射血分数正常的心力衰竭

Review Article 168 Heart Failure with Normal Ejection Fraction – New Diagnostic Criteria and Pathophysiological Advances Evandro Tinoco Mesquita1,2 e Antonio José Lagoeiro Jorge2 Hospital Pró-Cardíaco1, Rio de Janeiro, RJ; Universidade Federal Fluminense2, Niterói, RJ - Brasil Mailing Address: Evandro Tinoco Mesquita Rua General Polidoro, 192 - Botafogo, 22.280-000, Rio de Janeiro, RJ, Brazil. E-mail: etmesquita@gmail.com Manuscript received February 29, 2008; revised manuscript received May 09, 2008; accepted May 15, 2008. Summary Heart failure (HF) is a highly prevalent complex cardiovascular syndrome, and its clinical presentation is usually associated with ventricular dilatation, decreased contractility and reduced left ventricular ejection fraction (EF). However, in the past two decades studies have demonstrated that many patients with signs and symptoms of HF have normal EF (higher than 50%). The great challenge for doctors lies in the identification of patients presenting heart failure with normal ejection fraction (HFNEF) and this challenge seems to be mainly related to the high complexity of the syndrome and to the lack of a standardized method to confirm or exclude the diagnosis that could be used in the daily clinical practice. Unlike in heart failure with reduced ejection fraction (HFREF) in which one single parameter – EF lower than 50%, is sufficient to confirm the diagnosis of the syndrome, in HFNEF different diastolic indexes have been used to characterize the presence or absence of diastolic dysfunction (DD). The purpose of this review is to show new concepts related to the diastolic function that will help understand the cardiovascular pathophysiology of HFNEF, and to discuss the new guideline of the European Society of Cardiology for the diagnosis and exclusion of HFNEF based on cardiac function indices obtained using tissue Doppler imaging (TDI) and natriuretic peptide determination. Introduction Assessment of the overall cardiac performance using left ventricular (LV) ejection fraction measurement has raised heated debates and controversies regarding nomenclature, definition and diagnosis of HFNEF1. HFNEF is frequently referred to as diastolic heart failure (DHF) because of the presence of diastolic dysfunction (DD) characterized by reduced relaxation and increased ventricular stiffness2-4. However, the utilization of the term DHF may not be appropriate since the diastolic dysfunction does not occur only in these patients, but also in those with HF with systolic dysfunction. Thus, in the absence of a differentiated role for diastolic dysfunction, patients presenting with HF without EF reduction would be better defined by the term HFNEF than by DHF5. The differentiation between HFNEF and HFREF is based on the EF measurement by Doppler echocardiography, and this gives the impression that patients with HFNEF have only diastolic function changes with preserved systolic function. However, new techniques to evaluate cardiac function with measurement of the long axis velocity using tissue Doppler imaging have proven to be a more sensitive index for the assessment of systolic function than EF4. Thus, HFNEF would be the result of the systolic dysfunction of the ventricular muscular pump in the presence of a preserved performance of the hemodynamic pump6, that is, when the EF is analyzed separately from the left ventricle, the identification of myocardial contractility abnormalities may be missed4,6. Despite its unfavorable prognosis, HFNEF is currently a poorly valued clinical syndrome in comparison with other non-cardiac conditions such as cancer and diabetes, and heart diseases such as myocardial infarction.1 The little importance given to the diagnosis of HFNEF may be mainly related to the high complexity of the syndrome, poor approval by the medical establishment due to the difficulty in identifying a standardized method to quantify the diagnosis that could be used in the clinical practice, and also due to controversies involving the definition of diastolic dysfunction, as well as of criteria for the diagnosis of HFNEF1. Recently, the European Society of Cardiology published a new guideline on how to diagnose HFNEF using two algorithms to exclude or confirm the syndrome with emphasis on the findings of TDI and natriuretic peptides5. Epidemiology Different authors have demonstrated that HFNEF is currently the most common form of presentation of HF, with a prognosis similar to that of HFREF7,8. Epidemiological studies show that the prevalence of HFNEF is higher than 50% among patients with HF7,8. In a recent article published in Arquivos Brasileiros de Cardiologia, Moutinho et al observed a HFNEF prevalence of 64.2% in a population of patients seen in the Programa Médico de Família (Family Medical Program) in the city of Niterói, State of Rio de Janeiro, with signs and symptoms of HF9. It