Download Diastolic Heart Failure and Critical Illness

Diastolic Heart Failure and Critical Illness
R. Pirracchio and A. Mebazaa
z Introduction
Diastolic heart failure is a common entity the frequency of which is widely underestimated. Some data available in the literature suggest that nearly half the patients
with congestive heart failure (CHF) have preserved left ventricular (LV) ejection
fraction (LVEF > 50%) [1±4]. If CHF is clearly defined as a pathophysiological state
in which the heart is unable to pump blood at a rate commensurate with metabolic
demand or to do so only from an elevated filling pressure, several guidelines have
proposed that the diagnosis of CHF should require objective evidence of LV dysfunction, like an echographic measurement of LVEF [5]. As echographic signs of
diastolic heart failure are of poor sensibility and specificity, the use of such criteria
in the diagnosis of CHF leads to an underestimation of the frequency of diastolic
heart failure. Nevertheless, more than a pathophysiological distinction, differences
between systolic and diastolic heart failure are of clinical importance since diastolic
heart failure is supposed to be associated with a better long-term survival than
CHF [6, 7].
Very limited data are actually available concerning the clinical relevance of diastolic heart failure in the critical care setting. We will try to clarify those situations
of critical illness where identifying and treating diastolic heart failure could be of
clinical importance.
z Definitions and Diagnosis
Similar to systolic heart failure, diastolic heart failure is described as a chronic disease during which some acute decompensations can occur. These acute events can
either be de novo or appear during the evolution of the CHF.
Chronic Diastolic Heart Failure
Since the early 90s, various guidelines have been published in order to clarify the
definition and the diagnosis of diastolic heart failure [7±10]. According to the
American College of Cardiology and the American Heart Association, ªthe diagnosis of diastolic heart failure is generally based on the finding of typical symptoms
and signs of heart failure in patients with preserved left ventricular ejection fraction and no valvular abnormalities on echocardiographyº [9]. For the Study Group
on diastolic heart failure of the European Society of Cardiology, a diagnosis of dia-
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stolic heart failure should be made only in case of ªevidence of abnormal left ventricular relaxation, diastolic distensibility or diastole stiffnessº [7].
Vasan and Levy tried to rationalize the diagnosis with pragmatic criteria which
are not yet widely used in the cardiologic literature [8]. They separated three sequential steps for the diagnosis: (1) diagnosis of CHF, (2) preserved systolic LV
function (LVEF > 50%), (3) documentation of LV diastolic dysfunction if feasible.
Accordingly, the authors proposed to classify subjects suspected of suffering from
diastolic heart failure into three groups:
1) `definite diastolic heart failure', for patients with clinical evidence of CHF, objective evidence of preserved LVEF within 72 hours of the CHF event, and documentation of LV diastolic dysfunction
2) `probable diastolic heart failure', for patients having clinical evidence of CHF,
preserved LVEF without documentation of LV diastolic dysfunction (after exclusion of valvular diseases or core pulmonale)
3) `possible diastolic heart failure', for patients with clinical evidence of CHF, objective evidence of preserved systolic LV function but not at the time of the
CHF event, and no evidence of diastolic LV dysfunction.
A clinical setting typical of diastolic heart failure (Table 1) can upgrade a patient
from a `possible' to a `probable' diastolic heart failure.
Whether the diagnosis of diastolic heart failure requires some objective evidence
of diastolic failure still remains controversial. Zile et al. recently provided a prospective comparison of cardiac catheterization and echocardiography in patients
suspected of having diastolic heart failure (CHF symptoms and LVEF > 50%) [11].
The authors concluded that ªobjective measurement of LV diastolic function serves
to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without measurement of parameters that
reflect LV diastolic functionº [12].
Finally, from a clinical point of view, diastolic heart failure can be responsible
for symptoms that occur at rest, with less than ordinary physical activity, or with
ordinary physical activity. Thus, New York Heart Association classification (NYHA)
can be used in diastolic heart failure as well as in systolic heart failure. Of note, the
global incidence of diastolic heart failure may be underestimated if paraclinical investigations are only made at rest (see below).
