|Year : 2018 | Volume
| Issue : 1 | Page : 57-62
Serum leptin and future cardiovascular events in patients with acute coronary syndrome
Noha Hassanin Hanboly, Sameh Salama, Mervat Gaber, Omar Marzouk
Department of Cardiovascular Diseases; Department of Clinical Pathology, Cairo University, Cairo, Egypt
|Date of Web Publication||7-May-2018|
Dr. Noha Hassanin Hanboly
Department of Cardiovascular Diseases, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
Background: Coronary artery disease (CAD) is a major cause of death worldwide. Acute coronary syndrome (ACS) encompasses acute myocardial infarction and unstable angina. Leptin is 16-kDa hormone with pleiotropic actions in multiple organ systems. There is increasing interest in the potential role of leptin in the cardiovascular system. Studies comparing levels of leptin in patients with ACS to healthy matched controls, especially in the developing countries, are limited and rare.
Aim of Study: This study was conducted to study leptin in ACS patients, comparing the results to a healthy matched control group and correlating the levels to the in-hospital outcome.
Patients and Methods: The study was conducted at Cairo University Hospital. Serum leptin levels were studied in 50 patients admitted with the ACS (Group-I) compared to matched control group (Group-II) and correlating these levels to hospital morbidity and mortality. Diagnostic coronary artery catheterization was done to patients through femoral artery access to assess the severity and extent of CAD.
Results: Serum leptin levels were significantly higher in ACS group compared to the normal controls, (P = 0.001). Although not statistically significant leptin levels were increased in eventful compared to the uneventful group.
Conclusion: In patients with ACS, persistent elevation of serum leptin during serial measurements was invariably associated with worse in-hospital outcome. Positive correlation of serum leptin levels with other chronic inflammatory state such as obesity, hypertension, and female gender supports the hypothesis that leptin is a determinant of CAD possibly through its proinflammatory action.
Keywords: Acute coronary syndrome, coronary artery disease, serum leptin
|How to cite this article:|
Hanboly NH, Salama S, Gaber M, Marzouk O. Serum leptin and future cardiovascular events in patients with acute coronary syndrome. Nig J Cardiol 2018;15:57-62
|How to cite this URL:|
Hanboly NH, Salama S, Gaber M, Marzouk O. Serum leptin and future cardiovascular events in patients with acute coronary syndrome. Nig J Cardiol [serial online] 2018 [cited 2020 Oct 19];15:57-62. Available from: https://www.nigjcardiol.org/text.asp?2018/15/1/57/231972
| Introduction|| |
Leptin is a hormone made by adipocytes which regulate the amount of fat stored in the body by adjusting both the sensation of hunger and energy expenditures. Hunger is inhibited (satiety) when the amount of fat stored reaches a certain level. Leptin is then secreted and circulates through the body, eventually activating leptin receptors in the arcuate nucleus of the hypothalamus. Energy expenditure is increased both by the signal to the brain, and directly via leptin receptors on peripheral targets. The effect of leptin is opposite to that of ghrelin, the “Hunger hormone.”
Ghrelin receptors are on the same brain cells as leptin receptors, so these cells receive competing satiety and hunger signals. Leptin and ghrelin, along with many other hormones, participate in the complex process of energy homeostasis. Human leptin is a 16 kDa protein of 167 amino acids.
Leptin is produced primarily in the adipocytes of white adipose tissue, by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, pituitary, liver, and gastric chief cells.
Coronary heart disease (CHD) is a worldwide health epidemic. Although age-specific events related to CHD have fallen dramatically in the past few decades, the overall prevalence has risen as population's age and patients survive the initial coronary or cardiovascular (CV) event. Worldwide, 30% of all deaths can be attributed to CV disease (CVD), of which more than half are caused by CHD.
