Prospective randomized comparison of the safety and effectiveness of placement of endocardial pacemaker and defibrillator leads using the extrathoracic subclavian vein guided by contrast venography versus the cephalic approach.

The purpose of this prospective randomized study was to compare the safety and efficacy of the cephalic approach versus a contrast-guided extrathoracic approach for placement of endocardial leads. Despite an increased incidence of lead fracture, the intrathoracic subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by lead placement in the extrathoracic subclavian or axillary vein, these approaches have not gained acceptance. A total of 200 patients were randomized to undergo placement of pacemaker or implantable defibrillator leads via the contrast-guided extrathoracic subclavian vein approach or the cephalic approach. Lead placement was accomplished in 99 of the 100 patients randomized to the extrathoracic subclavian vein approach as compared to 64 of 100 patients using the cephalic approach. In addition to a higher initial success rate, the extrathoracic subclavian vein medial approach was determined to be preferable as evidenced by a shorter procedure time and less blood loss. There was no difference in the incidence of complications. In conclusion, these results demonstrate that lead placement in the extrathoracic subclavian vein guided by contrast venography is effective and safe. It was also associated with no increased risk of complications as compared with the cephalic approach. These findings suggest that the contrast-guided approach to the extrathoracic portion of the subclavian vein should be considered as an alternative to the cephalic approach.

Safety and effectiveness of placement of pacemaker and defibrillator leads in the axillary vein guided by contrast venography.

Despite evidence of an increased incidence of lead fracture, the infraclavicular subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by recently described approaches for lead placement in the axillary vein, these approaches have not gained widespread acceptance. The purpose of this study was to evaluate the safety and efficacy of an alternative technique for lead placement that uses contrast-guided venipuncture of the axillary vein with a 5Fr micropuncture introducer set. A total of 50 patients underwent an attempt at placement of pacemaker or implantable defibrillator leads via the axillary vein using this new technique. Patients were randomized into 2 groups based on whether the initial attempt at axillary vein access was performed medial or lateral to the rib cage margin. Lead placement was successfully accomplished in 49 of the 50 patients using this technique. Initial success was achieved in each of 25 patients randomized to the medial approach compared with 18 of 24 patients randomized to the lateral approach to the axillary vein (75%). In each of the 6 patients in whom the initial technique failed, lead placement was subsequently achieved with the medial approach. In addition to a higher initial success rate, the medial approach was determined to be preferable as evidenced by a shorter lead placement time, a smaller number of contrast injections, and a reduced requirement for additional micropuncture guidewires. There were no major complications associated with either approach. Contrast-guided venipuncture of the axillary vein is a safe and effective approach to placement of endocardial leads.

Adenovirus-mediated expression of a voltage-gated potassium channel in vitro (rat cardiac myocytes) and in vivo (rat liver). A novel strategy for modifying excitability.

Excitability is governed primarily by the complement of ion channels in the cell membrane that shape the contour of the action potential. To modify excitability by gene transfer, we created a recombinant adenovirus designed to overexpress a Drosophila Shaker potassium channel (AdShK). In vitro, a variety of mammalian cell types infected with AdShK demonstrated robust expression of the exogenous channel. Spontaneous action potentials recorded from cardiac myocytes in primary culture were abbreviated compared with noninfected myocytes. Intravascular infusion of AdShK in neonatal rats induced Shaker potassium channel mRNA expression in the liver, and large potassium currents could be recorded from explanted hepatocytes. Thus, recombinant adenovirus technology has been used for in vitro and in vivo gene transfer of ion channel genes designed to modify cellular action potentials. With appropriate targeting, such a strategy may be useful in gene therapy of arrhythmias, seizure disorders, and myotonic muscle diseases.

Metabolic oscillations in heart cells.

