Predictive value of heart-type fatty acid-binding protein for left ventricular remodelling and clinical outcome of hypertensive patients with mild-to-moderate aortic valve diseases

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Abstract

Heart-type fatty acid-binding protein (H-FABP), a marker of acute myocardial infarction and a soluble cytosolic protein, may be released following left ventricular remodelling in cardiac overloaded hearts caused by hypertension, aortic regurgitation (AR) or aortic stenosis (AS). Our aim was to investigate if H-FABP levels are associated with left ventricular remodelling and clinical outcome in hypertensive patients with AR or AS. H-FABP and brain natriuretic peptide (BNP) were measured, glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease (MDRD) equation, and left ventricular dimension at systole corrected for body surface area (LVDs/BSA) and relative wall thickness (RWT) were determined by echocardiography in hypertensive patients with mild-to-moderate AR (n=78), those with mild-to-moderate AS (n=73) and those without valvular heart diseases (HT) (n=50). H-FABP levels were significantly higher in AR (4.9±3 ng/ml) and in AS (4.5±3) than in HT (3.4±1) and BNP (65±73 pg/ml, 76±75, 35±22). H-FABP correlated with LVDs/BSA in AR (β=0.23, P<0.05), and RWT in AS (β=0.18, P<0.05) after adjustment for age, gender and all the other variables. AS and AR patients were prospectively followed up for cardiac events during 34±19 months. A multivariate Cox hazard analysis indicated H-FABP was an independent predictor of outcome both in AR (relative risk (RR)=7.61, 95% CI=2.39–25.3) and AS (RR=13.6, 95% CI=3.27–66.9). H-FABP, associated with left ventricular remodelling, is useful in predicting clinical outcome in hypertensive patients with mild-to-moderate aortic valve diseases.

Introduction

Plasma levels of heart-type fatty acid-binding protein (H-FABP), an early marker of acute myocardial infarction,1 have been identified to be an independent prognostic factor even in nonischemic heart failure.2 H-FABP leakage into the blood circulation in patients with heart failure is considered to be due to ongoing myocardial damage during the process of cardiac remodelling.

As a soluble cytosolic protein in the cardiac myocytes, it leaks into the blood circulation following myocardial damage.3 However, the precise mechanisms of H-FABP leakage in heart failure have not been fully clarified, and, to our knowledge, there are no reports regarding the relationship between left ventricular remodelling and plasma H-FABP levels in clinical settings.

Because of its smaller size and abundant expression, H-FABP may serve as a sensitive marker of ongoing cardiac injury following left ventricular remodelling even in minor heart failure such as mild-to-moderate aortic valve diseases.

Mild-to-moderate aortic regurgitation (AR) and aortic stenosis (AS) are regarded as benign disorders as they usually have haemodynamically nonsignificant lesions. However, mild and moderate AS has been reported recently to have worse clinical outcome than commonly assumed.4 Furthermore, hypertensive patients with AS develop cardiac symptoms on their early stages,5 and hypertensive patients with mild-to-moderate AR had an increased prevalence of left ventricular hypertrophy.6 Thus, hypertensive patients with mild-to-moderate aortic valve diseases are likely to have an accelerated process of left ventricular remodelling that can be associated with worse clinical outcome.

Our aim is two-fold: (1) to investigate if H-FABP levels are associated with cardiac remodelling, or left ventricular morphological changes in patients with coexisting hypertension and aortic valve diseases; and (2) to evaluate the prognostic value of H-FABP for poor clinical outcome in hypertensive patients with aortic valve diseases.

Methods

Study design

The study is based on a prospective cohort of 285 patients with hypertension and cardiac symptoms (exertional dyspnea or chest discomforts on exercise) who were referred for echocardiography from January 2000 to December 2001. Out of 285 subjects, 78 patients with mild-to-moderate AR, 73 patients with mild-to-moderate AS were enrolled in this study. Age-and-gender matched hypertensive patients without valvular heart diseases (n=50) served as control group. All these patients received antihypertensive medications at the time of entry. The study protocol was approved by the ethical committee of our hospital.