Table 1. Reasons to upgrade diagnosis from possible diastolic heart failure to probable diastolic heart
failure [8]
z Markedly elevated blood pressure (systolic BP > 160 mmHg or a diastolic BP > 100 mmHg) during
the episode of heart failure
z Echocardiographic concentric LV hypertrophy without wall-motion abnormalities
z A tachyarrhythmia with a shortened diastolic filling period
z Precipitation of event by the infusion of a small amount of intravenous fluid
z Clinical improvement in response to therapy directed at the cause of diastolic dysfunction (such as
lowering blood pressure, reducing heart rate, or restoring the atrial booster mechanism)
Diastolic Heart Failure and Critical Illness
Acute Decompensation of Diastolic Heart Failure
In critical illness, limited data are available in the literature. Diastolic heart failure
definition in critical illness is basically the same as in CHF and the diagnosis is
also based on the association of heart failure symptoms and a preserved LVEF. The
factors that promote fluid overload and precipitate heart failure are similar in diastolic heart failure and systolic heart failure [13].
If we consider acute diastolic heart failure as a pathological situation leading to
an impairment in LV diastolic filling, numerous clinical situations could be considered as acute diastolic dysfunction. For example, acute tamponade, acute right
heart failure, or acute mitral regurgitation may lead to LV filling abnormalities
[14]. Acute settings discussed below are those in which LV diastolic properties are
truly impaired. This includes acute exacerbation of chronic diastolic heart failure,
hypertensive crisis, severe sepsis, and myocardial ischemia.
z Epidemiology
It seems clear that the prevalence and the prognosis of diastolic heart failure are
highly dependant on age, gender, and above all the method used to diagnose diastolic heart failure.
Masoudi et al. [15] published in 2003 an epidemiological study in which 19 710
patients suffering from heart failure were analyzed. Thirty five percent had preserved LVEF. Among them, 79% were women, whereas only 49 of the 65% suffering
from systolic heart failure were women. Patients with diastolic heart failure were
1.5 years older than those with impaired ejection fraction.
Zile and Brutsaert [16] reviewed the data published during the last decade and
found that: in patients < 50 years, diastolic heart failure represented < 15% of the
cause of CHF; 50±70 years, the proportion rose to 33%, and > 70 years, up to 70%
of the CHF were due to diastolic heart failure.
The morbidity from diastolic heart failure remains very high, with a 1-year readmission rate approaching 50%. The morbidity varies according to age and underlying diseases [16, 17]. Data published in the early 90s reported less annual mortality
in diastolic heart failure than in systolic heart failure: 5 to 8% in diastolic heart
failure versus 10 to 15% in systolic heart failure [18, 19]. More recent studies have
reported higher mortality rates. Chen and colleagues [20] analyzed all inhabitants
of Olmsted County, Minnesota, between 1996 and 1997 with a new diagnosis of
diastolic heart failure. They reported mortality rates as high as 29% at 1 year, 39%
at 2 years, and 60% at 3 years. Again, it appears that age and the criteria chosen
for the diagnosis of diastolic heart failure can strongly affect the mortality rates.
z Pathophysiology of Diastolic Heart Failure
Left Ventricular Pressure/volume Relationship
Systolic, diastolic, and combined heart failure are commonly described using the
plotting of LV pressure-volume (P/V) loops.
In case of diastolic dysfunction (Fig. 1), the LV chamber is unable to fill at low
left-atrial pressures resulting in abnormalities in the P/V relationship during diastole. The diastolic P/V curve (compliance curve) is displaced upward and to the
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Fig. 1. Modification of the pressure/volume loop in
heart failure with normal ejection fraction (HFNEF)
also named diastolic heart failure, associating a
shift in the end-diastolic pressure-volume relationship (EDPVR) without any change in the endsystolic pressure-volume relationship (ESPVR).
From [46] with permission
Fig. 2. Pressure/volume (P/V) loops in two patients
with diastolic heart failure before (dashed line) and
after (dark solid line) sustained isometric handgrip.
From [21] with permission
left. Thus, for a given end-diastolic volume, end-diastolic pressures (also assessed
by the pulmonary artery occlusion pressure [PAOP]) are increased. Kawaguchi et
al. [21] recently demonstrated that although normal at baseline, P/V loops can be
altered during effort. Maneuvers like sustained isometric handgrips can uncover a
NYHA stade 2 diastolic heart failure (Fig. 2).
