如何看待射血分数正常的心力衰竭

Peer reviewed article 66 Review article SWISS MED WKLY 2010 ; 139 ( 5 –6 ) : 66–72 · www.smw.ch Heart failure with normal ejection fraction (HFNEF): is it worth considering? Coralie Blanche, Thierry Fumeaux, Ralf Polikar Internal Medicine and Intensive Care Unit, GHOL, Regional Hospital Nyon, Switzerland Summary A significant proportion of patients with heart failure happen to have a normal ventricular ejec- tion fraction at echocardiography during exami- nation. Previously called diastolic heart failure, it is nowadays referred to as heart failure with nor- mal ejection fraction (HFNEF) or HF with pre- served ejection fraction. The European Society of Cardiology, recognizing the importance of this type of heart failure, recently issued new definition criteria for it.This review will discuss the different steps that lead to such a diagnosis, as well as some new aspects of its pathophysiology. Finally, the management of this form of HF, that is not as straightforward as HF due to systolic dysfunction, will be discussed. Key words: heart failure; HFPEF; HFNEF; Diastolic dysfunction; BNP No financial support. Introduction Heart failure (HF) is a complex syndrome, re- sulting from structural or functional cardiac disor- ders that impair the ability of the cardiac pump to support a physiological circulation. HF is a fre- quent pathology in Switzerland, with a significant proportion of patients who need to be admitted to the hospital, and a high case fatality rate [1]. Ad- vances in the management of patients with left ventricular (LV) systolic dysfunction have resulted in a significant extension of life expectancy, but this is not the case for patients with HF in the ab- sence of echocardiographic LV systolic dysfunc- tion [2–5]. This type of HF is now being called Heart Failure with Normal Ejection Fraction (HFNEF) although HF with Preserved EF (HF- PEF), which probably better delineates the fact that systolic function is not completely normal in such patients but only apparently preserved, and diastolic heart failure (DHF) have also been used [6]. The European Society of Cardiology (ESC) recently underlined the clinical importance and complexity of HFNEF, and issued new definition criteria, based on clinical signs and/or symptoms of HF, echocardiographic and biological parame- ters [7]. This review will focus on the most recent data gained on the mechanisms of HFNEF, as well as on the results of the latest clinical studies on HFNEF. It is intended to help the general practi- tioner understand and apply the new ESC defini- tion of HFNEF into their daily practice. Clinical recognition and epidemiology Numerous publications report that many pa- tients who present with symptoms or signs of HF do not have decreased LV ejection fraction (LVEF). Data from recent studies show a preva- lence rate of HFNEF ranging from 30 to 50% in patients with HF, at least in patients with hospital admission [8–11].HFNEF patients are likely to be older women, in whom systolic hypertension and myocardial hypertrophy with fibrosis are the main contributors to cardiac dysfunction. The general prevalence of HFNEF seems to be on the rise, as a possible consequence of grow- ing recognition, population ageing and increases in hypertension and obesity prevalence [8]. Even though HFNEF mortality may be lower than in HFREF, high NYHA functional capacity carry a poor prognosis, whatever the LV systolic function. Finally, HFNEF patients have a reduced life expectancy, due to an increased risk of sudden cardiac death and acute HF, implying that these individuals have a significant functional cardiac disease [8, 10, 12]. For these reasons, HFNEF has become a public health problem and deserves more attention [8–10]. 67 SWISS MED WKLY 2010 ; 140 ( 5 –6 ) : 66–72 · www.smw.ch HFNEF implies some degree of LV filling al- teration despite an apparently normal LV systolic function: this so-called LV diastolic dysfunction (DD) results from various mechanisms,mainly ab- normal relaxation and decreased compliance, with a rise in LV end-diastolic pressure (LVEDP) [13]. Systolic function seems preserved, at least as as- sessed by 2D echocardiography, but this may be more complex, as this technique does not take into account all aspects of LV contractility. Diastolic function Diastolic function of the LV depends on active relaxation and on the stiffness characteristics of the ventricular wall [13].Diastolic dysfunction is not only the consequence of altered geometric and elastic properties of themyocardium, but is also influenced by pericardial distensibility, interventricular depen- dency, left atrial pressure, and electrical atrio-ven- tricular coupling. In addition, the vascular bed’s compliance and resistance may play a significant role in the development of diastolic dysfunction. Zile et al. invasively recorded