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J Thorac Cardiovasc Surg 2000;119:1194-1204
© 2000 The American Association for Thoracic Surgery

SURGERY FOR ACQUIRED CARDIOVASCULAR DISEASE

RADIO FREQUENCY HEATING OF CHRONIC OVINE INFARCT LEADS TO SUSTAINED INFARCT AREA AND VENTRICULAR VOLUME REDUCTION

From the Division of Cardiothoracic Surgery, Department of Surgery,^a the Department of Anesthesia,^b and the Division of Cardiology,^c School of Medicine of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center.

This work has been supported by a grant from Hearten Medical Inc, Tustin, Calif.

Address for reprints: Mark B. Ratcliffe, MD, VAMC Surgery 112D, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121 (E-mail: mark.ratcliffe{at}med.va.gov ).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
Objective: Myocardial infarct expansion and subsequent left ventricular remodeling are associated with increased incidence of congestive failure and mortality. Collagen is known to denature and contract when heated above 65°C. We therefore tested the hypothesis that radio frequency heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and left ventricular volume.
Methods: Thirteen male Dorset sheep underwent surgical coronary artery ligation. At least 14 weeks later, animals were randomized to either radio frequency infarct heating (95°C) with application of a restraining patch or a sham operation. Before treatment, after treatment, and 10 weeks later, left ventricular volume was measured with transdiaphragmatic echocardiography and myocardial infarct area was measured with an array of sonomicrometry crystals.
Results: Radio frequency infarct heating causes an acute decrease of 34% (–215 ± 82 mm²; P = .0002) in infarct area at end-diastole that is maintained at 10 weeks (–144 ± 79 mm²; P = .0002). Radio frequency infarct heating causes a downward trend in end-diastolic left ventricular volume measured by echocardiography of 20% (–15.7 ± 6.3 mL; P = no significant difference) and end-systolic left ventricular volume of 32% (–17.1 ± 9.8 mL; P = .09), which are significantly decreased at 10 weeks (–13.6 ± 22.3 mL; P = .007 and –15.3 ± 21.9 mL; P = .008, respectively). Radio frequency infarct heating causes an acute improvement in systolic function (P < .001), a sustained increase in left ventricular ejection fraction (+0.11%; P = .06), and preserved stroke volume.
Conclusion: Radio frequency heating of chronic left ventricular myocardial infarct causes a sustained reduction in infarct area and left ventricular volume. This technique may beneficially reverse infarct expansion and left ventricular remodeling after myocardial infarction.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
Myocardial infarct expansion and subsequent left ventricular (LV) remodeling are associated with an increased incidence of both congestive heart failure (CHF) and mortality. An increase in LV size after myocardial infarction is one of the most important adverse prognostic findings, ^1-6 and relatively small changes (25 mL) in end-systolic volume are associated with exponential increases in mortality. ⁶ Thus, both experimental and clinical studies support the hypothesis that increased ventricular volume is directly related to increased morbidity and mortality.

Recent studies suggest that drugs that prevent remodeling after myocardial infarction improve morbidity and mortality. Angiotensin-converting enzyme inhibitors have been shown to either slow or reverse remodeling after infarction ^4,7 and subsequently decrease the incidence of recurrent myocardial infarction, CHF, hospitalization, and death from cardiovascular causes. ⁸ In addition, ß-blockers improve morbidity and mortality and are associated with reduced LV volume. ^9,10

LV aneurysm repair also reduces ventricular volume and usually increases resting ejection fraction. ^11-13 However, aneurysm repair is associated with a modest operative mortality, and patients who have undergone patch aneurysmorrhaphy have experienced LV redilation at 1 year. ¹⁴ Despite the limitations of current surgical therapy, the early hemodynamic benefits have encouraged the search for surgical ventricular reduction techniques that have lower operative mortality and improved long-term results.

