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Vascular delay and intermittent stimulation: keys to successful latissimus dorsi muscle stimulation
Vascular Delay and Intermittent Stimulation: Keys to Successful Latissimus Dorsi Muscle Stimulation Abul Kashem, MD, PhD, William P. Santamore, PhD, Benjamin Chiang, MD, Lauren Unger, PhD, Ahsan T. Ali, MD, and A. David Slater, MD Division of Cardiovascular Research, Cardiology Section, Temple University, Philadelphia, Pennyslvania, and Division of Cardiothoracic Surgery, Department of Surgery, University of Louisville, Louisville, Kentucky
Background. The goal of this study was to obtain physiologically significant increases in peak left ventricular (LV) systolic pressure and stroke volume with latissimus dorsi muscle (LDM) stimulation in cardiomyoplasty (CMP). We hypothesized that preserving LDM integrity by vascular delay and intermittent stimulation would significantly increase LDM cardiac assistance. Methods. In 4 control dogs and 12 dogs that had undergone a vascular delay (VD) procedure, LV dysfunction was induced by intracoronary microsphere injections. Cardiomyoplasty surgery was performed 14 days later, followed by progressive LDM conditioning. In the control dogs and in 6 of the VD dogs, the LDM was stimulated 24 hours per day (VD plus constant stimulation [CS]). In the other 6 VD dogs, LDMs were stimulated on a daily schedule of 10 hours on and 14 hours off (VD plus interrupted stimulation [IS]). Latissimus dorsi muscle stimulated beats were compared with nonstimulated beats 9 weeks later. Results. In the control dogs, LDM stimulation had
minimal effects. In VD ⴙ CS and VD ⴙ IS, LDM stimulation increased peak LV pressure, stroke volume, stroke work, and stroke power (p < 0.05). However, these changes were greater in the VD ⴙ IS group, in which LDM stimulation increased peak aortic pressure by 17.6 ⴞ 1.7 mm Hg, peak LV pressure by 19.7 ⴞ 1.1 mm Hg, peak positive LV dp/dt by 398 ⴞ 144 mm Hg per second, stroke volume by 5.1 ⴞ 0.7 mL, stroke work by 10.9 ⴞ 0.9 gm 䡠 m, and stroke power by 122.7 ⴞ 11.6 gm 䡠 m per second (p < 0.05 compared with VD ⴙ CS). Quantitative morphometric analysis showed minimal LDM degeneration in the VD ⴙ IS group (7.5% ⴞ 1.1%), and VD ⴙ CS group (10.5% ⴞ 4.5%) compared with the control group (29.5% ⴞ 4.5%, p < 0.05). Conclusions. VD and IS considerably increased the LV assistance with LDM stimulation. Further studies of this combined approach to CMP should be planned.
C
and stroke volume with LDM stimulation in an experimental model of LV dysfunction. We hypothesized that a two-stage vascular delay procedure followed by intermittent stimulation would preserve LDM integrity, leading to increased LDM cardiac assistance.
(Ann Thorac Surg 2001;71:1866 –73) © 2001 by The Society of Thoracic Surgeons
ardiomyoplasty has been shown to inhibit progressive LV enlargement [1–3]. However, in experimental and clinical studies, systolic augmentation of LV function by the LDM has not been routinely observed; LV ejection fraction and peak systolic pressure remain almost identical in presence versus absence of electrical stimulation [4]. Acute mobilization and wrapping of the LDM around the heart causes LDM ischemia [5, 6]. Furthermore, incessant stimulation is detrimental to the LDM. In sheep, LDM stimulation applied 24 hours per day caused more than 40% fiber atrophy and loss of most contractile function, whereas stimulation limited to 10 hours per day caused only minimal fiber atrophy, fatty infiltration, and fibrosis [7]. In goats, Ianuzzo and colleagues [8] found that, compared with continuous stimulation, LDM stimulation limited to 12 hours per day preserved muscle architecture and was associated with less muscle degeneration, larger fiber areas, and lower density of connective tissue. The goal of the present study was to obtain physiologically significant increases in peak LV systolic pressure
Mongrel dogs weighing 22 to 27 kg were assigned to a control CMP group (n ⫽ 4), a group that underwent a vascular delay procedure followed by continuous stimulation (VD ⫹ CS; n ⫽ 6), and a group that underwent a vascular delay procedure followed by stimulation intermittently interrupted for 14 hours per day (VD ⫹ IS; n ⫽ 6). All study procedures were performed in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Accepted for publication Feb 21, 2001.
Vascular Delay
Address reprints requests to Dr Kashem, Temple University School of Medicine, Medical Research Bldg, Room 800A, 3420 N Broad St, Philadelphia, PA 19140; e-mail: [email protected].
After an overnight fast, the animals received intravenous (IV) sodium thiopental, 15 to 25 mg/kg, and intramuscular atropine, 0.01 mg/kg, and were intubated and venti-
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods
0003-4975/01/$20.00 PII S0003-4975(01)02571-1
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lated (Quantiflex, VMC Anesthesia Machine, Orchard Park, NY). Anesthesia was maintained with 2% isoflurane (Isoflurane Vaporizer, Oharda, Isotec 3, Aushell, GA), 0.5% to 1.0% nitrous oxide, and oxygen. Surface electrocardiogram (Hewlett Packard Model No. 78346A) and oxygen saturation were monitored continuously. Cefazolin sodium, 500 mg IV (Marsam Pharmaceutical Inc, Cherry Hill, NJ), 75 mg of gentamicin, and 75 mg intramuscular (Gentocin, Ayerst Laboratories Inc, Rouses Point, NY) were administered preoperatively. Lactated Ringer’s solution, 250 mL to 350 mL per hour IV was infused perioperatively. In the vascular delay groups (VD ⫹ CS and VD ⫹ IS), a 15 to 20 cm long oblique cutaneous incision was made under sterile surgical condition from the left axillary region toward the posterior iliac crest. The anterior border of the left LDM was identified and all perforating collateral branches supplying the muscle were ligated and severed [9 –11]. The spinal border of the muscle was identified and partially mobilized. The wounds were closed in layers using absorbable sutures.
LV Dysfunction In all animals (controls, VD ⫹ CS, and VD ⫹ IS), left ventricular dysfunction was induced by intracoronary injection of microspheres [12]. The left femoral artery was cannulated percutaneously with a 7 French catheter sheath, through which a 6 French left coronary Amplatz No. 1 catheter was advanced into the left main coronary artery under fluoroscopy. Contrast material (Renografin ⫺76, Bristol-Myers-Squibb Co, Princeton, NJ) was injected to verify the catheter position. Latex microspheres (3.0 to 6.0 ⫻ 106, 90 ⫾ 2 diameter; Polyscience Inc, Warrington, PA), mixed in 10 mL of normal saline, were injected into the coronary artery in fractionated doses until left venticular end-diastolic pressure had increased by 50% to 80%, and peak left ventricular pressure and aortic pressure decreased by 20%. The catheter and sheath were removed. The femoral artery was compressed externally for 20 to 30 minutes until hemostasis. All animals survived the intracoronary microsphere injections and were treated with IV injections of furosemide, 0.75 mg/kg, and rapid infusions of 500 L Ringer’s lactated saline solution. Postoperatively, sedation with Acepromazine, 0.5 mg IV, and analgesia with Buprenex hydrochloride, 0.3 mg IV, were administered as needed. A 2-week period was allowed for recovery and vascular remodeling.
CMP Procedure A standard CMP procedure was performed on all animals as described in previous articles [11, 13–15]. Under general anesthesia, with the animal in the right lateral position, a left lateral incision was performed in the midaxillary line. The LDM was dissected out and mobilized from the surrounding tissues and its distal insertions, preserving the thoraco-dorsal neurovascular bundle proximally. The tendon of the LDM was carefully isolated and severed. Two epimysial leads (Model YY38403403 Medtronic Inc, Minneapolis, MN) were im-
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planted on the pedicle with nylon sutures. The cathode was placed proximally on the muscle and the anode 6 to 8 cm distally. The stimulation threshold was measured with a Pacing System Analyzer (PSA 5311, Medtronic Inc, Minneapolis MN). A 4 to 5 cm section of the anterior portion of the left third rib, including its periosteum, was resected to allow the translocation of the LDM flap into the left pleural space. The proximal parts of a sensing myocardial lead and an aortic flow probe (20 mm) were introduced into the chest for later implantation onto the right ventricular anterior wall and ascending aorta, respectively. The epimysial and myocardial leads were tunneled subcutaneously and connected to a dual chamber synchronous cardiomyostimulator (SP 1005, Medtronic Inc, Minneapolis, MN) implanted in a subcutaneous pocket fashioned on the left side. The LDM flap was fixed to the periosteum of the second rib by polybraided 3-0 dexan suturing material to prevent tension on the muscle, and the wound was closed in layers. The heart was exposed through a median sternotomy with the animals in the supine position. After pericardiotomy, the ascending aorta was mobilized and an aortic flow probe (A-series 20-mm, Transonic Systems Inc, Ithaca, NY) was placed around the ascending aorta with a merocel sponge positioned between the flow probe and the aorta, and the distal end of the flow probe positioned subcutaneously. A posterior myocardial wrap was performed in a clockwise fashion with fixation to the pericardium. Bilateral chest tubes were inserted and connected to a water-seal drainage system. The sternum was closed using 4 or 5 parasternal wire sutures. All wounds were closed in layers. The animals were extubated. Postoperative analgesics and sedation with Buprenorphine hydrochloride, 0.3 to 0.6 mg IV, and acepromazine maleate, 0.25 to 0.5 mg intramuscular, were systematically administered, and the animals were positioned onto the right side overnight. Chest tubes were removed on the first postoperative day. Cefazolin 500 mg IV and gentamicin 75 mg IV every 12 hours, were administered for 72 hours postoperatively.
