FOCUS ISSUE: HYPERTROPHIC CARDIOMYOPATHYState-of-the-Art Papers
The 50-Year History, Controversy, and
Clinical Implications of Left Ventricular Outflow
Tract Obstruction in Hypertrophic Cardiomyopathy
From Idiopathic Hypertrophic Subaortic Stenosis
to Hypertrophic Cardiomyopathy
Barry J. Maron, MD,* Martin S. Maron, MD,† E. Douglas Wigle, OC, MD,§
Eugene Braunwald, MD‡
Minneapolis, Minnesota; Boston, Massachusetts; and Toronto, Ontario, Canada
Dynamic obstruction to left ventricular (LV) outflow was recognized from the earliest (50 years ago) clinical de-
scriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon unique in many
respects, as well as arguably the most visible and well-known pathophysiologic component of this heteroge-
neous disease. Over the past 5 decades, the clinical significance attributable to dynamic LV outflow tract gradi-
ents in HCM has triggered a periodic and instructive debate. Nevertheless, only recently has evidence emerged
from observational analyses in large patient cohorts that unequivocally supports subaortic pressure gradients
(and obstruction) both as true impedance to LV outflow and independent determinants of disabling exertional
symptoms and cardiovascular mortality. Furthermore, abolition of subaortic gradients by surgical myectomy (or
percutaneous alcohol septal ablation) results in profound and consistent symptomatic benefit and restoration of
quality of life, with myectomy providing a long-term survival similar to that observed in the general population.
These findings resolve the long-festering controversy over the existence of obstruction in HCM and whether out-
flow gradients are clinically important elements of this complex disease. These data also underscore the impor-
tant principle, particularly relevant to clinical practice, that heart failure due to LV outflow obstruction in HCM is
mechanically reversible and amenable to invasive septal reduction therapy. Finally, the recent observation that
the vast majority of patients with HCM have the propensity to develop outflow obstruction (either at rest or with
exercise) underscores a return to the characterization of HCM in 1960 as a predominantly obstructive
disease. (J Am Coll Cardiol 2009;54:191–200) © 2009 by the American College of Cardiology Foundation
It has now been more than 50 years since the first modern
descriptions of hypertrophic cardiomyopathy (HCM) by
Brock (1), in 1957, based on hemodynamics at cardiac
catheterization or operation, and by Teare (2), in 1958,
from the autopsy laboratory. Over that considerable period
of time, literally thousands of reports have been published
describing various elements of HCM (3–16). Consequently,
we now recognize HCM to be the most common familial
heart disease characterized by substantial heterogeneity with
respect to presentation, phenotypic expression, clinical
course, and genetic substrate, as well as the management
strategies applicable to this broad clinical spectrum.
Following initial reports from Brock (1) and others
(3,17–19) describing intraventricular systolic pressure gra-
dients regarded as examples of “functional stenosis of the
left ventricle,” dynamic obstruction to left ventricular (LV)
outflow rapidly achieved distinction as the most visible
feature of HCM, dominating the initial comprehensive
description of the disease (4) and other early reports.
However, outflow pressure gradients have also been the
source of periodic and often intense controversy regarding
their clinical and pathophysiologic significance (20–23).
Indeed, this uncertainty surrounding obstruction is typical
of the considerable confusion that in many other ways has
also influenced the understanding of this complex disease
within the cardiovascular community (5). Therefore,
having recently celebrated the 50th (golden) anniversary
of HCM, it seems particularly appropriate to revisit and
focus attention on the evolution in our understanding of
LV outflow obstruction, which has profoundly affected
From the *Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute
Foundation, Minneapolis, Minnesota; †Hypertrophic Cardiomyopathy Center, Tufts
Medical Center, and ‡TIMI Study Group, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts; and the §Division of Cardiology, Toronto
General Hospital, Toronto, Ontario, Canada.
Manuscript received April 29, 2008; revised manuscript received November 12,
2008, accepted November 12, 2008.
