Cell Transplantation - A Potential Therapy for Cardiac Repair in the Future?
(#2001-5583 ... January 31, 2002)

Helmut Gulbins, MD, B.M. Meiser, MD, H. Reichenspurner, MD, PhD, B. Reichart, MD
Department of Cardiac Surgery, University Hospital Grosshadern, Munich, Germany

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Abstract:

Purpose: Adult human myocardium cannot regenerate because cardiac muscle cells do not reenter the cell cycle. Myoblasts, cardiomyocytes, and stem cell-derived cardiomyocytes have been transplanted in experimental settings to replace lost myocardial tissue. The purpose of this paper is to review the experimental data about cell transfer onto myocardium and to highlight the advantages of the particular cell types used.

Background and Methods: Myoblasts or satellite cells are precursor cells attached to skeletal muscle fibers. The transfer of these cells onto damaged myocardium was demonstrated successfully in several animal models. Because myoblasts can be expanded in culture, a large number of cells can be obtained from only a small skeletal muscle specimen. These cells could be delivered locally by injection within a damaged myocardial area or by coronary infusion. However, only one group has been able to show an improvement in myocardial function after myoblast transfer. The second type of cells used experimentally for cell transfer were fetal cardiomyocytes. Fetal cardiomyocytes retain the ability to divide and therefore can be expanded in culture. The cells were integrated into the myocardial tissue, differentiated into normal cardiac muscle cells, and formed intercellular connections with host myocardial cells. The transplantation of these cells onto cryo-injured myocardium resulted in improved cardiac function in several animal models. Stem cell√derived cardiomyocytes can be selected from embryonic stem cells. These cells still divide and differentiate into different cardiac muscle cells (atrial, ventricular, and pacemaker). After transplantation into damaged myocardium in mice, they formed stable grafts and survived for at least 7 weeks. The selection of these cells has to be performed with care to prevent teratoma formation originating from single undifferentiated cells attached to the transferred cells. Recent experimental studies revealed the ability of bone marrow stem cells to differentiate into cardiomyocytes. These cells were transplanted into damaged myocardium via coronary perfusion. They survived for at least 4 weeks and showed differentiation toward cardiac muscle cells. The functional benefit of bone marrow stem cells, however, has not been clearly demonstrated, and there is a possibility of tumor formations originating from these cells.

Discussion: Myoblasts and bone marrow stem cell√derived cardiomyocytes would permit autologous cell transfer onto the myocardium. These cells can be easily obtained and expanded in culture. Gene transfer is also possible, and there are no ethical proscriptions against an autologous cell transfer. However, the integration and final differentiation of these cells in the heart tissue is not clear yet. Fetal cardiomyocytes, on the other hand, are integrated in the myocardial tissue, improve cardiac function, and can be expanded in culture. Their transfer would be allogenic, making immunosuppression necessary. Stem cell√derived cardiomyocytes could be used to replace all 3 types of cardiac muscle cells, and they can be expanded in culture. The possibility of teratoma formation makes a 100%- selection mandatory. At present, ethical concerns against working with human embryonic stem cells are a factor to be considered.

Conclusions: Cell transfer therapy has been shown to improve myocardial function in animal experiments. This finding indicates that a reduced myocardial function can be improved by cell transfer therapy. Stem cell√derived cardiomyocytes in particular, either of embryonic or bone marrow cell origin, would allow for selective replacement of pacemaker cells or atrial or ventricular cardiomyocytes.

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Published online before print February 24, 2003, doi:10.1161/01.CIR.0000061915.06069.93
This Article

(Circulation. 2003;107:1250.)
© 2003 American Heart Association, Inc.

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Brief Rapid Communications

Randomized Study Comparing Radiofrequency Ablation With Cryoablation for the Treatment of Atrial Flutter With Emphasis on Pain Perception
Carl Timmermans, MD; Gregory M. Ayers, MD; Harry J.G.M. Crijns, MD; Luz-Maria Rodriguez, MD
From the Department of Cardiology (C.T., H.J.G.M.C., L.-M.R.), Academic Hospital Maastricht, the Netherlands; and CryoCor, Inc, San Diego, Calif (G.M.A.).

