Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats

Summary The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 ± 1.2mmHg and 5.4 ± 0.6mmHg. Pranidipine reduced LVEDP and CVP to 13.6 ± 1.4mmHg (P < 0.01) and 2.5 ± 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 ± 0.04 and 0.47 ± 0.02g/kg; MI, 2.18 ± 0.05 and 0.79 ± 0.04g/kg;P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 ± 0.3mm (P < 0.01) (sham, 6.4 ± 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 ± 0.04 and 0.6 ± 0.03g/kg,P < 0.01) and LVDd (7.9 ± 0.2mm,P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 ± 2% vs MI, 15 ± 1%;P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 ± 1.1 m/s²; MI, 32.6 ± 2.1m/s²;P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases in β-myosin heavy chain (MHC), α-skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left ventricle and right ventricle at 4 weeks after the myocardial infarction were significantly suppressed by the treatment with pranidipine. On the other hand, depressed α-MHC was restored to normal levels by pranidipine in both regions. In conclusion, pranidipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.     

Splenectomy reduces fibrosis and preneoplastic lesions with increased triglycerides and essential fatty acids in rat liver cirrhosis induced by a choline‐deficient L‐amino acid‐defined diet

Aim: This study investigated whether splenectomy is of significance in non‐alcoholic steatohepatitis (NASH). Methods: Five‐week‐old Wistar rats were fed a choline‐deficient diet for 8 weeks to create a NASH model. A sham‐operation or splenectomy was then performed, and rats were killed 4 weeks later. Results: Liver fibrosis and liver preneoplastic lesions were significantly reduced in the splenectomy group compared to the sham‐operation group, and α‐smooth muscle actin (SMA) expression was significantly inhibited (liver fibrosis area: sham 8.63 ± 4.09%, splenectomy 5.45 ± 3.69%, P < 0.01; preneoplastic lesion size: sham 6.56 ± 3.68 ×10⁶ µm²/cm², splenectomy 4.63 ± 3.27 ×10⁶ µm²/cm², P < 0.05; the number of preneoplastic lesions: sham 8.33 ± 3.96/cm², splenectomy 5.17 ± 1.80/cm², P < 0.01; α‐smooth muscle actin‐positive area: sham 4.41 ± 2.48%, splenectomy 2.75 ± 1.66%, P < 0.01) On the other hand, liver triglycerides and essential fatty acids were significantly increased in the splenectomy group (liver triglycerides: sham 182 ± 35.0 mg/g, splenectomy 230 ± 35.0 mg/g, P < 0.05; liver linoleic acid: sham 17.2 ± 4.9 mg/g, splenectomy 23.3 ± 6.9 mg/g, P < 0.05; liver α‐linolenic acid: sham 118 ± 36.6 µg/g, splenectomy 162 ± 51.4 µg/g, P < 0.05). In addition, expressions of hepatic fatty acid metabolism‐related genes (e.g. acyl‐CoA oxidase, liver carnitine palmitoyl‐CoA transferase I, cytochrome P450 4A, long‐chain acyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase) were significantly inhibited in the splenectomy group. Conclusion: These findings suggest that spleen plays an important regulatory role in the fibrosis, preneoplastic lesion and lipid metabolism of liver in a rat choline‐deficient L‐amino acid model.     

Prolonged Therapy With Erythropoietin is Safe and Prevents Deterioration of Left Ventricular Systolic Function in a Porcine Model of Myocardial Infarction

BackgroundErythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI.Methods and ResultsMI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group). Inflammatory markers, bone marrow cell mobilization, and left ventricular function (by both echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. EPO therapy was associated with a significant increase in hemoglobin and mononuclear counts. D-dimer and C-reactive protein levels did not differ between groups. At week 6, EPO therapy prevented further deterioration of left ventricular ejection fraction (39 ± 2% vs. 33 ± 1%, P < .01) and improved wall motion score index (P < .02). Histopathology revealed increased areas of viable myocardium, vascular density, and capillary-to-myocyte ratio in the EPO therapy compared with the control (all P < .05).ConclusionProlonged EPO therapy after MI in a large animal model is safe and leads to an increase in viable myocardium, increased vascular density, and prevents further deterioration of left ventricular function. These results support future clinical studies in post-MI patients.     

