Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.

Limited information is available about transmural heterogeneity in cardiac electrophysiology in man. The present study was designed to evaluate heterogeneity of cardiac action potential (AP), transient outward K+ current ( I to1) and inwardly rectifying K+ current ( I K1) in human right ventricle. AP and membrane currents were recorded using whole cell current- and voltage-clamp techniques in myocytes isolated from subepicardial, midmyocardial, and subendocardial layers of the right ventricle of explanted failing human hearts. AP morphology differed among the regional cell types. AP duration (APD) at 0.5–2 Hz was longer in midmyocardial cells (M cells) than in subepicardial and subendocardial cells. At room temperature, observed I to1, on step to +60 mV, was significantly greater in subepicardial (6.9 ± 0.8 pA/pF) and M cells (6.0 ± 1.1 pA/pF) than in subendocardial cells (2.2 ± 0.7 pA/pF, P < 0.01). Slower recovery of I to1 was observed in subendocardial cells. The half-inactivation voltage of I to1 was more negative in subendocardial cells than in M and subepicardial cells. At 36°C, the density of I to1 increased, the time-dependent inactivation and reactivation accelerated, and the frequency-dependent reduction attenuated in all regional cell types. No significant difference was observed in I K1 density among the regional cell types. The results indicate that M cells in humans, as in canines, show the greatest APD and that a gradient of I to1 density is present in the transmural ventricular wall. Therefore, the human right ventricle shows significant transmural heterogeneity in AP morphology and I to1properties.

Interpretation: Persistent postoperative pain of nonanginal origin after cardiac surgery affected a substantial proportion of the study population. Future research is needed to determine whether interventions to modify certain risk factors, such as preoperative anxiety and the severity of pain before and immediately after surgery, may help to minimize or prevent persistent postoperative pain. Abstract Research E214CMAJ, April 15, 2014, 186 (7)

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The prevalence, severity, and effect of chronic postoperative pain after cardiac surgery should not be underestimated. Longitudinal prospective studies are needed to further evaluate risk factors, including inadequate postoperative pain relief in the acute period.

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at −80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

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