Collagen is known to denature and contract when heated above 65°C. ^15,16 Radio frequency (RF) heating has been used to cause collagen contraction and remodeling in shoulder ligaments ¹⁷ but has not previously been used to thermally denature infarct collagen. Unfortunately, heating makes collagen more likely to creep under load. ¹⁸ In addition, preliminary experiments performed in our laboratory documented that heated myocardial infarct tissue did redilate in the absence of patch restraint. We therefore tested the hypothesis that RF heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and LV volume.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
In brief, 24 male Dorset sheep underwent surgical ligation of the left anterior descending (LAD) and second diagonal (LADD) coronary arteries 40% of the distance from the apex to the base. At least 14 weeks later, the chronic LV infarct was exposed through a partial sternotomy. In a small group of preliminary animals (RF heat/no patch), the infarcted myocardium was heated to 95°C with an RF probe (MYDUS ventricular volume reduction device; Hearten Medical, Inc, Tustin, Calif). A second group of animals underwent RF infarct heating followed by patch coverage of the treated area (RF heat/patch). A third group of animals (control) served as sham-operated controls. All animals were studied in compliance with National Institutes of Health Publication No. 85-23 as revised in 1985.

Myocardial infarction
Adult castrated male sheep were anesthetized (induction with ketamine, 1 g intramuscularly; maintenance with isoflurane [Forane], 2%-4% inspired) and mechanically ventilated (tidal volume 15 mL/kg; model 309-0612-800, Ohio Medical Products, Madison, Wis). A 4- to 5-cm neck incision (either side) was made and catheters were inserted into the external jugular vein (16-gauge Angiocath catheter; Becton Dickinson, Franklin Lakes, NJ) and common carotid artery (20-gauge Angiocath catheter). An 8- to 10-cm thoracotomy was performed in the left fourth intercostal space with sterile technique. Antiarrhythmic drugs were given (procainamide, 20 mg/kg intravenously; lidocaine, 100 mg intravenously, and magnesium, 1 g intravenously). The LAD and LADD coronary arteries were sequentially ligated (15 minutes apart) at a point 40% of the distance from the apex to the base as previously described. ¹⁹ Incisions were closed in layers. Dopamine (5-10 µm · kg^–1 · min^–1 intravenously) was given for 24 hours if the systolic blood pressure was less than 80 mm Hg at the end of the procedure.

Infarct treatment
At least 14 weeks after myocardial infarction, sheep were anesthetized and their lungs were mechanically ventilated as described above. A 4- to 5-cm neck incision was made and catheters were inserted into the external jugular vein (16-gauge Angiocath catheter) and common carotid artery (20-gauge Angiocath catheter). An 8- to 10-cm lower partial sternotomy was performed and pericardial adhesions were divided. Lidocaine was given (100 mg intravenously). An array of epicardial sonomicrometry crystals was applied (Fig 1) and a pneumatic occluder was placed around the inferior vena cava (model OC24HD, In-Vivo Metric Inc, Healdsburg, Calif). A 5F transducer-tipped catheter (model MPC500, Millar Instruments, Inc, Houston, Tex) was inserted into the LV through a needle hole in the LV infarct.

View larger version (28K): [in this window] [in a new window]   Fig. 1. Schema of an experimental animal RF heating of LV infarct. An array of sonomicrometry crystals (Sono crystals) was place on the anterior (crystals 1-5 ), lateral (crystals 6-9 ), and inferior (crystals 10-12 ) epicardial surfaces of the LV. An echo probe (Echo) was inserted into the abdomen through a subxiphoid incision and a transdiaphragmatic long axis of the LV was obtained. The LV infarct was heated with a handheld radio frequency (RF) probe. Ao, Aorta; LV, left ventricle; LA, left atrium.

View larger version (117K): [in this window] [in a new window]   Fig. 2. A close-up picture of the handheld RF probe. A thermocouple measures epicardial temperature during heating.

Data collection
Transdiaphragmatic echocardiography and sonomicrometry measurements were obtained before and after RF infarct heating (before the patch was applied with the chest temporarily closed) and 10 weeks later. Propranolol (0.1 mg/kg intravenously) and atropine (1.0 mg intravenously) were administered before data collection to decrease autonomic reflexes. All data were collected with the same level of anesthesia (isoflurane, 1% inspired).

Echocardiography
A 2.5-MHz 2-dimensional echocardiography transducer (model 5000, General Electric Inc, Rancho Cordova, Calif) was inserted into the abdominal cavity through a subxiphoid incision. The modified long-axis echocardiographic view was chosen so that the aortic and mitral valves and LV apex were included. Each individual echocardiographic examination was recorded on a separate coded videotape. The LV long-axis echocardiogram was used to confirm myocardial infarction and to measure LV volume (LVV_Echo).

