This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca
Animals ; Calcium/metabolism* ; Myocardial Contraction ; Myocytes, Cardiac/metabolism* ; Phosphodiesterase Inhibitors ; Phosphoric Diester Hydrolases ; Rats ; Ryanodine Receptor Calcium Release Channel ; Sarcoplasmic Reticulum

OBJECTIVE: To investigate the protective effect of melatonin against myocardial ischemia reperfusion (IR) injury in isolated rat hearts and explore the underlying mechanisms. METHODS: The isolated hearts from 40 male SD rats were randomly divided into 4 groups (=10): the control group, where the hearts were perfused with KH solution for 175 min; IR group, where the hearts were subjected to global ischemia for 45 min followed by reperfusion for 120 min; IR+melatonin (Mel+IR) group, where melatonin (5 μmol/L) was administered to the hearts 1 min before ischemia and during the first 5 min of reperfusion, followed by 115 min of reperfusion; and IR+2, 3-butanedione monoxime (IR+BDM) group, where the hearts were treated with BDM (20 mmol/L) in the same manner as melatonin treatment. Myocardial injury in the isolated hearts was assessed based on myocardial injury area, caspase-3 activity, and expressions of cytochrome C and cleaved caspase-3 proteins. Cardiac contracture was assessed using HE staining and by detecting lactate dehydrogenase (LDH) activity and the content of cardiac troponin I (cTnI) in the coronary outflow, measurement of left ventricular end-diastolic pressure (LVEDP) and electron microscopy. The content of ATP in the cardiac tissue was also determined. RESULTS: Compared with those in the control group, the isolated hearts in IR group showed significantly larger myocardial injury area and higher caspase-3 activity and the protein expressions of cytochrome C and cleaved caspase-3 with significantly increased LDH activity and cTnI content in the coronary outflow and elevated LVEDP at the end of reperfusion; HE staining showed obvious fractures of the myocardial fibers and the content of ATP was significantly decreased in the cardiac tissue; electron microscopy revealed the development of contraction bands. In the isolated hearts with IR, treatment with Mel or BDM significantly reduced the myocardial injury area, caspase-3 activity, and protein expressions of cytochrome C and cleaved caspase-3, obviously inhibited LDH activity, lowered the content of cTnI and LVEDP, reduced myocardial fiber fracture, and increased ATP content in the cardiac tissue. Both Mel and BDM inhibited the formation of contraction bands in the isolated hearts with IR injury. CONCLUSIONS Mel can alleviate myocardial IR injury in isolated rat hearts by inhibiting cardiac contracture, the mechanism of which may involve the upregulation of ATP in the cardiac myocytes to lessen the tear of membrane and reduce cell content leakage.
Animals ; Heart ; drug effects ; Male ; Melatonin ; pharmacology ; therapeutic use ; Muscle Contraction ; drug effects ; Myocardial Reperfusion Injury ; drug therapy ; Myocytes, Cardiac ; drug effects ; Rats ; Rats, Sprague-Dawley

Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with IC₅₀ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect I(Na), I(Ks) or I(K1), but decreased I(hERG) in a dose-dependent manner (IC₅₀: 6.53 µM). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to 3 µM, but it at 10 µM induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.
Action Potentials ; Animals ; Antineoplastic Agents ; Aurora Kinases ; Cardiotoxicity ; Cell Division ; Cell Line ; Humans ; In Vitro Techniques ; Ion Channels ; Muscle Cells ; Myocardial Contraction ; Myocytes, Cardiac ; Phosphotransferases ; Rats ; Relaxation