ventricular pres- sures in patients with HFNEF, and confirmed the increase in LVEDP, together with smaller end-dia- stolic volumes, compared to controls [13]. They found evidence of a slower and incomplete relax- ation associated with an increased passive ventricu- lar stiffness, which could explain the high LVEDP. Westermann et al. confirmed these observations, with an invasive measure of ventricular pressure- volume loops in HFNEF patients: they showed an elevated LVEDP that might be due to higher LV stiffness and increased relaxation time [14]. These alterations were more marked during handgrip or tachycardia, but with a different pattern of altera- tions in these two situations, suggesting a complex mechanism of diastolic dysfunction during exercise, not only due to heart rate increase [15]. Tachycardia may reveal diastolic dysfunction and is often not well tolerated by patients with HF- NEF: Wachter et al. demonstrated that relaxation timewas prolonged inHFNEF, and that the normal frequency-dependent acceleration of relaxation was blunted, resulting in significant decrease of end-di- astolic volume and stroke volume with higher heart rates [16]. Eventually, recent and precise descriptions of diastolic function, by the association of echocardio- graphicmeasures of ventricular dimensions coupled with invasive measures of ventricular pressures us- ing an implantable device called e-PAD,addedmore evidence that diastolic distensibility is decreased in HFNEF [17, 18]. In the daily practice, the non-invasive evalua- tion of LV diastolic function is performed with transthoracic echocardiography (TTE). Early mi- tral diastolic flow (called Ewave), due to the ventric- ular relaxation, and late mitral diastolic flow (called A wave), secondary to the atrial kick, can be mea- sured with Doppler-imaging. The velocity ratio of these waves, called E/A ratio, has been used as an in- direct evaluation of ventricular filling pressure, and as a surrogate marker of diastolic function. Three grades of diastolic dysfunction have been defined. Grade I (E/A <1) is referred to as relaxation abnor- mality and is often encountered in elderly patients. Grade II (E/A >1) is called pseudo-normalization, since it is also recorded in young healthy individuals. As LA pressure increases further, relaxation time decreases and the contribution of the LA kick to LV filling diminishes, with a “restrictive” pattern (E/A >1,5 and DT <140 msec), referred to as Grade III. This range of severity has been shown to represent a negative prognostic marker, especially in patients with systolic dysfunction [19, 20]. However, the E/A ratio may not precisely re- flect diastolic function, partly because it is load de- pendant and it has variable performances [21, 22]. OtherTTE parameters give some indication on di- astolic function, such as the deceleration time of the Ewave, the isovolumic relaxation time, the left atrial size, and the LV wall thickness, and, as elegantly stated by L.Hatle, diastolic dysfunction is better as- sessed when all TTE and Doppler parameters are put together [23]. Tissue Doppler imaging (TDI) is a novel tech- nique, which allows analysis of global diastolic and systolic velocities of the myocardial wall. The E’ wave is the peak velocity of early diastolic myocar- dial lengthening, recorded at the mitral annulus. When combined with the E wave, measured with conventional Doppler, the E/E’ ratio is well corre- lated to LVEDP and is less load-dependent than E/A ratio [24–26]. It also correlates very well with HF symptoms, both in HFREF and HFNEF [27– 29]. An E/E’ ratio >15 has been chosen as a cut-off value for diastolic dysfunction, and a value <8 is sen- sitive enough to exclude it. When E/E’ ratio is between 8 and 15, other ap- proaches, such as pulmonary vein Doppler analysis, M-mode colorDoppler of LVfilling, the “time con- stant” of LV relaxation (t), the ‘stiffness’ constant of LV (b), the left atricular volume index (LAVI), and the left ventricular mass index (LVMI) can be used in conjunction with LA size [30]. However, in clini- cal practice, these novel approaches are not yet widely available, and cardiac catheterization remains the gold standard for filling pressure assessment. The E’/E ratio is of limited value in patients with abnormal relaxation but normal LVEDP at rest.Marked diastolic dysfunction can develop with exercise, and diastolic dysfunction can be missed, unless there is an LA enlargement. Likewise, some patients with a decrease in compliance without sig- nificant relaxation abnormality may have a normal E/E’, and once again LA size and blood flow Dop- pler analysis might then be the only clues of a dia- stolic dysfunction [23, 31]. Pathophysiology of HFNEF 68 Heart failure with normal ejection fraction (HFNEF): is it worth considering? Systolic function By definition, systolic function