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From the Cardiopulmonary Research Laboratory, Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Address correspondence and reprint requests to Michael R. Pinsky, MD, Department of Critical Care Medicine, University of Pittsburgh Medical Center, 606 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Address e-mail to pinskymr{at}ccm.upmc.edu.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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) as the relative distance, measured in degrees, that regional minimal volume differed from global end-systole. We also compared maximal stroke volume (SV), observed effective SV (that portion of regional SV contributing to total SV for each treatment), and calculated effective SV (total regional SV x cosine ). Dobutamine infusion increased homogeneity of regional relative to baseline. Both esmolol and ischemia significantly delayed (P < 0.05) apical contraction as quantified by increased (12.4° ± 28.1° to 27.4° ± 30.4° and 54.2° ± 32.6°, respectively) (mean ± sd) and decreased regional effective SV (4.7 ± 2.5 mL to 3.6 ± 2.2 mL and 4 ± 2.5 mL, respectively) relative to baseline. Our study indicates that intracoronary esmolol and ischemia induced qualitatively similar mechanical effects on myocardial function and that a sine wave model to estimate regional effective SV is a sensitive method to detect and quantify regional dyssynchrony induced by ischemia. Potentially, phase angle and regional amplitude analyses may prove to be effective measures to identify and quantify the beneficial effects of resynchronization therapies on myocardial function. |
Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Myocardial ischemia impairs cardiac pump function, not only by decreased amplitude of contraction but also through dyssynchronous contraction (5,6). In previous studies, we modeled regional contraction to approximate a sine wave and used this regional phase angle model to merge regional amplitude and synchrony to measure regional ejection effectiveness in a canine preparation with reversible dysfunction induced by intracoronary esmolol (7–9). Those data showed that regional phase angle analysis quantifies the impact of contraction dyssynchrony. However, esmolol may not represent a clinically relevant model for regional ischemia because regional ischemia is associated with hypercontractility in adjacent regions of the myocardium and differentially impairs contraction within the ischemic zone. Ehring and Heusch (19) studied the first 20 harmonics of systolic wall thickening during regional ischemia and noted that only the first harmonic and phase angle of systolic wall thickening were needed to describe ischemia-induced regional hypokinesis. Because adjacent reactive increased contractility may coexist with ischemia, it is unclear if simple phase-angle analysis of regional volumes would model the dyssynchrony induced by ischemia. Thus, our method may not result in similar accuracy assessing regional dyssynchrony during acute ischemia. Accordingly, we tested the hypothesis that our sine wave model and phase angle analysis of regional dyssynchrony in a canine model could also assess dyssynchrony of contraction during regional ischemia.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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A fluid-filled arterial catheter with multiple side holes was inserted into the thoracic aorta via the left femoral artery to measure arterial blood pressure and sample arterial blood. A double-lumen 12F catheter was inserted into the left external jugular vein to administer IV fluids. To verify cardiac outputs, a 7.5F balloon-tipped pulmonary artery catheter (List #5328, Model P7110-EP8-H, 9510 animal model; Baxter-Edwards, Santa Ana, CA) was introduced through the right external jugular vein and positioned in a branch of the pulmonary artery. To measure left ventricular (LV) volume on a continuous basis, a 6F, 11-pole multi-electrode dual excitation conductance catheter with a "j tip" (Webster Laboratories, Irvine, CA) was inserted through the aortic valve and into the LV via the right internal carotid artery. Positioning of the conductance catheter was verified by fluoroscopy and repeated inspection of regional pressure-volume signals with respect to time. The grouping of electrode signals into sequential stacked cylinders was done so as to create four regional volumes by grouping adjacent regional volumes into one region as recommended by the manufacturer. Thus, we created four sequential volume regions from apex to base. To measure instantaneous LV pressures, a micromanometer catheter (MPC-500; Milar, Houston, TX) was placed into the LV via the left common carotid artery.
A left lateral thoracotomy was performed through the fourth intercostal space and the heart was suspended in a pericardial cradle. To administer intracoronary esmolol, a 22-gauge x 1.25-inch IV catheter (Abbocath®) was placed into the left anterior descending (LAD) coronary artery. The catheter was heparin-locked to prevent thrombus formation, and care was taken to prevent air embolism. To induce regional ischemia, an encircling ligature was placed around the proximal LAD coronary artery just distal to the tip of the catheter.
