Download Diastolic Heart Failure Demystified - CHEST Journal

Diastolic Heart Failure Demystified*
Philip Andrew, MD
The mystery of diastolic heart failure (DHF), described by authorities as a “puzzle” and a “clinical
paradox,” stems from the following misperception: (1) that the normal ejection fraction implies
normal cardiac output (CO), (2) that therefore low CO is not operative (it is rarely mentioned in
relation to the pathophysiology of DHF), and (3) the congestive phenomena are due to the stiff
left ventricle. In fact, a normal ejection fraction is not a reliable indicator of normal CO; low CO
is the fundamental pathophysiologic abnormality of all heart failure (HF), whether systolic and/or
diastolic (or, indeed, “high output”); and increased ventricular stiffness is not the principal cause
of congestion in DHF. Pathophysiologic explorations supporting these understandings further
reveal the following: (1) the premise that a clinical event as dramatic as acute pulmonary edema
(systolic and/or diastolic) would be contingent on similarly dramatic acute hypertensive or
ischemic ventricular dysfunction, while intuitive, is unsubstantiated, and there is an alternate
explanation satisfying both theoretical and clinical observations; (2) contrary to general perception, DHF is no more vulnerable to diuretic-induced hypotension than systolic HF; (3) heart rate
reduction should not yet be considered an established therapeutic goal in DHF; (4) since HF is
HF whether systolic and/or diastolic, studies are likely to show that therapeutic similarities
outweigh differences except as the various agents might modify the underlying structural and/or
functional pathology; (5) although long evident that HF occurs by only two mechanisms (systolic
dysfunction and/or diastolic dysfunction), it has only recently been acknowledged that the mere
exclusion of one is diagnostic of the other; and (6) the definition of HF currently in widespread
use is unnecessarily confounded by neglect of the fundamental distinction between ventricular
dysfunction and failure.
(CHEST 2003; 124:744 –753)
Key words: cardiac output; diastole; diastolic function/dysfunction; diuretics/therapeutic use; ejection fraction;
end-diastolic volume; end-systolic volume; heart failure; pulmonary edema
Abbreviations: ACE ⫽ angiotensin-converting enzyme; CO ⫽ cardiac output; DDf ⫽ diastolic dysfunction;
DHF ⫽ diastolic heart failure; EDP ⫽ end-diastolic pressure; EDV ⫽ end-diastolic volume; HF ⫽ heart failure;
HR ⫽ heart rate; LV ⫽ left ventricle, left ventricular; LVEDP ⫽ left ventricular end-diastolic pressure; LVEF ⫽ left
ventricular ejection fraction; PED ⫽ pulmonary edema; RAAS ⫽ renin-angiotensin-aldosterone system;
RAASAT ⫽ renin-angiotensin-aldosterone system activation threshold; RV ⫽ right ventricle, right ventricular;
RVEDP ⫽ right ventricular end-diastolic pressure; SDf ⫽ systolic dysfunction; SHF ⫽ systolic heart failure
ventricular contractility, that is, systolic dysfunction
(SDf) defined as a left ventricular ejection fraction
(LVEF) ⬍50%.1 Diastolic dysfunction (DDf) is de-
fined as impaired ventricular filling and is the mechanism of diastolic heart failure (DHF), heart failure
(HF) with an LVEF ⱖ 50%.1 But even experts have
found DHF difficult to (a) understand: (“. . . we do
not really understand what is wrong with patients
who seem to have heart failure and apparently
preserved systolic function,”2 “. . . we do not understand it or know how to treat it,”3 and “. . . the
precise mechanisms . . . are incompletely understood
. . .”4) or to (b) accept: (“it’s uncertain . . . if an LVEF
value of 45% is depressed enough to initiate . . .
congestive HF,”5 and “many suspected of having this
syndrome . . . may not have heart failure at all”2).
Indeed, Gandhi et al1 characterized a normal
*From the Division of Medicine, Department of Cardiology,
Health Sciences Center, State University of New York Syracuse,
Syracuse, NY.
Manuscript received March 7, 2002; revision accepted November
20, 2002.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Philip Andrew, MD, 727 Washington St,
Watertown, NY 13601; e-mail: [email protected]
But I think the most likely reason of all
May have been that his heart was two sizes too small.
How the Grinch Stole Christmas, by Dr. Seuss
The Mystery
How Can the Heart Fail if the Ejection Fraction Is
Normal?
t is well understood and accepted that the mechI anism
of systolic heart failure (SHF) is impaired
744
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
Opinions/Hypotheses
LVEF within 72 h of hospitalization for congestive
HF as a “clinical paradox” and hypothesized that
“many . . . with acute [hypertensive] pulmonary
edema . . . have transient left ventricular systolic
dysfunction, which is no longer present . . . after
treatment.”1 They compared the LVEF during the
initial treatment of 38 patients presenting within 6 h
of the onset of acute hypertensive pulmonary edema
(PED) to a second LVEF 2 to 3 days later after
hypertension and congestion had resolved (Table 1).
Unexpectedly, the “during” LVEF was essentially
identical to the “after” LVEF not only in the 18patient DHF group but also in the remaining SHF
group (Table 1). The hypothesis was refuted, the
enigma of HF in the context of a normal LVEF
preserved; however, close inspection of the important work of Gandhi et al1 along with a focused
review of circulatory physiology reveals the true
mechanism of DHF and why it is not a mystery.
