Plasma catestatin level in patients with acute myocardial infarction and its correlation with ventricular remodelling
- 1Department of Cardiology, Peking University First Hospital, Beijing, P.R. China
- 2Department of Cardiology, Beijing Haidian Hospital, Beijing, P.R. China
- Correspondence to Wen-hui Ding, Department of Cardiology, Peking University First Hospital, Beijing 100034, P.R. China;
- Received 20 April 2012
- Revised 2 October 2012
- Accepted 14 November 2012
- Published Online First 8 December 2012
Background The evaluation of ventricular remodelling and functional recovery is essential in predicting the prognosis of patients with acute myocardial infarction (AMI).
Objective To determine the plasma catestatin level in patients with AMI, and investigate the association between plasma catestatin and heart function, and with left ventricular remodelling (LVR).
Methods Fifty-eight consecutive patients who were admitted within 12 h of the onset of their ST-segment elevation myocardial infarction symptoms between 1 October 2009 and 30 June 2011 were prospectively recruited. Circulating catestatin was measured by ELISA. All patients underwent an echocardiography examination during the first week; 31 patients had a second echocardiography examination 3 months after the myocardial infarction.
Results Plasma catestatin at the time of admission was significantly higher in patients than in normal controls. The level increased further in the first week after AMI. Three months after AMI, the plasma catestatin level of patients was comparable to that of normal controls. The plasma level of catestatin correlated with anterior AMI and left ventricular ejection fraction (LVEF) in the acute stage. Compared with patients without LVR, those with LVR had significantly higher level of plasma brain natriuretic peptide on day 7 and a significantly higher level of plasma catestatin on admission and on days 3 and 7 (p=0.033, p=0.001, p=0.006, p=0.021, respectively).
Conclusions Plasma catestatin levels were raised after AMI. An early increase of catestatin correlated with anterior AMI and LVEF. Plasma catestatin after the onset of AMI might be associated with the magnitude of progressive ventricular remodelling 3 months after AMI.
Deaths due to acute myocardial infarction (AMI) have decreased rapidly in recent years owing to revascularisation and drug treatment. However, the ventricular remodelling and functional recovery that occur after AMI are still major determinants of the long-term prognosis of patients with AMI.1 Evaluation of ventricular remodelling and functional recovery is therefore essential in predicting the prognosis of patients with AMI. Measures for evaluation of these processes are of great clinical importance.
AMI is associated with a complex pattern of neurohumoral activation, such as catecholamines, angiotensin II and aldosterone. Chromogranin A (CHGA) was found in secretory granules of chromaffin cells and postganglionic sympathetic neurons, where it was co-stored and co-released with catecholamines.2 Multiple proteolytic cleavage sites are present on CHGA, allowing the generation of several peptides with different actions, such as vasodilatation, negative inotropic actions, inhibition of catecholamine secretion and induction of apoptosis.3 Catestatin, one of the CHGA-derived fragments, discovered as a type of endogenous neuroendocrine peptide in 1988,4 may be involved in cardiovascular homoeostasis and the development of heart failure. The biological effects of catestatin include inhibition of nicotine-induced catecholamine release,5 ,6 stimulation of mast cells to release histamine,7 inhibition of the inactivation of nicotine receptors8 and chemostasis of monocytes.9 It acts also as an anti-endothelin-1 and pro-nitric oxide agent ex vivo10 and as a potent vasodilator in vivo.11 Therefore catestatin may be a new cardiac modulator and may have an important role in the process of myocardial infarction. In animal models, exogenous catestatin decreased the infarct area in rats.12 These results indicated that catestatin may have a cardiac protective role. Previous clinical studies found that plasma CHGA was increased in patients with acute coronary syndrome, and was associated with poor prognosis such as heart failure and death.13 We hypothesised that catestatin, the downstream product of CHGA, might play a part in the pathophysiological process of AMI.
In this study, we determined the plasma catestatin level in patients with AMI, and investigated the association between plasma catestatin and heart function, as well as ventricular remodelling.
