Laser myoplasty for hypertrophic cardiomyopathy

Laser Myoplasty for Hypertrophic Cardiomyopathy In Vitro Experience in Human Postmortem Hearts and In Vivo Experience in a Canine Model (Transarterial) and Human Patient (Intraoperative) JEFFREY M. ISNER, MD, RICHARD H. CLARKE, PhD, NATESA G. PANDIAN, MD, ROBERTA FORTIN DONALDSON, BS, DEEB N. SALEM, MD, MARVIN A. KONSTAM,

MD,

DOUGLAS D. PAYNE, MD, and RICHARD J. CLEVELAND, MD With the technical assistance of JOHN D. BONIN, MA, EDWIN W. LOJESKI, BA, and ALON AHRON

The feasibility of performing a myotomy/myectomy for hypertrophic cardiomyopathy (HC) by means of laser phototherapy was evaluated experimentally in vitro and in vivo, and the procedure then applied to a patient intraoperatively. In vitro experience revealed that the beam of an argon laser, delivered directly or via an optical fiber, could both cut and vaporize myocardium, producing a myotomy/ myectomy morphologically similar to that produced by the conventional blade technique. In vivo experiments, in which the beam of an argon laser was delivered via an optical fiber to the ventricular septum of a canine heart, confirmed that a laser myoplasty could be achieved in 4 of 5 dogs by a

transarterial approach. Finally, laser myoplasty was performed intraoperatively in a patient with HC, using a 200-p fiber interfaced with an argon laser. Measured laser power was 1.5 W; cumulative exposure was less than 4 minutes; the myoplasty was 4 X 1 X 0.5 cm. These investigations establish the feasibility of using laser therapy to create a myoplasty trough that is similar in appearance to that typically achieved by the conventional blade technique. Illumination of the intraventricular operative field and precise modeling of the myoplasty trough constitute the principal advantages of laser myoplasty for HC. (Am J Cardiol 1984; 53:1820-1825)

The application of laser phototherapy to the treatment of cardiovascular disease has been studied in vitro and in vivo in various animal models.‘-6 Reports of these studies, most of which have involved the treatment of coronary arterial stenoses, have indicated that the laser may offer potentially useful advantages over presently available therapies. We investigated the possible use of laser phototherapy in the treatment of hypertrophic postcardiomyopathy (HC), in vitro, using human mortem hearts, and in vivo, using a canine model. Based on this experimental work, laser phototherapy was then

used to perform a myotomylmyectomy HC. The present report summarizes investigations.

in a patient with the results of these

Methods Laser system: An argon ion laser (Model 164, SpectraPhysics) was used for all experimental and human work described herein. This laser emits a continuous beam of coherent light at a series of visible wavelengths from 454 to 514 nm. The beam that emerged from the laser with a diameter of 0.2 to 0.5 mm was reflected downward 90’ by an aluminized front surface mirror, and then through a forward aperture. In the in vitro experiments that involved human postmortem hearts, laser myoplasty was performed using a focused beam of laser light (and no optical fiber); for these experiments, the postmortem specimen was positioned 10 to 15 cm from the forward aperture and then manually repositioned to inscribe the desired myoplasty. For the remaining in vitro experiments, rather than simply using the focused beam of laser light to perform the myoplasty, the laser beam was delivered by a

From the Departments of Medicine (Cardiology), Pathology, and Surgery (Cardiothoracic), Tufts-New England Medical Center, and the Department of Chemistry, Boston University, Boston, Massachusetts. Manuscript received December 21, 1983; revised manuscript received February 22, 1984, accepted February 23, 1984. Address for reprints: Jeffrey M. Isner, MD, Box 70, New England Medical Center, 171 Harrison Avenue, Boston, Massachusetts 02111. 1620

