The Mechanism Actions of Astragaloside IV Prevents the Progression of Hypertensive Heart Disease Based on Network Pharmacology and Experimental Pharmacology.

Astragaloside IV (AS-IV) has been used to treat cardiovascular disease. However, whether AS-IV exerts a protective effect against hypertensive heart disease has not been investigated. This study aimed to investigate the antihypertensive and cardioprotective effects of AS-IV on L-NAME-induced hypertensive rats via network pharmacology and experimental pharmacology. The network pharmacology and bioinformatics analyses were performed to obtain the potential targets of AS-IV and hypertensive heart disease. The rat hypertension model was established by administrated 50 mg/kg/day of L-NAME for 5 weeks. Meanwhile, hypertension rats were intragastrically administrated with vehicle or AS-IV or fosinopril for 5 weeks. Cardiovascular parameters (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rates, and body weight), cardiac function parameters (LVEDd, LVEDs, and fractional shortening), cardiac marker enzymes (creatine kinase, CK-MB, and lactate dehydrogenase), cardiac hypertrophy markers (atrial natriuretic peptide and brain natriuretic peptide), endothelial function biomarkers (nitric oxide and eNOS), inflammation biomarkers (IL-6 and TNF-α) and oxidative stress biomarkers (SOD, MDA, and GSH) were measured and cardiac tissue histology performed. Network pharmacological analysis screened the top 20 key genes in the treatment of hypertensive heart disease treated with AS-IV. Besides, AS-IV exerted a beneficial effect on cardiovascular and cardiac function parameters. Moreover, AS-IV alleviated cardiac hypertrophy via down-regulating the expression of ANP and BNP and improved histopathology changes of cardiac tissue. AS-IV improved endothelial function via the up-regulation of eNOS expression, alleviated oxidative stress via increasing antioxidant enzymes activities, and inhibited cardiac inflammation via down-regulating IL-6 and TNF-α expression. Our findings suggested that AS-IV is a potential therapeutic drug to improve L-NAME-induced hypertensive heart disease partly mediated via modulation of eNOS and oxidative stress.

MicroRNA­20b­5p promotes ventricular remodeling by targeting the TGF­ß/Smad signaling pathway in a rat model of ischemia­reperfusion injury.

Myocardial ischemic injury results from severe impairment of the coronary blood supply and may lead to metabolic and ultrastructural changes, thereby causing irreversible damage. MicroRNA (miR)­20b­5p has been demonstrated to be involved in malignancies of the breast, colorectum, stomach, blood and oropharynx. The present study aimed to investigate the effects of miR­20b­5p on ventricular remodeling following myocardial ischemia­reperfusion (IR) injury in rats by targeting small mothers against decapentaplegic homolog 7 (Smad7) via the transforming growth factor­ß (TGF­ß)/Smad signaling pathway. A total of 70 adult male Sprague­Dawley rats were divided into seven groups: Sham group, IR group, negative control group, miR­20b­5p mimics group, miR­20b­5p inhibitors group, small interfering RNA (siRNA)­Smad7 group, and miR­20b­5p inhibitors + siRNA­Smad7 group. Dual luciferase reporter gene assays were used to verify the association between miR­20b­5p and Smad7. Myocardial infarction size, myocardial collagen volume fraction and perivascular collagen area were detected separately using triphenyltetrazolium chloride and Masson's staining. The rate of positive expression of Smad7 was detected using immunohistochemistry, and the expression levels of miR­20b­5p, TGF­ß1, Smad3 and Smad7 were detected using reverse transcription­quantitative polymerase chain reaction and western blot analyses. The findings revealed that miR­20b­5p inhibited Smad7. Compared with the sham group, the other six groups had increased myocardial infarction size, myocardial collagen, and expression of miR­20b­5p, TGF­ß1 and Smad3, and decreased expression of Smad7. Compared with the IR group, the miR­20b­5p mimics group and the siRNA­Smad7 group had increased myocardial infarction size and myocardial collagen, increased expression of TGF­ß1 and Smad3, and decreased expression of Smad7. The expression of miR­20b­5p was markedly increased in the miR­20b­5p mimics group, but did not differ significantly from that in the siRNA­Smad7 group. The results demonstrated that miR­20b­5p promoted ventricular remodeling following myocardial IR injury in rats by inhibiting the expression of Smad7 through activating the TGF­ß/Smad signaling pathway.

