Hemodynamically significant left ventricular outflow obstruction occurs in up to 25% of patients diagnosed with hypertrophic cardiomyopathy (HCM).1,2 A resting left ventricular outflow tract (LVOT) obstructive gradient of 30 mmHg or greater, adversely affects prognosis. Indeed it significantly correlates with an increased risk of death or progression to decompensated cardiac failure.3 Nonpharmacological therapeutic options for these patients with persistent and severe symptoms include dual-chamber pacing, percutaneous alcohol septal ablation and surgery.
While dual-chamber pacing is not regarded as a primary treatment option for those with severe symptoms and evidence of documented LVOT obstruction, it may be useful in the elderly as an alternative to a more invasive strategy.4 Since its introduction in 1995, the number of percutaneous alcohol septal ablations being performed has quickly overtaken the surgical myotomy-myectomy procedure as the treatment of choice for this patient cohort. Experienced centers have reported procedure-related death rates (1–2%) and morbidity similar to those encountered with surgical myectomy.5 Complete heart block requiring permanent pacemaker implantation occurs more frequently with alcohol ablation. However, controversy exists surrounding the long-term arrhythmogenic potential of LV scar formation and its impact on the risk of sudden cardiac death. In accordance with the American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on HCM, surgical myotomy-myectomy (the Morrow procedure) remains the definitive treatment.6
The clinical application of percutaneous catheter cryoablative therapy has developed rapidly in the field of interventional electrophysiology over the last 8 to 10 years. Potential advantages include the formation of homogenous transmural lesions within the myocardium, which are nonarrhythmogenic and maintain tissue architecture.7 Also, reports indicate that there is a lower thrombogenic potential for cryolesions8 and a reduced risk of atrioventricular (AV) block during ablation of AV nodal reentry tachycardia, together with a decrease in the incidence of procedure-related pain.9 However, it is the potential to preserve the intrinsic myocardial tensile strength, combined with the avoidance of an arrhythmogenic scar, which makes this technology most attractive for ablation of obstructive septal hypertrophy. The induction of controlled myocardial necrosis using cryoenergy to impair septal contractile function may reduce the LVOT gradient. Prior to undertaking this clinical study, we performed percutaneous cryoablation of the interventricular septum in 3 goats at the Massachusetts General Hospital in Boston, Massachusetts and found the lesions to be free of endocardial disruption or thrombus formation (DK – unpublished data). We describe 3 patients with symptomatic obstructive HCM who underwent percutaneous cryoablation of the interventricular septum.
Patients. Ethical approval for this study was obtained from the St. James’s Hospital Ethics Committee. After providing written, informed consent, 3 patients with symptomatic obstructive HCM who had not responded to optimized drug therapy were enrolled for PTESC. All 3 had previously undergone implantation of a dual-chamber pacemaker with implantable cardiac defibrillator (ICD) capability. Comprehensive transthoracic echocardiographic evaluation and exercise testing were performed in all patients. Using M-mode and two-dimensional measurements, the basal interventricular septal thickness was recorded in line with the American Society of Echocardiography’s guidelines.10 The peak instantaneous gradients from the LVOT were derived at rest and during exercise.11 A detailed record of baseline symptoms was made using the New York Heart Association Functional Classification (NYHA FC) questionnaire. Patient characteristics are provided in Table 1.
