Author + information
- Received March 30, 2011
- Revision received June 8, 2011
- Accepted June 14, 2011
- Published online November 22, 2011.
- Sherif F. Nagueh, MD⁎,⁎ (, )
- Bertron M. Groves, MD†,
- Leonard Schwartz, MD‡,
- Karen M. Smith, MD§,
- Andrew Wang, MD∥,
- Richard G. Bach, MD¶,
- Christopher Nielsen, MD#,
- Ferdinand Leya, MD⁎⁎,
- John M. Buergler, MD⁎,
- Steven K. Rowe, MD††,
- Anna Woo, MD‡,
- Yolanda Munoz Maldonado, PhD‡‡ and
- William H. Spencer III, MD#
- ↵⁎Reprint requests and correspondence:
Dr. Sherif F. Nagueh, Methodist DeBakey Heart Center, 6550 Fannin, SM-677, Houston, Texas 77030
Objectives The purpose of the study is to identify the predictors of clinical outcome (mortality and survival without repeat septal reduction procedures) of alcohol septal ablation for the treatment of patients with hypertrophic obstructive cardiomyopathy.
Background Alcohol septal ablation is used for treatment of medically refractory hypertrophic obstructive cardiomyopathy patients with severe outflow tract obstruction. The existing literature is limited to single-center results, and predictors of clinical outcome after ablation have not been determined. Registry results can add important data.
Methods Hypertrophic obstructive cardiomyopathy patients (N = 874) who underwent alcohol septal ablation were enrolled. The majority (64%) had severe obstruction at rest, and the remaining had provocable obstruction. Before ablation, patients had severe dyspnea (New York Heart Association [NYHA] functional class III or IV: 78%) and/or severe angina (Canadian Cardiovascular Society angina class III or IV: 43%).
Results Significant improvement (p < 0.01) occurred after ablation (∼5% in NYHA functional classes III and IV, and 8 patients in Canadian Cardiovascular Society angina class III). There were 81 deaths, and survival estimates at 1, 5, and 9 years were 97%, 86%, and 74%, respectively. Left anterior descending artery dissections occurred in 8 patients and arrhythmias in 133 patients. A lower ejection fraction at baseline, a smaller number of septal arteries injected with ethanol, a larger number of ablation procedures per patient, a higher septal thickness post-ablation, and the use beta-blockers post-ablation predicted mortality.
Conclusions Variables that predict mortality after ablation, include baseline ejection fraction and NYHA functional class, the number of septal arteries injected with ethanol, post-ablation septal thickness, beta-blocker use, and the number of ablation procedures.
Hypertrophic cardiomyopathy is the most common inherited cardiomyopathy (1). Hypertrophic cardiomyopathy patients with dynamic left ventricular outflow tract (LVOT) obstruction have higher morbidity and mortality (2). Treatment options for hypertrophic obstructive cardiomyopathy (HOCM) patients who remain symptomatic despite medical therapy are surgical myectomy and alcohol septal ablation. Although single-center studies have reported septal ablation results (3–15), there remains a need for prospective multicenter experience regarding the efficacy and safety of alcohol septal ablation and the predictors of survival after ablation.
The first report of septal ablation by Dr. Ulrich Sigwart (3) was published in 1995, and subsequently the first procedure was performed in North America in 1996. Since then, a group of investigators at 9 institutions in the United States and Canada (Methodist DeBakey Heart and Vascular Center, Houston, Texas; Medical University of South Carolina, Charleston, South Carolina; University of Colorado Hospital, Aurora, Colorado; Washington University School of Medicine at St. Louis, St. Louis, Missouri; University of Florida at Gainesville, Gainesville, Florida; Loyola University Medical Center, Maywood, Illinois; Duke University Medical Center, Durham, North Carolina; Heartland Regional Medical Center, St. Joseph, Michigan; University of Toronto, Toronto, Ontario, Canada) established a registry in 2000. They performed septal ablation using the same criteria for case selection and procedural and follow-up protocols. We herein report the experience of this multicenter registry.
