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European Journal of Heart Failure 2002 4(4):395-400; doi:10.1016/S1388-9842(02)00033-8
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© 2002 European Society of Cardiology

Diastolic heart failure: myth or reality?

Alain Cohen-Solal

Service de Cardiologie, Hôpital Beaujon 100 Boulevard du General Leclerc, 92110 Clichy, France alain.cohen-solal{at}bjn.ap-hop-paris.fr

Key Words: Diastole • Heart failure • Epidemiology • Diagnosis

It has long been considered that the presence of a dilated heart or a decrease in contractility was mandatory for a diagnosis of heart failure (HF). More than 15 years ago, various studies suggested that this was not always true and that pure ‘diastolic HF’ indeed existed in some patients with non-enlarged, often hypertrophied hearts, with apparently normal systolic function [1,2]. Hemodynamic studies in patients with hypertrophic cardiomyopathy have demonstrated that abnormalities of diastolic function of the left ventricle may lead to HF. However, this clinical form of HF has not been considered as important to date and no large controlled study has been conducted in such patients. In recent years, various studies have suggested that diastolic HF may account for more than 50% of the hospitalisations for HF in elderly patients [3–5]. In a survey conducted in France [5], 38% of the patients hospitalised for HF had a left ventricular (LV) ejection fraction (EF) at discharge greater than 45 and 53% had an EF greater than 40% (Fig. 1). In patients aged more than 78 years, 63% had an EF>45 and 37% had atrial fibrillation. Such figures were confirmed in the recent European IMPROVEMENT-Heart Failure Survey: among the 90% of echocardiograms reported as abnormal, only 51% were considered to show LV systolic dysfunction; when EF was reported, it was <40% in only 27% of the cases [6]. In the recent Euro Heart Failure Survey, among the 58% of patients with a record of LVEF, 46.6% of the patients had an EF>=40% [7]. In a survey conducted in Framingham [8], 52% of patients with incident HF had a normal LVEF. In the study by Rich et al. [9] on the effect of a multidisciplinary intervention to prevent HF rehospitalizations, mean LVEF was 45%. Even in China [10], 66% of patients with clinical signs of HF have normal systolic function. Although a first article on patients with normal systolic function by Topol et al. [11] appeared as early as 1985 in the New England Journal of Medicine, the next important article on this topic [12] and an accompanying editorial [13] in the same journal appeared recently, in 2001, suggesting than during all this time, diastolic HF was not considered either to exist or to be an important problem.


Figure 1
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  		Fig. 1 LVEF values in patients hospitalised in a national survey conducted in France in 120 hospital departments in 1997 [5]. More than 50% of the patients had an EF greater than 40%.

 
Nonetheless, other authors continue to be sceptical [14,15] and deny the fact that diastolic abnormalities may play such an important role in HF or even exist, and suggest that the diagnosis of diastolic HF is overestimated in a large number of cases. Vasan et al. have emphasized the poorly limited boundaries of the concept [16,17]: among patients with congestive HF, the prevalence of normal LV systolic performance in the published reports varies from 13 to 74% and the criteria for congestive HF, its chronicity and the age of the study sample affects the reported prevalence and prognosis of the disorder. There is also an obvious temporal and recruitment bias [18]: the prevalence of normal systolic function decreases from general medicine departments to specialized HF centres and increases in the most recent surveys conducted in the 1990s. Therefore, who is right? Those considering the emergence over the next few years of an epidemic of diastolic HF, or those considering that diastolic HF is a Loch Ness monster whose reality has never been unequivocally demonstrated?


   1. Delineation of the problem
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 1. Delineation of the...
2. Clinical profile and...
 3. The diagnostic problem
 4. Treatment: still an...
 5. Conclusion
 References
 
What is indeed the problem? It is that a significant number of patients, mainly after 70 years [4], have one or multiple episodes of HF with a normal or relatively preserved LV systolic function, or more precisely, a normal LVEF some time after the event [5,10,19]. Does this mean that these patients have ‘chronic diastolic HF’?

(a) We first have to recognize that a normal systolic function after the acute event does not exclude the possibility of a transient systolic dysfunction leading to HF which may rapidly recover: this can occur in cases of acute myocardial ischemia (Fig. 2), severe acute hypertension, temporary use of negative inotropic drugs, extremely rapid heart rate (‘rhythmic cardiomyopathy’). An acute mitral regurgitation can also rapidly disappear with treatment. In the recent article from Gandhi et al. [12], it was shown that in 25/29 patients presenting with acute hypertensive pulmonary oedema with a LVEF>=40% 3–5 days after the episode, LVEF was >=40% also during the episode of pulmonary oedema. However, in 4/29 patients, it was between 35 and 40% in the acute phase. Thus, EF measured at discharge may erroneously lead to diagnosis of acute HF despite a normal LV systolic function, although this is rare.


