European Journal of Heart Failure

European Journal of Heart Failure 2004 6(3):281-287; doi:10.1016/j.ejheart.2004.01.005

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© 2004 European Society of Cardiology

Can natriuretic peptides be used for the diagnosis of diastolic heart failure?

U. Dahlström

Department of Cardiology, Linköping University hospital Linköping, Sweden E-mail address: Ulf.Dahlstrom{at}lio.se

	Abstract

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
Many patients with heart failure have stiff hearts with an increased wall thickness and small volumes leading to diastolic dysfunction. Different definitions for diastolic heart failure have been proposed but today there is no generally accepted definition and there are few large controlled studies telling us how it should be managed. Natriuretic peptides (BNP or NT-proBNP) might be used to detect patients with diastolic dysfunction especially in those patients having a restrictive filling pattern or pseudo-normalised mitral flow pattern and in those, who are symptomatic. However, patients with relaxation abnormalities and mild symptoms or asymptomatic may have normal levels of the natriuretic peptides indicating no or only slight elevation of the left ventricular filling pressures. Thus low levels cannot be used as a rule out diagnosis of diastolic dysfunction.

Key Words: Diastolic heart failure • Patients • Natriuretic peptides

Received December 8, 2003; Accepted January 14, 2004

	1. Introduction

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
Traditionally chronic heart failure has been attributed to reduced systolic left ventricular function, accompanied by an increase in left ventricular filling pressures and volumes [1]. However, during the past 10 years it has become clear that many patients instead are suffering from impaired diastolic function with disturbances in the filling and the relaxation of the heart. These patients have stiff hearts with an increased wall thickness and small volumes [2–4]. There is no doubt today that diastolic heart failure is a pathophysiological clinical condition distinct from or concomitant with systolic heart failure [5,6].

From different studies we know that patients with systolic heart failure benefit from treatment with angiotensin-converting enzyme inhibitors [7], beta-receptor blockers [8] and spironolactone [9] resulting in reduced mortality and morbidity. Thus an early and correct diagnosis is of great importance for these patients. In patients with diastolic heart failure, we both lack large, convincingly positive, controlled trials telling us how to treat and we also have problems in identifying these patients.

The diagnosis in patients with systolic heart failure is based on clinical symptoms and/or signs of heart failure as well as evidence of abnormal cardiac function mostly assessed by use of echocardiography [10]. However, this method has limited availability and rather high costs.

It is not easy to diagnose diastolic heart failure accurately. The symptoms are non-specific, often being found in several other conditions. The diagnostic strategy includes objective measurement of diastolic function by use of Doppler-echocardiography. There are, however, drawbacks to using this method. Firstly, it is not widely available. Secondly, poor precision leads to misclassification because measurements are load dependent and vary with age making interpretation dependent on when the measurements were performed and on which medication.

An alternative diagnostic approach is to measure biochemical markers, e.g. natriuretic peptides, which are associated with cardiac dysfunction [11,12]. It is known that the secretion of natriuretic peptides (e.g. brain natriuretic peptide (BNP), and its biologically inactive fragment N-terminal proBNP (NT-proBNP)) are raised as the wall tension is increased in the failing heart [13,14]. BNP is produced primarily in ventricular myocytes and due to that elevations of BNP may more accurately reflect alterations in the structure and function of the ventricle. Previous studies have reported that BNP can be used in the diagnosis of systolic heart failure [12]. Therefore it is of interest to see if BNP or NT-proBNP can be of any help in the diagnosis of patients with diastolic heart failure/dysfunction.

The aim of this paper is to discuss whether these peptides may be of value in the diagnosis of patients with diastolic heart failure/dysfunction.

	2. Definition of diastolic heart failure/dysfunction

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
The European Society of Cardiology (ESC), in 1998, published guidelines for the diagnosis of diastolic heart failure, combining signs and symptoms of heart failure with an objective verification of impaired diastolic function (abnormal left ventricular relaxation, filling, diastolic distensibility and diastolic stiffness) and normal or almost normal systolic function [6].