June 1, 1964

200-p silica optical fiber (Quartz Products), the cladding of which was manually cut back for 2 mm from the distal tip of the fiber. The fiber was coupled at its proximal end to the argon laser by means of a positioner stage (Newport Corp.). The fiber was 4 to 6 m long. For in vivo canine experiments, the optical fiber was delivered to the left ventricular (LV) outflow tract by means of a specially designed No. 7Fr polyurethane catheter with a 2 cm stainless steel tip (Cordis Corp.). A preformed 60” bend was created in the catheter, 2 cm from the distal tip. For intraoperative human use, the optical fiber was first gas-sterilized using ethylene oxide and then positioned within a specifically designed hand-held aluminum cannula, the distal tip of which was angled at 35”. Output power, monitored by a power meter (Coherent, Inc.), was 1.2 to 2.4 W (power used in any of the in vitro or in vivo work described in this article refers to measured output); exposure time varied, depending on the experimental or therapeutic conditions. In vitro experiments: Hearts obtained at the time of postmortem examination from 2 patients with HC were used to evaluate the feasibility of performing a myotomy/myectomy by argon laser phototherapy. Both postmortem specimens had been opened in a manner designed to expose the LV endocardial surface of the ventricular septum; both had also been preserved in 10% phosphate-buffered formalin. In vitro studies were performed both in a dry field and in a heparinized blood field. Photoproducts liberated as a result of laser myoplasty were evaluated using myocardium, freshly obtained at necropsy. Four samples, each 1 cm2 in size, were placed in a quartz cuvette, submerged in saline solution and treated with a total output of 454 through 514 nm of an argon laser; energy consisted of a combination of up to 4.0 W power and 15 to 30 minutes exposure time. Vaporized products formed in gas phase were collected by withdrawing in a syringe a sample of the gas effluent; the gas effluent was then analyzed by gas chromatography (Varian Associates). Photoproducts dissolved in solution were analyzed by ultraviolet absorbance spectroscopy (Perkin-Elmer). In vivo experiments: Five mongrel dogs that weighed 25 to 35 kg were premeditated with acepromazine and atropine and then anesthetized with intravenous sodium pentobarbital, 20 mg/kg. Although these dogs did not have HC, they were

used to determine the feasibility of establishing contact between the optical fiber and ventricular septum of a beating heart of sufficient duration to produce a myotomy/myectomy. The dogs were ventilated with room air by a Harvard respirator. Two dogs were prepared open-chest to confirm that a myoplasty could be achieved (on the epicardial surface) in a beating heart; these 2 dogs then also underwent transarterial myoplasty. The other dogs underwent transarterial myoplasty only (closed chest). The guiding catheter that contained the optical fiber was inserted through the left common carotid artery in 2 dogs and the right femoral artery in 3 dogs, and then fluoroscopically advanced to the LV outflow tract. Measurements of intraarterial and intracardiac pressures obtained via the guiding catheter, using a Statham P23Db transducer, were used to confirm catheter position. Adequate contact between the tip of the optical fiber and the ventricular septum was indicated by damping of the pressure signal and confirmed by 2-dimensional echocardiography. Power output varied from 2.0 to 2.4 W; exposure time varied from 6 to 16 minutes. Four dogs were killed immediately after the laser myoplasty was completed; 1 dog was electively killed 7 days after laser myoplasty. The hearts of all 5 dogs were examined by gross and light microscopy. In vivo human application: Laser myoplasty was performed intraoperatively in a 42.year-old white woman. The