Acute coronary syndrome (ACS) is a unifying term representing a common end result, acute myocardial ischemia. Acute ischemia is usually, but not always, caused by atherosclerotic plaque rupture, fissuring, erosion, or a combination with superimposed intracoronary thrombosis and is associated with an increased risk of cardiac death and myonecrosis.
It encompasses acute myocardial infarction (MI) resulting in ST-segment elevation (STEMI) or non-ST-segment elevation (Non-STEMI) and unstable angina (UA). Recognizing a patient with ACS is important because the diagnosis triggers both triage and management. Patients with suspected ACS should be managed immediately with antiplatelet and anticoagulant therapies and considered for immediate revascularization mechanically or pharmacologically if new ST-segment elevation is noted. Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities. It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines. Oxidative stress plays a major role in the development of CV damage.
Although several studies have been done on leptin and coronary artery disease (CAD), most of them have been conducted on patients with stable ischemic heart disease or angiographically confirmed atherosclerosis irrespective of disease presentation. Moreover, studies comparing levels of leptin in patients with ACS to healthy-matched controls, especially in the developing countries, are limited and rare. For these reasons, it was decided to study leptin in ACS patients, comparing the results to a healthy matched control group and correlating the levels to the in-hospital outcome.
| Patients and Methods|| |
This is a prospective, observational, case–controlled study estimating serum leptin levels in 50 patients admitted with ACS (Group-I) compared to age- and sex-matched control group (Group-II) and correlating these levels to-hospital morbidity and mortality.
The study was conducted at Cairo University Hospital. The Research Ethics Committee of the hospital reviewed and approved the study protocol. Patient written consent was given by all the participants.
Exclusion criteria included contraindication to coronary angiography, refusal to perform coronary angiography, obesity (body mass index ≥30 kg/m 2), obstructive sleep apnea, or dexamethasone therapy for any reason.
All patients included in the study were subjected to full medical history taking including age, gender, CV risk profile such as hypertension, diabetes mellitus, smoking, and prior MI.
Diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL, or 2-h plasma glucose ≥200 mg/dL during standardized 75 g oral glucose tolerance test. General examination was performed, with estimation of body mass index calculated as: Weight (kg)/height (m 2).
Obesity was defined as BMI ≥30 kg/m 2. Hypertension was defined as persistent elevation of blood pressure above 140/90 mmHg on two or more occasions with the patient in a sitting position for at least 5 min.
Twelve-lead surface electrocardiogram (ECG) was performed to all patients to confirm the diagnosis of ACS, and for controls to have an objective evidence for the absence of CAD.
Transthoracic echocardiography was performed to all patients using General Electric VIVID 7 (GE Health Medical, Horten, Norway). The left ventricle ejection fraction was calculated, using the Simpson's rule, as the difference between end-diastolic volume and end-systolic volume divided by end-diastolic volume. Regional wall motion was assessed semiqualitatively with a scoring system based on a 17-segment model advocated by the American Society of Echocardiography.
Diagnostic coronary artery catheterization was done to patients with ACS, through femoral artery access, to assess the severity and extent of CAD. The total coronary atherosclerotic burden was quantified by the extent of plaque in the culprit artery which was given a score of 0: If the vessel was normal, 1: If it contained 1 or 2 plaques, 2: If it contained more than 2 plaques with intervening normal vessel segment, and 3: If it contained more than 2 plaques without intervening normal vessel segment producing continuous vessel wall irregularities.
Leptin measurements were done after an overnight fast on admission (Leptin-1), at hospital discharge (Leptin-2), and after 3 months (Leptin-3) for Group-I. Fasting leptin samples were obtained once from Group-II (Leptin-C).