Correspondence to Carl Timmermans, Department of Cardiology, Academic Hospital Maastricht, CARIM, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands. E-mail ccmm.timmermans@cardio.unimaas.nl

Abstract

Background— Radiofrequency ablation (RF) of atrial flutter (AFL) has a high procedural efficacy, a low recurrence rate, and reports of procedure-related pain. The aim of the present study was to compare RF with cryoablation (cryo) for the treatment of AFL, with emphasis on pain perception during application of energy.

Methods and Results— Fourteen patients (55±11 years, 11 males) with AFL were randomized to receive ablation of the cavotricuspid isthmus (CTI) by either RF or cryo. Cryothermia was delivered with the CryoCor Cryoablation System (10F, 6-mm tip), and radiofrequency energy was delivered with the use of an 8-mm–tip catheter. Pain was evaluated according to a visual analogue scale (VAS; 0 to 100). All patients in the cryo group were successfully ablated with a mean of 18 applications (9 sites), and RF was successful in 6 of 7 patients (not significant) with 13 applications (not significant). The mean temperature was -82°C and 55°C for cryo and RF, respectively. One patient in the cryo group perceived pain, versus all 7 patients in the RF group (P<0.05). The proportion of painful applications averaged 75.3% in the RF group and 2.0% in the cryo group (P<0.05), whereas the corresponding VAS for pain was 38.3±25.3 and 0.32±0.86, respectively (P<0.05). At 6-month follow-up, there were no recurrences of atrial flutter.

Conclusion— Cryo, as compared with RF, produces significantly less pain during application. Although in the present study there was no significant difference in efficacy, larger studies will be needed to definitively compare efficacy.

Key Words: atrial flutter • catheter ablation • arrhythmia

Introduction

Type I atrial flutter (AFL) has been successfully treated with transvenous radiofrequency ablation (RF) delivered to the cavotricuspid isthmus (CTI) with a high clinical success rate (85% to 100%).1–4 Unlike other supraventricular arrhythmias treated with RF, there are occasional recurrences of AFL after acutely successful procedures (5% to 10%).2,4 Although not systematically studied, it is recognized clinically that patients often report discomfort during RF.3,4

Recent advances in cryogenics technology have allowed for the development of catheter systems that can deliver cryoablation (cryo) energy from the tip of a transvenous catheter.5–7 The aim of the present study was to systematically compare RF with cryo for the treatment of AFL, with emphasis on pain perception during application of energy.

Methods

Study Patients
Fourteen consecutive patients with ECG-documented type I AFL were studied. On enrollment, patients were randomized to either cryo or RF. The hospital ethics committee approved the study, and patients gave informed consent. All patients were followed up for 6 months after the ablation.

Electrophysiological Study and Ablation Procedure
Patients were studied in the fasting state without sedation. Antiarrhythmic drugs were not discontinued before the procedure. As has been previously described, ablation was performed using a sequential application technique.1,2 Acute efficacy was defined as the presence of bidirectional isthmus conduction block and absence of arrhythmia induction.2

RF was performed with the use of an 8-mm–tip catheter (Biosense-Webster, Inc). The generator was set for 90-second delivery with a preset temperature of 70°C and a power limit of 55 W.

Cryo was delivered with the CryoCor Cryoablation System (CryoCor, Inc), which consists of a console and a 10F, 6-mm–tip catheter.5,7 Cryothermia was delivered twice at each catheter tip site for 4 minutes, allowing recovery of the temperature to approximately body temperature between each application.7

Pain was evaluated according to a Visual Analogue Scale (VAS) ranging from 0 to 100, with 0 correlating with the statement "no pain at all" and 100 with "the worst possible pain."8 The VAS score was determined at the end of each application.

