Ann Thorac Surg 2005;80:153-161
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Transmural Differences in Myocardial Function and Metabolism During Direct Left Ventricular to Coronary Artery Sourcing
Sandra de Zeeuw, PhD,
Cornelius Borst, MD, PhD,
Cees W.J. Verlaan,
Paul F. Gründeman, MD, PhD*
Experimental Cardiology Laboratory, Heart Lung Center, University Medical Center Utrecht, Utrecht, the Netherlands
Accepted for publication January 28, 2005.
Abbreviations and Acronyms EDL = end diastolic segment length; Endo = subendocardium; Epi = subepicardium; ESL = end systolic segment length; HR = heart rate (beats per min); ITA = internal thoracic artery; LAD = left anterior descending coronary artery; L min = minimum segment length; LV-CA bypass = left ventricle-coronary artery bypass; LV dP/dt max = maximal rate of rise in left ventricular pressure (mm Hg/s); LV dP/dt min = maximal rate of fall in left ventricular pressure (mm Hg/s); LVEDP = left ventricular end diastolic pressure (mm Hg); MAP = mean arterial pressure (mm Hg); PSS% = postsystolic shortening (%); RPP = rate pressure product (mm Hg · beats per min); SS% = systolic shortening (%)
* Address reprint requests to Dr Gründeman, Experimental Cardiology Laboratory, Heart Lung Center, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523 3584, CX Utrecht, the Netherlands (Email: p.f.grundeman{at}hli.azu.nl).
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Abstract
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BACKGROUND: We investigated the hypothesis that in the absence of collateral circulation, a left ventricle-coronary artery (LV-CA) bypass will maintain normal LV wall function and metabolism transmurally, both at rest and during stress, when the left anterior descending coronary artery (LAD) is acutely occluded proximally.
METHODS: In 18 anesthetized pigs (74 ± 7 kg, mean ± standard deviation), a covered stent was placed transmurally in the lateral wall of the beating LV and connected to the proximal LAD via an arterial graft. Subepicardial and subendocardial segmental shortening as well as interstitial lactate and glucose concentrations were measured regionally by sonomicrometry and microdialysis, respectively.
RESULTS: When the LAD was occluded proximally, direct left ventricular sourcing decreased the net LAD flow to 64 ± 25% of the native flow (n = 18, all animals). In the subepicardium, systolic shortening (SS) decreased to 87 ± 18% of baseline (p = 0.124), with the appearance of minor postsystolic shortening (PSS), and minor changes in interstitial lactate and glucose levels. In the subendocardium, in contrast, SS decreased to 54 ± 20% (p = 0.001). Marked PSS concurred with a sixfold increase in lactate (p = 0.008), and a 65 ± 31% decrease in glucose (p = 0.003), indicating subendocardial anaerobic metabolism. Stress induced by infusion of dobutamine increased lactate and decreased glucose concentration in the subepicardium to subendocardial levels, indicating transmural anaerobic metabolism.
CONCLUSIONS: In the anesthetized pig, direct sourcing by a LV-CA bypass distal to an acute coronary occlusion resulted in a 36% decrease in net forward coronary flow, subendocardial anaerobic metabolism, and loss of subendocardial contractile function at rest. These adverse effects extended into the subepicardium when the heart was stressed.
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Introduction
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| Dr Borst discloses that he has a financial relationship with Medtronic.
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Left ventricle-coronary artery (LV-CA) shunting as an alternative revascularization procedure has recently been restudied [1–5]. These experimental studies demonstrate that a net forward coronary flow between 46% and 70% of baseline flow was obtained [1, 6] which, in theory, may be just sufficient to prevent otherwise intractable angina [2]. The decline in myocardial function measured in those studies correlated well with the decline in net forward flow, suggesting perfusion-contraction matching [1, 6].