The Neglected Role of Low Output and the
Ejection Fraction Illusion
As suggested, “our tools [have] constrained our
thinking,”6 and in this case the tool is the echocardiograph. Its ready ability to supply an LVEF soon
preoccupied clinicians and researchers alike and was
largely responsible for the emergence of the “ventricular function model” of HF. Unfortunately, this,
along with other popular models of HF, including
the neurohormonal, cellular, molecular, genetic, and
inflammatory models,7 has obscured the essential
reality of HF (whether systolic and/or diastolic) and
the key to its understanding—that HF, as its proper
definition states, is inability of the heart “. . . to pump
blood at a rate commensurate with the requirements
of the metabolizing tissues. . . . ”8 Simply stated, low
cardiac output (CO) is not merely a feature of HF,
but is its primary pathophysiologic abnormality.
Thus, parameters of myocardial function (including
the LVEF) relate to HF only insofar as they accurately reflect CO. The LVEF does not accurately
reflect CO.
To illustrate, Table 2 is derived from standard left
ventricular (LV) volume data.9 Compared to the
SHF example, the LVEF in the DHF-1 example
(DHF due to mild- to-moderate DDf) is 30 percentage points higher but CO is identical, 30% below
normal. Remarkably, the LVEF in the DHF-2 example (DHF due to severe DDf) is another 10
percentage points higher yet provides the same low
CO. A normal LVEF can thus be very effective
camouflage for low CO.
Gandhi et al1 (Table 1) showed a mean LVEF 20%
higher (proportionally approximately 45% higher) in
the patients with DHF than in the patients with
SHF. Nevertheless, stroke volumes differed by at
most only 4 mL (7%). CO was actually lower in the
higher LVEF (DHF) patients, more a result of lower
heart rate (HR) than lower stroke volume. The point
remains that unless LV volumes, particularly LV
end-diastolic volume (LVEDV), are considered
along with the LVEF, and they rarely are, the LVEF
does not and cannot accurately predict stroke volume, hence CO. It therefore cannot predict HF.
Thus, the mystery of DHF stems from the misperception that the LVEF is a valid surrogate for CO. The
normal LVEF of DHF is then taken to imply that low
CO is not pathophysiologically operative, and the congestive phenomena are attributed to the stiff LV.
HF (Systolic and/or Diastolic)
The Obligatory Role of Low CO
Low CO is the pathophysiologic basis not only of
advanced HF (systolic and/or diastolic) but also of
the earliest stages of the underlying SDf and/or DDf,
long before HF is symptomatic or detectable at the
bedside.
Table 1—Cardiac Pump Function During and After Acute Hypertensive Pulmonary Edema*
SHF (n ⫽ 20)
DHF Compared to SHF
(n ⫽ 18), %
DHF (n ⫽ 18)
Variables
During
After
During
After
During
After
LVEDV, mL
LVESV, mL
LVSV, mL
HR, beats/min
LVEF, %
CO, L/min
131
78
53
87
40
4.6
138
83
55
77
40
4.3
85
36
49
79
58
3.9
94
37
57
66
61
3.8
⫺7
⫺9
⫹ 43
⫺ 15
⫹3
⫺ 15
⫹ 52
⫺ 12
*Derived from Gandhi et al.1 Since their article included no HR or volume data for the SHF group, these data were computed via spreadsheet
from the published DHF and combined DHF-SHF values. To achieve the best approximation of the original observations (available from the
author), LVEF values were then calculated from the computed volumes, minor deviations anticipated due to precision/rounding error.
LVESV ⫽ LV end-systolic volume; LVSV ⫽ LV stroke volume; LVEDV ⫽ left ventricular end-diastolic volume.
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
CHEST / 124 / 2 / AUGUST, 2003
745
Table 2—LVEF: Meaningless in Terms of Cardiac
Output Without the Coexisting LVEDV*
Variables
Normal
LVEDV, mL
LVESV, mL
LVSV, mL
HR, beats/min
LVEF, %
CO, L/min
⌬CO, from normal, %
120
50
70
60
60
4.2
0
SHF
DHF-1 DHF-2
250
100
85
200
50
35
50
50
50
60
60
60
20
50
60
3.0
3.0
3.0
⫺ 30 ⫺ 30 ⫺ 30
SDf
200
130
70
60
35
4.2
0
*Derived from Braunwald et al,9 whose angiographic volume indexes
are converted here to absolute volumes using nominal body surface
area (1.73 m2) and liberal rounding to facilitate interpretation (but
in all cases ⬍ 2%). DHF-1 ⫽ DHF due to mild-to-moderate DDf;
DHF-2 ⫽ DHF due to severe DDf; SDf ⫽ systolic dysfunction
without HF; see Table 1 for expansion of abbreviations.
Hemodynamic and Autonomic Responses to Low
CO: It is axiomatic that, except for transient imbalances, right ventricular (RV) and LV output must be
equal. Since SDf and/or DDf rarely, if ever, impair
the ventricles symmetrically, their earliest effect is to
unbalance the circulation, that is, to lower the output
of one ventricle more than the other.10,11 An example
is shown in Figure 1, where SDf and/or DDf transforms a normal LV output curve (Starling curve),
curve I, into curve II. With no immediate change in
LV end-diastolic pressure (LVEDP), LV output
drops11 from 5 to 2 L/min, point x. Meanwhile the
RV continues pumping 5 L/min (right-heart curves
are omitted from Fig 1 for clarity). The LV is thus
unable to empty the pulmonary circuit as fast as the
RV fills it, and pulmonary blood volume expands.
This shifts the normal pulmonary venous return12/
vascular function13 (Guyton) curve, A, upward to B,
re-setting the Starling-Guyton intersection to a
higher LVEDP and a partially compensating LV
output, 4.5 L/min (intersection II-B). Since total
blood volume is fixed, the volume expanding the
pulmonary circuit is equally and simultaneously removed from the systemic circuit. This shifts the
systemic Guyton curve and RV end-diastolic pressure (RVEDP) downward. Thus, by Starling’s law of
the heart and within a few heartbeats, the altered
Guyton curves simultaneously raise the lowered LV
output while lowering the normal RV output until
biventricular output re-equilibrates at an intermediate CO (intersection II-B).10,11 Low CO also evokes
a reflex sympathetic response proportional to its
hypotensive effect, the cardiostimulatory component
tending to shift the Starling curve back toward
normal.