Stimulation Protocols Cardiomyoplasty stimulation began with postoperative week 2. The LDM was progressively conditioned starting at 2 Hz, gradually increasing up to 33 Hz, at a pulse width of 180 s, interpulse interval of 25 ms, and burst durations of 180 to 210 ms, until postoperative week 9. The LDM was stimulated on every other cardiac cycle. In the control and the VD ⫹ CS groups, the cardiomyostimulator was turned on 24 hours per day. In the VD ⫹ IS group, cardiomyostimulation was limited to 10 hours continuously per day.
Hemodynamic Evaluation At 9 weeks after surgery, the dogs were reanesthetized with sodium pentothal, 10 to 15 mg/kg IV, followed by 2% isoflurane and 1% to 2% nitrous oxide, and ventilated through an endotracheal tube with a positive-pressure respirator. Analgesia with buprenorphine hydrochloride,
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0.3 to 0.6 mg IV, was administered before intubation, avoiding atropine. A 7 French catheter sheath was introduced into the right carotid artery for measurements of aortic pressure. A 6 French pigtail micromanometer tipped catheter with lumen (Model SPC 464D, MILLAR Instruments Inc, Houston, TX) was advanced through the catheter sheath, and placed in the ascending aorta. Another 7 French catheter sheath was introduced into the right femoral artery for placement under fluroscopic guidance of a 6 French pigtail micromanometer tipped catheter with lumen (Model SPC 464D MILLAR Instruments Inc, Houston, TX) into the left ventricle. Analog signals from the pressure transducers were amplified (PM-1000, CWE Inc, Admore, PA). The epimysial leads were disconnected from the SP1005 pacemaker and connected to an external muscle stimulator (Model 8800, Grass Systems Inc, Quincy, MA). A cardiotachometer detected the QRS waveform from the analog electrocardiographic signal and triggered the muscle stimulator. This resulted in synchronized LDM stimulation with the R wave. The aortic flow probe lead was dissected out from its subcutaneous position and connected to a flow meter (Model No. 206T, Transonic Systems Inc, Ithaca, NY) to measure aortic flow. Data were recorded simultaneously on a chart recorder (Model TA-11, Gould Instrument Systems Inc, Cleveland, OH) and on a computer (Micron computer, Micron Inc, Model No. M55PLUS2-P200-MT). The pressure, flow, and electrocardiographic signals were digitized by an A/D circuit board (Model AT-MIO 16.0E-10, Labview, National Instruments, low-pass and antialiasing filters, National Instruments, Austin, TX). The data were acquired with LABVIEW, version 4.0 software (Houston, TX). The stimulator pulse train duration was adjusted between 150 and 190 ms, pulse duration set at 0.5 ms, pulse frequency at 50 Hz, with an interpulse interval of 15 to 20 ms, and pulse train delay set at 20 to 80 ms after the R wave. The LDM was stimulated on every third or fourth beat. Three consecutive data sets were obtained. Each data set was 30 seconds long with the ventilator switched off during data acquisition to avoid respiratory variations. After the procedure, the animals were sacrificed by IV injection of 20 mL of potassium chloride.
Morphometric Measurements To determine the magnitude of LDM degeneration, the heart with the LDM still attached was removed and cut into 1-cm thick cross-sections. These sections were incubated in the dark in 0.05% nitroblue tetrazolium dye solution at 22°C for 40 minutes [16]. The viable areas were stained in blue and the nonviable areas remained purple. Digital pictures of the cross sections were obtained and tracings were obtained by area manometry of the Optimus software (Optimus, Paint, Eden Prairie, MN). The percentages of viable LDM along with weighted averages were calculated.
Data Analysis Using software developed in Visual Basic for Excel (Microsoft Excel 7.0, Microsoft Inc, Redwood, WA), hemody-
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namic variables were extracted from a digitally stored data file. Ectopic and postectopic cycles were excluded from the analysis. For each cardiac cycle, end-diastolic pressure, peak ventricular systolic pressure, peak positive and negative first derivative of the left ventricular pressure (⫹dp/dt, ⫺dp/dt), peak and end-diastolic aortic pressures were determined, and stroke volume, stroke work, and stroke power were calculated. The stimulated beats were compared with the immediate preceding nonstimulated beats. Both the absolute magnitudes of the changes and percent changes caused by LDM stimulation were calculated. Data are expressed as mean ⫾ standard error of the mean. Within each group, the hemodynamic variables of stimulated beats were compared with the immediate preceding nonstimulated beats by paired Student’s t test. Two-way analysis of variance was used for comparison and significance among the 3 groups, followed by unpaired Student’s t test with Bonferroni correction factor for multiple comparisons. A p value less than 0.05 was considered significant.
Results Figure 1 shows the hemodynamic data before and after intracoronary microsphere injections in the control, VD ⫹ CS, and VD ⫹ IS groups. In all groups, the hemodynamic impairment was similar: increased left ventricular enddiastolic pressure, decreased peak systolic left ventricular pressure, peak aortic pressure, stroke volume, and stroke work. Likewise, at final evaluation, there were no significant differences in left ventricular end-diastolic pressure, peak left ventricular pressure, and LV ⫹dp/dt between the 3 groups for the nonstimulated beats. Figures 2A, 2B, and 2C show representative data from a control animal, a VD ⫹ CS, and a VD ⫹ IS LDM stimulation experiment, respectively. Aortic flow, aortic and left ventricular pressures, left ventricular dp/dt, and electrocardiogram are shown. The LDM was stimulated on every third or fourth beat as seen on the electrocardiogram. In the control experiment, LDM stimulation caused minimal increases in aortic flow, pressures, and left ventricular dp/dt (Fig 2A). In the VD ⫹ CS experiment, LDM stimulation increased aortic flow, pressures, and left ventricular dp/dt (Fig 2B). In the VD ⫹ IS LDM stimulation experiment (Fig 2C), LDM stimulation caused very large increases in aortic flow, pressures, and left ventricular dp/dt. Table 1 summarizes the absolute changes in hemodynamic measurements with LDM stimulation. In the control group, LDM stimulation caused minimal, nonsignificant changes. In both the VD ⫹ CS and the VD ⫹ IS stimulation groups, LDM stimulation significantly increased peak aortic systolic and LV systolic pressures, peak positive LV dp/dt, stroke volume, peak aortic flow, stroke work, and stroke power. The differences between the control group and either the VD ⫹ CS or the VD ⫹ IS group were statistically significant (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation in the VD ⫹ IS group caused significantly greater increases in peak
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Fig 1. Hemodynamic measurements before and after intracoronary microsphere injections in control, vascular delay plus continuous stimulation ( VD ⫹ CS), and vascular delay plus intermittent stimulation ( VD ⫹ IS) experiments. (AoP ⫽ peak aortic systolic pressure; LVEDP ⫽ left ventricular end-diastolic pressure; LVP ⫽ peak left ventricular systolic pressure; Post ⫽ postoperative; Pre ⫽ preoperative; SV ⫽ stroke volume; SW ⫽ stroke work. *p ⬍ 0.05, LVEDP, SV, and SW compared preoperative versus postoperative intracoronary microsphere injections in each group; †p ⬍ 0.01, LVP compared preoperative and postoperative intracoronary microsphere injections in each group; ‡p ⬍ 0.01 AoP compared preoperative versus postoperative intracoronary microsphere injections in each group.)