However, the ESC guidelines have not yet gained general acceptance. The arguments against them have mainly focused on the fact that the measurements recommended are too complicated to use in clinical practice. Vasan et al. [15] suggested more rigorous criteria for the definition of diastolic heart failure including catheterisation within 72 h to evaluate filling pressures accurately. Due to practical difficulties, this approach although ideal, is not usable in clinical practice. However, ACC/AHA (American College of Cardiology) [16] Guidelines propose that if the patient has symptoms of heart failure but normal systolic function, the patient is classified as having heart failure with preserved systolic function, so that it is no longer mandatory to assess diastolic function objectively in these patients. Moreover, in a recently paper published by Cahill and co-workers [17] investigating patients admitted to hospital with a primary diagnosis of heart failure confirmed by clinical symptoms and signs, radiographic evidence of heart failure and clinical response to diuretic therapy, of the 99 patients with preserved systolic function (mean EF (ejection fraction) 55%) and no significant heart valve disease, only 43% met the inclusion criteria for diastolic heart failure as recommended in the ESC guidelines [6]. Using another type of echocardiographic parameter isovolumic relaxation time (IVRT) alone, <41% would be classified as diastolic heart failure. One may, therefore question whether the ESC guidelines are sensitive enough to diagnose patients with diastolic heart failure using non-invasive measurements. Jarnert et al. [18] have reported that Doppler tissue imaging is no more accurate than transmitral Doppler flow in diagnosing diastolic heart failure accurately and both were superior compared to the method of atrioventricular plane displacement. Thus, more sensitive, reproducible methods are needed to diagnose diastolic heart failure with non-invasive methods.

	3. Epidemiology of diastolic heart failure/dysfunction

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
Left ventricular diastolic dysfunction may arise as a consequence of various underlying conditions that result in a modification of the physical properties of the myocardium. These conditions include hypertension, diabetes and chronic ischemic heart disease [19,20]. We also know that atrial contraction is very important for the filling of the heart and especially in the elderly. Thus abbreviated filling in terms of sudden onset of atrial fibrillation may exacerbate diastolic dysfunction and sometimes even dramatic symptoms and signs (pulmonary congestion). Usually left ventricular diastolic dysfunction precedes systolic dysfunction, but can also be present for a longer period of time (years). Impairment of diastolic function appears to be age-related [21,22] and data suggest that while <10% of patients with heart failure below the age of 50 years have diastolic dysfunction this rises to 70% in patients aged over 80 years [23,24]. It has been stated that heart failure with preserved systolic function is primarily a disease of elderly women, most of whom have hypertension.

	4. Assessment of diastolic function

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
Regarding assessment of diastolic function we have no generally accepted single parameter as we have in patients with systolic heart failure (EF) as measurements can be complicated by progression of the disease, ageing and heart rate [25,26]. The best way to assess diastolic function is to perform invasive measurements and study the pressure/volume relationship and to measure left ventricular filling pressures but this is not feasible routinely. We need instead appropriate non-invasive measurements and, therefore most doctors today measure diastolic function by use of Doppler-echocardiography and estimate different measures such as IVRT, DT (deceleration time) and E/A ratio (E=early filling, A=atrial filling) or use tissue Doppler imaging or AV-plane displacement or magnetic resonance technique. Different, and sometimes opposite, deviations from normal diastolic measurements will be seen depending on whether the abnormality affects relaxation in initial diastole, or is mainly affecting left ventricular compliance, apparent at end-diastole. For example patients with abnormal left ventricular relaxation may develop an elevation in left atrial pressure as the disease progresses, which tends to normalise some of the Doppler abnormalities associated with impaired left ventricular relaxation [26]. This is known as pseudo-normalisation. Pulmonary venous flow profiles provide important complementary information, when they are recorded simultaneously and help to differentiate the E/A pattern from that of a normal person (Fig. 1).