Sonomicrometry array
An array of epicardial sonomicrometry crystals was placed on the LV infarct (2.3-mm crystal, Sonometrics Corp, London, Ontario, Canada) and noninfarcted residual myocardium (2.3-mm crystal with suture loops, Sonometrics Corp). Crystals were placed on the anterior (crystals 1-5), lateral (crystals 6-9), and inferior (crystals 10-12) epicardial surfaces of the LV. Sonomicrometry was performed with a digital sonomicrometer (model P150-64-2.5, Sonometrics Corp).

LV pressure was amplified (model M2103B, Electronics for Medicine, PPG Industries, Lenexa, Kan), calibrated with a mercury manometer, and zeroed to the level of the right atrium. LV pressure, sonomicrometry, and electrocardiogram were collected at steady state and during vena caval occlusions with respiration temporarily suspended. Vena caval occlusions were continued until LV peak pressure decreased to 40 mm Hg. Data were collected at 100.7 Hz for 30 seconds with a 4-channel (bipolar), 12-bit analog-to-digital converter housed in the digital sonomicrometer (model P150-64-2.5, Sonometrics Corp). Echocardiograms were obtained before vena caval occlusion.

Blood analysis
The blood samples were obtained before and after RF heating. Blood samples were collected in serum separator tubes and spun at 15,000 rpm for 10 minutes. Serum was frozen at –80°C before processing for plasma free hemoglobin, total creatine kinase, creatine kinase MB isoenzyme, and troponin T (AniLytics, Inc, Gaithersburg, Md). Total creatine kinase (model 717, Hitachi Inc, San Jose, Calif) and creatine kinase MB isoenzyme were determined by isoenzyme electrophoresis (Paragon system, Beckman Inc, Fullerton, Calif). Troponin T was processed with a cardiac-specific troponin T assay (F. Hoffmann-La Roche Ltd, Basel, Switzerland).

Data analysis
Echocardiography
Individual coded videotapes were analyzed in a blinded fashion. LVV_Echo was determined by a modified Simpson rule method (Imagevue, version 1.50, Nova Microsonics, Allendale, NJ). LVV_Echo at end-diastole and end-systole were defined as the video frames with the largest and smallest cross-sectional cavitary areas, respectively.

Sonomicrometry array
End-diastole was determined by the R wave of the electrocardiogram. Determination of end-systole was obtained from the LV pressure short-axis dimension relationship where endsystole was the point of maximal regional elastance.

The LV infarct area was calculated from the sonomicrometry data (Fig 1). The anterior infarct area was obtained by summing the 3 triangles subtended by intrainfarct sonomicrometry crystals (crystal triangles 3-4-8, 4-5-9, and 4-8-9 ). The surface area of each triangle was calculated by the following equation:

The 3-dimensional coordinates of the 13 crystals in a Cartesian reference frame were obtained by means of multidimensional scaling (3d_pen.exe, 09/03/98 version, Sonometrics Corp), as we have previously described. ²⁰ Ventricular volume enclosed by 12 crystals was subdivided into 11 tetrahedrons. The volume, V, of an individual tetrahedron bounded by 4 crystals with Cartesian coordinates, {x ₁,y ₁,z ₁},{x ₂,y ₂,z ₂},{x ₃,y ₃,z ₃} and {x ₄,y ₄,z ₄}

End-systolic pressures, LVP _Sono,ES, and volume, LVV _Sono,ES, were related by:
LVP _ES = E _ESLVV _Sono,ES + LVP _ES,0
where LVP _ES,0 is the y(pressure) intercept and E _ES is the slope of the LV elastance. End-diastolic pressure, LV _ED, and volume, LVV _Sono,ED, were related by:

Programmed electrical stimulation
After the completion of the sonomicrometry studies and a minimum 2-hour infusion of lidocaine, ventricular programmed electrical stimulation was performed (model DTU 110, Bloom Associate Inc, Narberth, Pa). A 6F quadripolar catheter was inserted through the carotid artery introducer and positioned in the left ventricle. Ventricular pacing was performed at a pulse width of 2.0 ms and at twice the diastolic pacing threshold or 2.5 mA if the former was less than 2.5 mA. Intracardiac and surface electrocardiographic signals were recorded on paper (model ES 1000, Gould Inc, Cleveland, Ohio). The programmed electrical stimulation protocol consisted of ventricular pacing from 2 ventricular sites (septum or free wall) at basic drive cycle lengths of 600 and 400 ms with up to 3 extrastimuli at each pacing site and drive cycle length. ²¹ Effective refractory period was determined at each pacing site at both drive cycle lengths. If ventricular tachycardia was induced, cardioversion by pacing was attempted. If this was unsuccessful, external defibrillation was attempted at 400 watt-seconds.