To measure regional myocardial shortening, 2 pairs of piezoelectric crystals were placed approximately 1 cm apart to a depth of 1.0–1.5 mm in the myocardium and aligned parallel with the longitudinal myocardial fibers. One pair was implanted in the anterior myocardium in the LAD coronary artery perfusion zone. A second pair was implanted in the lateral myocardium in the circumflex coronary artery perfusion zone. Crystal length signals were processed with a sonomicrometer (Model 120; Triton Technologies, San Diego, CA).
Immediately before termination of the experiment, 2 mL of 1% crystal violet dye was injected into the LAD artery catheter to document the size of the coronary perfusion zone. The dog was euthanized while under general anesthesia using IV injection of 10 mL of saturated KCl, and the heart was excised to document the position of the conductance catheter in the LV. The dyed area (LAD coronary artery perfusion zone) was excised and the remainder of the LV myocardium was dissected free and weighed postmortem.
The conductance catheter method of Baan et al. (10) for measuring ventricular volume was described and validated previously. Parallel conductance offset was determined with the saline dilution method (10) using 5 mL of 10 N saline injected into the right atrium.
Systemic dobutamine HCl (4.0 µg · kg–1 · min–1) was infused into a large central vein and induced a stable hemodynamic response within approximately 5 min. Dobutamine served as a positive control and increased contractility under baseline conditions while leaving the animal’s heart rate or mean arterial blood pressure in a normal physiological range for dobutamine infusion. Data were collected during dobutamine infusion 10–15 min after beginning the infusions. This treatment was referred to as dobutamine.
Intracoronary esmolol 750 µg/kg (10 mg/mL) was administered by bolus injection through the LAD catheter to induce apical dyskinesis as confirmed in real time by observation of the associated pressure-dimension loop. Infusion of esmolol induced transient regional dysfunction lasting at least 6 min; subsequent data were collected 3–6 minutes after induction of dyssynchrony. This treatment was referred to as esmolol.
Ligature occlusion of the LAD coronary artery was used to induce ischemia and apical dyskinesis as confirmed in real time by observation of the associated pressure-dimension loop. Subsequent data were collected from 3–6 min after the onset of regional ischemia. This treatment was referred to as ischemia.
Regional myocardial function was compared sequentially over 3 treatments and 3 baseline conditions: baseline, dobutamine, baseline 2, esmolol, baseline 3, and ischemia. Before each experimental treatment, values for measured variables for regional function were allowed to return to baseline. In practice, restoration of baseline was defined as return to prior baseline heart rate and arterial blood pressure, which occurred approximately 20 min after the dobutamine infusion was stopped and approximately 15 min after cessation of the esmolol infusion. Each experimental treatment (except ischemia) was alternated in a randomized block design to control for the order of the treatments and any possible time effects. Ischemia was always the last treatment because of the irreversible nature of that insult. Baseline measurements postischemia were planned but abandoned when 3 of 4 initial dogs developed intractable ventricular arrhythmias immediately on coronary artery reperfusion.
We recorded the following experimental variables: arterial blood pressure, LV pressure, LV dP/dt, intercrystal dimensions for the piezoelectric crystals, total and regional LV conductance (volume), and lead II of the electrocardiogram (ECG). All data were recorded on an eight-channel physiologic recorder (Gould, Cleveland, OH). Furthermore, all data were digitized and recorded on magnetic disk for subsequent analysis as described below.
Signals from two pairs of sonomicrometer dimension crystals were processed simultaneously on two synchronized channels using a four-channel sonomicrometer (Triton model 120, San Diego, CA). dP/dt was derived from the LV pressure signal using a differentiator (Gould) with a 100-Hz high cutoff and a 1-volt/s slope. Signals were collected and processed using a conductance catheter data processor and signal conditioner (Sigma 5DF; Leycom, Leyden, Netherlands). A four-electrode calibration chamber was used to determine blood conductivity ( value). Intermittent cardiac outputs were determined in triplicate using a 10-mL iced 0.9% NaCl bolus thermodilution technique (model 9520 cardiac output computer; Baxter-Edwards) before starting the protocol to calibrate stroke volume (SV) derived from the conductance catheter. The signal acquisition and analysis system consisted of an Apollo DN4000 Unix workstation (Hewlett-Packard, Palo Alto, CA) and an analog to digital RTS-132 A/D subsystem (SignifiCAT® RTS-132, Buffalo, NY).
The conductance catheter generated continuous regional volume signals with respect to time for each of four LV regions. Regional volume signals were summed to derive total LV volume. Regional and total LV maximum and minimum volumes were determined using replicate values averaged over 4 consecutive cardiac cycles. Regional end-systolic and end-diastolic volumes were defined as regional minimum and maximum volumes respectively. The sonomicrometer signals generated similar continuous signals of length dimension with respect to time. Mechanical diastole was defined arbitrarily to occur at the R wave of the ECG.
