Osadchii OE, Norton GR, McKechnie R, Deftereos D, Woodiwiss AJ. Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic ␤-adrenoreceptor activation. Am J Physiol Heart Circ Physiol 292: H1898 -H1905, 2007. First published December 8, 2006; doi:10.1152/ajpheart.00740.2006.-There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a ␤-adrenoreceptor agonist, for 3 mo to rats (0.1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic ␤-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as ␤ 1-and ␤2-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and ␤-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of ␣-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing ␤-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.isoproterenol; cardiac remodeling; contractility; inotropic responses THERE IS A STRONG RELATIONSHIP between increased cardiac chamber dimensions (cardiac dilatation) and poor clinical outcomes. In otherwise healthy people, cardiac chamber enlargement is associated with an increased morbidity and mortality (20,27) and the development of heart failure (34). Moreover, chamber dimensions predict clinical outcomes in patients with either mild or severe heart failure (19, 21, 32, 37). The contemporary explanation for the relationship between chamber dimensions and clinical outcomes is that chamber enlargement reflects a compensatory response of the failing myocardium to rest...

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