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Objective: The study evaluated the utility of transplanting bone marrow stromal cells in a porcine myocardial infarction model., Methods: A myocardial infarction was created by occluding the distal left anterior descending artery in pigs with coils and Gelfoam sponge. Sternal bone marrow was aspirated, and stromal cells were cultured and induced to differentiate to a myogenic phenotype with 5-azacytidine. Four weeks after coronary artery occlusion, sestamibi technetium single-photon emission computed tomographic scans were performed, and then either a graft of 100 x 10(6) bone marrow stromal cells (n = 5, 30% labeled with bromodeoxyuridine) or culture medium (n = 6) was injected into the infarct region. Four weeks later the tomographic scans were repeated and cardiac function was assessed with pressure and volume measurements. Morphologic and histologic characteristics of the heart were also studied., Results: Histologic examination found bromodeoxyuridine-labeled cells within the infarct region in islands that had sarcomeres and Z-bands and stained positively for cardiac specific troponin I. The bone marrow stromal cell transplant sites had a greater (P <.05) capillary density than did the control sites. The tomographic scans showed that the hearts with the cell transplants had increases in stroke volume, regional perfusion, and wall motion (P <.05 for all groups) relative to the control hearts. The pressure-volume analysis showed improvement (P <.05) in end-systolic elastance and preload recruitable stroke work in the transplantation group relative to the control group. The left ventricular chamber size was smaller (P <.05) and the scar thickness was greater (P <.05) in the hearts with transplanted cells than in the control hearts (P =.06)., Conclusion: 5-Azacytidine-treated bone marrow stromal cells transplanted into the myocardial infarct region formed islands of cardiac-like tissue, induced angiogenesis, prevented thinning and dilatation of the infarct region, and improved regional and global contractile function.

Inflammatory cytokines have been shown to have many cardiotoxic effects and to be activated in patients who have had a myocardial infarction (MI). Angiotensin-converting enzyme (ACE) inhibitors have been shown to have multiple beneficial effects after MI, but until now, their effects on cardiac cytokine expression were unknown. It was hypothesized that ACE inhibitors reduce cardiac cytokine expression and that this is associated with improved cardiac remodeling and hemodynamics. Rats had an MI created by coronary artery ligation and ACE inhibitors were started either early (day 1) or late (day 25) after MI and followed for a total of 28 days after MI. In the early-post-MI group, quinapril improved cardiac hemodynamics, improved ventricular remodeling, and prevented the increase in the expression of several cardiac cytokines (interleukin-1beta and -6) and reduced the cardiac expression of other cytokines (tumor necrosis factor-alpha and interleukin-5). The late introduction of quinapril (for 3 days) resulted in similar beneficial hemodynamic effects, and reductions in cardiac cytokines but did not result in improved cardiac remodeling. Thus, following MI, ACE inhibitors reduce cardiac cytokine expression both chronically and subacutely, an effect that may contribute to their beneficial effects after MI.

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.

Background: Congestive heart failure (CHF) is a disease that is characterized by progressive left ventricular (LV) dysfunction and dilatation. Oxidative stress is thought to contribute to the progression of CHF, and antioxidants have been shown to have beneficial effects when started early after myocardial infarction (MI). In this study, we tested whether the powerful antioxidant probucol would attenuate progression of CHF once it was established after MI in the rat., Methods and Results: Ligation of a coronary artery was used to create an MI in rats (n=266). Survivors were then randomized 20 days after MI to either probucol 61 mg. kg(-1). d(-1) or vehicle and followed up for a total of 100 days after MI. Studies of cardiac hemodynamics, LV remodeling, cardiac apoptosis and morphology, systemic neurohumoral activation, oxidative stress, and renal function were then evaluated. Probucol improved LV function (LV maximum rate of pressure rise from 3103 to 4250 mm Hg/s, P<0.05, and LV end-diastolic pressure decrease from 28 to 24 mm Hg, P<0.05), reduced pulmonary weights, prevented right ventricular systolic hypertension, and preserved renal function compared with vehicle. Probucol also prevented LV dilatation, prevented wall thinning (1.70 versus 1.42 mm, P<0.05), reduced cardiac fibrosis and cardiac apoptosis, attenuated increased myocardial cell cross-sectional area, and increased scar thickness., Conclusions: In chronic CHF, probucol exerts multiple beneficial morphological effects that result in better LV remodeling and function, reduced neurohumoral activation, and preserved renal function.