Diastolic Heart Failure and Critical Illness
Fig. 3. Left ventricular (LV) pressure/volume loops in combined systolo-diastolic
heart failure. LVEDP: left ventricular enddiastolic pressure
In case of systolic dysfunction (Fig. 3), LV contractility is depressed resulting in
abnormalities in the P/V relationship during systole. The end-systolic P/V slope
(LV systolic elastance slope) is shifted downward and to the right. In addition, the
LV end-systolic and end-diastolic volumes are increased. The P/V loop is shifted
upward and to the right but remains on the same diastolic P/V curve (LV compliance curve).
Some patients may have combined systolic and diastolic dysfunction (Fig. 3): a
modest increase in end-diastolic volume may result in a large increase in end-diastolic pressure if ventricular chamber compliance is markedly altered.
Diastole: New Concepts
According to Zile and Brutsaert [16], diastole can be defined as ªthe time period
during which the myocardium loses its ability to generate force and shorten and
returns to an unstressed length and forceº. Basically, this period represents the part
of heart revolution during which the ventricles are filling. Thus diastolic heart failure occurs when the ventricular chamber is unable to accept a volume of blood sufficient to maintain cardiac output at normal diastolic pressures.
The diastole process can be divided into two phases: the first represents LV pressure decline at constant volume, so called isovolumic relaxation; the second is LV
chamber filling so called auxotonic relaxation. From a cellular point of view, relaxation is a high energy-consuming process. Release of calcium from troponin C, detachment of the actin-myosin cross-bridge, phosphorylation of phospholamban
necessary to activate the ATPase-induced calcium sequestration into the sarcoplasmic reticulum, sodium/calcium exchanger-induced extrusion of calcium from the
cytoplasm, and return of the sarcomere to its rest length are all energy consumers.
Zile et al. recently performed a multicenter, prospective study using cardiac catheterization and echocardigraphy to assess the diastolic properties of the left ventricle in 47 patients suffering from diastolic heart failure and 10 normal controls [22].
The authors concluded that diastolic heart failure is characterized by alteration of
both LV active relaxation and passive stiffness that could be assessed by the following measures (Fig. 4):
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Fig. 4. Diagram of the method used to correct the measured value of left ventricular minimal diastolic
pressure for slow relaxation rate. Assuming the physiological concept that active relaxation could be completed after 3.5 s [47], it is possible to plot the decrease in the left ventricular pressure from the point of
aortic valve closure to the theoretical time at which ventricular pressure would approach zero in the absence of filling. By measuring the time from the closure of the aortic valve to Pmin, it is possible to determine the contribution of active relaxation to the left ventricular minimal pressure (Pmin). Thereafter,
by subtracting the pressure contribution of slowed relaxation from Pmin, it is possible to obtain a corrected pressure tracing and Pmin, which are used to calculate the corrected passive-stiffness constant.
From [22] with permission
z
z
z
z
s is the time constant of the isovolumic relaxation
Pmin is the LV minimal pressure after the opening of the mitral valve
PPre-A is the LV pressure just before atrial contraction
EDP is the end-diastolic pressure just after the atrial contraction.
Zile and colleagues [22] showed that in diastolic heart failure, in contrast to normal
subjects, relaxation was incomplete at the time of Pmin. Thus, s was abnormal and
Pmin increased with a positive correlation between s and Pmin. In their study, incomplete relaxation accounted for 7 Ô 1 mmHg of the measured Pmin. The authors
also reported increased EDP and decreased end diastolic volume (EDV), suggesting
increased ventricular stiffness in diastolic heart failure patients. These data suggest
that patients with heart failure and preserved ejection fraction have significant abnormalities in both active relaxation and passive stiffness.
Diastolic Heart Failure and Critical Illness
Antithesis: More than a Specific Alteration of Diastole?
Some authors recently emphasized that while diastolic parameters are often abnormal in heart failure with normal ejection fraction, they are not necessarily the major component of the dysfunction, nor do they necessarily explain the clinical features. Leite-Moreira et al. remind us that any rise in LV afterload can affect diastole
by prolonging relaxation, compromising filling and elevating end-diastolic pressures [23].