Patients and methods
Fifty-eight consecutive patients who were admitted within 12 h of the onset of their ST-segment elevation myocardial infarction symptoms between 1 October 2009 and 31 March 2011, were prospectively recruited. The diagnosis of acute ST-segment elevation myocardial infarction was established according to the 2004 American College of Cardiology/American Heart Association guidelines.14 Patients with chronic heart failure, malignancy, infection, chronic kidney disease, autoimmune disease or pheochromocytoma were excluded. Blood samples were drawn immediately after admission and on days 3 and 7 for the measurement of catestatin. Blood was taken from 21 patients after 3 months for the measurement of catestatin. Brain natriuretic peptide (BNP) was measured at admission and day 7 after AMI. Blood samples were obtained from 52 age- and gender-matched healthy blood donors as normal controls. Organic diseases were excluded by taking the disease history, and by routine physical and laboratory examination. The research complied with the Declaration of Helsinki and was approved by the ethic committee of our hospital. Informed consent for inclusion in the study was obtained from each participant.
Measurement of plasma catestatin
For blood samples, 10% EDTA-Na2 (1 mg/ml) and aprotinin (2500 IU/ml) were added to the samples. Plasma was extracted and stored at −80°C until used. Plasma catestatin level was measured by the catestatin ELISA kit (Phoenix Pharmaceuticals, Burlingame, California, USA) according to the manufacturer's instructions, as described previously.15 In brief, 25 ml primary antibody and 25ml biotinylated peptide were added to 50 ml/well of the standard, sample or positive control in the ELISA plate. The samples were incubated at room temperature for 2 h. The plates were washed four times with 350ml/well of assay buffer. Streptavidin horseradish peroxidase solution (10 ml/well) was added; the plates were incubated at room temperature for 1 h and washed four times with 350 ml/well of assay buffer. Then 100 ml of tetramethylbenzidine substrate solution was added and the plates were incubated at room temperature for 1 h. The reaction was terminated with 100 ml/well of 2 mol/l HCl. The optical density of absorbance was read at 450 nm.
BNP was measured by chemiluminescence immunoassay, cardiac troponin I (cTNI) by a fluorescent sandwich immunoassay technique and creatine kinase-MB (CK-MB) by a chemiluminescence microparticle immunoassay. All three measurement were carried out by the department of clinical laboratory of our hospital.
All patients underwent an echocardiography examination during the first week; 31 patients had a second echocardiography examination 3 months after the myocardial infarction. The examination was performed on a commercially available machine (GE Vivid 7, General Electric, Fairfield, Connecticut, USA) with 2–4 MHz transducers. The echocardiography examination was carried out with the participant in the left lateral decubitus position. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume and left ventricular ejection fraction (LVEF) were measured using a modified biplane version of Simpson's method with apical two- and four-chamber views. Measurements for up to three cycles were averaged. The investigator who performed the echocardiograms was blinded to the clinical and laboratory data of the patients. Left ventricular remodelling (LVR) at the third month of follow-up was defined as a >20% increase in LVEDV compared with baseline.16 ,17
Plasma levels of catestatin on admission, on days 3 and 7 and at 3 months were compared. Factors influencing the plasma level of catestatin in patients with AMI were analysed. Associations between plasma levels of catestatin and measures of ventricular remodelling were analysed. Quantitative variables are described as mean±SD for normally distributed data or median (range) for non-normally distributed data, as appropriate. Differences in quantitative parameters between groups were assessed by the t test (for normally distributed data) or non-parametric test (for non-normally distributed data). Pearson's test was used for correlation analysis. The association between different clinical parameters and plasma catestatin level was determined by multiple linear regression analysis. A p value of <0.05 was considered statistically significant. Analysis was carried out with SPSS software (V.13.0, SPSS Inc, Chicago, Illinois, USA).
The 58 patients with acute ST-segment elevation myocardial infarction (54 male, four female) were aged 60.3±11.8 years at diagnosis. The median duration from onset of symptoms to admission was 3.75 (range 2.45–6.13) h. Thirty patients (51.7%) had a history of hypertension; 18 patients (31.0%) had diabetes mellitus and 38 patients (65.5%) had a history of smoking. For the 58 patients, body mass index (BMI) was 24.9±3.0 kg/m2; fasting blood glucose 7.1±0.54 mmol/l; serum creatinine 78.0±16.0 μmol/l; serum total cholesterol level 4.20±0.96 mmol/l; triglycerides level 1.11 (0.79–1.62) mmol/l. On admission, the heart rates were 78±14 beats/min; systolic blood pressure 127±26 mm Hg and diastolic blood pressure was 78±17 mm Hg. Thirty-one patients (53.4%) were diagnosed with anterior myocardial infarction. Seven patients (12.1%) had a cardiac function with Killip class ≥ II. 53 patients (91.4%) received emergency percutaneous coronary intervention on admission.