All patients (some included in previous single-center reports) were evaluated by teams experienced in the management of hypertrophic cardiomyopathy patients. HOCM patients with advanced symptoms of exertional dyspnea and/or angina despite medical therapy were considered for septal ablation. Patients unable to tolerate medications because of side effects were offered septal reduction therapy. There were no patients with a depressed EF or in the dilated phase of the disease. The options of surgery and septal ablation were discussed with each patient, and the decision to proceed to septal ablation was individualized based on each patient's clinical status (as the presence of coexisting multiple vessel coronary artery disease or valvular heart disease requiring surgery), and then the informed patients made their own decisions to proceed to alcohol septal ablation. Of note, there were 320 myectomy procedures performed as the primary treatment for HOCM during the enrollment period of the registry. This includes isolated myectomy (n = 214) and myectomy combined with coronary artery bypass surgery, mitral valve repair, or aortic surgery (n = 106).
Patients had dynamic LVOT obstruction caused by systolic anterior motion of the mitral valve at rest (≥30 mm Hg) or provocation (≥60 mm Hg). None of the patients had anomalous insertion of the papillary muscle into the mitral valve, and mitral regurgitation was due to dynamic obstruction with a posterolaterally directed jet. Patients with primary mitral valve disease were referred for surgery. The majority of the patients (64%) had severe LVOT obstruction at rest. In the remaining patients, the qualifying gradient was provoked by Valsalva maneuver in 12.5%, dobutamine infusion in 13% (2-dimensional and Doppler imaging confirmed the presence of obstruction due to systolic anterior motion of the mitral valve and not intracavitary gradients; dobutamine has not been used since 2001), upright exercise in 1.6%, amyl nitrite in 4.3%, and post–premature ventricular contraction in 4.3%. All registry patients had basal septal hypertrophy (≥1.5 cm), and no intrinsic mitral valve disease. The procedure was not performed in 30 patients for different reasons including, among others, the inability to cannulate the left main coronary artery, coronary artery dissections, absence of target septal perforators by contrast echocardiography, and the inability to engage the balloon in the target vessel.
Echocardiographic measurements were performed following American Society of Echocardiography guidelines (16,17). Institutional review board approval was obtained at all sites, and patients provided written informed consent.
Alcohol septal ablation procedure
After coronary angiography, a temporary pacemaker was placed in the right ventricle for pacing should high-grade atrioventricular block develop. A catheter was typically placed in the left ventricle for continuous monitoring of LVOT gradient, and heparin was administered. The appropriate septal perforator branch was cannulated with a flexible-tip guidewire and short angioplasty balloon. After the balloon was inflated, radiographic contrast was injected through its lumen to ascertain that it was occlusive in the septal perforator branch and to exclude retrograde spillage of dye into the left anterior descending (LAD) coronary artery. If spillage was noted, the balloon was repositioned and angiography was repeated. Myocardial contrast echocardiography was performed by injecting contrast (echocardiographic contrast or agitated radiographic contrast) through the balloon lumen (1). The resultant enhanced echogenicity was used to identify the culprit septal segments involved with LVOT obstruction and identify whether the cannulated artery supplied remote territories to avoid the risk of remote infarction (this led to terminating the procedure in 4 patients). Ethanol was slowly injected over several minutes via the inflated balloon lumen. The balloon catheter was left inflated for 5 to 10 min after completing the alcohol infusion before it was deflated and removed. Repeat angiography was performed to determine whether the target septal perforator was occluded and the LAD coronary artery and its branches were patent. LVOT gradient was measured again and if it was >25 mm Hg, another septal perforator artery was identified and injected, if feasible. During the procedure, patients received narcotic analgesics and minor tranquilizers for chest pain. This algorithm was followed at the participating sites as deemed feasible (when other target septal vessels could be identified and cannulated).
