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The failing human heart is unable to use the Frank-Starling mechanism
R H Schwinger1, M Böhm, A Koch
1Universität zu Köln, Medizinische Klinik III, Germany.
Insights
Human heart failure impairs the force-tension relationship, preventing the left ventricle from responding to increased preload. Ouabain treatment and increased sarcomere length failed to improve contractility in failing heart muscle.
Area of Science:
- Cardiology
- Muscle Physiology
- Biochemistry
Background:
- The Frank-Starling mechanism is crucial for regulating cardiac output.
- Human left ventricular failure is associated with impaired contractility.
- The underlying mechanisms of impaired contractility in heart failure are not fully understood.
Purpose of the Study:
- To compare the force-tension relationship in failing and nonfailing human myocardium.
- To investigate the role of preload and inotropic stimulation in cardiac contractility.
- To elucidate the subcellular mechanisms of impaired contractility in heart failure.
Main Methods:
- Isometric force of contraction measurements in electrically driven left ventricular papillary muscle strips.
- Studies of force-tension relations under various preload conditions.
- Analysis of skinned-fiber preparations to assess tension-calcium relations and calcium sensitivity.
Main Results:
- Failing myocardium showed an impaired force-tension relation, with no increase in contraction force upon increased preload.
- Ouabain restored the force-tension relation in failing myocardium.
- Skinned fibers from failing myocardium exhibited increased calcium sensitivity but failed to show length-dependent activation.
Conclusions:
- Human heart failure is characterized by an impaired force-tension relationship.
- Subcellularly, this impairment may stem from a failure of myofibrils to increase calcium sensitivity with increased sarcomere length.
Abstract:
There is evidence that the failing human left ventricle in vivo subjected to additional preload is unable to use the Frank-Starling mechanism. The present study compared the force-tension relation in human nonfailing and terminally failing (heart transplants required because of dilated cardiomyopathy) myocardium. Isometric force of contraction of electrically driven left ventricular papillary muscle strips was studied under various preload conditions (2 to 20 mN). To investigate the influence of inotropic stimulation, the force-tension relation was studied in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured after stretching the preparations to 150% of the resting length. To evaluate the length-dependent activation of cardiac myofibrils by Ca2+ in failing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction gradually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle length, or cross-sectional area of the muscles between both groups. Pretreatment with ouabain (0.02 mumol/L) restored the force-tension relation in failing myocardium and preserved the force-tension relation in nonfailing tissue. In skinned-fiber preparations of the same hearts, developed tension increased significantly after stretching only in preparations from nonfailing but not from failing myocardium. The Ca2+ sensitivity of skinned fibers was significantly higher in failing myocardium (EC50, 1.0; 95% confidence limit, 0.88 to 1.21 mumol/L) compared with nonfailing myocardium (EC50, 1.7; 95% confidence limit, 1.55 to 1.86 mumol/L). After increasing the fiber length by stretching, a significant increase in the sensitivity of the myofibrils to Ca2+ was observed in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing human myocardium. On the subcellular level, this phenomenon might be explained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.