Impact of blood factors on endothelial cell metabolism and function in two diverse heart failure models.

Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. We tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects.

Metabolomic analysis of serum and myocardium in compensated heart failure after myocardial infarction.

Aims: To determine the metabolic adaptations to compensated heart failure using a reproducible model of myocardial infarction and an unbiased metabolic screen. To address the limitations in sample availability and model variability observed in preclinical and clinical metabolic investigations of heart failure.

Main Methods: Metabolomic analysis was performed on serum and myocardial tissue from rabbits after myocardial infarction (MI) was induced by cryo-injury of the left ventricular free wall.

Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes.

Intracoronary delivery of an adenovirus encoding fibroblast growth factor-4 in myocardial ischemia: effect of serum antibodies and previous exposure to adenovirus.

The presence of anti-adenoviral serotype 5 (Ad5) antibodies may limit the efficacy of Ad5-mediated gene transfer. We therefore tested the hypothesis that intracoronary delivery of an adenovirus encoding human fibroblast growth factor type 4 (Ad5.FGF4) would improve regional myocardial function in an animal model of ischemia when high antibody levels preexist or after a prior intracoronary dose of Ad5.

Nitroprusside increases gene transfer associated with intracoronary delivery of adenovirus.

Efficient gene transfer by vectors that can be easily delivered to target organs is desirable in clinical gene therapy. We tested the hypothesis that intracoronary infusion of the nitric oxide donor nitroprusside would increase the efficiency of adenovirus vector-mediated gene transfer to the heart. Intracoronary delivery of an adenovirus encoding murine adenylyl cyclase type VI (Ad.

Myocardial gene transfer and long-term expression following intracoronary delivery of adeno-associated virus.

Adeno-associated viral vectors (AAV) can direct long-term gene expression in post-mitotic cells. Previous studies have established that long-term cardiac gene transfer results from intramuscular injection into the heart. Cardiac gene transfer after direct intracoronary delivery of AAV in vivo, however, has been minimal in degree, and indirect intracoronary delivery, an approach used in an increasing number of studies, appears to be receiving more attention.

Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data.

This paper reports the preclinical data that were used to support clinical trials of intracoronary delivery of a replication-incompetent human adenovirus-5 vector encoding human fibroblast growth factor 4 (Ad5FGF4). Using stress-induced myocardial ischemia in pigs, intracoronary injection of Ad5FGF4 resulted in mRNA and protein expression of the transferred gene. Two weeks after gene transfer, regional stress-induced dysfunction and perfusion were ameliorated and improved function persisted for at least 12 weeks.

Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials.

The current published clinical literature on angiogenic gene therapy for the treatment of myocardial ischemia does not include a single randomized, placebo-controlled trial. Based on current clinical literature, it is an unproven therapy. Successful animal studies combined with published reports of good outcomes in patients enrolled in uncontrolled trials has led to the expectation that angiogenic gene therapy will ultimately become a clinical reality.

Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity.

Background: We tested the hypothesis that intracoronary injection of a recombinant adenovirus encoding adenylyl cyclase type VI (AC(VI)) would increase cardiac function in pigs.

Methods And Results: Left ventricular (LV) dP/dt and cardiac output in response to isoproterenol and NKH477 stimulation were assessed in normal pigs before and 12 days after intracoronary delivery of histamine followed by intracoronary delivery of an adenovirus encoding lacZ (control) or AC(VI) (1.4x10(12) vp).

Pulmonary gas exchange during exercise in pigs.

Increased ventilation-perfusion (VA/Q) inequality is observed in approximately 50% of humans during heavy exercise and contributes to the widening of the alveolar-arterial O2 difference (A-aDO2). Despite extensive investigation, the cause remains unknown. As a first step to more direct examination of this problem, we developed an animal model.

Angiotensin II blockade followed by growth hormone as adjunctive therapy after experimental myocardial infarction.

Background: Recombinant human growth hormone (rhGH) has shown beneficial effects on cardiac function after myocardial infarction (MI) in rats. High-dose angiotensin II (AT1) receptor blockade in normal rats inhibited the hypertrophic effect of growth hormone (GH), therefore we investigated whether GH effects after MI would be enhanced by giving it in sequence after remodeling had been inhibited by prior AT1 blockade (losartan, L).

Methods And Results: Rats given losartan for 10 weeks after MI followed by rhGH for 2 weeks (2 mg/kg twice a day, GH plus losartan) were compared with rats given losartan for 10 weeks followed by placebo for 2 weeks (placebo plus losartan group) and with untreated controls (n = 17-20/group).

Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart.

Exercise training induces coronary vascular adaptations. The goal of this study was to contrast the effects of training on capillary and arteriolar growth. Minipigs were trained for 1, 3, 8, and 16 wk and compared with controls.

Increased gene expression of plasminogen activators and inhibitors in left ventricular hypertrophy.

In the early stages of left ventricular hypertrophy (LVH) acute adaptive changes occur in the coronary vasculature as it remodels. Plasminogen activators (PAs) and inhibitors (PAIs) have the potential effects of proteolytic degradation that is relevant to tissue remodeling and angiogenesis. Our study focused on the possible roles of PAI-1, PAI-2, and uPA in tPA in myocyte hypertrophy and angiogenesis in the early and late stages of pressure overload induced left ventricular hypertrophy (LVH).

Regional deficits of myocardial blood flow and function in left ventricular pacing-induced heart failure.