Without a valve in the LV-CA bypass, massive coronary backflow to the LV cavity occurs during diastole caused by the precipitous drop in LV pressure at the onset of diastole [1]. Subendocardial perfusion, as a result, is down to 40% of native perfusion, whereas subepicardial perfusion remains at least 60% of native perfusion [6]. Unexpectedly, a comparable degree of coronary flow reduction induced by coronary artery constriction causes adequate subepicardial perfusion at the expense of subendocardial perfusion [7, 8]. The resulting subendocardial increase in lactate and decrease in glucose is the hallmark of anaerobiosis [9–11].
The impact of a coronary artery stenosis on transmural myocardial blood flow cannot be translated unambiguously to changes in coronary blood supply by a LV-CA bypass because, in the former condition, coronary flow is predominantly diastolic [12], whereas in the latter condition, flow is predominantly systolic [1, 6]. In previous studies with LV-CA shunting [1, 6], neither transmural myocardial metabolism nor contractile function was determined. Therefore, we investigated subepicardial and subendocardial LV wall function and metabolism in the pig, both at rest and in stress condition, when coronary blood supply was maintained by a LV-CA bypass after the coronary artery was acutely occluded proximally.
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Material and Methods
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Animals
All experiments were performed in accordance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press (revised 1996) and with prior approval by the Animal Experimentation Committee of the Faculty of Medicine, Utrecht University, The Netherlands. One day before the experiment, all animals received 560 mg of acetylsalicylic acid orally.
Anesthesia
After an overnight fast, Landrace pigs of either sex (74 ± 7 kg, n=18) were sedated with ketamine (10 mg/kg, intramuscular) and anesthetized with thiopental (4 mg/kg, intravenous [IV]) before they were intubated and connected to a respirator for intermittent positive pressure ventilation with a mixture of oxygen and air (1:1 vol/vol). A venous catheter was placed in the jugular vein for continuous administration of saline and anesthetic drugs. Anesthesia was maintained using 0.5% to 1.0% halothane and by continuous infusion of midazolam (0.3 mg/kg/h, IV), while analgesia was obtained by continuous infusion of sufentanylcitrate (1 µg/kg/h, IV) and muscle relaxation by infusion of pancuronium bromide (0.1 mg/kg/h, IV). To reduce the mechanical irritability of the heart during surgery, a bolus of propranolol was given (0.05 mg/kg, IV) prior to surgery.
Surgery
The surgical procedure has been described previously [13]. Briefly, the left anterior descending coronary artery (LAD) was suction stabilized as before [13] using one suction pod exclusively along the side of the right ventricle to prevent any influence of - 400 mm Hg suction on left ventricular performance. First, an auxiliary right internal thoracic artery (ITA) graft was anastomosed to the distal LAD. During proximal segmental LAD occlusion needed for the construction of the left ITA graft-proximal LAD anastomosis, the graft perfused the myocardium retrogradely thus preventing myocardial injury to the future area under study. For creation of a LV-CA bypass, a 4 to 5 cm segment of the left ITA was sutured end-to-end to a specially designed polytetrafluoroethylene covered stent (Percardia Inc, Merrimack, NH). After implantation of the stent [1], the left ITA conduit (free graft) was anastomosed to the proximal part of the LAD between the first and second diagonal branch (Fig 1). A snare was placed around the LAD proximal from the LV-CA bypass-LAD anastomosis for occlusion of the proximal LAD during direct blood supply from the LV. After the stent implantation, the temporary distal ITA graft was clamped during the further course of the experiment.
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Fig 1. Schematic presentation of the surgical procedure. First, a right internal thoracic artery (ITA) bypass to the distal left anterior descending (LAD) coronary artery was created to allow distal perfusion during the creation of the left ventricle-coronary artery (LV-CA) bypass. In this way the myocardial area of interest would be perfused at all times. The proximal LAD bypass had its origin in the LV lumen and consisted of a free left ITA graft (arterial conduit) with a polytetrafluoroethylene-covered stent at one end inserted through the LV wall. In this way direct left ventricular sourcing of the LAD was established. Blood flow was measured by placement of transonic flow probes ( ) on the mid-LAD (Qmid-LAD), and on the LV-CA bypass (QLV-CA bypass). To measure myocardial contractile performance, two pairs of ultrasonic echocrystals were embedded in the subendocardium and subepicardium. For measurement of myocardial metabolism, interstitial lactate and glucose concentrations were determined using microdialysis probes (T). During the protocol, the distal ITA-LAD bypass was closed and three different blood supply conditions were compared.
