Purpose: We conceptualized that hemodynamic changes induced by a simple trans-coronary sinus catheter intervention induce regenerative molecular pathways. During normal embryonic development hemodynamic pressure in the primitive beating heart tube is sensed by endocardial layers transducing this "mechanical" epigenetic information as normal developmental impulse enhancing structural maturation. Mechanotransduction induced by temporal elevation of blood pressure in cardiac veins by PICSO is believed to be the central signal in this process reopening the morphogenetic gate to reenter cardiac development thus inducing structural regeneration.
Methods: Patients were treated with PICSO after electrode testing during CRT placement for 20 minutes. Serum of PICSO and control patients was collected before and after the intervention or the equivalent time in controls. Septal cardiomyocytes of a heart transplant recipient with dilated cardiomyopathy were excised during heart transplantation and cultured. Serum of study patients was then co-cultivated and pre and post-interventional values were compared to controls. Furthermore HCM57 cardiomyocytes were incubated with patient's serum with or w/o PICSO treatment, pre- and post PM implantation and the time course of KLF-4 protein levels after PICSO-treated serum incubation compared to control serum.
Results: A significant enhancement of cardiomyocyte proliferation was observed when cocultivated with patient serum treated with PICSO as compared to pre-intervention and both control values. There was also a significant upregulation of the pluropotency marker KLF-4 protein in probes co-cultivated with PICSO sera coinciding with a 72% reduction in mortality in treated patients followed over 5 years.
Conclusion: Here we show that molecular and clinical evidence emphasizes the proposed hypothesis. The revival of an imbedded albeit dormant developmental process in the human adult and failing heart via activation of coronary venous endothelium can be restored. Proliferation of cardiomyopathic cardiomyocytes and the expression of pluripotent signaling molecules are surrogates indicating structural recovery. Reduction in mortality shown here close the gap between molecular findings and clinical significance. Although these data have to be corroborated in a large multicenter Trial, the ease of the intervention with a simple catheterization of the coronary sinus and with manageable treatment times ensure the great potential that a solution for the conundrum of cardiac regeneration might be within clinical reach.