Kawaguchi et al. measured LV P/V relations in 10 patients supposedly suffering
from diastolic heart failure, 9 asymptomatic normotensive age-matched subjects, 14
asymptomatic normotensive young subjects, and 25 age- and blood-pressurematched controls [21]. The authors reported a significant increase in both arterial
and end-systolic elastance (Ees, Ea) in diastolic heart failure patients and a positive
correlation between these two parameters. End-diastolic P/V relations were shifted
upward in diastolic heart failure patients but this study clearly emphasizes the fact
that end-diastolic P/V relation shift depends on the loading conditions. On the basis of such results, the authors discussed the following hypothesis: diastolic heart
failure is essentially due to a combined increase in Ees and Ea. This can influence
heart function in several ways: limitation of contractile reserve, high systolic pressure sensitivity to cardiac loading leading to huge hypertensive responses during
exertion, increase in myocardial energy consumption, and delay in ventricular
chamber relaxation. According to Kawaguchi et al., diastolic dysfunction is present
in CHF with normal ejection fractions, but the nature of end-diastolic P/V relations
are highly dependent on loading conditions and not merely due to diastolic dysfunction.
z Clinical Presentations
Chronic Diastolic Heart Failure
Diastolic heart failure generally occurs in women, in the elderly (50% after 70 years
of age), and in those with a history of hypertension. Apart from this, the clinical
presentation of diastolic heart failure has no other specificity and the diagnosis is
made based on the presence of symptoms of heart failure with preserved systolic
function. Table 2 summarizes the prevalence of specific symptoms of CHF in systolic versus diastolic heart failure [16]. The most frequent causes of diastolic heart
failure are listed in Table 3 [24].
Diastolic Heart Failure in Acute Situations
Acute Hypertensive Crisis: Ghandi and colleagues [25], recently performed a prospective observational study focusing on echocardiographic profiles at H0, H24 and
H72 in patients presenting with acute pulmonary edema and severe arterial hypertension. They wanted to test the hypothesis that such patients suffer from a transient LV systolic dysfunction due to the hypertensive crisis. By contrast to their initial hypothesis, they found that the LVEF and the regional wall motion were similar
during the acute episode and after 24 and 72 h of adequate treatment. Moreover
50% of their patients had preserved ejection fraction (LVEF > 50%) and 89% of the
patients who had a preserved ejection fraction after treatment also had no sign of
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Table 2. Prevalence of specific symptoms and signs in systolic (SHF) vs diastolic (DHF) heart failure [16].
Data are expressed as percent of patients in each group presenting with the specified symptom or sign
Symptoms
z Dyspnea on exertion
z Paroxysmal nocturnal dyspnea
z Orthopnea
Physical examination
z Jugular venous distension
z Rales
z Displaced apical impulse
z S3
z S4
z Hepatomegaly
z Edema
Chest radiograph
z Cardiomegaly
z Pulmonary venous hypertension
DHF (EF > 50%)
SHF (EF < 50%)
85
55
60
96
50
73
35
72
50
45
45
15
30
46
70
60
65
66
16
40
90
75
96
80
EF: ejection fraction
Table 3. Major causes of diastolic heart failure [24]
Myocardial
z Impaired relaxation
± Epicardial or microvascular ischemia
± Myocyte hypertrophy
± Cardiomyopathies
± Aging
± Hypothyroidism
z Increased passive stiffness
± Diffuse fibrosis
± Post-infarct scarring
± Myocyte hypertrophy
± Infiltrative (e.g., amyloidosis, hemochromatosis, Fabry's disease)
Endocardial
z Fibroelastosis
z Mitral or tricuspid stenosis
Epicardial/Pericardia
z Pericardial constriction
z Pericardial tamponade
Coronary microcirculation
z Capillary compression
z Venous engorgement
Other
z Volume overload of the contralateral ventricle
z Extrinsic compression by tumor
Diastolic Heart Failure and Critical Illness
systolic dysfunction during the acute episode. Similarly, in patients with an impaired ejection fraction, no differences were found between H0, H24 and H72, suggesting that acute diastolic failure may play a major role also in patients with baseline systolic dysfunction. The pathophysiology of transient diastolic heart failure in
hypertensive crisis remains poorly understood but it seems like diastolic heart failure could be uncovered by an acute hypertensive crisis. In case of diastolic heart
failure at rest, it is clear that a small increase in LV end-diastolic volume (LVEDV)
will lead to a marked elevation in LV end-diastolic pressure (LVEDP). But the explanation is less clear in patients without any diastolic dysfunction at rest. Some
authors proposed that hypertensive crisis would lead to a huge increase in coronary
perfusion pressure and thus in coronary turgor [26]. Nevertheless, it is unlikely that
an increase in coronary blood volume can cause by itself a significant increase in
wall thickness.