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Instrumentation and Measurements
Transit time flow probes (Transonic Systems, Inc, Ithaca, NY) were placed around the mid-LAD and the LV-CA bypass (Fig 1). Owing to measurement interference, local transmural myocardial function and metabolism had to be measured in separate animals. For the estimation of regional myocardial function, sonomicrometry was used. In the distribution area of the LV-CA bypass, two pairs of small piezoelectric crystals (Sonometrics Corporation, Ontario, Canada) were placed in the subepicardium and subendocardium (group 1, n = 7). Systolic shortening (SS) was calculated as ([EDL-ESL]/EDL)·100%, in which EDL (end diastolic length) and ESL (end systolic length) are the segment lengths at the onset of the rapid increase in LV pressure and at the minimum of the rapid decrease in LV pressure (LV dP/dtmin), respectively. Postsystolic shortening (PSS) or after-contraction is a relatively nonspecific diastolic hallmark of injured myocardium observed shortly after the aortic valve has closed (by definition at the onset of diastole at decreasing LV pressure) and was calculated as ([ESL-Lmin]/EDL)·100%, in which Lmin is the minimum segment length after end-systole. The PSS is not seen in normal myocardium [14].
For the measurement of regional interstitial lactate and glucose concentration in the subepicardial and subendocardial portion of the myocardium, microdialysis probes (CMA/20, Carnegie Medicine AB, Sweden) were placed in the heart muscle 1 mm below the epicardium and 1 mm in the layer close to the endocardium of the area perfused by the LV-CA bypass (group 2, n = 5; group 3, n = 6). Probes were perfused by modified Krebs-Henseleit phosphate buffer (NaHCO3 25 mM; NaCl 118 mM; KCl 4.7 mM; MgSO4·7H2O 1.2 mM; NaH2PO4 1.2 mM; CaCl2·2H2O 1.2 mM; pH 7.4) using a CMA/100 microinjection pump (2 µL/min). In the microdialysis samples, collected over a period of 10 minutes, lactate and glucose concentrations were analyzed, using a CMA/600 Microdialysis Analyser (Carnegie Medicine AB, Sweden), that represent a fraction of the actual interstitial levels. Measurement of myocardial metabolism started 120 minutes after implantation of the microdialysis probes (recovery period microdialysis probes).
Experimental Protocol
After a recovery period of minimally 30 minutes after surgery and instrumentation, the animals were allocated nonrandomly to group 1 (myocardial function, n = 7) and to groups 2 and 3 (myocardial metabolism, n = 5 and 6, respectively) (Fig 2). Group 1 consisted of 4 animals from a previous study [13] plus 3 extra animals from the current study.
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Fig 2. Schematic drawing of the experimental protocol. In protocol A, three different sources of blood were compared. Condition 1: baseline, blood supply by native LAD flow (LV-CA bypass occluded); condition 2: both proximal LAD and LV-CA bypass are open; condition 3: direct left ventricular sourcing, blood supply through the LV-CA bypass, proximal LAD is clamped. In group 1, hemodynamics (H) and contractile function (F) were measured at the end of each condition (5 minutes). In group 2 hemodynamics (H) were measured at 5 minutes of each condition, while microdialysis samples (M) were collected after 10 minutes. In protocol B, after 120 minutes condition 3, the heart was stressed by infusion of three consecutive concentrations of dobutamine (Dobu; 5, 10, and 20 µg/kg/min). Hemodynamics were measured at 5 minutes of each condition, while microdialysis samples were collected after 10 minutes. (LAD = left anterior descending coronary artery; LV-CA = left ventricle-coronary artery.)