Patients' clinical status was determined from clinic visits, phone interviews, and the Social Security death index. The use of negative inotropic drugs after the procedure was based on the symptomatic clinical status and the presence of residual dynamic obstruction.
Data are presented as mean ± SD for continuous variables and n (%) for categorical variables. Four tests were used to assess the assumption of normality: Shapiro-Wilks, Kolmogorov-Smirnov, Cramer-Von Mises, and Anderson-Darling. For data that did not have a normal distribution, the median value and the 25th to 75th quartiles are shown. Comparisons of continuous variables were made using the Student t test for variables with normal distribution, and the Wilcoxon rank-sum test for variables with a non-normal distribution. The Kaplan-Meier method was used to estimate survival. A Cox proportional-hazards model was applied to identify the independent predictors of death, and death or repeat septal ablation after the initial procedure. A p value <0.05 was considered significant.
Baseline clinical status
Table 1 presents a summary of the clinical status at baseline for the 874 patients. All patients had been treated with 1 or more cardiac medications including beta-blockers in 79%, calcium-channel blockers in 12%, and disopyramide in 11%. Patients who were not receiving beta-blockers were receiving calcium channel blockers and/or disopyramide. In addition, 14% had implantation of a permanent pacemaker or automatic implantable cardioverter-defibrillator before the ablation procedure. Despite previous treatments, 78% of patients were classified as New York Heart Association (NYHA) functional class III or IV congestive heart failure and 43% were Canadian Cardiovascular Society (CCS) class III or IV angina pectoris.
Septal ablation procedure
During ablation, 2.9 ± 1.5 ml of ethanol were injected (the average value of 2.9 ml used reflects the volume used in most early cases, and this has decreased in more recently performed ablation procedures). Ethanol was injected into a single septal perforator artery in 78% of patients, in 2 vessels in 20%, in 3 vessels in 1.4%, and 4 vessels in 0.4%. The mean (statistical mean) of peak creatine kinase was 1,188 ± 671 U/l, and patients stayed in the hospital an average of 3 days. Table 2 presents a summary of procedure-related complications; there were 6 deaths acutely related to the procedure. Five patients had ventricular fibrillation during ethanol injection or within the first 24 h after ablation in the coronary care unit. All 5 patients were successfully cardioverted to sinus rhythm. Six patients had episodes of nonsustained ventricular tachycardia in the acute setting with spontaneous resolution.
The mean follow-up duration was 776 ± 26 days (2% lost to follow-up because some patients live overseas). Significant clinical improvement was noted after ablation at the last follow-up with all patients included in the analysis. There were no patients in angina CCS class IV, and only 8 patients in angina CCS class III, 89% in CCS class I, and 8% in CCS class II (p < 0.05 vs. baseline). For NYHA functional class, 72.5% were in class I, 23% in class II, and 3.9% in class III, and 0.65% in class IV (p < 0.05 vs. baseline). Using the intention-to-treat analysis, 80% of patients were free of severe angina (CCS class IV) and severe dyspnea (NYHA class IV) at the last follow-up. Only 2.9% of the patients reported syncope after ablation (p < 0.05 vs. baseline). Some patients were still taking medications including beta-blockers in 38% and verapamil in 8%. The rest gradient at follow-up was 35 mm Hg (1st to 3rd quartiles: 16 to 46 mm Hg). Repeat septal ablation was performed in 112 patients (12.8%) due to persistent symptoms and dynamic obstruction, and myectomy was performed in 25 patients.
Two patients had an arteriovenous fistula, a femoral artery pseudoaneurysm developed in 2 patients, and 2 patients had a large hematoma with 1 receiving 2 U of blood transfusion. One patient had a large retroperitoneal hemorrhage, likely related to arterial access complications, and died 24 h after septal ablation. Vasovagal reactions with bradycardia and hypotension during sheath removal developed in 2 patients. Both responded well to atropine and intravenous fluids.
