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 Brian P. Shapiro, MD
Rick A. Nishimura, MD
Michael D. McGoon, MD
Margaret M. Redfield, MD
Mayo Clinic College of Medicine
Rochester, Minnesota
Left heart disease can cause pulmonary hypertension via multiple
mechanisms. In the past, a normal ejection fraction and the
absence of left-sided valve disease or congenital heart disease
provided reassurance that pulmonary hypertension was not
related to left-sided heart disease. However, it is now recognized
that patients with clinical heart failure commonly have a
normal ejection fraction, a syndrome referred to as diastolic
heart failure or heart failure with normal ejection fraction.1,2 As
reviewed below, the pathophysiologic mechanisms present in
patients with diastolic heart failure may be heterogeneous.
Although pulmonary hypertension has been reported in patients
with diastolic heart failure, its prevalence and severity remain
poorly defined.
Idiopathic pulmonary arterial hypertension (IPAH) has been
characterized as a disease of children and young adults,3,4 yet
increasingly the diagnosis is made in elderly persons.5,6 This
raises concern that some patients with dyspnea, unexplained
pulmonary hypertension, and a normal ejection fraction could
have diastolic heart failure with secondary pulmonary hypertension
related to chronic pulmonary venous hypertension.
However, as reviewed below, chronic right ventricular pressure
overload can cause left ventricular diastolic dysfunction. Thus,
a diagnostic dilemma arises in elderly dyspneic patients with
otherwise unexplained pulmonary hypertension and a normal
ejection fraction or when patients with a presumptive diagnosis
of IPAH undergo right heart catheterization and are found to
have an elevated pulmonary capillary wedge pressure (PCWP).
Do these patients have diastolic heart failure with secondary
pulmonary hypertension or is it IPAH causing left ventricular
diastolic dysfunction and elevated PCWP?
In this review, illustrative cases of both scenarios outlined
above are presented, followed by a discussion of diastolic heart
failure, novel concepts relevant to diastolic dysfunction and
secondary pulmonary hypertension, and the phenomenon of left
ventricular diastolic dysfunction related to chronic right ventricular
pressure overload. Lastly, potential diagnostic strategies
and implications for therapy are discussed.
CASE 1: A 79-year-old woman presented with acutely decompensated
heart failure after starting bosentan for pulmonary
hypertension. She had a history of paroxysmal atrial fibrillation
that began in 1986 and underwent a surgical MAZE procedure
in 1996 because of worsening tachypalpitations. Atrial fibrillation
recurred and an atrioventricular node ablation with pacemaker
implantation was performed later that year. In 1998 the
patient developed symptoms of dyspnea and peripheral edema
and was found to have pulmonary vascular congestion on chest
radiography. Echocardiography revealed Doppler evidence of
severe diastolic dysfunction, no mitral regurgitation and a normal
ejection fraction. A diagnosis of diastolic heart failure was
made and she was treated with diuretics. In 2000 she had
worsening dyspnea and peripheral edema and a repeat echocardiogram
demonstrated a normal ejection fraction, severe diastolic
dysfunction, and a right ventricular systolic pressure of 56
mmHg. The following year, her condition once again clinically
deteriorated. Repeat echocardiography was unchanged with the
exception of the right ventricular systolic pressure, which had
increased to 75 mmHg. She then underwent a work-up for other
secondary causes of pulmonary hypertension, but none were
identified and she was referred to the pulmonary hypertension
clinic. A right heart catheterization was performed that revealed
a pulmonary artery pressure of 73/25 mmHg and a PCWP of 26
mmHg (Figure 1) with very prominent V waves in the PCWP
wave form. Treatment was started with bosentan, an endothelin
receptor antagonist, but she experienced a rapid increase in
edema and dyspnea and had pulmonary edema on examination
and chest radiography.
 Figure 1. Case 1. Hemodynamic catheterization in an elderly woman with dyspnea and pulmonary hypertension. Electrocardiographic (ECG), aortic, pulmonary capillary wedge pressure (PCWP), and right atrial pressure tracings showing elevated PCWP and a large (50 mmHg) V wave during systole in the PCWP tracing.
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The question arises whether or not this patient had lateonset
IPAH with concomitant or secondary diastolic dysfunction
or diastolic heart failure with secondary pulmonary hypertension.