Electrograms were observed from the ablation catheter just before the delivery of energy. The amplitude of the atrial and ventricular component were then compared for the evaluation of pain versus catheter tip location.

Statistical Analysis
Results are expressed as mean±SD. Fisher exact test was used for comparing the proportions of patients with pain in the two groups. The within-patient proportion of painful applications and the mean pain amplitude were calculated for each patient in each group and compared by using a Wilcoxon rank-sum test. The effect of the treatment applied (RF or cryo) across applications was assessed with the general linear mixed model, which accounts for repeated measurements within patients and within catheter tip sites. All results were considered to be significant at P<0.05.

Results

Patient Characteristics
The patient characteristics are shown in Table 1. There were no significant differences with regard to these variables for the two groups.

TABLE 1. Patient Characteristics

Radiofrequency Ablation
Ninety-four applications were delivered to the 7 patients undergoing RF (mean, 13±11; range, 4 to 35). The mean temperature was 55±4 (range, 50 to 62)°C with a mean power of 46±8 (range, 33 to 55) W. After RF, bidirectional isthmus conduction block was present in 6 of 7 patients (86%). In the one patient in whom RF failed, 35 applications were delivered with only a prolongation in conduction indicating incomplete block. Procedure and fluoroscopy time for the RF was 2.6±1.5 (range, 1 to 5) hours and 44±39 (range, 9 to 120) minutes, respectively. There were no acute procedural complications. At 6-month follow-up, none of the 6 successfully ablated patients had recurrence.

Cryoablation
The seven patients had 125 applications delivered (mean, 18±4; range, 14 to 22; not significant versus RF) at a mean of 9±2 (range, 7 to 11) sites. The cryo parameters were: a mean nadir temperature of -84±5 (range, -73 to -92)°C and a mean temperature of -82±5 (range, -69 to -89)°C. In all patients, bidirectional isthmus block was obtained (100%, not significant versus RF). The procedure time was 4.1±1.4 (range, 2.5 to 6.5) hours, slightly but not significantly longer than in RF patients (P=0.077). With regard to fluoroscopy time, there was no difference as compared with RF (60±48; range, 12 to 152 minutes). There were no procedural complications. At 6-month follow-up, there were no recurrences of AFL.

Pain Perception
All RF patients perceived one or more of the applications as painful (VAS >0) versus only one patient (3 applications) in the cryo group (P=0.0047). The pain characteristics (proportion of painful applications and mean VAS) for each RF patient are shown in Table 2. For the one patient who perceived pain in the cryo group, 3 of 22 (13.6%) applications were painful with a mean VAS of 2.27±6.12. The overall mean pain proportion in the cryo group was 1.95±5.15%, and the overall group mean VAS was 0.32±0.86. This compares with 75.3±24.4% and a mean VAS of 38.3±25.3 for the RF group. When comparing the proportion of painful applications in the two groups, the result was highly significant (P<0.005). When comparing the mean VAS score across the two groups, accounting for repeated values among patients, a significant group effect was observed (P<0.0001), confirming the result that there was a difference in proportion of painful applications and mean VAS scores. When including the catheter tip site in the model but restricting the analysis only to RF patients, the analysis further revealed that VAS scores for applications in the atrioventricular groove (9.74±19.0) were significantly lower than for applications delivered in the atrium/atrium-inferior vena cava transition (28.6±29.8, P=0.011) but not less than the scores for applications given in the ventricle (25.0±27.8, P=0.086) (Table 3).

TABLE 2. Within-Patient Pain Characteristics in the RF Group

TABLE 3. VAS for Pain According to Treatment Group and Site of Catheter Tip

Discussion

The main finding of the present study is that cryo of the CTI, as compared with RF, results in nearly no application-related pain or discomfort. In this small population, both acute and chronic efficacy of cryo was not significantly different from that of RF. The efficacy seen in this study is higher than initially reported for other cryo systems when used to treat either AFL or other supraventricular tachycardias.6 This finding may be the result of the difference in catheter diameter, tip electrode size, or overall system performance.

