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TRANSLATIONAL PHYSIOLOGY

Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans

Departments of ¹Anesthesiology, ²Electrical and Computer Engineering, ³Surgery, and ⁴Physiology and Cell Biology, The Ohio State University, Columbus, Ohio

Submitted 3 August 2004 ; accepted in final form 10 June 2005

ABSTRACT

Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs. Here, interspecies differences in three MEI parameters (baseline, time to plateau onset, and plateau value normalized by baseline) were evaluated using Kruskal-Wallis ANOVA and post hoc tests (P < 0.05). Noteworthy differences in the MEI time to plateau onset were observed: In dogs, MEI ischemic plateau was reached after 46.3 min (SD 12.9) min of occlusion, a significantly longer period compared with that of pigs and humans [4.7 (SD 1.2) and 4.1 min (SD 1.9), respectively]. However, no differences could be observed between both animal species regarding the normalized MEI ischemic plateau value (15.3% (SD 4.7) in pigs, vs. 19.6% (SD 2.6) in dogs). For all studied MEI parameters, only swine values resembled those of humans. The severity of myocardial supply ischemia, resulting from coronary artery occlusion, is known to be dependent on collateral flow. Thus, because dogs possess a well-developed collateral system (unlike humans or pigs), they have shown superior resistance to occlusion of a coronary artery. Here, the early MEI time course after left anterior descending coronary artery occlusion, represented by the time required to reach ischemic plateau, was proven to reflect such interspecies differences.

ischemia; myocardium; diagnosis

Electrical impedance, a passive electrical property, has been shown to reflect the myocardial response to ischemia, being correlated not only with the associated functional abnormalities (19, 36), but also with the underlying ionic (2, 3, 28, 39) and metabolic (10, 14) changes in the myocardium. However, despite the general agreement that myocardial electrical impedance (MEI) increases significantly with supply ischemia (induced by coronary artery occlusion), the relevancy of its early time course to the understanding of the ischemic process is not clear. Using arterially blood-perfused rabbit papillary muscles, Kleber and colleagues (25) found that MEI increases in a biphasic manner during ischemia: an early increase immediately after the ischemic insult, a plateau phase, and thereafter a rapid increase thought to mark cellular uncoupling (2, 4, 28, 39).

We, like other investigators (4, 10, 14, 39), have observed (unpublished) similar patterns in dogs and pigs (7, 19) (see Fig. 1), two representative large-animal models traditionally used to study myocardial supply ischemia as can occur in humans (e.g., during beating-heart coronary artery revascularization). However, these species have well-documented physiological differences, especially regarding collaterals (26): whereas dogs possess a well-developed collateral system, pigs (like humans) generally lack it (26, 46) and therefore are more susceptible to supply ischemia (13, 16, 38). Thus we hypothesize that a formal comparison between the MEI response of dogs and pigs to coronary artery occlusion should highlight those MEI parameters that are able to differentiate between subjects with (e.g., dogs) and without (e.g., pigs) resistance to supply ischemia. To date, such comparison is lacking.

View larger version (27K): [in this window] [in a new window]   Fig. 1. Sample myocardial electrical impedance (MEI) data (z[n], ) measured on dog (A, obtained from Ref. 19) and swine (B, obtained from Ref. 7) showing the MEI biphasic rise after coronary artery occlusion (t = 0 min): early increase immediately after the ischemic insult (I), a plateau phase (II), and rapid increase thought to mark cellular uncoupling (III).

METHODS

MEI ischemic data were obtained from three previously presented studies (performed by this laboratory with prior institutional approval). Animal protocols were approved by the Institutional Lab Animal Care and Use Committee at this institution and adhered to the statutes of the Animal Welfare Act and the guidelines of the Public Health Service. The human protocol was approved by the Biomedical Sciences Institutional Review Board and complied with the Codes of Federal Regulations Title 45-Part 46 of National Institutes of Health and Title 21-Part 50 of the Food and Drug Administration.

