Disassociation between left ventricular mechanical and electrical properties in ischemic rat heart after G-CSF treatment.

OBJECTIVE: The effect of granulocyte colony-stimulating factor (G-CSF) on post-infarct ventricular remodeling remains controversial. We hypothesized that the timing of G-CSF administration after myocardial ischemia plays an important role in determining its efficacy. METHODS: Rat myocardial ischemia was induced by 60 min coronary ligation and reperfusion. Surviving animals received G-CSF after 1 h (E-G) or 24 h (D-G) of reperfusion randomly at 100 µg/kg/d for five consecutive days. 7 days or 3 months post-ischemia, rat hearts were quickly removed for ex vivo electrophysiological measurements or histological analysis (collagen disposition and angiogenesis) and metalloproteinase-2 and -9 activity assays (gelatin zymography). Left ventricular (LV) invasive hemodynamic analysis was performed in 3-month recovery animals before sacrifice. RESULTS: At 3 months post ischemia, LV mechanical remodeling was further impaired with early G-CSF administration (0.65 ± 0.17%, 13.21 ± 7.36 mmHg, -4,684 ± 1,560 mmHg/s) compared with the control group (0.28 ± 0.12%, 6.45 ± 3.43 mmHg, -6,267 ± 1,111 mmHg/s) and D-G group (0.34 ± 0.12%, 7.90 ± 5.33 mmHg, -6,227 ± 1,075 mmHg/s) as shown by increased expansion index (P < 0.01), deterioration of myocardial function with increased LVDP (P < 0.05), and decreased -dP/dt (max) (P < 0.05). By contrast, there was a significant increase in electrical properties including monophasic action potential (MAP) 90 dispersion (12.58 ± 4.46 vs. 30.56 ± 6.17 ms at 7 days; 18.54 ± 4.31 vs. 34.78 ± 5.24 ms at 3 months; P < 0.05 for both) and inducibility of ventricular arrhythmias (4.78 ± 1.19 vs. 11.58 ± 2.76 ms at 3 months; P < 0.05) with early G-CSF treatment compared with the control group. CONCLUSIONS: Both early and delayed administrations of G-CSF can improve electrophysiological properties after myocardial ischemia, but have no beneficial effects on LV mechanical remodeling.

Effects of intramyocardial injection of platelet-rich plasma on the healing process after myocardial infarction.

OBJECTIVE: Platelet activation and subsequent release of granules containing a variety of growth factors, at the site of injury, is crucial for the wound healing process. We postulated that a platelet-mediated paracrine effect may accelerate the healing process after myocardial infarction. METHODS: Allogenic platelet-rich and platelet-poor plasma (PRP and PPP) were collected from 15 healthy male Wistar rats. After thrombin activation, the level of vascular endothelial growth factor (VEGF) in PRP and PPP was measured by enzyme-linked immunosorbent assay. A rat model of myocardial infarction was induced by permanent ligation of the left anterior descending artery, and thrombin-activated PRP and PPP, respectively, were injected into the ischemic region. Seven days and 28 days after operation, surviving rats were killed. Ex-vivo left ventricular pressure-volume relationship was performed to evaluate passive diastolic function. Collagen analysis was performed by picrosirius red staining plus polarized microscopy. Angiogenesis and arteriogenesis were evaluated by immunofluorescent staining. RESULTS: After thrombin activation, VEGF level in PRP was significantly higher than that in PPP (187.5+/-45.5 vs. 30.1+/-7.8 pg/ml, P<0.01). Injection of thrombin-activated PRP into the infarcted area resulted in improvement of ventricular remodeling and accelerated healing, as demonstrated by limitation of ventricular expansion, attenuation of myocardial hypertrophy in the noninfarct region, facilitation of angiogenesis and arteriogenesis in the infarct. CONCLUSION: Injection of thrombin-activated PRP could modulate favorably the postinfarction remodeling process. Platelet-released VEGF may participate in this protective effect.

Neural remodeling may partly contribute to the abnormality of excitation-contraction coupling in heart failure.