Figure 2
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  		Fig. 2 Pressure–volume relationship of a normal left ventricle and in case of acute myocardial ischemia. Ischemia markedly reduces filling and increases end diastolic pressure by three mechanisms: (1) prolongation of relaxation; (2) decrease in chamber compliance with an upward shift of the end-diastolic pressure-volume relationship; (3) alteration in contractility figured by a rightward shift of the end-systolic pressure-volume relationship and a decrease in end-systolic elastance (Ees). This scheme illustrates that systolic and diastolic mechanisms both play a role in the sudden alteration in ventricular function resulting from ischemia. If EF is found to be normal afterwards, it is difficult to state which mechanism predominantly operated.

 
(b) Second, EF is not synonymous with systolic function: EF more accurately reflects ventriculo-arterial coupling than the systolic function of the LV [20]; it is dependent on the loading conditions, the heart rate, and the presence of a mitral regurgitation: substantial systolic dysfunction of the LV muscle may exist despite normal LVEF in the presence of a severe mitral regurgitation. For a small remodelled ventricle, a LVEF of 50% may be already associated with a reduction in stroke volume. Isolated right HF, HF secondary to mitral stenosis and pericardial effusion occur despite normal LVEF. Finally, some degree of systolic failure cannot be ruled out and prolonged relaxation experimentally is always associated with some alteration of myocardial systolic function [21]. EF or fractional shortening are indices of radial systolic function of the ventricle and recent studies using TM echocardiography or Doppler tissue imaging have suggested that longitudinal axis systolic function may be depressed early on in case of LV hypertrophy despite normal radial systolic function measured by conventional methods [22,23].

(c) Do these patients fulfill the criteria of ‘chronic’ HF? In general, HF here is transient and when etiological and precipitating factors are treated, these patients do not often complain of symptoms of chronic HF. Is it because they are truly asymptomatic? These patients are generally old and it may only be that they do not perform enough exercise to feel symptoms; only a cardiopulmonary exercise test may demonstrate a reduced age-adjusted exercise capacity, confirming the limitation of the circulatory reserve. Thus, until such a demonstration is performed, one has to consider that a pattern of acute intermittent, transient HF is the general rule. Resistance of congestion (dyspnea, oedema) to adequate medical treatment is much more rare than in cases of systolic dysfunction. Such resistance to treatment is generally only observed in true severe ‘diastolic’ dysfunction such as in primary hypertrophic cardiomyopathy, hypertrophy secondary to aortic stenosis, amyloidosis, hemochromatosis and in the diabetic heart. These patients really have a ‘stiff’ heart, which is impossible to fill correctly, with a permanent ‘restrictive’ profile both at Doppler and on hemodynamics. Their prognosis is poor.


   2. Clinical profile and mechanisms of heart failure
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 2. Clinical profile and...
3. The diagnostic problem
 4. Treatment: still an...
 5. Conclusion
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Patients hospitalised for HF who have a normal LVEF at discharge often have a unique clinical pattern. They are generally old (>70 years): Aronow et al. found that normal LVEF occurred in 50% of 572 older patients with CHF associated with prior myocardial infarction or hypertension prospectively studied [4]; they are frequently female and are generally treated by the general practitioner and not by the cardiologist. They often have a non-enlarged LV, with or without LV hypertrophy but often with a pattern of concentric LV remodelling (increased diameter/thickness ratio) [24], or an enlarged right ventricle in case of COPD, possibly altering LV filling within the non-extensive pericardial bag. They often have hypertension—systolic hypertension predominantly—myocardial ischemia or diabetes. It is important to consider that in most cases of hospitalisation, a precipitating factor is noticed; acute hypertension, myocardial ischemia, tachyarrhythmia by atrial fibrillation, fever, anaemia, increased salt intake, etc. Some may consider that HF in these cases is not the main cause of hospitalisation, explaining the different methods of coding the final diagnosis and perhaps differences in the reported prevalence of this form of HF.