aortic pressure (⫹5.3 mm Hg), peak LV pressure (⫹7.3 mm Hg), peak positive LV dp/dt (⫹160 mm Hg per second), stroke volume (⫹1.2 mL), peak aortic flow (⫹2.0 L/min), stroke work (⫹4.5gm 䡠 m), and stroke power (⫹71.2 gm 䡠 m per second). Figure 3 shows the percent changes in peak aortic pressure, peak LV pressure, and LV dp/dt caused by LDM stimulation. In the control group, LDM stimulation caused only minimal nonsignificant changes in pressures and dp/dt. In both the VD ⫹ CS and the VD ⫹ IS group, LDM stimulation significantly increased pressures and the LV dp/dt (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in aortic and ventricular pressures, and maximum LV dp/dt in the VD ⫹ IS group (p ⬍ 0.05). Figure 4 shows the percent changes in stroke volume and peak aortic flow caused by LDM stimulation. In the control group, LDM stimulation caused only minimal, nonsignificant changes in stroke volume and peak aortic flow. In both the VD ⫹ CS and the VD ⫹ IS group, LDM stimulation increased stroke volume and peak aortic flow significantly (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in stroke volume and peak aortic flow in the VD ⫹ IS group (p ⬍ 0.05). Figure 5 shows the percent changes in stroke work and stroke power caused by LDM stimulation. In the control group, LDM stimulation caused minimal, nonsignificant changes in stroke work and stroke power. In both the VD ⫹ CS and the VD ⫹ IS stimulation group, LDM stimulation increased stroke work and stroke power
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significantly (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in stroke work and stroke power in the VD ⫹ IS group (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation in the VD ⫹ IS group caused an additional increase in all of the following by: 37% in peak aortic pressure, 45% in peak LV pressure, 16% in maximum LV dp/dt, 36% in stroke volume, 62% in maximum peak aortic flow, 46% in stroke work, and 72% in stroke power. From the nitroblue tetrazolium staining and morphometric analysis in the control group, the average LDM area around the heart at the papillary muscle level was 28.8 ⫾ 1.5 cm2, whereas the nonviable LDM area was 6.6 ⫾ 0.4 cm2. In the VD ⫹ CS group, total and nonviable areas were 30.7 ⫾ 2.2 cm2 and 4.0 ⫾ 0.1 cm2, respectively. In the VD ⫹ IS group, total and nonviable areas were 31.7 ⫾ 1.2 cm2 and 2.1 ⫾ 1.0 cm2, respectively. The percentage of nonviable tissue in the LDM after CMP was 10.5% ⫾ 4.5% in the VD ⫹ CS group versus 7.5% ⫾ 1.1% in the VD ⫹ IS group. These differences did not reach statistical significance. However, in both groups the percentages were significantly lower than in the control group (28.5% ⫾ 3.4%; p ⬍ 0.05).
Comment Most clinical CMP studies have reported a significant improvement in functional class only, unaccompanied by measurable improvements in LV systolic function [17]. Distal muscle atrophy, loss of contractile function, muscle degeneration, and necrosis are probably responsible for these disappointing results [14, 18 –20]. Cardiomyoplasty operations involve severing the perforating intercostal arteries to the LDM, and transferring the muscle into the chest as a rotational flap. This causes distal LDM ischemia [21]. In addition, extensive fibrosis and degeneration of the distal LDM have been reported [13]. In goats, LDM injury correlated with poor hemodynamic outcome [22]. Clinically, magnetic resonance imaging showed that LDM thickness decreased from 19.6 mm at 15 days postoperatively to 7.6 mm at 24 to 52 months postoperatively [23]. Further, LDM signal intensity was comparable with thoracic muscles shortly after an operation, but by 24 months it resembled that of subcutaneous fat. Latissimus dorsi muscle atrophy has also been documented by echocardiography [24].
Vascular Delay Procedure The term vascular delay was coined by reconstructive surgeons to describe a procedure whereby a flap of tissue supported by a vascular pedicle is raised in 2 or more stages separated by intervals of 1 to 3 weeks [25]. In the first stage, the tissue is made subcritically ischemic, which stimulates revascularization. These vascular changes play a major role in protecting the tissue at the time of definitive flap transfer. As opposed to vascular delay, the term delay used in most CMP literature describes an unstimulated period after the wrapping of the
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Fig 2. (A) Representative tracings from a control animal: aortic flow (L/min), LV and aortic pressures (mm Hg), LV dP/dt (mm Hg/sec), and ECG. (B) Representative tracings from VD ⫹ CS experiment. (C) Representative tracings from VD ⫹ IS experiment. (CS ⫽ constant stimulation; ECG ⫽ electrocardiogram; IS ⫽ intermittent stimulation; LV ⫽ left ventricular; S ⫽ stimulated beats; VD ⫽ vascular delay.)
LDM around the myocardium, allowing healing of the striated muscle [17]. This delay in stimulating the LDM is not equivalent to vascular delay because it does not include an initial critical period of muscle ischemia. Tobin and colleagues [6] examined the intramuscular vascular distribution in LDMs by using radiograph planimetry in fresh human cadavers. Tobin and colleagues [6] found an average of 15 perforating intercostal arteries, contributing 67% of the LDM vascular supply. In
dogs, perforating intercostal arteries contributed 69% of the LDM arterial supply. These perforating intercostal arteries must be sectioned to mobilize the LDM. Distal muscle ishemia occurs when the entire LDM is acutely raised on a single neurovascular pedicle, a maneuver followed by a decrease in distal flow to 2.2 mL/min/100 g [5]. Several studies have examined the effects of VD on the LDM. In dogs, a 1-month VD period significantly in-
Table 1. Absolute Changes in Hemodynamic Measurements With LDM Stimulation
Controls VD ⫹ CS VD ⫹ IS
AoPmax (mm Hg)
LVPmax (mm Hg)
Max dp/dt (mm Hg/sec)
⫺1.5 ⫾ 9.7 12.3 ⫾ 1.2a,b 17.6 ⫾ 1.7a,b,c
⫺0.3 ⫾ 0.9 12.4 ⫾ 2.0a,b 19.7 ⫾ 1.1a,b,c
⫺29 ⫾ 8 238 ⫾ 67a,b a,b,c 398 ⫾ 144
a p ⬍ 0.05 ⫽ stimulated beats versus non-stimulated beats in each group. continuous stimulation group.
SV (mL) ⫺2.3 ⫾ 1.0 3.9 ⫾ 1.8a,b 5.1 ⫾ 0.7a,b b
Peak AoF (L/min)
SW (gm 䡠 m)
Stroke Power (gm 䡠 m/s)
0.1 ⫾ 0.3 2.2 ⫾ 0.8a,b 4.2 ⫾ 0.6a,b
⫺3.1 ⫾ 1.0 6.4 ⫾ 1.5a,b 10.9 ⫾ 0.9a,b,c
6.0 ⫾ 10.1 51.5 ⫾ 10.3a,b 122.7 ⫾ 11.6a,b,c
p ⬍ 0.05 compared to control response.
c
p ⬍ 0.05 compared to
AoPmax ⫽ maximum peak aortic pressure; CS ⫽ continuous stimulation; IS ⫽ intermittent stimulation; LVPmax ⫽ maximum peak left ventricular pressure; Max dp/dt ⫽ maximum peak first derivative of the left ventricular pressure; Peak AoF ⫽ maximum peak aortic flow; SV ⫽ stroke volume; SW ⫽ stroke work; VD ⫽ vascular delay.
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Fig 3. Effects of LDM stimulation on AoP, LVP, and dP/dt in control, continuous, and intermittent stimulation experiments. (AoPmax ⫽ maximum peak aortic systolic pressure; dP/dt ⫽ first derivative of left ventricular pressure; LDM ⫽ latissimus dorsi muscle; LV ⫽ left ventricular; LVPmax ⫽ maximum peak left ventricular systolic pressure; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation. *p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control response; ‡p ⬍ 0.05 compared with VD ⫹ CS group.)
creased muscle flap perfusion at rest and during exercise [10]. In dogs, Carroll and colleagues [9, 26] reported that VD significantly improved distal and overall LDM flap perfusion, survival, force of contraction, and fatigue resistance. Mannion and colleagues [21] have also reported a positive contribution of VD on LDM blood flow and fatigue rates. Others found VD of the LDM followed by CMP to preserve normal muscle architecture, resulting in significant increases in peak LV elastance and stroke volume with LDM stimulation immediately after the operation [27]. Last, the optimal length of VD is probably in the 1- to 3-week time period. Several studies have
Fig 4. Effects of LDM stimulation on SV and peak aortic flow in experiments with the control, VD ⫹ CS, and VD ⫹ IS groups. (LDM ⫽ latissimus dorsi muscle; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation.*p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control group; ‡p ⬍ 0.05 compared with VD ⫹ CS group.)