Myocardial Ischemia: Pennock and colleagues [27] analyzed by echocardiographic
and Doppler studies early and late hemodynamic consequences of a circumflex artery ligation in a rabbit model. One hour after the experimental infarct, the rabbits
exhibited significant alteration of the LV filling pattern: decrease in E and A waves,
A wave reversal velocities, and increase in the mean pulmonary venous systolic-todiastolic ratio. Three weeks after the coronary ligation, the rabbits still exhibited
significant abnormalities in filling pattern. Stugaard and colleagues [28] assessed
LV diastolic function in 20 patients during coronary angioplasty and in 8 anesthetized dogs during an experimental coronary occlusion. Diastolic function was explored using a recent Doppler technology, called M-mode Doppler, which allows
determination of the time difference between the occurrence of the peak velocity in
the apical region and in the mitral tip. The authors reported, in their patients, a
significant increase in time difference in comparison with normal values. Coronary
artery occlusion in dogs resulted in the same increase in time difference. Moreover,
the evolution in time difference was significantly correlated with the variation in
time constant of isovolumetric relaxation. Interestingly, the authors tried to investigate whether the changes in filling patterns were associated with ischemic induced
tachycardia, increase in intracavitary pressures, or reduction in stroke volume
rather than with the ischemic process itself. To answer this question, they performed successively pacing tachycardia, volume loading and caval restriction. None
of these procedures significantly altered the time difference.
Sepsis: The role of diastolic dysfunction in septic patients has been questioned
since the late 1980s. Stahl et al. showed in 1990 that, in a canine model of hyperdynamic sepsis, myocardial compliance was significantly altered [29]. Jafri et al. published, in the same year, a transmitral Doppler analysis of 13 patients in septic
shock, 10 with sepsis without shock, and 33 controls. They reported that, in septic
shock as well as in sepsis without shock, the LV filling pattern was significantly altered in comparison with controls [30]. More recently, Poelaert and colleagues [31]
characterized systolic and diastolic function in 25 consecutive patients in vasopressor dependant septic shock, using transesophageal echocardiography (TEE) and
pulmonary artery catheters. They found that 8 of the 25 patients had no regional
wall motion abnormality and a normal LV filling pattern (transmitral E/A wave ratio > 1; pulmonary vein S/D wave ratio > 1); 11 had evidence of abnormal left auricular filling (S/D < 1) but with a preserved systolic function and E/A wave ratio. According to the investigators, transmitral flow in this group could be considered as
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`pseudo-normalized'. Finally, 6 of the 25 patients exhibited both systolic and diastolic dysfunction. The authors concluded ªcardiac effects of septic shock can be expressed in various degrees, ranging from a normal pattern, through diastolic dysfunction up to both poor LV systolic and diastolic function resulting in combined
cardiogenic-septic shockº [31]. It should also be emphasized that impairment of
diastolic properties could be an independent predictor of mortality in severe sepsis
[32].
z Supplementary Investigations
Cardiac Catheterization
The gold standard for the diagnosis of diastolic heart failure is still cardiac catheterization with the assessment of increased ventricular filling pressures at normal
chamber volumes and preserved systolic function. With the use of a high-fidelity
micromanometer catheter, it is possible to acquire various data including LV pressure, rate of LV pressure decline (dP/dt), and the time constant of isovolumic relaxation (s).
Diastolic heart failure is characterized by a rise in LVEDP. Zile et al. found a
LVEDP above 16 mmHg in 92% of patients with heart failure and normal ejection
fraction [12]. Relaxation abnormality is characterized by an increase in the time
constant of isovolumic relaxation. In the series of Zile et al., s was abnormal
(³ 48 ms) in 79% of the patients.
Chamber stiffness can be assessed by analyzing the diastolic P/V relationship;
the stiffness is represented by the slope of the tangent drawn to the curve at any
point. Thus, operating stiffness changes throughout filling: lower at the beginning,
higher at the end. If LV stiffness increases, the P/V curve is shifted upward and to
the left, so that at any point the slope of the tangent becomes steeper.