Exclusion criteria

Patients were excluded if they had recent coronary artery diseases or cerebral infarction, skeletal muscle diseases, haemiplegia or immobilized states, aortic dissection, renal impairment (serum creatinine >2.0 mg/dl), malignant disorders and rheumatic diseases. Patients were excluded if they had plasma creatinine phosphokinase (CPK) or troponin T above cut-off levels (230 mU/ml and 0.02 μg/ml, respectively).

Echocardiography

All participants underwent transthoracic echocardiography on their stable states using a commercially available instrument (Philips Sonos 5500, Philips, Best, the Netherlands). Left ventricular diameter at systole (LVDs), left ventricular diameter at diastole (LVDd) and left ventricular posterior wall thickness (LVWT) were measured by M-mode echocardiography. LVDs were indexed by body surface area (LVDs/BSA). Relative wall thickness (RWT) was calculated as LVWT/LVDd multiplied by 2. The maximum aortic jet velocity was obtained by continuous wave Doppler echocardiography. The morphology of aortic valve was observed by B-mode and the presence of AR was evaluated by colour flow Doppler. The severity of regurgitation was assessed using regurgitant jet width ratio to left ventricular outflow tract width (AR ratio); an AR ratio <0.3 was defined as mild AR, 0.3–0.6 as moderate and >0.6 as severe. To avoid the entry of severe aortic valve diseases, patients with aortic jet velocity above 4.0 m/s or AR grade >0.6 were excluded from this study. Patients with a peak aortic jet velocity between 2.0 and 4.0 m/s and absence of more than mild AR were enrolled as mild-to-moderate AS.

Assessment of H-FABP and natriuretic peptides and estimation of glomerular filtration rate

Blood samples were drawn on the same day as echocardiography to measure troponin T (Enzymun test second-generation assay, Boehringer, Mannheim, Germany), H-FABP (MARKIT-M, Dainippon Pharmaceutical company, Osaka, Japan) and brain natriuretic peptide (BNP) (Shionoria, Shionogi, Osaka, Japan). CPK was measured using spectrophotometric method (Quickauto Neo CK, Shinotest, Sagamihara, Japan). Since H-FABP levels are influenced by renal function, glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease (MDRD) equation: estimated GFR (ml/min/1.73 m2)=186 × [serum creatinine]−1.54 × [age]−0.203 × 0.742 (if female) × 0.881 (race factor).

Follow-up

After the initial assessments, the hypertensive patients with aortic valve diseases were prospectively followed up for cardiac events. The cardiac events were defined as decompensation of heart failure, angina pectoris or myocardial infarction, new onset of atrial fibrillation and death due to cardiovascular problems. Decompensation of heart failure was determined if a patient, without clinical signs of ischemic event, complained of dyspnea or chest discomforts at rest or on exercise, accompanied by at least one of pulmonary congestion, edema and elevation of BNP levels.

Statistical analysis

Since distributions of H-FABP and BNP were positively skewed, the variables were log-transformed. The natural log-transformed levels were used in multiple linear regression analysis and the Cox proportional hazard analysis. Continuous variables were expressed as mean ±s.d. Comparisons between three groups were analysed by analysis of covariance followed by Dunnet's test for continuous variables, and χ2-test for categorical variables. To investigate a determinant factor for H-FABP levels either in AR and AS patients, a multiple linear regression analysis was performed, entering age, gender, estimated GFR, aortic jet velocity, RWT, LVDs/BSA and log BNP as explanatory variables. Age and estimated GFR were entered in this multiple model, since plasma H-FABP levels were reported to be influenced by age and renal impairment.

The predictive value of H-FABP for cardiac events was tested in AR patients and AS patients, separately, using a multivariate Cox proportional analysis. The variables entered in the multivariate model were age, gender, estimated GFR, aortic jet velocity, log H-FABP, log BNP, RWT and LVDs/BSA. The results are presented as relative risk and 95% confidence intervals.

Assignment of patients to a high-risk group was defined by a median level of H-FABP (3.8 ng/ml for AR and 3.6 ng/ml for AS, respectively). Cardiac event-free survival between high- and low-risk groups was analysed using Kaplan–Meier curve followed by the log-rank test.