Pretreatment with intravenous amiodarone improves the efficacy of ibutilide treatment on cardioversion rate and maintenance time of sinus rhythm in patients with persistent atrial fibrillation.

The aim of the present study was to assess the efficacy and safety of the pharmacological conversion of persistent atrial fibrillation (AF) using amiodarone or/and ibutilide. Seventy-nine consecutive patients (48 males and 31 females; mean age, 64.6±11.2 years; range, 40-80 years) with non-valvular chronic AF lasting >7 days (range, 7-97 days) that were admitted to hospital for elective pharmacological cardioversion were randomly assigned to receive treatment with intravenous ibutilide (1 mg plus an additional 1 mg if required; n=39) or intravenous amiodarone (300 mg) plus intravenous ibutilide (1 mg; n=40). Success rates of cardioversion were 51.3% (20/39 patients) for ibutilide alone and 71.8% (28/39 patients) for amiodarone + ibutilide (P<0.05). A comparable increase in the QTc interval was observed in the two groups. It was observed that the co-administration of amiodarone and ibutilide was safer than ibutilide alone with regard to the risk of ventricular arrhythmia. Forty-eight patients of successful cardioversion were personally contacted for follow-up. The result indicated that the sinus rhythm maintenance time of the amiodarone + ibutilide group (4.36±2.44 months) was significantly higher than that of the ibutilide group (2.34±1.75 months; P<0.01). In conclusion, pretreatment with intravenous amiodarone + ibutilide for pharmacological cardioversion of persistent AF is considered to be more effective and safer than treatment with ibutilide alone.

Comparison of QT Interval Readings in Normal Sinus Rhythm Between a Smartphone Heart Monitor and a 12-Lead ECG for Healthy Volunteers and Inpatients Receiving Sotalol or Dofetilide.

INTRODUCTION: A variety of medications ranging from antiarrhythmics to psychotropics, as well as conditions such as bradycardia, can prolong the QT interval, increasing the risk for life-threatening arrhythmias. Monitoring the corrected QT interval (QTc) is therefore critical for patient safety. The recent development of smart phone heart monitors (SHM) may allow for easier QTc monitoring. We sought to evaluate the accuracy of an SHM for assessing the QTc, as compared to the standard 12-lead ECG. METHODS AND RESULTS: We compared the QTc interval in lead-I and lead-II between an SHM and 12-lead ECG. Healthy volunteers and hospitalized patients in sinus rhythm being loaded on dofetilide or sotalol were included. Manual and automatic measurements were studied. Across 99 healthy volunteers, the SHM QTc demonstrated good agreement (bias = 4 milliseconds, standard deviation of bias = 11 milliseconds) compared to the 12-lead ECG, using the Bland-Altman method of agreement. Across all hospitalized patients, the SHM was capable of demonstrating QTc prolongation. Between the 12-lead ECG and SHM, lead-I measurements had reasonable agreement (bias = 3 milliseconds, standard deviation of bias = 46 milliseconds). A QTc of > 500 milliseconds was associated with a higher likelihood (OR = 12.0; 95% CI 1.5-111.4; P = 0.02) to not achieve perfect agreement. CONCLUSION: The SHM is accurate in measuring QTc interval in sinus rhythm when compared to 12-lead ECG in healthy volunteers. For patients receiving QT prolonging antiarrhythmics, SHM is capable of detecting QTc prolongation, and lead-I of the SHM is most accurate in measuring the QTc if < 500 milliseconds.

Streptomycin inhibits electrophysiological changes induced by stretching of chronically infarcted rat hearts.