The Neurohormonal Response to Low CO: The
renin-angiotensin-aldosterone system (RAAS) is so
exquisitely sensitive to low CO/reduced renal perfusion that it is activated physiologically by mere
postural changes.14 Thus, to the degree that CO after
ventricular re-equilibration and autonomic adjustments (Fig 1, intersection II-B) remains below the
RAAS activation threshold (RAASAT), the RAAS is
activated, stimulating renal fluid retention. This in
turn shifts the Guyton curves upward (pulmonary, B
to C; systemic, not shown) increasing biventricular
end-diastolic pressure (EDP), thence CO, until CO
reaches the RAASAT (intersection II-C). CO thus
compensated is maintained by persistent RAAS activation at the new higher set point. With further
ventricular dysfunction (Fig 1, Starling curve III),
the greater CO shortfall after hemodynamic and
autonomic stabilization (intersection III-D) requires
additional RAAS activation to compensate (intersection III-D to III-E).
For every Starling curve, there is a point of
optimum EDP, roughly coinciding with the onset of
the Starling “plateau,” above which ventricular output no longer significantly increases irrespective of
further increases in EDP. Note that the Figures
reverse the conventional axes of the Starling curve to
show the “height” of the EDP column more intuitively on the vertical axis (as did Starling himself15).
Thus, the Starling “plateau” is represented not horizontally as a plateau but vertically, as a “wall,” an
appropriate descriptor in the current vernacular as it
defines the maximum achievable output if the ventricle is “pushed to the wall” by EDP exceeding
optimum EDP. In the case of (normal) Starling
curve I, optimum EDP is 11 mm Hg (intersection
I-G). Compared to SDf, the Starling slope in DDF is
steeper, ensuring a higher optimum EDP and a
higher LVEDP at any given output.
With marked systolic dysfunction and/or DDf, the
Starling curve is confined to a position to the left of
the RAASAT (Starling curve IV). The RAAS is
thus persistently activated in an attempt to raise
the intractably low CO to the RAASAT.16 Since
the RAAS control loop is now endless, it will continue raising EDP at a rate proportional to the
RAASAT-CO shortfall ad infinitum above optimum
EDP (intersection IV-F) until therapy, reduced circulatory demand, improved ventricular function, or
death in PED intervenes. This process is not only
congestive, excessive, futile, and cardiovasculopathic,14 but also at least partly accounts for “failure
of effective (HF) therapy to reverse the renal sodium
retention that requires continued diuretic therapy”3
and the transience of aldosterone suppression during
angiotensin-converting enzyme (ACE)-inhibitor
therapy17,18 (the ACE-inhibitor escape phenomenon), observations authorities have found difficult
to explain.
746
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
Opinions/Hypotheses
Perspective: It should be noted that the determinants of LV output and EDP (the Starling and
Guyton curves and the RAASAT) are in a constant
state of flux. Thus, the static intersections in Figure
1 actually represent the aggregate of many intersections over time. In other words, low CO could be
compensated/normal at rest while uncompensated
with activity and other circulatory stresses, the
aggregate yielding a substantial CO RAASAT deficit.
It is advantageous that resting CO remains compensated (not absolutely/measurably low) until LV
dysfunction is advanced; however, it comes at the
cost of persistent RAAS activation with its cardiovasculopathic sequelae.14 This could account for
the long-term benefit of ACE-inhibitor therapy
in ventricular dysfunction even before overt HF
develops.19
Compensation also helps to conceal the pivotal
role of low CO. Indeed, some authors14,18,20 go as far
as to dismiss low CO altogether as the stimulus to
sustained RAAS activation in HF, attributing it to
hypovolemia. The misperception is compounded
when, having to concede that HF is a hypervolemic
state, RAAS activation is then mischaracterized as
“inappropriate,”14,18,20 inviting the distorted view
that HF is primarily a disorder of neurohormonal
control (the “neurohormonal model”) rather than of
fully or partially compensated low output.21
Acute Hypertensive PED (Systolic or Diastolic)
Figure 1. Responses to LV SDf and/or DDf. Modified from
Guyton.10 Dotted horizontal lines indicate LVEDP normal range.
Solid vertical line indicates RAASAT. Red “curves” (Guyton
curves) indicate pulmonary “venous return”12/“vascular function”13 and describe how LVEDP varies when LV output changes; they are actually straight lines at positive pressures and all
intersect the x and y axes, but for clarity only the normal curve,
A, is shown as such. Green curves (Starling curves) indicate how
LV output varies when LVEDP changes. Red circles indicate
intersections of the LV Starling curve and its upstream (pulmonary) Guyton curve and define LV output and LVEDP. RV
Starling and systemic Guyton curves are omitted for clarity. I
indicates a normal LV Starling curve (intersection I-A, LV output
5L/min, LVEDP 5 mm Hg; intersection I-G, optimal EDP). II
indicates mild LV SDf and/or DDf (point x, initial dysequilibrium; intersection II-B, after re-equilibration and autonomic
adjustments; intersection II-C, after RAAS compensation; diagnosis, LV dysfunction [CO ⫽ RAASAT, LVEDP not exceeding
top normal]). III indicates moderate LV SDf and/or DDf (intersection III-D, after re-equilibration and autonomic adjustments;
intersection III-E, after RAAS compensation; diagnosis, LV
failure [CO ⫽ RAASAT, LVEDP above top normal]). IV indicates marked/advanced LV SDf and/or DDf (intersection IV-F,
optimal EDP; diagnosis, uncompensated LV failure [CO
intractably below RAASAT, LVEDP above than top normal]).”
