Beck and back: a paradigm change in coronary sinus interventions--pulsatile stretch on intact coronary venous endothelium.

OBJECTIVES: Strategies to recover myocardium in therapeutically unresponsive patients are again under scrutiny, including techniques developed in the pioneering days of cardiothoracic surgery such as retroperfusion via the coronary sinus--the Beck procedure. An underestimated aspect of retroperfusion is the formation of new vessels. This early observation of neoangiogenesis may be an important mechanism in observed benefits. We hypothesized that periodic pressure elevation in coronary veins induces an analogy to shear stress angiogenic pulses by activating venous endothelium. Pulsatile stretch on venous endothelium can be achieved easily by a pressure-controlled intermittent balloon blockade of the coronary sinus outflow. METHODS: Three hours of myocardial ischemia was induced in 12 pigs. Pressure-controlled intermittent coronary sinus occlusion was applied in 6 animals 15 minutes after occlusion of the left anterior descending coronary artery. Postmortem myocardial specimens were taken, and heme oxygenase-1, vascular endothelial growth factor gene expression, and hypoxia-induced factor activity were measured. RESULTS: As compared with controls, treated animals released an angiogenic pulse by a 4-fold increase of heme oxygenase-1 gene expression in the infarct area (P < .001), together with a 2.5-fold enhanced transcription of vascular endothelial growth factor in the infarct (P < .006), border (P < .002), and remote (P < .02) areas, whereas hypoxia-induced factor activity was similar in both groups. A significant correlation (P < .01) of the achieved coronary sinus pressure elevation and gene expression was found. CONCLUSIONS: Mechanotransduction of pulsatile stretch on coronary venous endothelium by pressure-controlled intermittent coronary sinus occlusion induces heme oxygenase-1 and vascular endothelial growth factor gene expression, leaving the ischemic pathway of the hypoxia-induced factor activity unchanged. This cascade of molecular events closes the argument gap to historical reports of the Beck procedure on revascularization and myocardial salvage.

Prostaglandin E1 induces vascular endothelial growth factor-1 in human adult cardiac myocytes but not in human adult cardiac fibroblasts via a cAMP-dependent mechanism.

Prostaglandin E(1) (PGE(1)) has been used to treat pulmonary hypertension and peripheral artery occlusive disease and has been successfully employed for pharmacological bridging to transplantation in patients with chronic end-stage heart failure. In addition to its vasoactive effects PGE(1) was shown to stimulate angiogenesis in animal models. Recently we showed that PGE(1)-induced angiogenesis in hearts of patients with ischemic heart disease. We proposed that the angiogenic action of PGE(1) is mediated by vascular endothelial growth factor (VEGF). In the present paper we studied a possible effect of PGE(1) on the expression of VEGF-1 in cultured human adult cardiac myocytes (HACM) and cultured human adult cardiac fibroblasts (HACFB), respectively, to identify a cellular source of VEGF-1 in patients treated with PGE(1). We also aimed to delineate mechanisms involved in a possible regulation of VEGF-1 by PGE(1) in these cells. When HACM, isolated from human myocardial tissue, were treated with PGE(1), a significant up to 3-fold increase in VEGF-1 production could be observed. These results could be confirmed on the level of specific mRNA expression as determined by real-time polymerase chain reaction. The effect of PGE(1) on VEGF-1 expression could be blocked by H089, an inhibitor of cAMP-dependent protein kinase A. In HACFB, also isolated from human myocardial tissue, no effect of PGE(1) on VEGF-1 production was seen. If this effect of PGE(1) is also operative in the in vivo situation, one could speculate that cardiac myocytes could be a cellular source of PGE(1)-induced VEGF-1 expression in patients treated with this drug.