Alberto Dominguez-Rodriguez

Melatonin and circadian biology in human cardiovascular disease

Abstract:  Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24‐hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti‐inflammatory, chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.

Decreased nocturnal melatonin levels during acute myocardial infarction

Abstract: Acute myocardial infarction is accompanied by an increase in cellular oxidative stress in the pericardial coverings of the heart. Melatonin is a highly potent and efficient radical scavenger. Little research has been carried out concerning the relationship between this antioxidant and acute myocardial infarction in humans. In this work, serum levels of melatonin and parameters of oxidative stress, such as glutathione peroxidase and lipid peroxidation levels were examined in light/dark periods in patients with acute myocardial infarction. Twenty‐five patients diagnosed with acute myocardial infarction were studied and 25 patients with no evidence of coronary artery disease served as controls. Venous blood samples were obtained from the patients and control subjects to determine melatonin, glutathione peroxidase and lipid peroxidation; the samples were collected at 10:00 hr (light period) and 03:00 hr (dark period) in the first 24 hr after admission to the coronary care unit. Our results demonstrate the existence of differences between changes in melatonin levels in control subjects and acute myocardial infarction patients, revealing a reduced nocturnal elevation in the acute myocardial infarction group. Glutathione peroxidase levels were lower after acute myocardial infarction and did not show diurnal variations. In the control group, lipid peroxidation levels presented a light/dark pattern but in the acute myocardial infarction group diurnal variations of this parameter were lost. Our data show that acute myocardial infarction is associated with a nocturnal serum melatonin deficit as well as increased oxidative stress, suggesting that melatonin is, at least in part, depleted during the dark phase to reduce the free radicals formed in acute myocardial infarction.

Cardiogenic shock after primary percutaneous coronary intervention: Effects of levosimendan compared with dobutamine on haemodynamics

Levosimendan is a new calcium sensitizer with positive inotropic properties. Cardiac power output (CPO) has been shown to be instrumental in the diagnosis of cardiogenic shock (CS) and is an important determinant of outcomes.

Clinical Aspects of Melatonin in the Acute Coronary Syndrome

This review considers the actions of an endogenously produced molecule, melatonin, on heart diseases. Recent research has shown that inflammation plays a key role in coronary heart disease (CHD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions and activation of inflammation can elicit acute coronary syndromes (ACS). Scientific evidence from the last 15 years has suggested that melatonin has positive effects on the cardiovascular system. The presence of vascular melatoninergic receptor binding sites has been demonstrated; these receptors are functionally linked to vasoconstrictor or vasodilatory effects of melatonin. It has been shown that patients with CHD have a low melatonin production rate, especially those with higher risk of cardiac infarction and /or sudden death. Similarly to other organs and systems, the cardiovascular system exhibits diurnal and seasonal rhythms, including those in the heart rate, cardiac output and blood pressure. The suprachiasmatic nuclei of hypothalamus and, possibly, the melatoninergic system modulate the cardiovascular rhythms. The melatonin attenuates molecular and cellular damages resulting from cardiac ischemia/reperfusion in which destructive free radicals are involved. Anti-inflammatory and antioxidative properties of melatonin are also involved in the protection against vascular disease, i.e. atherosclerosis. The current brief summary of the literature provides an overview on the role of melatonin in the ACS.

The role of melatonin in acute myocardial infarction

Melatonin, a circadian hormone with marked antioxidant properties, has been shown to protect against ischemia-reperfusion myocardial damage, especially when administered during reperfusion period. Melatonin has cardioprotective properties via its direct free radical scavenging and its indirect antioxidant activity. Melatonin efficiently interacts with various reactive oxygen and reactive nitrogen species and it also upregulates antioxidant enzymes and downregulates pro-oxidant enzymes. In addition, melatonin demonstrated blood pressure lowering, lipid profile normalizing and anti-inflammatory properties. The lack of these cardioprotective effects due to insufficient melatonin levels might be associated with several cardiovascular pathologies including ischemic heart disease. Patients with acute coronary syndrome or after myocardial infarction were shown to have reduced nighttime melatonin levels and 6-sulfatoxymelatonin urinary excretion. These alterations might translate to increased cardiovascular risk observed in acute myocardial infarction patients with low melatonin levels; and a mutation in melatonin receptors might augment the risk for acute myocardial infarction. Therefore, it is expected that melatonin administration could play a clinically relevant role in the pharmacotherapy of ischemic heart disease; an assumption supported by low toxicity and high safety of melatonin.

