Jinyan Yang

Effect of chronic hypoxia on contents of urotensin II and its functional receptors in rat myocardium.

Abstract The cyclic peptide urotensin II (UII) has recently been cloned in mammals and reported to constrict rat pulmonary arteries potently. An enhanced maximal response was shown in rats exposed to chronic hypoxia. The aim of this study was to investigate changes in plasma and myocardial UII levels and its receptor sites in crude sarcolemma of ventricles from chronic hypoxic rats. We observed that rats exposed to chronic hypoxia for 4 weeks developed pulmonary hypertension and right ventricular hypertrophy. Compared with controls, the UII content in hypoxic rats was increased by 97.5% (45.24 ± 7.1 vs. 22.9 ± 3.24 pg/mg protein, P < 0.01) in the right ventricle and 33.2% (24.89 ± 0.99 vs. 18.68 ± 2.04 pg/mg protein, P < 0.01) in the left ventricle, respectively. However, there was no significant difference in plasma (27.44 ± 3.11 vs. 27.82 ± 5.57 pg/ml, P > 0.05) and lung tissue levels (34.03 ± 4.63 vs. 33.74 ± 4.06 pg/mg protein, P > 0.05) between the control and hypoxic groups. The time course of the binding of [125I]UII to crude ventricular sarcolemma was specific and time dependent. Scatchard plot analysis of the data demonstrated that the maximal number of specific binding sites (Bmax) in both the right and left ventricles was upregulated in the hypoxic group. Moreover, Bmax in the right ventricular specimens was upregulated to a greater extent than in the left ventricle (increased by 114% and 25% in the right and left ventricles, respectively, compared with control group, P < 0.01). In contrast, the UII binding affinity in right and left ventricular membranes from hypoxic rats was decreased (the dissociation constant Kd) increased by 20% and 33%, respectively compared with controls, P < 0.01). These results indicate that UII may act as an autocrine and/or paracrine hormone rather than as a circulating hormone, playing important roles in the development of ventricular hypertrophy induced by chronic hypoxia, and that the pathophysiologi-cal significance of UII in pulmonary and cardiovascular alteration induced by chronic hypoxia deserves further investigation.

The Role of Sulfur Dioxide in the Regulation of Mitochondrion-Related Cardiomyocyte Apoptosis in Rats with Isopropylarterenol-Induced Myocardial Injury

The authors investigated the regulatory effects of sulfur dioxide (SO2) on myocardial injury induced by isopropylarterenol (ISO) hydrochloride and its mechanisms. Wistar rats were divided into four groups: control group, ISO group, ISO plus SO2 group, and SO2 only group. Cardiac function was measured and cardiomyocyte apoptosis was detected. Bcl-2, bax and cytochrome c (cytc) expressions, and caspase-9 and caspase-3 activities in the left ventricular tissues were examined in the rats. The opening status of myocardial mitochondrial permeability transition pore (MPTP) and membrane potential were analyzed. The results showed that ISO-treated rats developed heart dysfunction and cardiac injury. Furthermore, cardiomyocyte apoptosis in the left ventricular tissues was augmented, left ventricular tissue bcl-2 expression was down-regulated, bax expression was up-regulated, mitochondrial membrane potential was significantly reduced, MPTP opened, cytc release from mitochondrion into cytoplasm was significantly increased, and both caspase-9 and caspase-3 activities were increased. Administration of an SO2 donor, however, markedly improved heart function and relieved myocardial injury of the ISO-treated rats; it lessened cardiomyocyte apoptosis, up-regulated myocardial bcl-2, down-regulated bax expression, stimulated mitochondrial membrane potential, closed MPTP, and reduced cytc release as well as caspase-9 and caspase-3 activities in the left ventricular tissue. Hence, SO2 attenuated myocardial injury in association with the inhibition of apoptosis in myocardial tissues, and the bcl-2/cytc/caspase-9/caspase-3 pathway was possibly involved in this process.

The PI3K/Akt pathway mediates the protection of SO(2) preconditioning against myocardial ischemia/reperfusion injury in rats.