Journal of the American College of Cardiology
© 2009 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 54, No. 3, 2009
Virtually from initial recognition
in the late 1950s, dynamic ob-
struction to LV outflow has been
regarded as an integral compo-
nent of HCM (Fig. 1). In fact, in
the early pre-echocardiographic
era (1960 to 1969), an outflow
gradient was a virtual prerequisite for the diagnosis of
HCM, either by physical examination (e.g., auscultation of
the characteristic systolic murmur) or by invasive measure-
ment of a peak systolic pressure gradient between LV cavity
and proximal outflow tract (4) (Fig. 2). Indeed, the nonob-
structive form of HCM, although recognized in the early
1960s (24,25), received little attention until the emergence
of M-mode echocardiography in the early 1970s (26–31).
Adding to the mystique surrounding obstruction in
HCM has been its dynamic nature (first described in 1962)
(32), in which pressure gradients can vary considerably with
a variety of pharmacologic and physiologic provocations
that reduce peripheral arterial pressure or ventricular vol-
ume, or enhance myocardial contractility, and may change
even after heavy meals or alcohol intake or spontaneously on
a day-to-day or hour-to-hour basis (4,32–34). Almost from
the inception, it was recognized that dynamic outflow
gradients could be provoked by physiologic exercise (4,35)
or a variety of nonphysiologic maneuvers including sympa-
thomimetic agents, such as infused isoproterenol or dobut-
amine, or by introducing premature ventricular beats, amyl
nitrite inhalation or nitroglycerin, as well as the Valsalva
With the possible exception of disopyramide (37), drug
therapy does not reliably mitigate intraventricular pressure
gradients (5) under basal (resting) conditions although
beta-blockade is known to blunt gradients provoked with
exercise (4). Spontaneous and permanent loss of outflow
obstruction appears to be largely confined to those circum-
stances in which substantial LV remodeling occurs, such as
with progression to the end-stage phase when systolic
dysfunction appears (38,39). Conversion from the nonob-
structive to obstructive state may be evident during adoles-
cence, with the development of the HCM phenotype, at the
time of accelerated growth and maturation (40).
Initially, several names were promoted to describe this
disease entity, each of which is dependent on the presence of
obstruction: idiopathic hypertrophic subaortic stenosis in
the U.S., muscular subaortic stenosis in Canada, and hyper-
trophic obstructive cardiomyopathy in the United Kingdom
(41). These terms persist occasionally, but rarely appear in
the current literature. Indeed, hypertrophic cardiomyopathy
predominates as the formal name for this disease (41),
because this terminology is inclusive allowing for both the
obstructive and nonobstructive forms of the disease.
Controversy and Dilemma
Although dynamic LV outflow gradients have been widely
recognized as clinical markers of HCM since the early
1960s, considerable controversy rapidly developed (20,23,
42–46) concerning the clinical implications of intraventric-
ular pressure differences that were identified with increasing
frequency in the catheterization laboratory and believed to
result from excessive muscular constriction of the proximal
outflow tract (18). Indeed, in an early description of surgical
myotomy and myectomy in the treatment of HCM, Mor-
row et al. (47) stated that “when the finger is introduced into
the left ventricle, the muscle mass is usually felt to be
hemispherical. . .forceful contraction of the outflow tract
upon the examining finger is evident during systole.” There-
fore, even though recognition of outflow gradients was
ultimately the impetus for the septal myectomy operation,
paradoxically, the surgical strategy of muscular resection was
originally devised to interrupt the outflow tract “contraction
ring” before the recognition 7 to 10 years later that systolic
HCM ? hypertrophic
LV ? left ventricular
SAM ? systolic anterior
Figure 1 Timeline
Timeline summarizes major events that comprise the history of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. ACC ? American College
of Cardiology; AHA ? American Heart Association; DDD ? dual-chamber; echo ? echocardiography; LVH ? left ventricular hypertrophy; SAM ? systolic anterior motion.
192 Maron et al.
History of Obstruction in HCM
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July 14, 2009:191–200
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Key Words: cardiomyopathies y hypertrophic y cardiac surgery y heart
catheterization y heart failure y heart failure treatment y hypertrophy.
200 Maron et al.
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JACC Vol. 54, No. 3, 2009
July 14, 2009:191–200