is important to point out that the demographics and comorbidities of patients with HF vary according to EF (Table 1)8. When patients with HFNEF are compared with those with HFREF, we can observe the first ones are older, more obese and most of them are females. Patients with HFNEF have a history of hypertension, diabetes and atrial fibrilation8. Key Words heart failure; diastole; systole; echocardiography, Doppler; stroke volume. Review Article 169 Table 1 – Epidemiology of heart failure stratified by EF Characteristics HFNEF n = 2167 HFREF n = 2429 p Mean age 74.4 years 71.7 years < 0.001 Male gender 44.3% 65.4% < 0.001 BMI > 30 41.4% 35.5% 0.002 Hypertension 62.7% 48.0% <0.001 CAD 52.9% 63.7% <0.001 Diabetes 33.1% 34.3% 0.61 Atrial fibrillation 41.3% 28.5% <0.001 BMI – Body Mass Index; CAD – Coronary Artery Disease; EF – ejection fraction; Adapted from Owan et al8 Key elements of the pathophysiology of cardiac dysfunction The normal diastolic function allows the heart to have adequate filling both at rest and during exercise, without the occurrence of increased diastolic pressures. However, changes in cardiac relaxation, the presence of myocardial hypertrophy, and remodeling are key defects that change the ventricular stiffness and filling pressures, thus leading to exercise intolerance, which would be the first symptom of HFNEF and the first determinant of reduced quality of life14. In the heart with diastolic dysfunction, EF remains normal for quite a while. Maintenance of the cardiac performance is due to a compensatory period composed of two phases – the systolic activation phase, and the systolic dysfunction phase of the muscular pump1. The systolic activation phase (Figure 1) is characterized by increased pressure, volume and ventricular flow, which is reversible and reflects the activation of all the adaptive mechanisms of the heart as a muscular and hemodynamic pump1. If cardiac stress is maintained, the systolic activation may progress to the systolic dysfunction phase (Figure 2)1. Therefore, the complete understanding of the systolic dysfunction of the muscular pump in the presence of a preserved performance of the hemodynamic pump, that is, normal EF, would undoubtedly be a key pathway to the understanding of the initial stage of the HF syndrome, which we call HFNEF1,4. Systolic Activation - Early relaxation delay V P EDV ESV Modulation of duration of systole Modulation of relaxation velocity - secondary to changes in duration of systole - sensitive to heart rate, neurohormones, load changes - Heterometric autoregulation - pressure or volume, hypertrophy I - Homeometric autoregulation - neurohormones, heart rate - Endothelial autoregulation - NO, BNP, cytokines time Figure 1 – Early relaxation delay (or prolonged contraction is – together with peak and increased contraction velocity – the typical characteristic of the Systolic Activation Phase of the muscular heart pump. Changes in relaxation velocity are merely an effect secondary to the delayed modulation of systole. Usually early relaxation delay does not lead to increased end-diastolic pressure/volume. P – LV pressure; V – LV volume; EDV – end diastolic volume; ESV – end systolic volume; NO – nitric oxide; BNP – B-type natriuretic peptide (reproduction authorized by Dirk L. Brutsaert 1). Although patients with HFNEF have a better prognosis than those with HFREF, they present significant morbidity and mortality, and the prognosis after hospitalization for HF is poor7,8,10, with a mortality rate of approximately 20% in one year9. Although strategies based on recent evidences for the treatment of HF have favorably modified the outcomes for patients with HFREF, studies have shown increased prevalence rates of HFNEF without change in mortality over the past 20 years8. HFNEF and HFREF – a single syndrome or not? There is no consensus as to whether HF should be considered a single syndrome or whether HFNEF and HFREF are two different clinical forms11. If HF were characterized as a single syndrome12, it would be defined by a progressive decline in the systolic performance that can be better evaluated by the analysis of velocities or measurements involving the long axis shortening using TDI than by using the EF measurement alone13. The theory that HF is not a single syndrome but rather two diseases is supported by structural, functional and molecular changes associated with the diastolic function as well as by clinical studies with pharmacological intervention showing that patients with HFNEF do not have the same response as patients with HFREF, thus suggesting the existence of different pathophysiological mechanisms11. We emphasize that it is totally artificial to split the two phases of the cardiac cycle (systole and diastole), but some authors11 have argued that in HFNEF the systolic function is completely normal, and that this clinical condition is