Atrial fibrillation is extremely common among patients
with diastolic dysfunction7 and more common among patients
with left heart disease than right heart disease. Demographic,
clinical, and echocardiographic information seemed to favor a
diagnosis of longstanding diastolic heart failure and would suggest
that her pulmonary hypertension is likely related to “reactive”
pulmonary hypertension and/or congestive pulmonary vasculopathy
as addressed below. However, she was treated with
bosentan on the basis of her worsening pulmonary hypertension.
In the absence of significant mitral regurgitation, the presence
of a large V wave indicates poor atrial compliance, and as
outlined below, reduction in atrial compliance may be an important mediator of secondary pulmonary hypertension in mitral
stenosis or in patients with heart failure regardless of ejection
fraction. Indeed, large atrial V waves in the absence of mitral
regurgitation can occur in patients with several types of cardiac
disease.8,9 This case also underscores the potential for development
of worsening pulmonary edema after the initiation of
pulmonary vasodilators. This may be related to the preferential
vasodilatory effect on the pulmonary vasculature with increased
blood flow to a noncompliant left ventricle as has been
described with inhaled nitric oxide.10-13 Alternatively, this may
be related to volume retention associated with endothelin
receptor antagonism.14
 Figure 2. Case 2.Hemodynamic catheterization in an elderly man
with dyspnea and pulmonary hypertension. At baseline, aortic, left
ventricular (LV), and left atrial (LA) pressures (transseptal approach)
were measured. The patient was hypertensive with elevated mean LA
pressures where the V wave exceeded 50 mmHg. Nitroglycerin
reduced the systemic pressure to 121/51 mmHg. With that the mean
LA pressure fell to 15 mmHg and the V wave dropped to 22 mmHg.
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CASE 2: A 72-year-old man with a history of long-standing
hypertension, atrial fibrillation, diabetes mellitus, and previous
aortic valve replacement for aortic stenosis and mitral valve
repair for mitral regurgitation presents with progressive dyspnea.
Echocardiography demonstrated a normal ejection fraction,
a normally functioning aortic prosthesis, diastolic dysfunction,
and biatrial enlargement. There was no mitral stenosis
and only mild mitral regurgitation. The right ventricular systolic
pressure was estimated at 51 mmHg. A right and left heart
catheterization using a transseptal approach was performed
and revealed systemic arterial hypertension with a central aortic
pressure of 170/63 mmHg. Contrast ventriculography
revealed only mild mitral regurgitation despite the systemic
hypertension. Transseptal left atrial and left ventricular pressures
revealed the absence of any significant transmitral gradient.
Left atrial pressure tracings demonstrated a large V wave
of over 50 mmHg with a mean left atrial pressure of 28 mmHg
(Figure 2). The pulmonary arterial systolic pressure was 48
mmHg. Nitroglycerin administration reduced the systemic pressure
to 121/51 mmHg and the V wave in the left atrium fell to
22 mmHg with a mean left atrial pressure of 15 mmHg.
The hemodynamic profile of this patient is one of diastolic
heart failure related to hypertensive heart disease with moderate
secondary pulmonary hypertension that was largely due to
the passive effects of pulmonary venous hypertension and still
reversible with normalization of the PCWP. Again, the presence
of large atrial V waves suggests decreased atrial compliance.
 Figure 3. Case 3. Doppler echocardiographic findings in a young woman with severe idiopathic pulmonary arterial hypertension. A. Short-axis view of the right (RV) and left (LV) ventricles in diastole at the mid-LV level. The RV is markedly enlarged while the LV is normal in size. There is a small pericardial effusion (PE). B. Short-axis view of the RV and LV in systole. The intraventricular septum is flattened, producing a D-shaped LV. The PE is more apparent in systole. C. Apical four-chamber view demonstrating the marked RV and right atrial (RA) enlargement.
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CASE 3: An otherwise healthy 30-year-old woman presents with
a 12-month history of progressive dyspnea, fatigue, and peripheral
edema. Physical examination revealed a markedly elevated
jugular venous pressure, loud S2P, parasternal lift, and peripheral
edema. Echocardiography showed normal left ventricular
size and function, systolic flattening of the interventricular septum
(D-shaped left ventricle), severe right ventricular and right
atrial enlargement, a small pericardial effusion (Figure 3), mild
tricuspid regurgitation, and severe pulmonary hypertension.
