Safety and Efficacy of Alcohol Septal Ablation in Patients with Symptomatic Concentric Left Ventricular Hypertrophy and Outflow Tract Obstruction

ABSTRACT: Background. Transcoronary septal ablation is efficacious for patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM) and outflow-tract gradient (OTG). However, while patients with symptomatic concentric left ventricular hypertrophy (CLVH) may develop OTG, the safety and efficacy of septal ablation in these patients is unknown. Objectives. To determine the potential safety and efficacy of transcoronary alcohol septal ablation in refractory, symptomatic patients with CLVH and significant OTG. Methods. We identified 9 patients (all female; age, 67.6 ± 8.7 years) with CLVH and OTG who underwent septal ablation on a compassionate basis and for symptomatic relief, with CLVH defined as left ventricular wall thickness > 15 mm in the absence of asymmetric septal hypertrophy. CLVH patients were compared with age-, sex- and OTG-matched HOCM patients (resting OTG, 56.7 ± 22.4 versus 58.3 ± 33.5 mmHg, respectively; p = 0.91). Results. In CLVH patients, mean resting OTG decreased to 22.8 ± 12.5 mmHg (p Conclusion. Septal ablation holds promise for the management of symptomatic CLVH with OTG. J INVASIVE CARDIOL 2010;22:586–591 ———————————————————— Concentric left ventricular hypertrophy (CLVH) is a common finding in middle- and older-aged patients. While the precise incidence is unclear, among adult participants in the Framingham Heart Study (age > 40 years), approximately 8% were found to have CLVH by echocardiography.¹ CLVH is classically associated with long-standing systemic hypertension. In one of the seminal publications on these patients, Topol et al² described a cohort of predominantly female patients with severe CLVH and hyperdynamic left ventricular function. As all patients were noted to have a history of hypertension, the condition was originally named “Hypertensive Hypertrophic Cardiomyopathy”.² As also described by Topol et al,² many of these patients suffer significant and disabling symptoms, typically including dyspnea, angina and fatigue. A small subset of patients with CLVH may also exhibit aortic outflow tract obstruction and gradient. The precise incidence of CLVH with outflow tract gradient (OTG) is unknown, and literature has been essentially limited to case reports and small series of patients.^3–8 Adding complexity, in older subjects it may be challenging to accurately differentiate hypertrophic obstructive cardiomyopathy (HOCM) due to gene mutation from hypertension-associated CLVH with OTG.³ Nevertheless, CLVH with OTG in the absence of a HOCM-type genetic mutation is a distinct clinical syndrome with cardinal features, including that it afflicts predominantly older women with a history of hypertension and an absence of a family history of HOCM.^3,4 Literature regarding specific treatment options for these patients has been especially sparse. Isolated case reports have suggested that patients with CLVH and OTG may experience modest hemodynamic and symptomatic improvement by treatment with angiotensin II antagonists,⁵ calcium channel antagonists or b-blocker therapy.⁸ However, given the similarity in etiology (hypertension), we speculate that physicians may often treat symptomatic CLVH with OTG in a similar fashion to heart failure with preserved ejection fraction (“diastolic dysfunction”) — i.e., adequate control of hypertension and the use of diuretics to control pulmonary congestion and peripheral edema.⁹
In contrast to the situation for CLVH with OTG, significant inroads have been made into treatment of HOCM. While remaining somewhat controversial, transcoronary alcohol septal ablation has emerged as a valid treatment modality in a subset of HOCM patients.^10,11 In brief, this procedure involves creating a limited subaortic myocardial infarction of the offending septal myocardium which encroaches on the outflow tract. Despite differences in etiology, CLVH with OTG shares a degree of anatomical similarity with HOCM, in particular the presence of excessive septal myocardium resulting in outflow tract obstruction. Given the non-specificity and general paucity of treatment options for CLVH with OTG, we elected to investigate the potential safety and efficacy of transcoronary alcohol septal ablation in a cohort of these patients with symptoms refractory to conventional medical management.