Plasma catestatin level in patients with AMI and controls
Plasma catestatin on admission was significantly higher in patients with AMI than in normal controls (1.00 (0.66–1.50) ng/ml vs 0.84 (0.56–1.17) ng/ml, p<0.05). The level of plasma catestatin increased on day 3 of AMI (1.12 (0.76–1.70)ng/ml, p<0.05, compared with that on admission). The level of plasma catestatin was even higher on day 7 (1.32 (0.81–1.73) ng/ml, p<0.01, compared with that on admission). Three months after AMI, the plasma level of catestatin was comparable with that of normal controls (0.92 (0.70–1.79) ng/ml vs 0.84 (0.56–1.17) ng/ml, p>0.05) (figure 1).
Factors that influenced the plasma level of catestatin in patients with AMI
The following factors were included in the univariate analysis: age, gender, BMI, LVEF, time to revascularisation, CK-MB, cTNI, etc. In the univariate analysis, the following parameters were found to be associated with the plasma level of catestatin: age, BMI, the site of AMI, and LVEF 1 week after AMI. These four parameters were included in the multiple linear regression analysis as covariates to investigate the independent predictors of the plasma level of catestatin on day 7 of AMI. It was shown that anterior AMI and LVEF on day 7 of AMI were independently associated with the plasma level of catestatin (table 1).
Associations between plasma levels of catestatin and ventricular remodelling 3 months after the onset of AMI
Thirty-one of the 58 patients underwent a second echocardiography examination 3 months after onset of AMI. Of these 31 patients, 30 received emergency percutaneous coronary intervention. All these patients received aspirin and statins; 24 (77.4%) received β blockers and 27 (87.1%) received angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
According to the definition of LVR described above, 7/31 (22.6%) patients had LVR at 3 months after the onset of AMI. Compared with the 24 patients without LVR, those with LVR had a significantly higher level of plasma BNP on day 7 and a significantly higher level of plasma catestatin on admission, on day 3 and day 7 (p=0.033, p=0.001, p=0.006, p=0.021, respectively) (table 2).
In this study, we showed that plasma catestatin levels increased after AMI. An early increase of catestatin correlated with anterior myocardial infarction and LVEF. The plasma catestatin level after the onset of AMI might be associated with LVR after AMI.
The reason for the increase of catestatin is not yet fully clear. In AMI, sympathetic system activation results from many factors, including pain, anxiety, decrease of blood pressure and anaerobic metabolism in the ischaemic area. Previous studies have shown that catecholaminergic activation in AMI, as measured by plasma adrenaline and noradrenaline, occurs within the first 4–18 h.18 Graham et al19 found that uncomplicated AMI was associated with a protracted sympathetic neural hyperactivity, which occurred early, persisted at 3 months and decreased at 6 months. We speculated that the increase of catestatin, the inhibitor of catecholamine release, after AMI reflected the compensation mechanism of catecholaminergic activation, which might reduce the harmful effect of catecholamine. Additionally, previous studies indicated that catestatin causes dilation of periphery vessels, reduces contractility of the heart and inhibits the positive inotropic action of isoproterenol and endothelin.20 Therefore, the increase of catestatin in patients with myocardial infarction may protect the myocardium.
We found that the catestatin in patients with anterior myocardial infarction was significantly higher than in those patients with inferior myocardial infarction. Anterior myocardial infarction is independently associated with the plasma level of catestatin. As we know, the number of sympathetic nerve endings and their receptors in the anterior wall is greater than that in the inferior wall. Previous studies found that in anterior myocardial infarction the sympathetic nerve system was activated more significantly.21 The higher level of catestatin in patients with anterior myocardial infarction is probably due to its endogenous inhibition of catecholamine.
