Our study has shown that, in unselected patients with acute MI, higher levels of copeptin at hospital arrival were associated to worse prognosis, as it is associated with higher hospital mortality and higher 1-year follow-up mortality. However, we did not find this association with HGF.
Copeptin have been associated with high mortality in patients with suspected acute coronary syndrome at hospital arrival in many previous studies. Balmelli et al. [22] found that high levels of copeptin measured at hospital arrival were associated with worse prognosis: higher hospital mortality and 1-year mortality, in their prospective study in patients presenting to the Emergency Department with symptoms suggestive of acute MI of less than 12 h; although, in this study, only 15.9% of patients were finally diagnoses of acute MI, being the other diagnoses unstable angina (14.0%), cardiac but noncoronary cause in 13.0%, noncardiac cause of chest pain in 48.4% and remained of unknown origin in 48.4% of patients included in the study. Maisel et al. [23] also found that high levels of copeptin were a powerful predictor of death at 180 days and hospitalization, in patients who arrived at hospital with chest pain within 6 h of pain onset; however, in this study the proportion of patients with acute MI was only 7.9%. Lattuca et al. [24] measured level of copeptin and cardiac troponin I at the beginning of percutaneous coronary intervention in unselected patients with acute ST-segment elevation myocardial infarction. They found that levels of copeptin were higher in patients who died during hospitalization, during the first 30 days after the myocardial infarction and at 1 year follow-up; performed a multivariate analysis associating one year mortality with the presence cardiogenic shock, increasing age, the presence of higher levels of copeptin (> 128.2 pmol/L) and radial access.
It has been demonstraed that the level of copeptin at admission has a superior prognostic compared to peak of cardiac troponin I. In this way, the ConTrACS study [25] evaluated the prognostic value of copeptin, measured at hospital arrival, in symptomatic patients with increased high sensitivity cardiac troponin T presenting to the Emergency Department. They demonstrated that patients with higher levels of copeptin had higher mortality in the entire cohort. Without differences when they analyzed only the group of patients who were finally diagnoses of acute coronary syndrome (27.6% vs 10.6% in patients with normal copeptin values, < 0.0001). Also, they found that the 30 days follow-up mortality were associated with higher levels of copeptin (4.5% vs 0.4% in patients with normal copeptin values, < 0.0001). Zellweger et al. [26] demonstrated that copeptin was strongly and independently associated with death during 720 days follow-up in diabetic patients with acute MI; even in those in which the diagnosis of acute MI was not finally confirmed.
One recent meta-analysis [27] evaluated the prognostic value of copeptin in patients with acute coronary syndrome and concluded that elevated copeptin was associated with higher mortality with a pooled sensitivity of 0.77% (95% CI: 0.59–0.89) and a pooled specificity of 0.60 (95% CI: 0.47–0.71). It included 6 studies, with a variable follow-up period between 30 days and 1 year.
Also, copeptin has been related with the development of post MI complications, as development of left ventricular dysfunction and heart failure after MI, what influences acute MI mortality [8, 9, 28].
In patients with ischemic heart disease, the prognosis value of serum levels of HGF has demonstrated contradictory results. In our study, we did not find an association between HGF levels and worse outcome in patients with acute MI.
Some authors have related high levels of HGF with a better prognosis. So, Yasuda et al. [29] measured HGF levels in 40 patients with acute MI who underwent coronary reperfusion therapy upon admission. They found an enhanced HGF secretion from the infarct region, which correlated inversely with the left ventricular end-diastolic volume index, left ventricular end-diastolic pressure and tau, and positively with left ventricular ejection fraction; so, they concluded that enhanced HGF secretion is associated with attenuation of ventricular remodeling and improvement in cardiac function. Heeschen et al. [30] found that high HGF serum levels in patients with refractory unstable angina were associated with low incidence of death and nonfatal myocardial infarction at six-month follow-up; although in this study, patients with higher HGF levels had more frequently collateral circulation and partial or complete retrograde filling in coronary angiogram study.
On the other hand, some studies show that HGF levels are significantly higher in patients with worse prognosis. Konopka et al. [12] measured levels of HGF as soon as possible after admission to hospital and 24 h afterward, in 104 patients with the first episode of ACS who were eligible for coronary angiography and, eventually, percutaneous coronary intervention. They found that 33 patients (32%) suffered the primary outcome of the study (a composite endpoint of death, MI, exacerbation of angina, heart failure, cardiovascular re-intervention, re-hospitalization due to cardiovascular causes and stroke). On them, the concentration of HGF observed was significantly higher than in patients without any complication, classified as the primary outcome during the three-month follow-up. This authors also measured HGF levels in 6 patients with acute MI during the first day of ACS (repeated 10 times during the first day) and once at discharge from hospital; and found a marked increase in HGF levels in the first measurement, that were reduced to almost normal values within 5 h, with a second increase of HGF levels during the first 24 h in those patients who had serious cardiovascular events in the acute stage of MI (cardiac arrest and early re-occlusion of the coronary artery) [31]. Lamblin et al. [14] found that levels of HGF were higher in patients who died or were rehospitalization for heart failure during 1-year follow-up after a first anterior wall Q‐wave MI. Susen et al.18 measured HGF levels at admission in 488 patients with acute MI referred for percutaneous coronary revascularization who were not receiving heparin and found that serum HGF levels were a strong and independent predictor of worse clinical events (a composite of death and non-fatal MI) during a median follow-up period of 14.9 months.
This study had several limitations. First, HGF and copeptin samples were obtained in a variable time since onset of symptoms, hence the rapid changes in serum levels may affect the results. Second, we did not make serial determinations of copeptin nor HGF, to see the evolution and peak maximum. Third, we cannot quantify exactly the clinical benefit associated with an improved risk stratification based on copeptin levels. Fourth, our study is only a descriptive study, not an interventional one, so we cannot evaluate the clinical impact of measurement of HGF and copeptin at hospital arrival.
Future studies are warranted to examine if those patients with high levels of copeptin could possibly benefit from revascularization of all the lesions found in the coronary angiography, prolong admission to the coronary unit or reinforcement of antiplatelet treatment, or even, anticoagulation therapy; closer follow-up or more rigorous control of treatment and risk factors. Fifth, we did not assess the relationship between the treatment received, HGF and copeptin levels and mortality.
We consider that the main strength of our study is that it has allowed us to obtain real world data, since it was carried-out under conditions of daily clinical practice.