What mechanisms are responsible for HF in these patients? Besides the classical pattern of dramatic alteration in diastolic function seen in hypertrophic cardiomyopathy, a more frequent situation is that of patients with latent or moderate diastolic dysfunction, because of prolonged relaxation and/or increased stiffness at rest, with little cardiac reserve to respond to stress (Figs. 2 and 3). This alteration of adaptive mechanisms can be summarized as follows:

– These patients cannot accelerate their relaxation to more rapidly fill the ventricles in case of tachycardia and reduction of the diastolic filling time, with even sometimes slowing of relaxation, especially during ischemia and hypertension. Whereas in the normal heart, filling is almost completed in early diastole, in the heart with prolonged relaxation, filling occurs throughout the entire diastole and tachycardia reduces filling. The worse situation here is represented by rapid atrial fibrillation because the contribution of the atrial systole, which may account for 30–40% of filling in sinus rhythm, is lost (Fig. 3).
– In addition, these patients cannot use the LV preload reserve because they would do it at the expense of increased filling pressures given their reduced chamber compliance [25]. This reduction in chamber compliance can be due to increased muscle stiffness (diabetes, ischemia, fibrosis, amyloidosis), changes in chamber geometry with increased relative wall thickness, with or without increase in LV mass, or due to compression of the left heart cavities in case of dilation of the right cavities (COPD, acute pulmonary embolism).
– Third, the compensatory heart rate reserve is reduced with age.
– Fourth, the compensatory increase in contractility via sympathetic stimulation is blunted because of the reduction of beta-adrenoceptors with age.
– Finally, the capacity to widen the arteriovenous oxygen difference to compensate for a reduction in cardiac output is reduced because of the physiological decrease in hemoglobin with age, decreasing the arterial content, and of the limited ability to extract more oxygen in the periphery.


Figure 3
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  		Fig. 3 Volume–time relationship of a normal left ventricle (plain line) and an aged left ventricle (dashed line). In the normal left ventricle, filling occurs mainly in early diastole; in the aged ventricle, filling lasts the whole diastole and atrial systole plays an important role. The deleterious consequences of a tachyarrhythmia by atrial fibrillation are different in the two cases. In the normal left ventricle, the abbreviation of diastolic filling time (1) and the loss of the atrial systole (2) have limited consequences in terms of filling (left part of the figure). On the contrary, in the aged ventricle, these two mechanisms (1+2) markedly reduce ventricular filling (right part of the figure).

 

   3. The diagnostic problem
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 1. Delineation of the...
 2. Clinical profile and...
 3. The diagnostic problem
4. Treatment: still an...
 5. Conclusion
 References
 
It is however clear that the diagnosis is difficult despite theoretically clear guidelines [26]. General practitioners are not familiar with the concept of systolic/diastolic dysfunction: in the IMPROVEMENT-HF Survey [6], nearly 40% of them were unaware of it. The risk of overdiagnosis in presence of dyspnea with a small heart thus exists and this may explain some recent reports suggesting a high rate of false diagnoses of diastolic HF in cases of dyspnea, especially by general practitioners [15]. Chest X-ray is not very helpful as the cardiac size may be normal. Cardiac Doppler is essential but has to be interpreted with care: the classical inversion of the E/A ratio (<1) is not a sign of pathologic diastolic HF [14]: it is naturally observed in the healthy elderly subjects and simply reflects the reduction of early diastolic filling with age resulting from the slowing of LV relaxation. In fact, a decreased E/A ratio in the presence of acute dyspnea, before any treatment by diuretics or nitrates, virtually excludes a diagnosis of diastolic HF. In the presence of an increase in pulmonary capillary wedge pressure, an increased or a ‘normalized’ E/A ratio should be found. Relying on only the diastolic mitral inflow profile after the acute event to set a diagnosis of diastolic HF is extremely risky. In the study of Caruana et al. [15], for example, among 109 patients with suspected diastolic HF by the general practitioner, 40 were obese and 54 had alteration in pulmonary function that may have explained symptoms. Other indices of diastolic dysfunction have been well described in the guidelines on diastolic HF of the Working Group on Cardiac Function of the ESC, which state that ‘diagnosis of diastolic HF requires three conditions: (1) presence of signs or symptoms of HF; (2) presence of normal or slightly reduced LVEF (EF<50%) and (3) presence of increased diastolic filling pressure’ [26]. Invasive assessment of LV diastole is laborious, requiring high-fidelity pressures and accurate measurements of volumes, and these are rarely needed to diagnose the condition. Finally, as recently shown by Zile et al. [27], clear signs or symptoms of HF and of a normal LV systolic function, generally equate altered diastolic function and an intensive search for an alteration in diastolic function is unnecessary. A favourable response of dyspnea to furosemide and a marked increase in plasma BNP level [28,29] are probably simpler and better arguments in favour of pulmonary congestion in the presence of dyspnea with a normal LV systolic function on echo than the results of a sophisticated hemodynamic evaluation.