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patient had been treated for known HC for 7 years. initially with propranolol (up to 320 n&day), and subsequently combined with verapamil (up to 240 mg/day). Despite combination medical therapy, she had recurrent presyncope. As the result of extreme fatigue at rest (New York Heart Association functional class IV), she discontinued virtually any exertion. On examination, a “spike-and-dome” configuration to the cartoid arterial pulse, a S-component precordial impulse on palpation, and a grade 3/6 holosystolic murmur, maximal at the LV apex on auscultation, were present; the murmur increased to grade 416 after a Valsalva maneuver. There were no diastolic murmurs. Two-dimensional echocardiography disclosed that the basal portion of the ventricular septum was 24 mm thick and the LV free wall was 12 mm thick. Both systolic anterior motion of the anterior mitral leaflet and early closure of the aortic valve leaflets were observed. Cardiac catheterization (performed without discontinuing the patient’s medications) disclosed a positive Brockenbrough sign and an intraventricular systolic pressure gradient of 45 mm Hg at rest, which increased to 107 mm Hg after the Valsalva maneuver. LV cineangiography disclosed systolic obliteration of the apical two-thirds of the LV cavity, systolic anterior motion of the anterior mitral leaflet, and 4+/4+ mitral regurgitation. The patient was recommended for myotomyl myectomy and gave informed consent to have it performed with argon laser phototherapy.

Results In vitro experiments: Nine myoplasties, 0.5 to 2.0 cm wide and 0.5 to 0.8 cm deep, were easily created in the basal portion of the ventricular septum (Fig. la) using either the native focused argon laser beam, or a hand-held optical fiber coupled to the laser. One to 4.2 W of power was required. An adequate myoplasty could be achieved over this range of powers by varying exposure time. Energy requirements were not altered significantly by performing the myoplasty in a blood-filled as opposed to dry field. However, less charring occurred in a blood-filled field than in a dry field. The fiber tip did not have to be placed in direct apposition to the myocardium; an adequate result was achieved with the fiber held approximately 1 mm above the myocardium. Gross inspection indicated that myocardial vaporization was limited to the target area. Examination by light microscopy disclosed a superficial zone of thermal injury along the perimeter of the myoplasty trough (Fig. lb). The gas effluent and the aqueous solution from the quartz cuvette in which samples of myocardium had been placed and then treated with laser phototherapy were analyzed for liberated photoproducts. The products formed in the gas effluent included hydrogen, light hydrocarbon fragments and carbon dioxide. The photoproducts dissolved in aqueous solution included protein fragments and nitrogen heterocyclic ring fragments, indicated by absorbance peaks in the visible spectral region, extending into the ultraviolet. These photoproducts indicate that the fundamental nature of laser irradiation of myocardium is incomplete thermal degradation. In vivo experiments: In 4 of the 5 dogs in which transarterial laser myoplasty was attempted, postmortem examination confirmed that a laser myoplasty had been achieved, including in 1 dog electively killed

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7 days after the procedure (Fig. 2). Two-dimensional echocardiography confirmed adequate septum-catheter contact and prospectively predicted the myoplasty site identified at postmortem examination. Gross examination of the myoplasty lesions disclosed variations in size and shape (Table I, Fig. 2). In dog 2, transmural rupture was intentionally produced in an attempt to determine the maximal energy level that could be delivered to the ventricular wall. Light microscopic examination of the myoplasty lesions created on the epicardial surface of the openchested dogs disclosed a range of myocyte injury lateral and deep to the myoplasty trough. The lateral and deep extent of myocyte necrosis varied directly with exposure time. (Power was kept constant.) Application of the optical fiber to inscribe a linear myoplasty trough at an

FIGURE 1. a, gross photograph shows 4 separate myopiasties (arrows) created in a human heart excised at the time of postmortem examination. The myoplasty trough to the far right (large arrow) indicates the approximate location of a myoplasty as it would be created intraoperatively for hypertrophic cardiomyopathy. This lesion is similar in width to that created intraoperatively in the patient described in the present report; the length and depth of the myoplasty lesion shown here, however, were less extensive than that created intraoperatively in the live patient. AML = anterior mitral leaflet; AV = aortic valve leaflet; NW = noncoronary sinus of Valsalva; RSV = right coronary sinus of Valsalva. b, photomicrograph of myoplasty lesion shown to the far left above. There is a superficial zone of thermal injury, which appears dark black, lining the perimeter of the myoplasty trough. Hematoxylin- eosin stain; original magnification X 5, reduced 50%.