Oscillatory rhythms underlie biological processes as diverse and fundamental as neuronal firing, secretion, and muscle contraction. We have detected periodic changes in membrane ionic current driven by intrinsic oscillations of energy metabolism in guinea pig heart cells. Withdrawal of exogenous substrates initiated oscillatory activation of ATP-sensitive potassium current and cyclical suppression of depolarization-evoked intracellular calcium transients. The oscillations in membrane current were not driven by pacemaker currents or by alterations in intracellular calcium and thus represent a novel cytoplasmic cardiac oscillator. The linkage to energy metabolism was demonstrated by monitoring oscillations in the oxidation state of pyridine nucleotides. Interventions which altered the rate of glucose metabolism modulated the oscillations, suggesting that the rhythms originated at the level of glycolysis. The metabolic oscillations produced cyclical changes in electrical excitability, underscoring the potential importance of this intrinsic oscillator in the genesis of cardiac arrhythmias.

Oscillations of membrane current and excitability driven by metabolic oscillations in heart cells.

Periodic changes in membrane ionic current linked to intrinsic oscillations of energy metabolism were identified in guinea pig cardiomyocytes. Metabolic stress initiated cyclical activation of adenosine triphosphate-sensitive potassium current and concomitant suppression of depolarization-evoked intracellular calcium transients. The oscillations in membrane current and excitation-contraction coupling were linked to oscillations in the oxidation state of pyridine nucleotides but were not driven by pacemaker currents or alterations in the concentration of cytosolic calcium. Interventions that altered the rate of glucose metabolism modulated the oscillations, suggesting that the rhythms originated at the level of glycolysis. The energy-driven oscillations in potassium currents produced cyclical changes in the cardiac action potential and thus may contribute to the genesis of arrhythmias during metabolic compromise.

Cellular mechanisms of delayed recovery of excitability in ventricular tissue.

It is well established that ventricular tissue, under some conditions, exhibits the phenomenon of postrepolarization refractoriness (PRR) in which the tissue excitability is depressed after an action potential. We have done parallel experiments on rabbit papillary muscles and on isolated rabbit ventricular cells to explain the cellular basis of this phenomenon, using elevated extracellular K+ concentration ([K+]o) (8 mM) to depolarize the tissue and the isolated cells. For isolated cells, we could separately measure cellular excitability (the inverse of the cellular current threshold) and the cellular responsiveness (the ability of the cell to generate inward current after excitation has occurred). We present two hypotheses that could explain the magnitude and time course of tissue PRR in terms of either changes in cellular excitability or changes in cellular responsiveness. We show that, although small changes in cellular excitability do occur, the predominant cellular mechanism for tissue PRR is the time course of recovery of the cellular responsiveness.

Cellular mechanism of the functional refractory period in ventricular muscle.

A premature action potential elicited in ventricular muscle during the functional refractory period of a preceding action potential requires an increased stimulus intensity for successful propagation. We measured the cellular basis for these relative decreases in tissue excitability during the recovery phase by performing parallel experiments on rabbit left papillary muscle and isolated rabbit ventricular cells in addition to conducting theoretical studies with numerical simulations of action potential initiation. For each experimental preparation, the pacing protocol consisted of a train of 10 stimuli (S1) at an S1-S1 interval of 500 msec with a premature stimulus (S2) of variable S1-S2 intervals following the tenth S1 action potential. The stimulus threshold for initiation of an S2 action potential (I2) was then measured as a function of the time of occurrence of the S2 stimulus relative to the time of 95% repolarization of the tenth S1 action potential (stimulus delay [SD] time). In the tissue preparation, the I2 increased sharply for SD times less than 0 msec to a value that was 100% above the S1 stimulus threshold for SD time = -5 +/- 2.4 msec (n = 8). Similar experiments on the isolated ventricular cell showed no increases in I2 as a function of SD time but rather significant decreases in both the action potential amplitude (APA) and the maximum rate of rise of the action potential upstroke (Vmax) of the S2 action potential. The APA and Vmax for the S2 action potential were decreased to 50% of the S1 action potential values for SD time = -5.2 +/- 2.1 msec and SD time = 0.3 +/- 1.6 msec, respectively (n = 8). Both parameters reached 100% recovery by SD time = 10 msec. These results and our numerical simulations are consistent with the hypothesis that the decreases in tissue excitability that occur with premature stimulation have a cellular mechanism as a result of a decrease in cellular responsiveness (APA, Vmax) rather than an intrinsic decrease in cellular excitability.