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In protocol A (acute direct ventricular sourcing in groups 1 and 2), the animals were subjected to three coronary blood supply conditions. First, native LAD flow was the unique coronary blood supply (LV-CA bypass occluded, condition 1). In condition 2, the LV-CA bypass was fully patent in competition with the native LAD. In condition 3, the proximal LAD was occluded and LAD perfusion was derived exclusively from the LV-CA bypass. In group 1, conditions 1–3 lasted 5 minutes and general hemodynamics and transmural myocardial function were measured at 5 minutes in each condition for 10 seconds (2 breathing cycles). In group 2, conditions 1–3 lasted 10 minutes during which the subepicardial and subendocardial dialysate samples were collected. In each condition, general hemodynamics were measured at 5 minutes for 10 seconds. In both groups, conditions 1–3 were repeated. First and second data sets were combined, averaged and used for statistical analysis.
In protocol B (150 minutes direct ventricular sourcing in group 3), hemodynamics and transmural myocardial metabolism measurements were taken over a period of 150 minutes. After baseline measurements (condition 1), the proximal LAD was occluded and mid-LAD flow was supplied exclusively by the LV-CA bypass for 120 minutes (condition 3). Thereafter, the heart was stressed with three increasing concentrations of dobutamine (5, 10, and 20 µg/kg/min).
Statistical Analysis
All data are presented as mean ± standard deviation. In protocol A, statistical comparison of the changes versus baseline and changes in myocardial metabolism or function in the subepicardium and subendocardium was tested using a paired Student’s t test. In protocol B, statistical comparison of the changes within the group was tested using repeated measures analysis of variance by general linear model.
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Results
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Protocol A: Acute Direct Ventricular Sourcing
General hemodynamics
In Table 1, changes in general hemodynamics, mid-LAD flow, and LV-CA bypass flow are listed. When both proximal LAD and LV-CA bypass were open (condition 2), a huge amount of blood passed through the LV-CA bypass to the LV cavity without affecting coronary flow distal to the LV-CA bypass as indicated by the unchanged mid-LAD flow. When LAD blood supply originated exclusively from the left ventricle (condition 3), the flow pattern in the mid-LAD changed from primarily diastolic flow during native blood supply to fivefold increased systolic flow (compared to baseline, p = 0.001) and torrential diastolic regurgitive flow. As a result, the net forward mid-LAD flow dropped to 61 ± 19% (p = 0.001, n=12) of baseline flow.
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Table 1. Changes in General Hemodynamics, Coronary Blood Flow, Myocardial Function, and Metabolism During Direct Ventricular Sourcing (Protocol A, Group 1 + 2, n = 12)
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Transmural myocardial contractile function
When both proximal LAD and LV-CA bypass were open (condition 2), there was no significant change in both net forward mid-LAD flow and subepicardial or subendocardial function (Table 1, Fig 3). During direct left ventricular sourcing (condition 3), subepicardial SS declined to 87 ± 18% of baseline value (p = 0.124) accompanied by minimal appearance of PSS (2.8 ± 1.7%, p = 0.007). In the sub-endocardium, SS significantly declined to 54 ± 20% of baseline value (p = 0.001) during direct left ventricular sourcing (condition 3), which was accompanied by the appearance of significant PSS (6.8 ± 3.8%, p = 0.005).
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Fig 3. Protocol A, group 1. Mean mid-LAD flow and regional systolic shortening (SS%) in the subepicardium and subendocardium of the area perfused by the LV-CA bypass during condition 2 (hatched bars: native + LV-CA bypass) and condition 3 (closed bars: LV-CA bypass). Condition 2: both proximal LAD and LV-CA bypass were fully patent. Condition 3: blood supply solely by the LV-CA bypass. Data are presented as % of baseline (BL, condition 1 native flow, mean ± standard error of the mean). *p < 0.05 vs BL. (LAD = left anterior descending coronary artery; LV-CA = left ventricle-coronary artery.)
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Transmural myocardial metabolism
During native blood supply (condition 1), or when the LV-CA bypass was additionally opened (condition 2), no transmural differences in dialysate lactate or glucose levels were found. During direct left ventricular sourcing (condition 3), dialysate lactate levels in the subepicardium doubled, while dialysate glucose levels remained unchanged (Fig 4). Only 2 of 5 animals were responsible for the average increase in lactate level.