The foregoing explains the chronic indolent course
of (systolic or diastolic) HF with its congestive and
hypoperfusive features but not its presentation as
acute hypertensive PED. The work of Gandhi et al1
provides further insight.
Evidently based on the unchanged normal LVEF
during and after acute hypertensive PED in their
DHF group, they considered it a “high probability
that the pulmonary congestion was due to isolated
transient DDf.”1 While admirably obtaining data at
the earliest feasible opportunity after acute PED
onset, technically their study did not include events
leading up to or initiating acute PED, as they
acknowledge. Thus, although it seems intuitive that a
clinical event as dramatic as acute hypertensive PED
would be predicated on a similarly acute change in
LV function, the data of Gandhi et al1 do not
establish this.
Even if their data did include events up to and
initiating acute PED, Gandhi et al1 did not specify
how they identified transient DDf, although lacking
evidence of transient SDf it is possible they simply
(and properly) accepted DDf as the only possible
alternative (see section on “Diagnosis”). It is intriguing that transient DDf remained attractive as the
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
CHEST / 124 / 2 / AUGUST, 2003
747
likely precipitator of diastolic acute hypertensive
PED even though evidence that transient SDf precipitated systolic acute hypertensive PED (intuitively
even more likely) was notably absent. Also, they were
unable to identify a triggering mechanism for acute
transient DDf (or SDf). They considered acute
ischemia,1 but neither they nor their colleagues in an
earlier study22 could confirm it, a finding supported
by the ordinary clinical observation that even the
most overt expressions of myocardial ischemia (angina pectoris and acute myocardial infarction) are
infrequently complicated by acute PED. They considered acute hypertension but did not interpret
their data as corroborative. Moreover, by ordinary
clinical observation, acute hypertension is also a
clinical event only occasionally associated with acute
PED even in the context of LV dysfunction.
These considerations thus cast reasonable doubt
on the premise that acutely impaired cardiac performance is the usual mechanism of acute hypertensive
PED. Could there be another explanation? Could
most acute hypertensive PED simply be an extension
of the chronic process of systolic and/or diastolic HF?
The effect of chronic RAAS activation is cumulative, inexorably raising extracellular volume and
biventricular EDP until CO reaches the RAASAT. If
this is not achieved at an LVEDP at or below
optimum EDP, LVEDP will operate on the nearvertical Starling wall, maximizing the effect of additional volume retention on LVEDP. This could set
the stage for acute volume loads to sharply elevate
LVEDP beyond the pulmonary capillary transudation point and precipitate acute PED (see section on
“Diuretics”). Since many acute myocardial infarctions are first cardiac events, venous pressure before
the event is likely to be normal, possibly accounting
for the infrequency of complicating acute PED, its
occurrence essentially confined to those with the
greatest acute ischemic insult and/or preexisting
ventricular dysfunction/low output.
However, disorders known to raise intravascular
and interstitial volume predispose to acute PED
despite normal or only minimally impaired ventricular function. Such is the case with bilateral renal
artery stenosis where acute PED is effectively prevented by successful renal revascularization alone.23
Thus, an “over-stuffed” circulation seems to be a
key predisposing substrate to acute PED, which
might then be precipitated by a relatively modest
additional volume load without necessarily involving
acute ventricular dysfunction. Such loads can result
from dietary indiscretion, lapse in HF therapy, or
postural change as occurs to lesser consequence in
orthopnea and paroxysmal nocturnal dyspnea. Further loss of renal perfusion has a similar effect as
when acute bradyarrhythmia/tachyarrhythmia lowers
CO. Increased physical activity or inflammatory illness also lower renal perfusion. Here, the hypermetabolic/inflamed (vasodilated) tissues create an
AV fistula effect. When CO is low and fixed, blood
flow thus diverted is at the expense of the kidneys.
The net effect is to shift the RAASAT to the right,
which, parenthetically, is also the basis of highoutput failure—low output (relative to the “. . . the
requirements of the metabolizing tissues. . . . ”8 as
represented by the RAASAT) is the unifying mechanism of all HF.
Once LVEDP exceeds the pulmonary capillary
transudation point, free fluid rapidly passes into the
pulmonary interstitial and alveolar spaces.24 The
resulting acute respiratory and emotional distress
then triggers an acute adrenergic response. Its vasoconstrictive component would explain the associated
acute hypertension.22 The chronotropic component
would tend to elevate HR and, as Gandhi et al1
noted, the inotropic component could mask acute
hypertension-induced systolic dysfunction. In any
case, CO during acute hypertensive PED was in fact
higher than the chronic/“after” value.1 Thus, whatever the mechanisms operative during the acute
event, the net effect seems to be more compensatory
than contributory.
Accordingly, the evidence that acute ventricular
dysfunction precipitates acute hypertensive PED is
weak at best, and there is good theoretical evidence
to the contrary.25 Thus it seems plausible, if not
likely, that it results from the combination of chronic
low CO with its attendant cumulative fluid retention
and a superimposed acute, often relatively modest,
volume challenge (see section on “Diuretics”). The
associated acute hypertension is most likely an adrenergic sequela. Ambulatory hemodynamic monitoring holds the promise of clearer insight.
