Insulin-Like Growth Factor 1 (IGF-1) Levels And Left Ventricular Meridional End Systolic Stress (LVMESS) Interrelationship In Middle-Aged And Elderly Obese Subject With Type 2 Diabetes

: Background: Left ventricular meridional end systolic stress (LVMESS) is a quantitative determinant index of LV afterload which is an essential determinant of LV performance. The key factors influencing LVMSS, notably ventricular wall thickness, chamber size and configuration are shown to be altered by both obesity and type2 diabetes mellitus (T2DM). There exist reports implicating high free insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) levels, with increased left ventricular mass index (LVMI), abnormal LV geometric remodelling, and A1c levels. Objective


INTRODUCTION:
Because of the biased validity of LV systolic function assessment by ejection fraction (EF) index, two other types of load independent estimates have been proposed for this purpose: the meridional LV wall stress which reflects the function of the longitudinal endocardial and epicardial fibers of the LV wall, has been used as an indirect measure of LV after load.The circumferential LV wall stress which is in line with the direction of the midwall circumferential fibers and has been used as a measure of myocardial contractility (1,2) .The concept of after load literally means the stress encountered by LV myofibrils as they contract against the end-diastolic volume/ intra -ventricular pressure.obese individuals with or without diabetes tend to develop left ventricular (LV) structural changes in response to the operating overload: volume overload causing chamber dilation in proportion to mass (eccentric hypertrophy), and pressure overload producing increased LV mass out proportion to volume (concentric hypertrophy).These patterns of hypertrophy are independent of arterial pressure and age (3,4). .Diabetic and hypertensive subjects have a higher likelihood to develop, impaired diastolic function, in addition to decreased afterload measured by meridional end-systolic stress, as compared with lean individual (5,6) .Indeed, DM exclusively, can elicit changes in cardiac structure and function which are independent of associated ischemic heart disease or hypertension or increased BMI (7,8) Mounting evidence indicate growth hormone (GH)/ Insulin growth factor 1(IGF-1) axis also known to contribute to LV structural and functional modulations: Circulating IGF-1 is synthesized primarily by the liver under the control of growth hormone (GH) (9) .However, IGF-1 can be synthesized by many other organs, including heart, and can act as an autocrine or a paracrine factor (10) .IGF-1 circulates bound to protein carriers (IGFBPs), which serve not only to transport IGF-1 in the circulation but also to prolong its half-life, modulate its tissue specificity and strengthen or neutralize its biological actions (11) As growth factors, both GH andIGF-1 modulate myocyte growth and hypertrophy in the developing heart.IGF-1 has been demonstrated to induce nitric oxide (NO) production in vitro and has vasodilatory properties consistent with an NO-mediated effect in vivo that induces cellular proliferation and differentiation.In addition, it exerts both inotropic and growth effects that can influence LV geometry ( 12,13) .However, until the time of preparation of this manuscript, studies on the impact of alteration of IGF-1 axis on meridional LV wall stress in obesity and obesity-related T2DM, are lacking.

Objectives
This study defined whether a relationship exsist between LVMESS and free LGF-1 plasma levels in obese middle age and elderly individuals with or without T2DM.

METHODOLOGY
A total of 145 participants were recruited from Al Najaf cardiac center, after having their verbal and written consent and approval from the ethical committee at our hospital.The subjects were classified into 3 groups.Group 1 subjects served as a control and were subdivided into group 1A, comprised healthy lean middle-aged (n=18, mean age 53±4.3yrs,andBMI 23±2.8 kg/ m 2 ), and healthy lean old aged individuals ( n=15; mean age 64±3.  .The inclusion criteria in this study were the exclusion of hypertension by an extensive examination, absence of cardiac or other chronic diseases, no metabolic disorders or pregnancy among women and good-quality echocardiograms at baseline evaluation.No subject was a competitive athletics.History should be taken to rule out medication intake, smoking habit, number of cigarette, duration of diabetes regarding diabetics' patients.The volunteers and patients had their body weight measured by using weight device with subject wearing no shoes.Height was measured by using a tape measure.Body mass index (BMI) was calculated as weight divided by height (kg/ m 2 ) according to the universal formula (14).
Left ventricular end systolic stress (LVMESS) can be calculated from the LV peak pressure P, the myocardial area "Am", and the LV cavity area "Ac" in the short-axis view at the papillary muscle level done at end-systole.LVESMS = 1.33P (Ac/Am) x 103 dyne/cm³.(Reported normal values for LVESMS between 65 to 73 dynes/ cm³ (15) .Echocardiography All patients had a resting echocardiography with commercially available tranthoracic echocardiography (Philips HDI 22100/ IE33, Bothell, A 98021-8431 made in USA) in cardiac center in AL Sader Teaching hospital, with the patients in partial left decubitus position.Twodimensional and M-mode echocardiography are utilized to assess end-systolic meridional stress and its relationship to left ventricular cavity length, end-systolic circumferential stress and its relationship with left ventricular internal diameter.