Light/dark patterns of soluble vascular cell adhesion molecule-1 in relation to melatonin in patients with ST-segment elevation myocardial infarction

Abstract:  Elevated levels of soluble cellular adhesion molecules have been reported in patients with acute coronary syndromes. Likewise, a relation between decreased nocturnal melatonin levels and coronary artery disease has been suggested. The aim of the present study was to investigate the day–night variations in the concentration of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) in patients with ST‐segment elevation myocardial infarction (STEMI) in relation to the light/dark melatonin pattern. Ninety consecutive patients with STEMI who were admitted to the Coronary Care Unit of our institution were studied. We also recruited 70 age‐ and gender‐matched healthy normal subjects. Blood samples were drawn at 09:00 and 02:00 hr, while patients were at rest, for the assessment of sVCAM‐1 and melatonin, which were measured using commercially available ELISA. In STEMI patients, melatonin concentrations maintained a diurnal variation, but the difference between nocturnal and diurnal levels was less than that in healthy subjects (P < 0.0001). In contrast to findings with melatonin, sVCAM‐1 levels showed no diurnal variations in control subjects. In the STEMI group, however, sVCAM‐1 concentration at 02:00 hr was significantly higher than that during the light phase (09:00 hr; 1391 ± 38 versus 1200 ± 43 ng/mL, P < 0.05). The results suggest that diurnal variations in endogenous sVCAM‐1 production in STEMI patients might be related to an attenuated circadian secretion of melatonin.

Prognostic Value of Admission Myeloperoxidase Levels in Patients With ST-Segment Elevation Myocardial Infarction and Cardiogenic Shock

Inflammation plays a critical role in acute myocardial infarction. One inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of in-hospital death in patients with ST-segment elevation myocardial infarction (STEMI) presenting with cardiogenic shock (CS) is unclear. Therefore, the aim of this study was to investigate the role of MPO as a predictor of in-hospital death in patients with STEMIs presenting with CS and treated with primary percutaneous coronary intervention. In 38 consecutive patients with CS complicating STEMIs who were treated with primary percutaneous coronary intervention, serum MPO levels were measured at coronary care unit admission using a commercially available enzyme-linked immunosorbent assay. The primary study end point was in-hospital cardiac death. Among the 38 patients included in the study, 20 died during their coronary care unit stays, whereas 18 survived. Compared with patients who survived, patients who died showed, at coronary care unit admission, higher serum MPO levels (81 +/- 28 vs 56 +/- 23 ng/ml, p <0.006). After controlling for different baseline clinical, laboratory, and angiographic variables, baseline serum MPO level was an independent predictor of in-hospital mortality on multivariate analysis (odds ratio 3.9, 95% confidence interval 1.8 to 7.5, p <0.001). In conclusion, admission MPO concentration is an independent predictor of in-hospital mortality in patients with STEMIs presenting with CS.

Intracoronary versus intravenous abciximab administration in patients with ST-elevation myocardial infarction undergoing thrombus aspiration during primary percutaneous coronary intervention—Effects on soluble CD40 ligand concentrations