Long-term captopril treatment improves diastolic filling more than systolic performance in rats with large myocardial infarction

Objectives. This study sought determine the effects of long-term angiotensin-converting enzyme (ACE) inhibition on left ventricular (LV) diastolic filling in postinfarction heart failure.Background. Long-term treatment with ACE inhibitors is beneficial in experimental animals and patients with heart failure. Because this treatment typically produces only small improvements in LV systolic function, we hypothesized that improvements in LV diastolic filling might contribute to the overall beneficial effects of ACE inhibitors after myocardial infarction (MI).Methods. We performed transthoracic echocardiographic-Doppler examinations in rats 1 and 6 weeks after transmural MI or sham operation. Rats with MI were randomized to no treatment (n = 10) or captopril (2 g/liter in drinking water, n = 8) after the baseline echocardiogram.Results. Six weeks after MI, untreated rats bad significant LV dilation compared with sham-operated rats (LV diastolic dimension [mean ± SEM] 10.7 ± 0.3 vs. 8.5 ± 0.3 mm, p < 0.05). Rats with untreated MI also had impaired fractional shortening (9 ± 1% vs. 34 ± 2%, p < 0.05) and depressed systolic thickening of the noninfarcted posterior wall (37 ± 3% vs. 65 ± 9%, p < 0.05). Rats with MI showed progressively restricted LV diastolic filling as assessed by transmitral Doppler recordings. At 6 weeks, peak early filling velocity (E) was increased (97 ± 3 vs. 77 ± 2 cm/s, p < 0.05), E wave deceleration was more rapid (23 ± 3 vs. 12 ± 1 m/s², p < 0.05), isovolumetric relaxation time was decreased (18 ± 1 vs. 24 ± 1 ms, p < 0.05), and late filling velocity was lower (26 ± 7 vs. 34 ± 1 cm/s, p < 0.05) in rats with MI versus sham-operated rats. Compared with rats with untreated MI, rats receiving captopril had similar LV diastolic dimensions (10.5 ± 0.35 vs. 10.7 ± 0.35 mm), slightly higher fractional shortening (16 ± 2% vs. 9 ± 1%, p < 0.05 [captopril MI vs. untreated MI]) and unchanged posterior wall thickening (49 ± 12% vs. 37 ± 3%, p = 0.3). In contrast, captopril almost completely normalized diastolic filling abnormalities (E velocity 82 ± 5 cm/s, p < 0.05 [captopril MI vs. untreated MI]; E wave deceleration rate 15 ± 2 m/s², p < 0.05 [captopril MI vs. untreated MI]; isovolumetric relaxation time 20 ± 1 ms).Conclusions. Long-term captopril treatment in rats with a large MI modestly limits LV remodeling and the development of systolic dysfunction but markedly improves the restrictive diastolic filling abnormalities that are seen in untreated rats.     