Fig 1 (A) Short-axis view of the left ventricle, at end-systole. (B) Apical four chamber view to assess LV diastolic length. Laboratory assay
Fasting blood samples for at least 12 hrs were collected according to a standardized protocol from each subject; 6 ml of blood was drawn.Filled syringes were kept at 5-10 c, protected from light, and transferred to a local laboratory for centrifugation.3 serum tubes for each sample were collected and freeze at -20°c until the time of assay.

Statistical Analyses
Data were analyzed as per age groups group I (20-40 yrs), group II (40-60 yrs), group III (60-80yrs); each age group was further divided into 3 groups according their BMI into lean those has BMI < 25 kg/m2; overweight, those with BMI ranging from 24.9-29.9kg/m2 and obese those with BMI > 30 kg/m2 .The results were expressed as mean and standard deviations.Analysis of variance (ANOVA) as well as correlation regression test and independent T test (using SPSS version 18) were applied to compare the study groups.Probability P value of < 0.05 was considered statistically significant (α≤0.05)  1 shows that, in lean middle-aged individuals, LVMESS did not show a statically significant difference between diabetics and healthy individuals.Whereas in obese middle-aged individuals, a significant decrease in LVMESS in diabetics was observed compared to healthy individuals.The LVMI showed a decrease in obese individuals in both diabetics and healthy subjects, but this decrease did not reach a significant level.LVM showed a significant increase in obese subjects in both diabetics and healthy individuals, but this increase did not reach a significant levels.In this age group, in diabetics and healthy individuals, the IGF-1 circulating levels, showed no significant differences among different BMIs.

RESULTS
Table2: Difference values of LVM in lean and obese healthy and diabetic subjects Table 2 shows that regarding LVM, There are a significant differences between lean and obese healthy middle age individuals (p=0.04),whereas no significant difference between lean and obese diabetic subject in the same age group (p=0.5)Table 3 shows that the elderly (>60yrs), in both diabetics and healthy individuals, the LVMESS did not show statistical significant variation at different BMIs, in both diabetics and healthy subjects.The LVMI did not show statically significant changes in different BMIs in both diabetics and healthy individuals.In this group, the GH did not show significant variation between diabetics and healthy individuals.The IGF-1 showed significant increase in diabetics, only in lean subjects (p < 0.01).No statistical significant changes in IGF-1 observed in obese subjects,.
Independent sample t-test, ** significant at (P≤0.05) Table 4 shows that in both healthy and diabetic individuals there are no significant difference in LVM between lean and obese subjects.(p=0.06;0.7 respectively).Table 3 shows that the elderly (>60yrs), in both diabetics and healthy individuals, the LVMESS did not show statistical significant variation at different BMIs, in both diabetics and healthy subjects.The LVMI did not show statically significant changes in different BMIs in both diabetics and healthy individuals.In this group, the GH did not show significant variation between diabetics and healthy individuals.The IGF-1 showed significant increase in diabetics, only in lean subjects (p < 0.01).No statistical significant changes in IGF-1 observed in obese subjects,.
Independent sample t-test, ** significant at (P≤0.05) Table 4 shows that in both healthy and diabetic individuals there are no significant difference in LVM between lean and obese subjects.(p=0.06;0.7 respectively).Table 3 shows that the elderly (>60yrs), in both diabetics and healthy individuals, the LVMESS did not show statistical significant variation at different BMIs, in both diabetics and healthy subjects.The LVMI did not show statically significant changes in different BMIs in both diabetics and healthy individuals.In this group, the GH did not show significant variation between diabetics and healthy individuals.The IGF-1 showed significant increase in diabetics, only in lean subjects (p < 0.01).No statistical significant changes in IGF-1 observed in obese subjects,.

