Published online before print February 7, 2005, doi: 10.1161/01.CIR.0000155257.33485.6D
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(Circulation. 2005;111:774-781.)
© 2005 American Heart Association, Inc.
Heart Failure |
Cardiomyocyte Stiffness in Diastolic Heart Failure
From the Laboratory for Physiology (A.B., J.v.d.V., J.G.F.B., G.J.M.S., W.J.P.), Institute for Cardiovascular Research, VUMC, Amsterdam, the Netherlands, and the Division of Clinical Physiology (A.B., Z.P., I.E.), Institute of Cardiology, UDMHSC, Debrecen, Hungary.
Correspondence to Prof Dr Walter J. Paulus, Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7,1081 BT Amsterdam, The Netherlands. E-mail wj.paulus{at}vumc.nl
Received August 24, 2004; revision received October 25, 2004; accepted November 5, 2004.
Background— Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance.
Methods and Results— DHF patients (n=12) had an LVEF of 71±11%, an LV end-diastolic pressure (LVEDP) of 28±4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5±4.0%, P<0.05) than did controls (n=8, 3.8±2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 µm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (Fpassive) in the absence of Ca2+ was almost twice as high (6.6±3.0 versus 3.5±1.7 kN/m2, P<0.001). Fpassive and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered Fpassive to control values.
Conclusions— DHF patients had stiffer cardiomyocytes, as evident from a higher Fpassive at the same sarcomere length. Together with CVF, Fpassive determined in vivo diastolic LV dysfunction. Correction of this high Fpassive by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.
Key Words: diastole • heart failure • myocytes • contractility • collagen
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