The estimated right ventricular systolic pressure calculated
from the tricuspid regurgitant velocity was 97 mmHg (107% of
systemic systolic blood pressure). Left ventricular diastolic
assessment with transmitral inflow pulsed-wave Doppler
revealed a reduced early-to-late (E/A) filling velocity ratio and a
prolonged deceleration time (Figure 4A), reduced pulmonary
venous diastolic flow velocity (Figure 4B), and reduced tissue
Doppler early diastolic septal annulus velocity (Figure 4C), all
suggesting the presence of impaired left ventricular relaxation
(grade I diastolic dysfunction). Right heart catheterization confirmed
severe pulmonary hypertension and elevated right ventricular
diastolic and right atrial pressures in the presence of a
normal PCWP.
 Figure 4. Case 3. Diastolic assessment of the left (LV) and right ventricle
(RV) using Doppler echocardiography in the young woman with
severe idiopathic pulmonary arterial hypertension shown in Figure 3.
LV diastolic assessment (left panels): A. Transmitral pulsed-wave
Doppler flow velocity profile. The early diastolic velocity (E) is
reduced and the late diastolic velocity (A) is increased. The deceleration
time of the E velocity is also increased. B. The pulmonary
venous inflow velocity profiles show reduced diastolic forward flow
(D) with most flow occurring during ventricular systole (S). C. The
mitral annular tissue Doppler profile measured at the septal aspect of
the mitral annulus. The early diastolic velocity (e’) is low (0.08
m/sec) for a young woman where the e’ velocity usually exceeds 0.10
m/sec and usually exceeds the late diastolic velocity (a’). The patterns
in A-C are consistent with impaired relaxation in the LV (grade I
diastolic dysfunction; see Figure 5). In contrast, diastolic assessment
of the RV (right panels) shows that the transtricuspid early diastolic
velocity (E) is increased with a shortened deceleration time and there
is very little filling in late diastole (A) (panel D). Doppler evaluation of
the hepatic veins (E) shows blunted systolic forward flow (S) and
marked increase in atrial reversal flow (AR). These findings are consistent
with reduced RV compliance and would indicate grade III or
IV RV diastolic dysfunction (see Figure 5 for complementary LV pattern).
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Although this patient has diastolic dysfunction (impaired
relaxation) related to her chronic right ventricular pressure
overload, it is not the type of diastolic dysfunction that will be
associated with increased filling pressures, at least at rest (see
discussion of echo assessment of diastolic function and Figure
5 below). No formal assessment of left ventricular compliance
was performed. However, even if reduced compliance was present,
it was not associated with elevated filling pressures in this
case. However, her transtricuspid inflow pattern showed a high
E/A ratio and a short deceleration time (Figure 4D) and her
hepatic vein Doppler flow pattern showed reduced systolic forward flow and increased atrial reversal velocities (Figure 4E); all
suggestive of severe right ventricular diastolic dysfunction with
reduced right ventricular compliance (grade III-IV diastolic dysfunction).
This is consistent with the elevated right atrial pressure
demonstrated at her catheterization.
The echocardiogram from this patient illustrates the effect
of severe right ventricular pressure overload on right and left
ventricular diastolic function. There is evidence of impaired
relaxation but no Doppler evidence of decreased left ventricular
compliance or elevated filling pressures. This is the type of
diastolic dysfunction most frequently observed in patients with
IPAH. The concept of ventricular interdependence and its effect
on left ventricular diastolic function is discussed in detail
below.