The trend toward longer procedure times associated with cryo is the result of longer, repeated applications at each catheter site (4 minutes versus 90 seconds and double cryoapplications). The similar number of applications required and the total fluoroscopy time substantiate the trend’s being due to application time and number. The method of application of cryothermia (twice, a 4-minute application on the same site) was based on previous cryo experiences in animals and in cardiac surgery.9,10 Further studies are needed to define the duration of individual cryoapplications and to evaluate the need for repeated cryothermia delivery, as they may impact significantly procedure duration and efficacy.

The present study is the first systematic evaluation in the nonsedated patient of pain associated with RF of the CTI. Although prior studies have reported that RF may induce patient discomfort, resulting in either the need for more sedation or analgesia, the present study quantifies ablation-induced pain.3,4 We clearly show that cryo produces nearly no pain, whereas RF produces pain in all patients. Ablation without pain is also of clinical importance when ablating in sites such as the coronary sinus and the atria, despite the use of conscious sedation. The mechanisms of the pain associated with RF remains unclear. We hypothesized that RF applied to thin structures, such as the right atrial wall or inferior vena cava, might be more likely to cause pain because of their proximity to the pericardium and therefore results in pericardial irritation. However, the results of the present study are not in agreement with this hypothesis. It is also possible that certain ablation sites directly stimulate cardiac sensory nerves, perceived by the patient as visceral pain.11

Conclusion


The present study shows that cryo is much less painful than RF for ablation of the cavotricuspid isthmus. Because of this advantage, cryo should be considered for cavotricuspid isthmus ablation and for ablations known to cause discomfort or pain with RF delivery. Although in this study there was no significant difference in efficacy, larger studies will be needed to definitively compare efficacy.

Footnotes

Dr Ayers is the founder and an employee of CryoCor, Inc.

Received October 31, 2002; revision received January 23, 2003; accepted January 23, 2003.

References

Rodriguez LM, Nabar A, Timmermans C, et al. Comparison of results of an 8-mm split-tip versus a 4-mm tip ablation catheter to perform radiofrequency ablation of type I atrial flutter. Am J Cardiol. 2000; 85: 109–112.[CrossRef]

Nabar A, Rodriguez LM, Timmermans C, et al. Isoproterenol to evaluate resumption of conduction after right atrial isthmus ablation in type I atrial flutter. Circulation. 1999; 99: 3286–3291.

Jaïs P, Shah D, Haïssaguerre M, et al. Prospective randomized comparison of irrigated-tip versus conventional-tip catheters for ablation of common flutter. Circulation. 2000; 101: 772–776.

Kirkorian G, Moncada E, Chevalier P, et al. Radiofrequency ablation of atrial flutter: efficacy of an anatomically guided approach. Circulation. 1994; 90: 2804–2814.

Timmermans C, Rodriguez LM, Van Suylen RJ, et al. Catheter-based cryoablation produces permanent bidirectional cavotricuspid isthmus conduction block in dogs. J Interv Card Electrophysiol. 2002; 7: 149–155.

Skanes AC, Dubuc M, Klein GJ, et al. Cryothermal ablation of the slow pathway for the elimination of atrioventricular nodal reentrant tachycardia. Circulation. 2000; 102: 2856–2860.

Rodriguez LM, Geller JC, Tse HF, et al. Acute results of transvenous cryoablation of supraventricular tachycardia (atrial fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, atrioventricular nodal reentry tachycardia). J Cardiovasc Electrophysiol. 2002; 13: 1082–1089.

Van den Hout JHC, Vlaeyen JWS, Houben RMA, et al. The effects of failure feedback and pain-related fear on pain report, pain tolerance, and pain avoidance in chronic low back pain patients. Pain. 2001; 92: 247–257.[CrossRef]

Rodriguez LM, Leunissen J, Hoekstra A, et al. Transvenous cold mapping and cryoablation of the AV node in dogs: observations of chronic lesions and comparison to those obtained using radiofrequency ablation. J Cardiovasc Electrophysiol. 1998; 9: 1055–1061.