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Fig 4. Protocol A, group 2. Mid-LAD flow, regional interstitial lactate (% of BL) and glucose (% of BL) concentrations in the subepicardium and subendocardium of the area perfused by the LV-CA bypass during condition 2 (hatched bars: native + LV-CA bypass) and condition 3 (closed bars: LV-CA bypass). Condition 2: both proximal LAD and LV-CA bypass were fully patent. Condition 3: blood supply solely by the LV-CA bypass (0–10 min and 11–20 min). Data are presented as % of BL (condition 1 native flow, mean ± standard error of the mean). * p < 0.05 vs BL. (BL = baseline; LAD = left anterior descending coronary artery; LV-CA = left ventricle-coronary artery.)
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In the subendocardium, acute direct left ventricular sourcing resulted in a fourfold and sixfold increase in dialysate lactate levels after 10 and 20 minutes (p = 0.017 and p = 0.008), respectively, which was accompanied by a decrease in dialysate glucose levels of 36 ± 22% (p = 0.009) and 65 ± 31% (p = 0.003) compared to baseline values, respectively. Subendocardial dialysate lactate levels were significantly higher than subepicardial dialysate lactate levels (p = 0.019), while dialysate glucose levels did not differ transmurally.
Protocol B: 150 Minutes Direct Ventricular Sourcing
General hemodynamics
Changes in general hemodynamics, mid-LAD flow, and LV-CA bypass flow are listed in Table 2. Direct left ventricular sourcing (condition 3) resulted in a net forward mid-LAD flow that varied between 74 ± 40% of native net forward mid-LAD flow after 30 minutes (p = 0.288) and 89 ± 54% of native net forward flow after 120 minutes (p = 0.441).
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Table 2. Changes in General Hemodynamics, Coronary Blood Flow, and Myocardial Metabolism During Direct Ventricular Sourcing Under Normal and Stress Conditions (Protocol B, Group 3, n = 6)
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Dobutamine infusion caused a concentration dependent increase in heart rate up to 145 ± 22 beats per minute (p = 0.002) and in LV dP/dtmax that was significant at all dobutamine infusion rates (p < 0.01). The mean net forward mid-LAD flow tended to decrease (Fig 5).
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Fig 5. Protocol B, group 3. Representative recording of mid-LAD flow pattern during native blood supply (condition 1, baseline [BL]) and during direct left ventricular sourcing with a LV-CA shunt (condition 3) at rest and in stress condition. Top graphs show the left ventricular pressure ([LVP], mm Hg), middle graphs show the mid-LAD flow pattern (mL/min), and bottom graphs show mean (closed bars), systolic (open bars), and diastolic (hatched bars) mid-LAD flow (mL/min). End diastole was defined as the onset of rapid increase in LV pressure, while end systole was defined at the maximal rate of fall in left ventricular pressure (LV dP/dt min). *p < 0.05 vs BL. Note that for completeness of this figure the data in the bottom graphs are presented as mean ± standard error of the mean, which are the same values as given in Table 2. (D = diastole; LAD = left anterior descending coronary artery; LV-CA = left ventricle-coronary artery; S = systole.)
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Regional myocardial metabolism
Although both dialysate lactate and glucose concentrations at baseline were higher than in protocol A, they did not differ significantly. During direct left ventricular sourcing (condition 3), subepicardial dialysate lactate levels reached a twofold increase after 30 minutes and remained augmented (Fig 6). In addition, dialysate glucose concentration decreased to 70% of baseline levels. In the subendocardium, in contrast, direct left ventricular sourcing instantaneously resulted in a threefold increase in dialysate lactate level, which was accompanied by a significant decrease in dialysate glucose level within 10 minutes to less than 20% of baseline levels. Within 20 minutes near maximum changes were reached and remained relatively stable. During the entire period of direct left ventricular sourcing, subendocardial dialysate lactate and glucose levels were significantly different from subepicardial levels.
