Beta blocker therapy modifies circadian rhythm acute myocardial infarction J.R. Garmendia-Leiza a,b, ⁎, J.M. Andres-de-Llano b , J. Ardura-Fernandez b , J.B. Lopez-Messa c , C. Alberola-Lopez d , P. Casaseca-Higuera d a “Jardinillos” primary care, Palencia, Spain b Chronobiology Research Group, University of Valladolid, Spain c Coronary-Care-Unit, Palencia Hospital, Palencia, Spain d Signal Theory Department, E.T.S.I. Telecomunicacion, University of Valladolid, Spain article info Article history: Received 5 December 2010 Accepted 13 December 2010 Available online 8 January 2011 Keywords: Myocardial infarction Beta-adrenergic blocker Circadian rhythm Dear editor, Some studies about the onset time of AMI revealed that the peak incidence of pain onset signaling the occurrence of AMI ranged from 08:00 to 11:00 h in presumably diurnally active persons [1,2]. A recent study published by our group showed a morning incidence peak as well [3]. Otherwise the use of beta blockers could be caused by an attenuation or complete removal of the peaks of incidence of myocardial ischemia and AMI [4,5]. When cardio selective beta blocker agents were used, no peaks of incidence were found [6]. The objective of this study is to evaluate, by means of a new method of analysis [7], the presence of circadian variation in the time of onset of AMI in subgroups of patients receiving beta-adrenergic blockade agents. Patients with diagnosis of AMI at ICU discharge in 119 Spanish hospitals, according to WHO criteria, were collected from the ARIAM database. Among the whole group of 14,952 AMI, we selected a subgroup of 2055 patients who were taking beta-blocker agents. The selected study variable was the time of onset of symptoms. In order to carry out the rhythmometric analysis, we record and round AMI onset time to the nearest integer hour for every patient. With the purpose of verifying the presence of circadian rhythm, we used the multiple-sinusoid cosinor analysis. We identify the periods of these new sinusoids by means of nonlinear optimization techniques but it is also common to infer them using their clinical meaning. Following the latter approach, three sinusoids with periods of 24, 12 and 8 h were used [7]. We obtained the parameters of the model (MESOR and two additional parameters per sinusoid, namely, a function of the amplitude and the acrophase), as previously stated, by linear least squares fitting. A simple inspection of the cosinor fit and the original data showed that the fit was acceptable, and we did not consider further goodness-of-fit tests worth taking. The characteristics of the study population were: The mean age was 66.5 ± 11.3 years old (64.8 ± 11 for males and 71.3 ± 9.2 for females). 46% were older than 70 years. Male/Female ratio was 72.9%/27.1%. 60.9% of AMI was Q-wave AMI. AMI location was anterior in 39.8%. 90.3% of AMI were alive at ICU discharge. In addition, previous cardiovascular risk factors were hypertension ⁎ Corresponding author. Chronobiology Research Group, University of Valladolid, Spain. Tel.: +34 983 423186; fax: +34 983 183812. E-mail address: garbi69@garbi6.jazztel.es (J.R. Garmendia-Leiza). (67.2%), reinfarction (50.8%), dyslipemia (49.3%), diabetes (34.5%) and smoking (23%). The analysis of the infarction onset time in the whole population and subgroups of patients receiving beta-blocker agents showed a highly significant circadian rhythm (p<0.00001 and p<0.0001 respectively). The overall acrophase (maximum peak) for the global population was at 9:57 am while the batiphase (minimum) was at 4:46 am. Patients taking beta-blocker agents presented slightly different values: 9:23 am and 4:56 am respectively. The sinusoidal pattern in the global population shows one single incidence peak, in the morning, and progressive decrease all through the day. In patients taking beta-blocker agents, the fitted curve shows a tri-modal profile, with peaks separated by approximately 8 h, and roughly located at times 0–1 h, 9–10 h and 17–18 h. Fig. 1 shows comparison between both groups. Previously published studies have demonstrated circadian variation in the time of onset of myocardial infarction. Some authors have reported that beta-adrenergic blockers are able to attenuate the CR of AMI [8]. Other authors maintain that these drugs are able to modify such a rhythm without an overall loss, by causing an attenuation in the morning incidence peak and drawing a sinusoidal curve with a lower dynamic range with harmonic components of periods 6–8–12 h [4,5,9–11]. Our study population shows circadian rhythm in the time instant of onset of AMI symptoms (Fig. 1). The 8-h period component is particularly visible. The treatment with beta-adrenergic blockers is one of the independent variables that may show a higher influence on the modifications detected in the CR of the AMI. Different physio- pathological mechanisms affected by the beta blocker agents may Fig. 1. Comparison between both fitted sinusoidal curves. In the continuous line, myocardial infarction general population, without treatment with beta-adrenergic blockade agents. In the pointed line, patients with acute myocardial infarction who were taking beta-adrenergic blocker agents. Original data and a 3-component sinusoidal fit. The values of the number of infarction cases are normalized to have zero mean and unity variance. The periods of the sinusoidal components used in the fit were, in all the cases, 24, 12 and 8 h. 316 Letters to the Editor