The studies were divided (by species) into three groups: 1) Data on dogs were taken from work performed by Howie et al. (19), who recorded MEI during acute coronary artery occlusion and reperfusion in anesthetized male dogs. For this interspecies validation study, all animals [n = 10, 22.8 kg (SD 2.0)] from the 120-min LADa occlusion group were chosen. 2) Pig data were collected by us as part of a study examining the preconditioning effects of high-dose adenosine on MEI (7). Here, seven (3 male, 4 female) juvenile pigs [n = 7, 28.1 kg (SD 1.0)] from the control (placebo) group, subjected to a 10-min acute LADa occlusion, were selected. 3) Humans were measured intraoperatively (with prior informed consent) during elective beating-heart left anterior myocardial revascularization (9, 20). At our institution, such procedure involves complete acute occlusion of the coronary artery being grafted (LADa), to achieve a clean operating field. In this study, we report on the MEI response to such procedural complete occlusion [13.2 min (SD 3.96)] of the LADa in seven (5 male, 2 female) patients [n = 7, 91.4 kg (SD 13.6)] with moderate preoperative (angiographically demonstrated) LADa stenosis (70–80%, inclusive).

Despite different aims, all experiments (for the selected groups) shared the same structure: a baseline period of at least 3 min, during which no interventions were made, followed by complete LADa occlusion. In all cases, isoflurane was used for anesthesia maintenance, hemodynamic variables (including temperature) were maintained within their normal physiological range, and MEI was measured with identical equipment and technique.

As previously described (8, 19), in open-chest conditions, two standard (commercial) temporary pacing wires (Medtronic Streamline 6500 or A&E Medical MYO/WIRE M-25, 8–13 mm² of exposed surface area) were sutured completely into the midmyocardial wall, 1 cm apart in the LADa distribution, and distal to the occlusion site (and stenosis, in the human case). From these leads, confirmed (visually) to be in the center of the region rendered ischemic by LADa occlusion, an MEI monitor developed at this laboratory was used to measure the complex MEI spectrum (8), a combination of the true electrical impedance spectrum of the myocardium and that of the electrode-tissue interface. In short, a computer-controlled circuit stimulated the myocardium with a subthreshold zero-mean bipolar current, consisting of two alternating rectangular pulses (±5 µA, 100 µs wide) generated 200 ms apart. The complex MEI spectrum was calculated as the ratio (at each frequency) of the current and voltage spectra resulting from the ensemble averages of 10 (positive) stimulus pulses and their respective responses (8). The frequency-domain resolution was either 5.4 (pigs and humans) or 100 (dogs) Hz (7, 8, 9, 19). Regardless, all studies reported (every 3 s) on the mean MEI modulus over the studied nonuniform frequency range (0.27–5.90 kHz, i.e., the spectrum's main lobe).

Analysis.   Because MEI has been shown to be sensitive to temperature, the electrode system's geometry, and its location in the myocardium (33, 35, 41–45), to reduce intersubject variability, we studied MEI changes expressed as percentages from baseline (normalized MEI, Z[n]). Here, baseline MEI (_b) was defined as the average of the 15 samples immediately preceding the coronary artery occlusion marker (n_o, inclusive).

Normalized data were analyzed by a moving-window technique. A rectangular window of length N (W_N [n], N = 30 or 1.5 min) was used, and successive windows overlapped by N–1 samples; within each window, the best linear fit (L[n], in a least-squares sense) to the MEI data was calculated. The slope of the fitted line was used as an estimate of the MEI first derivative at the center of the window ([n]). The estimated MEI first derivative served to detect the ischemic plateau onset time sample (n_p) as defined in Ref. 7; i.e., the sampled time point at which [n] has fallen to 3% of its maximum value (_p) (see Fig. 2). Once n_p was determined, the MEI ischemic plateau value (_p) was defined as the average of the 15 MEI measurements immediately after it (inclusive).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Sample data analysis procedure on swine data (obtained from Ref. 7). Top: original MEI measurements (z[n], ) indicating moving analysis window (WN) and best (mean-square) linear fit (L) at sample ni. Bottom: MEI first derivative ([n]) estimated from the linear fit (L[n]), indicating ischemic plateau threshold (p, i.e., 3% of the maximal derivative) and value at ni ([ni]). Occlusion marker (no) and ischemic plateau sample (np) are used to calculate baseline and ischemic plateau MEI values (b and p, respectively). Note: the fact that [n] appears to increase before coronary artery occlusion (no) is an artifact of the noncausal windowing technique used.

