Abstract
Cardiac regeneration remains a clinical target regardless of numerous therapeutic concepts. We formulated a hypothesis claiming that periodic coronary venous pressure elevation (PICSO; Pressure controlled Intermittent Coronary Sinus Occlusion) initiates embedded, but dormant developmental processes in adult jeopardized hearts. Hemodynamics in the primitive beating heart tube is sensed transducing “mechanical” epigenetic information during normal cardiac development. In analogy mechanotransduction via shear stress and pulsatile stretch induced by periodic elevation of blood pressure in cardiac veins reconnects this dormant developmental signal, setting regenerative impulses in the adult heart. Significant increase of hemeoxygenase-1 gene expression (p < 0.001) and vascular endothelial growth factor (VEGF) (p < 0.002) as well as production of VEGRF2 in experimental infarction underscores the resurgence of developmental stimuli by PICSO. Molecular findings correspond with risk reduction (p < 0.0001) in patients with acute coronary syndromes as well as observations in heart failure patients showing substantial risk reduction up to 5 years endorsing our hypothesis and preclinical experience that PICSO via hemodynamic power activates regenerative processes also in adult human hearts. These results emphasize that our proposed hypothesis “embryonic recall” claiming revival of an imbedded albeit dormant “epigenetic” process is able not only to sculpture myocardium in the embryo, but also to redesign structure in the adult and failing heart.
Highlights
Mammalian hearts are complex in development, structure and function
Syncytial cardiomyocytes slide along fibrous septations, electrical signals travel in preformed specialized cells and valves close and open ejecting blood according to contractile forces and circulatory demand
Is a re-activation of imprinted developmental processes per se able to restart programs able to recover the dys-functioning adult heart [6]? This implicates that we reopen the door of an embryonic process in a very early stage, so that signals originating from this procedure rewire developmental steps regaining structural integrity
Summary
Mammalian hearts are complex in development, structure and function. From single heart tubes spatiotemporal gene expression patterns, cytoplasmatic gradients, signaling of various origin, cellular migration, transformations and even epigenetic influences as local hemodynamics add to the ultimate heart design. It is not surprising that this unique organ needs cellular homeostasis to guarantee longlasting adaptive function. What is little appreciated is the fact that even in this tight structural straightjacket, 50% of cardiomyocytes are renewed during a lifespan of individual humans showing that the basic principles of regeneration per se persist in adult hearts [2]. It may very likely be, that paracrine signals originating from the ―non cardiomyocytes‖ and extracellular matrix might be the ―controller‖ of coordinated repair [1,2,3]. Several concepts spanning from genetic engineering, cellular reprogramming and stem cell transplantation have been tried, some of them reaching the clinical arena under scrutiny of randomized trials [5]
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