We tested the hypothesis that activation of AMP-activated protein kinase (AMPK) promotes myocardial glycogenolysis by decreasing glycogen synthase (GS) and/or increasing glycogen phosphorylase (GP) activities. Isolated working hearts from halothane-anesthetized male Sprague-Dawley rats perfused in the absence or presence of 0.8 or 1.2 mM 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an adenosine analog and cell-permeable activator of AMPK, were studied. Glycogen degradation was increased by AICAR, while glycogen synthesis was not affected. AICAR increased myocardial 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranotide (ZMP), the active intracellular form of AICAR, but did not alter the activity of GS and GP measured in tissue homogenates or the content of glucose-6-phosphate and adenine nucleotides in freeze-clamped tissue. Importantly, the calculated intracellular concentration of ZMP achieved in this study was similar to the K m value of ZMP for GP determined in homogenates of myocardial tissue. We conclude that the data are consistent with allosteric activation of GP by ZMP being responsible for the glycogenolysis caused by AICAR in the intact rat heart.

The size and location of the marginated pool of neutrophils (PMNs) in rabbit lungs were evaluated, and the rate of exchange of the PMNs with the circulating pool was determined. 99mTc-labeled erythrocytes (99mTc-RBCs) and 125I-labeled macroaggregated albumin (125I-MAA) were used to determine RBC transit times in the pulmonary circulation. Radiolabeled PMNs were studied on their first passage through the lungs. After 10 min of circulation, the lungs were fixed, gamma counted, and prepared for morphometric and autoradiographic studies; 74 +/- 3% of the PMNs was retained in the lungs on the first passage, and 23 +/- 2% was within the pulmonary marginated pool 10 min later. The regional PMN retention and the rate of exchange between the marginated and circulating PMN pools in the lung were directly related to RBC transit time. The radiolabeled PMNs distributed similarly to the unlabeled cells within the microvasculature and had a similar exchange rate between the marginated and circulating pools (1.4 +/- 0.2%/s using labeled cells and 1.5 +/- 0.5%/s using unlabeled cells). The marginated pool was located primarily within alveolar capillaries and contained two to three times as many PMNs as the total circulating pool.

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of a-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.Development of the tissue-specific cells of the heart, the cardiac myocytes, has been extensively studied in vivo. Myocytes proliferate throughout fetal and early postnatal development, followed by a transition whereby proliferation ceases and further cardiac growth occurs through an increase in myocyte size rather than number (5, 9). The factors that control myocyte proliferation and the transition from hyperplastic to hypertrophic growth are unknown.Recent interest has centered on the role of proto-oncogenes in cellular development. In particular, c-myc has been implicated in controlling both proliferation and differentiation in various cell types (29). Increased expression of c-myc in chicken embryo fibroblasts results in an increase in the rate of proliferation of these cells (34). In hematopoietic cells, the expression of c-myc decreases concomitant with differentiation, and if these cells are made to constitutively express c-myc, differentiation is prevented (10,13,25,33 genes) encode proteins that induce myogenic determination in skeletal muscle. These genes all share regions of similarity with c-myc, suggesting a potential interaction of these gene products with c-myc, or with a common intracellular target, in regulating skeletal muscle differentiation. Although expression of these particular myogenic determination genes has not been observed in heart (4, 11, 43...

Glucocorticoids impair insulin sensitivity. Because insulin resistance is closely linked to increased incidence of cardiovascular diseases and given that metabolic abnormalities have been linked to initiation of heart failure, we examined the acute effects of dexamethasone (DEX) on rat cardiac metabolism. Although injection of DEX for 4 h was not associated with hyperinsulinemia, the euglycemichyperinsulinemic clamp showed a decrease in glucose infusion rate. Rates of cardiac glycolysis were unaffected, whereas the rate of glucose oxidation following DEX was significantly decreased and could be associated with augmented expression of PDK4 mRNA and protein. Myocardial glycogen content in DEX hearts increased compared with control. Similar to hypoinsulinemia induced by streptozotocin (STZ), hearts from insulin-resistant DEX animals also demonstrated enlargement of the coronary lipoprotein lipase (LPL) pool. However, unlike STZ, DEX hearts showed greater basal release of LPL and were able to maintain their high heparin-releasable LPL in vitro. This effect could be explained by the enhanced LPL mRNA expression following DEX. Our data provide evidence that in a setting of insulin resistance, an increase in LPL could facilitate increased delivery of fatty acid to the heart, leading to excessive triglyceride storage. It has not been determined whether these acute effects of DEX on cardiac metabolism can be translated into increased cardiovascular risk.

. Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am J Physiol Heart Circ Physiol 287: H1055-H1063, 2004. First published April 22, 2004 10.1152/ajpheart.00925.2003.-Adaptation of myocardial energy substrate utilization may contribute to the cardioprotective effects of regular exercise, a possibility supported by evidence showing that pharmacological metabolic modulation is beneficial to ischemic hearts during reperfusion. Thus we tested the hypothesis that the beneficial effect of regular physical exercise on recovery from ischemia-reperfusion is associated with a protective metabolic phenotype. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured in isolated working hearts from sedentary control (C) and treadmill-trained (T: 10 wk, 4 days/wk) female Sprague-Dawley rats submitted to 20 min ischemia and 40 min reperfusion. Training resulted in myocardial hypertrophy (1.65 Ϯ 0.05 vs. 1.30 Ϯ 0.03 g heart wet wt, P Ͻ 0.001) and improved recovery of function after ischemia by nearly 50% (P Ͻ 0.05). Glycolysis was 25-30% lower in T hearts before and after ischemia (P Ͻ 0.05), whereas rates of glucose oxidation were 45% higher before ischemia (P Ͻ 0.01). As a result, the fraction of glucose oxidized before and after ischemia was, respectively, twofold and 25% greater in T hearts (P Ͻ 0.05). Palmitate oxidation was 50 -65% greater in T than in C before and after ischemia (P Ͻ 0.05), whereas lactate oxidation did not differ between groups. Alteration in content of selected enzymes and proteins, as assessed by immunoblot analysis, could not account for the reduction in glycolysis or increase in glucose and palmitate oxidation observed. Combined with the studies on the beneficial effect of pharmacological modulation of energy metabolism, the present results provide support for a role of metabolic adaptations in protecting the trained heart against ischemia-reperfusion injury. exercise training; cardiac hypertrophy; ischemia-reperfusion; energy metabolism EPIDEMIOLOGICAL DATA clearly show that regular physical exercise exerts a protective effect against the morbidity and mortality associated with ischemic heart disease (34, 38, 44). Regular physical activity decreases the incidence of myocardial infarction (34,38,44). Furthermore, the survival rate after a myocardial infarction is greater in active individuals compared with sedentary ones (34).Several studies using trained rat models have demonstrated that these epidemiological observations can be at least partly attributed to a decreased susceptibility of the heart to ischemia-reperfusion injury (4, 5). In isolated heart perfusions, this translates into an improved recovery of contractile function (4, 5) and a reduction of cytosolic enzyme release (20) during reperfusion after global ischemia. Similar protective effects are also observed in models of left coronary occlusion in vivo: myocardial infarct size is reduced (30), pressure work is maintained at higher levels during and after ischemia (16,39),...

As with conventional AVR surgery, transcatheter AVR may result in impaired atrioventricular conduction. Physicians and patients should be aware of the potential for AV block and pacemaker dependence.

E osinophilic myocarditis (EM) is a rare, potentially fatal disease if left untreated. The spectrum of clinical presentation is wide. The present report describes three different clinical presentations of EM. It also demonstrates the response to steroid therapy with complete recovery of ventricular function and the disappearance of inflammatory cell infiltrate in a repeat endomyocardial biopsy (EMB). The incidence, etiology, histopathology, clinical manifestations, diagnosis, treatment and prognosis of EM are discussed. CASE PRESENTATIONS Case 1A 40-year-old man presented to the emergency department with a history of flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath. He had a 13-year history of psoriasis treated with topical steroids, phototherapy and intralesional steroids. He was not asthmatic, had no allergies and did not take any regular medications. There was no significant animal or bird exposure history. He was self-employed as a carpet cleaner.On arrival, he was in no acute distress, afebrile, with a heart rate of 90 beats/min and a blood pressure of 85/50 mmHg. A general physical examination was unremarkable except for a psoriatic plaque on the right leg without nail or joint involvement. Cardiovascular examination showed no jugular venous distension, gallops, rubs or murmurs.Blood work revealed only an elevated eosinophil count of 1.1×10 9 /L (normal values less than 0.4×10 9 /L) and troponin I of 46 µg/L (normal values less than 0.1 µg/L); the results of other laboratory tests are shown in Table 1. An electrocardiogram (ECG) revealed T wave inversion in the anterolateral leads, and the chest radiograph was normal. The diagnosis of acute coronary syndrome (ACS) was made and he was referred to a tertiary centre for selective coronary angiogram (SCA), which revealed normal coronary arteries. The echocardiogram showed mildly impaired global left ventricular (LV) systolic function with a visually estimated ejection fraction (EF) of 50%; there were no valvular lesions.The EMB showed changes of EM with inflammatory cell infiltrates that appeared to follow the interstitial and perivascular tissue planes and were also localized within the subendocardial tissues. The infiltrates were composed of mononuclear inflammatory cells, as well as eosinophils. In many locations, eosinophils were very prominent. Occasional myocytes showed degeneration or necrosis, but this was not a prominent feature. There was no vasculitis and no microorganisms were seen. Special stains for iron and amyloid were negative.The patient was started on oral prednisone at 1 mg/kg/day, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. At one-month follow-up, he had no recurrence of his initial symptoms, and the eosinophil count became normal at 0. Although the etiology of eosinophilic myocarditis (EM) is not always apparent, several causes are identified, including hypersensitivity to a drug or substance, with the heart as the target organ. However, symptoms and sign...

Thus, glycogen contributes significantly to aerobic myocardial glucose use under these experimental conditions, and the glucose derived from glycogen is oxidized preferentially compared with exogenous glucose. Additionally, substantial myocardial glycogen turnover occurs, and the manner in which glycogen is degraded does not fit the ordered hypothesis of "last glucose on, first glucose off."