Objectives: The goal of this study was to evaluate whether reducing the potentially deleterious effects of oxidative stress with the potent anti-oxidant probucol improves prognosis after myocardial infarction (MI) in rats., Background: Oxidative stress has been documented in patients early and late after MI, particularly when it is associated with congestive heart failure., Methods: Rats surviving acute MIs for 24 h (n = 247) were assigned to vehicle or probucol (61 mg/kg, daily) for four weeks, at which time cardiac hemodynamic, morphologic and molecular measurements were done., Results: In rats with large MIs, probucol improved survival (87.9%) when compared with vehicle (50.6%) (p < 0.001). Probucol also partially preserved left ventricular (LV) systolic but not diastolic function. Probucol increased scar thickness and decreased cardiac fibrosis but did not modify LV hypertrophy or dilation. Finally, probucol decreased cardiac oxidative stress, as assessed by measuring cardiac malondialdehydes, and decreased the cardiac expression of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 but did not modify fetal gene re-expression in rats with large MIs., Conclusions: This study indicates that the anti-oxidant probucol markedly improves post-MI survival in rats despite few demonstrable effects on cardiac remodeling or hemodynamics. Its beneficial effects may, however, be associated with reduced cardiac fibrosis, oxidative stress and expression of pro-inflammatory cytokines.

Inflammatory cytokines have been shown to be activated in congestive heart failure (CHF). This activation is likely the result of the convergence of a number of factors, several of which could be attenuated with the use of an Angiotensin converting enzyme (ACE) inhibitor. In order to assess this, rats had a myocardial infarction (MI) created by coronary artery ligation and were followed for 28 days without treatment to permit the development of CHF. At that time, the ACE inhibitor quinapril was started, or rats remained untreated and were followed a further 56 days for a total of 84 days. Half of the untreated rats had quinapril started 3 days prior to sacrifice, on day 81. Starting quinapril at either 28 or 81 days had little effect on cardiac hemodynamics, or ventricular remodeling. Quinapril did however attenuate the MI-induced rise in cardiac cytokine expression (tumor necrosis factor-alpha [TNF-alpha], interleukin-1beta, -5 and -6). Thus, in CHF, ACE inhibitors attenuate the rise in cardiac cytokine expression. This study helps to identify a new mechanism by which ACE inhibitors may exert their beneficial effects in CHF.

Carvedilol (20 mg/kg, bid) or vehicle was given to rats surviving a myocardial infarction (MI) 24 h (n = 409). In rats with large MI, carvedilol partially preserved left ventricular (LV) function and intrinsic myocardial contractility and reactivity to beta-adrenergic stimulation. Carvedilol led to scar thickening, increased LV hypertrophy, and decreased cardiac fibrosis but did not prevent LV dilatation. Carvedilol reduced cardiac expression of interleukin-1beta but did not prevent cardiac fetal gene re-expression or modify cardiac oxidative stress. Despite these beneficial effects, carvedilol decreased survival (38.8%, versus vehicle, 50.6%) due to excessive early mortality. Thus, post-MI carvedilol has many beneficial effects, however, in this study it increased post-MI mortality, perhaps due to excessive hypotension.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the efficacy of ARBs on the survival of patients with heart failure when compared to placebo or ACEIs.To determine the efficacy of ARBs on hospitalization rates in patients with heart failure when compared to placebo or ACEIs.