Nonobstructive Hypertrophic Cardiomyopathy Out of the Shadows
Hypertrophic cardiomyopathy was first recognized as a disease of obstruction to left ventricular outflow, hence, its early names and acronyms such as idiopathic hypertrophic subaortic obstruction. The nonobstructive subset of patients, incapable of developing mechanical impedance to left ventricular outflow at rest or with physiologic exercise, was initially recognized by the Braunwald group at the National Institutes of Health >50 years ago in the preimaging era, and is now recognized as comprising about one-third of hypertrophic cardiomyopathy patients. Nevertheless, until recently, and for 25 years, this substantial patient subset has been largely ignored and incompletely understood in terms of its clinical significance and consequences. However, the newfound interest in nonobstructive hypertrophic cardiomyopathy with recent cohort data permits more robust clarity of this subset, as well as the overall disease spectrum. As a group, patients with nonobstructive disease experience a largely stable clinical course at relatively low risk for progressive heart failure symptoms to New York Heart Association class III/IV in (90%). On the other hand, there is a small but important subgroup of 10% at risk for developing drug-refractory advanced heart failure sufficient to justify consideration for heart transplant as the only definitive treatment option. This recognition closes a significant gap in understanding the natural history of hypertrophic cardiomyopathy, also underscoring that the disease is not uniformly grim but instead consistent with extended longevity, thereby providing many patients with a measure of reassurance.
Hypertrophic cardiomyopathy is a relatively common genetic heart disease with heterogeneous morphology, natural history, and clinical presentation, as well as demonstrating a diverse hemodynamic spectrum.1, 2, 3, 4, 5, 6, 7Hypertrophic cardiomyopathy has long been characterized primarily as a disease of dynamic left ventricular outflow tract obstruction that provided the disease with its first names, that is, idiopathic hypertrophic subaortic stenosis, hypertrophic obstructive cardiomyopathy, and muscular subaortic stenosis.8, 9, 10, 11, 12, 13 Indeed, dynamic subaortic gradients, whether present at rest or provoked with a variety of pharmacologic or mechanical interventions, or elicited with exercise have, at times, been considered equivalent to the disease itself. Effective management of left ventricular outflow obstruction, a cause of progressive limiting symptoms, consists of invasive septal reduction procedures, that is, most prominently surgical septal myectomy, the gold standard for reversing heart failure and restoring quality of life and an expectation of longevity, but alternatively, percutaneous alcohol septal ablation for selected patients.14, 15, 16, 17
Notably, over the years much less attention has been directed toward the natural history of hypertrophic cardiomyopathy patients who are not capable of generating outflow gradients under any conditions, including with physiologic exercise.18, 19, 20, 21, 22, 23, 24 In the early years, some investigators even suggested that such patients without obstruction should be regarded as a distinct and separate disease entity.
Indeed, generally greater clinical importance has been attached to the obstructive form of hypertrophic cardiomyopathy reflected by its dominance in the literature, given that there are only 5 original papers18, 19, 20, 22,23 and one editorial21 in PubMed dedicated to (or concerned primarily with) nonobstructive hypertrophic cardiomyopathy. Four of these 6 papers appeared only in the last year, fully 25 years after the previous publication with only 25 patients19 (Figure 1). This disproportionality in published data is of note because the nonobstructive form of hypertrophic cardiomyopathy comprises fully about one-third of a referral-based population.18
In the early 1960s, the Braunwald group at the National Institutes of Health (Bethesda, Md) was largely responsible for the first report describing the clinical features of hypertrophic cardiomyopathy, which at that time was based largely on recognition of the dynamic left ventricular outflow tract gradient.8 However, it is less well appreciated that these same investigators, almost from the beginning, utilizing clinical, hemodynamic, and angiographic observations from diagnostic cardiac catheterization simultaneously recognized the nonobstructive form of hypertrophic cardiomyopathy,23 concluding that: “idiopathic (often familial) left ventricular hypertrophy could occur without as well as with obstruction”9, 23 (Figure 1).
The advent of modern noninvasive imaging of hypertrophic cardiomyopathy (with echocardiography) in the early 1970s substantially changed diagnosis of this disease by allowing much greater recognition of the nonobstructive form.24 Nevertheless, over the following several decades, attention to the clinical course and outcome of this nonobstructive patient subgroup was limited by a variety of factors, including the management of outflow gradients dominating the dialogue, and the lack of standard criteria for defining nonobstructive disease. For example, a diverse array of invasive or noninvasive maneuvers or interventions have historically been employed to provoke outflow tract obstruction in patients without rest gradients, including post-premature ventricular contraction response (Brockenbrough), amyl nitrite inhalation, Valsalva maneuver, or infusion of drugs such as isoproterenol or dobutamine.8, 13, 25
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-Barry J. Maron, MD, Ethan J. Rowin, MD, Martin S. Maron, MD, Eugene Braunwald, MD
This article originally appeared in the February 2017 issue of The American Journal of Medicine.