postconditioning. The injured myocardium showed a significantly lower MCE compared to remote myocardium (94 ± 55 vs. 113 ± 49; p < 0.001). When patients were divided into four quartiles of MCE in the injured myocardium (MCE injured myocardium), patients with low MCE injured myocardium had: significantly lower ejection fraction (EF) than patients with high MCE injured myocardium, larger infarct size and area at risk, smaller myocardial salvage and more frequent occurrence of microvascular obstruction on late gadolinium enhancement. MCE in the remote myocardium revealed that patients with larger infarction also had significantly decreased MCE in the non-infarcted, remote area. Conclusion: CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. These findings indicate that CMR first-pass perfusion may be a feasible method to evaluate myocardial injury after STEMI in addition to conventional CMR parameters. [ABSTRACT FROM AUTHOR]

Purpose: Myocardial computed tomography perfusion (CTP) allows the assessment of the functional relevance of coronary artery stenosis. This study investigates to what extent the contour sharpness of sequences acquired by dynamic myocardial CTP is influenced by the following noise reduction methods: temporal averaging and adaptive iterative dose reduction 3D (AIDR 3D). Materials and methods: Dynamic myocardial CT perfusion was conducted in 29 patients at a dose level of 9.5±2.0 mSv and was reconstructed with both filtered back projection (FBP) and strong levels of AIDR 3D. Temporal averaging to reduce noise was performed as a post-processing step by combining two, three, four, six and eight original consecutive 3D datasets. We evaluated the contour sharpness at four distinct edges of the left-ventricular myocardium based on two different approaches: the distance between 25% and 75% of the maximal grey value (d) and the slope in the contour (m). Results: Iterative reconstruction reduced contour sharpness: both measures of contour sharpness performed better for FBP than for AIDR 3D (d = 1.7±0.4 mm versus 2.0±0.5 mm, p>0.059 at all edges; m = 255.9±123.9 HU/mm versus 160.6±123.5 HU/mm; p<0.023 for all edges). Increasing levels of temporal averaging degraded contour sharpness. When FBP reconstruction was applied, contour sharpness was best without temporal averaging (d = 1.7±0.4 mm, m = 255.9±123.9 HU/mm) and poorest for the strongest levels of temporal averaging (d = 2.1±0.3 mm, m = 142.2±104.9 HU/mm; comparison between lowest and highest temporal averaging level: for d p>0.052 at all edges and for m p<0.001 at all edges). Conclusion: The use of both temporal averaging and iterative reconstruction degrades objective contour sharpness parameters of dynamic myocardial CTP. Thus, further advances in image processing are needed to optimise contour sharpness of 4D myocardial CTP. [ABSTRACT FROM AUTHOR]

Background: To date there is scarce published evidence reporting the dual blood supply reaching anterior papillary muscle (APM), which descends from both major coronary arteries. Such a vascular configuration can prevent the dysfunction of right ventricular entire valvular system in case of the occlusion of proximal part of either right coronary artery (RCA) or left coronary artery (LCA). The aim of our study was to determine the vascular pattern of APM blood supply which originates from two main coronary arteries, in the context of the APM and septomarginal trabecula (SMT) topography. Methods: The study was carried out using tissue obtained from 36 human hearts. The material was divided into four morphological types of SMT/APM arrangement. Vascularization and blood supply pattern of papillary muscle was investigated following the analysis of multiple tissue cross sections. The origin of APM arterial supply was traced back to both main coronary arteries. Cross-sectional area of the arteries was estimated at the base of APM and compared within mixed male-female population, aged 18–76. Results: We noted that as much as 78% of entire APM material had a blood supply vasculature originating from both LCA and RCA branches. In contrast, 22% of cases APM was supplied by a single coronary artery, while in each case it proved to be LCA. We have never found APM arterial supply provided exclusively by RCA. In case of double AMP blood supply an average of total cross-section area of the arteries branching from LCA, was noted to be in excess of two and a half times bigger in type III and more than two times bigger in type IV, as compared with the arteries originating from RCA. Conclusions: Our research confirm the possibility of double blood supply which vascularizes APM, but the finding does not necessarily apply in all cases. However, APM seems to be predominantly vascularized by arteries deriving from LCA, regardless of their morphological type. [ABSTRACT FROM AUTHOR]