Methods

Subjects. Patients with CLVH and OTG (and HOCM) undergoing percutaneous alcohol septal ablation were prospectively identified and entered into our single-center, institutional review board-approved interventional database. All patients undergoing interventional procedures are entered into the database within 24 hours of their intervention. Initial data captured include baseline clinical characteristics, procedural details, details of events occurring immediately post procedure, subsequent in-hospital clinical course, laboratory data, and other test results associated with the index procedure. Follow-up data are routinely collected by contacting patients or their primary care provider at 30 days and 1 year post procedure. As required, mortality and other key data are obtained by contact with the primary physician and/or via the Social Security database. Patients included in this study were drawn from the database as of November 2009, at which time an additional telephone and/or mail survey was performed to capture final long-term follow-up data. We identified 9 patients, refractory to maximum tolerated medical management, who fulfilled the criteria for CLVH with OTG (see below) and underwent alcohol septal ablation on a compassionate basis and for symptomatic relief. These procedures were performed between October 2003 and June 2009. The presence and severity of outflow tract obstruction/gradient was initially assessed by echocardiography and was subsequently confirmed at catheterization prior to alcohol ablation. CLVH, adjudicated by 2 independent observers, was defined as left ventricular wall thickness of > 15 mm in the absence of asymmetric hypertrophy and also in the absence of a family history of hypertrophic cardiomyopathy (obstructive or non-obstructive). Family pedigrees were obtained where possible and all patients with a potential family history of hypertrophic cardiomyopathy were excluded as CLVH subjects. As a limitation to this study, due to the fact that many of these procedures were performed prior to the widespread availability of genotyping for HOCM, genetic confirmation of a HOCM gene causing mutation (or its exclusion in CLVH patients) was not able to be performed. CLVH patients were compared with age-, sex- and resting OTG-matched patients with HOCM who also underwent alcohol septal ablation during the same period. These HOCM patients were retrospectively identified by searching our interventional database using the parameters of age, sex and OTG, with final case matching performed on the basis of hierarchical “best match” according to these criteria. This was a prospectively collected registry series; these patients were not enrolled in a clinical trial. Therefore, as per usual practice, follow-up echocardiography was at the discretion of the referring physician. At the outset of this study, it was deemed that any attempted centralized review or adjudication of these non-standardized, uncontrolled and ad hoc follow-up echocardiograms would be unlikely to yield scientifically meaningful data. Alcohol septal ablation procedure. Alcohol septal ablation was exclusively performed by the same 2 operators. The procedure was conducted according to standard contemporary practice, as described elsewhere.^10,12Statistical analysis. Parametric data were analyzed by 2-tailed Student’s t-test and non-parametric data by Mann-Whitney test. Within-group comparisons were performed using paired analysis, while between-group comparisons were unpaired. Differences were deemed significant if p was Results Patient characteristics were typical of those with CLVH and OTG (Table 1, Figure 1). Of note and consistent with the known phenotype of this condition,^2–4,7,13 all patients who underwent alcohol septal ablation for CLVH with OTG at our institution during this study period were female. Matched HOCM patients were generally similar to those with CLVH and OTG (and were also all female). However, patients with CLVH and OTG were more likely to be taking diuretics (p At baseline, patients in the CLVH and HOCM groups had similar resting OTG, gradient post-VEB and left ventricular end diastolic pressure (LVEDP) (difference in baseline parameters between groups; p = 0.91, 0.12, 0.50, respectively; Table 3, Figure 2). Alcohol septal ablation was associated with a significant reduction in resting and post-VEB OTG in both groups (Table 3, Figure 2). Similarly, LVEDP was reduced in both groups following septal ablation (Table 3, Figure 2). The magnitude of reduction in these parameters was similar between groups, and there was no statistically significant difference in the degree of change of resting OTG, gradient post-VEB or LVEDP between CLVH and HOCM patients (Table 3). Correspondingly, following alcohol septal ablation, patients in the CLVH and HOCM groups had similar resting OTG, gradient post-VEB and LVEDP (difference in post-ablation parameters between groups; p = 0.25, 0.47, 0.55, respectively; Table 3, Figure 2). The degree of mitral regurgitation was similar at baseline and did not change significantly in either group following septal ablation (Table 3). Baseline New York Heart Association (NYHA) class was similar between CLVH and HOCM patients (3.6 ± 0.5 versus 3.3 ± 0.5, respectively; p = 0.51; Table 1). Long-term follow-up data were available for all subjects at a mean of 34.9 ± 23.9 months post ablation. From baseline to long-term follow-up, there was no difference in the mean number of antihypertensive medications taken by either the CLVH or HOCM groups (p = 0.18 and 0.42, respectively; Table 1). CLVH and HOCM patients reported a marked and similar improvement in heart failure symptoms (NHYA class: 1.2 ± 0.5 versus 1.4 ± 0.5, respectively; p Discussion Percutaneous transluminal alcohol septal myocardial ablation was first performed in 1994.