芪丹通脉片对心肌梗死后大鼠心肌纤维化重构的影响

目的:观察益气活血复方芪丹通脉片（qidan tongmai tablet,QDTMT）对大鼠心肌梗死(MI)后心功能及左心室非梗死区心肌纤维化的影响。方法: 以结扎SD大鼠左冠脉前降支法建立MI模型,随机分为假手术(Sham)组、MI组、MI+QDTMT小剂量(MI-QDTMTL)组和MI+QDTMT大剂量(MI-QDTMTH)组。术后24 h各组均用生理盐水配制成等体积药液灌胃4周,4周后以多普勒超声评价心脏功能;测定心室的质量/体质量(HW/BW);以MASSON染色检测非梗死区胶原的含量;用RT-PCR法检测非梗死区转化生长因子-β1（TGF-β1）、Ⅰ型胶原蛋白（Collagen type 1,Col1）及Ⅲ型胶原蛋白（Collagen type 3,Col3）mRNA的表达水平。采用大鼠羟脯氨酸（HYP）的ELASA试剂盒检测非梗死区中HYP的含量。结果: ①术后4周心功能:与MI组比较,MI-QDTMTL组和MI-QDTMTH组左室舒张末期内径(LVEDD)和HW/BW均降低,而射血分数(EF)升高（P<0.01或P<0.05）;②非梗死区心肌胶原蛋白的含量: MI-QDTMTL组胶原和MI-QDTMTH组胶原含量均低于MI组（P<0.01）;MI-QDTMTH组胶原的含量明显低于MI-QDTMTL组(P<0.01);③非梗死区TGF-β1、Col1、Col3mRNA的表达:与MI组比较,MI-QDTMTL组、MI-QDTMTH组的TGF-β1 Col1、Col3 mRNA均显著降低(P<0.01或P<0.05);MI-QDTMTH组TGF-β1、Col1、Col3 mRNA的表达显著低于MI-QDTMTL组(P<0.05);④非梗死区HYP的含量: MI-QDTMTL组与MI-QDTMTH组HYP的含量低于MI组(P<0.05,P<0.01); MI-QDTMTH组HYP的含量低于MI-QDTMTL组(P<0.05)。结论: QDTMT通过下调MI交界区TGF-β1、Col1、Col3 mRNA的表达及HYP产生,进而抑制MI后非梗死区反应性胶原的过度沉积,且高剂量组比低剂量组的疗效更好,为防治MI后非梗死区心肌纤维化重构,改善心脏功能提供了新的治疗思路。     

Alterations in myofilament function contribute to left ventricular dysfunction in pigs early after myocardial infarction

Myocardial infarction (MI) initiates cardiac remodeling, depresses pump function, and predisposes to heart failure. This study was designed to identify early alterations in Ca2+ handling and myofilament proteins, which may contribute to contractile dysfunction and reduced beta-adrenergic responsiveness in postinfarct remodeled myocardium. Protein composition and contractile function of skinned cardiomyocytes were studied in remote, noninfarcted left ventricular (LV) subendocardium from pigs 3 weeks after MI caused by permanent left circumflex artery (LCx) ligation and in sham-operated pigs. LCx ligation induced a 19% increase in LV weight, a 69% increase in LV end-diastolic area, and a decrease in ejection fraction from 54+/-5% to 35+/-4% (all P<0.05), whereas cardiac responsiveness to exercise-induced increases in circulating noradrenaline levels was blunted. Endogenous protein kinase A (PKA) was significantly reduced in remote myocardium of MI animals, and a negative correlation (R=0.62; P<0.05) was found between cAMP levels and LV weight-to-body weight ratio. Furthermore, SERCA2a expression was 23% lower after MI compared with sham. Maximal isometric force generated by isolated skinned myocytes was significantly lower after MI than in sham (15.4+/-1.5 versus 19.2+/-0.9 kN/m2; P<0.05), which might be attributable to a small degree of troponin I (TnI) degradation observed in remodeled postinfarct myocardium. An increase in Ca2+ sensitivity of force (pCa50) was observed after MI compared with sham (DeltapCa50=0.17), which was abolished by incubating myocytes with exogenous PKA, indicating that the increased Ca2+ sensitivity resulted from reduced TnI phosphorylation. In conclusion, remodeling of noninfarcted pig myocardium is associated with decreased SERCA2a and myofilament function, which may contribute to depressed LV function. The full text of this article is available online at http://circres.ahajournals.org.     

Growth Hormone Attenuates Early Left Ventricular Remodeling and Improves Cardiac Function in Rats With Large Myocardial Infarction