RESULTS

As it has been previously shown (7, 9, 19), MEI increased immediately and significantly (P < 0.05) from baseline after LADa occlusion, reaching an ischemic plateau value subsequently. This held true for all subjects and species studied. However, significant interspecies differences, in both the magnitude and timing of such changes, were observed (see Table 1 and Fig. 3), with the time to MEI plateau onset showing the most remarkable variation.

View larger version (31K): [in this window] [in a new window]   Fig. 3. Sample normalized MEI data (Z[n]) after coronary artery occlusion. Original MEI measurements on representative pig (, from Ref. 7), dog (, from Ref. 19), and human (, from Ref. 9) indicating occlusion marker (no, t = 0 min). Insets: estimated MEI first derivatives for each subject, indicating ischemic plateau threshold (p, i.e., 3% of its maximum value). Observe that [n] in the dog does not fall below the ischemic plateau threshold, i.e., MEI does not reach ischemic plateau.

Although baseline measurements showed significant differences between dogs and pigs, no differences could be observed between these two species regarding their normalized ischemic plateau value, a parameter traditionally used to correlate MEI with ischemia (2, 3, 10, 14, 19, 25, 28, 39) and other diseased states of the myocardium (15, 29). Normalized MEI reached 19.6 (SD 2.6) and 15.3% (SD 4.7) at plateau in dogs and pigs, respectively. Interestingly, humans, who also showed baseline differences with canine data, had a lower normalized ischemic plateau value [11.0% (SD 6.0), P < 0.05]. It should be noted that, regarding all MEI parameters studied (time to plateau onset, baseline and normalized ischemic plateau value), swine and human groups were only distinguishable by the wider distribution of values observed in humans (as expected owing to the intrinsic variability of coronary artery disease).

DISCUSSION

The degree of myocardial collaterization is recognized as an important interspecies differentiating factor (13, 16) and has been shown to influence the extent and severity of myocardial ischemic injury directly (22, 38). Thus, because canines possess a well-developed collateral system, unlike humans or pigs, they have been shown to have remarkably higher resistance to supply ischemia as reflected by reduced rates of ATP depletion (38) and smaller infarcts (13). Here, the MEI ischemic time course, represented by the time from coronary artery occlusion to MEI ischemic plateau onset, was shown to reflect such interspecies differences in collaterization.

Although originally attributed to a rapid collapse of the intravascular and interstitial spaces ("vascular collapse") (25), the exact mechanism determining the early behavior of MEI under acute ischemia remains unknown. Kleber et al. (12, 47) demonstrated that initial impedance rise during zero-flow ischemia is sensitive to osmotically induced cell swelling (i.e., to changes of the extra- to intracellular volume relationship). As such, the time-dependent concentrations of intra- and extracellular ions (such as calcium, [Ca²⁺]_i, hydrogen, [H⁺]_i, and potassium, [K⁺]_e; brackets denote concentration) (3, 28, 39), anaerobic by-products, and ATP (10, 14, 40) found on the ischemic myocardium have been shown to play an important role. For example, extracellular potassium ([K⁺]_e) accumulation during ischemia is documented to follow a triphasic time course (18, 24) similar to that of MEI. Furthermore, the secondary rise (i.e., third phase) of both parameters is closely coupled in time (2, 28, 39). Owens et al. (28) demonstrated that such terminal (secondary) rise signals ischemic electrical cell-to-cell decoupling, and only occurs after a significant accumulation in [Ca²⁺]_i and [H⁺]_i [as initially suggested by Cascio and colleagues (2)].