DHF
Mechanism
Low CO: Because CO is perceived as normal in
DHF, it is rarely considered, descriptions such as:
“. . . inability . . . to . . . expel sufficient blood,”26 and
“the major . . . manifestations relate to inadequate
CO”26 conspicuously applied to SHF but not to
DHF. Meanwhile in DHF, the focus is on the
DDf/“stiffness”/“backward failure” component: “. . . a
primary impairment of diastolic function that results in
the need for elevated atrial pressure to maintain/ensure
adequate filling,”27 and “the major . . . manifestations
relate principally to the elevation of filling pressures.”26
Of course the ventricle is always adequately filled;
indeed, it is reasonably viewed as overfilled not only
in DHF but also in SHF. The point is that in DHF,
748
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
Opinions/Hypotheses
as in any restrictive cardiomyopathy, the enddiastolic capacity (EDV) to which it can be filled is
low, “two sizes too small.”28 Low stroke volume/CO
further requires an end-systolic volume “two sizes
too big” to match the low EDV, presumably the
result of (1) the inherent mechanical limit to cardiomyocyte shortening, and/or (2) Frank-Starling
forces constrained by the constrained EDV.
Ventricular Stiffness: While DD/ventricular “stiffness” has captured the spotlight as the presumed
cause of pulmonary congestion in DHF, Figure 1
shows that it cannot be the dominant factor. Indeed,
without the ability of the normal pulmonary Guyton
curve (Fig 1, curve A) to shift upward, LVEDP could
never exceed its y-intercept (11 mm Hg) regardless
of LV stiffness. The Guyton y-intercept (hence the
vertical position of the entire Guyton curve on the
pressure axis) varies inversely with the capacity and
directly with the volume contained by the vascular
circuit it represents, the slope varying with vascular
resistance. Guyton curves are unaffected by DD or
any other characteristic of their downstream ventricle.11,25 They shift upward purely because of the
increased vascular volume and tone resulting from
the hemodynamic, autonomic, and neurohormonal
responses to low output. This occurs most dramatically with type IV left ventricle Starling curves—the
associated pulmonary Guyton y-intercept, hence
LVEDP will rise ad infinitum above optimum EDP
(intersection IV-F) with no additional ventricular dysfunction.
Starling curves of type IV, representing advanced
ventricular dysfunction, cannot by definition be compensated at a LVEDP below the pulmonary capillary
transudation point. Moreover, they have a nearvertical Starling wall that predisposes to abrupt
increases in LVEDP. Thus, they are a likely substrate
for acute PED. Accordingly, the “after” stroke volume observed by Gandhi et al1 could represent the
uncompensated/intractably low CO state characteristic of these curves, and it was essentially identical in
the SHF and DHF groups (55 mL and 57 mL,
respectively). Alternatively, the “after” stroke volumes could be normal/compensated. If so, the occurrence of acute PED 2 to 3 days earlier could only
be explained, in either group, by an antecedent
aggregate RAASAT-CO deficit. Thus, whether the
“after” stroke volumes were low or compensated,
they were essentially equal in both groups—if there
is no mystery/paradox in SHF, there should likewise
be no mystery/paradox in DHF.
Therapy
Diuretics: The notion that DHF is more vulnerable than SHF to the hypotensive effect of diuretics
and other preload-reducing agents is widely echoed.27,29,30 The premise seems to be that since a
stiffer LV requires a higher EDP to maintain a given
EDV/stroke volume, stroke volume will fall faster as
EDP falls.
This premise, like all partial truths, is misleading.
Figure 2 shows normal RV and LV Starling curves as
examples of greater and lesser ventricular compliance, respectively. As EDP falls from point a to b,
LV stroke volume falls ⬍ 9 mL (point c to d), but RV
stroke volume falls ⬎ 12 mL (point e to f). Thus,
Figure 2. RV and LV Starling curves in normal and in acute
PED, modified from Bradley.31 Subjects were all men. The
published “representative” normal stroke volume is adjusted here
to correspond with the male norm for the “modified Simpson’s
rule” echocardiographic method.47 Descriptions are the same as
in Figure 1, except for the following: gold lines indicate RV
Starling curves; blue circles indicate intersections of the RV
Starling curve and its upstream (systemic) Guyton curve defining
RV output and RVEDP; dotted horizontal line indicates normal
LVEDP— normal RVEDP overlies the x-axis in this example;
dashed horizontal lines indicate ventricular end-diastolic pressures.
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
CHEST / 124 / 2 / AUGUST, 2003
749
when EDP varies, stroke volume, CO, and BP vary
less, not more, in DHF than in SHF.
The “stiff LV” premise is not only flawed, it is
unrelated to the effect of diuretics on stroke volume/
CO/BP. While it is true that the LV Starling curve
determines LVEDP and the output at which both
ventricles equilibrate when the LV is the weaker/
“rate-limiting” ventricle, once the circulation equilibrates to this output it is actually the RV that
determines any diuretic-induced change in CO.31
This is simply because the initial effect of diuretics is
to lower central venous pressure/RVEDP. This lowers RV output. To comply with the imperative of
circulatory balance, the then relatively higher LV
output will progressively deplete pulmonary blood
volume, thus lowering LV output until it re-equilibrates with the diuretic-induced lower RV output.
Thus, it is the RV, not the LV, that is the principal
determinant of CO when central venous pressure is
the primary hemodynamic disturbance,10 its effect
directly proportional to RV compliance.
