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Ann Thorac Surg 2000;69:1811-1816
© 2000 The Society of Thoracic Surgeons

Original articles: Cardiovascular

Excimer versus carbon dioxide transmyocardial laser revascularization: effects on regional left ventricular function and perfusion

Jeffrey S. Martin, MDa, Umer Sayeed-Shah, MDa, John G. Byrne, MDa, Mark H.D. Danton, FRCSa, Kathryn Q. Flores, MDa, Rita G. Laurence, BSa, Lawrence H. Cohn, MDa

a Division of Cardiac Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA

Address reprint requests to Dr Byrne, Division of Cardiac Surgery, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115
e-mail: jgbyrne{at}bics.bwh.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Transmyocardial laser revascularization (TMR) has been established with the carbon dioxide (CO2) laser. The largely unstudied excimer laser creates channels through chemical bond dissociation instead of thermal ablation, thereby avoiding thermal injury. We sought to compare the effects of CO2 and excimer TMR in a porcine model of chronic ischemia.

Methods. Pigs underwent ameroid constrictor placement on the circumflex artery to create chronic ischemia. TMR was performed with CO2 (n = 8) or excimer (n = 8) laser 6 weeks later; controls (n = 7) had ameroid placement only. Regional myocardial blood flow (RMBF), determined by radioactive microspheres, and regional myocardial function, determined by percent segmental shortening (%SS), were assessed 18 weeks after ameroid placement.

Results. Values are mean ± SD. In the ischemic zone, RMBF (mL/min/g) was improved in the CO2 (0.73 ± 0.19) and excimer (0.78 ± 0.22) groups when compared with controls (0.55% ± 0.12%, p < 0.05). %SS was also improved in the CO2 (15.2% ± 5.5%) and excimer (15.3% ± 5.1%) groups when compared with controls (8.0% ± 4.2%, p < 0.05).

Conclusions. Excimer and CO2 TMR significantly improve RMBF and regional function in this porcine model of chronic myocardial ischemia despite fundamentally different tissue interactions.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
The Food and Drug Administration (FDA) recently approved transmyocardial laser revascularization (TMR) with a high-energy carbon dioxide (CO2) laser, as sole treatment for patients with chronic myocardial ischemia not amenable to conventional percutaneous or surgical revascularization. CO2 TMR has resulted in reduced angina scores, medication requirements, and hospital admissions for the majority of patients undergoing the procedure [1–3]. Clinical improvements have correlated with improved myocardial perfusion [1–3] and regional function [4]. Although the mechanism by which TMR produces clinical benefits has yet to be determined, increased myocardial perfusion through angiogenesis has been suggested as the most likely mechanism [5, 6]. The myocardial injury created by the laser induces an inflammatory response, which in turn may trigger the release of numerous cytokines and growth factors that lead to neovascularization [7]. If this is the case, results after TMR may differ with the type of laser employed.

Clinical and experimental studies evaluating TMR have used almost exclusively the CO2 laser, which operates in the infrared spectrum. It creates channels through thermal ablation and produces a well-defined pattern of collateral thermal injury [8]. The excimer laser, which operates in the ultraviolet spectrum, creates channels through the dissociation of chemical bonds, thereby minimizing thermal damage to surrounding tissue [8, 9]. The effects of excimer TMR on ischemic myocardium, however, have not been evaluated. In this study, we compared the effects of excimer and CO2 TMR on regional myocardial blood flow (RMBF) and left ventricular function in an established porcine model of chronic myocardial ischemia [10, 11].


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Ameroid placement
All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). Thirty-two yorkshire pigs, mean weight 16.5 ± 2.1 kg, underwent premedication with intramuscular telazol (5 mg/kg), and the administration of intravenous MgSO4 (2 mg), Bretyllium (3.5 mg/kg), and Ancef (1 mg). Animals were intubated and mechanically ventilated (North American Drager,Telford, PA). Anesthesia was maintained with 2% isoflurane/100% O2. The heart was exposed through a mini-left thoracotomy through the second interspace, and the pericardium was incised and suspended. The proximal circumflex coronary artery was dissected at its takeoff from the left main coronary artery. A 2.5-mm ameroid constrictor (Research Instruments, Corvallis, OR) was placed around the proximal circumflex artery to induce chronic regional ischemia (Fig 1). A 28F chest tube was inserted and placed on suction. The pericardium and chest wall were closed routinely. The animals were extubated and the chest tubes removed. Animals were allowed to recover for 6 weeks so that ameroid constriction and incomplete collateralization could occur. The animals were randomized to either the control group, in which no laser intervention was performed, or one of two laser groups.



