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(Circulation. 1997;95:1981-1982.)
© 1997 American Heart Association, Inc.

Articles

Induced Septal Infarction

A New Therapeutic Strategy for Hypertrophic Obstructive Cardiomyopathy

Eugene Braunwald, MD

From the Department of Medicine, Brigham and Women's Hospital, Boston, Mass.

Correspondence to Eugene Braunwald, MD, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Key Words: Editorials • cardiomyopathy • infarction • hypertrophy

	Introduction

Top Introduction References

 
It is well known that patients with hypertrophic obstructive cardiomyopathy (HOCM) respond in a paradoxical manner to a variety of stimuli. Early in the development of our understanding of this condition, it was observed that drugs such as digitalis, sympathomimetic amines, and nitroglycerin that benefit patients with many other forms of heart disease intensify obstruction to left ventricular outflow and exert an adverse clinical effect on patients with HOCM.¹ In contrast, pharmacological agents such as disopyramide and verapamil, which depress myocardial contractility and sometimes provoke heart failure in patients with dilated hearts, are often beneficial in HOCM patients. Similarly, pregnancy and the associated hypervolemia, which so frequently aggravate other forms of heart disease, often reduce symptoms in patients with HOCM. In this issue of Circulation, another seemingly paradoxical therapy is reported: the induction of a localized myocardial infarction, which appears to be beneficial in patients with this condition.²

The basis for these paradoxical responses is clear. Obstruction to left ventricular outflow in HOCM is caused by the systolic approximation of the anterior leaflet of the mitral valve and the hypertrophied, superior portion of the interventricular septum. The obstruction is dynamic, with increases in contractility aggravating the obstruction and depressions in contractility exerting the opposite effect.

Four distinct strategies for the management of HOCM, based on an appreciation of this pathophysiology, are currently used:

1. The first strategy, and one that is still widely employed, consists of surgical incision into and excision of a portion of the asymmetrically hypertrophied subaortic portion of the ventricular septum. Myotomy/myectomy (often termed the "Morrow procedure" after its originator³ ), in addition to widening the left ventricular outflow tract, often causes a left intraventricular conduction defect that may contribute to the hemodynamic and clinical benefits observed in many patients. However myotomy/myectomy remains a complicated operation with a surgical risk of death close to 5%.

2. The second operation developed for HOCM is mitral valve replacement.⁴ As stated above, the anterior leaflet of the mitral valve forms one boundary of the left ventricular outflow tract, and the exaggerated motion of this leaflet is responsible for the echocardiographic sign that is almost pathognomonic for this condition: systolic anterior motion of the mitral valve. Although mitral valve replacement is quite effective hemodynamically, this operation is not a simple one either, both because the small left ventricular cavity may interfere with the prosthetic valve and because it carries the burdens of any valve replacement, ie, the need for lifetime anticoagulation or the threat of late valve deterioration.

3. The pharmacological strategy began with the use of ß-adrenoceptor blockers in 1964, when it was first observed that these agents prevent adrenergically mediated intensification of obstruction.^{5 6} Two other negative inotropic drugs, verapamil and disopyramide, have also been useful therapeutically. The pharmacological strategy, although widely applied, provides only modest hemodynamic and clinical benefits. It should not be surprising to those who have had the opportunity to examine the massively hypertrophied and grossly remodeled heart of a patient with HOCM that drugs cannot be very effective in this condition.

4. The fourth, and least understood, therapeutic strategy is dual-chamber pacing.⁷ Presumably, by shortening the AV interval and modifying the sequence of ventricular depolarization, dual-chamber pacing interferes with the narrowing of the outflow tract resulting from the systolic thickening of the hypertrophied ventricular septum and the anterior motion of the mitral valve resulting from simultaneous contraction of the papillary muscles. Although the outflow gradient can be reduced by dual-chamber pacing, it is not yet clear that a lasting symptomatic benefit can be achieved nor that the natural history of the condition is improved.

Enter now a fifth therapeutic strategy: induced infarction of the subaortic portion of the interventricular septum. Appreciating the important contribution made by this structure to outflow tract obstruction in HOCM, Sigwart et al⁸ demonstrated in 1982 that brief occlusion of the septal artery with a balloon catheter causes transient reductions in the outflow pressure gradient. This was followed by a preliminary report⁹ describing the induction of localized septal infarction with ethanol infusion into the septal coronary artery in three patients. Knight et al² have now extended this ingenious approach to 18 patients, and the reported results are quite favorable. At 3-month follow-up, the intraventricular pressure gradient, estimated by Doppler echocardiography, was reduced on average to one third of the preprocedural level, and the patients described symptomatic improvement. It is notable that Gietzen, Kuhn, and their colleagues have reproduced the results obtained by Knight et al, both with transient ischemia^{10 11} and ethanol-induced infarction of the septum.¹²