Cryoablation system. Cryoablation was performed using a 7 Fr 4 mm tip cryocatheter via a transportic approach in Patient 1 and for the subsequent 2 patients, a 9 Fr 8 mm-tip quadripolar cryocatheter with 3 and 2 mm spacing between the distal and proximal electrodes (Freezor® MAX, CryoCath Technologies, Inc., Montréal, Québec, Canada) via a transseptal approach was employed (Figure 1). A detailed technical description of catheter design and function has been provided elsewhere.12
Percutaneous septal cryothermal catheter ablation procedure. Prophylactic antibiotics and conscious sedation were administered intravenously. The defibrillation capability of the implantable cardiac defibrillator was inactivated for the duration of the procedure. Simultaneous left ventricular and aortic pressure measurements confirmed a significant resting subvalvular gradient in each case. A transarterial retrograde approach for the LVOT was used for Patient 1. Access was gained via a right femoral artery 10 Fr sheath. For the other 2 cases, an antegrade approach was employed (Figures 2 and 3). Under fluoroscopic guidance, transseptal access to the left atrium was obtained using a 10 Fr transseptal Mullins sheath via the right femoral vein. This antegrade approach facilitated catheter-septal contact by allowing a parallel electrode orientation with the endocardium of the LVOT, whereas the retrograde transaortic approach had resulted in a more perpendicular electrode orientation. Intravenous heparin was infused to maintain an activated clotting time of at least 300 seconds in all cases. Heparin was administered after the successful transseptal puncture in Patients 2 and 3. Left ventricular pressure tracings were recorded prior to and throughout the procedure. This was done using a 4 Fr pigtail catheter inserted via the left femoral artery in all cases. A total of 20–32 cryo applications, each of 240 seconds’ duration, were applied to the LVOT septum under fluoroscopic guidance. The mean sustained temperature was -88˚C. Echocardiography was carried out after the procedure to exclude pericardial effusion and at 24 hours post-cryoablation. Patients underwent 48 hours of continuous electrocardiographic monitoring prior to discharge. Serial cardiac enzymes including troponin T (TnT) and creatine phosphokinase (CK) together with CK-MB fraction were measured at baseline and 24 hours postprocedure. In addition to continued beta blockade with bisoprolol, dual antiplatelet therapy of aspirin and clopidogrel was prescribed for 1 month.
Between March 2005 and May 2006, 3 patients (2 male, 1 female) with a mean age of 38.15 years (range 22.6–49.05) underwent PTESC. Procedural details are given in Table 2. All 3 patients had severe drug refractory symptoms attributable to obstructive HCM. Peak instantaneous LVOT gradients for patients 1, 2 and 3 were 70, 126 and 100 mmHg, respectively. The total cryoablation time was longest at 128 minutes for Patient 1. The corresponding time for Patients 2 and 3 was 92 and 80 minutes, respectively. The mean procedure duration was 183.7 minutes.
Acute procedural success, defined as a significant reduction (more than 50%) in LVOT gradient at the end of septal cryoablation, was achieved in 2 of the 3 cases. All 3 procedures were well tolerated with no major adverse cardiovascular/cerebrovascular events (MACCE). MACCE were defined as death from any cause, major arrhythmia, cardiac tamponade, stroke (as assessed by routine neurological assessment before and after the procedure and before hospital discharge), urgent or emergent conversion to surgery, emergent percutaneous coronary intervention, cardiogenic shock, endocarditis, blood loss requiring transfusion or aortic dissection. None of the patients reported pain related to the application of cryothermal energy. The peak procedure-related rises in CK were 130.4, 184.3 and 63 IU/L for Patients 1, 2 and 3, respectively. The corresponding troponin T measurements at 24 hours post-cryoablation were 0.60, 0.57 and 0.52 g/L (normal values < 0.01 g/L).
At 6-month follow up, patient symptoms and echocardiographic parameters were documented. Patient 1 had a mild improvement in dyspnea. Echocardiographic examination showed an interventricular septum diastolic value of 21 mm (no reduction from baseline), and a peak instantaneous LVOT gradient of 44 mmHg (a reduction of 26 mmHg). Neither of the other 2 patients reported any symptomatic improvement post-cryoablation. A follow-up echocardiographic study of Patient 2 recorded an interventricular septal diameter of 22 mm, and a peak LVOT gradient of 49 mmHg. This was a reduction of 95 mmHg with respect to pre-ablation recordings. This patient reported no improvement in symptoms at 6 months, but on follow up to 1 year, the patient reported complete abolition of symptoms associcated with sustained improvement in gradient (< 50 mmHg at 1 year). The corresponding results for Patient 3 were 18 mm and 107 mmHg, respectively (a reduction of 23 mmHg), with no reduction in symptoms. Patient 2 experienced the largest drop in the LVOT gradient of 95 mmHg.