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  		Fig 1. Experimental model depicting ameroid placement, ischemic and nonischemic zones, crystal placement, and RMBF determination.

 
Excimer TMR (n = 9)
Animals received the same premedication and anesthesia as above. A left thoracotomy was performed through the fifth interspace, and the pericardium was incised and suspended. Adhesions were dissected away to reveal the left ventricular free wall. An excimer laser (CVX-300; Spectranetics, Colorado Springs, CO) was used to place 16 to 17 transmural channels in the distribution of the circumflex artery (Fig 1). Laser parameters were set at a fluence of 35 mJ/mm2, 30 pulses per second, and a fiberoptic length of 1.5 cm, based on a maximal ventricular thickness of 1.25 cm. The fiberoptic catheter (1-mm outer diameter) was advanced at a rate of 1 mm/s with a customized drive box (US Surgical Corp, Norwalk, CT). Penetration of the ventricle was confirmed by pulsatile bleeding, which was stopped with mild manual pressure. Channel density was approximately one channel/cm2, with care taken to avoid coronary vessels. A chest tube was inserted, and the pericardium and chest wall were closed. Animals were extubated and the chest tubes removed. Animals were allowed to recover for 12 weeks.

CO2 TMR (n = 9)
Animals underwent the same procedure as above except that an 800-W CO2 Heart Laser (PLC Systems, Franklin, MA) was used to create 14 to 19 transmural channels (16 J, pulse width 20 ms) in the distribution of the circumflex artery. Left ventricular (LV) penetration was confirmed and bleeding stopped with mild pressure.

Terminal study
All animals were recovered 18 weeks from the time of ameroid placement (12 weeks after TMR for the excimer and CO2 groups). They were premedicated with intramuscular telazol (5 mg/kg) and intubated via a tracheostomy that was created while masking with 7% isoflurane/100% O2. Mechanical ventilation was initiated, and anesthesia was maintained with 3% isoflurane/100% O2. Central venous access was established via the left internal jugular vein. Intravenous MgSO4 (2 mg) and Bretyllium (3.5 mg/kg) were given. A 16-gauge catheter was inserted in the left femoral artery for interval blood gas determination. A median sternotomy was performed, the pericardium incised and suspended, and adhesions were lysed. The superior and inferior vena cavae were encircled with an umbilical tape for intermittent bicaval occlusions.

Instrumentation
Five-French Millar Micro-Tip pressure transducing catheters (Millar Instruments, Houston, TX) were inserted in the left carotid artery and in the LV. An electromagnetic flow probe (Carolina Medical Electronics, King, NC) was placed around the ascending aorta and flow was measured on a square wave electromagnetic flowmeter (Carolina Medical Electronics). A 6-French pigtail volume conductance catheter (Cordis Webster, Baldwin Park, CA) was placed in the LV through a small apical stab wound and held in place with a purse-string suture. A Sigma 5 volume transducer (Leycom, Zoetermeer, Netherlands) was used to measure blood resistivity (necessary for volume calibration) and continuous LV volume.

The ischemic zone was defined as the area between the first and third obtuse marginal branches of the circumflex coronary artery (Fig 1). The nonischemic zone was defined as the zone between the first diagonal branch of the LAD and the LAD. One pair of 5-MHz hemispherical piezoelectric ultrasonic crystals (Triton Technology Inc, San Diego, CA) were placed in the subendocardium approximately 1 cm apart, parallel to the atrioventricular groove, in both ischemic and nonischemic zones, to measure segmental shortening. A sonomicrometer (Triton Technology Inc, San Diego, CA) was used to transduce the crystal signals.

Measurements
Analog data were digitized at 200 Hz and stored on a personal computer using Lab View hardware and software (National Instruments, Austin, TX). The Lab View software, customized in our laboratory, was used for data analysis and calculations. To calculate parallel conductance, 15 mL of hypertonic saline (12.5% NaCl) was injected into the pulmonary artery over 15 beats to transiently alter the conductivity of blood. With the ventilator off, data were recorded over multiple cardiac cycles during saline injection, steady state, and bicaval occlusions. At least 10 cardiac cycles were used to calculate each parameter, and data runs containing premature ventricular contractions were excluded. The volume-offset of the conductance catheter was calculated by examining the data from the hypertonic saline injections. A linear regression was performed between maximum and minimum LV conductance volumes for each cardiac cycle during the transient increase in blood conductivity. The volume-offset was determined by calculating the intersection of the regression line with the line of identity. Using steady-state data, the volume gain was determined by performing a linear regression between the cumulative ejected volumes from the conductance catheter and the integral of the aortic flow for each time point during ejection. The slope of the regression line was defined as the volume gain.