Principles of the test
The DRG Leptin enzyme-linked immunosorbent assay (ELISA) is a solid phase ELISA based on the sandwich principle for the quantitative in vitro diagnostic measurement of leptin in serum. The microtiter wells were coated with a monoclonal antibody directed toward a unique antigenic site on a leptin molecule. An aliquot of patient's sample containing endogenous leptin was incubated in the coated well with a specific biotinylated monoclonal anti-leptin antibody. A sandwich complex was formed. After incubation, the unbound material is washed off, and a Steptavidin Peroxidise Enzyme Complex was added for detection of the bound leptin. Having added the substrate solution, the intensity of color developed was proportional to the concentration of leptin in the patient sample. Data were analyzed to detect the correlation of serum leptin level on admission, at discharge, and at follow-up with in-hospital heart failure, arrhythmias, stroke, and death.
Data were statistically described regarding mean ± standard deviation, median and range, or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was done using Student t- test for independent samples in comparing two groups when normally distributed and Mann–Whitney U test for independent samples when not normally distributed. Comparison of normally distributed numerical variables between more than two groups was done using one-way analysis of variance test while Kruskal–Wallis test was used in nonnormal data. For comparing categorical data, Chi-square (χ2) test was performed. Exact test was used instead when the expected frequency is <5. P < 0.05 was considered statistically significant. All statistical calculations were done using computer program SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) release 15 for Microsoft Windows (2006).
| Results|| |
In the study cohort, 72% of both groups were male and 28% were female. Body mass index was 25 ± 3 and 26 ± 3 kg/m 2 for Group-I and Group-II, respectively. About 16% of patients in Group-I presented with UA, 44% with Non-STEMI, and 40% with STEMI. 54% of patients were hypertensive and diabetics [Table 1].
The median leptin level for Group-I was 4.8, 4.8, and 5 ng/dL for Leptin-1, Leptin-2, and Leptin-3 respectively; and that for Group-II was 4.5 ng/dL. Serum leptin levels were significantly higher in patients presenting with ACS (Group-I) compared to the controls (Group-II) (P = 0.001) [Figure 1]. There was no statistically significant difference between cases and controls regarding age and BMI (P = 0.47 and 0.27, respectively).
Ejection fraction and wall motion score index values among the diseased group were 47% ±11% and 2.6 ± 0.8, respectively. Moreover, 92% of patients had wall motion abnormalities at rest.
Coronary angiographic study
Of the diseased group revealed that 24% had one-vessel disease. Two and three or more vessel disease was found in 52% and 24%, respectively. All cases had more than 70% diameter stenosis of the culprit artery, 54% of them had 1 or 2 plaques in the culprit artery, 38% had more than 2 plaques with intervening normal vessel segment, and 8% had more than 2 plaques without intervening normal vessel segment producing continuous vessel wall irregularities.
In-hospital and short-term cardiovascular events
Thirty-four patients (68%) reached one of the study endpoints (eventful group), and 16 patients (32%) did not (uneventful group). During hospitalization, the in-hospital outcome of heart failure, arrhythmia, both heart failure and arrhythmia, stroke, and death were seen in a total of 18 patients. The patients were also followed up for 6 months. During the follow-up period, the combined endpoint of chest pain recurrence, UA, fatal or nonfatal acute MI, stroke, rehospitalization, and death was seen in a total of 29 patients [Table 2].
Leptin-1, and leptin-2 levels were positively correlated with BMI, hypertension, and female gender in the diseased group [Figure 2].
|Figure 2: Scatter plot of correlation between leptin-1 and body mass index in diseased group|
Click here to view
There was no statistically significant difference in serum leptin levels between diabetics and nondiabetics (P = 0.37) and also between the patients admitted with NonST elevation-acute coronary syndrome, and those with ST elevation-acute coronary syndrome (P values for leptin-1, leptin-2, and leptin-3 were 0.48, 0.57, and 0.3, respectively). Although not statistically significant, leptin 1, 2, and 3 levels were increased in eventful compared to the uneventful group [Table 3].
