Abstract 19458: Left Ventricular Myofilament Mechanics and Crossbridge Kinetics in Patients With Hypertension and Type 2 Diabetes
Background: Hypertension and diabetes lead to complex changes in the myocardium, which may include altered myofilament mechanics. We studied differential adaptations in myofilament mechanics in patients with hypertension (Htn) and combined Htn + type 2 diabetes mellitus (DM) compared with controls (Cntl) without Htn or DM.
Methods: Myocardial tissue was obtained by intra-operative epicardial biopsy in male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction (7 HTN, 10 Htn+DM, 6 Cntl). Biopsies were dissected, demembranated, and attached between a length motor and force transducer at sarcomere length 2.2 μm and 37°C. Myofilaments were calcium activated from pCa 8 to pCa 4.5, and crossbridge kinetics were examined by small-amplitude sinusoidal length perturbation analysis.
Results: Half-maximal calcium concentration (pCa50) was similar in the three groups. Maximal calcium-activated isometric tension was lower (P<0.05) in Htn (11.2±1.2 mN/mm2) versus Cntl and Htn+DM (respectively, 20.2±2.7 and 18.6±1.8 mN/mm2). Concordantly, crossbridge-dependent stiffness under rigor conditions was reduced (P<0.05) in Htn (417±38 mN/mm2) versus Cntl and Htn+DM (respectively, 658±194 and 583±114 mN/mm2) indicating that the reduced isometric tension in Htn was due in part to reduced crossbridge stiffness. Crossbridge attachment time (Ton) was similar in the three groups at maximum calcium activation. However, Ton was prolonged (P<0.05) in Htn (14.7±1.7 ms) versus Cntl and Htn+DM (respectively, 9.9±0.7 and 10.4±0.9 ms) at pCa 6.5 and other calcium conditions between pCa 7–6.
Conclusions: These data suggest that crossbridge activation with prolonged Ton causes excessive diastolic “tone” under relaxed conditions and contributes to impaired diastolic function in males with Htn. The prolonged Ton in Htn reflects a slowed myosin detachment rate which may arise from reduced crossbridge stiffness, as we have observed in mouse cardiomyopathy models. Surprisingly, concomitant DM appears to either inhibit or reverse this abnormality. These findings reinforce the concept that alterations in myofilament mechanics that are not evident from measurement of pCa50 may play a role in abnormalities of diastolic function.
- © 2010 by American Heart Association, Inc.