THE FAILING HUMAN HEART IS UNABLE TO USE THE FRANK-STARLING MECHANISM

There is evidence that the failing human left ventricle in vivo subjec ted to additional preload is unable to use the Frank-Starling mechanis m. The present study compared the force-tension relation in human nonf ailing and terminally failing (heart transplants required because of d ilated cardiomyopathy) myocardium. Isometric force of contraction of e lectrically driven left ventricular papillary muscle strips was studie d under various preload conditions (2 to 20 mN). To investigate the in fluence of inotropic stimulation, the force-tension relation was studi ed in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured aft er stretching the preparations to 150% of the resting length. To evalu ate the length-dependent activation of cardiac myofibrils by Ca2+ in f ailing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction grad ually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle lengt h, or cross-sectional area of the muscles between both groups. Pretrea tment with oua-bain (0.02 mu mol/L) restored the force-tension relatio n in failing myocardium and preserved the force-tension relation in no nfailing tissue. In skinned-fiber preparations of the same hearts, dev eloped tension increased significantly after stretching only in prepar ations from nonfailing but not from failing myocardium. The Ca2+ sensi tivity of skinned fibers was significantly higher in failing myocardiu m (EC(50), 1.0; 95% confidence limit, 0.88 to 1.21 mu mol/L) compared with nonfailing myocardium (EC(50), 1.7; 95% confidence limit, 1.55 to 1.86 mu mol/L). After increasing the fiber length by stretching, a si gnificant increase in the sensitivity of the myofibrils to Ca2+ was ob served in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing hum an myocardium. On the subcellular level, this phenomenon might be expl ained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.