OBJECTIVE: To investigate stretch-induced electrophysiological changes in chronically infarcted hearts and the effect of streptomycin (SM) on these changes in vivo. METHODS: Sixty Wistar rats were divided randomly into four groups: a control group (n=15), an SM group (n=15), a myocardial infarction (MI) group (n=15), and an MI+SM group (n=15). Chronic MI was obtained by ligating the left anterior descending branch (LAD) of rat hearts for eight weeks. The in vivo blockade of stretch-activated ion channels (SACs) was achieved by intramuscular injection of SM (180 mg/(kg∙d)) for seven days after operation. The hearts were stretched for 5 s by occlusion of the aortic arch. Suction electrodes were placed on the anterior wall of left ventricle to record the monophasic action potential (MAP). The effect of stretching was examined by assessing the 90% monophasic action potential duration (MAPD90), premature ventricular beats (PVBs), and ventricular tachycardia (VT). RESULTS: The MAPD90 decreased during stretching in both the control (from (50.27±5.61) ms to (46.27±4.51) ms, P<0.05) and MI groups (from (65.47±6.38) ms to (57.47±5.76 ms), P<0.01). SM inhibited the decrease in MAPD90 during inflation ((46.27±4.51) ms vs. (49.53±3.52) ms, P<0.05 in normal hearts; (57.47±5.76) ms vs. (61.87±5.33) ms, P<0.05 in MI hearts). The occurrence of PVBs and VT in the MI group increased compared with that in the control group (PVB: 7.93±1.66 vs. 1.80±0.86, P<0.01; VT: 7 vs. 1, P<0.05). SM decreased the occurrence of PVBs in both normal and MI hearts (0.93±0.59 vs. 1.80±0.86 in normal hearts, P<0.05; 5.40±1.18 vs. 7.93±1.66 in MI hearts, P<0.01). CONCLUSIONS: Stretch-induced MAPD90 changes and arrhythmias were observed in chronically infarcted myocardium. The use of SM in vivo decreased the incidence of PVBs but not of VT. This suggests that SACs may be involved in mechanoelectric feedback (MEF), but that there might be other mechanisms involved in causing VT in chronic MI.

Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF.

In order to investigate the effects of testosterone-replacement therapy on peripheral blood stem cells and angiogenesis after acute myocardial infarction, a castrated rat acute myocardial infarction model was established by ligation of the left anterior descending coronary followed by treatment with testosterone. CD34(+) cells in myocardium and in peripheral blood after 1 and 3 days were measured by immunohistochemistry and flow cytometry, respectively. In the early phase of acute myocardial infarction, the expression levels of hypoxia-inducible factor 1a (HIF-1a), stromal cell-derived factor 1a (SDF-1a) and vascular endothelium growth factor (VEGF) in ischemic myocardium were determined by real time RT-PCR and immunohistochemistry, respectively. Infarct size, cardiomyocyte apoptosis, capillary density and cardiac function were assessed after 28 days. These results showed that the number of CD34(+) cells in the peripheral blood and in myocardium was significantly decreased in castrated rats, and the early expression levels of HIF-1a, SDF-1a and VEGF in the myocardium were also decreased. Furthermore, reduced capillary density, worsened cardiac function, increased infarct size and cardiomyocyte apoptosis at 28 days post-infarction were found in castrated rats. But these adverse effects could be reversed by testosterone-replacement therapy. These findings suggested that testosterone can increase the mobilization and homing of CD34(+) cells into the ischemic myocardium and further promote neoangiogenesis after myocardial infarction. The pro-angiogenesis effect of testosterone-replacement therapy is associated with the enhanced expression of HIF-1a, SDF-1a and VEGF in myocardium after myocardial infarction.

Regional differential expression of TREK-1 at left ventricle in myocardial infarction.

BACKGROUND: Altered membrane electrophysiology contributes to arrhythmias after myocardial infarction (MI). TREK-1 channel is essential in various physiological and pathological conditions through its regulation on resting membrane potential and voltage-dependent action potential duration. OBJECTIVES: The aim of this study was to investigate changes in gene expression and electrophysiology of TREK-1 in the left ventricle in a MI model. METHODS: Fifty-five rats were divided into 5 groups: sham-operated group, 6 hours, 24 hours, 3 days, and 7 days post MI group (n=11 per group). TREK-1 messenger RNA (mRNA) expression level in the infarct region (IR) and infarct border region (IBR) were quantified by real-time polymerase chain reaction (PCR), and TREK-1 current density at the IBR was recorded with whole-cell patch-clamp technique. RESULTS: TREK-1 mRNA expression decreased significantly in both endocardial and epicardial cells in the infarct region after MI. Conversely, TREK-1 increased significantly in endocardial and epicardial cells from the IBR (P<0.01). Current density of TREK-1 at IBR increased significantly in both epicardial and endocardial cells after MI (P<0.01). CONCLUSIONS: TREK-1 demonstrates specific changes in expression and electrophysiological function in left ventricle post MI. These results suggest that TREK-1 may participate in pathophysiologic alteration and electrical remodelling of left ventricular myocardium after MI, which may eventually lead to post-MI ventricular arrhythmias.

