Rethinking the Selection Criteria for Alcohol Septal Ablation — Is It Time to Push the Envelope?

First described over 15 years ago, alcohol septal ablation has evolved into an accepted alternative to surgical myectomy in patients with hypertrophic obstructive cardiomyopathy and drug-refractory debilitating symptoms.¹ In appropriately selected patients, marked reductions in left ventricular outflow tract gradient (both resting and provokable), left ventricular end-diastolic pressure, mitral regurgitation and global ventricular hypertrophy are noted, with associated improvements in diastolic function and New York Heart Association (NYHA) Functional Class.^2–6 Indeed, there is little disagreement today that clinical improvements mirror those of surgical myectomy, with the exception of a higher incidence of permanent pacemaker placement and a slightly, but significantly, higher residual gradient.³ Historically, strict clinical, echocardiographic and coronary criteria have been employed when considering alcohol septal ablation.⁷ Clinically, patients must carry a diagnosis of hypertrophic cardiomyopathy (HCM) and have NYHA Class III–IV symptoms despite optimal medical therapy, typically a combination of high-dose beta-blockade, calcium channel-blockers and/or disopyramide. Echocardiographic criteria include asymmetrical septal hypertrophy, as defined by a septum-to-posterior wall thickness ratio > 1.3:1, systolic anterior motion (SAM) of the anterior leaflet of the mitral valve, associated posteriorly directed mitral regurgitation and septum thickness > 1.6 cm but 3 Despite these impressive results, significant controversy remains regarding the preferred treatment modality for patients in need of invasive management. Those favoring surgical myectomy tout its four-decade-long experience, the fact that more severe and mid-cavity hypertrophy may be resected along with complex repair of the mitral valve and chords as needed, and that risk of arrhythmia post surgery appears low, and perhaps lower than would be expected in a similar, but untreated, HCM population.^8,9 In addition, they argue that alcohol septal ablation is limited by intrinsic coronary anatomy, making its effectiveness somewhat less reliable. In contrast, those favoring alcohol septal ablation tout its minimally invasive nature, speedier recovery and comparable clinical outcome in real-world experience, despite its inherent anatomic limitations. Perhaps most controversial is the concern that alcohol septal ablation might exacerbate the underlying arrhythmogenic substrate already present in those with HCM through the creation of a septal scar. Nonetheless, a detrimental effect on survival has not been noted post ablation. On the contrary, recent data support a positive effect on mortality and sudden cardiac death comparable to that seen with surgical myectomy, suggesting that overall improvements in cardiac function, including the elimination of gradient and significant regression of hypertrophy, may more than offset any scar-related arrhythmogenic effects.¹⁰ Against this background debate regarding the optimal invasive management, it is easy to understand why the alcohol septal ablation procedure has rarely strayed from the strict inclusion criteria listed above. Specifically, HCM patients with extreme septal hypertrophy > 3.0 cm, mid-cavitary obstruction or concentric hypertrophy and/or concomitant intrinsic mitral or other valve pathology have traditionally been subsets in whom clinical success would be expected to be reduced and in whom surgical myectomy has remained the gold standard. In this context, the matched case series by Kovacic et al¹¹ in this issue of the Journal is especially intriguing. The authors retrospectively review their experience with alcohol septal ablation in patients with severe concentric hypertrophy and outflow tract obstruction in whom a diagnosis of HCM was not only in doubt but unlikely. In doing so, they ask explicitly whether one needs to have HCM to qualify for alcohol septal ablation and whether asymmetric hypertrophy is a requisite anatomic finding. In essence, they ask, should the procedure target a specific pathophysiology or be confined solely to a specific genetic disease? Matched to patients with HCM for age, gender and baseline gradient, they find similar positive effects on post-procedure gradient, end-diastolic pressure, NYHA Class and overall symptom status that are maintained over the intermediate term, and conclude that alcohol septal ablation may indeed be a useful procedure in a wider cohort of patients, with HCM or not, who have a dynamic obstructive pathophysiology. In truth, a firm diagnosis of HCM is not always present in those treated for the disease, regardless of whether invasive therapies are utilized. Indeed, genetic testing, only recently commercially available, uncovers just 60–65% of patients. Traditionally, therefore, a relatively firm diagnosis has only been possible when clear asymmetry or focal hypertrophy (especially apical) is noted, particularly in the absence of other causes of hypertrophy (such as uncontrolled hypertension or aortic valve stenosis). Thus, it is not only possible but likely that patients without the HCM genotype have inadvertently undergone both surgical myectomy and alcohol septal ablation for the relief of outflow tract obstruction. As a result, one could argue that we have always targeted the dynamic outflow tract obstruction pathophysiology itself with our therapies (both pharmacologic and invasive), with outcomes linked to how thoroughly the obstruction is relieved, whether or not a genetic basis for the obstruction was present. The pathophysiology of dynamic outflow tract obstruction occurs in multiple disease states including genetically-mediated HCM, hypertensive heart disease of the elderly, severe concentric hypertrophy (as in patients with uncontrolled hypertension, such as those with end-stage renal disease), and the underfilled hyperdynamic ventricle, among others. Except for the latter, which resolves with hydration, relief of outflow tract obstruction might be expected to improve symptoms and promote partial regression of hypertrophy. Indeed, a developing concept is that severe outflow tract obstruction (whether due to asymmetric or concentric hypertrophy, or other subvalvular anomaly) likely serves as an impetus for further hypertrophy and diastolic dysfunction, a cycle that can only be broken by effective relief of the obstruction itself. Although most of these states respond to medical therapy, a subset may prove refractory, prompting consideration of invasive therapies as seen in the current series. Thus, despite being a small case series, the current evaluation raises awareness around three important developing concepts that, although not currently accepted, perhaps warrant further discussion. First, it may be reasonable for alcohol septal ablation (and surgical myectomy) to target a distinct pathophysiology of dynamic outflow tract obstruction refractory to medical therapy, as opposed to any particular disease, namely HCM. Second, alcohol septal ablation perhaps need not be limited to asymmetric hypertrophy, but rather to cases in which a high degree of success can be predicted based on precise determinations of the location of the obstruction and the likelihood that available septal perforators subtend the offending myocardium, as guided by myocardial contrast echocardiography. Finally, recognition of this pathophysiology, as opposed to the HCM disease state, should perhaps trigger a change in management from one that targets afterload reduction and congestion (as in the traditional treatment for hypertension-related hypertrophy and diastolic dysfunction) to one that targets the outflow tract obstruction itself with hydration, negative inotropic agents, avoidance of pure afterload-reducing medications and septal reduction therapy, when appropriate.

References

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———————————————————— From the Department of Medicine, Division of Cardiovascular Disease, Winthrop University Hospital, Mineola, New York. The author reports no conflicts of interest regarding the content herein. Address for Correspondence: Srihari S. Naidu, MD, Assistant Professor of Medicine, SUNY – Stony Brook School of Medicine, Director, Cardiac Catheterization Laboratory, Interventional Cardiology Fellowship Program & Hypertrophic Cardiomyopathy Treatment Center, Winthrop University Hospital, Mineola, NY 11501. E-mail: ssnaidu@winthrop.org