should be nor- mal or preserved in HFNEF, at least when mea- sured with echocardiography.However,TTEmay be misleading, because it only evaluates radial shortening and doesn’t take into account other as- pects of systolic function, such as longitudinal shortening, circumferential twist, and regional ab- normalities. This is important, since loss of longi- tudinal motion of the LV is the most obvious change associated with ageing, and because radial shortening is often increased in the early stage of diabetic and hypertensive heart disease [32–34].As elderly, diabetic and hypertensive subjects repre- sent a significant proportion of HFNEF patients, the relative preservation of LVEF may lead to a wrong impression. LV systolic function can nowadays be evalu- ated more precisely with TDI. LV longitudinal shortening is assessed by the amplitude of mitral annular shortening, and when associated with the evaluation of systolic myocardial velocities, this approach yields a much better detection of global and regional systolic dysfunction thanTTE.With this tool, it has been shown that systolic function may be altered not only in HFREF, but also in pa- tients with HFNEF [35–37]. Other recently de- veloped techniques, such as strain rate imaging (SRI) which uses the time integral of the velocity gradient between two adjacent myocardial seg- ments, may also be better at detecting regional and global alterations of systolic function [38]. The application of these new techniques shows that LV systolic function is, in fact, probably slightly altered in patients with HFNEF:Tan et al. have studied HFNEF patients by various echocar- diographic techniques, both at rest and at exercise, and have shown that HFNEF patients have sys- tolic segmental alterations, such as lower apical rotation, decreased ventricular suction and re- duced untwisting, and that these alterations are more pronounced at exercise [15]. One can con- clude that standard TTE doesn’t seem to have perfect diagnostic performance for systolic func- tion, and that EF doesn’t reflect systolic function in its entirety, and may seem normal because of a change in ventricular geometry. Based on a mathe- matical model, Maclver et al have shown that EF preservation in HFNEF is probably related to in- creased muscle mass and increased radial thicken- ing of the ventricular wall, compensating for the reduced long-axis shortening [39]. All these data suggest that indeed HFNEF and HFREF may represent a continuum, and not separate entities. Cellular alterations associated with HFNEF Van Heerbeck et al. demonstrated that the myocardiumof patients withHFNEF andHFREF present the same degree of histological fibrosis, but that cardiomyocytes express different isoforms of the constitutive cytoskeletal protein titin, which increases diastolic compliance upon phosphoryla- tion [40]. The N2B isoform expressed in HFNEF is stiffer and its increased expression may contrib- ute to the increased ventricular stiffness, and par- ticipate in the development of diastolic dysfunc- tion. Diagnosis of HFNEF HF is a clinical syndrome and may present in either acute or chronic form. Acute onset of dys- pnea and/or congestion will often lead to hospital- ization, and the clinical suspicion of HF is high in most cases. More chronic symptoms, such as dys- pnea on exertion, nocturnal paroxysmal dyspnea, orthopnea, or fatigue, may be the only features of HF, particularly in the outpatient setting and aren’t specific of any type of HF. Signs and symptoms of HF result from ele- vated LV filling pressure and/or low cardiac out- put, which may be the consequence of either in- complete emptying, as in systolic dysfunction, or impaired ventricular filling as in diastolic dysfunc- tion. Therefore, the clinical presentation of HF- PEF and HFNEF share similarities such as a third heart sound, elevated jugular venous pressure and signs of pulmonary congestion, which, in the past, had been considered to be the hallmark of LV sys- tolic dysfunction but are also found in patients with diastolic dysfunction. As their performance characteristics may vary, classical symptoms and signs are not sufficient for the diagnosis of HF (fig. 1) [41].The Framingham criteria are sensitive but moderately specific, and apply poorly to non congestive or moderate HF (table 1) [42–45]. In the daily practice, the physician firstly needs to confirm that HF is the cause of the pa- Figure 1 Diagnostic value of symptoms and signs of HF. Adapted with permission from Brunner-La Rocca [41] and Schweiz Med Forum 2007;7(Suppl. 