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The Otsuka Long-Evans Tokushima fatty rat is an animal model of Type 2 diabetes mellitus (DM), which is characterized by diastolic dysfunction associated with decreased sarcoplasmic reticulum [Ca.sup.2+]-ATPase (SERCA2a). The aim of this study was to examine whether gene transfer of SERCA2a can influence coronary blood flow and cardiomyocyte diameter in this model. DM rats were injected with adenovirus carrying SERCA2a (DM+SERCA) or [beta]-galactosidase gene (DM+[beta]Gal). Coronary blood flow was measured in cross-circulated excised hearts 3 days after infection. Although in all groups coronary blood flow remained unchanged even if left ventricular (LV) volume or intracoronary [Ca.sup.2+] infusion was increased, the DM+SERCA group showed a sustained increase in coronary blood flow compared with the other groups. This result suggests that the sustained high coronary blood flow is a specific response in SERCA2a-overexpressed hearts. Although the LV weight-to-body weight ratio (LV/BW) and cardiomyocyte diameter were higher in the DM and DM+[beta]Gal groups than in the non-DM group, in the DM+SERCA group, these measurements were restored to non-DM size. The percentages of collagen area in the three DM groups was significantly higher than results shown in non-DM rats, and there were no significant differences in collagen area percentage among the three DM groups. These results suggest that a lowered LV/BW by SERCA2a overexpression is due mainly to reduced size of cardiomyocytes without any changes in collagen area percentage. In conclusion, in DM failing hearts, SERCA2a gene transfer can increase coronary blood flow and reduce cardiomyocyte size without reduction in collagen production. gene therapy; heart failure; diabetes mellitus; cardiomyocyte hypertrophy

We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 [micro]g/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 [micro]g/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone (n = 10). After 8 wk of treatment, the animals underwent eehocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density (P < 0.05) and by a higher number of EPC (P < 0.05). Both darbepoetin doses increased the hematocrit, whereas Mi+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone. erythropoietin; cardioprotection; myocardial infarction; remodeling; cells

The octapeptide angiotensin II (ANG II) can modulate cardiac contractility and is increased in heart failure, where contractile function is impaired. In rat cardiac myocytes, 1 [micro]M of ANG II produces a negative inotropic effect (NIE) (24.6 [+ or -] 5% reduction). However, the subcellular signaling involved in this effect remains elusive. We examined the mechanisms and signaling events involved in the reduction in contractile function induced by the peptide in indo-1-loaded rat cardiomyocytes. The results showed that the NIE of ANG II was not associated with a parallel decrease in the intracellular [Ca.sup.2+] transient, indicating that a decrease in myofilament responsiveness to [Ca.sup.2+] underlies the reduction in contractility. We assessed the role of PKC, tyrosine kinases, reactive oxygen species (ROS), and mitogen-activated protein kinases (MAPKs) in the NIE of the peptide. Pretreatment of ceils with the NAD(P)H oxidase inhibitor diphenyleneiodonium chloride or with the superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid did not affect the ANG II-induced NIE. Moreover, ANG II-induced ROS production, after 20 min of incubation with the peptide, could not be detected with the use of either the fluorophore 5-(6)-chloromethyl-2', 7'-dichlorodihydrofluorecein diacetate or lucigenin-enhanced chemiluminescence. In contrast, the ANG II-induced NIE was abrogated by the inhibitors of PKC (calphostin C), tyrosine kinase (genistein), and p38 MAPK (SB-202190). Furthermore, the NIE was significantly exacerbated (60 [+ or -] 10% reduction) by p38 MAPK overexpression. These results exclude the participation of ROS in the NIE of the peptide and point to PKC and tyrosine kinase as upstream mediators. Furthermore, they reveal p38 MAPK as the putative effector of the reduction in myofilament responsiveness to [Ca.sup.2+] and the decrease in contractility induced by the peptide. myocardium; calcium transients; mitogen-activated protein kinase

The purpose of this study is to evaluate the feasibility of percutaneous antegrade myocardial gene transfer (PAMGT). A consistent and sate technique for in vivo gene transfer is required for clinical application of myocardial gene therapy. PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and alter adenosine (25 [micro]g) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of [10.sup.11] plaqueforming units in each coronary artery) carrying [beta]-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n = 9); in another set of animals, PAMGT was performed without coronary vein blockade (n = 5). At 1 wk after gene delivery, the animals were killed. Quantitative [beta]-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative [beta]-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. [beta]-Galactosidase activity increased significantly in the [beta]-galactosidase group compared with the saline group: 1.34 [+ or -] 0.18 vs. 0.81 [+ or -] 0.1 ng (P [less than or equal to] 0.01) in the left ventricular wall and 0.91 [+ or -] 0.1 vs. 0.66 [+ or -] 0.07 ng (P [less than or equal to] 0.05) in the right ventricular wall. PAMGT with selective coronary venous blockade is feasible, reproducible, and safely achieved in a large-animal model. gene therapy; catheterization; balloon; occlusion

Researchers have found two genetic variants that predispose people to congestive heart failure. Genetic variants are often called polymorphisms. Both the gene variations would cause excessive stimulation of the heart by epinephrine and norepinephrine. This would also explain why some patients with congestive heart failure do not respond to ACE inhibitors and beta blockers.

A 55-year-old man with chest pain and a heart arrhythmia called second-degree heart block was diagnosed with Lyme disease that affected his heart. Lyme disease is caused by a bacterium that is transmitted by ticks.

Alterations in cAMP-dependent phosphorylation of phospholamban were investigated to ascertain whether they cause reduced SR Ca2+-ATPase activity in human heart failure. Compared with nonfailing human myocardium, protein levels of phospholamban and SR Ca2+-ATPase were unchanged. The results showed that the impaired SR function in human end-stage heart failure may be attributed to a reduction in cAMP-dependent phosphorylation of phospholamban.