Epidemiological studies have linked vitamin D deficiency to an increased incidence of myocardial infarction and support a role for vitamin D signalling in the pathophysiology of myocardial infarction. Vitamin D deficiency results in the development of secondary hyperparathyroidism, however, the role of secondary hyperparathyroidism in the pathophysiology of myocardial infarction is not known. Here, we aimed to explore further the secondary hyperparathyroidism independent role of vitamin D signalling in the pathophysiology of myocardial infarction by inducing experimental myocardial infarction in 3-month-old, male, wild-type mice and in mice lacking a functioning vitamin D receptor. In order to prevent secondary hyperparathyroidism in vitamin D receptor mutant mice, all mice were maintained on a rescue diet enriched with calcium, phosphorus, and lactose. Surprisingly, survival rate, cardiac function as measured by echocardiography and intra-cardiac catheterisation and cardiomyocyte size were indistinguishable between normocalcaemic vitamin D receptor mutant mice and wild-type controls, 2 and 8 weeks post-myocardial infarction. In addition, the myocardial infarction-induced inflammatory response was similar in vitamin D receptor mutants and wild-type mice, as evidenced by a comparable upregulation in cardiac interleukin-1-β and tumor-necrosis-factor-α mRNA abundance and similar elevations in circulating interleukin-1-β and tumor-necrosis-factor-α. Our data suggest that the lack of vitamin D signalling in normocalcaemic vitamin D receptor mutants has no major detrimental effect on cardiac function and outcome post-myocardial infarction. Our study may have important clinical implications because it suggests that the secondary hyperparathyroidism induced by vitamin D deficiency, rather than the lack of vitamin D signalling per se, may negatively impact cardiac function post-myocardial infarction. [ABSTRACT FROM AUTHOR]

L-arginine supplementation has been related to increased maximum strength and improvement of hemodynamic parameters in several diseases. The aim of our study was to evaluate the effect of L-arginine supplementation and resistance training on muscle mass, hemodynamic function and DNA damage in healthy rats subjected to a low-arginine concentration diet. Twenty three Wistar rats (290-320g) were divided into 4 groups: Sedentary (SED-Arg, n = 6), Sedentary+Arg (SED+Arg, n = 6), Resistance Training (RT-Arg, n = 5), Resistance Training+Arg (RT+Arg, n = 6). Trained animals performed resistance training protocol in a squat apparatus adapted for rats (4 sets of 10–12 repetitions, 90s of interval, 4x/week, 65–75% of One Maximum Repetition, for 8 weeks). Comet assay was performed to measure DNA damage in leukocytes. The resistance training induced higher muscle mass in trained groups. The L-arginine supplementation increased both gastrocnemius and left ventricle to body mass ratio and increased left ventricle contractility without changing hemodynamic variables. The SED+Arg group showed higher concentration of extracellular heat shock protein 72 (eHSP72) and total testosterone, as well as lower uric acid concentration in blood versus SED-Arg group. The administration of isolated L-arginine supplementation and its association with resistance training promoted less damage in leukocytes DNA. In conclusion, the L-arginine supplementation showed synergistic effect with resistance training regarding leukocyte genomic stability in a low-L-arginine diet scenario. [ABSTRACT FROM AUTHOR]

Background: Point-of-care ultrasonography (PoCUS) is a rapidly evolving discipline that aims to train non-cardiologists, non-radiologists clinicians in performing bedside ultrasound to guide clinical decision. Training of PoCUS is challenging, time-consuming and requires large amount of resources. The objective of our study was to evaluate if this training process can be simplified by allowing medical students self-train themselves with a web-based cardiac ultrasound software. Methods: A prospective, single blinded, cohort study, comparing performance of 29 medical students in performing a six-minutes cardiac ultrasound exam. Students were divided into two groups: self-learning group, using a combination of E-learning software and self-practice using pocket ultrasound device compared to formal, frontal cardiac ultrasound course. Results: All 29 students completed their designated courses and performed the six-minutes exam: 20 students participated in the frontal cardiac ultrasound course and 9 completed the self-learning course. The median (Q1,Q3) test score for the self-learning group was higher than the frontal course group score, 18 (15,19) versus 15 (12,19.5), respectively. Nevertheless, no statistically significant difference was found between the two study groups (p = 0.478). All students in the self-learning course group (9/9, 100%) and 16 (16/20, 80%) of students in the frontal ultrasound course group obtained correct alignment of the parasternal long axis view (p = 0.280). Conclusions: Self-learning students combining E-learning software with self-practice cardiac ultrasound were as good as students who received a validated, bedside, frontal cardiac ultrasound course. Our findings suggest that independent cardiac ultrasound learning, combining utilization of E–learning software and self-practice, is feasible. Self-E- learning of cardiac ultrasound may serve as an important, cost-effective adjunct to heavily resource consuming traditional teaching. [ABSTRACT FROM AUTHOR]

