CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 4, July/August 2010
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AFRICA
authors observed a statistically significant percentage of patients
with clinical diagnosis of heart failure and normal ejection frac-
tion (EF
>
45%) to be suffering from abnormalities in active
relaxation or passive compliance.
18,19
The degree of involvement that left ventricular diastolic
dysfunction plays in preserved ejection fraction heart failure is
debatable and has been the major argument made by those that
believe diastolic heart failure is the correct diagnosis for patients
with heart failure and normal ejection fraction, given that these
patients do not suffer from significant valvular, pericardial or
pulmonary disease. Left ventricular diastolic dysfunction has
also been found to be present in patients with heart failure and
reduced ejection fraction, a form of heart failure that was origi-
nally believed to be mainly secondary to a systolic dysfunction
pathophysiology.
20
Clinical studies in patients with diastolic dysfunction
In 1972 Gaasch and colleagues performed some of the first stud-
ies to evaluate the possible effects of left ventricular diastolic
dysfunction. The authors described that left ventricular diastolic
dysfunction has a negative impact on systolic function through
its limitation of the Frank-Starling mechanism.
21
Patients with
conditions such as left ventricular hypertrophy have elevated left
ventricular end-diastolic pressure and decreased compliance,
which affects the length–tension relationship by decreasing
muscle fibre stretch at any given peak systolic stress. This might
explain why decreased exercise tolerance is one of the first clini-
cal symptoms associated with echocardiographically diagnosed
diastolic dysfunction.
Exercise tolerance in patients with left ventricular diastolic
dysfunction who are asymptomatic at rest may be compromised
secondary to the inability to enhance diastolic filling by the
degree necessary to increase the cardiac output during exercise
without causing an abnormal elevation in left atrial pressure.
Diastolic dysfunction has been found to be aggravated by exer-
cise, especially with an increase in blood pressure. Recent stud-
ies have observed the development of left ventricular diastolic
dysfunction in the presence of hypertension prior to the devel-
opment of ventricular hypertrophy.
22,23
Left ventricular diasto-
lic dysfunction can therefore represent myocardial end-organ
damage prior to progression to clinically relevant heart failure,
although further trials are needed to support this hypothesis.
The magnitude of asymptomatic left ventricular diasto-
lic dysfunction in the general population is still unclear. In an
attempt to determine the prevalence of pre-clinical diastolic
dysfunction, Redfield
et al
. performed a cross-sectional survey
of 2 042 randomly selected residents over the age of 45 years
in Olmsted County, Minnesota.
24
The authors found the preva-
lence of asymptomatic echocardiographically diagnosed diasto-
lic dysfunction to be 28%, with an increased prevalence seen
in older patients, diabetics, and in patients with cardiovascular
disease (hypertension, coronary artery disease, cardiomyopa-
thies).
A prospective trial in 206 patients with the clinical diagnosis
of heart failure (NewYork Heart Association Grade II or higher)
reported that, based on echocardiographic parameters, 91% of
102 patients with an EF greater than 50% had some degree of
diastolic dysfunction, and 92% of 71 patients with an EF of
less than 40% suffered from left ventricular diastolic dysfunc-
tion.
25
Patients with reduced ejection fraction were more likely
to have moderate to severe diastolic dysfunction in comparison
to patients with preserved ejection fraction (27 vs 62%, respec-
tively).
In patients with heart failure with preserved EF, left ventricu-
lar diastolic dysfunction was accompanied by left ventricular
hypertrophy, while in patients with heart failure and reduced EF,
left ventricular diastolic dysfunction was associated with left
ventricular dilation and marked systolic dysfunction. The overall
prognosis and mortality appears to be significantly influenced by
the degree of left ventricular diastolic dysfunction in heart failure
patients, regardless of ejection fraction.
26
Clinical studies in patients with diastolic heart failure
The American College of Cardiology and the American Heart
Association (ACC/AHA) Task Force has previously stated that
a definitive diagnosis can be made in heart failure patients with
preserved EF if there is a decreased rate of ventricular relaxa-
tion with elevated LV filling pressure, clarifying the need for
coexistence of normal contractility (LV systolic function) and
LV volume.
27
In further assessing such assumptions, Baicu
et al.
compared 75 patients with heart failure and normal ejection frac-
tion with 75 patients without cardiovascular disease.
After analysing both echocardiographic parameters and
data derived from cardiac catheterisation, it appeared that left
ventricular systolic function, contractility and performance was
intact in patients with presumed diastolic heart failure (with
normal ejection fraction).
28
In a review of data on left ventricular
structure and function in heart failure patients with normal ejec-
tion fraction and hypertension, Zile and Lewinter have argued
that left ventricular end-diastolic volume is within the normal
range in patients with diastolic heart failure.
29
The frequently quoted CHARM-preserved trial was one of
two large trials, studying a total of 3 023 patients with heart
failure with preserved EF of more than 40%, treated with the
angiotensin receptor blocker candesartan.
30
After a median
follow up of 36.6 months, fewer candesartan-treated patients
were hospitalised for heart failure compared with the placebo
group (402 vs 566,
p
=
0.014), but there was no significant
difference with regard to cardiovascular mortality. As an impor-
tant finding on the side, a significant 40% reduction was seen
in the development of new diabetes mellitus in the candesartan
group compared with the placebo group (4 vs 7%,
p
=
0.005).
This has gained even more interest in view of recently published
data on diabetes as an independent predictor of cardiovascular
morbidity and mortality in heart failure patients, regardless of
their EF,
31
underlining the importance of controlling risks and
co-morbidities in patients with diastolic heart failure.
The I-PRESERVE trial, published in 2008, studied 4 128
heart failure patients 60 years of age and older with an EF of at
least 45% who were randomly assigned to receive 300 mg of the
angiotensin receptor antagonist irbesartan or placebo. Primary
event rates as assessed as a composite of death from any cause
or hospitalisation for a cardiovascular cause in the irbesartan and
placebo groups were 100.4 and 105.4 per 1 000 patient-years,
respectively,
32
which was not significantly different. In conclu-
sion, neither candesartan (in the CHARM preserved trial) nor
irbesartan (in I-PRESERVE) improved survival in these large
trials in patients with pure diastolic heart failure.