Diastolic Heart Failure
Epidemiologic studies have established that 50% of patients
with a clinical diagnosis of heart failure have preserved ejection
fraction and this entity has been referred to as diastolic heart
failure.1,2 Patients with diastolic heart failure are generally elderly
but a significant subset are somewhat younger. Although
there is a predominance among women, the syndrome also frequently
affects men. More recently, the term “heart failure with
normal ejection fraction” has been suggested because of concerns
that diastolic dysfunction may not be present in all
patients.15,16
Risk factors for diastolic heart failure beyond advanced age
and female sex include hypertension, coronary artery disease,
and risk factors for coronary artery disease, including diabetes.1
Although classically described in patients with left ventricular
hypertrophy, echocardiographic evidence of left ventricular
hypertrophy is not uniformly present. Indeed, fewer than 50%
of patients have left ventricular hypertrophy in several series of
patients with diastolic heart failure.17,18
Although the diagnosis of diastolic heart failure is predicated
on the presence of clinical heart failure, a normal ejection
fraction, and the absence of significant left-sided valve disease,
the proper methods to confirm the presence of diastolic dysfunction
remain controversial. To characterize left ventricular
diastolic function, invasive assessment of the two primary components
of diastolic function, left ventricular relaxation and
compliance, is needed.
The degree of impairment in left ventricular relaxation can
be quantified by calculating the time constant of isovolumic
relaxation (tau) from a high fidelity left ventricular pressure
tracing. Impairment in relaxation likely contributes to symptoms
of dyspnea with exercise where brisk relaxation is needed
to enhance early diastolic filling without increased left atrial
pressures. Patients with significantly impaired relaxation are
dependent on left ventricular filling during atrial contraction
(atrial kick) to maintain filling without increased atrial pressure
and thus are prone to develop acute diastolic heart failure associated
with the onset of atrial fibrillation. As the speed and
extent of left ventricular relaxation are very dependent on afterload,
relaxation may become severely impaired with hypertensive
episodes19 and contribute to elevation in mean left atrial
pressures, as is likely the case in patients with a normal ejection
fraction (hypertensive pulmonary edema).20
Assessment of alterations in left ventricular compliance
depends on demonstration of an upward and leftward shift of
the end diastolic pressure volume relationship (LV-EDPVR) such
that the left atrial pressure required to fill the left ventricle to a
normal volume is markedly elevated. Marked reduction in left ventricular compliance is
clearly present in patients
with rare diseases such as
infiltrative cardiomyopathy
due to amyloidosis, in those
with primary restrictive cardiomyopathies,
and in some
patients with hypertrophic
cardiomyopathy. In these
patients, blood pressure is
low, left ventricular volumes
are normal to reduced, and
left atrial pressures are
chronically elevated. Attempts
to lower atrial pressures
with diuretic therapy
often result in hypotension as
left ventricular filling is
dependent on markedly elevated
filling pressures.
Whether the more typical
patients with diastolic heart
failure (who are often hypertensive)
have reduced left
ventricular compliance remains
somewhat controversial.
21 Demonstration of
reduced compliance mandates
the need for the instantaneous assessment of left ventricular
pressure and volume over a range of pressures and volumes
produced by increasing or decreasing preload. Highly
accurate instantaneous assessment of left ventricular volume
and pressure is very difficult to obtain. In humans, use of the
conductance catheter is really the only means of reliably obtaining
such data; although some studies have used echocardiography
and left ventricular pressure tracings. Further, even once
armed with the data defining the LV-EDPVR, the curvilinear
nature of the relationship, which is rarely perfectly monoexponential,
makes it difficult to derive a single parameter that
reflects the steepness and position of the relationship, and
advanced analyses are needed.22
 Figure 5. Doppler echocardiographic assessment of diastolic function. E, peak early filling velocity; A, velocity at atrial contraction; DT, deceleration time; Adur, A duration; ARdur, AR duration; S, systolic forward flow; D, diastolic forward flow; AR, pulmonary venous atrial reversal flow; e’, velocity of mitral annulus early diastolic motion; a’, velocity of mitral annulus motion with atrial systole; DT, mitral E velocity deceleration time. From Redfield et al.25
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Comprehensive Doppler echocardiography can be very useful
in gaining information regarding diastolic function and filling
pressures. Doppler patterns (Figure 5) consistent with
impaired relaxation with normal filling pressure (grade I diastolic
dysfunction), impaired relaxation with moderate elevation
of filling pressures (grade II diastolic dysfunction), impaired
relaxation with severe elevation of filling pressures that can be
reversed with preload-reducing maneuvers (grade III diastolic
dysfunction), or impaired relaxation with severe elevation of filling
pressures that can not be reversed with preload reducing
maneuvers (grade IV diastolic dysfunction) have been described
and validated against invasive assessment of left ventricular
relaxation and filling pressures.23-25 Equating these Doppler
patterns with the severity of diastolic dysfunction makes several
assumptions and paramount among these is that the elevation
of filling pressures detected by these parameters is mediated
by a reduction of left ventricular compliance. Supportive
of this assumption is the fact that this grading system has been
shown to correlate with worsening
prognosis, suggesting
that the elevated filling pressures
reflected in the Doppler
measurements are the result
of progressive ventricular
remodeling and diastolic dysfunction
rather than transient
volume overload. Unfortunately,
this may not be the
case in every patient. Further,
diastolic assessment is somewhat
difficult to perform,
requires informed interpretation,
and is limited by atrial
fibrillation, tachycardia, conduction
defects, and atrial
systolic dysfunction. Left atrial
enlargement may also be a
good indicator of chronic atrial
pressure overload and complements
the Doppler assessment.