Objectives. We sought to investigate the cardiac effects of growth hormone (GH) administration during the early phase of pathologic remodeling in a rat model of large myocardial infarction (MI).Background. Recent evidence suggests that exogenous administration of GH evokes a hypertrophic response and increases left ventricular (LV) function in vivo in rats with normal or chronically failing hearts. We hypothesized that these effects would attenuate ventricular remodeling early after MI.Methods. Fifty-eight male rats underwent sham operation (n = 19) or had induced MI (n = 39). The day after the operation, the infarcted rats were randomized to receive 3 weeks of treatment with GH, 3 mg/kg body weight per day (n = 19) or placebo (n = 20). Echocardiography, catheterization and isolated whole heart preparations were used to define cardiac structure and function.Results. Growth hormone caused hypertrophy of the noninfarcted myocardium in a concentric pattern, as noted by higher echocardiographic relative wall thickness at 3 weeks and by morphometric histologic examination. Left ventricular dilation was reduced in the GH-treated versus placebo group (echocardiographic LV diastolic diameter to body weight ratio 2.9 ± 0.1 vs. 3.5 ± 0.2 cm/kg; p < 0.05). In vivo and in vitro cardiac function was improved after GH treatment. Despite elevated insulin-like growth factor-1 (IGF-1) serum levels in GH-treated rats, myocardial IGF-1 messenger ribonucleic acid was not different among the three groups, suggesting that an increase in its local expression does not appear necessary to yield the observed effects.Conclusions. These data demonstrate that early treatment of large MI with GH attenuates the early pathologic LV remodeling and improves LV function.(J Am Coll Cardiol 1997;29:1109–16)© 1997 by the American College of Cardiology     

Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction

Nitric oxide (NO) is an important modulator of cardiac performance and left ventricular (LV) remodeling after myocardial infarction (MI). We tested the effect of cardiomyocyte-restricted overexpression of one NO synthase isoform, NOS3, on LV remodeling after MI in mice. LV structure and function before and after permanent LAD coronary artery ligation were compared in transgenic mice with cardiomyocyte-restricted NOS3 overexpression (NOS3-TG) and their wild-type littermates (WT). Before MI, systemic hemodynamic measurements, echocardiographic assessment of LV fractional shortening (FS), heart weight, and myocyte width (as assessed histologically) did not differ in NOS3-TG and WT mice. The inotropic response to graded doses of isoproterenol was significantly reduced in NOS3-TG mice. One week after LAD ligation, the infarcted fraction of the LV did not differ in WT and NOS3-TG mice (34+/-4% versus 36+/-12%, respectively). Four weeks after MI, however, end-systolic LVID was greater, and fractional shortening and maximum and minimum rates of LV pressure development were less in WT than in NOS3-TG mice. LV weight/body weight ratio was greater in WT than in NOS3-TG mice (5.3+/-0.2 versus 4.6+/-0.5 mg/g; P<0.01). Myocyte width in noninfarcted myocardium was greater in WT than in NOS3-TG mice (18.8+/-2.0 versus 16.6+/-1.6 microm; P<0.05), whereas fibrosis in noninfarcted myocardium was similar in both genotypes. Cardiomyocyte-restricted overexpression of NOS3 limits LV dysfunction and remodeling after MI, in part by decreasing myocyte hypertrophy in noninfarcted myocardium.     

Hypoxia training attenuates left ventricular remodeling in rabbit with myocardial infarction

Objective Previous studies showed that hypoxia preconditioning could protect cardiac function against subsequent myo-cardial infarction injury. However, the effect of hypoxia on left ventricular after myocardial infarction is still unclear. This study therefore aims to investigate the effects of hypoxia training on left ventricular remodeling in rabbits post myocardial infarction. Methods Adult male rabbits were randomly divided into three groups： group SO （sham operated）, group MI （myocardial infarc-tion only） and group MI-HT （myocardial infarction plus hypoxia training）. Myocardial infarction was induced by left ventricular branch ligation. Hypoxia training was performed in a hypobaric chamber （having equivalent condition at an altitude of 4000 m, FiO214.9%） for 1 h/day, 5 days/week for four weeks. At the endpoints, vascular endothelial growth factor （VEGF） in the plasma was measured. Infarct size and capillary density were detected by histology. Left ventricular remodeling and function were as-sessed by echocardiography.Results After the 4-week experiment, compared with the group SO, plasma VEGF levels in groups MI （130.27 ± 18.58 pg/mL,P〈 0.01） and MI-HT （181.93 ± 20.29 pg/mL,P〈 0.01） were significantly increased. Infarct size in Group MI-HT （29.67% ± 7.73%） was deceased remarkably, while its capillary density （816.0 ± 122.2/mm2） was significantly increased. For both groups MI and MI-HT, left ventricular end-diastolic and end-systolic dimensions were increased whereas left ventricular ejection fraction was decreased. However, compared with group MI, group MI-HT diminished left ventricular end-diastolic （15.86 ± 1.09 mm,P〈 0.05） and end-systolic dimensions （12.10 ± 1.20 mm,P〈 0.01） significantly and im-proved left ventricular ejection fraction （54.39 ± 12.74 mm,P〈 0.05）.ConclusionHypoxia training may improve left ven-tricular function and reduce remodeling via angiogenesis in rabbits with MI.     