There were 8 LAD artery dissections related to the use of stiff guidewires during early experience; this complication did not occur in later procedures. Among those who had dissection, 1 patient died, and another underwent emergency coronary artery bypass surgery. Five had successful stent implants, and 1 was observed without intervention. Three had Thrombolysis In Myocardial Infarction LAD artery flow grade 1 with normal left ventricular (LV) EF at follow-up.
Cardiac tamponade occurred in 4 patients: in 3, it was secondary to right ventricular perforation by the temporary pacemaker and in 1 during the attempts to cannulate a septal perforator artery. All were successfully treated with pericardiocentesis.
Acute pulmonary edema developed in 2 patients that responded to intravenous diuretics. A fatal ventricular septal defect developed within 24 h after septal ablation in 1 patient who had coexistent mild aortic stenosis. Progressive mitral regurgitation that was treated by surgery occurred in the periprocedural period in 2 patients, and 5 others needed surgery at later follow-up. There was no evidence of papillary muscle infarction in these patients, and none of the patients had infarction of the LV posterior wall or apex. In 2 of the 5 patients with the late development of progressive mitral regurgitation, flail mitral leaflets developed on longer follow-up and required surgery for that reason, and the etiology in the remaining 3 patients is unknown. Two cerebrovascular events occurred in the periprocedural period: 1 patient had a status of confusion after the ablation, and in the other, dysphasia developed 8 h post-procedure that spontaneously resolved.
Ventricular fibrillation occurred in 14 patients (1.6%), occurring during ethanol injection or within the first 24 h after the procedure in 5 patients. Ventricular tachycardia occurred in 35 patients (3.9%), and of these, it occurred in 9 patients in the acute setting. All were successfully cardioverted. Thus, the average annual rate of ventricular tachycardia/ventricular fibrillation was 3.9%. Permanent high-grade heart block occurred in 78 patients (8.9%) who received a permanent pacemaker. The incidence of pacemaker implantation decreased with time per site as the technical modifications were implemented. To have meaningful statistical comparisons, we compared the incidence of pacemaker implantation over time at sites where >50 procedures were performed. At these sites, the average rate decreased from 28% to 6.5%. Aside from the previously mentioned arrhythmias, 6 patients had transient atrial fibrillation/supraventricular tachycardia with spontaneous resolution.
A total of 94 patients had an implantable cardioverter-defibrillator (ICD) implanted after alcohol septal ablation. The decision to implant an ICD was at the discretion of the treating cardiologist who considered the risk factors for sudden cardiac death. These included family history of sudden cardiac death in a first-degree relative, a history of syncope, maximum wall thickness ≥3 cm, blood pressure response during exercise, and nonsustained ventricular tachycardia on a Holter monitor. On average, patients had 1.5 risk factors for sudden cardiac death. Appropriate ICD discharge for ventricular arrhythmias occurred in 11 patients over the follow-up period with an average annual ICD discharge rate of 1.2%.
Of the 874 patients, 81 died (9.3%). The etiology was cardiac in 25 patients and noncardiac in 25 patients, and in 31 patients, the cause of death could not be determined. Table 3 shows the survival rates after ablation.
Clinical and echocardiographic variables at baseline and 3 months post-ablation, as well as procedural variables were evaluated as potential predictors of death. Age and peak creatine kinase levels did not predict mortality. The univariable baseline predictors of death were NYHA functional class (p = 0.02) and EF (p = 0.01). Importantly, a higher EF, even though within the normal range, was associated with a significantly lower likelihood of death after septal ablation. Procedural predictors of mortality included the volume of ethanol injected (higher volume was associated with lower mortality; p < 0.001), and the number of arteries injected with ethanol (more arteries injected with ethanol was associated with lower mortality; p = 0.007). Post-procedural predictors were all concordant in showing that a more effective ablation was associated with a lower likelihood of death. These included, among others, smaller septal thickness 3 months post-ablation (p = 0.03), more symptomatic improvement as assessed by a lower NYHA functional class (p < 0.001), not taking beta-blockers (p = 0.002) or verapamil (p = 0.049) post-ablation, and the absence of the need for repeat septal ablation procedures (p < 0.001).