approximate rate of 0.5 mm/s resulted in myocyte necrosis 2 mm deep and lateral to the myoplasty trough. Fixed application of the optical fiber to a single site for a protracted period of time (20 minutes) resulted in a wedge of transmural necrosis. In vivo human application: The patient’s chest was opened and the patient was placed on cardiopulmonary bypass using standard techniques. The aorta was cross-clamped and cardioplegic solution was infused into the aortic root. A longitudinal aortotomy was performed 5 mm above the aortic valve. The aortic valve cusps were then retracted and the LV cavity visualized from above. The thickest portion of the ventricular septum was at the base of the heart and bulged into the LV outflow tract. The cannula that contained the most distal portion of the optical fiber was used to manually inscribe a myotomy/myectomy trough by making repeated vertical sweeps along the apex-to-base (major) axis of the ventricular septum (Fig. 3); these sweeps were made caudad to the junction of the right and left coronary cusps to avoid damage to the conduction system. Power output was 1.5 f 0.5 W; cumulative exposure was 3.5 minutes. The myotomy/myectomy trough was 4.0 cm long, 0.5 cm wide and 1.0 cm deep. The heart was closed in routine fashion. The aortic cross-clamp time was 31 minutes. The patient separated from cardiopulmonary bypass without difficulty. Total time on cardiopulmonary bypass was 71 minutes. The patient’s postoperative course was uncomplicated, and the patient was discharged on the eighth postoperative day. Medications at the time of discharge included propranolol, 40 mg/day, and aspirin. At 6-month follow-up,

FIGURE 2. Punctate lesion created in the apical portion of the ventricular septum using an optical fiber delivered via a guiding catheter in vivo in a dog. The dog was electively killed 1 week after laser myoplasty.

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TABLE I

Experimental

Transarterial

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Myoplasty in 4 Dogs ___

Dimensions of Myoplasty (mm) Width

Depth

(W)

Exposure (min)

Total Energy

Length

Shape of Lesion

Power

Dog 1 z

8

6

2

Linear Pinpoint Circular

2.0 2.2

16 :z

1920 2640 1980

4

1

1

7

Pinpoint

2.0

12

1440

the patient had improved to New York Heart Association functional class II. Postoperative hemodynamic investigation is pending. Discussion Most patients with HC can be successfully managed with medical therapy, consisting of P-adrenergic re.ceptor blockade7,* or agents that interfere with transmembrane calcium ion transport through the so-called slow channel.gJO For patients who do not respond to therapy with these agents, however, the only alternative is a ventricular septal myotomy/myectomy (Morrow procedure)r1J2 or myotomy alone. r3,14Both operations are performed through a complete median sternotomy. After cardiopulmonary bypass is instituted, an aortotomy is created and the LV outflow tract visualized below the aortic valve. Retracting the valve cusps, multiple incisions (myotomy) are then made in the thickened basal portion of the ventricular septum. The Morrow procedure includes removal of 0.5 to 2.0 g of septal myocardium (myectomy).12 Other investigatorsi3J4 limit the operation to a myotomy alone. Either procedure produces persistent clinical and hemodynamic improvement in most patients.13-l5 The wavelength of light emitted by the argon laser suggested that this laser might be useful for the surgical treatment of HC. The wavelength of light emitted by

(J)