View larger version (8K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Different types of diastolic dysfunction measured by Doppler-echocardiography.

 
Despite the limitations of Doppler-echocardiography, it has emerged as the best non-invasive method of diagnosing diastolic dysfunction in routine clinical settings. There is, however, an ongoing discussion over which echocardiographic parameter, should be used for evaluating diastolic function in the broader routine clinical setting.

	5. Treatment of diastolic heart failure/dysfunction

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
As mentioned in the introduction we do not know how to treat patients with diastolic heart failure/dysfunction since large randomised and controlled trials are lacking. Recently, a large trial (>3000 patients) the preserved part of the CHARM study was published [27]. This study evaluated the effect of the angiotensin II blocker candesartan or placebo in addition to conventional treatment in patients with clinical heart failure and EF>40%. The primary endpoint cardiovascular death and hospitalisation due to worsening heart failure was not significantly changed, indicating that addition of candesartan to conventional treatment was not of clinical benefit in patients included in the study. We have recently completed a Swedish randomised, placebo-controlled multi-center trial evaluating the effects of carvedilol on diastolic function in patients with heart failure patients with preserved left ventricular systolic function (EF>45%) and abnormal diastolic function. One hundred and thirteen patients were included and 97 completed the whole study. Baseline characteristics of the patients are shown in Table 1. Most of the included patients had a diastolic relaxation abnormality and most had only mild symptoms of dyspnoea at exertion. At the end of the study (after 8 months) there was a statistically significant improvement in E/A ratio in patients treated with carvedilol. Thus treatment with carvedilol resulted in a significant improvement of the diastolic function and the E/A ratio was the most useful parameter to identify the improvement [28]. BNP and NT-proBNP were measured before and at the end of the study. The blood samples were drawn while the patient was fasting and resting in the supine position. The samples were collected in pre-chilled plastic tubes containing EDTA, centrifuged immediately and then stored at –70 °C until analysed. Plasma BNP was analysed using a direct and specific non-extraction immunoradiometric assay for human BNP (ShionoRIA). Plasma NT-proBNP was analysed using a method described by Talwar et al. [29]. There was no change between or within the different groups (carvedilol group and placebo group) (Table 2). The mean values of both the measured peptides were normal but there was great variation between patients. There were trends for both BNP and NT-proBNP to increase into the upper normal reference range after treatment with carvedilol. One explanation might be that carvedilol initially induces a slight increase in the left ventricular filling pressure (by depressing myocardial contractility), which may be corrected by longer term treatment.

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics

 

View this table: [in this window] [in a new window]   Table 2 Plasma concentrations of BNP and NT-proBNP values before and after treatment in the two treatment groups carvedilol and placebo

 
The lack of elevation of natriuretic peptides strengthen our interpretation that the patients included in the study were too healthy to show benefit with carvedilol. In conclusion, patients included in this study had diastolic dysfunction based on relaxation abnormalities but no activation of the natriuretic peptides Thus, we could not use BNP or NT-proBNP in the clinical routine to detect patients with mild relaxation abnormalities.

	6. Diastolic heart failure/dysfunction in elderly patients

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
In another study in a primary care setting we contacted all patients aged 65–82 years, living in the small community of Kinda in the South–Eastern region of Sweden, who visited the primary health care station, with symptoms possibly associated with heart failure [30]. Only patients living in a nursing home or unable to cooperate during the examinations were excluded. Invitations to participate were given to 548 patients and 510 (93%) accepted participation. Focusing on those patients with isolated diastolic dysfunction (Table 3), the patients were divided into two groups, those with relaxation abnormalities (n=79) and those who had a pseudonormal pattern (n=13). The mean age was approximately 72 years and in the pseudonormal group there was a tendency to have more patients in New York Heart Association functional (NYHA) class III, ischemic heart disease, treatment with beta-blockers and with a higher mean value of NT-proBNP indicating more severely diseased patients. Table 3 also shows the characteristics for patients with left ventricular systolic dysfunction defined as ejection fraction below 50% as well as patients with both normal systolic and diastolic function. In Table 4 NT-proBNP values in patients with diastolic dysfunction due to a pseudonormal pattern and relaxation abnormalities are grouped by the NYHA-class.