However, using paired ventricular myocytes, Sugiura et al. demonstrated that (electrical) junctional conductance changes with ATP concentration, independently of intracellular free gap-closing ions (such as [Ca²⁺]_i) (40), thus suggesting also a direct relationship between active ionic transport and the MEI. In other words, they proposed that the depletion of myocardial high-energy stores (e.g., during ischemia) leads to increases in intercellular electrical impedance (the reciprocal of electrical conductance) by means of modifying the ATP-mediated ionic conductivity through the cellular membranes.

Interestingly, the activation of ATP-dependent potassium channels has been shown not only to be mediated by myocyte swelling (30), but also to affect the timing and magnitude of early [K⁺]_e accumulation (34), a well-established cause of early electrical disturbances during ischemia (27). The role of these channels as part of the underlying mechanism behind changes in the passive electrical properties of ischemic myocardium is further strengthened by the recent observations of Bollensdorff et al. (1). They demonstrated that ATP-dependent potassium-channels mediate extracellular sodium influx to the myocytes, and, therefore, [Ca²⁺]_i overload leading to cell-to-cell uncoupling.

Hence, a slower MEI progression to plateau after coronary artery ligation (as observed on canine myocardium) is suggestive not only of delayed breakdown in cellular (ionic) homeostasis but also of slower ATP depletion rates (i.e., of a less damaging ischemic process). This is in good agreement with the classic results of Schaper and colleagues (38) and with the slower [K⁺]_e accumulation in ischemic canine myocardium reported by David et al. (6) [evident compared with results from swine (18, 39)].

As a result, the MEI timing similarities observed between swine and human data indicate that the passive electrical properties of human myocardium early during coronary artery occlusion are closely modeled by those in pigs. Furthermore, given MEI's metabolic ties, this supports the argument that pigs are a better model than dogs for acute myocardial supply ischemia as can occur in humans (26), at least for moderately diseased patients (as those studied here) expected to have a poorly developed collateral system (5, 31).

On the other hand, whereas close MEI time courses may reflect comparable myocardial metabolisms during ischemia, the observed interspecies differences in MEI baseline and normalized plateau values (the other parameters studied) could be suggestive of specialization in the myocardial tissue ultrastructure, as suggested in the literature (36, 42, 45). However, as stated above, MEI measurements have been shown to be affected by temperature (44), electrode separation (33, 41), depth (43, 45), and orientation (relative to the muscle fibers) (35, 41, 42, 45). For instance, Steendijk and colleagues (42) reported significantly different MEI values for measurements made longitudinally and transversely across canine myocardial fibers [313 (SD 49) and 487 ·cm (SD 49) at 5 kHz, respectively]. Hence, because the spacing and orientation of the temporary pacing wires (used to acquire MEI data) on the beating heart are difficult to control, conclusions based on the absolute difference among baseline values between the species are not possible.

Furthermore, as the normalized MEI plateau value indicated coronary artery occlusion precisely but failed to differentiate between the (clearly different) ischemic processes on dogs and pigs, this study emphasizes the relevance of the early ischemic MEI time course. Here, the MEI temporal behavior after coronary artery occlusion (parameterized as the time to reach MEI ischemic plateau) reflected the higher collateral density of canine myocardium, acting, perhaps, as a direct indicator of ischemic resistance and metabolism. Therefore, MEI timing parameters could be a valuable tool during surgical myocardial revascularization procedures, in which cardioprotective techniques that seek to enhance the myocardial endurance to ischemia (e.g., cardioplegic arrest, preconditioning, etc.) are currently performed blindly, i.e., with minimal online indication of their success.

In conclusion, this study not only confirms MEI as a valid online myocardial ischemia monitor, but it highlights the importance of including parameters sensitive to the MEI time course in the ischemia monitoring process.

FOOTNOTES

Address for reprint requests and other correspondence: C. L. del Rio, Dept. of Anesthesiology, The Ohio State Univ., 410 West 10th Ave., Doan Hall N416, Columbus, OH 43210 (e-mail: del-rio.4{at}osu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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