Developmental changes in the electrophysiologic properties of rabbit papillary muscles.

We studied the electrophysiological properties of adult (AD) and newborn (NB) rabbit papillary muscles in vitro with superfusion of normal Tyrode's solution, solutions with elevated [K+]o, and in solutions with various concentrations of tetrodotoxin. In control solutions, the NB papillary muscles had a more negative resting membrane potential (-83.6 +/- 1.2 versus -80.0 +/- 1.5 mV), a higher rate of rise of phase 0 (134 +/- 5 versus 120 +/- 5 V/S) and a higher, longer-lasting action potential plateau than the AD papillary muscles. Exposure to elevated [K+]o led to a significant post-repolarization refractoriness in AD papillary muscles that was more than that for NB papillary muscles even when NB papillary muscles were depolarized to the same resting membrane potential as the AD papillary muscles. The NB papillary muscles were comparatively resistant to tetrodotoxin in terms of percent reduction of conduction velocity and percent rise in the current threshold for excitation. The conduction velocity for AD papillary muscles in control solution (66 +/- 6 cm/s) was more than for NB papillary muscles (44 +/- 4 cm/s), which would not be expected from the data on the rate of rise of the action potential, suggesting that the cable properties of NB papillary muscles (specifically a greater surface to volume ratio of the ventricular cells) are also significantly different from the AD papillary muscles.

Modulation of the Purkinje-ventricular muscle junctional conduction by elevated potassium and hypoxia.

Action potential transmission in the canine ventricle normally occurs from the Purkinje (P) system into the ventricular muscle (VM) at specific P-VM junction sites. Transitional (T) cells are located between the Purkinje and the ventricular (V) cells at these P-VM junction sites. It has been shown that exposure to elevated [K+]0 in combination with hypoxia produces an increase in the P-VM conduction time. To examine this increase in P-VM conduction time, simultaneous measurements of the action potential upstrokes of T cells and the activation times of the local P and V cells at P-VM junctional sites were obtained from in vitro canine papillary muscles. The effects of elevated [K+]0 and hypoxia on conduction from P cells to T cells was then compared with the conduction from T cells to V cells to assess the relative contribution of each to the increase in the P-VM conduction time. We found that this intervention has approximately equal effects on the two sequential steps involved in P-VM conduction. We then analyzed the increased delay from T cells and V cells on the basis of three hypothetical mechanisms: 1) increased coupling resistance, 2) decreased V cell excitability, and 3) decreased cellular responsiveness of the T cells. Our results show that the effects of elevated [K+]0 and hypoxia on T-VM delay can be accounted for by a decreased responsiveness of the T cells without any significant electrical uncoupling between T and V cells or decrease in VM excitability.

Effects of hypoxia on atrioventricular node of adult and neonatal rabbit hearts.

We used an isolated perfused heart model to assess the effects of graded hypoxia (95, 45, 20, 10, or 0% O2, exposure for 5 min) on the adult and neonatal (0-3 days) rabbit atrioventricular (AV) node. The AV nodal function was assessed by measuring the A-H interval at a constant atrial pacing cycle length, the longest pacing cycle length resulting in Wenckebach periodicity [Wenckebach cycle length (WCL)] and the AV nodal effective refractory period (AVNERP). The A-H intervals remained stable in neonatal hearts until O2 saturation was decreased to 10%. On the other hand, the A-H intervals began to increase in adult rabbit hearts at 20% O2. In 95% O2, the AV nodal WCL was longer in adult hearts than in the neonatal hearts (165 +/- 8 ms vs. 142 +/- 7 ms). The effect of hypoxia on the AV nodal WCL was significantly greater in adult hearts than in neonatal hearts when the O2 saturation was decreased to 20% (a 54% increase in adults vs. a 14% increase in neonates, P = 0.02). The difference was greater at lower levels of O2. In 95% O2 at comparable basis driving cycle length (240 ms), the A-H intervals were equal in neonatal and adult hearts (43 +/- 3 vs. 43 +/- 7 ms), but the AVNERP of the neonates was significantly longer than that of the adults (133 +/- 21 vs. 97 +/- 19 ms, P = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tissue geometry on initiation of a cardiac action potential.