While the RV determines LV output in this context, the LV Starling curve determines the LVEDP
at which this occurs (Fig 2, acute PED).31 After
venesection, RVEDP fell 5 mm Hg (point g to b),
lowering stroke volume 1 mL (point h to i). This
required LVEDP to fall 13 mm Hg (point j to k) for
ventricular output to re-equilibrate. Thus, the Starling slope disparity magnified the change in RVEDP
by a factor of 13/5 ⫽ 2.6.31 These observations explain how a modest diuresis (and/or systemic venodilation as with IV isosorbide dinitrate32) can so
rapidly and remarkably reverse acute PED and how
surprisingly small acute volume loads (their effect
amplified by the high venous tone characteristic of
HF) can so readily provoke it.31
The potent effect of Starling slope disparity further implies that, more than just another physiologic
curiosity, ventricular interdependence is a crucial
safety factor. If the RV Starling curve did not to some
extent parallel an impaired LV Starling curve, that is,
if some degree of Starling slope parity were not
maintained, minor increases of RVEDP would more
readily inundate the pulmonary circuit.
Ventricular interdependence has the further effect
of linking LVEDP to RVEDP. Indeed, LVEDP is
determined by the sum of RVEDP plus transmural
LV filling pressure (true LV preload).33 Thus, diuretics lower LVEDP in two ways: (1) by lowering
pulmonary blood volume/the pulmonary Guyton
curve, and (2) by lowering systemic blood volume/
RVEDP, which then lowers the LV Starling curve.34
A LV Starling curve thus lowered lessens the likelihood that an increase in RVEDP would drive
LVEDP high enough to precipitate acute PED; an
overstuffed circulation would have the opposite effect, as previously discussed.
When RVEDP is at or below optimum EDP (in
SHF and/or DHF), that is, on the RV Starling slope,
lowering RVEDP will begin to decrease CO significantly. This is disadvantageous, of course, but when
LVEDP remains high despite RVEDP at or near
optimum EDP, some degree of CO loss might have
to be accepted to minimize dyspnea.
In the final analysis, in SHF and/or DHF, therapeutic preload reduction is routinely undertaken
without foreknowledge of Starling curves and is thus
an inherently empirical exercise. Since its initial
effect on stroke volume/CO/BP is a function of RV,
not LV compliance, hypotension is no more likely in
diastolic than in systolic LV failure, and it can be
confidently avoided in either only if a “cushion” of
jugular venous pressure (2 to 3 mm Hg above top
normal) is preserved.
LV Volume: It was recently recommended that the
“initial step in treating DHF is to reduce pulmonary
congestion by decreasing LV volume . . . ”5; but since
inadequate LV EDV is the very basis of DHF, its
additional primary lowering, without a concomitant
greater lowering of LV end-systolic volume, could
only further limit stroke volume/CO. This would
increase, not decrease, LVEDP/pulmonary congestion.
Heart Rate: Finally, recommendations to reduce
HR in DHF, “The initial step in treating . . . DHF
[includes] . . . reducing heart rate”29 and by how
much, “Although the optimal heart rate must be
individualized, an initial goal might be a resting heart
rate of 60 to 70 bpm [beats/min] with a blunted
exercise-induced increase in heart rate”29 merit careful scrutiny. Gandhi et al1 showed that EDV and
stroke volume were indeed lower during (but not
necessarily a direct result of) the higher HR of acute
PED (Table 1). Nevertheless, CO was in fact slightly
higher suggesting a net benefit (or at least no
detriment) to the higher HR, a benefit that might be
even greater at higher HRs. In any case, the premise
that prolonging the diastolic filling interval will increase EDV/stroke volume enough to overcome the
lower HR is tenuous since resistance to further
filling is fundamental to DHF. The resting HR goal
of “60 to 70 bpm” attributed by this author29 to
Levine35 was based on the presumption that DDf is
hydraulically analogous to mitral stenosis (H. J.
Levine, MD; personal communication; May 2002). It
is evident that ventricular filling past an obstruction
will be time dependent, but in DDf filling is restricted, not obstructed; therefore, the applicability
750
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
Opinions/Hypotheses
of primarily lowering a normal HR in patients with
DHF is dubious.
Controlling supraventricular (including sinus)
tachycardia might well be another matter, particularly if it is perceived as having a causal or aggravating role in an acute decompensation. However,
tachycardia occurred in only a small minority of the
patients of Gandhi et al1 (only 17% had a HR ⬎ 97
beats/min assuming a normal HR distribution).
Moreover, by ordinary clinical observation, treating
the congestive phenomena to prompt and substantial
effect alone commonly controls, if not spontaneously
converts, nonchronic supraventricular tachycardias.
Therefore, it is reasonable to infer that they, too, are
frequently secondary phenomena in acute HF. Also,
in the context of acute HF and its associated hyperadrenergic state, supraventricular tachycardia is relatively resistant to control/conversion. This often
necessitates an aggressive pharmacologic regimen,
itself inviting an unfavorable risk/benefit ratio. Indeed, with a 95% short-term survival using only
standard treatment excluding antiarrhythmics except
digitalis,36 the adage “the enemy of good is better”
might apply to more aggressive antiarrhythmic therapy, at least in terms of mortality. In any case, an
imperative to apply specific antichronotropic or antiarrhythmic measures is exceptional unless there is
associated acute ischemia, hypotension, or lack of a
prompt response to anticongestive therapy, in which
case rate control and/or direct current cardioversion
is appropriate, as long established.
Overview: Other presumed therapeutic distinctions are the subject of ongoing trials; but, as we have
seen, whereas the structural or functional pathology
underlying systolic dysfunction and DDf might vary,
its pathophysiologic sequela (low CO) does not: HF
is HF whatever its cause, and it is truly the final
common pathway of cardiac disease. Thus, except
where the underlying pathology might be affected,
therapeutic similarities are likely to outweigh differences. This is supported by ordinary clinical observation and the limited data presently available.37– 41
Diagnosis
The diagnosis of DHF has for some time been
encumbered by the perceived need to specifically
document DDf. Assuming an adequate HR, whatever the primary pathology—myocardial, valvular,
pericardial, etc.—there are two, and only two mechanisms by which any pump (including the heart) can
fail to deliver an adequate output: inadequate ventricular discharge (SDf) and/or insufficient ventricular charge (DDf). Thus, not surprisingly, Zile et al42
confirmed that a normal LVEF has in fact always
accurately identified DHF, obviating the vexatious43
task of specifically documenting the subtle, multiple,
indirect, technically challenging, variable, and unreliable echocardiographic and Doppler signs of DDf.