Heart failure (HF) is a major and growing public health problem in the world. About 50% of deaths in HF occur suddenly due to malignant arrhythmia. Therefore, exploring the further mechanisms of chronic HF and finding new therapy targets are essential for the progression of HF treatment. Recently, some published papers suggested that myocardial neural remodeling and abnormal excitation-contraction (EC) coupling might partly contribute to the development of HF and sudden cardiac death. Even though a few studies have demonstrated that the sympathetic nerve system (SNS) may have significant impact on the functional states of myocardial EC coupling through the beta-adrenergic signaling pathway, so far, it still remains unknown that whether neural remodeling affects the EC coupling. Studies from Marks' group demonstrated that 70% of cardiac ryanodine receptors (RyR2), which located on the sarcoplasmic reculum (SR) controlling intracellular Ca(2+) release and muscle contraction in the heart, from failing hearts were abnormal and only 15% exhibited the most severe defects. In addition, Litwin et al. observed that temporal and spatial heterogeneities in local Ca(2+) release events in a rabbit model of HF after myocardial infarction. Because some studies have demonstrated that chronic SNS hyperactivity in HF led to protein kinase A (PKA) hyperphosphorylation of RyR2 in the heart, and the myocardial sympathetic nerve distribution become heterogeneous in the setting of HF. Thus, it is reasonable for us to propose the hypothesis that neural remodeling may partly account for the abnormality of EC coupling in HF.

Increased levels of interleukin-6 and matrix metalloproteinase-9 are of cardiac origin in acute coronary syndrome.

OBJECTIVES: To investigate the association between inflammatory mediators, matrix degrading enzymes and acute coronary syndrome (ACS) and the impact of early reperfusion therapy on circulating biomarkers. DESIGN: Peripheral serum levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) were determined in 134 patients with ACS. These biomarkers were serially monitored in ten patients with intravenous thrombolytic therapy (IVT). RESULTS: Serum levels of IL-6, hs-CRP and MMP-9 were higher in unstable angina (UA) and myocardial infarction (MI) groups than in control or SA group (p<0.05). Peripheral IL-6 level in patients with MI was greater after percutaneous coronary intervention (PCI) (p<0.01) or IVT (p<0.05). Serial concentration determination revealed marked elevation of serum IL-6 and MMP-9 levels, both reaching peak values (like creatine kinase-MB). CONCLUSIONS: Elevated levels of IL-6, hs-CRP and MMP-9 provide a link between inflammation, matrix degradation and the development and progression of ACS. IL-6 and MMP-9 appear to be released mainly from vulnerable plaque or necrotic myocardium during the acute phase of MI.

Enhancement of endogenous defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage.

Hypertension-induced target organ damage (TOD), is one of the leading causes of morbidity and mortality. Reactive oxygen species (ROS) play an important role in the pathogenesis and development of hypertension. It has been suggested that hypertension-induced TOD is related to the level of oxidative stress, but is in part independent of the level of blood pressure. Therefore, in addition to anti-hypertensive drug therapy, novel strategies against ROS, will provide additional benefits to patient with hypertension. Vitamin E has long been supplemented as an effective antioxidant. However, the potential hazardous effects of vitamin E supplementation as antioxidant revealed by recent studies make its clinical and routine use prudent. Therefore, novel approaches capable of enhancing endogenous system to defend against ROS are required. Here, we propose that enhancement of intrinsic defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage, owing to its role in activating and constitution of native vital proteins and/or enzymes against oxidative stress, and the fact that scarcity of selenium can not be supplemented by normal food, and potentially extra benefits by supra-normal intake.

Anti-oxidant effects of atorvastatin in dexamethasone-induced hypertension in the rat.

1. Dexamethasone (Dex)-induced hypertension is characterized by endothelial dysfunction associated with nitric oxide (NO) deficiency and increased superoxide (O2-) production. Atorvastatin (Ato) possesses pleiotropic properties that have been reported to improve endothelial function through increased availability of NO and reduced O2- production in various forms of hypertension. In the present study, we investigated whether 50 mg/kg per day, p.o., Ato could prevent endothelial NO synthase (eNOS) downregulation and the increase in O2- in Sprague-Dawley (SD) rats, thereby reducing blood pressure. 2. Male SD rats (n = 30) were treated with Ato (50 mg/kg per day in drinking water) or tap water for 15 days. Dexamethasone (10 microg/kg per day, s.c.) or saline was started after 4 days in Ato-treated and non-treated rats and continued for 11-13 days. Systolic blood pressure (SBP) was measured on alternate days using the tail-cuff method. Endothelial function was assessed by acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction in aortic segments. Vascular eNOS mRNA was assessed by semi-quantitative reverse transcription-polymerase chain reaction. 3. In rats treated with Dex alone, SBP was increased from 109 +/- 2 to 133 +/- 2 mmHg on Days 4 and Day 14, respectively (P < 0.001). In the Ato + Dex group, SBP was increased from 113 +/- 2 to 119 +/- 2 mmHg on Days 4 to 14, respectively (P < 0.001), but was significantly lower than SBP in the group treated with Dex alone (P < 0.05). Endothelial-dependent relaxation and eNOS mRNA expression were greater in the Dex + Ato group than in the Dex only group (P < 0.05 and P < 0.0001, respectively). Aortic superoxide production was lower in the Dex + Ato group compared with the group treated with Dex alone (P < 0.0001). 4. Treatment with Ato improved endothelial function, reduced superoxide production and reduced SBP in Dex-treated SD rats.