Background: Pacing-induced congestive hear, failure has become a preferred model for the study of the pathogenesis of dilated cardiomyopathy. However, little is known regarding regional myocardial blood flow and function during the development of heart failure in this model.

Methods And Results: To determine whether regional differences in myocardial blood flow are associated with regional dysfunction in ventricular pacing-induced heart failure, regional myocardial blood flow (radioactive microspheres) and regional wall thickening (transthoracic echocardiography) were measured in pigs studied at weekly intervals during the progression of heart failure induced by rapid pacing from the lateral wall of the left ventricle (220 +/- 9 bpm for 26 +/- 4 days).

Hypertonic saline/dextran treatment for severe pressure-driven hemorrhage in dehydrated conscious swine.

Although dehydration impairs the response to a fixed volume hemorrhage, both 7.5% hypertonic saline/6% dextran 70 (HSD: 4 mL/kg) and standard Ringer's lactate (33 mL/kg) are effective resuscitation fluids. However, the efficacy of resuscitation during continuing hemorrhage remains in question.

Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat.

Background: Insulin-like growth factor-1 (IGF-1) appears to have favorable cardiac effects associated with left ventricular remodeling early after myocardial infarction in the rat. The present study was designed to determine whether IGF-1 combined with growth hormone would be beneficial later as well, when infarct healing and cardiac remodeling have occurred.

Methods And Results: Four weeks after coronary occlusion, 36 rats were randomized to IGF-1 (3 mg.

Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart.

Increased coronary blood vessel development could potentially benefit patients with ischemic heart disease. In a model of stress-induced myocardial ischemia, intracoronary injection of a recombinant adenovirus expressing human fibroblast growth factor-5 (FGF-5) resulted in messenger RNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved, effects that persisted for 12 weeks.

Nitric oxide synthesis inhibition does not improve the hemodynamic response to hemorrhagic shock in dehydrated conscious swine.

Nitric oxide (NO) may influence the hemodynamic response to hemorrhage. To test this hypothesis, the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was administered to conscious, dehydrated swine during a 37% blood volume hemorrhage and a 180 min recovery period without fluid resuscitation. L-NAME (.

Myocardial high-energy phosphate and substrate metabolism in swine with moderate left ventricular hypertrophy.

Background: Although left ventricular hypertrophy (LVH) is frequently associated with impaired coronary vasodilator reserve, it is uncertain whether this leads to myocardial ischemia under physiological conditions. The goal of the present study was to determine whether swine with moderate LVH exhibit metabolic evidence of ischemia when myocardial oxygen requirements are increased.

Methods And Results: Myocardial metabolism was evaluated in an open-chest anesthetized preparation at baseline and during dobutamine infusion in 13 adolescent pigs with moderate LVH induced by supravalvular aortic banding and 12 age-matched control pigs.

Hypertonic saline/dextran versus lactated Ringer's treatment for hemorrhage in dehydrated swine.

To determine the efficacy of low-volume resuscitation in dehydrated subjects, 7.5% hypertonic saline/6% dextran 70 (HSD) and lactated Ringer's (LR) treatments were compared in conscious pigs dehydrated for 48 hr prior to a 37% blood volume hemorrhage. Pigs randomized to treatment were resuscitated with equivalent sodium loads of either HSD (4 ml/kg) or LR (33.

Clinical significance of coronary vascular adaptations to exercise training.

Coronary vascular adaptations to exercise training have been extensively studied at the microscopic level in animals and correlated with direct and indirect measurements of myocardial blood flow in patients with coronary artery disease. Animals have permitted more extensive study. These findings have generally supported an increased blood flow to the myocardium with exercise training.

Effects of dobutamine and arbutamine on regional myocardial function in a porcine model of myocardial ischemia.

Objectives: The present study was performed to determine the mechanisms for catecholamine-induced wall motion abnormalities and to compare the diagnostic efficacy of two catecholamines: arbutamine and dobutamine.

Background: Catecholamine stress echocardiography is used to induce regional wall motion abnormalities for the detection of coronary artery disease, but the mechanism by which these abnormalities occur is unknown.

Methods: Ten pigs were instrumented with left circumflex coronary artery ameroid constrictors, sonomicrometers to measure transmural wall thickening in the left circumflex (ischemic) and left anterior descending (control) coronary artery beds and a pressure gauge to measure left ventricular pressure and its first derivative (dP/dt).

Factors associated with vasopressin release in exercising swine.

This study examined the effect of dynamic exercise on vasopressin release in the miniswine and factors that may elicit this response (n = 15). Thus lysine vasopressin (LVP), the catecholamines epinephrine and norepinephrine (EPI and NE), plasma renin activity (PRA), and plasma volume, Na+, and osmolality were measured before and during treadmill running at work intensities of 60, 80, and 100% of each swine's maximal heart rate reserve (HRR). LVP increased in a progressive manner similar to that of humans, ranging from 5.

Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia.

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery.

Effects of feeding on muscle blood flow during prolonged exercise in miniature swine.

Eight exercise-trained miniature swine were studied during prolonged treadmill runs (100 min) under fasting and preexercise feeding conditions. Each animal ran at identical external work loads that corresponded to 65% of the heart rate reserve (210-220 beats/min) for the two exercise bouts. Cardiac outputs and stroke volumes were higher and heart rates lower for fed than for fasting runs (P less than 0.