Granulocyte-colony Stimulating Factor Treatment of Chronic Myocardial Infarction

Purpose  

The aim of this study was to investigate the impact of granulocyte-colony stimulating factor (G-CSF) administration on cardiac function of rats with chronic myocardial infarction through two different protocols: high dose short term and low dose long term protocols.     

Coordination of hypothalamic and pituitary T3 production regulates TSH expression

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3′-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.     

The effect of acute exercise session on thyroid hormone economy in rats

The hypothalamic-pituitary-thyroid axis is affected by acute exercise, but the mechanisms underlying thyroid function changes after exercise remain to be defined. The aim of this study was to elucidate the effects of a session of acute exercise on the treadmill at 75% of maximum oxygen consumption on thyroid function of rats. Male Wistar rats were divided into five groups: control (without exercise), and killed immediately after (0 min) or 30, 60, and 120 min after the end of the exercise session. A significant increase in serum tri-iodothyronine (T(3)) occurred immediately after the exercise, with a gradual decrease thereafter, so that 120 min after the end of the exercise, serum T(3) was significantly lower than that in controls. Total thyroxine (T(4)) increased progressively reaching values significantly higher than that in the control group at 120 min. T(3)/T(4) ratio was significantly decreased 60 and 120 min after the exercise, indicating impaired T(4)-to-T(3) conversion. Liver type 1 deiodinase activity (D1) significantly decreased at 60 and 120 min, while pituitary D1 increased progressively from 30 to 120 min after the exercise, and thyroid D1 was increased only immediately after the end of the exercise. Brown adipose tissue (BAT) type 2 deiodinase activity (D2) was significantly lower at 30 min, but pituitary D2 remained unchanged. No change in serum thyrotropin was detected, while serum corticosterone was significantly higher 30 min after the exercise. Our results demonstrate that decreased liver D1 and BAT D2 might be involved in the decreased T(4)-to-T(3) conversion detected after an exercise session on the treadmill.     

Cellular cardiomyoplasty in large myocardial infarction: Can the beneficial effect be enhanced by ACE‐inhibitor therapy?

BACKGROUND: Cellular cardiomyoplasty with bone marrow derived stromal (MSC) and mononuclear (BMNC) cells has been shown to improve performance of infarcted hearts. We performed a comparative study with MSC and BMNC and tested the hypothesis that captopril treatment could enhance the beneficial effect of cell therapy in large myocardial infarctions. METHODS: Male syngeneic Wistar rats underwent experimental infarction and were randomized to receive 1-3 x 10(6) MSC, 10(8) BMNC or vehicle (BSS group). Two additional groups were treated with captopril and received 1-3 x 10(6) MSC (Cap.MSC) or vehicle (Cap). RESULTS: The ejection fraction (EF%) of MSC and BMNC-treated rats was higher than in the BSS rats, eight weeks after transplantation (33.0+/-4.0, 34.0+/-2.0 and 20.0+/-2.0% respectively, P<0.01). Both captopril-treated groups improved EF% similarly. But only captopril plus MSC treatment almost restored cardiac function to control levels, 8 weeks after injection (60.50+/-5.40% vs. 41.00+/-4.50% in Cap.MSC and Cap respectively, P<0.05). Many DAPI-labelled cells were found in the scar tissue of the left ventricle only in the Cap.MSC group. CONCLUSIONS: Cell transplantation with both MSC and BMNC produced a similar stabilisation of heart function, but the success of the cell engraftment and the recovery of cardiac performance were dependent on concomitant treatment with captopril.     

G-CSF does not improve systolic function in a rat model of acute myocardial infarction

Abstract Objective Granulocyte colony-stimulating factor (G-CSF) has been reported to improve cardiac performance by increasing the number of bone marrow stem cell in the peripheral circulation. The aim of this study was to investigate the impact of G-CSF administration on cardiac function in a rat model of acute myocardial infarction. Methods Recombinant human G-CSF (Filgrastim, 100 μg/kg, sc) twice a day during seven consecutive days (G-CSF group, n=13) or vehicle (control group, n=10) was administrated three hours after left anterior coronary artery ligation. Cardiac performance was evaluated 19–21 days after myocardial infarction by electro- and echocardiography, hemodynamic and treadmill exercise test. Results Both infarcted groups exhibit impaired cardiac function compared to sham-operated rats. Moreover, all cardiac functional parameters were not statistically different between G-CSF and infarcted group at resting conditions as well as after treadmill exercise stress test. There was no sign of cardiac regeneration and infarct size was not different on histological analysis between groups Conclusions These data clearly shows that G-CSF treatment was unable to prevent cardiac remodeling or to improve cardiovascular function in a rat model of acute myocardial infarction, by permanent LAD ligation, despite bone marrow stem cell mobilization.     