DISCUSSION
In certain progressive metabolic disorders, such as obesity, and obesity related T2DM, the impact of alteration in the circulatory IGF-1 levels, on overall myocardial performance has featured the interest of several studies.
The present results showed increased LVM in obese individuals with or without diabetes , these results are consistent with the previous studies demonstrating both obesity and type 2 diabetes could cause abnormalities in cardiac geometry (remodeling) and function independent of coronary artery ischemia and hypertension (16,17) .Hence, according to laplace's law, the LVMSS decreased in these patient (tables 3 and 4).Our data contradict with study ofPostel-Vinay etal. (18).Their conclusion was that increased systolic function measured by increased shortening fraction and lower wall stress could occur in obese young adult.The discrepancy of the results may be attributed to the differences in the measuresused for estimation of LV systolic function.
In the present study, age related to IGF-1 levels were demonstrated.IGF-1 levels relatively increased in middle aged and decreased in the elderly obese individuals.No significant correlations were found between IGF-1 and BMI or other indices of adiposity.These results corroborates with the past investigations (19) .
Regarding the proposedlink between LV mass and free IGF-1 circulating levels, our data showed a multifaceted interrelationship which was also in agreement with otherresearchers.A negative correlation between IGF-1 and LVM observed in the lean and obese elderly, with or without diabetes.Whereas a positive correlation observed in lean and obese middle aged with or without diabetes (20) .Owing to its load independency, we implemented the use LV meridional stress as a parameter of LV Afterload measure to reflect LV systolic function taking into account the closely inter-related factors that are known to influence LV systolic function notably, the BMI, LV ventricular mass and and GH/IGF-1 axis.Of note, the reported normal IGF-1 plasma levels by several investigators are wide raged and conflicting.This inconsistency was attributed to differences in age, sex and the degree of obesity (20) .In an attempt to study the free GH/IGF-1 levels in middle-aged Korean obese males, Maccaarioetal (21) showed in obese individuals, The GH level was reduced, whereas IGF 1 level did not differ significantly.However, the author reported that inconsistent results presented by others due to differences in age, sex and the degree of obesity.
In this study, non-linear relationship existed between IGF-1 levels and LVMSS in age adjusted obese groups.Non significant relationship in the young, significant inverse relationship in the middle aged diabetics and negative but non significant association in the elderly healthy obese.A wide range of mechanisms involving interactions among several factors.The inconsistency of these findings could be explained by the following : 1) IGF-1 bioactivity is more in young and middle aged, a decreased bioavailabiliy in the elderly (21,22 ) , 2) GH/IGF-1 deficiency contributes to physiological age-related cardiovascular modifications, such as decrease in the number of cardiomyocytes (22) , 3) a wide range of IGF-1 normal plasma levels have been reported by considerable number of literature, 4) a possible IGF-I /leptin interplay: it has been shown an inverse association between leptin and IGF1, 5) in the obese, there could be an interplay between leptin, GH-IGF-1 axis and insulin resistance.In the obese, it has been shown that GH/IGF-1 axis can be altered at different levels, And finally, The GH secretion is blunted GH secretion may be paired with either normal, low or high IGF-1 levels.IGF-binding protein-1 (IGFBP-1) and IGFBP-2 plasma levels are blunted due to inhibition by insulin, which is generally increased in obese subjects (22,23).
It is pertinent to point out that total IGF-1 concentrations do not necessarily reflect IGF-1 activity.Recently, the IGF-1/IGFBP-3 molar ratio has been indicated to reflect the amount of unbound and biologically active IGF-1 (23) .However, a low level in old age may indicate impaired LV function, though this notion necessitates large sample studies.

CONCLUSION
IGF-1 level-LVMESS relationship can be modulated by age, obesity and obesity related diabetes.The inverse association of IGF-1 level with LVMESS in middle aged diabetics and elderly healthy obese subjects may raise the speculation of its utility as a predictor for assessment of LV systolic function.

RECOMMENDATION
It is suggested that using IGF-1 plasma levels in the elderly with or without T2DM could aid as predictor for LV global systolic dysfunction .However, larger sample size are to be considered.