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Fig 5. Effects of LDM stimulation on stroke work and stroke power in experiments with the control, VD ⫹ CS and VD ⫹ IS groups. (LDM ⫽ latissimus dorsi muscle; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation; SW ⫽ stroke work; SP ⫽ stroke power. *p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control response; ‡p ⬍ 0.05 compared with continuous stimulation group.)
shown a loss of the benefit of VD with longer time periods (9 weeks and longer), possibly caused by to collaterals reforming that have to be subsequently cut to move the LDM [28, 29].
Intermittent Stimulation Another approach to minimize LDM injury is intermittent stimulation; ie, daily periods of rest. In rabbits, continuous stimulation decreased muscle weight by 26% [30]. However, when stimulation was limited to 8 hours per day, muscle weight remained at 95% of the controls. In another rabbit study, 10-Hz stimulation on a schedule of 1 hour on and 1 hour off was associated with significantly greater muscle preservation than 10-Hz continuous stimulation [31]. In goats, intermittent stimulation on a schedule of 16 hours on and 8 hours off resulted in less LDM degeneration, larger fiber areas (228%), and a lower connective tissue density than continuous stimulation [8]. In cats, stimulation for 8 hours per day preserved muscle mass and also resulted in a smaller decrease in active muscle tension [32]. In addition to reducing degeneration, intermittent stimulation prevents the complete conversion to type I fibers. With intermittent stimulation, Ianuzzo and colleagues [8] reported an 80% conversion to slow type I fibers. Arpesella and colleagues [7, 33] tested whether an intermediate state of muscle transformation could be maintained indefinitely, thus sustaining a faster and stronger contraction. The continuously stimulated LDM was white in appearance, atrophic, and fibrotic, nearly completely transformed to slow-type fibers. After 1 year of 10 hours per day stimulation, only 10% atrophy and minor fatty infiltration and fibrosis of the LDM was observed. The LDM still contained 45% fast type myosin, of which half were of the less prone to fatigue myocin heavy chain 2A (MHC 2A) type. The continuously stim-
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ulated LDM generated only 0.5 W of external power, while the 10 hours per day LDM generated 2 W of external power without fatigue. Comparing long-term continuous versus intermittent stimulation, Duan and colleagues [34] found that intermittent stimulation prevented power loss in fatigue-resistant muscles.
Literature Comparison In a review article, we summarized the results of 6 chronic animal CMP studies [35]. In these chronic CMP studies, LDM stimulation caused only small and physiologically insignificant increases in LV pressure (4%), stroke volume (8%), and stroke work (8%). These results are very similar to the results from the control group in the present study: LDM stimulation increased LV pressure by 1%, stroke volume by 7%, and stroke work by 5%. Over the last several years, the goal of our laboratory was to obtain physiologically significant increases in peak LV systolic pressure and stroke volume with LDM stimulation. In an initial study, we measured the effects of LDM stimulation 2 weeks after a CMP operation, a time at which LDM stimulation is usually initiated in humans [14]. In 4 of 11 experiments, LDM stimulation had no effect on LV function, and in the remaining experiments, LDM stimulation caused only a small increase in LV pressure, stroke work, and LV dp/dt. Thus, without preconditioning most of the potential LDM assistance was already lost by 2 weeks. We have found VD essential to obtain large, consistent improvements in hemodynamic measurements with LDM stimulation [11, 15]. In the next study, half the animals underwent a VD procedure 2 weeks before a CMP operation [11]. Again, the effects of LDM stimulation were measured 2 weeks after a CMP operation. With VD, LDM stimulation caused large increases in peak LD systolic pressure (20%), stroke volume (45%), and stroke work (64%) [11]. These data confirm the efficacy and indispensable nature of the VD procedure in CMP, without which LDM stimulation lost most of its hemodynamics effects within 2 weeks after the initial operation. These data, however, were obtained 2 weeks after the CMP operation, before chronic LDM conditioning. Therefore, the present study determined whether the VD would remain beneficial after LDM training. At 9 weeks after CMP, in the group that was stimulated 24 hours per day (the current clinical practice), LDM simulation increased peak LV pressure by 15%, stroke volume by 25%, and stroke work by 46%. These increases are considerably larger than previously reported in chronic experimental studies [35]. However, these increases are considerably smaller than our previous results obtained 2 weeks after CMP operation. These results suggest that other simulation modes are needed to maintain the long-term LDM contribution to LV systolic performance. Intermittent stimulation was tested in the present study. Now, LDM stimulation resulted in significantly larger increases in peak LV pressure (22%), stroke volume (34%), and stroke work (67%) than continuous stimulation. In total, these studies indicate that the combination of VD and IS are essential to
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obtain physiologically important increases in LV pressure, stroke volume, and stroke work with LDM stimulation.
Implications The assistance of every cardiac cycle by the LDM may be an unattainable goal. Instead, LDM assistance to cardiac function may be best offered at times of increased demands. The measurement of daily physical activity in young, healthy volunteers by accelerometer showed that only 4.2% of the day (about 1 hour per day) was spent in physical activities requiring ⱖ 4 METS [36]. Thus, a few hours of support would markedly improve the quality of life of a patient with heart failure. This would allow the patient to engage in more activities and recreation, including golf, gardening, or light swimming.
Conclusions In conclusion, combining VD with IS allowed large increases in LV pressure and stroke volume with LDM stimulation. Additional experiments are needed to confirm these results over longer periods of observation. If they are confirmed, however, changes in techniques of CMP for the treatment of patients with congestive heart failure should be strongly considered.
This study was supported in part by NIH grant No. HL-60084 and a grant of the Jewish Hospital for Heart and Lung Foundation. Our thanks to Dr James Sharp, Dr Karla Stevens, Nancy Hughes, Edwin Ford, Dorothy Wilson, and Tracey Girard for their dedicated care of the animals in the preoperative and postoperative period. The authors express their gratitude to Medtronic, Inc (Minneapolis, MN) for providing technical support.
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Barker JH. Vascular delay of the latissimus dorsi muscle: an essential component of cardiomyoplasty. Ann Thorac Surg 1997;63:1034– 40. Isoda S, Yano Y, Jin Y, Walters HL, III, Kondo J, Matsumoto A. Influence of a delay on latissimus dorsi muscle flap blood flow. Ann Thorac Surg 1995;59:632– 8. Ali AT, Santamore WP, Chiang BY, Dowling RD, Tobin GR, Slater AD. Vascular delay of the latissimus dorsi provides an early hemodynamic benefit in dynamic cardiomyoplasty. Ann Thorac Surg 1999;67:1304–11. Lavine SJ, Prcevski P, Held AC, Johnson V. Experimental model of chronic global left ventricular dysfunction secondary to left coronary microembolization. J Am Coll Cardiol 1991;18:1794 – 803. Cheng W, Michelle J, Spinale FG, Sink JD, Santamore WP. Effects of cardiomyoplasty on biventricular function in canine chronic heart failure. Ann Thorac Surg 1993;55:893–901. Chiang BB, Ali AT, Storey J, et al. Variable effects of cardiomyoplasty on left ventricular function. Artif Organs 1997;21: 1277– 83. Chiang BB, Ali A, Kashem A, et al. Two step cardiomyoplasty with vascular delay: effect of stimulation of latissimus dorsi muscle on diastolic function. ASAIO J 1999;45:350–5. Pang CY, Yang RZ, Zhong A, Xu N, Boyd B, Forrest CR. Acute ischaemic preconditioning protects against skeletal muscle infarction in the pig. Cardiovasc Res 1995;29:782– 8. Chachques JC, Grandjean PA, Carpentier A. Patient management and clinical follow-up after cardiomyoplasty. J Card Surg 1991;6(Suppl 1):89–99. Furnary AP, Chachques JC, Moreira LF, et al. Long-term outcome, survival analysis, and risk stratification of dynamic cardiomyoplasty. J Thorac Cardiovasc Surg 1996;112: 1640–50. El Oakley RM, Jarvis JC. Cardiomyoplasty: a critical review of experimental and clinical results. Circulation 1994;90: 2085–90. Magovern GJ, Sr, Simpson KA. Clinical cardiomyoplasty: review of ten-year United States experience. Ann Thorac Surg 1996;61:413–9. Mannion JD, Velchik M, Hammond RL, et al. Effects of collateral blood vessel ligation and electrical conditioning on blood flow in dog latissimus dorsi muscle. J Surg Res 1989;47: 332– 40. Lucas CM, Van der Veen FH, Cheriex EC, et al. Long-term follow up (12 to 35 weeks) after dynamic cardiomyoplasty. J Am Coll Cardiol 1993;22:758– 67. Kalil-Filho R, Bocchi E, Weiss RG, et al. Magnetic resonance imaging evaluation of chronic changes in latissimus dorsi cardiomyoplasty. Circulation 1994;90:II-102– 6.
