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Editorial
Defining Diastolic Dysfunction
William Grossman, MD
T
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he human intellect has an almost irresistible urge to categorize and simplify. Thus, over the years, heart failure has
been classified as forward or backward, right or left,
compensated or decompensated. These distinctions, which were
made primarily on the basis of data obtained from the history and
physical examination, provided a conceptual framework for thinking about heart failure and for rationalizing therapeutic decisions
(eg, digitalis to increase cardiac output in “forward” failure). As
information routinely available to the clinician has been extended
from the history and physical examination to now include precise,
noninvasive characterization of ventricular volumes and aortic flow,
it has been increasingly recognized that the pathophysiology of
heart failure cannot be assessed adequately by the older classifications. For example, it is now appreciated that “backward” heart
failure with elevated ventricular filling pressures and consequent
pulmonary or peripheral edema can result from either systolic or
diastolic ventricular dysfunction. In fact, epidemiological and casecontrol studies of individuals presenting with clinical heart failure
have estimated that 40% to 50% of such patients have normal
systolic function and presumed diastolic heart failure.1–4 For example, Senni et al,1 from the Mayo Clinic, reported that 43% of
patients with clinical congestive heart failure and adequate echocardiographic assessment of ejection fraction show normal/preserved
left ventricular function. Although the prognosis of patients with
heart failure and preserved systolic function has generally been
regarded as intermediate between normal subjects and patients
whose heart failure is associated with depressed systolic function,
the recent Mayo study1 calls this into question, showing both
systolic and diastolic heart failure to have a similar prognosis, at
least over the first 3 to 4 years of follow-up.
failure? Workers in the field usually will start with the
pathophysiological definition that diastolic heart failure is
present when an elevated filling pressure is necessary to
achieve normal ventricular filling (ie, filling of the ventricle
to a normal end-diastolic volume).5 Many investigators will
further subdivide diastolic heart failure into cases in which
the increased resistance to diastolic ventricular filling is
mechanical and external to the ventricular myocardium (eg,
constrictive pericarditis, mitral stenosis) and those in which
increased resistance to diastolic filling is intrinsic to the
myocardium (eg, myocardial hypertrophy, fibrosis, ischemia,
or infiltrative cardiomyopathies such as amyloidosis). These
categorizations are far from perfect, and the interested observer can easily identify conditions or devise clinical scenarios that do not fit within this rather simple approach. The
important point, however, is that even to meet this rather
flawed pathophysiological definition of diastolic heart failure,
knowledge of intracardiac pressures and volumes is required.
Even with precise measurements of ventricular chamber
pressures and volumes, the fact that diastolic abnormalities
may be functional and transient makes the timing of the
clinical and investigative studies of critical importance. Just
as the diagnosis of Prinzmetal’s angina may be impossible
unless one carries out appropriate ECG and/or coronary
angiographic studies both during and after an episode of
coronary artery spasm, so it may be impossible to tell whether
an episode of flash pulmonary edema in a patient with
3-vessel coronary disease was due to transient systolic or
diastolic dysfunction. In fact, studies in patients with elevated
left ventricular filling pressure due to acute myocardial
ischemia indicate that both systolic and diastolic left ventricular dysfunction coexist in such patients,6,7 with diastolic
dysfunction predominating in some but not in others.
In the context of these difficulties, the article by Vasan and
Levy8 in this issue of Circulation deserves careful attention.
On the basis of their extensive experience in the Framingham
Study and their review of the literature, these authors propose
a scheme for the definition of definite, probable, and possible
diastolic heart failure. They make the cogent argument that
although numerous clinical trials have examined and defined
appropriate therapy for the treatment of systolic heart failure
(clinical heart failure associated with depressed left ventricular ejection fraction), the optimal treatment of diastolic heart
failure has not been determined. Appropriate clinical trials
await the development of rigorous and widely acceptable
entry criteria to define the study population. Vasan and Levy
suggest that definite diastolic heart failure is present if there
is definitive evidence of congestive heart failure (clinical
symptoms, signs, supporting tests such as chest radiograph,
typical clinical response to treatment with diuretics, with or
without documentation of elevated left ventricular filling
pressure or a low cardiac index) coupled with objective
See p 2118
Should all patients with a clinical diagnosis of congestive
heart failure and normal ventricular systolic function by
echocardiogram be regarded as having diastolic heart failure?
The answer to this question is simple: Of course not. Patients
with sudden onset of severe mitral or aortic regurgitation may
present with pulmonary edema and a normal left ventricular
ejection fraction but would not be regarded by most clinicians
as having diastolic heart failure. So what is diastolic heart
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the UCSF Medical Center, University of California, San
Francisco.
Correspondence to William Grossman, MD, Meyer Friedman Distinguished Professor of Medicine, University of California, San Francisco,
Chief, Cardiology Division, UCSF Medical Center, 505 Parnassus Ave, Box
0124, San Francisco, CA 94143-0124. E-mail [email protected]
(Circulation. 2000;101:2020-2021.)