To measure alterations in regional phase angles independent of heart rate, we divided the cardiac cycle into 360° and defined LV global end-systole (minimal total volume) as 0°. Regional end-systolic phase angle () was defined as the relative distance, measured in degrees, that regional minimal volume differs from global end-systole. Regional phase delays were defined arbitrarily as positive and phase advances as negative values. Regional end-systole was also defined relative to the R wave of the ECG. We adopted a model of LV contraction that assumed that ejection approximates a sine wave and that the relative contribution of regional ejection to total LV ejection should equal the product of the maximal regional SV and the cosine of the phase angle . If the region contracts synchronously with the total LV, then = 0°, cosine = 1 and all the regional SV contributes to LV ejection. If the contracting region reaches its minimal volume either before or after total LV end-systole, then a proportion of its contraction equal to 1-cosine of this phase shift will not contribute to total LV SV.
Because heart rates change among treatments, we further characterized the timing of regional myocardial contraction independent of phase angle by determining the systolic time interval of regional systole. The systolic time interval measures duration of regional end-systole in milliseconds from the R wave of the QRS or from global end-systole. We studied the systolic time interval because it quantifies the effect of phase angle and heart rate on regional contraction.
To quantify regional SV independent of global ejection, we defined maximal SV as the difference of the maximum and minimum regional volume (or segmental length) independent of markers of total LV ejection. To quantify the contribution of regional SV to global ejection, we defined observed effective SV using maximums and minimums of the total LV volume as gated markers of that portion of regional SV that contributes to total LV ejection. Calculated effective SV was defined according to our model as the product of regional cosine and regional maximal SV as described above. To quantify that portion of regional SV that does not contribute to global ejection, we defined ineffective SV as the difference between maximal SV and effective SV.
All data were reported as mean ± sd. Regional phase shifts, systolic time intervals, maximum SVs, and effective SVs were compared across treatments and among regions of the myocardium using repeated-measures analysis of variance. Post hoc analysis was accomplished using Tukey’s comparisons or Student’s t-tests. Differences associated with a P value <0.05 were considered significant. All statistical test results were examined graphically using standardized normal probability plots to ensure residuals were normally distributed.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Systemic hemodynamic data for baseline, dobutamine, esmolol, and ischemia treatments are summarized in Table 1. Systemic dobutamine infusion increased heart rate 11%, mean arterial blood pressure by 17%, and maximum LV dP/dt 83% but increased minimum LV dP/dt by 55% compared with baseline (P 
0.05). Intracoronary esmolol decreased heart rate 10%, mean arterial blood pressure 21%, and maximum dP/dt by 41%, while it increased minimum dP/dt 55% and LV end-diastolic pressure 192% compared with baseline (P 0.05). Ischemia decreased mean arterial blood pressure 14% and increased LV end-diastolic pressure 249% compared with baseline (P 0.05). Ischemia affected overall hemodynamics less significantly than dobutamine or esmolol.
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Observed phase angles () ranged –67 to 101 degrees (6.6 ± 29 degrees; mean ± sd, n = 160) for basal, chordal, papillary, and apical regions. Systemic dobutamine decreased apical and papillary relative to other treatments (P 0.05) (Table 2) and also decreased the heterogeneity of regional with respect to other treatments (Fig. 1).
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Esmolol and ischemia increased heterogeneity of regional with respect to other treatments (Table 2). Esmolol delayed contraction in apical regions only, whereas ischemia delayed contraction in apical sono and papillary regional volume segments relative to baseline (P 0.05) (Fig. 2). Esmolol advanced contraction in basal regions, whereas ischemia advanced contraction in chordal and basal regions (P 0.05). Thus, ischemia induced more dyssynchrony in a larger affected region (apical and papillary) and more compensatory response in remote regions than did esmolol.
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Systolic time intervals with respect to the R wave of the ECG decreased 12% (global value) with dobutamine infusion and increased 13% after administration of an intracoronary bolus of esmolol (P 0.05), reflecting corresponding alterations in heart rate. Systolic time intervals relative to global end-systole were delayed in apical and papillary regions (340% and 362%, respectively) and advanced in chordal and basal regions (273% and 600%, respectively) for ischemia (P 0.05).
Systolic time intervals with respect to global end-systole were more advanced in apical and more delayed in basal regions for ischemia than for esmolol, dobutamine, or baseline (P 0.05). Ischemia induced less hemodynamic effects but induced greater dyssynchrony and a larger unaffected region (chordal and basal) than did intracoronary esmolol (Table 2).