The LVEF was also independently associated with the level of catestatin in myocardial infarction. The relationship between catestatin and LVEF indicated that the increase of catestatin after myocardial infarction is probably related to cardiac function and size of infarction. Penna et al12 used isolated rat heart as an ischaemic/reperfusion model. They found that when exogenous catestatin was administered before reperfusion, infarct size was reduced and left ventricular function was improved. The improved systolic function suggested that catestatin had a direct anti-stunning and anti-contracture effect. Therefore, the increase of plasma catestatin in patients with overt myocardial dysfunction after myocardial infarction might be a protective compensation reaction.
Cardiac remodelling after myocardial infarction is characterised by changes in the size, shape and function of the heart. At the organ level, important pathological features of postinfarction LVR include infarct expansion, myocardial hypertrophy and global ventricular dilatation.22 Infarct expansion would increase left ventricular systolic and diastolic volumes with resultant increase in wall stress, closely associated with a worse prognosis in patients with heart failure. Therefore it is important to identify prospectively patients likely to have ventricular remodelling and treat them adequately to prevent progression.
We have demonstrated that patients with LVR had a significantly higher level of plasma catestatin than those without. This indicated that catestatin was also associated with ventricle remodelling after myocardial infarction, and the mechanism is different from BNP. It has been shown that the sympathetic nervous system is activated rapidly soon after coronary artery occlusion.23 The level of plasma adrenaline and noradrenaline increased within a few hours after myocardial infarction.18 The increase of catecholamine activates β-adrenergic receptors, which results in contraction of arteries, an increase of the cardiac afterload and augmentation of wall stress. Catecholamine also increases myocardial oxygen consumption and decreases myocardial oxygen supply, which could lead to infarct extension. Therefore, activation of the sympathetic nervous system plays a significant role in ventricular remodelling soon after myocardial infarction. An early rise of catestatin and inhibition of catecholamine may compensate for the ill effect of catecholamine on ventricular remodelling. Jansson et al3 reported that the CHGA level on day 1, which is the precursor of catestatin, was independently associated with the long-term mortality and heart failure hospitalisations in patients with acute coronary syndrome. The relationship between early increase of catestatin and long-term prognosis of patients with ST-segment elevation myocardial infarction requires further research.
The limitation of this study was that only 21 of the 58 patients had blood samples and echocardiography data available at 3 months. Therefore, further research with a larger sample size is needed to confirm the results.
Plasma catestatin levels increased after acute myocardial infarction (AMI).
Early increase of catestatin correlated with anterior myocardial infarction and left ventricular ejection fraction.
Plasma catestatin after the onset of AMI was associated with left ventricular remodelling 3 months after AMI.
Current research questions
The relationship between early increase of catestatin and long-term prognosis of patients with ST-segment elevation myocardial infarction is worth further research.
A study with larger sample size is needed to verify the result.
Catestatin is worth investigating in coronary heart disease, not restricted to acute myocardial infarction.
Mahapatra NR. Catestatin is a novel endogenous peptide that regulates cardiac function and blood pressure. Cardiovasc Res 2008;80:330–8.
Mahata SK, O'Connor DT, Mahata M et al. Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest 1997;100:1623–33.
Kruger PG, Mahata SK, Helle KB. Catestatin (CgA3442364) stimulates rat mast cell release of histamine in a manner comparable to mastoparan and other cationic charged neuropeptides. Regul Pept 2003;114:29–35.
Penna C, Alloatti G, Gallo MP et al. Catestatin improves post-ischemic left ventricular function and decreases ischemia/reperfusion injury in heart. Cell Mol Neurobiol 2010;30:1171–9.
Meng L, Ye XJ, Ding WH et al. Plasma catecholamine release-inhibitory peptide catestatin in patients with essential hypertension. J Cardiovasc Med 2011;12:643–7.
Contributors LM collected the data and wrote the manuscript. JW collected the data. PH provided the samples from the healthy controls. YY and L-tQ performed the echocardiography examination. W-hD and B-wZ designed and directed the study.
Funding This study was supported by a grant from the Medical Development of the Capital (2009–3026).
Competing interests None.
Patient consent Obtained.
Ethics approval Ethics committee of Peking University First Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.