Holman WI, Iskeshita M, Douglas JM, et al. Cardiac cryosurgery: effects of myocardial temperature on cryolesion size. Ann Thorac Surg. 1983; 35: 386–393.

Randall WC, Ardell JL. Functional anatomy of the cardiac efferent innervation. In: Kulbertus HE, Franck G, eds. Neurocardiology. Mount Kisco, NY: Futura Publishing Company; 1988: 3–24.

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(Circulation. 2002;106:I-46.)
© 2002 American Heart Association, Inc.

Surgery for Valvular Heart Disease

The Effect of Cryo-Maze Procedure on Early and Intermediate Term Outcome in Mitral Valve Disease: Case Matched Study
Hiroyuki Nakajima, MD; Junjiro Kobayashi, MD; Ko Bando, MD; Kazuo Niwaya, MD; Osamu Tagusari, MD; Yoshikado Sasako, MD; Takeshi Nakatani, MD; Soichiro Kitamura, MD
From the Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan.

Correspondence to Junjiro Kobayashi, MD, Department of Cardiovascular Surgery, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail jkobayas@hsp.ncvc.go.jp

Abstract

Background The maze procedure is an effective way to treat atrial fibrillation (AF) associated with mitral valve disease. In a last several years, cryoablation was substituted for atrial incision in many reports to simplify the maze procedure. However, there has been no comparative study to delineate the feasibility of the use of cryoablation.

Methods and Results We compared the early and intermediate-term results of the maze procedure including pulmonary venous isolation from the left atrium using cryoablation (CM) with our conventional (Kosakai) maze procedure (KM) including encircling incision around the orifices of pulmonary veins. One hundred and 10 pairs of patients were matched in the age, left atrial dimension >70 mm, duration of AF >0 years, previous cardiac surgery, mechanical valve implantation and concomitant aortic valve procedures. CM required significantly shorter cardiopulmonary bypass time (186±56 minute versus 214±47 minute, P=0.001) and aortic cross-clamp time (134±43 minute versus 144±37 minute, P=0.03) than KM with less chest tube drainage (590±353 mL versus 745±618 mL, P=0.02) for 12 hours after operation. The sinus rhythm restoration rate in CM group (85.4%) was comparable with KM group (86.4%) at discharge. In the late results, the actuarial freedom from recurrence of sustained AF at 3 years in CM group (97.7%) was not significantly (P=0.11) different from that in KM group (90.4%). The actuarial freedom from stroke at 3 years in CM group was 99.0%.

Conclusion The modification of the maze procedure including cryoablation for pulmonary venous isolation provided less aortic cross-clamp time and less amount of chest tube drainage with the comparable recovery and maintenance of sinus rhythm with KM. CM is a reliable and less invasive surgical option for the AF associated with mitral valve disease.
Key Words: mitral valve disease • maze procedure • atrial fibrillation • cryoablation

Introduction

To eliminate atrial fibrillation (AF) and restore sinus rhythm after mitral valve operation prevents stroke,1,2 decreases the late mortality,2 and improves cardiac function with the recovery of atrial contraction2,3 and the quality of life.2,4 The conventional maze procedure requires large left atrial incisions and sutures, and prolongs cardiac ischemic time. Therefore, the conventional full maze procedure has a potential risk of postoperative complications, such as bleeding, low output syndrome and sick sinus syndrome.2

In a last decade, various modifications of the maze procedure have been developed by many surgeons.6–15 Most of these modifications include the sutureless interruption of the myocardial conduction in the left atrium especially for isolation of pulmonary veins (PV),6–11 which is the critical part as a trigger site of initiation of AF.17–19 The cryoablation is 1 of the common ways of substitution for atrial incision in the maze procedure6–8 and early results of these trials in small population were seemed to be acceptable.6–11 However, the rationale of cryoablation for PV isolation has not been proved because no comparative study has been previously reported.