^14,15 Since its inception, the procedure has undergone significant refinement, such that it can now be performed with mortality rates and gains in functional improvement that are comparable to open surgical myectomy, the “gold standard” invasive treatment for patients with HOCM and OTG.¹⁶ In a recent meta-analysis, Agarwal et al¹⁶ identified that the only significant limitations of septal ablation, as compared to surgical myectomy, appear to be increased conduction abnormalities and the need for permanent pacemaker implantation, and a higher residual post-intervention OTG. Nevertheless, septal ablation offers several distinct advantages over open surgical myectomy in that it is minimally invasive, with faster recovery times and the ability to be performed in patients who are judged to be high-risk surgical candidates. In this report, we describe what we believe to be the first series of patients undergoing alcohol septal ablation for CLVH with OTG. The major novel findings of this work are as follows: 1) In patients with CLVH and significant OTG, alcohol septal ablation was performed with similar safety and complication rates as in matched patients with HOCM; 2) Acute procedural improvements in resting OTG, OTG post-VEB and LVEDP were significant and similar in magnitude to improvements seen in patients with HOCM; and 3) At long-term follow up, patients with CLVH and OTG reported sustained improvements in heart failure symptoms, also of a magnitude similar to matched HOCM patients. Taken as a whole, these findings suggest that alcohol septal ablation offers promise for the management of patients with refractory CLVH and OTG. Reflective of contemporary practice, almost all patients in this study were receiving beta blocker therapy. Interestingly, while disopyramide is another agent that is recommended for patients with HOCM, only 1 patient in each group was receiving this medication. We speculate that this may have been due to concerns for adverse side effects in these elderly patients. Dual-chamber pacemaker implantation is another, albeit controversial, treatment option for HOCM.¹⁰ Of relevance, older persons with HOCM and multiple comorbidities represent perhaps one of the few groups in which pacemaker therapy may be appropriate.¹⁰ Nevertheless, as is particularly the case for elderly patients with other comorbidities, the relative benefits and disadvantages of all alternate and second-line therapies, including septal ablation and dual-chamber pacemaker implantation, need to be carefully evaluated on a case-by-case basis. Our study raises several interesting questions regarding the cardiovascular anatomy and physiology of CLVH with OTG. The fact that both resting and post-VEB OTG were reduced by septal ablation suggests that, at least from a functional perspective, the anatomy of the offending septal myocardium and the ensuing outflow disturbance are somewhat similar in patients with HOCM versus CLVH with OTG. Indeed, the strikingly similar changes observed in the physiologic parameters measured, as well as the sustained symptomatic improvements, at least indirectly suggest that some of the favorable ventricular remodeling changes that occur when HOCM patients undergo septal ablation may also occur with CLVH and OTG. Of relevance, it has been noted in HOCM patients undergoing alcohol septal ablation that by 6 months post procedure there is improved diastolic function, with decreased end-diastolic pressures, improved left ventricular relaxation times, improved compliance and increased early left ventricular filling.^17,18 In addition, 2 years after septal ablation for HOCM, there is regression of left ventricular hypertrophy, with decreased left ventricular wall thickness in remote (non-ablated) regions and decreased overall left ventricular mass.