Unfortunately, no other
noninvasive assessment of
diastolic function exists.
Although less frequently
performed in clinical practice,
similar Doppler interrogation
of the tricuspid inflow and hepatic vein inflow can be
performed to gain insight into right ventricular diastolic function,
as illustrated in Case 3.
Given the difficulty in accurately characterizing diastolic
function underscored above, few studies have assessed diastolic
function in patients with diastolic heart failure. Invasive
assessment of impaired ventricular relaxation and reduced ventricular
compliance has been demonstrated in a landmark study
of patients with heart failure and normal ejection fraction.17
Another small but elegant invasive study did not demonstrate a
significant alteration in either relaxation or compliance as compared
to elderly hypertensive patients without heart failure
despite the presence of elevated left ventricular diastolic pressures
in heart failure patients.19 However, in these patients
blood pressure and left ventricular diastolic pressure increased
dramatically in association with marked impairment in relaxation
with exercise. In such patients, arterial stiffening, which
promotes labile hypertension and load-dependent diastolic dysfunction,
may be an important mechanism contributing to diastolic
heart failure even if resting diastolic function is not
markedly aberrant. Another study that did not characterize diastolic
function invasively but used Doppler assessment of left
ventricular filling pressures and 3-D echocardiography to assess
volume suggested that volume expansion with normal systolic
and diastolic function may produce the clinical syndrome in
some patients.21 It is quite likely that heart failure with normal
ejection fraction is a heterogeneous condition with multiple
mechanisms contributing to chronic pulmonary venous hypertension.18
Pulmonary Hypertension
That left-sided heart failure is the most common cause of pulmonary
hypertension has long been recognized.26 The passive
effect of pulmonary venous hypertension elevates pulmonary
artery pressure. However, patients also develop “reactive” pulmonary
hypertension with increases in the transpulmonary gradient.
This component of pulmonary hypertension may be related
to humoral factors and endothelial dysfunction in chronic
heart failure associated with severe systolic dysfunction or
mitral stenosis.27 Finally, chronic pulmonary venous hypertension
may lead to congestive pulmonary vasculopathy characterized
by pulmonary arteriolar remodeling with medial hyperplasia
and intimal fibrosis.28 Pulmonary hypertension related to
reactive pulmonary hypertension and/or congestive pulmonary
vasculopathy result in pulmonary hypertension beyond that
associated with the passive effects of pulmonary venous hypertension
and may not be reversible with acute reduction in pulmonary
venous pressures or acute pulmonary vasodilator infusion.
Similarly, if medications have normalized resting PCWP or
if PCWP primarily becomes elevated with exertion or when
blood pressure fluctuates, it may be possible for patients with
diastolic heart failure to have elevated pulmonary arterial pressures
but a normal PCWP at rest at catheterization and provocative
measures may be needed to demonstrate the pulmonary
venous hypertension.