Increased expression and function of the myocardial Na–K–2Cl cotransporter in failing rat hearts

Abstract Recent studies indicate a role of the Na–K–2Cl cotransporter (NKCC) in regulation of myocardial function. However, potential pathophysiological properties of NKCC in conditions like myocardial infarction (MI) and heart failure have not been explored. We investigated the cellular localization of myocardial NKCC and whether myocardial NKCC levels are changed upon induction of post-infarction heart failure in rats. Immunohistochemical analysis demonstrated extensive distribution of NKCC in normal rat myocardium with fairly strong expression in cardiomyocytes, fibroblasts, vascular endothelial cells, as well as smooth muscle cells. Myocardial mRNA levels of NKCC were investigated at 2, 7 and 28 days after induction of MI or sham operation, but no changes were found. Cardiomyocytes and non-cardiomyocytes were isolated 7 days after induction of MI or sham operation. An ∼2-fold increase of the NKCC mRNA levels was found in isolated cardiomyocytes from heart failure rats compared to that of sham-operated rats (P < 0.001), whereas a trend towards decreased mRNA levels of NKCC in isolated non-cardiomyocytes was observed. In addition, we found a bumetanide sensitive ⁸⁶Rb⁺ influx mechanism present in the hearts after induction of MI (P < 0.05). Thus, our data indicate cardiomyocyte specific increase in NKCC mRNA levels and increased NKCC activity in post-infarction heart failure. Our results may indicate a potential role of NKCC during post-infarction remodeling.     

Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats

Hypoxia-inducible factor (HIF)-1α and-2α have diverse actions on the myocardium, but the importance of direct effects on cardiac myocytes is unclear. To define their regional accumulation and association with cardiomyocyte cell cycle change after myocardial infarction (MI), a rat MI model was established by occluding the coronary arteries. To further prove a causative relationship between HIF and cell cycle regulation, cultured cardiomyocytes were transfected with adenoviral vectors carrying HIF-1α and HIF-2α. Two weeks after MI, both HIF-1α and HIF-2α mRNA were moderately increased in the infarcted left ventricle and noninfarcted left ventricle; HIF-2α amplification was also detected in areas of the interventricular septum and the right ventricle. In concordance with the changes in mRNA levels, immunohistochemistry signals of HIF-1α and HIF-2α were characterized by different regional distributions. In the myocardium adjacent to the infarcted tissue, a significant correlation between HIF-1α or HIF-2α and Ki-67 labeling index was observed (P < 0.001). Immunohistochemical double staining showed that HIF positive cardiomyocytes underwent DNA synthesis. Cardiomyocytes treated with HIF-1α or -2α expressed Ki-67, phosphohistone H3, and bromodeoxyuridine effectively in vitro. In conclusion, HIF-1α and HIF-2α had a distinct spatial expression pattern in a rat model of ischemic heart disease. Both HIF subunits might be potent stimuli for cardiomyocytes to re-enter the cell cycle and initiate DNA synthesis. These authors contributed equally to this work.     

