Background-The process of arteriogenesis after occlusion of a major artery is poorly understood. We have used high-resolution microcomputed tomography (-CT) imaging to define the arteriogenic response in the mouse model of hindlimb ischemia and to examine the effect of placental growth factor-1 (PlGF-1) on this process. Methods and Results-After common femoral artery ligation, -CT imaging demonstrated formation of collateral vessels originating near the ligation site in the upper limb and connecting to the ischemic calf muscle region. Three-dimensional -CT and quantitative image analysis revealed changes in the number of segments and the segmental volume of vessels, ranging from 8 to 160 m in diameter. The medium-size vessels (48 to 160 m) comprising 85% of the vascular volume were the major contributor (188%) to the change in vascular volume in response to ischemia. Intramuscular injections of Ad-PlGF-1 significantly increased Sca1 ϩ cells in the circulation, ␣-actin-stained vessels, and perfusion of the ischemic hindlimb. These effects were predominantly associated with an increase in vascular volume contributed by the medium-size (96 to 144 m) vessels as determined by -CT. Conclusions-High-resolution -CT delineated the formation of medium-size collaterals representing a major vascular change that contributed to the restoration of vascular volume after ischemia. This effect is selectively potentiated by PlGF-1. Such selective enhancement of arteriogenesis by therapeutically administered PlGF-1 demonstrates a desirable biological activity for promoting the growth of functionally relevant vasculature.

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Aims Activation of phosphoinositide‐3 kinase (PI3K) is essential for cell growth, relating to adaptive and maladaptive cardiac hypertrophy. This longitudinal canine study was designed to investigate the role of PI3Kα and PI3Kγ in cardiac remodelling during congestive heart failure (CHF) and cardiac recovery (CR). Methods and results All dogs were surgically instrumented. Congestive heart failure was induced by cardiac pacing for 3–4 weeks and CR was allowed by terminating pacing for 5–6 weeks after induction of HF. Control dogs had sham surgery, but did not undergo pacing. Left ventricular (LV) contractile function was depressed in CHF and restored to 80–90% of the normal level in CR, with a 25% increase in LV weight. The expression of PI3Kγ was increased four‐fold in CHF, but returned to control levels in CR. In contrast, the expression of PI3Kα in CHF was not different from that in controls, but increased three‐fold in CR and was accompanied by increases in phosphorylation of Akt (five‐fold), GSK‐3β (five‐fold), β‐catenin (three‐fold), mTOR (two‐fold), and P70S6K (two‐fold). Conclusion Our results indicate that PI3K isoforms are regulated differently during the course of CHF/CR and that the selective activation of PI3Kα, through Akt, GSK‐3β, and mTOR signalling pathways, may be involved in the development of cardiac compensatory hypertrophy and functional restoration.

We compared the cardiac inotropic, chronotropic, and myocardial O 2 consumption (MVO 2 ) responses to the sodium (Na ϩ ) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenylmethyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the ␤-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10 -100 g/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt max (55 Ϯ 7%), and fractional shortening (62 Ϯ 9%), accompanied by increases in cardiac stroke work (111 Ϯ 18%) and minute work (34 Ϯ 10%) and decreases in heart rate (33 Ϯ 4%). Dobutamine (2-15 g/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 Ϯ 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 g/kg/min) increased MVO 2 by 23 Ϯ 7% (P Ͻ 0.05), whereas LY341311 (100 g/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO 2 was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O 2 utilization in the failing heart while providing inotropic support comparable to a ␤-receptor-mediated agonist.A variety of therapeutic strategies have been applied to augment the depressed left ventricular function of heart failure, particularly during periods of acute decompensation (Packer, 1988;Rahimtoola, 1989;Shipley and Hess, 1995). Current clinically available inotropic agents that act via elevation of cyclic AMP, such as dobutamine and phosphodiesterase inhibitors; are associated with tachycardia, significant changes in preload or afterload or increases in myocardial O 2 consumption (MVO 2 ), and decreases in myocardial mechanical efficiency (Katz, 1986;Simaan et al., 1988). Recently, there has been interest in agents that either increase myofibrillar Ca 2ϩ availability or directly sensitize myocardial cells to Ca 2ϩ without the participation of cAMP (Ruegg, 1986;Doggrell et al., 1994;Mathew and Katz, 1998). One strategy has been the development of Na ϩ channel enhancers that prolong the open state of Na ϩ channels, increasing net Na ϩ influx and the activity of reverse mode Na ϩ /Ca 2ϩ exchange (for review, see Steinberg et al., 1998). This leads to a decrease in net Ca 2ϩ efflux and increases in intracellular free Ca 2ϩ (Romey et al., 1987;Scholtysik, 1989). Sodium channel enhancers have been shown to elicit positive inotropic effects in isolated cardiac tissues from experimental animals and from human papillary muscles obtained from normal as well as...

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(min)) decreased by 25 +/- 2% (P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 +/- 5% and 25 +/- 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) increased by 62 +/- 10% (P < 0.05) and the stiffness constant (k) increased by 66 +/- 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 +/- 25% and 63 +/- 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.