Histology
A sternotomy was performed and the pericardial adhesions were divided. The heart was rapidly excised, a cannula was secured in the ascending aorta, and 1 L of 10% neutral buffered formalin solution was infused from a height of 1 m. Perfusion fixation was continued for 20 minutes. The heart was immersed for an additional 24 hours in 10% neutral buffered formalin solution. Transmural thin sections were obtained from the center of the infarct in a plane parallel to the long axis of the heart. Sections were stained with periodic acid–Schiff and van Gieson stains.

Statistical analysis
All values were expressed as mean ± standard deviation. All measurements were compared with analysis of variance (Proc Mixed, SAS System for Windows, version 6.12, SAS Institute, Inc, Cary, NC). In each case, the difference between pre-treatment and post-treatment values was used as the dependent variable and the absolute pre-treatment value was used as a covariate. ²² Elastance and diastolic compliance relationships were compared with a repeated-measures multiple linear regression (Proc Regress, SAS System for Windows, version 6.12, SAS Institute, Inc) (see the appendix).

	Results

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
A total of 24 sheep began the study. Six animals were eliminated during the study for various reasons. Four animals died at the time of myocardial infarction. Two additional animals were excluded from the study after coronary ligation. One animal was found to not have an infarct at the time of infarct treatment, and the other had a ventricular arrhythmia during sonomicrometry crystal placement. It was resuscitated but removed from the study. Two sheep that were killed immediately after RF infarct heating were used for histologic examination only. Three sheep were used in the preliminary RF heat/no patch group. The remaining 13 animals were randomized to either RF infarct heating plus patch (RF heat/patch) (n = 6) or sham-operated control (n = 7). Finally, 1 animal in the RF heat/patch group was removed from the study because a deep sternal wound infection developed at postoperative week 3.

Acute effect of RF heating
Heating with RF causes the treated tissue to turn gray and "pucker." After the entire infarct has been treated, the infarct appears to have flattened and the ventricular apex (sonomicrometry crystal 5) appears to move onto the anterior LV wall. The rim of uninfarcted myocardium at the edge of RF heating becomes erythematous and slightly swollen. However, there are no statistically significant changes in creatine kinase, creatine kinase MB isoenzyme, or troponin T (Table I). Levels of plasma free hemoglobin are also unchanged, suggesting that RF infarct heating does not cause intravascular hemolysis. Blood from one of the control animals was hemolyzed (hemoglobin value 124.8 mg/dL) and has been excluded from analysis as an outlier. There were no significant arrhythmias associated with RF heating and no animals required inotropic support.

View larger version (20K): [in this window] [in a new window]   Fig. 3. The acute effect of RF heating on end-systolic elastance (EES) and diastolic compliance. A, Comparison of EES before and after RF heating. B, Comparison of diastolic compliance before and after RF heating. LV volume is calculated from sonomicrometry array data (LVVsono). The volume intercept but not the slope of EES was significantly different after treatment. Diastolic compliance was not significantly different after treatment. Degradation of sonomicrometry signals precluded calculation of pressure-volume relationships at 10 weeks. *P < .001 (difference in LV volume intercept).

View larger version (58K): [in this window] [in a new window]   Fig. 4. Histologic studies of infarcts immediately after and 10 weeks after RF infarct heating. A, Immediately after RF heating, coagulated protein in the infarct appears brown to purple on van Gieson stain. Note that evidence of RF heating (RF) extends approximately 50% of the way through the infarct wall into the deep dense collagen layer. Sham-operated control (B) and RF heat/patch animals (C) are shown at 10 weeks. The sham control shows the normal infarct architecture with a loose superficial collagen layer with abundant adipocytes (A) and a deep dense collagen layer. The treated section shows patch remnants (P) and a thin capsule (C). The superficial collagen layer is now composed of dense collagen (DC). The deep layers in the sham-operated control and treatment sections are similar. Epi, Epicardium; Endo, endocardium; VVG, van Gieson; PAS, periodic acid–Schiff.

