Myocardial mechanical load induced by increased preload or afterload is a strong trigger for myocardial remodeling and maladaptation. The acute inotropic force response is characterized by the Frank-Starling mechanism and the slow force response. We hypothesized that the acute force response in human myocardium adapts with repetitive increases in mechanical load. Myocardial muscle strips were isolated from atrial and ventricular myocardium obtained as excess tissue during planned cardiac surgery.

Strips were mounted in a force transducer and gradually stretched to obtain maximal force response (100%) and total relaxation reserve (TRR; reduction in diastolic tension with a step to 88% maximal length). Length was altered from 88% (rest, recovery) to 98% (load) of the maximal force response (1 Hz stim). Protocols included 15 min of load (index stretch, IS) followed by 10 min of recovery (IR) without or with a 15 min preconditioning stretch (PS) followed by 10 min of recovery (PR) before IS.

In human ventricular myocardium we observed a significant increase in developed force between the IS and PS at 1 and 5 min, but not at 15 min. In addition, diastolic tension was significantly lower  (on average by 6.6±4.9% of TRR compared to PS, n= 15 strips from 11 patients) and single beat relaxation was significantly faster in IS (on average 8.2±7% lower single beat relaxation constant compared to PS). Comparing IS in parallel experiments without and with PS confirmed improved lusitropy with preconditioning. We also observed lower diastolic tension in the recovery phase (IR vs. PR (on average by 3.3±3.3% of TRR compared to PR) and IR with vs. IR without mechanical preconditioning), but no change in developed force and single beat relaxation during recovery. Interestingly, mechanical preconditioning was not observed in human atrial myocardium (n= 19 strips from 12 patients). We currently explore the impact of mitochondrial Ca2+ uptake (Ru360) and the late sodium current (ranolazine) on mechanical preconditioning in human myocardium.

In summary, human ventricular but not atrial myocardium acutely adapts to a repetetive increase in mechanical load.