Soluble factors from multipotent mesenchymal stromal cells have antinecrotic effect on cardiomyocytes in vitro and improve cardiac function in infarcted rat hearts

The mechanisms underlying the functional improvement after injection of multipotent mesenchymal stromal cells (MSCs) in infarcted hearts remain incompletely understood. The aim of this study was to investigate if soluble factors secreted by MSCs promote cardioprotection. For this purpose, conditioned medium (CM) was obtained after three passages from MSC cultures submitted to 72 h of conditioning in serum-free DMEM under normoxia (NCM) or hypoxia (HCM) conditions. CM was concentrated 25-fold before use (NCM-25X, concentrated normoxia conditioned medium; HCM-25X, concentrated hypoxia conditioned medium). The in vitro cardioprotection was evaluated in neonatal ventricular cardiomyocytes by quantifying apoptosis after 24 h of serum deprivation associated with hypoxia (1% O(2)) in the absence or presence of NCM and HCM (nonconcentrated and 25-fold concentrated). The in vivo cardioprotection of HCM was tested in a model of myocardial infarction (MI) induced in Wistar male rats by permanent left coronary occlusion. Intramyocardial injection of HCM-25X (n = 14) or nonconditioned DMEM (n = 16) was performed 3 h after coronary occlusion and cardiac function was evaluated 19-21 days after medium injection. Cardiac function was evaluated by electro- and echocardiogram, left ventricular catheterization, and treadmill test. The in vitro results showed that HCM was able to decrease cardiomyocyte necrosis. The in vivo results showed that HCM-25X administered 3 h after AMI was able to promote a significant reduction (35%) in left ventricular end-diastolic pressure and improvement of cardiac contractility (15%) and relaxation (12%). These results suggest that soluble factors released in vitro by MSCs are able to promote cardioprotection in vitro and improve cardiac function in vivo.     

INHIBITION OF BRAIN RENIN–ANGIOTENSIN SYSTEM IMPROVES DIASTOLIC CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATS

• 1 Recently, we demonstrated that oral captopril treatment improved diastolic function and attenuated cardiac remodelling after myocardial infarction (MI) in rats. Considering the feasible role of the brain renin–angiotensin system (RAS) in heart failure, in the present study we investigated the role of the captopril injected intracerebroventricularly (i.c.v.) on the progression of cardiac dysfunction.
• 2 Male Wistar rats underwent experimental MI or sham operation. Infarcted animals received daily i.c.v. injections of captopril (approximately 200 mg/kg; MI + Cap) or saline (MI) from 11 to 18 days after infarction. Electro‐ and echocardiogram assessments were performed before and after i.c.v. treatment (10 and 18 days after MI, respectively). Water and hypertonic saline ingestion were determined daily between 12 and 16 days after MI.
• 3 Electrocardiograms from the MI and MI + Cap groups showed signs that resembled large MI before and after i.c.v. treatment. However, despite similar systolic dysfunction observed in both groups, only captopril‐treated rats exhibited reduced left ventricular (LV) dilatation and improved LV filling, as assessed by echocardiograms, and low levels of water ingestion compared with the saline‐treated control group.
• 4 The results of the present study suggest that the brain RAS may participate in the development of cardiac dysfunction induced by ischaemia and that inhibition of the brain RAS may provide a new strategy for the prevention of diastolic dysfunction.

     

STUDY OF GLOMERULAR FUNCTIONS IN NEONATES

Glomerular function of neonates (25 full term and equal number of preterm neonates) at birth, on day seven and day fourteen were estimated by endogenous Creatinine clearance (CCr). The Preterm were divided into three groups viz. Group I (Gestation age (GA) 30-32 weeks), Group II (GA 33-34 weeks) and Group III (GA 35-36 weeks). Group IV consisted of 25 term neonates. Serum creatinine (in mg/dl) in all the groups of preterm ranged from 0.92 ± 0.153 to 1.204 ± 0.154 and in term neonate from 0.562 ± 0.175 to 1.148 ± 0.247 showing that the levels were inversely proportional to the period of gestation. Besides the Serum Creatinine levels in all groups of Preterm as well as term neonates were found to fall significantly (p < 0.001) during the first and second week. Glomerular filtration rate (GFR) in Group I were 16.603 ± 2.519, 19.786 ± 2.078 and 23.720 ± 2320 on day one, seven and fourteen respectively showing progressive improvement during the first two weeks. The GFRs were also found to be directly proportional to the GA. In addition the levels of GFR were found increasing significantly during the second week compared to that on day seven in all the groups of preterm neonates. GFR''s in Group I & II on all the three occasions were significantly lower (p < 0.001) than those of term counterparts, however the GFR on the first day in Group III neonates was lower than group IV, the difference was insignificant (p > 0.05). The increase in GFR in Group I on the three occasions was linear but insignificant (p > 0.05). The rise was more rapid & significant (p < 0.001) during the second week in Groups II & III. On the contrary the rate of improvement of GFR in full terms was quite rapid during the first week and gradual over the second week of life.KEY WORDS: GFR preterm & term neonates, Serum creatinine