Echocardiography
Echocardiography provides some fundamental information, such as the normality
of LVEF (LVEF > 50%). As demonstrated by Gandhi et al., measurements of ejection
fraction even performed several days after an episode of acute exacerbation of CHF
correlate with acute measurements [25].
Several echographic criteria have been studied in order to provide a non-invasive assessment of LV diastolic function. The first is the mitral inflow profile. This
flow usually has two components: the E wave, which reflects early diastolic filling,
and the A wave, which represents the subsequent contribution from atrial systole.
These waves are influenced by LV relaxation, LV compliance, and atrial pressure.
Normal diastole is characterized by a predominant E wave, showing that most of
the LV filling occurs during the early phase of diastole. Mitral inflow abnormalities
are of three types:
z in mild diastolic dysfunction, relaxation is impaired, and atrial contraction contributes relatively more to ventricular filling: A wave > E wave, with prolonged E
wave deceleration time (usually > 240 ms)
z in moderate diastolic dysfunction, relaxation is impaired, LV compliance is decreased, and atrial pressure increased: pseudonormal pattern with an E wave
again predominant, but the E wave deceleration time is shorter
Diastolic Heart Failure and Critical Illness
z in severe diastolic dysfunction, LV compliance is extremely low: restrictive pattern with high E wave velocity, usually more than twice the A wave velocity.
Zile et al. reported a lack of sensitivity of the mitral inflow analysis for the diagnosis of diastolic heart failure. In their study [12], the E/A ratio was abnormal in only
48% of the patients presenting signs of CHF with a normal ejection fraction. The E
wave deceleration time was found to be more sensitive (abnormal in 64% of the patients).
Pulmonary vein flow can also be measured. There are two waves of pulmonary
vein flow, one during systole, the other during diastole. The elevation of the left atrial pressure impairs atrial filling and the pulmonary vein diastolic wave becomes
predominant. Nevertheless, pulmonary vein flow abnormalities poorly discriminate
systolic and diastolic heart failure.
New, promising modalities like Doppler tissue imaging or color M-mode mitral
flow propagation wave need to be validated [33, 34].
Other: Neuroendocrine Profile
B-type natriuretic peptide (BNP) is now recognized as a specific marker of heart failure in patients presenting with acute dyspnea [35]. This peptide also seems to be of
interest for the distinction of diastolic heart failure and lung disease in emergency settings. In a study by Maisel et al., when patients with diastolic heart failure were compared with patients without CHF, a BNP value of 100 pg/ml had a sensitivity of 86%, a
negative predictive value of 96%, and an accuracy of 75% for detecting abnormal diastolic dysfunction [36]. In this series, patients with diastolic heart failure had significantly lower BNP levels than those with systolic heart failure (413 pg/ml vs 821 pg/ml,
p < 0.001). Nevertheless, the authors concluded that BNP adds a modest discriminatory value in differentiating diastolic from systolic heart failure.
z Treatment
Very few data are currently available concerning the therapeutic strategy for diastolic heart failure. The guidelines are essentially based on pathophysiological concepts and on a small number of prospective clinical trials.
General Treatment
The general treatment of diastolic heart failure has two major goals: to limit the
consequences of the cardiac filling abnormalities and to control the factors responsible for the diastolic dysfunction.
Symptom-targeted therapy should focus on the reduction of pulmonary congestion at rest and during exercise. The two ways of reducing pulmonary capillary
pressure are to optimize blood volume and to improve LV filling. LV diastolic pressures can be substantially decreased by the reduction in LV diastolic volumes. Indeed, because of the steep diastolic P/V relation, a small decrease in diastolic volume can lead to a great decrease in diastolic pressure. Thus, diuretics to reduce
global blood volume and nitrates to decrease central blood volume could be considered as a first step of symptomatic treatment. The second step of symptom-tar-
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geted therapy should focus on improving diastolic filling. Therefore, heart rate control should be considered as a major issue. In fact, tachycardia and non-sinus
rhythms are poorly tolerated in patients with diastolic heart failure. First, rapid
heart rates induce an increase in myocardial oxygen consumption, and a decrease
in coronary perfusion time, both promoting myocardial ischemia even in the absence of underlying coronary disease. Second, tachycardia may shorten diastolic
time and thus lead to an incomplete filling. Third, recent data suggest that, in diastolic heart failure, relaxation velocity does not increase in response to tachycardia
and may even decrease. This may contribute to the elevation of the end diastolic
pressures. Furthermore, the loss of sinus rhythm and thus atrial systole is usually
poorly tolerated. Beta-blockers, nondihydropyridine calcium-channel blockers like
verapamil can be prescribed in order to prevent tachycardia and to improve filling
[37, 38]. Finally, it is still not clear whether digitalis may be of interest in the treatment of diastolic heart failure. In the Digitalis Investigation Group trial, the subgroup of patients with normal ejection exhibited fewer symptoms and lower hospitalization rates under digitalis treatment. As long as the pathophysiological interest
of digitalis drugs remains unclear in diastolic heart failure, more evidence is
needed of their effects before extending their use to these patients.