Background: Prior studies suggested that myocardial deformation is superior to conventional measures for assessing ventricular function. This study aimed to evaluate right ventricular (RV) myocardial deformation in response to increased afterload. Patients with the RV in the systemic position were compared with patients with the RV in the sub-pulmonic position with normal or only slightly elevated systolic right ventricular pressure. Correlations between global longitudinal strain (GLS), radial strain, atrioventricular plane displacement (AVPD), and exercise capacity were evaluated. Methods: 44 patients with congenital heart defect were enrolled in the study. The control group consisted of seven healthy volunteers. All patients underwent cardiovascular magnetic resonance (CMR) and cardiopulmonary exercise testing. We assessed biventricular myocardial function using CMR based feature tracking and compared the results to anatomic volumes. Results: Strain analysis and displacement measurements were feasible in all participants. RVGLS and RVAVPD were reduced in both study groups compared to the control group (p<0.001). Left ventricular (LV) radial strain was significantly lower in patients with a systemic RV than in those with a subpulmonic RV and lower than in controls (p<0.001). Both LVAVPD and RVAVPD were significantly depressed in patients compared to controls (p<0.05). RVAVPD was more depressed in patients with a high systolic RV pressure than in those with normal RV pressure (p<0.001). RVAVPD did not correlate with exercise capacity in either study group. Exercise capacity in both patient groups was depressed to levels reported in previous studies, and did not correlate with RVGLS. Conclusions: Both study groups had abnormal myocardial deformation and increased RV volumes. RVGLS in patients was lower than in controls, confirming the effect of increased afterload on myocardial performance. [ABSTRACT FROM AUTHOR]

Although oxygen therapy rapidly improves arterial oxygen saturation in idiopathic pulmonary arterial hypertension, the effects of chronic administration of oxygen are unknown. The purpose of the present study was to investigate the effects of chronic oxygen therapy on the histological changes and survival rate in rats with idiopathic pulmonary arterial hypertension. Idiopathic pulmonary arterial hypertension was induced by monocrotaline injection. The rats were then randomly assigned to receive or not receive oxygen therapy (O2 group and non-O2 group, respectively). The rats in the O2 group were exposed to a high (90%) oxygen environment from day 17 following injection of monocrotaline, when hypoxemia was first observed. The pulmonary arteriole walls were significantly thicker in monocrotaline-injected rats than in saline-injected rats as vehicle on day 19 and were significantly thicker in the rats that received oxygen therapy than in the rats that did not. Right ventricular inflammations were significantly higher in monocrotaline-injected rats than in saline-injected rats on day 19 and were significantly higher in the rats that received oxygen therapy than in the rats that did not. By day 20 after injection of monocrotaline, the survival rate was significantly lower in the rats that received oxygen therapy than in those that did not. Superoxide dismutase activity in the lungs was higher in monocrotaline-injected rats than in saline-injected rats on day 19 after monocrotaline injection and was also higher in the saline-injected rats that received oxygen therapy than in the saline-injected rats that did not. No interaction was detected between monocrotaline injection and oxygen therapy. These results suggest that chronic oxygen therapy worsens the histological changes and survival rate in idiopathic pulmonary arterial hypertension. The fact that degradation of the histological changes and survival rate was accompanied by increase in superoxide dismutase activity suggests that antioxidant capacity may contribute to the degradation. [ABSTRACT FROM AUTHOR]