Results

Baseline characteristics of the patients

Clinical characteristics that could influence plasma H-FABP levels such as age and estimated GFR did not differ among the three patient groups (Table 1).

Table 1 Basic clinical characteristics

H-FABP, natriuretic peptides and echocardiographic findings

Plasma levels of H-FABP, BNP and the parameters of echocardiographic findings of hypertensive patients are summarized in Table 2. H-FABP and BNP levels were greater in AR and AS than in hypertensive patients without valvular diseases (control group). LVDs/BSA values in AR patients were greater than those of the control group. RWT values of AS patients were greater than those of AR patients and of the control group. Troponin T levels were below cut-off level (0.02 ng/ml) in all the participants.

Table 2 H-FABP, BNP and echocardiographic findings

Correlations between H-FABP and other parameters of left ventricular findings

To investigate relationship between plasma H-FABP levels and echocardiographic findings, multiple linear regression analysis was performed (Table 3). In the regression model, log H-FABP levels were correlated with Ds/BSA in AR and with RWT in AS, after the adjustment for age, gender, estimated GFR and the other variables.

Table 3 A multiple linear regression model for log H-FABP levels either in hypertensive patients with aortic regurgitation and in those with aortic stenosis

Cardiac events and survival analysis

The patients were prospectively followed up for cardiac events. During the follow-up period of 34±19 months, 46 events occurred out of 151 patients. In hypertensive patients with AR, worsening of heart failure developed in 13, angina pectoris in five, cardiac death in five and new onset of atrial fibrillation in one during the follow-up period of 35±18 months. In hypertensive patients with AS, worsening of heart failure developed in nine, angina pectoris in seven, cardiac death in five and new onset of atrial fibrillation in one during the follow-up period of 33±19 months. Cardiac death occurred exclusively in elderly patients (mean age of patients who developed cardiac death=85±5 years) and due to angina and sudden death.

Patients with higher levels of H-FABP (stratified by median levels) were associated with worse prognosis both in AR (Figure 1) and AS (Figure 2) groups. H-FABP independently predicted cardiac events both in AR and AS patient groups after the adjustment with age, gender, log BNP, estimated GFR and the echocardiographic findings in the multivariate Cox proportional hazard analysis (Table 4). BNP was an independent predictor of cardiac events in AS patient group in the same model.

Figure 1
figure1

Cumulative survival of high- and low-risk patients group stratified by the median H-FABP level of 3.8 ng/ml in hypertensive patients with mild-to-moderate AR.

Figure 2
figure2

Cumulative survival of high- and low-risk patients group stratified by the median H-FABP level of 3.6 ng/ml in hypertensive patients with mild-to-moderate AS.

Table 4 Multivariate Cox proportional hazard analysis of biochemical and echocardiographic predictors of outcome either in hypertensive patients with AR and in those with AS

Discussion

The present study has two major findings. First, H-FABP levels were associated with the morphological changes of left ventricle: with left ventricular dilation in AR and with left ventricular hypertrophy in AS. Second, H-FABP level was an independent predictor of cardiac events after adjustment for other parameters of left ventricular dysfunctions in medically treated hypertensive patients with mild-to-moderate aortic valve diseases.

Processes occurring ventricular remodelling include dilation and reshaping of the left ventricle, myocyte hypertrophy and ongoing myocyte loss.7 As for left ventricular remodelling in patients with aortic valve diseases, hypertrophy usually develops to normalize wall stress; in AS concentric hypertrophy and in AR eccentric hypertrophy.8 Furthermore, left ventricular remodelling is clinically important in predicting the prognosis of aortic valve diseases. Rossi et al.9 reported that left ventricular morphological changes were predictors of worsening symptoms in severe AS. Left ventricular dilation determined by echocardiography has been widely utilized as a marker of valve replacement surgery in AR.