Using univariate logistic regression analysis, variables associated with the prediction of adverse in-hospital outcome were the presence of renal or hepatic dysfunction, systolic left ventricle dysfunction, and the coronary atherosclerotic burden (i.e., the extent of plaque in the culprit artery). Moreover, the current study showed that Non-STEMI and the presence of a diagnostic ECG on admission (notably ST-segment elevation) were predictors of 6 months follow-up events [Figure 3].
|Figure 3: Predictors of in-hospital outcome and follow up cardiovascular events using univariate logistic regression analysis|
Click here to view
| Discussion|| |
It is widely acknowledged that CVDs became the leading cause of mortality and a major cause of morbidity in adults worldwide over the course of the 20th century. Of these diseases, CAD is the single most common cause. Older age, dyslipidemia, hypertension, tobacco smoking, male sex, diabetes mellitus, and family history of the premature coronary disease are among the more common and well recognized.
Leptin is a 16-kDa protein composed of 167 amino acid peptides encoded by an obesity gene, and it has an important function in the regulation of body weight. There is increasing interest in the potential role of leptin in the CV system, as accumulating evidence suggests that leptin is involved in angiogenesis, vascular and endothelial function, and myocyte proliferation. Thus, examination of leptin signaling may provide insight into the complex relationship between obesity and CV disease. Human studies on leptin and (CAD) have reported variable results. In populations without CAD, a few studies have shown leptin to be associated with increased risk of incident CAD, while others found no association.
In this prospective study, the presence of renal or hepatic dysfunction, impaired left ventricular ejection fraction, Non-STEMI, and presence of a diagnostic ECG on admission were predictors of future CV events.
This is in agreement with another study which concluded that mild to moderate renal impairment independently predicted death and MI in patients with ACS at 30-day and 6-month follow-up, and supported the development of more aggressive strategies for preventing and treating ACS in patients with renal insufficiency.
The presence of more extensive plaque in the culprit coronary artery was significantly correlated with a greater risk of adverse in-hospital events, which is concordant with another study conducted by Ambrose who found that significant lesions with irregular borders, overhanging edges, intraluminal filling defects, and with plaque ulceration were related to the subsequent in-hospital clinical instability.
The novel finding of the study was that plasma leptin levels were significantly higher in patients presenting with ACS compared to controls, which is consistent with a study by Stangl et al. showing higher serum leptin concentrations in patients with CAD than controls matched for age, gender, and BMI, suggesting that leptin could contribute to the development of CVD, possibly via activation of the sympathetic nervous system.
The study also showed that admission and predischarge leptin levels positively correlated with BMI, hypertension, and even after adjustment to BMI, with female gender, demonstrating the inflammatory mechanisms of leptin; although they negatively correlated with current smoking status. These findings were also in accordance with the previous study.
There was no statistically significant difference in serum leptin levels between diabetics and nondiabetics, in contrast to the study conducted by Krasnodebski et al. which concluded that plasma leptin levels were significantly lower in nondiabetics compared to diabetic patients.
Median serum leptin levels correlation to-or as acting as a predictor of-the occurrence adverse in-hospital outcome or for the short-term CV events such as chest pain recurrence, UA, fatal or nonfatal acute MI, stroke, re-hospitalization, and death, although was statistically not significant possibly due to a small sample size, the median level of predischarge samples did not fall and was even slightly higher than median admission samples in patients who had adverse in-hospital outcome of heart failure, arrhythmia, stroke, and death compared to patients who did not experience any of these events.
Moreover, we found that persistent elevation or increase of leptin during hospital admission could be a risk factor for having adverse events during this period. However, more studies confirming this observation are warranted. Other studies found that there was a trend for an increase in the mean serum leptin levels with increasing number of diseased vessels. There was no correlation between serum leptin levels and outcome neither during the hospitalization nor at 9 months follow up.
| Conclusion|| |
The study showed that leptin levels were increased in patients with ACS which suggested a significant role of leptin in the development of atherosclerosis. Moreover, there was a persistent elevation of leptin during hospital admission in patients who had one or more adverse in-hospital events compared to patients who did not experience any events.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Brennan AM, Mantzoros CS. Drug insight: The role of leptin in human physiology and pathophysiology – Emerging clinical applications. Nat Clin Pract Endocrinol Metab 2006;2:318-27.