咪达普利对陈旧性心肌梗死代偿区心肌T型钙电流的作用

应用咪达普利(Imi)对家兔陈旧性心肌梗死(OMI)模型进行干预,探讨其对OMI心室肌细胞T型钙电流(ICaT)的影响。选择健康家兔按体重随机分为OMI、假手术组与Imi组。OMI组:采用冠状动脉前降支结扎法制备OMI模型;假手术组:手术与OMI组同,只是不结扎冠状动脉,同样喂养8周;Imi处理组:对OMI家兔口服Imi0.625mg·kg-1·d-1连续8周进行干预。取心脏分离左室游离壁代偿区三层心肌细胞,全细胞膜片钳技术记录ICaT。结果显示,家兔OMI代偿区心肌细胞发生心肌肥厚,细胞膜ICaT密度较假手术组明显增加,当刺激电位为-30mV时,其电流密度从0.35±0.02pA/pF增至2.36±0.12pA/pF(P<0.01)。Imi组代偿区心肌细胞膜ICaT密度降至0.83±0.11pA/pF。ICaT的激活曲线左移,激活曲线斜率增加。Imi组二者改变均减小。但3组心肌细胞ICaT的失活曲线和失活后恢复曲线基本不变。结论:OMI家兔代偿区发生心肌肥厚,ICaT明显增加,Imi可以逆转家兔OMI代偿区心肌肥厚,降低ICaT的电流密度。     

Time dependence of left ventricular recovery after delayed recanalization of an occluded infarct-related coronary artery: findings of a pilot study

Objectives. We sought to test the hypothesis that late recanalization of infarct-related coronary arteries (IRAs) improves long-term left ventricular (LV) function.Background. Reperfusion within 24 h of an acute myocardial infarction (MI) has been shown to improve myocardial healing and to reduce infarct expansion. Uncontrolled data suggest that there may be a time window of several weeks for such an effect.Methods. Sixteen asymptomatic patients 10 ± 4 days after a first Q wave anterior wall MI with persistent left anterior descending coronary artery occlusion and infarct-zone akinesia were randomized to immediate (2 weeks) or delayed (3 months) angioplasty. Repeat catheterization and cardiac magnetic resonance imaging (MRI) were performed after 3 and 12 months.Results. Angiography 3 months after MI revealed that LV ejection fraction (LVEF) had increased ([mean ± SD] 54.4 ± 4.3% vs. 63.9 ± 7.4%, p < 0.01) as a result of improved regional function (p < 0.01) and LV end-systolic volume had decreased (p < 0.002), whereas LV end-diastolic volume remained unchanged. With delayed angioplasty, LVEF, infarct zone wall motion and LV volumes did not improve. Cardiac MRI at baseline and at 3 and 12 months confirmed these findings and extended them up to 1 year, indicating that delayed angioplasty could no longer improve LV function because of marked LV dilation (p < 0.01). Immediate angioplasty had a high success rate, but restenosis (50%) was accompanied by new severe angina as a clinical indicator of salvaged myocardium, which did not occur after delayed angioplasty.Conclusions. This pilot study in selected patients supports the hypothesis that myocardial viability persists (“hibernation”) for 2 to 3 weeks but not for 3 months after MI, during which time it may be worthwhile to restore blood flow to a large myocardial territory, even in asymptomatic patients, to improve long-term LV function.     

Combined effects of irbesartan and carvedilol on expression of tissue factor and tissue factor pathway inhibitor in rats after myocardial infarction

The objective of this study was to investigate the effects of irbesartan, carvedilol, and irbesartan plus carvedilol on the expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) mRNA and protein in rat myocardium after myocardial infarction (MI). MI was induced in male Wistar rats by ligation of the anterior descending branch of the left coronary artery. Irbesartan at 50 mg/kg/day, carvedilol at 1 mg/kg/day, irbesartan plus carvedilol, or placebo was administered intragastrically; expression of TF and TFPI mRNA and protein was determined by RT-PCR and Western blot analysis. The relative left ventricle weights were lower in all three treatment groups than in the placebo group, with the lowest relative weight in the irbesartan plus carvedilol group (P < 0.001). The size of the infarcted area was lower in the carvedilol and the combined groups than in the placebo group (P < 0.001). The levels of expression of TF and TFPI mRNA and protein were lower in the combined group than in the placebo group or the carvedilol group (P < 0.001). Treatment with irbesartan plus carvedilol reduced the expression of TF and TFPI mRNA and protein after MI in rats, and combined treatment with both agents had greater effects than the single agents alone. These findings suggest that the beneficial effects of these drugs may include anticoagulation and that combined therapy with both agents is an option that should be evaluated further.     