Taxol inhibits stretch-induced electrophysiological alterations in isolated rat hearts with acute myocardial infarction.

Mechanosensitive channels have been determined to work as transducers of mechanoelectric feedback in the heart, which is associated with the generation of arrhythmias. Recent studies have investigated the role of the cytoskeleton in ion channels control. This study explored the ability of taxol to inhibit stretch-induced electrophysiological alterations in the ischemic myocardium. Thirty-two Wistar rats were randomly divided into four groups: normal control group (n=9), taxol group (n=7), myocardial infarction (MI) group (n=9), and MI+taxol group (n=7). After Langendorff perfusion, the isolated hearts were stretched for 5 s by balloon inflation to 0.2 or 0.3 mL. The effects of stretching on 90% monophasic action potential duration (MAPD(90)), premature ventricular beats (PVB), and ventricular tachycardia (VT) were observed for 30 s. Stretching increased MAPD(90) in both the normal control and MI groups, but MAPD(90) increased more in the MI group for the same degree of stretch. Taxol (5 mumol L(-1)) had no effect on MAPD(90) under baseline, unstretched conditions, but MAPD(90) in the taxol group was slightly increased after stretching compared with the normal control group (P>0.05). However, taxol reduced MAPD(90) in infarcted myocardium (P<0.05 at DeltaV=0.3 mL). The incidences of PVB and VT in the MI group were higher than in the normal control group (both P<0.01). Taxol had no effect on the occurrence of arrhythmias in normal myocardium, but it inhibited PVB and VT in infarcted hearts (both P<0.01). Thus changes in MAPD and the occurrence of arrhythmias caused by mechanical stretching of the myocardium could be inhibited by taxol in isolated rat hearts during AMI, indicating the involvement of tubulin in mechanoelectric feedback in AMI.

Neuroprotective effects of testosterone upon cardiac sympathetic function in rats with induced heart failure.

The current study was designed to determine whether castration with or without testosterone replacement resulted in changes in cardiac sympathetic nerve activity in rats with heart failure induced by isoproterenol. At eight weeks post-castration, dysfunction of the cardiac sympathetic nerve system was aggravated as indicated by elevated plasma norepinephrine, reduced myocardial norepinephrine content and tyrosine hydroxylase (TH) protein. These effects of castration were reversed by testosterone replacement, as indicated by decreased plasma norepinephrine, increased myocardial norepinephrine and density of TH-labeled nerve fibers, as well as by an upregulated expression of myocardial TH protein. We also explored whether the neuroprotective effect of testosterone was influenced by the antiandrogen, flutamide. Interestingly, flutamide failed to block these testosterone-induced neuroprotective effects on the cardiac sympathetic nervous system in castrated rats with heart failure. These results provide the first evidence that endogenous testosterone deprivation in rats significantly worsened cardiac sympathetic function during pathophysiological changes associated with heart failure, and testosterone replacement reversed these adverse effects. These neuroprotective effects of testosterone, may, in part, be mediated through an upregulation in TH protein, but do not appear to involve the androgen receptor. Therefore, androgens may play an important role in modulating pathophysiological changes in the cardiac sympathetic nervous system that result from heart failure and our findings suggest the potential for beneficial effects of testosterone in the treatment of this condition.

Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction.