Specific Treatment
The renin-angiotensin-aldosterone system seems to play a great role in the development of diastolic heart failure and particularly in myocardial remodeling and in
fluid retention. Naturally, ACE inhibitors, angiotensin receptor antagonists, and aldosterone antagonists have been proposed in the treatment of diastolic heart failure. A small short-term study performed by Aronow and colleagues focused on the
effect of enalapril on diastolic heart failure in elderly patients with prior myocardial
infarction [39] and reported a benefit in terms of exercise capacity. The CHARMpreserved study was a multicenter, randomized, double blinded study comparing,
in diastolic heart failure, the effects of a selective angiotensin-receptor blocking
agent (candesartan) versus a placebo [40]. Between 1999 and 2000, 3023 patients
NYHA class II to IV, with a LVEF higher than 40% were enrolled in the study
(1514 in the candesartan group, 1509 in the placebo group). After 36 months of follow-up, the authors could only conclude that candesartan significantly reduced the
rate of hospitalization. No other differences were observed between the two groups.
Losartan, another angiotensin-receptor blocker has been shown to increase exercise
tolerance [41].
New agents targeting intracellular calcium homeostasis are currently under evaluation. MCC-135 is one of these drugs, which is supposed to improve calcium reuptake by the sarcoplasmic reticulum. MCC-135 is currently under evaluation in a
phase II, double-blind, placebo-controlled study in patients suffering from CHF
NYHA II and III and either systolic or diastolic heart failure [42].
Levosimendan is a calcium sensitizer modulating the interaction between troponin and calcium. This inotropic drug has recently been proposed to improve cardiac performance after an acute episode of myocardial ischemia [43]. Twenty-four
patients were randomized after percutaneous angioplasty to receive either placebo
or levosimendan. In the treated group, LVEDV and the time constant of isovolumic
LV pressure fall significantly decreased, indicating an obvious improvement in the
diastolic function.
Diastolic Heart Failure and Critical Illness
Finally, nitric oxide (NO)-donor effects have also been investigated. Paulus et al.
[44] performed intracoronary injections of sodium nitroprusside in normal hearts.
The authors showed that NO-donors caused an earlier onset of LV relaxation, a fall
in LV minimum and end-diastolic pressures, an increase in LVEDV and a down
and rightward displacement of the LV diastolic P/V relation. These results are consistent with a direct NO-induced improvement in diastolic function. Interestingly,
the stimulation of endogenous NO release from the coronary endothelium, by intracoronary infusion of a substance P agonist, produced similar results [45].
z Conclusion
In summary, diastolic heart failure is a very common pathology, the incidence of
which is frequently underestimated. While diastolic heart failure is recognized as
the mechanism involved in CHF with a preserved LV function, it seems that diastolic dysfunction can also account for acute heart failure occurring in critical care
situations. Hypertensive crisis, sepsis, and myocardial ischemia are frequently associated with acute diastolic heart failure. The diastolic dysfunction can affect either
active relaxation, passive stiffness, or both. With a better understanding of cardiomyocyte function, intracellular calcium metabolism impairment appears to be involved frequently in the development of diastolic failure. Symptomatic treatment focuses on the reduction of pulmonary congestion and the improvement of LV filling.
Specific treatments are lacking, but encouraging data are emerging concerning the
use of renin-angiotensin-aldosterone axis blockers, NO donors, or new agents such
as levosimendan.
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