Cardiac (left ventricular) remodelling may be defined as genome expression, molecular, cellular, interstitial changes that are manifested clinically as changes of size and function of the heart after cardiac injury.7 There seems to be no direct clinical or experimental evidences linking H-FABP leakage with the process of left ventricular remodelling, as far as we know. However, several clinical studies have indicated that H-FABP is a sensitive marker of minor myocardial injury in heart failure.3 In addition, H-FABP has been reported recently to be a prognostic marker in patients with nonischemic dilated cardiomyopathy,10 and to be correlated with the size of Thallium-201 perfusion defects in patients with hypertrophic cardiomyopathy.11 An experimental study has indicated that the appearance of cardiac troponin T and I in the circulation was assumed to be proportional to chronic loss of these proteins from injured myocardium associated with left ventricular remodelling in porcine hearts of postinfarction left ventricular remodelling model.12 These results have led us to speculate that H-FABP leakage may be associated with left ventricular remodelling or morphological changes in cardiac overloaded hearts.

In our study, although troponin T levels remained below cut-off levels in all the participants, H-FABP levels were significantly elevated in hypertensive patients with AR and in those with AS than in those without valvular diseases. There are two possible mechanisms of H-FABP leakage into the circulation; first, irreversible myocardial injury caused by cell necrosis or apoptosis and second reversible disturbances of cell membrane metabolism.13 Cardiac overload or continuous mechanical stress results in disturbances in cell membrane integrity so that cell membrane become permeable to small size molecule such as H-FABP,14 since the prevention of membrane leaks is an energy-dependent process in which myocardial plasma membranes become permeable to macromolecule under conditions of energy storage.13 In comparison with troponin T that is bound to myocyte structure, H-FABP, soluble small-sized protein abundantly expressed in cytosol, is more likely to leak into the blood circulation at minor membrane injury or disintegration. Thus, H-FABP may be a sensitive marker of ongoing minor myocyte injury in less-severe heart failure patients.

Mild and moderate AS have been considered a benign disease for many years; however, Rosenhek et al.4 have recently reported that outcome of mild and moderate AS is worse than commonly assumed; with event-free survival with the end points defined as death or aortic valve surgery at 5 years. They also reported that the degree of aortic valve calcification and aortic peak jet velocity were predictors of the clinical outcomes. In our study, aortic jet velocity was not an independent prognostic factor both in AR and AS patients. This discrepancy regarding aortic jet velocity as a predictor of outcome may be attributable to the facts that a greater proportion of our study population consisted of patients older than those of Rosenhek et al, and that aortic valve surgery was not included in the end points.

Prevalence of mild-to-moderate AR in population-based studies has been reported as 8–13%.15 Hypertensive patients with mild-to-moderate AR had an increased prevalence of eccentric left ventricular hypertrophy.6 These results indicate that hypertensive patients concomitant with mild-to-moderate AR are high-risk population that may predispose to heart failure; however, to our knowledge, there were no recent reports regarding the prognosis of these patients population. Our study is the first report of the clinical outcome of hypertensive patients with mild-to-moderate AR.

Several clinical studies have revealed that BNP reflects onset of cardiac symptoms16, 17 or predicts the progression of valve severity18, 19 both in AS and AR. BNP is a predictor of clinical outcome in severe AS.20 In line with these reports, the present study showed that BNP was the independent prognostic factor on multivariate analysis in AS patients. H-FABP and BNP can be a sensitive marker of deterioration even in AS of their early stages.

The limitations of our study

Since H-FABP is eliminated by renal clearance, raised levels of H-FABP in our study may represent mild renal dysfunction. Mild renal dysfunction has emerged as a strong predictor of outcome in heart failure patients.21 We can not exclude the possibility that elevated levels of H-FABP in our patients simply reflect subclinical renal dysfunction; however, relationships between H-FABP levels and the degree of left ventricular morphological changes were significant even after the adjustment for estimated GFR using the MDRD equation in a multiple regression model. H-FABP may be a comprehensive marker of heart failure representing both cardiac and renal dysfunction.

In our study, most of the cardiac events, particularly cardiovascular death, occurred in very elderly patients. We do not know if the results of our study can be applied to younger age groups. However, the mean age of our patient population (70 years old) is representative of heart failure patients in the general population.

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Correspondence to M Iida.

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Keywords

  • H-FABP
  • BNP
  • left ventricular remodelling
  • cardiac overload
  • aortic valve diseases

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