Steady-state data were used to calculate heart rate (HR), mean pressures, LV volumes, percent segmental shortening (%SS), ejection fraction (EF), LV stroke work (SW), maximal rate of rise in LV pressure (dP/dtmax), and preload-adjusted maximal power (Pmax/EDV2). Percent segmental shortening, an index of regional myocardial function, was calculated by the following equation: 100x (diastolic segment length - systolic segment length/diastolic segment length). The left ventricle pressure/volume loop was integrated to calculate SW. Pmax/EDV2 is the instantaneous maximal product of aortic pressure and aortic flow corrected for end diastolic volume [12]. Bicaval occlusion data were used to generate work loops at varying preloads in order to calculate preload recruitable stroke work (PRSW) and end-systolic elastance (Ees), both of which are load-independent indices of LV function [13, 14].

Blood flow determination
Regional myocardial blood flow (RMBF) was determined in the ischemic and nonischemic zones of 4 animals randomly selected from each group, with radioactive microspheres using an established technique [15]. Measurements were performed at baseline after hemodynamic data were collected. A 16-gauge catheter was placed in the left atrium for the injection of 15-µm 113Sn radioactive microspheres (NEN, Boston, MA). The 16-gauge catheter in the left femoral artery was used for reference blood sample withdrawal. The microsphere suspension was sonicated for 15 minutes and shaken for 2 minutes before injection. Injection was carried out over 20 seconds with approximately 9 x 106 microspheres being injected in a volume of 10 mL. Reference blood sample withdrawal was performed at a rate of 9.8 mL/min with a withdrawal pump (Harvard, South Natick, MA). The withdrawal was initiated 10 seconds before injection and carried out 2 minutes after its completion. After arresting the heart, two transverse slices containing ischemic and nonischemic zones were used to determine RMBF (Fig 1). Within each slice, the ischemic zone was divided into five samples and the nonischemic zone was divided into three samples. Each sample was further divided into subendocardial and subepicardial layers. Each heart sample was weighed and counted with a gamma counter (Packard Instruments Co, Downers Grove, IL) along with the reference blood sample. Counts obtained for each heart sample were multiplied by the known reference withdrawal rate and divided by the reference blood sample count to determine RMBF (expressed as mL/min/g). The ratio of subendocardial to subepicardial RMBF was calculated in both ischemic and nonischemic zones (endo/epi ratio).

Gross assessment
Hearts were arrested with an intracardiac injection of 80 meq KCl. The ameroid constrictor was dissected and examined, and hearts were systematically sectioned and examined grossly for the presence of myocardial infarction.

Statistical analysis
All statistical analysis was performed using Sigma Stat software (SPSS Inc, Chicago, IL). Analysis of variance was used to compare data among groups. Significant differences were established at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Values are reported as mean ± standard deviation. Mean animal weight at the time of sacrifice was 73.0 ± 10.7 kg. Seven animals experienced sudden cardiac death 1 to 4 weeks after ameroid placement, leaving 25 animals for randomization. Autopsies did not reveal gross myocardial infarction. In the excimer group, 1 animal died from ventricular fibrillation during creation of the third laser channel, leaving 8 animals for analysis in this group. This animal was in atrial fibrillation before TMR. In the CO2 group, 1 animal died from ventricular fibrillation during retraction of the heart, leaving 8 animals for analysis in this group.

Ameroid constrictors from all remaining animals were examined at the time of sacrifice and found in each case to be completely occluding the circumflex artery. Gross heart sections did not demonstrate myocardial infarction.

Hemodynamic data
There were no significant differences in mean arterial pressure (MAP), left ventricular end diastolic pressure (EDP), or end diastolic volume index (EDVI) among groups (Table 1). In the CO2 group, the stroke volume index (SVI) was higher and the heart rate was lower compared with the other groups (p < 0.05), though the cardiac index (CI) was not significantly different.


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  		Table 1. Hemodynamic Measurements

 
Global left ventricular function
There were no significant differences in indices of global left ventricular function among groups, though values in both TMR groups were trending towards improvement (Table 2).


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  		Table 2. Indices of Global LV Function

 
Regional myocardial function
In the nonischemic zone, there was no significant difference in %SS among groups (Fig 2A). However, in the ischemic zone, %SS was greater in the CO2 (15.2% ± 5.5%) and excimer (15.3% ± 5.1%) groups compared with the control group (8.6% ± 4.1%, p < 0.05; Fig 2B). There was no significant difference in %SS between TMR groups.



