Copyright © 2005, The European Society of Cardiology
Screening for isolated diastolic dysfunction – a bridge too far?
Department of Cardiovascular Medicine, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK
roxy.senior{at}virgin.net
* Corresponding author: Tel.: +44 208 869 2548; fax: +44 208 864 0075.
Please see page 85 for the article by Nielsen et al. (doi: 10.1016/j.euje.2004.07.004) to which this editorial pertains.
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Introduction |
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 Top Introduction What is the pathophysiological...What is the evidence...How is LVDD most...References |
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Advances in our ability to reduce the immediate mortality associated with acute coronary syndrome and hypertension have resulted in an inexorable increase in chronic myocardial dysfunction. In the United Kingdom
2% of the population have left ventricular systolic dysfunction (LVSD), which develops with an incidence of 10 per 1000 among persons older than 65 and is expanding in absolute terms with the demographic transition.1 The mortality of heart failure approaches 50% for patients with NYHA Class IV symptoms.2 Notable advances in the treatment of LVSD have resulted from widespread implementation of pharmacological, revascularisation, device and rehabilitation therapies; this is especially true if treatment is initiated early in the disease. An inevitable next step is therefore to extend and translate the successes of LVSD to identifying and treating its less familiar co-conspirator "Left ventricular diastolic dysfunction" (LVDD). For this proposition to be practicable, a number of interdependent questions need to be resolved:- What is the pathophysiological basis of LVDD?
- What is the evidence that LVDD contributes to ill-health?
- How is LVDD most effectively identified?
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What is the pathophysiological basis of diastolic heart failure? |
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TopIntroductionWhat is the pathophysiological...What is the evidence...How is LVDD most...References |
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While rare clinical and experimental causes of "pure" myocardial diastolic dysfunction are recognised, in which active ventricular relaxation fuelled by ATP or passive ventricular distension dependent on myocardial mass and viscoeleastic properties are impaired, LVDD is more heterogeneous. Similar to LVSD, the pathophysiological debate will probably be resolved by recognising that most patients have a varying combination of an abnormally stiff ventricle with an abnormal active relaxation (
) or passive filling (end-diastolic pressure–volume relationship – EDPVR) that is exacerbated by dynamic neurohormonal loading through varying central volume expansion and increased heart rates. This combination chronically raises LV filling and left atrial pressures (LAP) ultimately resulting in heart failure.3 |
What is the evidence that diastolic heart failure contributes to ill-health |
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TopIntroductionWhat is the pathophysiological...What is the evidence...How is LVDD most...References |
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Heart failure with a normal ejection fraction (HFNEF) is common; exploration of a variety of cross-sectional population-based studies indicate that at least a third increasing to greater than half of all patients presenting with heart failure have a normal (
50%) or near-normal ejection fraction (EF).4–6 HFNEF is common in elderly patients, in females, in those with an increased body-mass index, in Afro-Americans, in hypertensive patients especially with left ventricular hypertrophy, in diabetics, in those with coronary disease and in renal failure. The annualised mortality ranges from 5 to 8% annually for HFNEF; compared with 10–15% among patients with LVSD. However, morbidity and hospitalisation associated with LVDD and LVSD appear to be comparable.7 In short there is little doubt that HFNEF is an emergent and pressing clinical problem. |
How is LVDD most effectively identified? |
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TopIntroductionWhat is the pathophysiological...What is the evidence...How is LVDD most...References |
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HFNEF has been incorrectly interchangeably used with LVDD. This is based on the flawed assumption that appropriate symptoms in the context of supposedly preserved (EF), must implicate diastole. It has been shown in several studies that EF has only moderate correlation with hard-endpoints.8,9 Other measures of systolic function, i.e. end-systolic volume, end-systolic wall stress and long axis function may be abnormal in presence of a normal EF.10,11 A normal EF is therefore no guarantee of normal systolic function. Furthermore, notwithstanding the fact that obesity or pulmonary disease will inevitably be included in the HFNEF cohort, the lack of a coherent, homogenous and universally accepted pathophysiological model for LVDD coupled with the ready availability of Doppler echocardiography, has resulted in a number of Doppler measurements being advocated by authorities as parameters of diastolic function without systematic validation.12,13