[Effect of angiotensin II and its receptor antagonist on electrophysiology and L-type calcium current in guinea cardiac myocytes].

OBJECTIVE: To evaluate the effect of angiotensin II (Ang II) and its receptor antagonist on action potential duration and L-type calcium current density of cardiac myocytes. METHODS: Single myocyte of the ventricle in guinea was isolated. Action potentials were recorded using a conventional glass microelectrode filled with 3 mol/L KCl solution. Membrane patch clamp whole cell recording technique was used to investigate L-type calcium current maximum in holding potential of -40 mV, length of time 200 ms, command potential 0 mV. RESULTS: Ang II induced arrhythmia of multiple electrophysiologic mechanisms. Action potential amplitude, 90% of action potential duration (APD90), and resting membrane potential (RMP) were significantly decreased or shortened after being perfused Ang II for 1 minute compared with controls. 30% of action potential duration (APD30), 50% of action potential duration (APD50), effective refractory period (ERP) were also shortened significantly after perfused Ang II for 3 minutes compared with controls. Ang II increased the L-type calcium maximum current density after a perfusion of 5 minutes, but losartan perfusion for 1 minute decreased the L-type calcium maximum current density, and it further decreased after perfusion for 3 minutes. However, the current voltage relationship curve was unchanged. CONCLUSION: Ang II could decrease amplitude of monophasic action potential, rest membrane potential, shorten duration of monophasic action potential and effective refractory period, increase maximum current density of voltage dependent L-type calcium, and possess the effect of inducing arrhythmia. Losartan decreased maximum current density of voltage dependent L-type calcium.

Atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.

To assess the antioxidant effects of atorvastatin (atorva) on dexamethasone (dex)-induced hypertension, 60 male Sprague-Dawley rats were treated with atorva 30 mg/kg/day or tap water for 15 days. Dex increased systolic blood pressure (SBP) from 109 +/- 1.8 to 135 +/- 0.6 mmHg and plasma superoxide (5711 +/- 284.9 saline, 7931 +/- 392.8 U/ml dex, P < 0.001). In this prevention study, SBP in the atorva + dex group was increased from 115 +/- 0.4 to 124 +/- 1.5 mmHg, but this was significantly lower than in the dex-only group (P' < 0.05). Atorva reversed dex-induced hypertension (129 +/- 0.6 mmHg, vs. 135 +/- 0.6 mmHg P' < 0.05) and decreased plasma superoxide (7931 +/- 392.8 dex, 1187 +/- 441.2 atorva + dex, P < 0.0001). Plasma nitrate/nitrite (NOx) was decreased in dex-treated rats compared to saline-treated rats (11.2 +/- 1.08 microm, 15.3 +/- 1.17 microm, respectively, P < 0.05). Atorva affected neither plasma NOx nor thymus weight. Thus, atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.

[China coronary secondary prevention study: analysis of patients with different myocardial infarction history].

OBJECTIVE: To assess whether Xuezhikang was effective in the secondary prevention of coronary heart disease (CHD) for patients with different length of myocardial infarction (MI) history. METHODS: 2135 patients with MI history of 28 days to 3 months and 2735 patients with MI history of 3 months to 60 months were recruited separately to receive treatment with Xuezhikang capsule or placebo. The primary end-points were nonfatal myocardial infarction and death from CHD. RESULTS: The occurrence of coronary events were found to be not statistically significantly different for the two groups of patients. For patients with MI history of 28 days to 3 months, Xuezhikang significantly reduced the risk of CHD events by 56.7% (P < 0.0001) and resulted in a 48.6% (P = 0.0002) risk reduction in all-cause mortality as compared with placebo. For patients with MI history of 3 months to 60 months, Xuezhikang significantly decreased the risk of CHD events by 35.3% (P = 0.0008) and led to a 20.0% (P = 0.1181) risk reduction in the all-cause mortality as compared with placebo. Adverse effects and abnormal laboratory parameters did not differ significantly in the two groups of patients. CONCLUSIONS: Xuezhikang is more effective for patients with MI history of 28 days to 3 months as compared with patients with MI history of 3 months to 60 months. Patients with MI history should be treated with Xuezhikang early in order to achieve better prevention of CHD.