To investigate the changes of inducible cAMP early repressor (ICER) and phosphodiesterase 3A in rats after myocardial infarction and to evaluate the beneficial effects of valsartan on cardiac function and ventricular remodeling. Rats were split into four groups: sham-operation group, pre-myocardial infarction group (valsartan administration 2 weeks before myocardial infarction), post-myocardial infarction group (valsartan administration after myocardial infarction) and myocardial infarction group (vehicle after myocardial infarction). Echocardiograph and hemodynamic data were measured and cardiocyte apoptosis was estimated by TUNEL staining. ICER, cAMP response element binding protein (CREB), phosphodiesterase 3A and Bcl-2 mRNA expression levels were assayed by real-time reverse transcriptase polymerase chain reaction and protein expression was measured using immunoblot analysis. ICER and CREB mRNA expression in the myocardial infarction group were higher and phosphodiesterase 3A and Bcl-2 mRNA expression were lower than the sham-operation group (Ps<0.01). Following the improvement of cardiac function and ventricular remodeling, ICER and CREB mRNA in pre- and post- myocardial-infarction groups were down-regulated, and phosphodiesterase 3A and Bcl-2 mRNA were up-regulated (P<0.05). The changes brought on by valsartan pre-myocardial infarction were stronger than post-myocardial infarction (P<0.05). These data suggest that there is a phosphodiesterase 3A-ICER positive-feedback loop leading to myocyte apoptosis and ongoing development of heart failure after myocardial infarction. Maintaining the function of phosphodiesterase 3A or reducing ICER may be an effective way to prevent myocardium apoptosis and heart dysfunction. Valsartan can ameliorate ventricular remodeling and heart failure by inhibiting the expression of ICER and increasing the expression of phosphodiesterase 3A.

[Effect of phalloidin on electrophysiological changes induced by stretch of myocardial infarcted hearts in rats].

The present study aimed to explore whether the stretch of ischemic myocardium could modulate the electrophysiological characteristics via mechanoelectric feedback (MEF), as well as the effect of phalloidin on the electrophysiological changes. Thirty-two Wistar rats were randomly divided into 4 groups: control group (n=9), phalloidin group (n=7), myocardial infarction (MI) group (n=9), MI + phalloidin group (n=7). The acute myocardial infarction (AMI) was conducted by ligation of the left anterior descending (LAD) coronary artery for 30 min in isolated rat heart. The volume alternation of a water-filled latex balloon in the left ventricle produced the stretch of myocardium. After perfused on Langendorff, the isolated hearts were stretched for 5 s by an inflation of 0.1, 0.2 and 0.3 mL separately and the effect of stretch was observed for 30 s, including the left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), ±dp/dt(max), monophasic action potential duration at 90% repolarization (MAPD90), and occurrence of premature ventricular beats (PVB) and ventricular tachycardia (VT). The stretch caused an increase of MAPD(90) in both control and MI rats (P<0.05, P<0.01). Moreover, MAPD(90) in MI group increased more significantly than that in the control group at the same degree of stretch (P<0.05, P<0.01). Phalloidin (1 µmol/L) had no effect on MAPD(90) in basal state. After stretch, MAPD(90) in phalloidin group slightly increased but was not significantly different from that in the control group. However, phalloidin reduced MAPD(90) in infarcted myocardium, especially when ΔV=0.3 mL (P<0.05). The incidence rates of PVB and VT in MI group were higher than that in the control group (both P<0.01). And there was no significant difference in the incidence rates of PVB and VT between phalloidin group and control group. Phalloidin inhibited the occurrence of PVB and VT in infarcted hearts (both P<0.01). LVSP and +dp/dt(max) in MI group obviously decreased (P<0.01 vs control). With application of phalloidin, LVSP slightly, but not significantly increased in infarcted hearts, while -dp/dt(max) significantly increased (P<0.05). It is suggested that MI facilitates the generation and maintenance of malignant arrhythmias, while phalloidin obviously inhibits the occurrence of arrhythmias.

The effect of streptomycin on stretch-induced electrophysiological changes of isolated acute myocardial infarcted hearts in rats.