© 2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
2020
Grossman
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evidence of normal left ventricular systolic function (left
ventricular ejection fraction ⱖ50%) within 72 hours of the
heart failure event and objective evidence of left ventricular
diastolic dysfunction (eg, abnormal LV relaxation/filling/
distensibility indices on cardiac catheterization). It is not
likely that many patients in common clinical practice will
meet these criteria for definite diastolic dysfunction, and
therefore, Vasan and Levy propose criteria for probable
diastolic heart failure that will include definitive clinical
evidence of heart failure and objective evidence of normal
LV systolic function within 72 hours of the heart failure event
but no conclusive information on LV diastolic function.
Finally, Vasan and Levy allow for possible diastolic heart
failure in the patient for whom there is clinical evidence of
congestive heart failure coupled with evidence of normal LV
systolic function outside the 72-hour window and in whom
evidence for LV diastolic dysfunction is lacking. Despite the
difficulties inherent in their attempts, this classification may
serve as a valuable framework that will facilitate the design of
appropriate clinical trials to test the efficacy of specific
therapeutic agents in the treatment of diastolic heart failure.
Certain simple deficiencies of the Vasan-Levy classification
could be easily addressed by the addition of appropriate exclusion criteria. If strictly applied, their definition of probable
diastolic heart failure would include individuals with acute
mitral or aortic regurgitation or purely mechanical causes of
diastolic heart failure (such as mitral stenosis or constrictive
pericarditis); this could be avoided by adding screening for these
exclusionary criteria as part of the definition. Accordingly, to
have a diagnosis of probable diastolic heart failure, you would
need to satisfy both the inclusionary characteristics listed in
Vasan and Levy’s article and a list of exclusionary characteristics. Certain problems remain that will be difficult to sort out.
For instance, it is now clear that the majority of patients with
what is currently called “systolic heart failure” also have diastolic dysfunction of various degrees. In fact, there is some
evidence9 –11 that much of the pathophysiological derangement
in patients with advanced systolic heart failure and cardiomyopathy may be a result of intrinsic abnormalities of myocyte
calcium handling. Drugs or targeted gene therapy that inhibit
phospholamban, inhibit the production of phospholamban, or
increase the production of sarcoplasmic/endoplasmic reticulum
Ca2⫹-ATPase (SERCA) while decreasing the phospholamban/
SERCA ratio (eg, thyroid hormone) might improve both systolic
and diastolic dysfunction, working primarily through a diastolic
mechanism.12–15 Another problem may arise because diastolic
heart failure, as defined by Vasan and Levy,8 will include a
mixed bag of pathological entities, such as amyloidosis, ventricular hypertrophy, diffuse myocardial fibrosis, and intermittent
myocardial ischemia, each of which may be expected to respond
quite differently to therapeutic interventions. These important
distinctions will need to be kept in mind in the design of clinical
trials of potential new therapeutic approaches to diastolic heart
failure. Such trials are a realistic possibility, now that it has been
shown that drugs that block the renin-angiotensin system,16,17 as
well as NO donors or drugs that enhance NO release,18 –20
improve diastolic function in humans.
Defining Diastolic Dysfunction
2021
In the context of these limitations and caveats, Vasan and
Levy have taken an important first step toward the development of clinical trials needed to help us identify appropriate
therapy for the patient with diastolic heart failure.
References
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Bailey KR, Redfield MM. Congestive heart failure in the community: a
study of all incident cases in Olmsted County, Minnesota, in 1991.
Circulation. 1998;98:2282–2289.
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Congestive heart failure in subjects with normal versus reduced left
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7. Paulus WJ. Upward shift and outward bulge: divergent myocardial effects of
pacing angina and brief coronary occlusion. Circulation. 1990;81:1436–1439.
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diagnostic criteria. Circulation. 2000;102:2118 –2121.
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of cardiac contractile dysfunction. N Engl J Med. 1991;325:625–632.
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treatment with captopril and the thyroid hormone analogue 3,5diiodothyropropionic acid: a new approach to improving left ventricular
performance in heart failure. Circulation. 1993;88:1289 –1298.
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RJ. Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the ␤2-adrenergic receptor is associated with reduced phospholamban protein. J Clin Invest. 1996;97:1618 –1623.
16. Friedrich SP, Lorell BH, Rousseau MF, Hayashida W, Hess OM, Douglas
PS, Gordon S, Keighley CS, Benedict C, Krayenbuehl HP, Grossman W,
Pouleur H. Intracardiac angiotensin-converting enzyme inhibition
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17. Warner JG Jr, Metzger C, Kitzman DW, Wesley DJ, Little WC. Losartan
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hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567–1562.
18. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on
left ventricular relaxation and diastolic distensibility in humans. Circulation. 1994;89:2070 –2078.
19. Heymes C, Vanderheyden M, Bronzwaer JGF, Shah AM, Paulus WJ.
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KEY WORDS: Editorials
䡲 diastole 䡲
heart failure
Defining Diastolic Dysfunction
William Grossman
Circulation. 2000;101:2020-2021
doi: 10.1161/01.CIR.101.17.2020
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