View larger version (12K): [in this window] [in a new window]   Fig. 5. Effect of RF heating without patch (RF heat/no patch) on the infarct area in a single representative animal (infarct triangle 9-5-4). Note that the infarct area is acutely decreased but redilates over the next several weeks.

View larger version (19K): [in this window] [in a new window]   Fig. 6. Effect of RF heating and patch (RF heat/patch) on end-diastolic infarct area. In each case the treated group is in orange and the sham control is in dark red. RF heating acutely decreased end-diastolic infarct area by 34%. The effect was maintained at 10 weeks. End-systolic infarct area is not shown but was nearly identical. aP = .0002; bP = .0002.

View larger version (18K): [in this window] [in a new window]   Fig. 7. Effect of RF heating and patch (RF heat/patch) on LV volume. A, Effect on end-diastolic LV volume. B, Effect on end-systolic LV volume. In each case the treated group is in orange and the sham control is in dark red. RF heating decreased end-diastolic and end-systolic LV volume by 20% and 32%, respectively. Both end-diastolic and end-systolic volume reduction were maintained at 10 weeks. Note the continued adverse remodeling in the sham-operated controls. aP = .007; bP = .008.

The effect of RF infarct heating in sham-operated and treated animals is seen at 10 weeks. Remnants of the patch are seen at the epicardial surface (Fig 4, C ) in the treated specimen. In addition, there is a thin capsule of collagen directly under the patch (C), and collagen in the outer half of the infarct wall appears to be more densely packed (DC). Otherwise, the infarct wall is indistinguishable from those of sham-operated control specimens (Fig 4, B ).

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
The primary finding of this study is that RF heating of chronic ovine LV infarct causes a sustained reduction in infarct area and LV volume. These reductions in LV volumes are associated with an acute improvement in systolic function (E_ES), a sustained increase in LV ejection fraction, and preserved stroke volume. This technique may beneficially reverse infarct expansion and LV remodeling after myocardial infarction and reduce the incidence of associated CHF and mortality.

Ventricular volume reduction
An increase in LV size after myocardial infarction is an important adverse prognostic finding. ^1-4 Conversely, factors that slow or reverse remodeling after infarction may lead to improved ventricular function, morbidity, and mortality. In this study, RF heating of infarct scar resulted in an acute reduction in LV end-diastolic (20%) and end-systolic volumes (32%). As demonstrated in recent pharmacologic trials, this extent of ventricular volume reduction has direct clinical relevance. Angiotensin-converting enzyme inhibitors are one of the most effective therapies for patients with CHF after myocardial infarction and have been shown not only to increase survival, but also to preserve ventricular geometry and size. ⁴ In a substudy of the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, enalapril treatment for 1 year resulted in a –13 mL/mm² (–9%) decrease in left ventricular end-diastolic volume index, compared with a +13 mL/mm² (+9%) increase in the placebo-treated patients (radionuclide ventriculography; total n = 39; P = .008). ⁷ This decrease in volume represented a 17% difference in end-diastolic volume, compared with a 20% difference in this study.

Although surgical LV aneurysm repair has been extensively studied, the effect of repair on ventricular function remains unclear. LV aneurysm plication reduces ventricular volume and usually increases resting ejection fraction. ^11-13 In this study, RF heating caused an acute improvement in systolic function (E_ES) and a sustained increase in LV ejection fraction. However, it is incorrect to conclude that overall ventricular function has improved if ejection fraction or E_ES increases after aneurysm repair or partial ventriculectomy. ^23-25 We have previously suggested that the success of an operation that surgically remodels ventricular size, shape, or regional stiffness depends on how the procedure affects both end-systolic and diastolic pressure-volume relationships and how those changes affect the stroke work/end-diastolic pressure relationships. ^23,24 In this study, an unchanged stroke volume and a downward but nonsignificant trend in end-diastolic pressure suggest that the Starling relationship is either unchanged or slightly improved. These findings are similar to those after aneurysm plication in the sheep. ²³