OBJECTIVE: To investigate the effects of interval training on calcium transient and contractile function in ischemic ventricular myocytes of rats with myocardial infarction and their synchronization. METHODS: Twenty-four male sprague-dawley rats in three years old, were randomly divided into three groups (n=8): sham-operated group(S), sedentary MI group(MI) and MI with interval training group (ME). The MI model was established by ligation of the left anterior descending coronary artery. The rats in ME group started training 1 week after MI operation. The S model was established by threading only without ligation. ME model took one week adaptive training, 10 m/min and 30 min/d, then took subsequently 8-week aerobic interval training: 10 min×10 m/min, then reran the rats with 2 intensities 15 m/min×6 min and 25 m/min×4 min, 1 h/d, 5 d/week. After training 24 hours, the cardiomyocytes of all groups were isolated by using the Langendorff fusion system. The contractile function and calcium transient of single ventricular myocyte in myocardial infarction adult rats were detected by IonOptix. Calcium transients were measured as [Ca] amplitude, departure velocity, ratio, TTB50％, TTP and TTP50%, return velocity and ratio amplitude. PTA, SL, ±dl/dtmax and SL shortening% were tested to evaluate contractility. RESULTS: Compared with S, the levels of [Ca] amplitude, departure velocity, ratio amplitude and return velocity, SL shortening%, PTA and ±dl/dtmax of MI were decreased(P＜0.01), the levels of TTP, TTP50% and TTB50% of MI were increased(P＜0.01); Compared with MI, the levels of departure velocity, ratio amplitude, return velocity and [Ca] amplitude of ME were increased(P＜0.01), the levels of TTB50%, TTP and TTP50% of ME were decreased(P＜0.01, P＜0.05). The levels of SL shortening%, PTA and ±dl/dtmax of ME were increased(P＜0.01, P＜0.05). CONCLUSION Interval training can improve calcium transient and contractile function of single ventricular myocyte in myocardial infarction adult rats.
Animals ; Calcium ; physiology ; Male ; Myocardial Contraction ; Myocardial Infarction ; pathology ; Myocytes, Cardiac ; physiology ; Physical Conditioning, Animal ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To assess magnetic resonance imaging (MRI) features of coronary microembolization in a swine model induced by small-sized microemboli, which may cause microinfarcts invisible to the naked eye. MATERIALS AND METHODS: Eleven pigs underwent intracoronary injection of small-sized microspheres (42 microm) and catheter coronary angiography was obtained before and after microembolization. Cardiac MRI and measurement of cardiac troponin T (cTnT) were performed at baseline, 6 hours, and 1 week after microembolization. Postmortem evaluation was performed after completion of the imaging studies. RESULTS: Coronary angiography pre- and post-microembolization revealed normal epicardial coronary arteries. Systolic wall thickening of the microembolized regions decreased significantly from 42.6 +/- 2.0% at baseline to 20.3 +/- 2.3% at 6 hours and 31.5 +/- 2.1% at 1 week after coronary microembolization (p < 0.001 for both). First-pass perfusion defect was visualized at 6 hours but the extent was largely decreased at 1 week. Delayed contrast enhancement MRI (DE-MRI) demonstrated hyperenhancement within the target area at 6 hours but not at 1 week. The microinfarcts on gross specimen stained with nitrobluetetrazolium chloride were invisible to the naked eye and only detectable microscopically. Increased cTnT was observed at 6 hours and 1 week after microembolization. CONCLUSION: Coronary microembolization induced by a certain load of small-sized microemboli may result in microinfarcts invisible to the naked eye with normal epicardial coronary arteries. MRI features of myocardial impairment secondary to such microembolization include the decline in left ventricular function and myocardial perfusion at cine and first-pass perfusion imaging, and transient hyperenhancement at DE-MRI.
Animals ; Coronary Angiography/*methods ; Coronary Vessels/*pathology ; Disease Models, Animal ; Embolism/*pathology ; Female ; Heart/radiography ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging/*methods ; Microspheres ; Myocardial Contraction/physiology ; Myocardial Infarction/*pathology ; Myocardium/pathology ; Nitroblue Tetrazolium ; Staining and Labeling ; Swine ; Troponin T/blood ; Ventricular Function, Left

BACKGROUND: Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes. METHODS: We measured hemodynamic effects using a digital analysis system after Intralipid(R) and Lipofundin(R) MCT/LCT were infused into hearts hanging in a Langendorff perfusion system. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy. RESULTS: Infusion of Lipofundin(R) MCT/LCT 20% (1 ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs-Henseleit solution (1 ml/kg) (P = 0.003, 95% confidence interval [CI], 2.4-12.5). Lipofundin(R) MCT/LCT 20% had a more positive inotropic effect than that of Intralipid(R) 20% (P = 0.009, 95% CI, 1.4-11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin(R) MCT/LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid(R) (P < 0.05, 95% CI, 0.0-1.9). CONCLUSIONS: These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level.
Animals ; Blood Pressure* ; Calcium* ; Drug-Related Side Effects and Adverse Reactions ; Emulsions ; Heart* ; Hemodynamics ; Humans ; Microscopy, Confocal ; Myocardial Contraction ; Parenteral Nutrition, Total ; Perfusion ; Rats* ; Triglycerides

A 7-month-old girl with no medical history was treated with mechanical circulatory support due to myocarditis. Her cardiac contractility did not improve despite more than one week of extracorporeal membrane oxygenation treatment. Thus, we planned a heart transplant. However, a high level of cytomegalovirus was found in blood laboratory results by quantitative polymerase chain reaction. The patient's heart contractility recovered to normal range four days after ganciclovir treatment. She was discharged with slightly decreased cardiac contractility with a left ventricular ejection fraction of 45%.
Cytomegalovirus* ; Extracorporeal Circulation ; Extracorporeal Membrane Oxygenation* ; Female ; Ganciclovir* ; Heart ; Humans ; Infant* ; Myocardial Contraction ; Myocarditis* ; Polymerase Chain Reaction ; Reference Values ; Stroke Volume