SV varied among regions according to the method used to define regional end-systole (Table 3). Regional maximal SVs were greater than effective SVs at baseline because of dyssynchrony present in the normal heart. Differences between effective and maximal SVs increased with heterogeneity of the regional phase angles.
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Effective SVs were more sensitive measures of decreased regional amplitude than maximal SVs. Effective SVs decreased 15%–24% with esmolol and ischemia in apical and papillary regions but were unchanged by dobutamine infusion (P 0.05) relative to baseline. Maximal SVs decreased 17%–28% with esmolol and ischemia in papillary regions but were not decreased in apical regions during ischemia (P 0.05). Although maximal SVs decreased in the apical regions with esmolol, they were not decreased during ischemia (P 0.05). Effective and maximal total SVs decreased in all regions (excluding the chordal region) with esmolol compared with baseline (P 0.05) probably reflecting systemic recirculation of esmolol.
Observed effective SV and calculated effective SV (calculated as the product of maximal SV and cosine for the regions) were highly correlated with one other (r2 = 85%, P < 0.01, Table 3, Fig. 3). Close examination of Figure 3 indicates observed effective SV was under-estimated by calculated effective SV in the papillary and apical areas of the same 2 dogs in which regional ranged 68 to 101 degrees (84 ± 16 degrees; mean ± sd, n = 4 outliers).
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Maximal crystal shortening in the apical region was decreased with esmolol but was not altered by ischemia (Table 3). Effective crystal shortening in the apical region was decreased by both esmolol and ischemia, further demonstrating the utility of measuring regional shortening relative to global end-ejection. Dobutamine increased maximal and effective SV in the apical region (P 0.05).
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Although cardiac dyssynchrony is common, it is difficult to model because of uncertainties in quantifying regional systole and the amplitude of regional contraction. Regional wall motion has been quantified using digitalized ventriculograms and temporal Fourier analysis (11,12). Unfortunately this method fails to combine temporal and spatial dysfunction as a single index, and it is difficult to apply at the bedside (13). A variety of other methods, including echocardiography, have also been used to detect dyssynchrony, but most have proven insensitive or limited by "semi-quantitative" subjective visual assessment techniques (14). We have shown that tissue Doppler echocardiography can also quantify regional dyssynchrony (15), but routine clinical application awaits development of analytical methods to reliably quantify dyssynchrony in heterogeneously contracting myocardium. A sine wave model of dyssynchrony appears to offer a sensitive method to detect and quantify regional dyssynchrony and can be applied in real time on a beat-to-beat basis.
The need to define dyssynchrony has clinical relevance because techniques to reverse contraction dyssynchrony, referred to as "cardiac resynchronization," have been used to treat patients with end-stage heart failure (16). Resynchronization therapy improves cardiac function by selectively pacing myocardium only when it reduces dyssynchrony. Patients likely to benefit from resynchronization have been identified using echocardiography (16), but clinical application of new resynchronization techniques has been delayed by a paucity of standardized techniques to identify and assess dyssynchrony in real time (17,18).
Phase angle analysis of regional myocardial function is not a novel approach. It has been used to analyze regional sonomicrometer thickness crystals in dogs by applying a temporal Fourier transform (19). Unfortunately, in that study the data were not analyzed relative to markers of total LV systole. The phase shift between unaffected and affected regions, however, was found to correlate strongly with regional thickening. Extending this approach to interface with global markers of LV performance, we showed that esmolol altered phase angles in both affected and remote regions relative to global ejection (15). Importantly, these phase angle and effective SV changes also manifest themselves as direct changes in the mechanical contractile behavior of the heart when assessed relative to regional echocardiographic tissue Doppler imaging (15) and both segmental and global LV pressure-volume relations (8). Steendijk et al. (17) used methods similar to ours to describe regional dyssynchrony. These authors used conductance catheters to quantify lags between regional and global volumes in contracting hearts. Their dispersion index compared regional and global volumes throughout systole to quantify lags in regional contraction. This method corresponds to our phase angle analyses. Their internal flow fraction index determines whether contraction (regional volumes) were effective (contributing to global ejection) or ineffective similar to our effective stroke volume analysis. Steendijk et al. studied coronary artery disease and heart failure in humans, whereas we tested our model in animals using intracoronary esmolol or regional ischemia. Both methods quantify dyssynchrony by comparing markers of regional contraction to global contraction.