Aim:To explore the mechanisms underlying the protection by SO2 preconditioning against rat myocardial ischemia/reperfusion (I/R) injury.Methods:Male Wistar rats underwent 30-min left coronary artery ligation followed by 120-min reperfusion. An SO2 donor (1 μmol/kg) was intravenously injected 10 min before the ischemia, while LY294002 (0.3 mg/kg) was intravenously injected 30 min before the ischemia. Plasma activities of LDH and CK were measured with an automatic enzyme analyzer. Myocardial infarct size was detected using Evans-TTC method. The activities of caspase-3 and -9 in myocardium were assayed using a commercial kit, and the levels of p-Akt, Akt, PI3K and p-PI3K were examined with Western blotting.Results:Pretreatment with SO2 significantly reduced the myocardial infarct size and plasma LDH and CK activities, as well as myocardial caspase-3 and -9 activities in the rats. Furthermore, the pretreatment significantly increased the expression levels of myocardial p-Akt and p-PI3K p85. Administration of the PI3K inhibitor LY294002 blocked all the effects induced by SO2 pretreatment.Conclusion:The results suggest that the PI3K/Akt pathway mediates the protective effects of SO2 preconditioning against myocardial I/R injury in rats.

Postural orthostatic tachycardia syndrome with increased erythrocytic hydrogen sulfide and response to midodrine hydrochloride.

OBJECTIVES To evaluate the use of erythrocytic hydrogen sulfide (H2S) in predicting the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN Fifty-five children were included in this study, involving 28 children with POTS (POTS group) and 27 healthy children (control group). Children in the POTS group received midodrine hydrochloride treatment. Erythrocytic H2S production was measured; a receiver operating characteristic curve was used to assess if erythrocytic H2S could predict the therapeutic response to midodrine hydrochloride treatment. RESULTS H2S production from erythrocytes was significantly higher in the POTS group than in the control group (P < .01). H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders (P < .05). The change in symptom score and baseline erythrocytic H2S production had a positive linear relationship (P < .01). There was also a positive correlation with the change in heart rate (P < .05). The receiver operating characteristic curve showed an area under curve value of 0.813. Erythrocytic H2S production yielded a sensitivity of 78.9% and a specificity of 77.8% in predicting the efficacy of midodrine hydrochloride therapy for children with POTS. CONCLUSION Erythrocytic H2S could serve as a useful predictor of therapeutic response to midodrine hydrochloride in children with POTS.

Flow-mediated vasodilation as a predictor of therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome.

This study was designed to explore the value of flow-mediated vasodilation (FMD) as a predictor of therapeutic response to midodrine hydrochloride (MD) in children with postural orthostatic tachycardia syndrome (POTS). One hundred and eight children diagnosed with POTS and 20 healthy control children were enrolled. All children with POTS received MD and were followed up for 3 months. FMD of brachial artery for each participant was measured by vascular ultrasound. Symptom scores, FMD values, and head-up test (HUT)/head-up tilt test (HUTT) outcomes were investigated before and after treatment. A receiver operating characteristic curve was used to explore the value of FMD as a predictor. Baseline FMD (%) and increased heart rate (beats per minute) during HUT/HUTT were significantly greater in children with POTS compared with control children (FMD: 11 ± 3% vs 6 ± 2%, p <0.001; increased heart rate: 38 ± 9 vs 7 ± 7 beats/min, p <0.001, respectively). Before treatment, MD responders had greater FMD values than MD nonresponders (p <0.05). Symptom scores, excessive increases in heart rate during HUT, and increased FMD values were all reduced significantly after treatment (all p <0.05). The receiver operating characteristic curve for the predictive value of FMD showed the area under the curve to be 0.790 (95% confidence interval: 0.679 to 0.902; p <0.001) at 1-month and 0.803 (95% confidence interval: 0.669 to 0.936; p <0.01) at 3-month therapy. FMD of 9.85% had a high sensitivity (1-month therapy: 71.6%; 3-month therapy: 74.4%) and specificity (1-month therapy 77.8%; 3-month therapy: 80%). In conclusion, FMD is a predictor of the efficacy of MD for treating children with POTS.