We used rabbit ventricular papillary muscles and isolated rabbit ventricular muscle cells to compare the effects of a decrease in cardiac excitability. For the papillary muscles, we defined tissue excitability as the inverse of the current required to initiate a propagated action potential from a local stimulus. For the isolated cells, we defined cellular excitability as the inverse of the current required to initiate a membrane action potential. For papillary muscles, lidocaine with elevated extracellular K+ concentration ([K+]o) decreased maximum rate of rise of membrane potential (Vmax), decreased conduction velocity, and strongly decreased tissue excitability. For the isolated cells, lidocaine with elevated [K+]o decreased Vmax but had little effect on cellular excitability. We interpret our results on the differences of effect on tissue excitability vs. cellular excitability as a consequence of the syncytial nature of the papillary muscle. The cell-to-cell electrical connections produce an electrical load on the locally stimulated region. This electrical load makes the tissue excitability dependent on the amount of inward current that the locally excited cells and the surrounding cells can generate. We simulated these phenomena with numerical solutions of action potential initiation in an isopotential cell compared with a two-dimensional disk of excitable tissue. The simulation results recreate the basic experimental observation that the sensitivity of the current threshold to agents that lower inward current is markedly larger for multidimensional current flow from a source compared with an isopotential system.

Adenosine and hypoxia effects on atrioventricular node of adult and neonatal rabbit hearts.

An isolated perfused heart model was used to assess the effects of hypoxia and adenosine on the adult and neonatal (1-5 days) rabbit atrioventricular (AV) node. The AV nodal function was assessed by the A-H interval at a constant atrial pacing cycle length and by the longest pacing cycle length resulting in Wenckebach periodicity. We defined the pacing cycle length at or below which the AV node demonstrated Wenckebach periodicity as the Wenckebach cycle length. Adenosine produced a smaller dose-dependent increase in A-H interval in neonates than in adults, but the increase in Wenckebach cycle length was similar in the two age groups. When the hearts were exposed to 5 min of hypoxia the increase of Wenckebach cycle length was greater for adults than for neonates. The change in Wenckebach cycle length in adults caused by hypoxia was significantly greater than that caused by 1 mM adenosine. In addition, in adults aminophylline could partially attenuate the increase in Wenckebach periodicity caused by adenosine, but aminophylline could not attenuate the increase in Wenckebach cycle length caused by hypoxia. We conclude that in the rabbit AV node 1) the adenosine effect in neonates is similar to that in adults; 2) neonates are relatively resistant to acute hypoxia compared with adults; and 3) the response to acute hypoxia in adults cannot be totally explained by the adenosine release theory.

Alterations in endocardial activation of the canine papillary muscle early and late after myocardial infarction.

Permanent coronary occlusion produces time-dependent changes in surviving subendocardial cellular properties. We compared the functional alterations in Purkinje (P) and ventricular muscle (VM) activation early (24 hr) and late (4 weeks or greater) after permanent coronary occlusion in an in vitro preparation of canine papillary muscle. High-density extracellular (1 to 2 mm resolution) and selected intracellular recordings were made in five animals early and seven animals late during stimulation of a free-running P strand. Activation patterns of P and VM layers from ischemic and unaffected papillary muscles were compared in the same animal. Average P layer conduction velocity was determined in normal and ischemic regions with the use of a linear array of recording and stimulating electrodes. Purkinje activation was altered little in the early phase of infarction, while healing was associated with a generalized 25% reduction in P layer conduction velocity and localized block and fragmentation of P waveforms. Intracellular recordings at sites of nonsynchronous P activation revealed electrotonic interaction between cell groups. At 24 hr, small groups of VM were present but with abnormal activation patterns in regions of necrosis with fragmented and delayed extracellular waveforms produced by partially uncoupled groups of cells. Local delay and block could be modulated by rate and site of stimulation. After healing, VM activation abruptly stopped at the visual infarct border, marked by a characteristic "end potential." These studies demonstrate important differences in the functional attributes of the P and VM layers studied early and late after coronary occlusion. Alterations in cell-to-cell relationships are likely very important in determining abnormalities of activation in both settings.