Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure

Objective: Myocardial cellular electrophysiology and intracellular Ca2+ reg ulation are altered in heart failure. The extent of these changes may vary within the layers of the ventricular wall. To examine this, cell size, acti on potential and intracellular Ca2+ transient characteristics (Fura-2) were measured in single cardiac myocytes from sub-epicardial, mid-myocardial, a nd sub-endocardial regions of the left ventricle of rabbits with heart fail ure. Methods: Myocytes were isolated from animals with heart failure induce d by chronic coronary artery ligation and from sham operated controls. Tran s-membrane potential was measured using high resistance microelectrodes ele ctrodes (30 M Omega; 2 M KCl). Fura-2 was loaded into cells by incubation w ith the AM form. Subsequent fluorescence measurements were used to measure intracellular Ca2+ concentration at a range of stimulus frequencies. Result s: Resting cell length was significantly greater in the heart failure group ; similar to 115% of control values in sub-epicardial and mid-myocardial ce lls, and similar to 108% in sub-endocardial cells. Using criteria described by previous studies on other mammalian hearts, functional M cells were ide ntified by a higher maximum rare of depolarisation and longer action potent ial duration at 90% repolarisation(APD(90)) compared to the two other myocy te sub-types. In the heart failure group, APD(90) and Ca2+ transient durati on (CaD50) were prolonged in sub-epicardial and M cells but shortened in su b-endocardial myocytes. These changes were significant at lower stimulus fr equencies, but the relative effect diminished at higher frequencies (3 Hz). Peak systolic [Ca2+] was reduced in sub-epicardial and M cells but increas ed in sub-endocardial cells in the heart failure group compared to controls . At higher stimulus frequencies, end diastolic Ca2+ levels were lower in s ub-epicardial cells but higher in sub-endocardial myocytes of the heart fai lure group compared with controls. Ln general, changes were greater in hear t failure animals with more severe in vivo ventricular dysfunction (ejectio n fraction less than or equal to 44%). Conclusions: Heart failure was assoc iated with an increased cell size throughout the left ventricle, but the fo rm of the changes in electrophysiology and Ca2+ transient were dependent on the myocyte sub-type. In particular sub-endocardial cells displayed marked ly different changes compared to the other myocyte sub-types. (C) 2000 Else vier Science B.V. All rights reserved.