In the present study, we examined the rationale of cryoablation for PV isolation by comparing the early and intermediate-term results of our conventional maze procedure.

Methods

Patients
Between May 1992 and June 2001, 414 patients underwent the maze procedure associated with mitral valve operation. Since September 1998, 119 patients underwent cryo-maze procedure (CM), 244 underwent Kosakai maze procedure (KM) before introduction of CM, and 51 underwent the other modified maze procedure. The choice of procedure depended on the period when operation was performed. One hundred and 10 pairs of patients were matched. Only hospital survivors were assigned to this study. The matching variables were the age, the preoperative duration of AF >10 years, preoperative left atrial dimension >70 mm, the history of previous cardiac surgery, and concomitant aortic valve operation. These were reported to be negative predictive factors for regaining sinus rhythm after the maze procedure,12,13,16 procedural time or postoperative bleeding. The patients were selected from the preoperative and operative database except for the clinical results to exclude the bias. There was a significant difference in NYHA functional class in 2 groups. The incidences of preoperative history of stroke and associated coronary artery disease in CM group were significantly higher than those in KM group. Cardiothoracic ratio on the chest X-ray film, the voltage of f-wave in V1 lead on ECG and left ventricular dimension were similar in both groups (Table 1).

TABLE 1. Preoperative Patient Characteristics

Operative Procedure
The details of operative technique of our conventional maze procedure were described previously.13 KM is composed of PV isolation by incision and suture, and cryoablation for the interruption of macro-reentry circuits in the left and right atriums (Figure 1).

Figure 1. (A). Conventional (Kosakai) maze procedure. (B). cryo-maze procedure. The major difference between the conventional and cryo-maze procedure is the use of cryoablation for pulmonary venous isolation from the left atrium.

The scheme of current CM is described in Figure 1. The major difference between KM and CM is the use of cryoablation for PV isolation from the left atrium. We incised only right-sided left atrium in CM just for simple mitral valve operation. Cryoablation was applied on the atrial endocardium to -80°C cold for 2 minutes with 20° angled 4 cm linear probe (CCS-200, Cooper Surgical, Shelton, CT). Another difference is the site of cryoablation on the interatrial septum. Cryoablation was performed between fossa ovalis and right atrial incision (Figure 1). We avoid injury on the sinus node or sinus node artery in CM. Right atrial appendage was fully preserved and left atrial appendage was partially preserved in CM. Concomitant procedures were similar in both groups (Table 1). As for myocardial protection, crystalloid cardioplegia had been used early in the period of KM but not in CM group at all. We preferably use tepid blood cardioplagia these years.

Postoperative Management
Electrocardiogram (EKG) was continuously monitored until cardiac rhythm became stable. Perioperative AF or atrial flutter was treated with group Ia and Ic antiarrhythmic drugs. Cardioversion was performed if necessary. Verapamil or beta blocker was added for the treatment of high ventricular rate. Group III antiarrhythmic drugs, sotalol or amiodarone, have never been used. Antiarrhythmic drugs were gradually withdrawn 3 months after operation.

Warfarin was routinely administered to all patients for 3 months. If the sinus rhythm was constantly maintained, anticoagulation therapy could be terminated in patients with mitral valve repair or biological valve implantation. Then small dose of aspirin was given if the contraction of left atrium was absent or left atrial dimension was over 55 mm.

These postoperative antiarrhythmic and anticoagulation strategy were the same in both groups.

Follow-Up Data
The status of patients was determined by referring to medical records and correspondence with the responsible physicians. All the events were recorded in detail. Patients were followed up by EKG, chest roentgenogram, and echocardiography with pulsed Doppler study every 3 months. We defined the sinus rhythm on EKG if the P-wave was present. Follow-up was complete by outpatient clinic or mail interview in all patients. The mean follow-up time was 18.8±10.8 months for CM and 64.1±27.4 months for KM.