The final proportional hazards model for prediction of mortality post-alcohol septal ablation (Table 4) indicated that for each percentage increment in baseline EF, the hazard rate decreased by 2%. Likewise, an increase in the number of arteries injected with ethanol was associated with a decrease in the hazard rate of 22% per vessel injected. On the other hand, for each millimeter greater septal thickness at 3-month follow-up, the hazard ratio increased by 21%. The hazard of dying for those patients taking beta-blockers was 1.32 times higher than the hazard of those patients not taking beta-blockers at 3-month follow-up. The highest hazard ratio was conferred by the number of procedures performed, whereby for each procedure increase of 1, the hazard ratio increased by 66%.
The Figure 1 shows the chi-square results of 3 models for prediction of mortality after septal ablation: one that includes baseline variables, a second with procedural variables added, and a third with 3-month follow-up data included.
The final proportional hazards model (Table 5) for prediction of mortality or repeat septal reduction therapy included NYHA functional class and EF at baseline, the number of arteries injected with ethanol, and the septal thickness and use of negative inotropic drugs 3 months after ablation.
The current report is the first North American multicenter registry of alcohol septal ablation for patients with HOCM. Given the low feasibility of an adequately powered randomized trial of septal ablation versus surgical myectomy (18), registry data represent an important source of evidence regarding the efficacy and safety of alcohol septal ablation, although registry results still have inherent limitations due to the absence of a randomized control or an alternative treatment group.
Current perspectives on the registry results
Previous single-center studies reported a significant improvement of symptoms after alcohol septal ablation. The improvement of symptomatic status after septal ablation has varied among the different studies, but the findings of the registry are rather similar to other reports in which 2% to 10% of patients were left in an advanced NYHA functional class after ablation (7,9,10,12,13).
The overall survival rate noted in the registry at 1 year (97% vs. 98%) is similar to that seen in a disease-free general population included in previous studies (19), but the 5- (86% vs. 95%) and 9- to 10-year (74% vs. 88%) survival rates are lower. However, when compared with HOCM patients who did not undergo septal reduction therapy included in other series (19), survival appears better after alcohol septal ablation (1 year: 97% vs. 90%, 5 years: 86% vs. 79%, 9 to 10 years: 74% vs. 61%).
A number of studies have already been published comparing survival after alcohol septal ablation with that after myectomy. The results of the registry are similar to some of these. All-cause mortality for the registry is higher than that reported for myectomy in some studies in which the 5-year survival rate was 96% (19), and the 10-year survival rate was 83% to 90% after myectomy (19,20). For life-threatening ventricular arrhythmias, the event rate is also higher in the registry when the incidence of this outcome after myectomy is considered. Of note, a single-center study noted a higher risk of sudden death after septal ablation compared with surgery (15), and another study noted a reduction in sudden cardiac death (0.24% per year) with myectomy (21).
The LVOT gradient after septal ablation in the registry is higher than that reported in surgical series. This is likely due to the dependence of alcohol septal ablation on successful cannulation of target arteries that supply the culprit septal segments, whereas surgery produces direct relief.
Notwithstanding, it should be noted that the goal of the registry at its inception was not to compare the outcome of alcohol septal ablation with surgical myectomy, and it should not be judged as such. In particular, the groups in the cited studies and the registry patients were neither matched nor randomized, and only a randomized trial can accurately compare the effect of either procedure on mortality in HOCM patients. The current recommendations are for surgery when the patient is not high risk, whereas alcohol septal ablation is considered for high-risk surgical patients after a thorough discussion of the risks and benefits (1).