AIMS: To explore whether the stretch of ischaemic myocardium could modulate the electrophysiological characteristics, especially repolarization via mechanoelectric feedback (MEF), as well as the effect of streptomycin (SM) on these changes. Methods Thirty-six wistar rats were randomly divided into four groups: control group (n = 9), SM group (n = 9), myocardial infarction (MI) group (n = 9), and MI + SM group (n = 9). After perfused on Langendorff, the isolated hearts were stretched for 5s by a ballon inflation of 0.2mL. After being stretched, the effect of the stretch was observed for 30s, including the 20, 20-70, 70, and 90% monophasic action potential duration (MAPD), i.e. MAPD(20), MAPD(20-70), MAPD(70), and MAPD(90), respectively, premature ventricular beats (PVB), and ventricular tachycardia (VT). Results The stretch caused a decrease in MAPD(20-70) (both P <0.01) and an increase in MAPD(90) (both P <0.01) in both control and MI groups. Moreover, the MAPD(90) in the MI group had increased more significantly than that in the control group (P <0.05). A concentration of 200 micromol/L of SM had no influence on both MAPD(20-70) and MAPD(90) of basic state (P > 0.05, except MAPD(20-70) between the control and SM groups, P < 0.01), whereas it had reduced the length of MAPD(90) (P < 0.05) and inhibited the decrease in MAPD(20-70) induced by the inflation. There was a decrease in the tendency of MAPD(70) after the stretch (P = NS) and SM had reversed the tendency, whereas MAPD(20) had no obvious changes after inflation. The incidence rate of PVB and VT in the MI group was higher than that in the control group after inflation (P < 0.01). The 200 micromol/L SM reduced the incidence rate of PVB, and obviously inhibited the occurrence of VT (P < 0.01). CONCLUSIONS: Stretch could alter the electrophysiological activities of myocardium via MEF, which could enhance in acute myocardial infarction and facilitate the generation and maintenance of malignant arrhythmias. SM could significantly inhibit the occurrence of arrhythmias, which may correlate with the effect on blocking stretch-activated ion channels.

[Correlation of hyponatremia with plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure].

OBJECTIVE: To observe the changes of plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure (CHF) and their correlation with hyponatremia. METHODS: Plasma levels of PRA, ADH, and BNP were measured by radioimmunology in 76 CHF patients. Forty-one out of 76 CHF patients with hyponatremia and 35 CHF patients without hyponatremia were identified by serum sodium. The rates of rehospitalization within 3 months were compared in two groups. RESULTS: Levels of plasma renin activity, ALD, and BNP in CHF patients with hyponatremia were notably higher than those in patients without hyponatremia classified by New York Heart Association (NYHA) grade II - IV: PRA [(2.7 +/- 1.0) ng.ml(-1).h(-1) vs. (1.8 +/- 0.7) ng.ml(-1).h(-1), (4.3 +/- 1.2) ng.ml(-1).h(-1) vs. (3.0 +/- 0.9) ng.ml(-1).h(-1), (5.6 +/- 1.3) ng.ml(-1).h(-1) vs. (3.5 +/- 1.1) ng.ml(-1).h(-1), respectively, P < 0.05], ADH [(59.7 +/- 17.4) ng/L vs. (48.6 +/- 15.3) ng/L, (68.4 +/- 17.6) ng/L vs. (56.3 +/- 19.2) ng/L, (75.3 +/- 20.0) ng/L vs. (51.4 +/- 16.2) ng/L, respectively, P < 0.05] and BNP [(276.4 +/- 75.2) ng/L vs. (185.3 +/- 55.3) ng/L, (380.1 +/- 113.6) ng/L vs. (258.5 +/- 62.1) ng/L, (564.0 +/- 125.2) ng/L vs. (405.3 +/- 102.9) ng/L, respectively, P < 0.05]. In the simple regression analyses, hyponatremia was negative correlated with PRA, ADH and BNP (r = -0.31, P < 0.05; r = -0.28, P < 0.05, r = -0.80, P < 0.01). The rate of rehospitalization within 3 months in hyponatremia group was higher than that in control group. CONCLUSIONS: There is relation of hyponatremia to the changes of plasma renin activity, antidiuretic hormone and brain natriuretic peptide in chronic heart failure. Hyponatremia may accelerate the excretion of plasma PRA, ADH and BNP in chronic heart failure. Neuroendocrine activation in patients of congestive heart failure with hyponatremia is higher than that of normal natremia group.