¹⁹ For HOCM, the observation that partial regression of left ventricular hypertrophy occurs after OTG relief implies that a component of the increased left ventricular muscle mass may be due to the increased workload that is imposed by the outflow obstruction itself. While speculative, the possibility that the same physiology may be operative in CLVH with OTG leads to the attractive hypothesis that the left ventricular hypertrophy and increased muscle mass that occurs in these patients may also be at least partially reversible by alcohol septal ablation. Unfortunately, because the patients presented in this report underwent septal ablation on a compassionate basis and for an unproven indication, they did not undergo systematic and rigorously controlled imaging studies either before or after the procedure. Therefore, we are unable to pursue this important question with the current cohort of subjects. However, we are now prospectively investigating the possibility that the pathobiology of CLVH with OTG involves a self-perpetuating “vicious cycle,” whereby outflow tract obstruction increases the workload of the left ventricle, increasing left ventricular hypertrophy, and thereby further compromising the outflow tract and increasing OTG. Also related to the compassionate basis under which these interventions were performed and the subsequent absence of long-term follow-up imaging studies, a potential methodological issue with this study is the adequacy of our acute measurement of changes in OTG and LVEDP as surrogates for the longer-term improvement in these parameters and other aspects of ventricular hemodynamics. However, the long-term symptomatic improvements we observed argue strongly in favor of the durability of the acute procedural results. In addition, we note that several other investigators have previously documented an acute reduction in LVEDP following septal ablation,²⁰ and that this acute reduction is reflective of subsequent longer-term improvements.²¹ In a study of 62 patients undergoing septal ablation for HOCM, Gietzen et al²¹ observed a virtually identical acute reduction in LVEDP with septal ablation as in our study (18 ± 5 mmHg pre- versus 14 ± 5 mmHg post procedure). At subsequent follow up, these investigators found that the initial acute reduction in LVEDP was durable, with the LVEDP at 2 weeks (12 ± 3 mmHg) and 7 months (14 ± 3 mmHg) closely reflecting the initial acute improvement.²¹ Furthermore, even in studies where the acute improvement in LVEDP has been marginal, a highly significant reduction in this parameter has been observed at 6 and 12–18 months after the procedure.22 Moreover, the acute reduction in outflow gradient observed in patients with CLVH and OTG in our study is entirely consistent with the procedural results routinely observed in patients with HOCM undergoing this procedure.¹⁰ Taken together, these data offer strong evidence to suggest that septal ablation in patients with CLVH and OTG is likely to be physiologically and functionally efficacious in the long term. Interestingly, while the majority of studies report reduced mitral regurgitation following septal ablation, the degree of mitral regurgitation was unchanged following septal ablation in our study. We speculate that several factors may account for this observation. Firstly, across all subjects, the mean baseline degree of mitral regurgitation was only mild-to-moderate. Therefore, the possibility of observing a major reduction in regurgitation may have been minimal from the outset. Furthermore, the low numbers of subjects added to the unlikelihood that a statistically significant reduction would be observed. Finally, unlike the majority of younger HOCM subjects who typically undergo this procedure, these were elderly patients who potentially had additional underlying intrinsic mitral valve disease. It has been shown in prior studies that patients with intrinsically abnormal mitral valves do not routinely experience a marked reduction in regurgitation following reduction of septal outflow obstruction.²³Study limitations. This study has several limitations. It was a prospectively collected but largely retrospective analysis of a small number of subjects. The study was also non-blinded, and used a retrospectively matched group of control patients as a comparator. Due to ethical considerations and the observational nature of this study, standardized pre-procedure and long-term follow-up imaging studies were not performed.

Conclusion

This study demonstrates the provisional safety and efficacy of alcohol septal ablation when performed on appropriate patients with CLVH and OTG. As evidenced by the mean NYHA class heart failure classification of 3.6 at baseline, our experience has been that patients suffering CLVH with OTG may be severely symptomatic and grossly debilitated by their condition. Particularly given the lack of treatment options, we conclude that percutaneous alcohol septal ablation is a promising therapy and warrants further investigation for the management of refractory CLVH with significant OTG.

References

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———————————————————— From the Cardiac Catheterization Laboratory, Cardiovascular Institute, Mount Sinai Hospital, New York, New York. ^†Contributed equally to this work. Disclosure: Samin Sharma reports membership on the following speakers bureaus: Abbott, Boston Scientific, Cordis, Lilly, and The Medicines Company. Manuscript submitted August 11, 2010, provisional acceptance given September 7, 2010, final version accepted September 15, 2010. Address for correspondence: Dr. Annapoorna Kini, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029. E-mail: annapoorna.kini@mountsinai.org