Harvey A. Lardin

Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity

Rationale: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (INa), reducing the net cytosolic Ca2+ efflux. Objective: Oxidative stress in the DOCA-salt model may increase late INa, resulting in diastolic dysfunction amenable to treatment with ranolazine. Methods and Results: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E′:sham, 31.9±2.8, sham+ranolazine, 30.2±1.9, DOCA-salt, 41.8±2.6, and DOCA-salt+ranolazine, 31.9±2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16±0.01 versus sham+ranolazine, 0.18±0.01 versus DOCA-salt, 0.23±0.2 versus DOCA-salt+ranolazine, 0.17±0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, &tgr;, improving with ranolazine (DOCA-salt, 0.18±0.02, DOCA-salt+ranolazine, 0.13±0.01, sham, 0.11±0.01, sham+ranolazine, 0.09±0.02 seconds; P=0.0004). Neither late INa nor the Ca2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca2+ response and cross-bridge kinetics. Conclusions: Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.

The Relationship between Ventricular Repolarization Duration and RR Interval in Normal Subjects and Patients with Myocardial Infarction

Objectives: When either ventricular myocardium becomes ischemic or autonomic nervous system activity changes with age, the relationship between ventricular repolarization duration and RR interval will change as well. We studied the relationship between ventricular repolarization duration and RR interval among normal subjects in different age groups and between patients with myocardial infarction (MI) and age-matched healthy subjects. Methods: Ventricular repolarization duration variability (RDV) spectra were separated into RR-dependent and RR-independent components. We compared spectral measures among normal subjects in different age groups and between patients with MI and age-matched healthy subjects. Results: The RR-dependent component of RDV spectra, which is correlated with autonomic nervous system activity, significantly decreased with age for healthy subjects. The RR-independent component significantly increased in MI patients compared to age-matched healthy subjects. Conclusions: We demonstrated the increase in RDV upon decreasing age and in the presence of MI. Our results support the idea that the RR-dependent part corresponds to the physiology-related part of the RDV spectra and the RR-independent part corresponds to the pathology-related part of the RDV spectra. Our study suggests that these spectral measures are likely to be helpful in the evaluation of a patient with MI and merit further investigation.