In this study, RF heating led to a sustained reduction in LV volume. In contrast, other forms of aneurysm repair have been associated with postoperative redilation. Dor and associates ¹⁴ have described an acute reduction in LV end-diastolic volume from 116 ± 51 mL/m² to 79 ± 23 mL/m² after patch aneurysmorrhaphy in human beings; however, end-diastolic volume rose to 94 ± 29 mL/m² at 1 year. ¹⁴ Similarly, in sheep that have undergone linear aneurysm plication, the ventricle redilates at 10 weeks. ²³ The cause of this postoperative remodeling is unclear but may be related to an increase in border zone wall stress. Aneurysm repair may increase border zone wall stress by increasing residual stress, ²⁶ altering border zone myocyte fiber angles, and changing the stiffness of the aneurysm/aneurysm repair. ²⁷ We suggest that RF heating and epicardial patch restraint reduce LV volume without a significant increase in border zone fiber stress. However, further animal experiments are necessary to confirm this.

Thermal heating of collagen
Heating above 65°C causes collagen to denature and contract. ^15,16 Multiple factors affect the degree of contraction, including the amount of cross-linking, age, pH, water content, ²⁸ temperature, ¹⁵ and load during heating. ¹⁶ Unloaded bovine chordae tendineae contract approximately 30% when heated to 65°C, but contraction increases to 65% when chordae are heated to 85°C. ¹⁵ In this study, epicardial temperature at the treatment site was maintained at 95°C. However, histologic studies documented evidence of heating extending 50% of the way through the infarct wall. This suggests that more aggressive heating might have increased infarct shrinkage without damage to circulating blood. However, further animal experiments are necessary to confirm this.

The amount of heat-induced contraction is affected by load during heating and may be reduced as much as 33% at 65.0 dyne · cm^–2 x 10³. ^16,29 Since we ²⁶ have previously estimated end-systolic stress in the chronic ovine infarct to be between 315 and 703 dyne · cm^–2 x 10³, a greater amount of infarct shrinkage might have occurred if the LV had not been under physiologic pressure. For instance, if RF infarct heating is performed during cold cardioplegic arrest, greater shrinkage may occur. However, the pattern of heat propagation would be altered by the lower ambient temperature and the lack of a heat sink from circulating endocardial blood.

Heating acutely increases collagen compliance ³⁰ and heated collagen partially recovers when temperature returns to normal. ¹⁵ In addition, heating may make collagen more likely to creep and fail under load. For instance, human tendons heated with an Nd:YAG laser exhibited a 70% decrease in load to failure. ¹⁸ In a pilot study performed in our laboratory, 3 animals with infarcts that were heated with RF without a restraining patch redilated in the days after treatment. In subsequent animals, a patch was tacked to the epicardial surface of the treated infarct to prevent infarct re-expansion. The polyester material was chosen because it is inextensible and would resist infarct redilation.

Limitations
A potential limitation of this study is that it does not define the number of patients who would benefit from the procedure. This study investigates the effect of RF heating on predominantly collagen-rich scar tissue. However, the ratio of nontransmural to transmural myocardial infarctions is increasing, ³¹ and the majority of infarcts seen in the human operating room are not confluent scar but some mixture of collagen and viable myocardium. The cause of this is unclear but may be related to prompt revascularization with thrombolytics and angioplasty. We suggest that RF heating of salt-and-pepper infarcts that are mostly collagen will still be beneficial despite some myocyte loss. In fact, Nagueh and associates ³² have recently shown that hibernating myocardium with greater than 25% collagen do not recover with revascularization. ³²

Conclusion and future directions
This study demonstrates that RF heating of LV aneurysm causes sustained reductions in LV infarct area and volumes, with preservation of stroke volume and improvements in ejection fraction. This procedure has the potential to be accomplished with minimally invasive techniques and to provide significant clinical benefit. Future studies will address the effect of this procedure on more heterogeneous myocardial infarctions.

	Appendix: Repeated-measures multiple linear regression

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
To determine whether elastance differed at different experimental time points (ie, before RF heating, after RF heating) and between groups (RF heat/patch, control), we used repeated-measures multiple linear regression in which dummy variables represented the experimental time points, groups, and individual animals. ^33,34 The regression model used was:

LVP _ES = ß₀ + ß₁ LVV _Sono,ES + ß_2i A _i + ß_3i A _i LVV _Sono,ES + ß_4i T _i + ß_5i T _i LVV _Sono,ES + ß_6iG _i + ß_7iG _iLVV _Sono,ES + ß_8iT _iG _i + ß_9iT _iG _iLVV _Sono,ES

where A _i is the effects-coded dummy variable representing individual animals and T _i and G _i are the reference-coded dummy variables representing time points and group. ^33,34 For instance, the A_i term represents the effect of an individual animal on the pressure intercept, LVV_ES,0, and the A_iLVV_ES term represents the effect on slope, E_ES. Dummy-variable methods of this type are a standard way of allowing for between-subject variability in linear regression analysis. ^33,34

As with elastance, a repeated-measures multiple linear regression model was used in which dummy variables represented the experimental time points and individual animals. The regression model used was:

Ln(LVP _ED + 1) = ß₀ + ß₁ LVV _Sono,ED + ß_2i A _i + ß_3i A _i LVV _Sono,ED + ß_4i T _i + ß_5i T _iVV _Sono,ED ß_6iG _i + ß_7iG _iVV _Sono,ES + ß_8iT _iG _i + ß_9iT _iG _iVV _Sono,ES
where A _i, T _i, and G _i are defined as above. A log transformation was used. ³⁴

	Appendix: Discussion

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 
Dr Richard Cochran (Madison, Wis). Dr Ratcliffe I would like to compliment you on a unique and provocative study. Use of RF heating to cause collagen contraction and so to treat ventricular aneurysm is an intriguing concept. This becomes even more appealing if this technology can be used by thoracoscopic techniques, as you imply. However, I have a problem with the study, I have a few questions, and I also have one point of disagreement.

My first problem is that this is an incomplete study. Some of the experiments are ongoing. Six animals that had this technique are still surviving with the patch in place. A critical aspect of the study is whether this is going to be a long-term result. Would you comment on this, please?

Dr Ratcliffe. When this abstract was submitted, only the acute results of the experiment had been analyzed. All of the animals, including the sham-operated and the treated animals, were kept alive and observed for 10 weeks after the RF infarct heating. Preliminary analysis of those results suggests that the reduction in infarct area and LV volume have been maintained in the treatment group, but in the sham-operated animals the LV volume continued to increase. The study is now finished and the results of the long-term phase are being analyzed.

Dr Cochran. How often do you think this technique will be used? In our practice the incidence of LV aneurysm is markedly decreased with lytic use, earlier catheterization and reperfusion, and the angiotensin-converting enzyme inhibitors with remodeling that you have alluded to.

Dr Ratcliffe. The incidence of LV aneurysm is presently unknown. The last reports in the literature are from the late 1980s and quote instances between 10% and 15%. I agree that prompt revascularization with either thrombolytic agents or angioplasty has decreased the occurrence.

However, some people have silent myocardial infarctions. They do not get to the hospital in time to have effective revascularization with thrombolytic agents or angioplasty, and subsequently they undergo ventricular remodeling and aneurysm formation.

A more interesting question is that in the operating room we often see what we call "salt-and-pepper" infarcts, infarcts that have some admixture of collagen and remaining viable myocardium. In infarcts that have mostly collagen and a few residual myocytes, is this technique appropriate, and is it appropriate to kill some of those myocytes that are entrapped in collagen and unable to functionally recover if revascularized?

Dr Cochran. That was the statement that I disagreed with, because we have no evidence from your study or clinically that those salt-and-pepper infarcts develop into aneurysms. I think to sacrifice myocytes for a potential benefit would be unwarranted.

Going back to some of the follow-up questions: Do you think an angiotensin-converting enzyme inhibitor or ß-blockade control in this experimental model would have been appropriate, since that is conventional therapy?

Dr Ratcliffe. It would have been another appropriate control.

Dr Cochran. I am unfamiliar with this patch material. Why did you not choose something like polytetrafluoroethylene, since we are familiar with its mechanical properties? Is this material new?

Dr Ratcliffe. The polyester patch was chosen because it was stiff. As I mentioned, heating makes the collagen shrink but it may suddenly re-expand. The goal was to place an epicardial patch that would prevent sudden re-expansion.

	Acknowledgments

 
We thank Stan Glantz for his support and help with statistical methods.

	Footnotes

 
Read at the Twenty-fifth Annual Meeting of The Western Thoracic Surgical Association, Olympic Valley (Lake Tahoe), Calif, June 23-26, 1999.

	References

Top Abstract Introduction Methods Results Discussion Appendix: Repeated-measures... Appendix: Discussion References

 

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