Although common in patients with left heart disease, the
development of pulmonary hypertension is highly variable. The
factors that predispose to development of significant pulmonary
hypertension in the presence of chronic pulmonary venous
hypertension are not fully understood. As noted above, the presence
of humoral activation and endothelial dysfunction likely
play a role. Although early case reports described severe pulmonary
hypertension in patients with diastolic heart failure, the
frequency with which patients with diastolic heart failure develop
pulmonary hypertension and its severity remain poorly
defined.29,30 Klapholz et al described the presence of pulmonary
hypertension in patients with diastolic heart failure in a
larger series of patients with diastolic heart failure and found
that the average right ventricular systolic pressure in patients
hospitalized with diastolic heart failure was 47 mmHg using
Doppler echocardiography.31 In patients with aortic stenosis,
most of whom had a normal ejection fraction, the severity of
diastolic dysfunction rather than the severity of aortic stenosis
correlated best with the severity of pulmonary hypertension and
a significant number of patients developed severe pulmonary
hypertension.32 Similarly, in patients with heart failure and a
reduced ejection fraction (systolic heart failure), it was the
severity of concomitant diastolic dysfunction rather than ejection
fraction or cardiac output that correlated best with the
severity of pulmonary hypertension.33 Thus, diastolic dysfunction
associated with valvular disease, reduced ejection fraction,
or in isolation is the common mediator that results in chronic
pulmonary venous hypertension and secondary pulmonary
hypertension. It is therefore not unexpected that patients with
diastolic heart failure will develop pulmonary hypertension.
It seems reasonable to expect that elderly persons would be
more susceptible to the development of pulmonary hypertension
as age related systemic vascular stiffening has been consistently
reported34-37 and age-related pulmonary artery stiffening
may well occur. Interestingly, age-related increases in
arterial stiffening are worse in women than in men.34,37-40 Thus,
the elderly women patients who develop diastolic heart failure
may also be more prone to developing pulmonary hypertension
in response to chronic pulmonary venous hypertension associated
with diastolic heart failure. Alternatively, some patients
may have a primary pulmonary arteriopathy of late onset and
have concomitant (but unrelated) diastolic dysfunction related
to their age.
Atrial compliance is a little studied factor that may contribute
to the pathophysiology of diastolic heart failure and predispose
to pulmonary hypertension as well. Insight into the role
of atrial compliance comes from early hemodynamic studies
where large left atrial V waves were described in patients with
various cardiac diseases in the absence of mitral regurgitation.
8,9 The large V wave represents large increases in left atrial
pressure in response to the atrial filling that occurs during
ventricular systole (closed mitral valve), and thus reflects
reduced atrial compliance. Although much focus is placed on
left ventricular diastolic pressures in mediating chronic pulmonary
venous hypertension, it is meanleft atrial pressure that
reflects the degree of pulmonary vascular congestion41 and high
left atrial pressure during ventricular systole contributes to elevated
mean left atrial pressure. Indeed, in patients with mitral
stenosis, two recent studies demonstrate that in the absence of
mitral regurgitation, the presence of reduced atrial compliance
as reflected by large atrial V waves was a potent independent
predictor of the severity of pulmonary hypertension in mitral
stenosis.42,43
Left Ventricular Diastolic Dysfunction in
Chronic Right Ventricular Pressure Overload
Chronic right ventricular pressure overload can affect left ventricular
diastolic function in several ways. Changes in left ventricular
relaxation as well as in compliance (characterized by
the LV-EDPVR) have been described.
Left ventricular relaxation is under the triple control of load,
myocardial properties, and the uniformity of load in space and
time.44 In chronic right ventricular pressure overload, the load
on the intraventricular septum is dramatically increased and as
it hypertrophies, the myocardial properties of the septum are
altered. The motion of the intraventricular septum in systole
and diastole is asynchronous. All these factors could contribute
to impairment in global left ventricular relaxation. In Doppler
echocardiographic studies of IPAH, impaired relaxation with
decreased E/A ratio and increased isovolumic relaxation time
and deceleration time have been consistently reported.45-50 An
“impaired relaxation” pattern (grade I diastolic dysfunction) is
usually associated with normal left ventricular filling pressures
and indeed, patients with severe IPAH entered into clinical trials
must have normal PCWP. Thus, based on Doppler echocardiographic
studies, the effect of chronic right ventricular pressure
overload on relaxation appears unassociated with increases
in left ventricular filling pressure.