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  		Fig 2. Segmental shortening. (A) Nonischemic zone; (B) ischemic zone. *p < 0.05 versus controls.

 
Regional myocardial blood flow
Regional myocardial blood flow was not less than 0.3 mL/min/g in any sample, arguing against the presence of myocardial infarction. In the nonischemic zone, RMBF (mL/min/g) was not significantly different among groups (Fig 3A). In the ischemic zone, RMBF was greater in the CO2 (0.73 ± 0.19) and excimer (0.78 ± 0.22) groups compared with the control group (0.55 ± 0.12, p < 0.05; Fig 3B). There was no significant difference in RMBF between the two TMR groups.



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  		Fig 3. Regional myocardial blood flow. (A) Nonischemic zone; (B) ischemic zone. *p < 0.05 versus controls.

 
The endo/epi RMBF ratio was not significantly different among groups in the nonischemic zone (Fig 4A), but was greater in the ischemic zone of the CO2 (1.02 ± 0.23) and excimer (1.06 ± 0.26) groups compared with the control group (0.79 ± 0.14, p < 0.05; Fig 4B).



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  		Fig 4. Endocardial/epicardial RMBF ratio. (A) Nonischemic zone; (B) ischemic zone. *p < 0.05 versus controls.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The CO2 laser operates in the infrared spectrum at a wavelength of 10.6 µm and creates channels through thermal ablation, creating a well-defined pattern of collateral tissue injury [8]. The laser energy is absorbed by water molecules, which are heated to a supervibrational state. This vibrational energy is transferred to organic molecules, breaking molecular bonds necessary for channel formation and producing excess heat, which causes thermal injury and necrosis of neighboring tissue [9]. In contrast, the excimer laser operates in the ultraviolet spectrum at a wavelength of 308 nm and is not absorbed by water. The excimer laser possesses much greater photon energy, which is sufficient to cause peptide bond dissociation through direct photon collisions, greatly decreasing heat production and collateral thermal damage [8, 9]. Despite fundamentally different modes of channel creation and patterns of collateral injury, excimer and CO2 TMR produce indistinguishable improvements in regional left ventricular function and RMBF. Although not specifically addressed in this study, improved myocardial perfusion through angiogenesis is the most likely mechanism for the observed results [5–7, 16].

A porcine model was chosen because pigs have a relative paucity of native collateral vessels. This ameroid model of gradual circumflex coronary artery occlusion creates a reproducible zone of collateral-dependent myocardium that closely resembles patients with end-stage chronic myocardial ischemia [17]. Six weeks were allowed after ameroid placement to assure complete circumflex occlusion before performing TMR. Animals were allowed to recover 3 months after TMR because previous clinical studies have shown that TMR-induced improvements in myocardial perfusion become apparent at this time [1–3].

From a technical standpoint, the two lasers are equally easy to use. Excimer TMR takes slightly longer to perform, however, because it requires multiple pulses to create full-thickness channels. In contrast, the CO2 laser creates full-thickness channels with a single pulse. This has led to concerns about arrhythmias with the excimer laser because it pulses over multiple cardiac cycles, increasing the likelihood of a pulse falling on the T wave of the EKG [18]. The single pulse of the CO2 laser is synchronized with the R wave of the electrocardiogram. Lastly, the fiberoptic delivery system of the excimer laser makes it amenable to a percutaneous approach that is not possible with the CO2 laser.

Improvements in RMBF after TMR were more pronounced in the subendocardium as evidenced by the higher ischemic zone endo/epi ratio when compared with controls. This is in agreement with clinical studies that have demonstrated improved subendocardial perfusion after TMR [2]. A porcine ameroid model of chronic myocardial ischemia exhibits a larger decrease in subendocardial RMBF and hence a decreased endo/epi ratio [17]. In this study, laser-treated animals exhibited endo/epi ratios similar to normal myocardium. Finally, it is not surprising that load-dependent and -independent indices of global left ventricular function were not significantly improved, because this is a model of chronic regional ischemia and not heart failure. Typically patients with depressed ventricular function are not considered for TMR [1, 3].

Conclusion
Despite fundamentally different tissue interactions, both excimer and CO2 TMR improve regional left ventricular function and perfusion in this porcine model of chronic myocardial ischemia. Further studies delineating the molecular basis of TMR and laser tissue interactions are needed to determine the mechanism of the observed results.


   Footnotes
 
Doctor Martin’s research is supported by US Surgical Corporation, through a grant from the Harvard Center for Minimally Invasive Surgery.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication December 1, 1999.




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