the argon laser (454 to 514 nm) is in the visible portion (400 to 700 nm) of the electromagnetic spectrum. This is in contrast to other lasers used for biomedical applications, such as carbon dioxide and neodymium-YAG, which emit light at wavelengths in the invisible, infrared portion of the spectrum. As emphasized by Morrow,12 to be successful, “the myotomy incisions must extend to the apical termination of the muscular ridge” of the thickened ventricular septum, and “For this to be accomplished, the knife must be plunged into the septum until it is out of sight, completely.” Because the wavelength of light emitted by the argon laser (488 to 514 nm) is in the visible range, the intraventricular operative field is constantly illuminated; as a result, the tip of the optical-fiber “knife” is never out of sight. Muscle, including cardiac muscle, is composed in large part of myoglobin. The basic myoglobin molecule is constructed in such a way that the component electron energy states can absorb from the visible range of the electromagnetic spectrum only wavelengths in the blue and green regions (454 to 514 nm) of the spectrum.16 (The remaining wavelengths, such as those in the red region, 600 to 700 nm, are reflected back from the myoglobin molecule, resulting in the red hue of myoglobin-containing muscle.) Thus, the wavelength of argon laser light is well matched to the electronic absorption spectrum of myoglobin. As a result, absorbed Aortic

Metal Cannula containing Optical Fiber

Knurled knob

FIGURE 3. Laser myoplasty as performed intraoperatively in the patient described in the present report. Sagittal view shows the longitudinal extent (dashed line) of the myopiasty. The myoplasty was 10 mm deep. This is further illustrated in the inset below in which the septum is viewed through the aortic valve leaflets, with the anterior mitral leaflet retracted.

Through AV)

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light energy may be efficiently converted into heat energy that can initiate a localized, intense thermal reaction, and vaporize the target (myocardium) tissue. Transformation of the target myocardium into a vapor phase is equivalent to a myectomy achieved simultaneously with a myotomy. The initial in vitro experiments performed in human postmortem specimens indicated that a laser myoplasty could be easily accomplished at a low energy level. Power required was consistently less than 2.5 W. Exposure time required was consistently less than 30 seconds. The morphologic features of the myoplasty were made to approximate a myotomy by simply performing a single linear inscription of laser light along the “long” (apex-to-base) axis of the ventricular septum. A final result analogous to a myotomylmyectomy was achieved by performing a contiguous series of such inscriptions until the myoplasty trough was modeled to the requisite dimensions. Analysis by light microscopy of the myoplasty trough created in vitro disclosed that histologic alterations were limited to a zone of thermal injury along the perimeter of the trough. Analysis of the products collected in vitro after argon laser irradiation of myocardium indicates that the fundamental nature of the laser-initiated process is thermal, rather than photoreactive. Both the products formed in the gas phase (carbon dioxide, hydrogen and light hydrocarbon fragments) and the products dissolved in aqueous solution (protein fragments and nitrogen heterocyclic ring fragments) are those expected as the result of thermal degradation (pyrolysis) of a protein chain or porphyrin ring. The series of canine experiments was carried out to evaluate the feasibility and consequences of laser myoplasty performed in vivo. First, the results of laser myoplasty performed on the epicardial surface of the open-chest dog hearts disclosed no qualitative characteristics of myocardium in vivo that alter the power requirements for laser myoplasty, compared to myocardium obtained in the fresh or fixed state postmortem. Second, light microscopic analysis of the myoplasty troughs created both on the epicardial surface of the open-chest dogs and on the endocardial surface (transarterially) in the closed-chest dogs disclosed that the extent of myocardial.injury was proportional to the duration of laser light exposure (power was kept constant). Thus, when the optical fiber was applied in a linear fashion to inscribe a myoplasty trough at a rate of 0.5 mm/s, the lateral spread of apparent myocycte injury was limited to 2 mm; in contrast, fixed application of the optical fiber to a single site for 20 minutes resulted in transmural rupture. The intraoperative experience described in this report is limited to a single patient; it must therefore be regarded as preliminary and the results must be interpreted with caution. Experience with this patient, however, suggested at least 2 advantages of laser phototherapy in the treatment of HC. First constant illumination of the intraventricular operative field facilitates exposure of the apical portion of the proturberant