Statistical Analysis
Continuous variables are expressed as the mean values±SD. The clinical profiles of the 2 groups were compared by Wilcoxon rank sum test or Fisher’s exact test. Longitudinal data were estimated by the Kaplan-Meier method and differences of 2 groups were compared by Cox-Mantel method.

Results

Early Results
Cardiopulmonary bypass time and aortic cross clamp time in KM group (214±47 minutes and 144±37 minutes) were significantly (P=0.001 and P=0.03) longer than in CM group (186±56 minute and 134±43 minute).

Reexploration for bleeding was required in 2 cases (1.8%) in CM group and in 5 cases (4.5%) in KM group (P=0.25). The amount of chest tube drainage for 12 hours in ICU in CM group (590±353 mL) was significantly (P=0.02) smaller than that in KM group (745±618 mL). The patients who required high dose catecholamine (dopamine >8 µg/kg/min) were more frequently seen in KM group (4.5%) than CM group (0%) (P=0.02). The incidence of other early complications was the same in both groups (Table 2).

TABLE 2. Operative Results and Early Complications

On discharge from hospital, sinus rhythm was regained 94 patients (85.4%) after CM and 95 patients (86.4%) after KM. There was no significant difference between 2 groups. Perioperative recurrence of AF was seen in 59 patients (54%) in CM groups and in 66 patients (60%) in KM group. There was no significant difference in the incidence of perioperative AF (Table 2).

Late Results
There were only 2 late deaths (1.8%) in KM group. One died of anticoagulation related intestinal bleeding, and the other died of cerebral infarction. One patient in CM group, who underwent mitral valve repair and regained sinus rhythm, suffered from cerebral infarction 4 months after the operation.

The actuarial survival rate at 3 years was 91.7% in CM group and 98.0% in KM group (P=0.32) (Figure 2). The actuarial freedom from stroke at 3 years was 99.0% in CM group and 99.0% in KM group (P=0.68). There was no significant difference between 2 groups (Figure 3).

Figure 2. Actuarial survival rate. CM=cryo-maze procedure, KM=Kosakai maze procedure.


Figure 3. Actuarial freedom from stroke.

Three patients underwent redo mitral valve replacement in KM and 2 patients in CM. All of these 5 patients underwent mitral valve repair or commissurotomy combined with the maze procedure. One patient had angina pectoris and successfully treated with catheter intervention for significant coronary artery disease (Table 3). The event-free survival rate as assessed by the freedom from cardiac death, thromboembolism, reoperation, and anticoagulation-related hemorrhage at 3 years was 88.5% in CM group and 96.2% in KM group (P=0.31).

TABLE 3. Intermediate and Late Results

The actuarial freedom from recurrence of sustained AF at 3 years was 99.0% in CM group and 90.4% in KM group. There was no significant difference between the groups (P=0.11) (Figure 4).

Figure 4. Actuarial freedom from recurrence of sustained AF.

Discussion

The correction of mitral valve disease alone is not sufficient to restore sinus rhythm in the majority of the patients.3,15,20 The maze procedure during the mitral valve operation is the only effective way to facilitate the recovery of sinus rhythm and eliminate the morbidity of AF.1 The sinus rhythm recovery rate was relatively low (59% to 90%) in mitral valve disease compared with isolated AF, probably because of the dilated left atrium and degenerated myocardium.3,6–8,13,16 To improve the successful rate and decrease the complications in the maze procedure, we had imposed restrictions on the indication of the maze procedure and modified the operative procedures.12,13