Therefore, the reality is not a new epidemic of ‘chronic diastolic HF’, but the emergence, with aging and with the increase in survival of hypertensive and ischemic patients, together with the increasing prevalence of diabetes, of a new population of old people with intrinsic ‘physiological’, moderate diastolic dysfunction, poor cardiac reserve and intermittent HF generally caused by the same characteristic and repetitive factors.


   4. Treatment: still an orphan disease
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 3. The diagnostic problem
 4. Treatment: still an...
5. Conclusion
 References
 
This population has, to date, been entirely excluded from the large clinical trials conducted in HF. Thus, there is today no clear reason to treat patients following an episode of HF with normal systolic function, especially when the latter was the result of transient myocardial ischemia or rapid atrial fibrillation, with the ‘triple therapy’: loop diuretic, high doses angiotensin-converting-enzyme inhibitors (ACE-I) and beta-blockers. The results of some small studies showing that verapamil [30,31] or beta-blockers can improve ventricular function in hypertrophic cardiomyopathy cannot be necessarily applied to the rest of this population, although there are serious arguments suggesting that they may be efficacious. Beta-blockers for example, can improve ischemia, hypertension, reduce heart rate and perhaps preserve remodelling. ACE-inhibitors [32–35], angiotensin II receptors antagonists [36], diuretics, NO donors [37,38] and spironolactone [39,40] can also be used both to treat the etiologic factors and to various degrees to improve some aspects of the diastolic dysfunction (regression of fibrosis, prolongation of the diastolic filling time, improvement in relaxation, reversal of concentric remodelling,...). They may even be deleterious sometimes: diuretics are often overused in aged patients with preserved systolic function after acute decompensation leading to dehydration. The role of digoxin is less clear and theoretically limited. Other drugs are under investigation such as advanced glycation end-product crosslink breakers in diabetes or systolic hypertension [41]. One also may question the need for a background standard treatment besides the treatment of the etiologic factors (ischemia, hypertension) and the prevention of the decompensating factors (ex: arrhythmias). Etiologies are often multiple (age, hypertension, ischemia) and treating only one of them may be insufficient: in a recent study of patients with ‘flash’ pulmonary oedema with normal LVEF, revascularisation alone did not prevent the recurrence of the episodes of HF [42]. Some studies are currently in progress that may partially help to respond to the question of the background treatment of these patients. In SENIORS, patients with LVEF below and above 35%, aged more than 70 years, will randomly receive a placebo or nebivolol, a new beta-blocker with vasodilating activities, in addition to standard treatment. In an arm of the CHARM study (CHARM-preserved), patients with HF and LVEF greater than 40% will receive after randomisation candesartan, an angiotensin II receptor antagonist or a placebo. In PEP-CHF, elderly patients with HF and normal EF will receive an ACE-inhibitor or a placebo. Morbidity and mortality will be the end-point of these trials.


   5. Conclusion
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 1. Delineation of the...
 2. Clinical profile and...
 3. The diagnostic problem
 4. Treatment: still an...
 5. Conclusion
References
 
Thus, it is definitively possible to have a history of chronic or, more often, intermittent HF, despite a relatively preserved LV systolic function; this situation is not at all rare and may account for a large number of the hospitalisations for HF in recent years, especially in the the elderly. The concept of HF with preserved systolic function is probably heterogeneous and comprises cases of clearly altered diastolic dysfunction (hypertrophic cardiomyopathy, amyloidosis, diabetes) as well as cases of transient HF where the combination of moderate diastolic dysfunction, mild systolic dysfunction, reduced compensatory mechanisms and precipitating factors operate altogether. General practitioners are not familiar with the concept of diastolic dysfunction. We cannot tell them to apply the results of ‘evidence-based medicine’ to the general population of patients with HF, simply because to a large extent, this population is different from that of the current large clinical trials and we do not have a clear answer based on robust clinical studies. It is now time to close this gap.


   References
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 3. The diagnostic problem
 4. Treatment: still an...
 5. Conclusion
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