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24. Yoshiya T, Tsukube T, Okada M, Mukai T, Kashem MA. Echocardiographic evaluation of latissimus dorsi muscle flap in cardiomyoplasty [Abstract]. Chest 1996;110:4 –22S. 25. Cormack GC, Lamberty BG. The arterial anatomy of skin flaps. London: Churchill Livingstone 1986:43– 44. 26. Carroll, SM, Carroll CM, Stremel RW, et al. Vascular delay and administration of basic fibroblast growth factor augment latissimus dorsi muscle flap perfusion and function. Plast Reconstr Surg 2000;105:964–71. 27. You J, Landymore RW, Fris J. Effect of cardiomyoplasty on systolic and diastolic function. Eur J Cardiothorac Surg 1995; 9:672–7. 28. Mannion JD, Acker MA, Hammond RL, Faltemeyer W, Duckett S, Stephenson LW. Power output of skeletal muscle ventricles in circulation: shot-term studies. Circulation 1987; 76:155– 62. 29. Mannion JD, Hammond RL, Stephenson LW. Hydraulic pouches of canine latissimus dorsi: potential for left ventricular assistance. J Thorac Cardiovasc Surg 1986;91:534– 44. 30. Pette D, Mu¨ller W, Leisner E, Vrbova G. Time dependent effects on contractile properties, fiber population, myosin light chains and enzymes of energy metabolism in intermittently and continuously stimulated fast twitch muscles of the rabbit. Pflugers Arch 1976;364:103–12. 31. Lexell J, Jarvis J, Downham D, Salmons S. Stimulationinduced damage in rabbit fast-twitch skeletal muscles: a quantitative morphological study of the influence of pattern and frequency. Cell Tissue Res 1993;273:357– 62. 32. Ferguson AS, Stone HE, Roessmann U, Burke M, Tisdale E, Mortimer JT. Muscle plasticity: comparison of a 30-Hz burst with 10-Hz continuous stimulation. J Appl Physiol 1989;66: 1143–51. 33. Arpesella G, Mikus PM, Pierluca L, et al. Activity-rest regimen of latissimus dorsi stimulation for cardiomyoplasty: anatomy, isomyosins and sustained power of sheep LD up to one year. Basic Applied Myology (http://www bio unipd it/bam/bam html) 1997;7:45–53. 34. Duan C, Trumble DR, Scalise D, Magovern JA. Intermittent stimulation enhances function of conditioned muscle. Am J Physiol 1999;276:R1534 – 40. 35. Santamore WP, Ali A, Stremel R, et al. Strategies for preserving muscle function for improved systolic assist in dynamic cardiomyoplasty. Basic Applied Myology 1998;8: 51– 8. 36. Matthews CE, Freedson PS. Field trial of a threedimensional activity monitor: comparison with self report. Med Sci Sports Exerc 1995;27:1071– 8.
Background. The goal of this study was to obtain physiologically significant increases in peak left ventricular (LV) systolic pressure and stroke volume with latissimus dorsi muscle (LDM) stimulation in cardiomyoplasty (CMP). We hypothesized that preserving LDM integrity by vascular delay and intermittent stimulation would significantly increase LDM cardiac assistance. Methods. In 4 control dogs and 12 dogs that had undergone a vascular delay (VD) procedure, LV dysfunction was induced by intracoronary microsphere injections. Cardiomyoplasty surgery was performed 14 days later, followed by progressive LDM conditioning. In the control dogs and in 6 of the VD dogs, the LDM was stimulated 24 hours per day (VD plus constant stimulation [CS]). In the other 6 VD dogs, LDMs were stimulated on a daily schedule of 10 hours on and 14 hours off (VD plus interrupted stimulation [IS]). Latissimus dorsi muscle stimulated beats were compared with nonstimulated beats 9 weeks later. Results. In the control dogs, LDM stimulation had
minimal effects. In VD ⴙ CS and VD ⴙ IS, LDM stimulation increased peak LV pressure, stroke volume, stroke work, and stroke power (p < 0.05). However, these changes were greater in the VD ⴙ IS group, in which LDM stimulation increased peak aortic pressure by 17.6 ⴞ 1.7 mm Hg, peak LV pressure by 19.7 ⴞ 1.1 mm Hg, peak positive LV dp/dt by 398 ⴞ 144 mm Hg per second, stroke volume by 5.1 ⴞ 0.7 mL, stroke work by 10.9 ⴞ 0.9 gm 䡠 m, and stroke power by 122.7 ⴞ 11.6 gm 䡠 m per second (p < 0.05 compared with VD ⴙ CS). Quantitative morphometric analysis showed minimal LDM degeneration in the VD ⴙ IS group (7.5% ⴞ 1.1%), and VD ⴙ CS group (10.5% ⴞ 4.5%) compared with the control group (29.5% ⴞ 4.5%, p < 0.05). Conclusions. VD and IS considerably increased the LV assistance with LDM stimulation. Further studies of this combined approach to CMP should be planned.
C
and stroke volume with LDM stimulation in an experimental model of LV dysfunction. We hypothesized that a two-stage vascular delay procedure followed by intermittent stimulation would preserve LDM integrity, leading to increased LDM cardiac assistance.
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ardiomyoplasty has been shown to inhibit progressive LV enlargement [1–3]. However, in experimental and clinical studies, systolic augmentation of LV function by the LDM has not been routinely observed; LV ejection fraction and peak systolic pressure remain almost identical in presence versus absence of electrical stimulation [4]. Acute mobilization and wrapping of the LDM around the heart causes LDM ischemia [5, 6]. Furthermore, incessant stimulation is detrimental to the LDM. In sheep, LDM stimulation applied 24 hours per day caused more than 40% fiber atrophy and loss of most contractile function, whereas stimulation limited to 10 hours per day caused only minimal fiber atrophy, fatty infiltration, and fibrosis [7]. In goats, Ianuzzo and colleagues [8] found that, compared with continuous stimulation, LDM stimulation limited to 12 hours per day preserved muscle architecture and was associated with less muscle degeneration, larger fiber areas, and lower density of connective tissue. The goal of the present study was to obtain physiologically significant increases in peak LV systolic pressure
Mongrel dogs weighing 22 to 27 kg were assigned to a control CMP group (n ⫽ 4), a group that underwent a vascular delay procedure followed by continuous stimulation (VD ⫹ CS; n ⫽ 6), and a group that underwent a vascular delay procedure followed by stimulation intermittently interrupted for 14 hours per day (VD ⫹ IS; n ⫽ 6). All study procedures were performed in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Accepted for publication Feb 21, 2001.
Vascular Delay
Address reprints requests to Dr Kashem, Temple University School of Medicine, Medical Research Bldg, Room 800A, 3420 N Broad St, Philadelphia, PA 19140; e-mail: [email protected].
After an overnight fast, the animals received intravenous (IV) sodium thiopental, 15 to 25 mg/kg, and intramuscular atropine, 0.01 mg/kg, and were intubated and venti-
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Material and Methods
0003-4975/01/$20.00 PII S0003-4975(01)02571-1
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lated (Quantiflex, VMC Anesthesia Machine, Orchard Park, NY). Anesthesia was maintained with 2% isoflurane (Isoflurane Vaporizer, Oharda, Isotec 3, Aushell, GA), 0.5% to 1.0% nitrous oxide, and oxygen. Surface electrocardiogram (Hewlett Packard Model No. 78346A) and oxygen saturation were monitored continuously. Cefazolin sodium, 500 mg IV (Marsam Pharmaceutical Inc, Cherry Hill, NJ), 75 mg of gentamicin, and 75 mg intramuscular (Gentocin, Ayerst Laboratories Inc, Rouses Point, NY) were administered preoperatively. Lactated Ringer’s solution, 250 mL to 350 mL per hour IV was infused perioperatively. In the vascular delay groups (VD ⫹ CS and VD ⫹ IS), a 15 to 20 cm long oblique cutaneous incision was made under sterile surgical condition from the left axillary region toward the posterior iliac crest. The anterior border of the left LDM was identified and all perforating collateral branches supplying the muscle were ligated and severed [9 –11]. The spinal border of the muscle was identified and partially mobilized. The wounds were closed in layers using absorbable sutures.