The disadvantages of the conventional maze procedure are the long atrial suture line and the prolongation of cardiac ischemic time, which causes postoperative bleeding,3 ventricular dysfunction, and occasional injury of sinus node artery. In addition, we speculate that excessive atrial incision can be a cause of the impairment of postoperative atrial contraction and possibly increase the focus of the reentry. And "cut-and-sew" technique in the encircling incision and suture around the orifices of PV was time-consuming and somewhat technically demanding,3,15 and reexploration for bleeding was mostly attributed to this suture line in our experience. To resolve these problems, many surgeons have modified the maze procedures. In common, incision and suture for PV isolation substituted by the sutureless devices such as cryoablation or radiofrequent ablation6–11,21 and recent minimally invasive cardiac surgery accelerates such a modification. On the other hand, PV has the important role as the trigger of the initiation of AF. Haissaguerre and colleagues17 reported 94% of the ectopic foci were present in the PV and Chen and colleagues18,19 reported that PV contributed to the initiation of AF in 88 to 93% of patients. Therefore some surgeons believe that incision and suture for PV isolation from the left atrium is mandatory to restore sinus rhythm.14,15,22,23 However, there has been no comparative study to elucidate the feasibility of the use of devices or the obligation of atrial incision and suture, especially for PV isolation.24

Cryoablation is advantageous in the aspect of the minimal damage on endocardium and creating the transmural homogeneous lesions.24,25 It has been successfully used for the treatment of cardiac arrhythmia for a long time. During mitral valve operation, our current procedure of CM requires no additional atriotomy. The left atrium was incised in almost the same length as a standard right-sided left atriotomy, which was essential for the approach to the mitral valve. And the left atrial appendage was just ligated from the epicardial side. This method simultaneously has benefits to preserve the mechanical function and atrial natriuretic peptide secretion,26 which could decrease the incidence of the fluid retention and requirement of high dose of catecholamine after CM.

The use of the cryoablation for PV isolation is advantageous in shorter procedural time and decreased risk of bleeding, the satisfactory rate of sinus rhythm recovery, and its maintenance in the intermediate term follow-up, comparing with PV isolation with cut-and-sew technique. CM shortened the aortic cross clamp time by 10 minutes. It takes only 20 to 25 minutes of additional aortic cross clamp time in mitral valve operation. Less amount of chest tube drainage in CM group is attributed to the shorter cardiopulmonary bypass time and diminished left atrial incisional line. The sinus rhythm restoration and maintenance rate of CM group were as good as those in KM group in our series. On the contrary, Izumoto and colleagues6 reported that the recurrence of AF during 5 years after operation was as high as 22% when they use cryoablation in their modified procedure. The deprived intermediate outcome of their series is probably because of inappropriate applications of the cryoablation. We have frozen the tissue up to -80°C as long as 2 minutes under bloodless field to create completely transmural cryolesions.

The maze procedure is not mandatory in patients with AF who undergo mitral valve surgery. Therefore, it should be as less invasive as possible as an adjunctive procedure. Minimally invasive surgery including robotic surgery21 has been introduced into the mitral valve operation last 6 years. Surgeons who are good at minimally invasive mitral valve repair demand minimally invasive maze procedure. If the maze procedure must be composed of cut-and-sew technique, the minimally invasive mitral valve operation is restricted. Our results proved the rationale of the cryoablation instead of cut-and-sew technique in the maze procedure, and will spread the future of the maze procedure with concomitant minimally invasive mitral valve surgery.

The drawback of the present study is the operation was not randomly assigned for CM and KM in a certain period. There might be some bias in this study. KM was gradually replaced by CM in a couple of months. We are more accustomed to the procedure and postoperative care in CM from the beginning. And the advance in the cardioplegic solution has been notable for several years, and it could be related to the requirement of inotropic support in some cases after KM. However, the bias is considered to be negligible in sinus rhythm recovery rate and maintenance, because preoperative profiles were completely matched in 2 groups.

In conclusion, the cryo-maze procedure including cryoablation for PV isolation was as reliable as the conventional maze procedure.

References

Cox JL, Ad N, Palazzo T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation. J Thorac Cardiovasc Surg. 1999; 118: 833–840.

Kobayashi J, Sasako Y, Bando K, et al. Eight-year experience of combined valve repair for mitral regurgitation and maze procedure. J Heart Valve Dis. 2002; 11: 165–172.

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