View this table: [in this window] [in a new window]   Table 3 Basal characteristics of the patients included in the primary care study

 

View this table: [in this window] [in a new window]   Table 4 NT-proBNP values in patients with diastolic dysfunction grouped by the NYHA-class

 
Studies have demonstrated a correlation between left ventricular filling pressures and concentrations of natriuretic peptides, although with great variation [31,32]. One explanation for this variation might be that filling pressures are determined by both loading conditions and diastolic function [33]. In studies of patients with hypertension and especially those with left ventricular hypertrophy elevations of concentrations of natriuretic peptides have been detected [34]. Yamomoto et al. also found that patients with hypertension and relaxation abnormalities have elevated levels of BNP.

In contrast to other investigators we found no overall increase in NT-proBNP concentration when patients with isolated diastolic dysfunction were compared with patients with normal cardiac function. However, the group was heterogeneous as judged from echocardiographic examinations, with the majority of our patients having relaxation disturbances. This represents mild diastolic dysfunction with only slightly increased filling pressures. The patients with pseudonormal E/A mitral flow or restrictive filling pattern had more severe dysfunction and, as expected, had increased concentrations of NT-proBNP (Table 3), which has also been shown by Yu et al. [35]. Patients who are asymptomatic and have minor relaxation abnormalities have fairly normal concentrations of the natriuretic peptides. Talwar et al. also found no elevation of natriuretic peptide levels in patients with hypertension and a normal systolic cardiac function even if they had left ventricular hypertrophy [36].

Interestingly, as a group, the patients with relaxation disturbances in our study had decreased NT-proBNP concentrations, i.e. there was a bimodal distribution of values in diastolic dysfunction. At present we can only speculate on the reasons for this unexpected finding. Natriuretic peptides inhibit angiotensin II induced proliferation of cardiac fibroblasts [37]. Patients with relaxation disturbances have increased myocardial fibrosis and increased interstitial matrix formation. There is some similarity between these morphologic changes and those observed in mice with targeted disruption of the BNP gene [38]. In the group with the disrupted BNP allele multifocal fibrotic lesions appeared in the myocardium in spite of an absence of signs of hypertension or ventricular hypertrophy. Hypothetically, BNP may act as an antifibrotic factor in humans similar to what Ogawa et al. [39] proposed for mice. Low BNP secretion in relation to physiologic demands might, therefore predispose to myocardial fibrosis, which would indicate a clinical interest in low BNP concentrations in relation to the functional status of the heart. In support of these suggestions, Tsuruda et al. [40] recently showed that BNP is produced in cultured cardiac fibroblasts and decreases collagen biosynthesis.

	7. In summary

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 
The natriuretic peptides (BNP or NT-proBNP) have a role in detecting patients with diastolic dysfunction especially in those patients having a restrictive filling pattern or pseudo-normalized mitral flow pattern and in those, who are symptomatic. Patients with relaxation abnormalities and mild symptoms or who are asymptomatic may have normal levels of the natriuretic peptides indicating no or only slight elevation of the left ventricular filling pressures. Thus low levels cannot be used as a rule out diagnosis of diastolic dysfunction. However, if there are high concentrations of the natriuretic peptides there is a need for further investigation with echocardiography to verify the diagnosis of abnormal cardiac function.

	References

Top Abstract 1. Introduction 2. Definition of diastolic... 3. Epidemiology of diastolic... 4. Assessment of diastolic... 5. Treatment of diastolic... 6. Diastolic heart... 7. In summary References

 

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