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Fig 6. Regional interstitial lactate (% of BL) (top) and glucose (% of BL) (bottom) concentrations in the subepicardium (open circles) and subendocardium (black circles) of the area perfused by the left ventricle-coronary artery (LV-CA) bypass during an extended period of direct left ventricular sourcing. At time point 0, baseline (BL) measurements were taken (condition 1, native flow), which was followed by 150 minutes direct left ventricular sourcing (condition 3). The first 120 minutes were at rest and the remaining 30 minutes (grey area) under stress conditions induced by infusion of 3 consecutive concentrations of dobutamine (5, 10, and 20 µg/kg/min). Data were presented as % of BL (condition 1, native flow, mean ± standard error of the mean). * p < 0.05 vs BL (condition 1: native blood supply);  p < 0.05 vs 120 min LV-CA bypass (condition 3).
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Increased myocardial work by dobutamine infusion caused a dose dependent increase in dialysate lactate concentration in the subepicardium, reaching near subendocardial levels at the highest concentration of dobutamine infusion (Fig 6). Dialysate glucose levels slightly decreased but were still significantly higher than subendocardial dialysate glucose levels. In the subendocardium, dobutamine infusion had no additional detrimental effect on dialysate lactate and glucose levels.
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Comment
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The major findings in this study were: (1) direct left ventricular sourcing to coronary artery distal to an acute proximal LAD ligation decreased the net forward mid-LAD flow to 64 ± 25% of native flow; (2) at rest, no significant changes in contractile function or in lactate and glucose metabolism were found in the subepicardium; (3) at rest, a decreased contractile function was accompanied by an increase in interstitial lactate concentration and a decrease in interstitial glucose concentration in the subendocardium; and (4) increased myocardial work by infusion of dobutamine instigated a conversion from aerobic metabolism to anaerobic metabolism in the subepicardium as well. This study unequivocally provides evidence for subendocardial ischemia at rest during direct left ventricular blood supply to a coronary artery distally to a proximal acute coronary occlusion.
The 36% decline in coronary flow during direct left ventricular sourcing resulted in transmural differences in myocardial function. Subendocardial myocardial segmental shortening decreased to 54% of baseline function, whereas subepicardial myocardial segmental shortening hardly changed. These findings are consistent with the transmural perfusion results in pigs [1] and dogs [6]. Due to the rise in extravascular pressure in the myocardial wall during systole [15, 16], subendocardial perfusion declines to less than 40% of native perfusion during direct left ventricular sourcing, while subepicardial perfusion remains above 60% of native perfusion [6]. In the present study, subepicardial function and metabolism did not change at rest significantly. The minor increase in lactate levels in the subepicardium was caused by 2 animals in group 2, in which lactate showed at least a twofold increase, indicating borderline subepicardial ischemia. In the other 3 animals no changes in lactate or glucose were observed, indicating that in these animals the subepicardium was sufficiently perfused by the LV-CA bypass. It is not clear, from the combination of perfusion data with contraction data as reported earlier [1, 6], whether myocardial function is down regulated due to underperfusion or whether ischemia causes a deterioration of myocardial function. Thus, to arrive at a decisive answer, we studied transmural myocardial metabolic state in addition to function.
In the subendocardium, the instantaneously halved contractile function during direct left ventricular sourcing was accompanied by an immediate increase in interstitial lactate concentration and a decline in interstitial glucose. The combined glucose uptake and lactate efflux are evidence for subendocardial ischemia [9]. Consistent with other canine and porcine studies, in which the LAD was partially or completely occluded [9, 11, 17], interstitial lactate concentrations increased rapidly and remained stable after about 20 minutes. The observed decline in subendocardial interstitial glucose is attributed to a diminished delivery due to reduced perfusion [17] as well as to an increased uptake for metabolization to lactate [10].
When the heart was stressed by dobutamine infusion, the unfavorable metabolic state in the subendocardium did not further deteriorate, it is possible that the energy disbalance, ie, anaerobiosis, had reached a maximum. In the subepicardium, however, lactate production increased dose dependently, indicating a stepwise conversion from aerobic metabolism under resting conditions to anaerobic metabolism under stress conditions. In the presence of normal porcine coronary flow, increased myocardial work induced by dobutamine infusion causes no changes in either interstitial or coronary venous lactate, suggesting that the cellular energy balance is maintained [18]. In this acute setting, our data demonstrate that during direct left ventricular sourcing coronary flow reserve in the subendocardium was already depleted under resting conditions, and that the remaining coronary flow reserve was insufficient in the subepicardium to cope with the increase in myocardial demand.