LV Dysfunction In all animals (controls, VD ⫹ CS, and VD ⫹ IS), left ventricular dysfunction was induced by intracoronary injection of microspheres [12]. The left femoral artery was cannulated percutaneously with a 7 French catheter sheath, through which a 6 French left coronary Amplatz No. 1 catheter was advanced into the left main coronary artery under fluoroscopy. Contrast material (Renografin ⫺76, Bristol-Myers-Squibb Co, Princeton, NJ) was injected to verify the catheter position. Latex microspheres (3.0 to 6.0 ⫻ 106, 90 ⫾ 2 diameter; Polyscience Inc, Warrington, PA), mixed in 10 mL of normal saline, were injected into the coronary artery in fractionated doses until left venticular end-diastolic pressure had increased by 50% to 80%, and peak left ventricular pressure and aortic pressure decreased by 20%. The catheter and sheath were removed. The femoral artery was compressed externally for 20 to 30 minutes until hemostasis. All animals survived the intracoronary microsphere injections and were treated with IV injections of furosemide, 0.75 mg/kg, and rapid infusions of 500 L Ringer’s lactated saline solution. Postoperatively, sedation with Acepromazine, 0.5 mg IV, and analgesia with Buprenex hydrochloride, 0.3 mg IV, were administered as needed. A 2-week period was allowed for recovery and vascular remodeling.
CMP Procedure A standard CMP procedure was performed on all animals as described in previous articles [11, 13–15]. Under general anesthesia, with the animal in the right lateral position, a left lateral incision was performed in the midaxillary line. The LDM was dissected out and mobilized from the surrounding tissues and its distal insertions, preserving the thoraco-dorsal neurovascular bundle proximally. The tendon of the LDM was carefully isolated and severed. Two epimysial leads (Model YY38403403 Medtronic Inc, Minneapolis, MN) were im-
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planted on the pedicle with nylon sutures. The cathode was placed proximally on the muscle and the anode 6 to 8 cm distally. The stimulation threshold was measured with a Pacing System Analyzer (PSA 5311, Medtronic Inc, Minneapolis MN). A 4 to 5 cm section of the anterior portion of the left third rib, including its periosteum, was resected to allow the translocation of the LDM flap into the left pleural space. The proximal parts of a sensing myocardial lead and an aortic flow probe (20 mm) were introduced into the chest for later implantation onto the right ventricular anterior wall and ascending aorta, respectively. The epimysial and myocardial leads were tunneled subcutaneously and connected to a dual chamber synchronous cardiomyostimulator (SP 1005, Medtronic Inc, Minneapolis, MN) implanted in a subcutaneous pocket fashioned on the left side. The LDM flap was fixed to the periosteum of the second rib by polybraided 3-0 dexan suturing material to prevent tension on the muscle, and the wound was closed in layers. The heart was exposed through a median sternotomy with the animals in the supine position. After pericardiotomy, the ascending aorta was mobilized and an aortic flow probe (A-series 20-mm, Transonic Systems Inc, Ithaca, NY) was placed around the ascending aorta with a merocel sponge positioned between the flow probe and the aorta, and the distal end of the flow probe positioned subcutaneously. A posterior myocardial wrap was performed in a clockwise fashion with fixation to the pericardium. Bilateral chest tubes were inserted and connected to a water-seal drainage system. The sternum was closed using 4 or 5 parasternal wire sutures. All wounds were closed in layers. The animals were extubated. Postoperative analgesics and sedation with Buprenorphine hydrochloride, 0.3 to 0.6 mg IV, and acepromazine maleate, 0.25 to 0.5 mg intramuscular, were systematically administered, and the animals were positioned onto the right side overnight. Chest tubes were removed on the first postoperative day. Cefazolin 500 mg IV and gentamicin 75 mg IV every 12 hours, were administered for 72 hours postoperatively.
Stimulation Protocols Cardiomyoplasty stimulation began with postoperative week 2. The LDM was progressively conditioned starting at 2 Hz, gradually increasing up to 33 Hz, at a pulse width of 180 s, interpulse interval of 25 ms, and burst durations of 180 to 210 ms, until postoperative week 9. The LDM was stimulated on every other cardiac cycle. In the control and the VD ⫹ CS groups, the cardiomyostimulator was turned on 24 hours per day. In the VD ⫹ IS group, cardiomyostimulation was limited to 10 hours continuously per day.
Hemodynamic Evaluation At 9 weeks after surgery, the dogs were reanesthetized with sodium pentothal, 10 to 15 mg/kg IV, followed by 2% isoflurane and 1% to 2% nitrous oxide, and ventilated through an endotracheal tube with a positive-pressure respirator. Analgesia with buprenorphine hydrochloride,
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0.3 to 0.6 mg IV, was administered before intubation, avoiding atropine. A 7 French catheter sheath was introduced into the right carotid artery for measurements of aortic pressure. A 6 French pigtail micromanometer tipped catheter with lumen (Model SPC 464D, MILLAR Instruments Inc, Houston, TX) was advanced through the catheter sheath, and placed in the ascending aorta. Another 7 French catheter sheath was introduced into the right femoral artery for placement under fluroscopic guidance of a 6 French pigtail micromanometer tipped catheter with lumen (Model SPC 464D MILLAR Instruments Inc, Houston, TX) into the left ventricle. Analog signals from the pressure transducers were amplified (PM-1000, CWE Inc, Admore, PA). The epimysial leads were disconnected from the SP1005 pacemaker and connected to an external muscle stimulator (Model 8800, Grass Systems Inc, Quincy, MA). A cardiotachometer detected the QRS waveform from the analog electrocardiographic signal and triggered the muscle stimulator. This resulted in synchronized LDM stimulation with the R wave. The aortic flow probe lead was dissected out from its subcutaneous position and connected to a flow meter (Model No. 206T, Transonic Systems Inc, Ithaca, NY) to measure aortic flow. Data were recorded simultaneously on a chart recorder (Model TA-11, Gould Instrument Systems Inc, Cleveland, OH) and on a computer (Micron computer, Micron Inc, Model No. M55PLUS2-P200-MT). The pressure, flow, and electrocardiographic signals were digitized by an A/D circuit board (Model AT-MIO 16.0E-10, Labview, National Instruments, low-pass and antialiasing filters, National Instruments, Austin, TX). The data were acquired with LABVIEW, version 4.0 software (Houston, TX). The stimulator pulse train duration was adjusted between 150 and 190 ms, pulse duration set at 0.5 ms, pulse frequency at 50 Hz, with an interpulse interval of 15 to 20 ms, and pulse train delay set at 20 to 80 ms after the R wave. The LDM was stimulated on every third or fourth beat. Three consecutive data sets were obtained. Each data set was 30 seconds long with the ventilator switched off during data acquisition to avoid respiratory variations. After the procedure, the animals were sacrificed by IV injection of 20 mL of potassium chloride.
Morphometric Measurements To determine the magnitude of LDM degeneration, the heart with the LDM still attached was removed and cut into 1-cm thick cross-sections. These sections were incubated in the dark in 0.05% nitroblue tetrazolium dye solution at 22°C for 40 minutes [16]. The viable areas were stained in blue and the nonviable areas remained purple. Digital pictures of the cross sections were obtained and tracings were obtained by area manometry of the Optimus software (Optimus, Paint, Eden Prairie, MN). The percentages of viable LDM along with weighted averages were calculated.
Data Analysis Using software developed in Visual Basic for Excel (Microsoft Excel 7.0, Microsoft Inc, Redwood, WA), hemody-
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namic variables were extracted from a digitally stored data file. Ectopic and postectopic cycles were excluded from the analysis. For each cardiac cycle, end-diastolic pressure, peak ventricular systolic pressure, peak positive and negative first derivative of the left ventricular pressure (⫹dp/dt, ⫺dp/dt), peak and end-diastolic aortic pressures were determined, and stroke volume, stroke work, and stroke power were calculated. The stimulated beats were compared with the immediate preceding nonstimulated beats. Both the absolute magnitudes of the changes and percent changes caused by LDM stimulation were calculated. Data are expressed as mean ⫾ standard error of the mean. Within each group, the hemodynamic variables of stimulated beats were compared with the immediate preceding nonstimulated beats by paired Student’s t test. Two-way analysis of variance was used for comparison and significance among the 3 groups, followed by unpaired Student’s t test with Bonferroni correction factor for multiple comparisons. A p value less than 0.05 was considered significant.