39):3–14 S, http://www.medicalforum.ch HF: Heart failure MI: myocardial infarction COPD: chronic obstructive pulmonary disease 69 Heart failure with normal ejection fraction (HFNEF): is it worth considering? tient’s presenting symptoms and signs, and then to distinguish between HFREF and HFNEF. The most recent guidelines, including the ESC algo- rithm, recommend that the diagnosis of HF be based upon ECG, chest X-ray and measurement of natriuretic peptides, and confirmed by echocar- diographic evaluation, which in addition will help differentiate HFREF from HFNEF (fig. 2 and 3) [6, 41]. Brain natriuretic peptide (BNP) and its pre- cursor (NT-proBNP) are produced by cardiomy- ocytes in response to volume or pressure overload, and are very sensitive markers, so that HF is unlikely in presence of normal levels [46–48]. Specificity is not as good, because blood levels are influenced by many factors, such as age, BMI and kidney function, and may increase in various clini- cal situations. This is why the ‘rule-in’ cut-off val- ues may differ in various guidelines, and the inter- pretation of these values always has to be cautious and linked to the clinical situation [46, 49]. It has to be emphasized that, in recent years, natriuretic peptides have been made readily available in each emergency room and private practice, and have Major criteria – Paroxysmal nocturnal dyspnea – Neck vein distention – Rales – Radiographic cardiomegaly – Acute pulmonary edema – S3 gallop – Increased central venous pressure (>16 cm H 2 O at right atrium) – Hepatojugular reflux –Weight loss >4.5 kg in five days in response to treatment Minor criteria – Bilateral ankle edema – Nocturnal cough – Dyspnea on ordinary exertion – Hepatomegaly – Pleural effusion – Decrease in vital capacity by one third from maximum recorded – Tachycardia (heart rate >120 beats/min.) Table 1 Framingham criteria for the diagnosis of heart failure (HF): HF is diagnosed when 2 major criteria OR 1 major criteria plus 2 minor criteria are present. Figure 2 ESC diagnosis algorithm. How to diagnose HFNEF Symptoms or signs of heart failure Normal or mildly reduced left ventricular systolic function LVEF >50% and LVEDVI <97 mL/m 2 Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness Invasive Haemodynamic measurements mPCW >12 mm Hg or LVEDP >16 mm Hg or r >48 ms or b >0.27 Biomarkers NT-proBNP >220 pg/mL or BNP >200 pg/mL TD EIE’ >8 TD EIE’ >15 15 >EIE’ >8 Biomarkers NT-proBNP >220 pg/mL or BNP >200 pg/mL Echo – blodflow Doppler EIA –50yt <0.5 and DT –50yt >280 ms or Ard-Ad >30 ms or LAVI >40 mL/m 2 LVMI >122 g/m 2 (/); >149 g/m 2 (?) or Atrial fibrillation HFNEF Reproduced with permission from Paulus et al. [7]. HFNEF: heart failure with normal ejection fraction LVEF: left ventricular ejection fraction LVEDVI: left ventricular end-diastolic volume indexed to body surface LV: left ventricular mPCW: mean pulmonary capillary wedge pressure LVEDP: left ventricular end-diastolic pressureTD: tissue Doppler LAVI: left atrial volume indexed to body surface area LVMI: left ventricular mass indexed to body surface area. See text for other abbreviations. 70 Heart failure with normal ejection fraction (HFNEF): is it worth considering? been better validated than the various echo-Dop- pler variables for the diagnosis and prognosis of HF.Therefore, they are often put forward by most experts for the diagnosis of HFNEF (fig. 3) and used as inclusion criteria in most ongoing studies of HFNEF [46]. After the diagnosis of HF has been made, dia- stolic dysfunction must be proved to confirm the presence of HFNEF. The hallmark of diastolic dysfunction is elevated filling pressures, such as LVEDP and pulmonary capillary wedge pressure (mPCWP), which can be measured invasively [7]. However, invasive haemodynamic studies are rarely undertaken and non invasive parameters are most often used to confirm diastolic dysfunction. TTE is the most widely available confirma- tory tool for HF, and the ESC and Swiss guide- lines both recommend its use. As already dis- cussed, it can distinguish between HFNEF and HFREF, but also gives clues for the etiology of HF. In addition,TTE has a prognostic value, since low EF, LV remodeling and LV restrictive filling patterns are associated with a high mortality.TTE has some limitations, and cardiac catheterization should be considered for more accurate measure- ment of LVEDP and PCWP. Figure 3 Use of BNP for the diagnosis of HF. Adapted and reproduced with permission from Maisel et al. [46] HF: heart failure Clinical suspicion of HF BNP levels BNP <100 pg/ml HF very improbable (<2%) BNP 100–400 pg/ml Past history of HF HF probable (75%) BNP >400 pg/ml HF very probable (>98%) Management of HFNEF As HFNEF is associated with significant morbidity and mortality [1], patients should have regular medical visits to evaluate worsening of signs and symptoms, associated with regular echo- cardiographic evaluations, in order to initiate ap- propriate therapy in case of a worsening of systolic function.Cardiovascular risk factors should be de- tected and treated. Rapid or unexpected deteriora- tion should be quickly assessed by cardiologists. Medi