While patients must have normal PCWP to be diagnosed
with IPAH, there is considerable evidence that chronic right
ventricular pressure overload can cause reduced left ventricular
compliance. The external forces affecting the LV-EDPVR include right ventricular pressure and pericardial pressure.51,52
The effect of right ventricular pressures on the LV-EDPVR is
termed “ventricular interdependence” and is accentuated in
the presence of an intact pericardium. Visner et al. used both
acute and chronic canine pulmonary banding models and
showed that the LV-EDPVR was shifted leftward (decreased
compliance) by acute or chronic right ventricular pressure overload.
53,54 The shift in the LV-EDPVR with acute right ventricular
pressure overload was related to ventricular interdependence
with decreases in left ventricular volume related to leftward
shift of the intraventricular septum as right ventricular pressures
increased. These effects were also apparent in chronic
right ventricular pressure overload, but a decrease in myocardial
compliance (as assessed by the stress-strain relationship)
was also seen. This effect, not seen in acute right ventricular
pressure overload, suggests that chronic right ventricular pressure
overload alters intrinsic left ventricular myocardial properties.
Whether this effect is wholly mediated by the altered intraventricular
system or whether the left ventricular free wall
myocardium also becomes abnormal is unclear. However, Little
et al showed that the effect of right ventricular pressures on the
LV-EDPVR was attenuated in the presence of chronic right ventricular
pressure overload produced by pulmonary artery banding
in the dog.52 Consistent with concepts introduced by
Sunagawa et al, Little’s study showed that when the stiffness of
the septum was greater than the stiffness of the left ventricular
free wall, right ventricular pressures had less effect on the LVEDPVR.
Although this study was performed in the absence of
the pericardium, Blanchard et al showed that the pericardium
remodels in chronic right ventricular pressure overload and that
pericardiotomy did not alter right or left ventricular filling pressures
or cardiac output.55
Although these animal studies and limited studies in the
human56,57 confirm adverse effects of right ventricular pressure
overload on left ventricular diastolic function, the clinical significance
of left ventricular diastolic dysfunction associated
with chronic right ventricular pressure overload is difficult to
appreciate. In the studies of Little and Visner, dogs with acute
and chronic right ventricular pressure overload had left ventricular
diastolic pressures that were not different from those of
control dogs. Although the compliance of the left ventricle was
reduced, it was not reduced enough to result in elevated left
ventricular filling pressures. Similarly, in humans with chronic
pulmonary hypertension related to thromboembolic disease,
indices of left ventricular diastolic compliance were reduced
and improved after thrombectomy, but PCWP was normal both
before and after surgery.57 Lastly, patients entered into IPAH
trials have severe pulmonary hypertension, often with severe
right ventricular remodeling and dysfunction and yet have normal
PCWP. These studies would suggest that while left ventricular
diastolic function is altered in IPAH, it is not perturbed
enough to result in elevated PCWP. However, as most studies
describing hemodynamics in IPAH were performed in the context
of a drug trial (where patients with elevated PCWP are
excluded), the frequency of left ventricular diastolic dysfunction
severe enough to result in elevated filling pressures in
patients with IPAH may be underrecognized.
Strategies for Diagnosing Diastolic Heart Failure
in the Setting of Pulmonary Hypertension
It is likely that diastolic heart failure is an underrecognized
cause of pulmonary hypertension and that otherwise unexplained
dyspnea and pulmonary hypertension in elderly patients
with a normal ejection fraction and normal valves should
prompt consideration of diastolic heart failure as well as IPAH.
Yet, distinguishing between diastolic heart failure with secondary
pulmonary hypertension and IPAH with secondary diastolic
dysfunction can be quite challenging.
Echocardiography may be helpful and evidence of left ventricular
hypertrophy, left atrial enlargement, and Doppler evidence
of advanced diastolic dysfunction (grades II–IV) may
favor the diagnosis of diastolic heart failure. However, not all
patients with diastolic heart failure have echocardiographic evidence
of left ventricular hypertrophy and not all echocardiographic
laboratories perform a comprehensive diastolic assessment
nor measure left atrial volume.
All patients with significant pulmonary hypertension should
undergo right heart catheterization and if the PCWP is elevated
(15 mmHg), a diagnosis of isolated pulmonary arteriopathy
cannot be made even if there is a significant transpulmonary
gradient.58 In patients with an elevated PCWP, one should look
for evidence of systemic hypertension and if present, use of a
systemic vasodilator to lower arterial pressures should be considered.