The ERK1/2 signaling pathway is involved in sulfur dioxide preconditioning-induced protection against cardiac dysfunction in isolated perfused rat heart subjected to myocardial ischemia/reperfusion.

Ischemia/reperfusion injury (IRI) occurs frequently during reperfusion of ischemic myocardium, and preconditioning has been regarded as one of the best strategies to prevent myocardial injury during the ischemia/reperfusion process. Our previous studies indicated that a small dose of sulfur dioxide (SO2) used as preconditioning exerts cardioprotection. However, the mechanisms underlying the cardioprotection remain unclear. The present study was designed to examine if the extracellular regulated protein kinases 1/2 (ERK1/2) signaling pathway mediated protection against cardiac dysfunction after SO2 preconditioning in isolated rat hearts subjected to ischemia/reperfusion (I/R). Langendorff heart perfusion was performed in vitro, where 56 male Wistar rats were randomly divided into seven groups: control group, 5 μmol/L SO2 group (S5), 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) + 5 μmol/L SO2 (PD98059 + S5) group, PD98059 group, I/R group, 5 μmol/L SO2 + I/R (S5 + I/R) group and PD98059 + 5 μmol/L SO2 + I/R (PD98059 + S5 + I/R) group. Cardiac function and myocardial phosphorylated ERK1/2 protein were measured. We found that I/R in isolated rat heart resulted in cardiac dysfunction with a significant increase in phosphorylated ERK1/2 protein. SO2 preconditioning markedly suppressed phosphorylated ERK1/2 protein and improved cardiac function in isolated rat heart with I/R (p < 0.05). However, pre-treatment with PD98059 could prevent the above effects of SO2 preconditioning. In conclusion, SO2 preconditioning protected against cardiac dysfunction in isolated rat heart subjected to I/R via suppression of the over-activation of the ERK1/2 signaling pathway.

Risk Factors for Postural Tachycardia Syndrome in Children and Adolescents

Background Postural tachycardia syndrome (POTS) is prevalent in children and adolescents and has a great impact on health. But its risk factors have not been fully understood. This study aimed to explore possible risk factors for children and adolescents with POTS. Methods and Findings 600 children and adolescents (test group) aged 7–18 (11.9±3.0) years old, 259 males and 341 females, were recruited for identifying its risk factors. Another 197 subjects aged from 7 to 18 (11.3±2.3) years old were enrolled in the validation group. Heart rate (HR) and blood pressure (BP) were monitored during upright test. Risk factors were analyzed and sensitivity and specificity for predicting POTS were tested via receiver operating characteristic curve. Among 600 subjects, 41 were confirmed with POTS patients (6.8%) based on clinical manifestation and upright test. The results showed a significant difference in daily water intake, the daily sleeping hours, supine HR, HR increment and maximum HR during upright test between POTS and the unaffected children (P<0.05). Likelihood of POTS would increase by 1.583 times if supine HR was increased by 10 beats/min (95%CI 1.184 to 2.116, P<0.01), by 3.877 times if a childs water intake was less than 800 ml/day (95%CI 1.937 to 7.760, P<0.001), or by 5.905 times (95%CI 2.972 to 11.733, P<0.001) if sleeping hours were less than 8 hours/day. Supine HR, daily water intake and sleeping hours showed the capability of predicting POTS in children and adolescents with an AUC of 83.9% (95% CI: 78.6%–89.1%), sensitivity of 80.5% and specificity of 75%. Furthermore, in validation group, predictive sensitivity and specificity were 73.3% and 72.5%. Conclusion Faster supine HR, less water intake and shorter sleeping hours were identified as risk factors for POTS.