Individually, both dual-chamber pacing and induced localized septal infarction reduce but usually do not abolish the obstruction. Therefore, it would be interesting to determine whether their combination, performed at a single sitting in the catheterization laboratory, might be more effective than either procedure alone.¹³

With the development of a fifth strategy for the management of HOCM, we appear to have an embarrassment of therapeutic riches. But do we really? Although all five strategies reduce obstruction and improve symptoms, no truly objective clinical benefit or favorable effect on the natural history of HOCM has been documented with any. One cannot help but wonder whether any strategy designed only to relieve outflow tract obstruction will substantially alter the natural history of this condition. HOCM differs sharply from discrete valvular or subvalvular obstruction to left ventricular outflow. In these conditions, relief of the obstruction essentially results in a "cure," unless the myocardium has been irreversibly damaged by the prolonged pressure overload and resultant secondary ventricular hypertrophy. In HOCM, now known to be a genetic abnormality of sarcomeric proteins associated with a marked disarray of myocytes,¹⁴ left ventricular outflow tract obstruction is only one, and often not the most important, physiological abnormality.

The hemodynamic abnormality that is most prevalent in HOCM is diastolic ventricular dysfunction, which causes an increased resistance to ventricular filling and elevation of the ventricular diastolic pressure despite a normal or even reduced left ventricular cavity size. A second abnormality, and perhaps the most important from the point of view of patient survival, is the propensity to serious tachyarrhythmias and sudden death. There is no evidence that any of the five therapeutic strategies now available diminish the frequency of sudden death, and only one (verapamil¹⁵ ) has been clearly shown to affect diastolic dysfunction favorably.

An objective evaluation of the several options available for the treatment of HOCM is clearly overdue. A classic, multicenter, clinical trial comparing the five available therapeutic strategies with a control, nontreated (or placebo-treated) group is probably not feasible. However, a prospective registry involving detailed characterization of the patients and careful assessment of the effects of therapy could provide very useful information. The National Heart, Lung, and Blood Institute has achieved conspicuous success with the use of carefully designed prospective registries, both in elucidating the natural history of a condition (eg, primary pulmonary hypertension¹⁶ ) as well as in understanding the benefits and risks of a therapeutic procedure (eg, percutaneous transluminal coronary angioplasty¹⁷ ). It seems logical, therefore, for the NHLBI, which has carried out and supported so much important work on HOCM, to organize such a registry that will provide the information needed to allow selection of the optimal therapy for patients with this condition.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

1. Braunwald E, Lambrew CT, Rickoff SD, Ross J Jr, Morrow AG. Idiopathic hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients. Circulation. 1964;30(suppl IV):3-119.
   
2. Knight C, Kurbaan AS, Seggewiss H, Henein M, Gunning M, Harrington D, Fassbender D, Gleichmann U, Sigwart U. Nonsurgical septal reduction for hypertrophic obstructive cardiomyopathy: outcome in the first series of patients. Circulation. 1997;95: 2075-2081.
   
3. Morrow AG, Lambrew CT, Braunwald E. Idiopathic hypertrophic subaortic stenosis, II: operative treatment and the results of pre- and postoperative hemodynamic evaluations. Circulation. 1964;30(suppl IV):120-151.
   
4. Krajcer Z, Leachman RD, Cooley DA, Coronado R. Septal myotomy-myomectomy versus mitral valve replacement in hypertrophic cardiomyopathy: ten-year follow-up in 185 patients. Circulation. 1989;80:157-164.
   
5. Harrison DC, Braunwald E, Glick G, Mason DT, Chidsey CA, Ross J Jr. Effects of ß-adrenergic blockade on the circulation, with particular reference to observations in patients with hypertrophic subaortic stenosis. Circulation. 1964;29:84-98. [Abstract/Free Full Text]
   
6. Cohen LS, Braunwald E. Amelioration of angina pectoris in idiopathic hypertrophic subaortic stenosis with beta-adrenergic blockade. Circulation. 1967;35:847-851. [Abstract/Free Full Text]
   
7. Slade AK, Sadoul N, Shapiro L, Chojnowska L, Simon JP, Saumarez RC, Dodinot B, Camm AJ, McKenna WJ, Aliot E. DDD pacing in hypertrophic cardiomyopathy: a multicentre clinical experience. Heart. 1996;75:44-49. [Abstract/Free Full Text]
   
8. Sigwart U, Grbie M, Essinger A, Rivier JL. L'effet aigu d'une occlusion coronarienne par ballonet de la dilatation transluminale. Schweiz Med Wochenschr. 1982;45:1631. Abstract.
   
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