We infer that in the pig, an animal without collateral circulation, the lack of blood supply in diastole is the cause of the myocardial supply-demand imbalance. The only way to attain adequate delivery of blood throughout the cardiac cycle would be incorporation of a functional valve in the LV-CA conduit to block diastolic regurgitive flow. In two pilot studies in which rabbit aortic valves were incorporated into the LV-CA bypass, diastolic regurgitive flow was prevented and net forward flow remained 100% of native LAD flow. We infer from this observation that a true valve or a valvelike mechanism would greatly enhance the efficacy of the LV-CA bypass.
Limitations of the Animal Model
To allow the direct measurement of LV-CA bypass flow, the surgical implantation of the LV-CA bypass differed from the implantation method in humans by the use of an ITA graft to connect the left ventricle to the coronary artery [13]. Owing to mutual interference of simultaneous measurements of myocardial function and metabolism, these measurements had to be made in separate series of animals. This is not a major limitation, however, because the flow data were similar in the function and metabolism groups (Tables 1 and 2). In protocol A, in addition, changes in myocardial function showed a temporal correspondence to changes in myocardial metabolism in both subepicardium and subendocardium (Figs 3 and 4) as well as to perfusion data measured by microspheres in other studies [1, 6].
The present experimental animal model did not include a chronic coronary stenosis with myocardial ischemia upon exercise and associated collaterals. In the chronically ischemic animal, the effect of collateral flow on subendocardial myocardial perfusion, metabolism, and function during direct left ventricular sourcing remains to be established. Under the condition of the present porcine experiment (normal hearts and acute total coronary occlusion) the technique is of no value. However, when a clinical LV-CA bypass was implanted distal to a high-grade stenosis, exercise stress testing did not induce signs of myocardial ischemia or chest pain [2]. In that clinical study, however, other coronary arteries received conventional bypasses at the same time and the impact of collaterals is unknown. Furthermore, in the clinical setting the connection is created by making an arteriotomy and subsequently stab a VSTENT across the bottom of the coronary artery through the myocardium into the left ventricle, as described by Boekstegers and colleagues [1]. Using the VSTENT the cardiac surgeon does not need a graft from the ITA, but still has to close the arteriotomy with a patch. These patients were operated on the arrested heart using cardiopulmonary bypass. It is conceivable that the VSTENT can be implanted on the beating heart under segmental coronary occlusion using a local cardiac wall stabilizer, even in the condition of poor ventricular function when the heart is not hoisted. The existence of poor target vessels may be a serious obstacle. It is unknown to us whether the current technique is applicable in the end to patients with small gracile coronary vessels as often is found in the diabetic patient. Therefore, we are currently exploring alternative routes for vascular access and perfusion (venous retroperfusion in the chronic ischemic pig model).
In conclusion, in the pig direct sourcing by an LV-CA bypass distal to an acute LAD occlusion acutely produced subendocardial ischemia and reduction in contractile function at rest, whereas subepicardial function and metabolism remained unchanged. Under stress conditions, however, epicardial function also deteriorated and metabolism turned into anaerobiosis, transmurally. The efficacy of LV-CA bypass in the chronic ischemic model needs to be established.
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Acknowledgments
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The authors acknowledge the constructive contributions from the Center of Biostatistics, University of Utrecht, Merel Schurink, Tjaakje Visser, and Hannelie M. Engbers from the University Medical Center Utrecht, and colleagues from the Utrecht University Central Animal Facilities. This research was supported by an unconditional grant from Percardia, Inc.
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Invited commentary
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Ann. Thorac. Surg. 2005 80: 161-162.
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G. DiLuozzo and T. A. Salerno
Invited commentary
Ann. Thorac. Surg.,
July 1, 2005;
80(1):
161 - 162.
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Abstract
Introduction