Atorvastatin prevented and partially reversed adrenocorticotropic hormone-induced hypertension in the rat.

1. Adrenocorticotropic hormone (ACTH)-induced hypertension is associated with nitric oxide (NO) deficiency and increased oxidative stress. Atorvastatin (Ato), an HMG-Co-enzyme-A reductase inhibitor has been reported to enhance availability of NO. The aim of the study was to assess whether pretreatment with Ato would prevent the development of ACTH-induced hypertension and whether established ACTH-induced hypertension could be reversed with subsequent administration of Ato in rats. 2. Male Sprague-Dawley rats (n = 60) were treated with Ato (30 mg/kg per day in drinking water) or tap water for 15 days. ACTH (0.2 mg/kg per day s.c) or saline was started 4 days after Ato treatment or non-treated rats and continued for 11-13 days (prevention study). In the reversal study, Ato was given on day 8 of ACTH/Saline treatment for 5 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. 3. Adrenocorticotropic hormone treatment increased SBP (110 +/- 2-136 +/- 2 mmHg, P < 0.001) and aortic superoxide production (P < 0.001). Ato alone did not alter SBP, but Ato pretreatment prevented ACTH-induced hypertension compared with that in rats treated with ACTH alone (118 +/- 2 and 136 +/- 2 mmHg, respectively, P cent < 0.01). Ato partially reversed ACTH-induced hypertension (124 +/- 3 and 136 +/- 2 mmHg, respectively, P cent < 0.05). Plasma nitrate/nitrite (NOx) was decreased in ACTH-treated rats compared with saline treated rats (6.6 +/- 0.4 saline and 4.5 +/- 0.5 micromol/L ACTH, P < 0.001). Atorvastatin affected neither plasma NOx nor aortic superoxide production. 4. Atorvastatin prevented and partially reversed ACTH-induced hypertension in the rat.

[Comparable analysis of in-hospital mortality in patients with acute myocardial infarction].

OBJECTIVE: To investigate the change of the mortality of AMI and influence factors within 20 years. METHODS: Clinic data of 134 AMI patients from 1980 to 1983, 354 AMI patients from 1990 to 1993 and 817 AMI patients from 2000 to 2003 were comparably analyzed. RESULTS: In hospital mortality of AMI was 22.4% from 1980 to 1983, 14.4% from 1990 to 1993 and 9.2% from 2000 to 2003, respectively (P < 0.01). The decrease of in-hospital mortality in male was more significant than in female (P < 0.01). The corresponding factors for decrease of mortality were younger than 60 years old, first onset of AMI, successful rescue of cardiac arrest and reperfusion management of infarction relative artery. The disadvantage factor was female. CONCLUSIONS: Improvement of medical and reperfusion management of AMI conduced in significant decreases of hospital mortality.

[Analysis of factors correlated to death and reinfarction in patients with acute myocardial infarction].

OBJECTIVE: To identify the predictors of death and reinfarction in patients with acute myocardial infarction (AMI) treated with urokinase (UK) thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). METHODS: In ambispective cohort study, 97 cases of AMI were treated with UK thrombolytic therapy, while 93 cases of AMI were treated with PTCA. The patients' data about clinical outcome during hospital and follow-up periods were collected. Death and reinfarction were defined as adverse event. To analyze the correlative factors and independent predictors of death and reinfarction, the spearman rank correlation and multivariate logistic regression modeling were performed. RESULTS: During hospital,incidences of adverse event were 15.46 percent and 6.45 percent in UK and PTCA groups respectively. In follow-up period, they were 30.93 percent and 9.68 percent respectively. Age, Q wave leads, Kill ip class, heart failure in hospital, the history of hypertension and myocardial infarction were positive correlation with adverse event, whereas history of smoking, systolic blood pressure and ejection fraction (EF) showed negative correlation with the adverse event. The interventional therapy, associated with lower mortality and reinfarction rate, was the independent predictor for adverse event in UK and PTCA groups during hospital and follow-up periods. Furthermore, it was the only independent predictor for PTCA group. In UK group, the adverse event also was independently predicted by age, heart failure and Q wave leads in hospital and by age, heart failure during follow-up period. There was negative correlation between preinfarction angina and adverse event, and positive correlation between thrombolysis and adverse event inpatients undergone rescue PTCA. CONCLUSION: Interventional therapy is crucial independent predictor for adverse event of patients suffering from AMI. The adverse event is also predicted by age, Q wave leads and heart failure. The history of preinfarction angina is negative correlation with the adverse event in hospital, due to, maybe, myocardium ischemia preconditioning.