Defining HF (Systolic and/or Diastolic)
The foregoing groundwork provides an opportunity to address the equally vexatious issue of defining
HF. As has long been evident and as Table 2 attests,
“not all patients with congestive HF have systolic
dysfunction,” and “not all those with systolic dysfunction have symptoms of congestive HF.”44 These
observations prompted the suggestion that “the term
congestive HF used in the traditional way is no
longer useful,”44 implying that the “traditional” definition equates or at least correlates HF with LVEF.
In fact, just as “coronary artery disease” and “coronary heart disease” are associated but not synonymous, LVEF and HF are associated but not synonymous. The disturbing reality is that despite the
manifest nonequivalence of LVEF and HF, many
clinicians and researchers and at least one prominent
and influential classification of heart disease45 continue to accept a low LVEF as an independent
diagnostic criterion of HF. Conceptual clarity, not to
mention rational therapy and research, would be
served if the diagnosis of ventricular dysfunction
were strictly distinguished from the diagnosis of HF.
Setting what exactly is the optimum definition of
HF is arguably a lot less problematic than might be
presumed. Thus, while low CO is the pathophysiologic essence of HF, its disadvantage as a diagnostic
test is that its measurement requires an imaging or
invasive procedure; it is compensated at rest in all
but marked ventricular dysfunction, thus requiring
an exercise procedure in this large subset; and its
“normal” range is always relative to the individual’s
contemporaneous (and labile) RAASAT over time,
thus limiting the utility of a “snapshot” value.
Fortunately, as allowed by the full proper definition of HF: “. . . [inability of the heart] . . . to pump
blood at a rate commensurate with the requirements
of the metabolizing tissues or . . . can do so only from
an elevated filling pressure,”8 the constant feature in
untreated HF is high ventricular EDP with or
without congestive sequelae (see Fig 1 legend for
diagnostic criteria). Thus, until other markers such as
plasma natriuretic peptides are better established,
high EDP remains (1) the most clinically accessible
(as jugular venous pressure), (2) timely (radiographic
and renal function markers typically lag 24 to 72 h),
and (3) useful criterion of HF despite its limitations—jugular hypertension has been shown 81%
sensitive46 (the undetected 19% presumably due to
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
CHEST / 124 / 2 / AUGUST, 2003
751
Starling height disparity), and 80% specific46 (the
false-positive 20% presumably due to a rate-limiting
right ventricle) for an LVEDP ⱖ 18 mm Hg. It is
certainly the most economical. It is also the most
diagnostically rational and clearly preferable to the
present state of confusion— diagnostic limitation is
one thing, diagnostic misdirection another.
ACKNOWLEDGMENT: Special appreciation is given to Arthur
C. Guyton, MD, for his enormous contribution to circulatory
physiology, providing the foundation of this article; colleagues
Collins F. Kellogg, MD, and Laverne R. Vandewall, DO, for their
support; the Samaritan Health Sciences Library in Watertown
(Ellen Darabaner, Jeff Garvey); the Syracuse University Health
Sciences Library (Catherine Whaley), and its LEAP online
reference resource; and my beloved son, Gosha.
20
21
22
23
24
References
1 Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis
of acute pulmonary edema associated with hypertension.
N Engl J Med 2001; 344:17–22
2 Petrie MC, Caruana L, Berry C, et al. “Diastolic heart failure”
or heart failure caused by subtle left ventricular systolic
dysfunction? Heart 2002; 87:29 –31
3 Cohn JN, Francis GS. Cardiac failure: a revised paradigm
[editorial]. J Card Fail 1995; 1:261–266
4 Agmon Y, Lessick J, Reisner SA. Heart failure with a normal
ejection fraction [letter]. Circulation 2002; 105:e48
5 Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart
failure in subjects with normal versus reduced left ventricular
ejection fraction: prevalence and mortality in a populationbased cohort. J Am Coll Cardiol 1999; 33:1948 –1955
6 Libby P. The acute coronary syndromes: have our tools
constrained our thinking? ACC Curr J Rev 2000; 9:20 –22
7 Parmley WW. Surviving heart failure: Robert L. Frye lecture.
Mayo Clin Proc 2000; 75:111–118
8 Braunwald E, Zipes DP, Libby P. Heart disease: a textbook of
cardiovascular medicine. 6th ed. Philadelphia, PA: Saunders,
2001; 534
9 Braunwald E, Zipes DP, Libby P, eds. Heart disease: a
textbook of cardiovascular medicine. 6th ed. Philadelphia, PA:
Saunders, 2001; 482
10 Guyton AC. Circulatory physiology 1: Cardiac output and its
regulation: Philadelphia, PA: W.B. Saunders, 1963; 416 – 417
11 Berne RM, Levy MN. Cardiovascular physiology. 8th ed. St.
Louis, MO: Mosby, 2001; 216
12 Guyton AC, Lindsey AW, Abernathy JB, et al. Venous return
at various right atrial pressures and the normal venous return
curve. Am J Physiol 1957; 189:609 – 615
13 Levy MN. The cardiac and vascular factors that determine
systemic blood flow. Circ Res 1979; 44:739 –747
14 Weber KT. Aldosterone in congestive heart failure. N Engl
J Med 2001; 345:1689 –1697
15 Patterson SW, Starling EH. On the mechanical factors which
determine the output of the ventricles. J Physiol 1914;
48:357–379
16 Guyton AC, Jones CE, Coleman TG. Circulatory physiology
1: Cardiac output and its regulation. 2nd ed. Philadelphia, PA:
Saunders, 1973; 458
17 Struthers AD. Aldosterone escape during angiotensinconverting enzyme inhibitor therapy in chronic heart failure.
J Card Fail 1996; 2:47–54
18 Weber KT. Aldosterone and spironolactone in heart failure
[editorial]. N Engl J Med 1999; 341:753–755
19 Effect of enalapril on mortality and the development of heart
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
failure in asymptomatic patients with reduced left ventricular
ejection fractions. The SOLVD Investigators [published erratum appears in N Engl J Med 1992; 327:1768]. N Engl
J Med 1992; 327:685– 691
Schrier RW, Abraham WT. Hormones and hemodynamics in
heart failure. N Engl J Med 1999; 341:577–585
Andrew P. Renin-angiotensin-aldosterone activation in heart
failure, aldosterone escape [letter]. Chest 2002; 122:755
Kramer K, Kirkman P, Kitzman D, et al. Flash pulmonary
edema: association with hypertension and reoccurrence despite coronary revascularization. Am Heart J 2000; 140:451–
455
Bloch MJ, Trost DW, Pickering TG, et al. Prevention of
recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement. Am J
Hypertens 1999; 12:1–7
Guyton AC, Hall JE. Textbook of medical physiology. 10th
ed. Philadelphia, PA: W.B. Saunders, 2000; 449
Burkhoff D, Tyberg JV. Why does pulmonary venous pressure rise after onset of left ventricular dysfunction: a theoretical analysis. Am J Physiol 1993; 265:H1819 –H1828
Braunwald E. Harrison’s principles of internal medicine. 15th
ed. New York, NY: McGraw-Hill, 2001; 1320
Elesber AA, Redfield MM. Approach to patients with heart
failure and normal ejection fraction. Mayo Clin Proc 2001;
76:1047–1052
Geisel TS. How the grinch stole Christmas, by Dr. Seuss.
New York, NY: Random House, 1957
Zile MR, Brutsaert DL. New concepts in DD and diastolic
heart failure: part II; Causal mechanisms and treatment.
Circulation 2002; 105:1503–1508
Garcia MJ. Diastolic dysfunction and heart failure: causes and
treatment options. Cleve Clin J Med 2000; 67:727–729,733–
738
Bradley RD. Studies in acute heart failure. London, UK: E.
Arnold, 1977; 36 –38
Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of
high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate
in severe pulmonary oedema. Lancet 1998; 351:389 –393
Tyberg JV, Belenkie I, Manyari DE, et al. Ventricular
interaction and venous capacitance modulate left ventricular
preload. Can J Cardiol 1996; 12:1058 –1064
Ludbrook PA, Byrne JD, McKnight RC. Influence of right
ventricular hemodynamics on left ventricular diastolic pressure-volume relations in man. Circulation 1979; 59:21–31
Levine HJ. Optimum heart rate of large failing hearts. Am J
Cardiol 1988; 61:633– 636
Bertini G, Giglioli C, Biggeri A, et al. Intravenous nitrates in
the prehospital management of acute pulmonary edema. Ann
Emerg Med 1997; 30:493– 499
The effect of digoxin on mortality and morbidity in patients
with heart failure. The Digitalis Investigation Group. N Engl
J Med 1997; 336:525–533
Mandinov L, Eberli FR, Seiler C, et al. Diastolic heart failure.
Cardiovasc Res 2000; 45:813– 825
Philbin ejection fraction, Rocco TA Jr. Use of angiotensinconverting enzyme inhibitors in heart failure with preserved
left ventricular systolic function. Am Heart J 1997; 134:188 –
195
Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive
heart failure in the community: a study of all incident cases in
Olmsted County, Minnesota, in 1991. Circulation 1998; 98:
2282–2289
Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan
improves exercise tolerance in patients with DD and a
752
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
Opinions/Hypotheses
42
43
44
45
hypertensive response to exercise. J Am Coll Cardiol 1999;
33:1567–1572
Zile MR, Gaasch WH, Carroll JD, et al. Heart failure with a
normal ejection fraction: is measurement of diastolic function
necessary to make the diagnosis of diastolic heart failure?
Circulation 2001; 104:779 –782
Caruana L, Petrie MC, Davie AP, et al. Do patients with
suspected heart failure and preserved left ventricular systolic
function suffer from “diastolic heart failure” or from misdiagnosis? A prospective descriptive study. BMJ 2000; 321:215–218
Petrie M, McMurray J. Changes in notions about heart
failure. Lancet 2001; 358:432– 434
New York Heart Association Criteria Committee, Dolgin M,
ed. Nomenclature and criteria for diagnosis of diseases of the
heart and great vessels. 9th ed. Boston, MA: Little Brown,
1994; 234
46 Butman SM, Ewy GA, Standen JR, et al. Bedside cardiovascular examination in patients with severe chronic heart
failure: importance of rest or inducible jugular venous distension. J Am Coll Cardiol 1993; 22:968 –974
47 Schiller NB, Shah PM, Crawford M, et al. Recommendations
for quantitation of the left ventricle by two-dimensional
echocardiography. American Society of Echocardiography
Committee on Standards, Subcommittee on Quantitation of
Two-Dimensional Echocardiograms. J Am Soc Echocardiogr
1989; 2:358 –367
www.chestjournal.org
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21997/ on 05/07/2017
CHEST / 124 / 2 / AUGUST, 2003
753