To discuss the protective effect of aralosides (AS) on I/R-induced rat myocardial injury. The adult rat ventricular myocyte ischemia model was established through perfusion with sodium lactate perfusate and reperfusion with Ca(2+) -containing Tyrode's solution simulation. The cell contraction and ion concentration synchronization determination system was applied to detect the effect of AS on single I/R cell contraction and Ca2+ transients. According to the findings, AS could increase resting sarcomere length, contraction amplitude, ± dL/dt(max), calcium transient amplitude and speed of post-reperfusion myocardial cells (P < 0.05, P < 0.01), and decrease in time for achieving 90.0% of maximum relaxation, time for achieving peak value, resting calcium ratio, contraction period [Ca2+] i, time for achieving 50.0% of maximum relaxation and attenuation rate of intracellular calcium transient (P < 0.05, P < 0.01). Therefore, it is suggested that AS improved the post-reperfusion cell contraction and injury of calcium homeostasis.
Animals ; Aralia ; chemistry ; Biological Transport ; drug effects ; Calcium ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Male ; Muscle Contraction ; drug effects ; Myocardial Ischemia ; drug therapy ; metabolism ; physiopathology ; surgery ; Myocardial Reperfusion ; Myocytes, Cardiac ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley ; Saponins ; administration & dosage

Cardiac resynchronization therapy (CRT) has been shown to reduce the risk of death and hospitalization in patients with advanced heart failure with left ventricular dysfunction. However, controversy remains regarding who would most benefit from CRT. We performed a meta-analysis, and meta-regression in an attempt to identify factors that determine the outcome after CRT. A total of 23 trials comprising 10,103 patients were selected for this meta-analysis. Our analysis revealed that CRT significantly reduced the risk of all-cause mortality and hospitalization for heart failure compared to control treatment. The odds ratio (OR) of all-cause death had a linear relationship with mean QRS duration (P=0.009). The benefit in survival was confined to patients with a QRS duration > or =145 ms (OR, 0.86; 95% CI, 0.74-0.99), while no benefit was shown among patients with a QRS duration of 130 ms (OR, 1.00; 95% CI, 0.80-1.25) or less. Hospitalization for heart failure was shown to be significantly reduced in patients with a QRS duration > or =127 ms (OR, 0.77; 95% CI, 0.60-0.98). This meta-regression analysis implies that patients with a QRS duration > or =150 ms would most benefit from CRT, and in those with a QRS duration <130 ms CRT implantation may be potentially harmful.
Bundle-Branch Block/physiopathology ; Cardiac Resynchronization Therapy/*methods ; Cardiac Resynchronization Therapy Devices ; Defibrillators, Implantable ; Electrocardiography ; Heart Failure/mortality/physiopathology/*therapy ; Humans ; Myocardial Contraction/*physiology ; Treatment Outcome ; Ventricular Dysfunction, Left/mortality/physiopathology/*therapy

BACKGROUNDHemorrhagic shock (HS) results in myocardial contractile dysfunction. Studies showed that 17β-estradiol protects the myocardium against contractile dysfunction. The study investigated the cardioprotective effects of treatment with 17β-estradiol before resuscitation following 1 h of HS and resuscitation.

METHODSMale Sprague-Dawley rats were assigned to 2 sets of experimental protocols: Ex vivo and in vivo treatment and resuscitation. Each set had three experimental groups (n = 6 per group): Normotensive (N), HS and resuscitation (HS-R) and HS rats treated with 17β-estradiol (E) and resuscitated (HS-E-R). Rats were hemorrhaged over 60-min to reach a mean arterial blood pressure of 40 mmHg. In the ex vivo group, hearts were resuscitated by perfusion in the Langendorff system. In the 17β-estradiol treated group, 17β-estradiol 280 µg/kg was added for thefirst 5 min. Cardiac function was measured. Left ventricular generated pressure (LVGP) and +dP/dt were calculated. In the in vivo group, rats were treated with 17β-estradiol 280 µg/kg s.c. after 60-min HS. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30-min to restore normotension.

RESULTSTreatment with 17β-estradiol before resuscitation in ex vivo treated and resuscitated isolated hearts and in the in vivo treated and resuscitated rats following HS improved myocardial contractile function. In the in vivo treated group, LVGP and +dP/dt max were significantly higher in 17β-estradiol treated rats compared to the untreated group (LVGP 136.40 ± 6.61 compared to 47.58 ± 17.55, and +dP/dt 661.85 ± 49.88 compared to 88.18 ± 0.85). Treatment with 17β-estradiol improved LVGP following HS.

CONCLUSIONSThe results indicate that treatment with 17β-estradiol before resuscitation following HS protects the myocardium against dysfunction.

Animals ; Estradiol ; therapeutic use ; Male ; Myocardial Contraction ; drug effects ; Myocardium ; pathology ; Rats ; Rats, Sprague-Dawley ; Resuscitation ; Shock, Hemorrhagic ; drug therapy