septal ridge. Second, the incisions created by the conventional blade technique essentially define the obligatory boundaries of the myectomy; a myotomylmyectomy that is too limited may produce an inadequate clinical result, whereas one that is too extensive may result in septal rupture. l&l5 In contrast, argon laser phototherapy allows controlled and precise modeling of the myectomy trough. Comprehensive evaluation of laser myoplasty for the treatment of HC will require postoperative hemodynamic investigation (which for logistical reasons is still pending) and experience with additional patients. Until such data are available, laser myoplasty must be considered investigational. Nevertheless, both the in vitro experience with human postmortem specimens and the in vivo intraoperative experience show that a myoplasty trough morphologically similar to that achieved by conventional blade technique may be accomplished using laser therapy. Subsequent investigations are needed to establish that this similarity in morphologic appearances translates into a comparable degree of clinical and hemodynamic improvement. The fact that our patient remains improved 6 months postoperatively and the fact that the operation was unattended by any complications are encouraging. That transarterial myoplasty might ultimately become a feasible approach to the treatment of medically refractory hypertrophic cardiomyopathy is suggested by several findings in our in vivo canine studies. First, 2-dimensional echocardiography was useful in determining the intracardiac location of the myoplasty catheter, including the site on the ventricular septum engaged by the myoplasty catheter, and the adequacy of septum-catheter contact. Second, it is realistic to perform a laser myoplasty in a beating heart; active systolic contractions, including the augmented contraction of a postventricular ectopic beat, do not necessarily result in dislodgement of the myoplasty catheter. Third, laser myoplasty may be performed in a blood-filled field. Fourth, superficial alteration of the myocardium after the initiation of laser myoplasty does not diminish subsequent absorbance of the laser light by the underlying myocardium. As a result, the underlying myocardium may be vaporized to any desired depth. This was best illustrated in the dog in which transmural rupture was intentionally produced by protracted exposure. Finally, the fact that in vitro irradiation of myocardium produces a paucity of gaseous photoproducts, and the fact that all but hydrogen are water-soluble, suggests that transarterial laser myoplasty is unlikely to result in air embolism. Acknowledgments: The laser and fiberoptics system used in these experiments were provided by Dr. Clarke under support from the U.S. Army Research Office, the U.S. Department of Energy and the National Institutes of Health. Martin Beck, Cordis Corporation, Miami, FL, constructed the guiding catheters used in the canine experiments. The patient described in the present report was referred to our institution by Dr. Alan Weinshel, New Bedford, MA. The patient is being followed by Dr. Charles Harris, Charlotte, NC.

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1974;81:650-680. 9. Rosing DR, Kent KM, Borer JS, Seides SF, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. I. Hemodynamic effects Circulation 1979;60: 1201-1207. 10. Lorell BH, Paulus WJ, Grossman W, Wynne J, Cohn PF, Braunwald E. Improved diastolic function and systolic performance in hypertrophic cardiomyopathy after nifedipine. N Engl J Med 1980; 303:801-803. 11. Morrow AG, Fogarty TJ, Hannah M Ill, Braunwald E. Operative treatment in idiopathic hypertrophic subaortic stenosis: techniques and the results of pre- and post-operative hemodynamic assessments. Circulation 1968;37:589-603. 12. Morrow AG. Hypertrophic subaortic stenosis. Operative methods utilized to relieve left ventricular outflow obstruction. J Thorac Cardiovasc Surg 1978;76:423-430. 13. Bigelow WG, Trimble AS, Auger P, Marquis V, Wigle ED. The ventriculomyotomy operation for muscular subaortic stenosis. A reappraisal. J Thorac Cardiovasc Surg 1966;52:524-524. 14. Jeffery DL, Signorini W, Flemma RJ, Lepley D, Jr, Mullen DC. Left ventricular myotomy. Physiologic approach to surgical therapy for IHSS. Chest 1981;80:550-556. 15. Maron BJ, Merrill WH, Freier AP, Kent KM, Epstein SE, Morrow AG. Long-term clinical course and symptomatic status of patients after operation for hypertrophic subaortic stenosis. Circulation 1978;57:1205-1213. 16. Dolphin D. The Porphyrins. Academic Press, New York, 1978:186.