due to DD alone. Hence, HFNEF and HFREF should be considered different clinical entities11. These studies are based on global measurements derived from the LV volume pressure curve that do not take into consideration regional changes of the long axis function4, which are compensated by an increase in contractility of the LV short axis. The pressure/volume curve may thus remain normal despite significant changes in the ventricular architecture and shape1. Arq Bras Cardiol 2009; 93(2):168-174 Mesquita & Jorge HFNEF pathophysiology and diagnosis Review Article 170 Abnormal relaxation Abnormal relaxation (DD) is a functional alteration of the heart and one of the three mandatory criteria for the diagnosis of HFNEF, and should not be mistaken for or used as synonymous with HFNEF15. The best way to demonstrate that patients with HFNEF have abnormal relaxation is to show whether the end-diastolic pressure/volume ratio (EDPVR) is higher when compared to its normal value. Certain conditions such as hypertrophy (hypertensive heart disease, hypertrophic cardiomyopathy and/or aortic stenosis) and myocardial ischemia affect relaxation making it slower and incomplete, thus leading to increased EDV15. The P/EDV-R allows for the demonstration that not only is the intraventricular diastolic pressure elevated but also that this elevation is seen in ventricles presenting decreased filling volume11. Demonstration of increased EDPVR is important because in the absence of this alteration, the EDV may be increased because of an increase in preload, such as can be observed in patients with aortic and mitral regurgitation with no contractility impairment and no significant change in the relaxation properties, andbecause a surgical correction of the alteration also corrects the overload16. Cardiac hypertrophy Ventricular hypertrophy is considered an adaptive mechanism of the heart in face of an increased load. Through intracellular mechanisms this overload may elicit different responses that can or not be associated with functional myocardial impairment17. The concept of hypertrophy is based on the identification of increased heart weight which is mainly determined by the increase in cardiomyocyte size.17 We should not forget that cardiac muscle cells comprise the least percentage of all myocardial cells; however, given that they are the largest cells, variation in their size will determine a significant impact on the final heart weight17. The hypertrophic response may be triggered by natural overload mechanisms such as those determined by growth, pregnancy, and those induced by physical activity, or also by pathological mechanisms such as hypertension, heart valve stenosis and regurgitation, cardiomyopathy, and myocardial infarction. Pathological hypertrophy is accompanied by loss of contractility. The analysis of the fibers of the LV long axis on TDI shows decreased contraction in hypertrophic hearts4 due to hypertension in comparison with normal hearts or athletes’ hearts with physiological hypertrophy17. Ventricular remodeling The main pathophysiological difference between HFNEF and HFREF is the increased ventricular volume and the change in the ventricular shape because of the remodeling process2. Myocardial infarction is a powerful stimulus to the remodeling process, leading to enlargement of the LV and reduction of EF, whereas in the hypertensive heart disease the remodeling is a slow process, with LV hypertrophy leading to LV systolic and diastolic dysfunction, in which the compensatory increase in radial contraction tends to normalize the EF. However, in late stages, remodeling will occur with LV volume increase and the patient will go from HFNEF to HFREF1. Currently, the use of medications that act on remodeling have proven to be efficient in the treatment of HF, and signs of reverse remodeling are a powerful predictor of clinical improvement2. Diagnosing HFNEF in the clinical practice The first step in the assessment of HF is to establish its diagnosis by the presence of signs and symptoms and, when available, with BNP determination. Next, a heart imaging method should be used to objectively assess LV function and determine the main etiology and its mechanisms (HFNEF, HFREF, pericardial diseases and heart valve diseases). The third step is to determine whether remodeling is already present (increased ventricular volume), and finally, to look for the presence of additional deleterious factors such as dyssynchrony, arrhythmias, and metabolic and electrolyte changes2. The ESC guideline5 presents an algorithm model (Figures 3 and 4) on how to diagnose and how to exclude HFNEF using the new concepts of cardiac function and TDI measurements. It establishes three mandatory stages to diagnose HFNEF, which are: presence of signs or symptoms for the diagnosis of HF, presence of greater than 50% EF, and evidences of diastolic dysfunction (relaxation, filling and stiffness)5. Figure 2 – The early systolic dysfunction stage is characterized by worsened relaxation, which is slow or incomplete, with progressive loss of capacity to modulate the early relaxation. Worsened relaxation may result in increased end diastolic volume/pressure. The grey vertical bar right before peak P and peak ESV shows the transition between intracellular contraction and the relaxation process. P – LV pressure; V – LV volume; EDV – end diastolic volume; EDV – end diastolic volume (reproduction authorized by Dirk L. Brutsaert 1). Systolic dysfunction - Relaxation worsening V P EDV ESV Etiology Mechanisms Failure of the triple control - inadequate load - inadequate inactivation - load non-uniformities and inadequate inactivation Stages II and III hypertrophy Mild ischemia time Arq Bras Cardiol 2009; 93(2):168-174 Mesquita & Jorge HFNEF pathophysiology and diagnosis Review Article 171 Signs and symptoms of HF The signs and symptoms of HF include peripheral edema, hepatomegaly, lung crepitations, pulmonary edema, fatigue and breathlessness. Breathlessness is the most common symptom and also leads to a greater difficulty in the differential diagnosis5. This difficulty is more frequently seen in elderly and obese patients, who represent the largest proportion of patients with HFNEF7. Unlike hospitalized patients who are admitted with a classical presentation of HF which usually leaves no doubt as to the diagnosis, outpatients frequently complain of breathlessness with no detectable signs of congestion, which leads to the need for tests to confirm the diagnosis5. Normal or mildly abnormal systolic left ventricular function The choice of a cut-off point to the EF value to discriminate HFNEF from HFREF remains arbitrary5. The ESC guideline established the value of EF≥50% as necessary for the assessment according to recent recommendations of the American Society of Echocardiography and of the European Association of Echocardiography5. Criteria for the presence of normal EF need to be implemented with measures of ventricular volume. Thus EDV, which must be indexed to body surface, should not exceed 97 ml/m2 for the diagnosis of HFNEF5. Evidences of abnormal LV relaxation The first question is whether it is necessary to evaluate relaxation changes in all patients with suspected HFNEF5. Considering this possibility, Zile et al18 tested the hypothesis that measurements of diastolic function are not always necessary to establish the diagnosis of HFNEF. The authors evaluated patients with HF who had EF >50% and evidences of concentric remodeling and demonstrated that 92% of these patients had high end-diastolic pressure and all had at least one abnormal relaxation index, abnormal filling or stiffness. In this group of patients, the DD parameters obtained did not add data for the diagnosis, but only confirmed DD18. We should keep in mind that this study evaluated patients with history of established HF and, therefore, these data cannot be extrapolated to patients presenting only symptoms of breathlessness19. An important finding of this study is that the evidence of concentric remodeling has implications for the diagnosis of HFNEF and is a potential substitute for the characterization of diastolic dysfunction18,20. The study shows that a LV wall mass index > 122g/m2 for women and > 149 g/m2 for men is sufficient evidence for the diagnosis of HFNEF when TDI is not conclusive or when plasma BNP is elevated18. Assessment of the left ventricular function using TDI TDI has a fundamental role in the assessment of this process since the clinical presentation of HFNEF is indistinguishable from that of HFREF and the EF measurement is certainly not relevant. Thus, assessments of systolic and diastolic dysfunction using measurements of the long axis and strain velocity in early diastole (E’) with TDI are more important5,14,21. The development of new TDI techniques13 has provided greater accuracy in the assessment of the ventricular function. In a recent study, Wang et al20 showed that the measurement of strain velocity in early diastole (E’) is a strong predictor of mortality in comparison with clinical data and standard echocardiography. This measurement is easy to be taken and adds significant value to the clinical management of patients with HF20,22. E’ has proven to be a strong predictor of the prognosis of HF, since this measurement reflects both the LV systolic and diastolic function. Additionally, the subendocardial fibers, which are responsible for contraction of the long axis, may be more susceptible to the effect of fibrosis, hypertrophy and ischemia due to their position, and this would explain why E’ is a good marker of the disease5. Another frequently used echocardiographic parameter is the measurement of the early mitral valve flow velocity (E), which can be obtained either at the septal or