Results Figure 1 shows the hemodynamic data before and after intracoronary microsphere injections in the control, VD ⫹ CS, and VD ⫹ IS groups. In all groups, the hemodynamic impairment was similar: increased left ventricular enddiastolic pressure, decreased peak systolic left ventricular pressure, peak aortic pressure, stroke volume, and stroke work. Likewise, at final evaluation, there were no significant differences in left ventricular end-diastolic pressure, peak left ventricular pressure, and LV ⫹dp/dt between the 3 groups for the nonstimulated beats. Figures 2A, 2B, and 2C show representative data from a control animal, a VD ⫹ CS, and a VD ⫹ IS LDM stimulation experiment, respectively. Aortic flow, aortic and left ventricular pressures, left ventricular dp/dt, and electrocardiogram are shown. The LDM was stimulated on every third or fourth beat as seen on the electrocardiogram. In the control experiment, LDM stimulation caused minimal increases in aortic flow, pressures, and left ventricular dp/dt (Fig 2A). In the VD ⫹ CS experiment, LDM stimulation increased aortic flow, pressures, and left ventricular dp/dt (Fig 2B). In the VD ⫹ IS LDM stimulation experiment (Fig 2C), LDM stimulation caused very large increases in aortic flow, pressures, and left ventricular dp/dt. Table 1 summarizes the absolute changes in hemodynamic measurements with LDM stimulation. In the control group, LDM stimulation caused minimal, nonsignificant changes. In both the VD ⫹ CS and the VD ⫹ IS stimulation groups, LDM stimulation significantly increased peak aortic systolic and LV systolic pressures, peak positive LV dp/dt, stroke volume, peak aortic flow, stroke work, and stroke power. The differences between the control group and either the VD ⫹ CS or the VD ⫹ IS group were statistically significant (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation in the VD ⫹ IS group caused significantly greater increases in peak
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Fig 1. Hemodynamic measurements before and after intracoronary microsphere injections in control, vascular delay plus continuous stimulation ( VD ⫹ CS), and vascular delay plus intermittent stimulation ( VD ⫹ IS) experiments. (AoP ⫽ peak aortic systolic pressure; LVEDP ⫽ left ventricular end-diastolic pressure; LVP ⫽ peak left ventricular systolic pressure; Post ⫽ postoperative; Pre ⫽ preoperative; SV ⫽ stroke volume; SW ⫽ stroke work. *p ⬍ 0.05, LVEDP, SV, and SW compared preoperative versus postoperative intracoronary microsphere injections in each group; †p ⬍ 0.01, LVP compared preoperative and postoperative intracoronary microsphere injections in each group; ‡p ⬍ 0.01 AoP compared preoperative versus postoperative intracoronary microsphere injections in each group.)
aortic pressure (⫹5.3 mm Hg), peak LV pressure (⫹7.3 mm Hg), peak positive LV dp/dt (⫹160 mm Hg per second), stroke volume (⫹1.2 mL), peak aortic flow (⫹2.0 L/min), stroke work (⫹4.5gm 䡠 m), and stroke power (⫹71.2 gm 䡠 m per second). Figure 3 shows the percent changes in peak aortic pressure, peak LV pressure, and LV dp/dt caused by LDM stimulation. In the control group, LDM stimulation caused only minimal nonsignificant changes in pressures and dp/dt. In both the VD ⫹ CS and the VD ⫹ IS group, LDM stimulation significantly increased pressures and the LV dp/dt (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in aortic and ventricular pressures, and maximum LV dp/dt in the VD ⫹ IS group (p ⬍ 0.05). Figure 4 shows the percent changes in stroke volume and peak aortic flow caused by LDM stimulation. In the control group, LDM stimulation caused only minimal, nonsignificant changes in stroke volume and peak aortic flow. In both the VD ⫹ CS and the VD ⫹ IS group, LDM stimulation increased stroke volume and peak aortic flow significantly (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in stroke volume and peak aortic flow in the VD ⫹ IS group (p ⬍ 0.05). Figure 5 shows the percent changes in stroke work and stroke power caused by LDM stimulation. In the control group, LDM stimulation caused minimal, nonsignificant changes in stroke work and stroke power. In both the VD ⫹ CS and the VD ⫹ IS stimulation group, LDM stimulation increased stroke work and stroke power
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significantly (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation caused significantly greater percent changes in stroke work and stroke power in the VD ⫹ IS group (p ⬍ 0.05). Compared with the VD ⫹ CS group, LDM stimulation in the VD ⫹ IS group caused an additional increase in all of the following by: 37% in peak aortic pressure, 45% in peak LV pressure, 16% in maximum LV dp/dt, 36% in stroke volume, 62% in maximum peak aortic flow, 46% in stroke work, and 72% in stroke power. From the nitroblue tetrazolium staining and morphometric analysis in the control group, the average LDM area around the heart at the papillary muscle level was 28.8 ⫾ 1.5 cm2, whereas the nonviable LDM area was 6.6 ⫾ 0.4 cm2. In the VD ⫹ CS group, total and nonviable areas were 30.7 ⫾ 2.2 cm2 and 4.0 ⫾ 0.1 cm2, respectively. In the VD ⫹ IS group, total and nonviable areas were 31.7 ⫾ 1.2 cm2 and 2.1 ⫾ 1.0 cm2, respectively. The percentage of nonviable tissue in the LDM after CMP was 10.5% ⫾ 4.5% in the VD ⫹ CS group versus 7.5% ⫾ 1.1% in the VD ⫹ IS group. These differences did not reach statistical significance. However, in both groups the percentages were significantly lower than in the control group (28.5% ⫾ 3.4%; p ⬍ 0.05).
Comment Most clinical CMP studies have reported a significant improvement in functional class only, unaccompanied by measurable improvements in LV systolic function [17]. Distal muscle atrophy, loss of contractile function, muscle degeneration, and necrosis are probably responsible for these disappointing results [14, 18 –20]. Cardiomyoplasty operations involve severing the perforating intercostal arteries to the LDM, and transferring the muscle into the chest as a rotational flap. This causes distal LDM ischemia [21]. In addition, extensive fibrosis and degeneration of the distal LDM have been reported [13]. In goats, LDM injury correlated with poor hemodynamic outcome [22]. Clinically, magnetic resonance imaging showed that LDM thickness decreased from 19.6 mm at 15 days postoperatively to 7.6 mm at 24 to 52 months postoperatively [23]. Further, LDM signal intensity was comparable with thoracic muscles shortly after an operation, but by 24 months it resembled that of subcutaneous fat. Latissimus dorsi muscle atrophy has also been documented by echocardiography [24].
Vascular Delay Procedure The term vascular delay was coined by reconstructive surgeons to describe a procedure whereby a flap of tissue supported by a vascular pedicle is raised in 2 or more stages separated by intervals of 1 to 3 weeks [25]. In the first stage, the tissue is made subcritically ischemic, which stimulates revascularization. These vascular changes play a major role in protecting the tissue at the time of definitive flap transfer. As opposed to vascular delay, the term delay used in most CMP literature describes an unstimulated period after the wrapping of the
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Fig 2. (A) Representative tracings from a control animal: aortic flow (L/min), LV and aortic pressures (mm Hg), LV dP/dt (mm Hg/sec), and ECG. (B) Representative tracings from VD ⫹ CS experiment. (C) Representative tracings from VD ⫹ IS experiment. (CS ⫽ constant stimulation; ECG ⫽ electrocardiogram; IS ⫽ intermittent stimulation; LV ⫽ left ventricular; S ⫽ stimulated beats; VD ⫽ vascular delay.)
LDM around the myocardium, allowing healing of the striated muscle [17]. This delay in stimulating the LDM is not equivalent to vascular delay because it does not include an initial critical period of muscle ischemia. Tobin and colleagues [6] examined the intramuscular vascular distribution in LDMs by using radiograph planimetry in fresh human cadavers. Tobin and colleagues [6] found an average of 15 perforating intercostal arteries, contributing 67% of the LDM vascular supply. In
dogs, perforating intercostal arteries contributed 69% of the LDM arterial supply. These perforating intercostal arteries must be sectioned to mobilize the LDM. Distal muscle ishemia occurs when the entire LDM is acutely raised on a single neurovascular pedicle, a maneuver followed by a decrease in distal flow to 2.2 mL/min/100 g [5]. Several studies have examined the effects of VD on the LDM. In dogs, a 1-month VD period significantly in-
Table 1. Absolute Changes in Hemodynamic Measurements With LDM Stimulation
Controls VD ⫹ CS VD ⫹ IS
AoPmax (mm Hg)
LVPmax (mm Hg)
Max dp/dt (mm Hg/sec)
⫺1.5 ⫾ 9.7 12.3 ⫾ 1.2a,b 17.6 ⫾ 1.7a,b,c
⫺0.3 ⫾ 0.9 12.4 ⫾ 2.0a,b 19.7 ⫾ 1.1a,b,c
⫺29 ⫾ 8 238 ⫾ 67a,b a,b,c 398 ⫾ 144
a p ⬍ 0.05 ⫽ stimulated beats versus non-stimulated beats in each group. continuous stimulation group.
