OBJECTIVE The goal of the present study was to examine the ability of failing myocardium to respond to enhanced preload with an increase in force development. METHODS The effect of various preload conditions (2.5-15 mN) on force development was studied in right ventricular trabeculae carneae from explanted human failing hearts with ischemic cardiomyopathy (ICM, n = 5, 42 preparations) or idiopathic dilated cardiomyopathy (DCM, n = 9, 77 preparations). To determine the severity of cardiac impairment we measured the positive inotropic effect of beta-adrenoceptor stimulation and calcium (ISO/Ca2+ ratio) and the expression of atrial natriuretic peptide (ANP) mRNA in all hearts. RESULTS (1) Force of contraction increased with stepwise augmentation of preload (length at 2.5 mN preload to length of maximal force development) from 3.7 +/- 0.5 (ICM) and 2.7 +/- 0.4 (DCM) to 8.3 +/- 0.9 and 6.5 +/- 0.8 mN/mm2, respectively (p < 0.05). (2) The ISO/Ca2+ ratio was 0.40 +/- 0.04 (ICM) and 0.35 +/- 0.03 (DCM), respectively. (3) ANP mRNA was expressed in all preparations, albeit at greatly varying levels (ICM 22.5 +/- 6.1 and DCM 18.7 +/- 4.7 normalized arbitrary units). (4) Contraction experiments performed in left ventricular tissue (n = 3, 32 preparations) essentially confirmed the results. CONCLUSIONS The Frank-Starling mechanism is preserved in terminally failing human hearts irrespective of the underlying etiology. We found no relation between the severity of cardiac impairment as assessed by either ANP expression or the ISO/Ca2+ ratio and the ability of failing human myocardium to respond to enhanced preload with an increase in force development.