Enhancement of left ventricular function by glucose-insulin-potassium infusion in acute myocardial infarction

Twenty-eight patients admitted to the hospital with suspected acute myocardial infarction underwent baseline studies within 12 hours of onset of symptoms. Patients were then randomized to receive control infusion (0.45 percent sodium chloride at 20 ml/hour) (15 patients) or glucoseinsulin-potassium infusion (300 g glucose, 50 units regular insulin, 80 mEq KCl/liter water at 1.5 ml/kg per hour) (13 patients) for 48 hours. All patients received 0.45 percent sodium chloride for 2 more days. Coronary arteriograms and left ventriculograms were obtained in 26 (93 percent) of 28 patients 2 to 3 weeks after infarction.Radionuclide ejection fraction improved during glucose-insulin-potassium infusion (49 ± 4 to 55 ± 5 percent, p < 0.01). Before discharge, the angiographic ejection fraction was greater in the glucose-insulin-potassium recipients than in control patients (43 ± 3 versus 35 ± 3 percent, p < 0.05). Radionuclide ejection fraction decreased in all control patients during the study (42 ± 4 to 37 ± 3 percent, p < 0.0005) and did not change significantly in the treated group (49 ± 4 to 43 ± 5 percent, p = not significant [NS] by paired t test). Regional wall motion analysis revealed an increase in ejection fraction in the “infarcted zone” in the treated group only (44 ± 7 to 54 ± 8 percent, p < 0.01) during glucose-insulin-potassium infusion. There was also a significant decrease in ejection fraction in the “noninfarcted zone” in the control group only (50 ± 4 to 45 ± 4 percent, p < 0.01).During experimental infusion pulmonary arterial end-diastolic pressure decreased in the glucose-insulin-potassium group (17 ± 2 to 12 ± 2 mm Hg, p < 0.01) without changing significantly in the control group. Calculated end-diastolic and end-systolic volume indexes changed in opposite directions in the two groups during experimental infusion (end-diastolic volume index 80 ± 5 to 90 ± 9 ml/m² in the control group versus 70 ± 9 to 55 ± 6 ml/m² in the treated group, p < 0.005 for change from baseline value between groups and the end-systolic volume index 48 ± 6 to 55 ± 8 ml/m² in the control group versus 39 ± 8 to 26 ± 5 ml/m² in the treated group (p < 0.01 for change from baseline value between groups).These data suggest that glucose-insulin-potassium infusion after acute myocardial infarction in human beings (1) increases global ejection fraction, (2) Increases ejection fraction in the “infarcted zone” without changing ejection fraction in the “noninfarcted zone”, and (3) decreases pulmonary arterial end-diastolic pressure and end-diastolic and end-systolic volumes.     

Impact of Timing and Dose of Mesenchymal Stromal Cell Therapy in a Preclinical Model of Acute Myocardial Infarction

BackgroundAlthough mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI.Methods and ResultsSprague-Dawley rats were used. Allogeneic prospectively isolated MSC (“low” dose 1 × 10⁶ or “high” dose 2 × 10⁶ cells) were delivered by transepicardial injection immediately after MI (“early-low,” “early-high”), or 1 week later (“late-low,” “late-high”). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration.ConclusionsThe nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.     

Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction

Objectives. The purpose of our study was to assess the prognostic importance of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease (CAD) and left ventricular (LV) dysfunction.Background. The amount of dysfunctional but viable myocardium predicts the functional improvement after revascularization and may offer more precise risk stratification of patients referred for bypass surgery or coronary angioplasty.Methods. Two hundred and seventy-four consecutive patients with CAD and LV ejection fraction ≤40% underwent low-dose dobutamine echocardiography for viability assessment. One hundred and thirty-three of them were revascularized using either coronary artery bypass surgery (118 patients) or coronary angioplasty (15 patients) and entered this study. To quantify the amount of dysfunctional but viable myocardium, wall motion was scored using 16-segment model. The dysfunctional segments were defined as viable if they exhibited improvement in their thickening by at least 1 grade with dobutamine infusion. The patients were followed up for a mean period of 20 ± 12 months (range, 2 to 48) for cardiac mortality and nonfatal cardiac events including myocardial infarction, unstable angina pectoris requiring hospitalization and hospitalization for heart failure. Standard follow-up echocardiography was performed 3 to 6 months after revascularization.Results. Twenty-nine patients exhibited a large amount of dysfunctional but viable myocardium (≥6 segments, group A), 60 patients had a small amount of dysfunctional but viable myocardium (2 to 5 segments, group B) and 44 patients were found to have dysfunctional myocardium irreversibly damaged (group C). Similar prerevascularization LV ejection fractions of 35% ± 5%, 34% ± 4%, 36% ± 4% in groups A, B and C increased to 47% ± 6% (p < 0.01 vs. baseline, p < 0.01 vs. groups B and C), to 40% ± 5% (p < 0.01 vs. baseline) and to 37% ± 6% (p = NS vs baseline), respectively, after revascularization. The greatest functional improvement after revascularization in group A patients was accompanied by a lower rate of cardiac events during follow-up (2 vs. 18 in group B, p < 0.05, and vs. 17 in group C, p < 0.01) and better cardiac event-free survival according to Kaplan–Meier survival analysis (p < 0.05 vs. groups B and C, respectively).Conclusion. In revascularized patients with CAD and moderate or severe LV dysfunction, the presence of a large amount of dysfunctional but viable myocardium identifies patients with the best prognosis.     

Repeated Low-dose of Erythropoietin is Associated with Improved Left Ventricular Function in Rat Acute Myocardial Infarction Model

Objective To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial infarction (MI). Methods Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into five groups: MI treated with single high dose (MT1, 5,000 U/kg, n = 10), single high dose (5,000 U/kg) and repeated high doses (MTHi, 1,000 U/kg twice a week; n = 8), or single high dose (5,000 U/kg) and repeated low doses (MTLo, 750 U/kg once a week, n = 10), MI non-treated (MNT, n = 10), sham (S, n = 5). Echocardiography was performed 3.6 ± 1.5 days and 43.7 ± 2.3 days post MI. Collagen deposition and infarct size were measured on histological sections using computerized image analysis. Apoptosis was assessed by ApopTag staining. Results Baseline fractional shortening (FS) was similar between groups. Six weeks after MI the FS of MTLo (26.9%) was significantly higher compared to MNT (17.8%), MT1 (19.5%) and MTH (22.3%) (p = 0.01). However, remodeling indices (end diastolic and end systolic areas, LV circumference) did not improve in the Epo groups, and even worsened in the MTHi group. There was significantly less collagen staining in non-infarct areas in MT1 and MTHi groups compared to MNT and MTLo (0.38 ± 0.3%, 0.49 ± 0.34%, vs 0.89 ± 0.41%, 0.95 ± 0.33%, respectively, p < 0.001). The number of ApopTag positive nucleus was significantly higher in the MNT group compared to the MT1, MTHi, MTLo groups (14.4 ± 8, 7.6 ± 4, 5.8 ± 7, 4.8 ± 5, respectively, p = 0.01 for trend). Conclusion Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.     

Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma

Objective Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma. Design Retrospective follow-up study. Patients Forty-three patients (mean age 56 ± 14 years), treated by transsphenoidal surgery for non-functioning pituitary macroadenoma, were included in this analysis. Results Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 ± 0.37 to 0.75 ± 0.36 (P < 0.01) (right eye), and from 0.60 ± 0.32 to 0.82 ± 0.30 (P < 0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 ± 0.36 to 0.82 ± 0.34 (P < 0.05) (right eye), and from 0.82 ± 0.30 to 0.88 ± 0.27 (P < 0.05) (left eye). Conclusion Visual acuity improves progressively after surgical treatment for non-functioning pituitary macroadenomas, at least within the first year after transsphenoidal surgery.