Erythrocytic Hydrogen Sulfide Production Is Increased in Children with Vasovagal Syncope

OBJECTIVES To explore the differences in erythrocyte hydrogen sulfide (H2S) production in children with vasovagal syncope (VVS). STUDY DESIGN A total of 54 children including 27 with VVS, aged 6-16 years (mean age 11.3 ± 3.3 years), and 27 healthy children, aged 3-17 years (mean age 10.4 ± 1.8 years) were included in the study. Children with VVS had symptoms of dizziness, pallor, blurred vision, nausea, and some had syncope. Erythrocyte H2S production was measured by a sulphur-sensitive electrode. Flow-mediated dilation (FMD) of brachial artery was measured for each patient by vascular ultrasound. RESULTS H2S production from erythrocytes was significantly increased in the children with VVS compared with controls (P < .01). The erythrocytic H2S production in the VVS-vasoinhibitory subgroup was obviously higher than that in VVS-cardioinhibitory (P < .05) and VVS-mixed inhibitory subgroups (P < .05). FMD in the VVS-vasoinhibitory subgroup was greater than that in the VVS-cardioinhibitory (P < .05) and the VVS-mixed subgroups (P < .05). The erythrocytic H2S production had a positive linear correlation with FMD in children with VVS (P < .05). CONCLUSIONS Increased erythrocyte H2S production may be involved in the pathogenesis of VVS in children.

Modified Calgary score in differential diagnosis between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope in children.

The present study was designed to analyse the usefulness of a modified Calgary score system during differential diagnosis between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope through a large sample sized clinical investigation. The study included 213 children, including 101 boys and 112 girls, with cardiac syncope or postural orthostatic tachycardia syndrome-associated syncope in the age group of 2-19 years (mean 11.8 ± 2.9 years). A modified Calgary score was created, which was analysed to predict differential diagnoses between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope using a receiver operating characteristic curve. The median of modified Calgary scores for cardiac syncope was -5.0, which significantly differed from that of postural orthostatic tachycardia syndrome (0.0; p < 0.01). The sensitivity and specificity of a differentiation score of less than -2.5 was 96.3% and 72.7%, respectively. Owing to the fact that the modified Calgary score was an integer, when less than -3.0 the diagnosis could be considered as cardiac syncope. The modified Calgary score could be used to make an initial differential diagnosis between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope in the clinic.

A cross-sectional study on upright heart rate and BP changing characteristics: basic data for establishing diagnosis of postural orthostatic tachycardia syndrome and orthostatic hypertension

Objective We aimed to determine upright heart rate and blood pressure (BP) changes to suggest diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) and orthostatic hypertension (OHT) in Chinese children. Methods In this cross-sectional study, 1449 children and adolescents aged 6–18 years were randomly recruited from two cities in China, Kaifeng in Henan province and Anguo in Hebei province. They were divided into two groups: 844 children aged 6–12 years (group I) and 605 adolescents aged 13–18 years (group II). Heart rate and BP were recorded during an active standing test. Results 95th percentile (P95) of δ heart rate from supine to upright was 38 bpm, with a maximum upright heart rate of 130 and 124 bpm in group I and group II, respectively. P95 of δ systolic blood pressure (SBP) increase was 18 mm Hg and P95 of upright SBP was 132 mm Hg in group I and 138 mm Hg in group II. P95 of δ diastolic blood pressure (DBP) increase was 24 mm Hg in group I and 21 mm Hg in group II, and P95 of upright DBP was 89 mm Hg in group I and 91 mm Hg in group II. Conclusions POTS is suggested when δ heart rate is ≥38 bpm (for easy memory, ≥40 bpm) from supine to upright, or maximum heart rate ≥130 bpm (children aged 6–12 years) and ≥125 bpm (adolescents aged 13–18 years), associated with orthostatic symptoms. OHT is suggested when δ SBP (increase) is ≥20 mm Hg, and/or δ DBP (increase) ≥25 mm Hg (in children aged 6–12 years) or ≥20 mm Hg (in adolescents aged 13–18 years) from supine to upright; or upright BP≥130/90 mm Hg (in children aged 6–12 years) or ≥140/90 mm Hg (in adolescents aged 13–18 years).