Green ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, et al.
The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7. Genome Res 1995;5:5-12.
Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: A review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 2002;26:1407-33.
Anderson RN. U.S. Decennial Life Tables for 1989–91. United States Life Tables Eliminating Certain Causes of Death. Vol. 1. Hyattsville, MD: National Center for Health Statistics; 1999.
Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: Part I: Evolving concepts. J Am Coll Cardiol 2005;46:937-54.
Braunwald E, Jones RH, Mark DB, Brown J, Brown L, Cheitlin MD, et al
. Unstable Angina: Diagnosis and Management. AHCPR Publication 94–0602. Rockville, MD: Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, U.S. Public Health Service, U.S. Department of Health and Human Services; 1994. p. 1.
Martínez-Martínez E, Jurado-López R, Cervantes-Escalera P, Cachofeiro V, Miana M. Leptin, a mediator of cardiac damage associated with obesity. Horm Mol Biol Clin Investig 2014;18:3-14.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9.
Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults – The evidence report. National Institutes of Health. Obes Res 1998;6 Suppl 2:51S-209S.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al.
2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA 2014;311:507-20.
Pellikka PA, Nagueh SF, Elhendy AA, Kuehl CA, Sawada SG; American Society of Echocardiography, et al.
American Society of Echocardiography recommendations for performance, interpretation, and application of stress echocardiography. J Am Soc Echocardiogr 2007;20:1021-41.
Hamsten A, Walldius G, Szamosi A, Dahlen G, de Faire U. Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction. Circulation 1986;73:1097-110.
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al.
Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation 2011;123:e18-209.
Yang R, Barouch LA. Leptin signaling and obesity: Cardiovascular consequences. Circ Res 2007;101:545-59.
Sattar N, Wannamethee G, Sarwar N, Chernova J, Lawlor DA, Kelly A, et al.
Leptin and coronary heart disease: Prospective study and systematic review. J Am Coll Cardiol 2009;53:167-75.
Brennan AM, Li TY, Kelesidis I, Gavrila A, Hu FB, Mantzoros CS, et al.
Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: A prospective cohort study. Diabetologia 2007;50:1178-85.
Karakas M, Zierer A, Herder C, Baumert J, Meisinger C, Koenig W, et al.
Leptin, adiponectin, their ratio and risk of coronary heart disease: Results from the MONICA/KORA Augsburg study 1984-2002. Atherosclerosis 2010;209:220-5.
Al Suwaidi J, Reddan DN, Williams K, Pieper KS, Harrington RA, Califf RM, et al.
Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation 2002;106:974-80.
Ambrose JA. Prognostic implications of lesion irregularity on coronary angiography. J Am Coll Cardiol 1991;18:675-6.
Stangl K, Cascorbi I, Laule M, Stangl V, Vogt M, Ziemer S, et al.
Elevated serum leptin in patients with coronary artery disease: No association with the Trp64Arg polymorphism of the beta3-adrenergic receptor. Int J Obes Relat Metab Disord 2000;24:369-75.
Söderberg S, Ahrén B, Jansson JH, Johnson O, Hallmans G, Asplund K, et al.
Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999;246:409-18.
Krasnodebski P, Bak MI, Opolski G, Karnafel W. Leptin in acute myocardial infarction and period of convalescence in patients with type 2 diabetes mellitus. Kardiol Pol 2010;68:648-53.
Khafaji HA, Bener AB, Rizk NM, Al Suwaidi J. Elevated serum leptin levels in patients with acute myocardial infarction; correlation with coronary angiographic and echocardiographic findings. BMC Res Notes 2012;5:262.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]