In this small feasibility study, we report the first known percutaneous interventricular septal cryoablation performed in obstructive HCM. There is considerable experience with percutaneous catheter cryoablation for the treatment of supraventricular tachycardia since its development in the late 1990s,13 including a multicenter prospective study with 154 patients.9 More recently, catheter cryoablation has proved to be safe and painless in the treatment of right ventricular outflow tract (RVOT) tachycardia, with high procedural success being achieved.14 In addition, myocardial lesions produced by cryothermal energy have unique properties compared to those resulting from conventional radiofrequency ablation. Myocyte cell death is induced by a complex process, which involves the formation of intracellular ice and ischemic necrosis resulting from thrombus formation and microcirculatory flow cessation at about 30–45 minutes after cryoablation.15 Compared with radiofrequency energy, cryolesion formation causes a more focal and discrete lesion with less endothelial disruption, resulting in a lower thrombogenic potential.16 This is particularly advantageous when ablating within the systemic cardiac chambers. Surgical myotomy-myectomy typically involves the excision of 5–10 g of septal myocardium encompassing an area from adjacent to the aortic valve to beyond the distal margins of the mitral valve leaflets. The resultant resting LVOT gradient is usually 10 mmHg or less.17 By comparison, TASH procedures result in areas of myocardial infarction approximating 3–10% of the LV mass and 20% of the interventricular septum. This is reflected by a rise in CK release of 400 to 2,500 units.6 A contrast-enhanced magnetic resonance imaging study of 24 patients who underwent TASH found that the mean induced infarction size was 20 ± 9 g, which corresponded to 10 ± 5% and 31 ± 16% of total and septal LV mass, respectively.18 A reduction in the resting LVOT gradient to less than 25 mmHg is usually seen in the months following post-infarct ventricular remodeling.
In the 3 cases presented in this study, the peak CK elevations at 24 hours were small and were not accompanied by any significant electrocardiographic changes of ischemia. Despite the delivery of quantities of cryoenergy in excess of those previously demonstrated to produce ventricular necrosis to a depth of 5 mm2, the reduction in LVOT gradient was modest in comparison to surgical myectomy. Due to the excessive myocardial hypertrophy seen with obstructive HCM, it is likely that not enough cryoenergy was applied to induce transmural or even a significant subendocardial infarction necessary to substantially impair septal contraction. The immediate reduction in the LVOT gradient seen in Patients 1 and 3 was not maintained during follow up. This likely impairment of septal contractility was transient, and may be analogous to hibernating myocardium. LVOT gradients at 6-month follow up remained hemodynamically significant in each case. Controlled cryoablation of the septal myocardium to a greater depth enabling the generation of transmural necrosis may potentially result in LVOT gradient reductions comparable with TASH or surgery. The LVOT has a particularly high systolic blood flow, especially in patients with HOCM. This heat sink or warming effect may have contributed to the modest impact of cryothermy at this site. We attempted to address this effect by using a longer electrode with greater diameter and changing to a transseptal approach, which enabled a more parallel electrode orientation to the LVOT interventricular septum, in contrast to the perpendicular orientation from the a transaortic approach. Despite the use of larger catheters, the procedures were well tolerated and no adverse events were encountered. In addition, there were no significant arrhythmias experienced by the patients in the 6 months post-cryoablation.
We report the first known experience in man of the percutaneous application of cryoenergy as a possible treatment modality for obstructive HCM. In this very small series of patients, percutaneous septal cryoablation did not result in a significant and sustained reduction in LVOT gradient in 2 of the 3 cases. However, PTESC was found to be safe and associated with a moderate sustained reduction in LVOT gradient in 2 of the 3 patients. With this small treatment number, extrapolation of the definitive efficacy of this novel procedure is obviously limited. However, we believe that with further development, there may be considerable potential for cryoablation as an alternative percutaneous treatment strategy for septal hypertrophy. Further technical developments may enable the generation of myocardial septal necrosis with resultant LVOT gradient reduction while avoiding the formation of a thrombogenic or arrhythmogenic substrate. Finally, it should be emphasized that current recommended treatment options for obstructive HCM are either percutaneous alcohol septal ablation or surgical myectomy.
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- Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;248:295–303.
- Maron BJ, Nishimura RA, McKenna WJ, et al. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, cross-over study (M-PATHY). Circulation 1999;99:2927–2933.
- Gietzen FH, Leuner CJ, Raute-Kreinsen U, et al. Acute and long-term results after transcoronary ablation of septal hypertrophy (TASH). Catheter interventional treatment for hypertrophic obstructive cardiomyopathy. Eur Heart J 1999;20:1342–1354.
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- Lang, R M, Bierig M, Devereu RB, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, Developed in Conjunction with the European Association of Echocardiography, a Branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463.
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