Our sine wave model for calculating effective SV has intrinsic limitations. A visual examination of our data indicates calculated effective SV may have under-estimated observed effective SV whenever phase delays of regional exceeded 68° (Fig. 3). This tendency to under-estimate calculated effective SV beyond 68° may have resulted from the fact that a sine function decreases steeply as it approaches its inflection point at ±90° and thus may be a less predictive model whenever regional approaches 90° relative to global end-systole. This potential limitation warrants further investigation, but the good correlation between observed and calculated effective SVs proved the model was predictive whenever regional phase delays were <68° (r2 = 93%, n = 156).
We defined dyssynchrony as regional ventricular contraction that does not summate to create global end-systole. Phase angle analysis does not describe regional dyssynchrony occurring during diastole. If dyssynchronous contraction or relaxation altered diastolic filling, phase angle analysis during filling would need to be studied. We have not performed such a study, nor are we aware of other methods to assess diastolic dyssynchrony.
We used a larger dose of esmolol in this study than in our prior study (9.0 mg) (8). The effects on regional dysfunction were similar, but the larger dose had unintended consequences in remote cardiac regions. Low doses of esmolol produced hyperkinesis in surrounding regions similar to that observed with ischemia (20), but this degree of hyperkinesis was not observed with larger doses. Systemic recirculation of esmolol with higher doses may have attenuated compensatory responses to regional dysfunction, as evidenced by reduced arterial blood pressure and heart rate with larger doses. To the extent that these changes in arterial blood pressure, though not significant, may have influenced regional contraction, then the esmolol control group may not reflect regional dyskinesis of a pure myocardial nature. As a result there was less contrast in between affected and remote regions in large-dose studies.
It is possible that less myocardium was affected by ischemia than esmolol even though both interventions involved a similar myocardial mass equivalent to a small-to-medium-sized heart attack in humans (21). Collateral blood flow may have minimized ischemia; whereas collateral spread of esmolol may have enlarged the size of that corresponding affected area.
Some baseline dyssynchrony observed in our studies could have been permanent artifacts of normal contraction. However, they were eliminated by dobutamine. Thus, we doubt that treatment-specific differences observed in our studies were influenced by structural cardiac dyssynchrony. A degree of baseline dyssynchrony occurs in normal hearts (22). Dyssynchrony that resolved with administration of inotropes has been demonstrated in humans without heart disease (23). Thus, some degree of dyssynchrony is normal and potentially represents a phase-dependent contractile reserve that can be recruited to improve pump function independent of the amplitude of regional contraction (8).
Parallel conductance artifact produces uncertainty in determining absolute volumes using conductance catheters. We corrected for this using the hypertonic saline calibration method and a dual-field method of determining conductance (24). We confirmed previously that relative conductance volumes are accurate (15) despite potential parallel conduction artifacts (10,25). Thus, we doubt that parallel conductance artifacts influenced treatment-specific differences in our studies.
Volume signals obtained by conductance catheters were compared along the longitudinal axis of the LV, but this separation is anatomically not correct. Ischemia affected only a portion of the apical regions with some myocardium unaffected and, as a result, phase angles reflect aggregate physiological function of the region, but not anatomical patterns in wall motion. This point is clearly illustrated by the qualitative differences in the piezoelectric crystal data for the involved segment, as compared with the regional volume data for the same segment.
Finally, all ischemia treatments were preceded by both dobutamine and esmolol infusions. Potentially, these drugs could have had persistent effects on regional performance during ischemia. However, baseline measures before inducing ischemia were similar to other baseline data, suggesting that if any mechanical impact of drugs was present, it was below the threshold for detection.
Our study indicates that intracoronary esmolol and ischemia induced qualitatively similar mechanical effects on myocardial function and that a sine wave model to estimate regional effective SV is a sensitive method to detect and quantify regional dyssynchrony induced by ischemia. Potentially, phase angle and regional amplitude analyses may prove effective measures to identify and quantify the beneficial effects of resynchronization therapies on myocardial function.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supported, in part, by the US Veterans Administration and NIH HL073198 and HL67181.
Financial assistance for Dr. Strum was provided by the physicians of Ontario through the Arthur Bond Scholarship granted by Physician’s Services Incorporated Foundation, Toronto, Canada.
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REFERENCES |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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  L. Johnson, H. K. Kim, M. Tanabe, J. Gorcsan, D. Schwartzman, S. G. Shroff, and M. R. Pinsky Differential effects of left ventricular pacing sites in an acute canine model of contraction dyssynchrony Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3046 - H3055. [Abstract] [Full Text] [PDF]
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