As evident from our pathophysiological discussion, a simplified view of LVDD assumes that at least a component of intrinsic myocardial relaxation abnormality. Initially diminished active relaxation () prolongs and reduces early diastolic filling. Since the transmitral flow is dependent on the gradient between LA and LV pressure, impaired relaxation lengthens and reduces the maximum early transmitral velocity (E) resulting in the oft-quoted E/A reversal and a prolonged isovolumetric relaxation – deceleration time (IVRT/DT). As relaxation failure progresses and is coupled with a failure of ventricular passive capacitance, the atria fail to decant their contents into the stiff ventricle. An increasingly preloaded left atrium with higher LAPs supervenes; this is especially the case if central venous volume is increased (filling). The higher LA–LV gradient drives and hence "normalises" the impaired parameters (pseudonormal). Once the LAP is sufficiently high a supranormal E/A with short IVRT/DT "restrictive" pattern is noted.14 The fundamental influence of LAP and filling status on these parameters is self-evident; a corollary of which is that transmitral Doppler provides only partial insights into the intrinsic state of the myocardium. Moreover, as well as being load-dependent, these pulsed-wave parameters are dependent on patient conditions such as age and heart rate, afterload, valvular disease (which may vary with transient ischaemia), and position of the sample volume cursor. While it is likely that these parameters will be accurate in patients with manifest LVSD, in whom LAP is consistently high,15,16 in those with a normal EF the independent variability of LA filling and ventricular relaxation render simple pulsed-wave Doppler transmitral parameters subject to significant error.17,18 With this backdrop, Nielsen et al., in this issue investigated the role of these relatively simple Doppler parameters in determining the prognosis of patients with known heart disease.19 This study confirms the physiological predictions and the results of recent cohort studies demonstrating the relative inadequacy of conventional transmitral Doppler indices of diastolic function. Nielsen et al. show not surprisingly that these parameters at best have only a weak association with morbidity and mortality. They reiterate the important point that while easily measured, indiscriminate use of transmitral Doppler parameters is at best misleading and at worst may result in inadvertent iatrogenic misadventure.
In contradistinction, Tissue Doppler echocardiography (TDI) and its derivatives (e.g. strain rate imaging) by directly measuring the velocity of myocardial rather than blood motion are not as susceptible to the vagaries of incipient loading conditions. The ability to interrogate the relaxation of longitudinal subendocardial muscle provides a relatively accurate surrogate for (). The capacity to directly assess and strip away the contribution of active ventricular relaxation from the transmitral flow in principle permits an accurate assessment of LAP. Consequently, the ratio of peak early transmitral flow velocity (E) to the peak tissue Doppler early myocardial annular velocity (Ea) – E/Ea is a potentially robust parameter of transmitral blood flow qualified by intrinsic ventricular function, where E/Ea<8 suggests normal filling pressures and E/Ea >15 suggests filling pressures >16mm Hg.20 Although highly appealing and easy to measure, with a high specificity and positive predictive value, it is not flawless. Irrespective of methodological strategies (medial vs lateral annular Ea measurements) recent studies have suggested that assessment of E/Ea in controls and those with mild LVDD rather than in those with LVSD has a relatively low sensitivity; a "normal" E/Ea does not exclude raised filling pressures.18,20
Another promising parameter to assess LV filling is LA volume (LAV) indexed to body surface area and its rate of change may provide an integrated assessment of the severity and duration of elevated filling pressures.15 Their use derives from the simple premise that chronically elevated LAPs act on the LA matrix and result in its expansion. As such they may reflect a more consistent view of filling pressures than an instantaneous point estimate based on Doppler parameters. Increased left atrial dimensions are known to segregate with cardiovascular disease and mortality.21,22 However, in early LVDD, LAVs are unlikely to be significantly increased and may therefore be uninformative. Further, few studies have reliably advocated the conversion of the more readily measurable LA dimensions to LAV; consequently the measurement of LAV per se has not yet been generally embraced but may become so.23
Nevertheless, an increased LAV, through LaPlace's law corresponds to an increased wall tension at any given filling pressure. This stretch stimulates the release of a number of natriuretic peptides, including Pro-BNP and its derivatives; plasma BNP measurements might therefore provide an alternative, easy to measure, relatively cheap and labour-free indicator of filling pressures. Its use is already established in LVSD. While the rationale for BNP is sound, similarly to LAV and TDI, it appears that although patients with significantly raised LAPs have raised BNP, well-treated or mild relaxation abnormalities may fail to significantly raise BNP levels. Thus, as with echo parameters, BNP may be insufficiently sensitive for assessing mild disease.24
In this issue, it is apparent that Nielsen et al. raise more questions than they answer. Whilst calls to elucidate the fundamental basis of LVDD are ever-present, a pressing need exists to agree upon and prospectively study a combination of load-independent myocardial parameters (E/Ea, LAV or BNP) based on cohort studies. Physiologically homogenous patients must then be included in well-designed biological hypothesis-generating or rational trials. Such studies are underway.25 Only in this way will patients be effectively stratified and their disease trajectory modified.
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- Senior R. Personal communication.
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Related articles in Eur J Echocardiogr:
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Eur J Echocardiogr 2005 6: 85-91.[Abstract] [Full Text]
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