Predictors of mortality after septal ablation
Mortality after ablation is affected by a number of variables. These can have opposite effects on the outcome of the procedure, and in a given patient, the balance between these factors determines mortality. We herein discuss some of these predictors. A critical amount of myocardial necrosis at the correct location is important to achieve an effective reduction in the LVOT gradient. Accordingly, the amount of ethanol injected and the number of septal vessels occluded were among the independent predictors in the multivariable model. These results are consistent with the other observations from the registry, namely, that lower septal thickness after ablation and the lack of a need for beta-blockers are associated with lower mortality. We believe that the worse outcome in patients taking a beta-blocker is not due to the medication per se, but to suboptimal results of ablation necessitating their use. The findings of the study should not be interpreted to support withdrawal of medications after ablation in the presence of a clinical indication.
There are reasons to believe and previous studies to support the premise that effective treatment of dynamic obstruction can lead to lower mortality. These include previous studies that have shown higher risk of death (2), including sudden cardiac death (22) in HOCM patients with dynamic obstruction. In addition, McLeod et al. (21) reported on the reduction of sudden cardiac death after myectomy. The mechanisms involved could be related to regression of LV hypertrophy and improving the balance between myocardial oxygen demand and coronary blood supply due to lower LV intracavitary pressure after septal reduction therapy.
In the multivariable model, LV systolic function was another variable that determined mortality. Myocardial necrosis can be well tolerated in HOCM patients with normal systolic function but can have a negative effect in patients in whom LV contractile reserve is reduced. We noted that a lower EF, albeit in the normal range, was a predictor of worse outcome. However, we could not identify a threshold EF beneath which mortality increases, and we view this finding as hypothesis generating that merits additional evaluation with more sensitive indices of LV systolic function as myocardial strain.
The worse outcome with repeat ablation procedures observed in our series may be related to a number of factors. These may include the fact that patients who require repeat procedures have a higher baseline risk, that there is a detrimental effect of inadequate initial ablation on outcome as well as the possibility that repeat ablation procedures can increase the risk of LV dysfunction and arrhythmias. The latter possibility is supported by the detrimental impact of a lower baseline EF (albeit in the normal range) and repeat ablation on outcome, the link being a lower contractile reserve to start with to which the loss of myocardial mass, as a result of septal infarction, is added.
Alcohol septal ablation is an invasive procedure that carries the risk of death and significant morbidity. This mandates careful patient selection and its performance by experienced operators. The registry results support the recommendation of trying to achieve the most successful hemodynamic response with the initial ablation procedure, if technically feasible, as opposed to accepting high residual gradients and repeating the ablation at a later date. In addition, the higher mortality in patients undergoing a second procedure can be a reason to consider myectomy in place of a repeat alcohol septal ablation.
Given the limitations of registry studies, our results cannot prove cause and effect regarding the factors identified as predictors of death versus the possibility that the identified variables are markers of a higher risk group. The findings on routine ICD interrogation after ablation were not captured in all patients, but the occurrence of an appropriate ICD discharge was evaluated. The etiology of death was not adjudicated by an independent committee but was determined at each institution by the principal investigator. There are well-known challenges in ascertaining the cause of death. In fact, it is possible to create more than a 4-fold range of cardiac death rates using an identical clinical database despite objective, pre-specified criteria (23). Accordingly, it was most prudent to use total mortality in the multivariable models.
Displaced, elongated, and redundant mitral valve leaflets contributing to dynamic obstruction could be a reason for suboptimal results with alcohol septal ablation in some patients. Although patients with an anomalous papillary muscle insertion were not considered for septal ablation, the length of the anterior mitral leaflet was not specifically captured, and we cannot comment on the impact of this variable on outcomes. Of note, surgery is effective in patients with redundant leaflets because the surgeon can readily address the mitral valve abnormalities during the operation (24,25).
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Canadian Cardiovascular Society
- ejection fraction
- hypertrophic obstructive cardiomyopathy
- implantable cardioverter-defibrillator
- left anterior descending
- left ventricular
- left ventricular outflow tract
- New York Heart Association
- Received March 30, 2011.
- Revision received June 8, 2011.
- Accepted June 14, 2011.
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