INTRODUCTION CD40 ligand has been suggested to play a pathogenic role in atherogenesis and coronary artery disease progression. Clinical studies suggest that intravenous (IV) abciximab administration attenuates the acute inflammatory response associated with percutaneous coronary intervention (PCI). The anti-inflammatory effects of intracoronary (IC) versus IV administration of abciximab have not been systematically investigated. We assessed changes in soluble CD40 ligand (sCD40L) concentrations in response to IC versus IV abciximab in patients with ST-elevation myocardial infarction (STEMI) undergoing thrombus-aspirating device during primary PCI. METHODS Patients were randomized to receive IC (n=25) or IV (n=25) bolus abciximab followed in every case by a 12-h IV abciximab infusion. sCD40L was measured immediately before the administration of abciximab (baseline) and 60min post bolus administration. RESULTS Clinical baseline and angiographic characteristics were similar in both patient groups. Similarly, there were no significant differences in baseline serum sCD40L levels in the IC group compared to IV group (116.6+/-42.13pg/mL vs 124.9+/-43.04pg/mL, P=0.49). At 60min post PCI, however, sCD40L levels decreased by 23% (P<0.001) in the IC group and by 11% (P<0.001) in the IV group. sCD40L levels 60min post PCI were significantly reduced, particularly in the IC group compared to the IV group (73.04+/-12.21pg/mL vs 99.92+/-25.89pg/mL, P<0.001). CONCLUSION In STEMI patients undergoing primary PCI, IC bolus administration of abciximab was associated with a larger reduction in sCD40L levels compared to standard IV bolus. Whether this more powerful anti-inflammatory effect of IC abciximab translates into improved clinical outcomes deserves investigation.

Decreased level of melatonin in serum predicts left ventricular remodelling after acute myocardial infarction

Abstract:  As experimental studies suggest that melatonin is cardioprotective after myocardial infarction (MI), this study sought to investigate the relationships between circulating levels of melatonin and left ventricular (LV) remodelling in patients after acute MI. This prospective study included 161 patients (age 61 ± 3 yr; 78% men) undergoing primary percutaneous coronary intervention who were assessed echocardiographically at hospital discharge (day 3–7) and at 12 months. LV remodelling was defined as >20% increase in LV end‐diastolic volume at 12‐month follow‐up compared with baseline. Serum melatonin concentrations were measured at admission, during the light period. Twenty‐four patients showed LV remodelling, and 137 had no evidence of LV remodelling. Patients with LV remodelling had lower levels of melatonin at study entry [9.96 (8.28–11.03) versus 16.74 (13.77–19.59) pg/mL, respectively; P < 0.0001]. Multivariate analysis showed that melatonin levels (OR = 2.10, CI 95% 1.547–2.870, P < 0.001) were an independent predictor of LV remodelling at 12‐month follow‐up. Receiver operating characteristic (ROC) analysis showed an area under the curve of 0.959 (CI 95% 0.93–0.98; P < 0.0001). To our knowledge, this is the first study to show the relationship between melatonin and LV remodelling during the chronic phase post‐MI.

Utility of Levosimendan, a New Calcium Sensitizing Agent, in the Treatment of Cardiogenic Shock Due to Myocardial Stunning in Patients With ST-Elevation Myocardial Infarction: A Series of Cases

T degree of necrosis produced by ST-elevation myocardial infarction (STEMI) prior to coronary reperfusion, together with a variable amount of myocardial stunning, may have important prognostic repercussions. When both concur, they may give rise to a state of shock and heart failure requiring adequate treatment, classically aimed at increasing contractility (with inotropic drugs), reducing preload and postload (with vasodilating drugs), and attempting to control the cardiac remodeling process (with beta-blockers and angiotensin-converting enzyme inhibitors). The intravenous inotropic drugs currently available (amines and phosphodiesterase inhibitors) improve contractility by increasing intracellular concentrations of free calcium, but they may have potentially deleterious effects by increasing myocardial energy consumption and underlying ischemia and may even produce myocardial necrosis, cardiotoxicity, and arrhythmia. Levosimendan belongs to a new group of inotropic agents developed for cardiovascular therapy: those that enhance the sensitivity of myofilaments to calcium. This drug has positive inotropic and vasodilatory properties, as well as cardioprotective effects, which makes it particularly interesting and beneficial in this clinical context. This is especially so when complicated by cardiogenic shock (CS) due to severe left ventricular dysfunction. We sought to evaluate the acute hemodynamic effects of levosimendan in patients with STEMI revascularized by primary percutaneous coronary intervention (PCI), who subsequently presented CS secondary to severe left ventricular systolic dysfunction.