SV (mL) ⫺2.3 ⫾ 1.0 3.9 ⫾ 1.8a,b 5.1 ⫾ 0.7a,b b
Peak AoF (L/min)
SW (gm 䡠 m)
Stroke Power (gm 䡠 m/s)
0.1 ⫾ 0.3 2.2 ⫾ 0.8a,b 4.2 ⫾ 0.6a,b
⫺3.1 ⫾ 1.0 6.4 ⫾ 1.5a,b 10.9 ⫾ 0.9a,b,c
6.0 ⫾ 10.1 51.5 ⫾ 10.3a,b 122.7 ⫾ 11.6a,b,c
p ⬍ 0.05 compared to control response.
c
p ⬍ 0.05 compared to
AoPmax ⫽ maximum peak aortic pressure; CS ⫽ continuous stimulation; IS ⫽ intermittent stimulation; LVPmax ⫽ maximum peak left ventricular pressure; Max dp/dt ⫽ maximum peak first derivative of the left ventricular pressure; Peak AoF ⫽ maximum peak aortic flow; SV ⫽ stroke volume; SW ⫽ stroke work; VD ⫽ vascular delay.
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Fig 3. Effects of LDM stimulation on AoP, LVP, and dP/dt in control, continuous, and intermittent stimulation experiments. (AoPmax ⫽ maximum peak aortic systolic pressure; dP/dt ⫽ first derivative of left ventricular pressure; LDM ⫽ latissimus dorsi muscle; LV ⫽ left ventricular; LVPmax ⫽ maximum peak left ventricular systolic pressure; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation. *p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control response; ‡p ⬍ 0.05 compared with VD ⫹ CS group.)
creased muscle flap perfusion at rest and during exercise [10]. In dogs, Carroll and colleagues [9, 26] reported that VD significantly improved distal and overall LDM flap perfusion, survival, force of contraction, and fatigue resistance. Mannion and colleagues [21] have also reported a positive contribution of VD on LDM blood flow and fatigue rates. Others found VD of the LDM followed by CMP to preserve normal muscle architecture, resulting in significant increases in peak LV elastance and stroke volume with LDM stimulation immediately after the operation [27]. Last, the optimal length of VD is probably in the 1- to 3-week time period. Several studies have
Fig 4. Effects of LDM stimulation on SV and peak aortic flow in experiments with the control, VD ⫹ CS, and VD ⫹ IS groups. (LDM ⫽ latissimus dorsi muscle; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation.*p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control group; ‡p ⬍ 0.05 compared with VD ⫹ CS group.)
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Fig 5. Effects of LDM stimulation on stroke work and stroke power in experiments with the control, VD ⫹ CS and VD ⫹ IS groups. (LDM ⫽ latissimus dorsi muscle; VD ⫹ CS ⫽ vascular delay plus continuous stimulation; VD ⫹ IS ⫽ vascular delay plus intermittent stimulation; SW ⫽ stroke work; SP ⫽ stroke power. *p ⬍ 0.05 stimulated beats versus nonstimulated beats in each group; †p ⬍ 0.05 compared with control response; ‡p ⬍ 0.05 compared with continuous stimulation group.)
shown a loss of the benefit of VD with longer time periods (9 weeks and longer), possibly caused by to collaterals reforming that have to be subsequently cut to move the LDM [28, 29].
Intermittent Stimulation Another approach to minimize LDM injury is intermittent stimulation; ie, daily periods of rest. In rabbits, continuous stimulation decreased muscle weight by 26% [30]. However, when stimulation was limited to 8 hours per day, muscle weight remained at 95% of the controls. In another rabbit study, 10-Hz stimulation on a schedule of 1 hour on and 1 hour off was associated with significantly greater muscle preservation than 10-Hz continuous stimulation [31]. In goats, intermittent stimulation on a schedule of 16 hours on and 8 hours off resulted in less LDM degeneration, larger fiber areas (228%), and a lower connective tissue density than continuous stimulation [8]. In cats, stimulation for 8 hours per day preserved muscle mass and also resulted in a smaller decrease in active muscle tension [32]. In addition to reducing degeneration, intermittent stimulation prevents the complete conversion to type I fibers. With intermittent stimulation, Ianuzzo and colleagues [8] reported an 80% conversion to slow type I fibers. Arpesella and colleagues [7, 33] tested whether an intermediate state of muscle transformation could be maintained indefinitely, thus sustaining a faster and stronger contraction. The continuously stimulated LDM was white in appearance, atrophic, and fibrotic, nearly completely transformed to slow-type fibers. After 1 year of 10 hours per day stimulation, only 10% atrophy and minor fatty infiltration and fibrosis of the LDM was observed. The LDM still contained 45% fast type myosin, of which half were of the less prone to fatigue myocin heavy chain 2A (MHC 2A) type. The continuously stim-
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ulated LDM generated only 0.5 W of external power, while the 10 hours per day LDM generated 2 W of external power without fatigue. Comparing long-term continuous versus intermittent stimulation, Duan and colleagues [34] found that intermittent stimulation prevented power loss in fatigue-resistant muscles.
Literature Comparison In a review article, we summarized the results of 6 chronic animal CMP studies [35]. In these chronic CMP studies, LDM stimulation caused only small and physiologically insignificant increases in LV pressure (4%), stroke volume (8%), and stroke work (8%). These results are very similar to the results from the control group in the present study: LDM stimulation increased LV pressure by 1%, stroke volume by 7%, and stroke work by 5%. Over the last several years, the goal of our laboratory was to obtain physiologically significant increases in peak LV systolic pressure and stroke volume with LDM stimulation. In an initial study, we measured the effects of LDM stimulation 2 weeks after a CMP operation, a time at which LDM stimulation is usually initiated in humans [14]. In 4 of 11 experiments, LDM stimulation had no effect on LV function, and in the remaining experiments, LDM stimulation caused only a small increase in LV pressure, stroke work, and LV dp/dt. Thus, without preconditioning most of the potential LDM assistance was already lost by 2 weeks. We have found VD essential to obtain large, consistent improvements in hemodynamic measurements with LDM stimulation [11, 15]. In the next study, half the animals underwent a VD procedure 2 weeks before a CMP operation [11]. Again, the effects of LDM stimulation were measured 2 weeks after a CMP operation. With VD, LDM stimulation caused large increases in peak LD systolic pressure (20%), stroke volume (45%), and stroke work (64%) [11]. These data confirm the efficacy and indispensable nature of the VD procedure in CMP, without which LDM stimulation lost most of its hemodynamics effects within 2 weeks after the initial operation. These data, however, were obtained 2 weeks after the CMP operation, before chronic LDM conditioning. Therefore, the present study determined whether the VD would remain beneficial after LDM training. At 9 weeks after CMP, in the group that was stimulated 24 hours per day (the current clinical practice), LDM simulation increased peak LV pressure by 15%, stroke volume by 25%, and stroke work by 46%. These increases are considerably larger than previously reported in chronic experimental studies [35]. However, these increases are considerably smaller than our previous results obtained 2 weeks after CMP operation. These results suggest that other simulation modes are needed to maintain the long-term LDM contribution to LV systolic performance. Intermittent stimulation was tested in the present study. Now, LDM stimulation resulted in significantly larger increases in peak LV pressure (22%), stroke volume (34%), and stroke work (67%) than continuous stimulation. In total, these studies indicate that the combination of VD and IS are essential to
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obtain physiologically important increases in LV pressure, stroke volume, and stroke work with LDM stimulation.
Implications The assistance of every cardiac cycle by the LDM may be an unattainable goal. Instead, LDM assistance to cardiac function may be best offered at times of increased demands. The measurement of daily physical activity in young, healthy volunteers by accelerometer showed that only 4.2% of the day (about 1 hour per day) was spent in physical activities requiring ⱖ 4 METS [36]. Thus, a few hours of support would markedly improve the quality of life of a patient with heart failure. This would allow the patient to engage in more activities and recreation, including golf, gardening, or light swimming.
Conclusions In conclusion, combining VD with IS allowed large increases in LV pressure and stroke volume with LDM stimulation. Additional experiments are needed to confirm these results over longer periods of observation. If they are confirmed, however, changes in techniques of CMP for the treatment of patients with congestive heart failure should be strongly considered.
This study was supported in part by NIH grant No. HL-60084 and a grant of the Jewish Hospital for Heart and Lung Foundation. Our thanks to Dr James Sharp, Dr Karla Stevens, Nancy Hughes, Edwin Ford, Dorothy Wilson, and Tracey Girard for their dedicated care of the animals in the preoperative and postoperative period. The authors express their gratitude to Medtronic, Inc (Minneapolis, MN) for providing technical support.
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