Prompt reduction in PCWP with normalization of blood
pressure supports the diagnosis of diastolic heart failure.
Provocative testing with exercise in elderly patients with pulmonary
hypertension in whom diastolic heart failure is suspected
may be useful. Marked elevation in PCWP and blood pressure
with exercise would support the diagnosis of diastolic heart
failure that could be causing the patients’ symptoms and their
pulmonary hypertension. Patients with severe IPAH should not
experience increases in PCWP during exercise59. Additionally,
one should look for evidence of reduced atrial compliance (large
V waves in the PCWP tracing). Exercise testing may also be
helpful and if associated with marked increases in PCWP, a
diagnosis of diastolic heart failure would be supported.59
Finally, if diastolic heart failure is strongly suspected, care
should be taken with use of vasodilators that are very selective
for the pulmonary vasculature (such as inhaled nitric oxide) as
increases in right heart output in the presence of a noncompliant
left ventricle may result in further increases in left atrial
pressure and pulmonary edema, as outlined above.10-13
Therapeutic Implications
To date, patients with pulmonary hypertension and a PCWP of
15 mmHg or greater have been excluded from pulmonary arterial
hypertension drug trials. It remains unclear how often
patients with suspected pulmonary arterial hypertension and an
elevated PCWP are treated with new therapies and whether they
experience benefit. Similarly, whether patients with diastolic
heart failure and pulmonary hypertension would benefit from
specific treatment of the pulmonary hypertension is unclear.
Although use of epoprostenol was associated with increased
mortality in patients with systolic heart failure,60 the mechanism
responsible for the increased mortality is unclear and the
outcome in diastolic heart failure, or with alternate agents, may
be different and deserves consideration.
Back to the Patients
Case 1. This patient demonstrates the progressive development
of pulmonary hypertension on a background of longstanding
and fairly well documented diastolic heart failure. We would
speculate that she has secondary pulmonary hypertension and
not IPAH of late onset. While her pulmonary hypertension may
be characterized by some as “out of proportion to her left heart
disease,” without knowledge of severity of her chronic pulmonary
venous hypertension, one can not conclude that is the
case. Certainly, chronic pulmonary venous hypertension related
to mitral stenosis (the ultimate diastolic dysfunction) can result
in severe pulmonary hypertension that is accompanied by
increased transpulmonary gradient and that can take months to
years to resolve after treatment of mitral stenosis.
Treatment for diastolic heart failure is supportive as no therapy
has been documented to improve outcomes in this condition.
Thus, consideration of specific therapy for pulmonary
hypertension in such patients is not unreasonable. As the use of
agents for IPAH have been expanded to patients with pulmonary
hypertension related to connective tissue disease, expansion to
use in patients with diastolic heart failure and secondary pulmonary
hypertension would be a reasonable avenue for investigation.
However, the potential for worsening pulmonary congestion
must be recognized, as was observed in this patient.
Case 2. This patient demonstrates a milder form of pulmonary
hypertension secondary to diastolic heart failure. In this
case, the pulmonary hypertension is largely related to the passive
effect of the pulmonary venous hypertension and is acutely
reversible. The diagnosis of diastolic heart failure with secondary
pulmonary hypertension is much easier to make in this
instance.
Case 3. This patient has IPAH and has diastolic dysfunction
but does not have elevated PCWP. The impairment in left ventricular
relaxation mediated by the abnormal septum and septal
motion causes characteristic changes in the left ventricular
diastolic parameters that are generally associated with normal
filling pressures at rest. Although decreases in left ventricular
compliance related to ventricular interdependence have been
described in animal models, and could lead to elevated left ventricular
filling pressures, elevated left ventricular filling pressures
are not commonly seen in patients with IPAH. However,
as formal assessment of left ventricular compliance with pressure
volume analysis over a range of preloads was not performed
in this patient, we can not exclude the presence of
decreased compliance with normal PCWP related to decreased
filling as a result of her severe pulmonary hypertension and
right ventricular dysfunction. In contrast, she has severe right
ventricular systolic and diastolic dysfunction with elevated right
ventricular diastolic pressure.
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