Left ventricular hypertrophy (LVH) is a common and important form of cardiac remodeling in the context of chronic kidney disease (CKD) . This concentric remodeling is more common than eccentric remodeling in patients with CKD. For years, it was believed that the extent of concentric remodeling in CKD is directly related with the degree of systemic hypertension . This solid belief has markedly regressed over the last years. It is now increasingly evident that LVH is not a uniform process and is rather a multifactorial disease than single factor disorder. Metabolic and genetic abnormalities are thought to impact LV type and rapidity of remodeling. Buono et al.  demonstrated in his retrospective series in 2013 that LVH is better linked to BMI rather than systolic blood pressure. Watanabe et al.  demonstrated that insulin resistance which is a common metabolic abnormality encountered in CKD patients is closely linked to LVH . El Saiedi et al.  demonstrated in recent studies that obesity operates by causing left ventricular diastolic dysfunction even in the absence of LVH. The linkage between hyperinsulinism and LVH has also been elucidated in neonates born with of congenital hyperinsulinism and infants of diabetic mothers . This linkage can explain the findings of Buono et al.  that high BMI is associated with LVH as with higher BMI insulin resistance rises progressively and this might be the underlying etiology behind LVH in CKD patients.
It is also well recognized that subendocardial ischemia develops with progressive LVH due to the progressive decline of blood flow to the subendocardium with myocardia thickening. The subendocardium is the least vascular layer of the myocardium being supplied by the tiniest peripheral branches of the large epicardial coronary branches. The detrimental effect of LVH on myocardial perfusion and the mentioned relationship between insulin resistance and LVH are poorly examined in the context of CKD. A new technique termed transmural strain has recently been elucidated to allow discrimination if the observed myocardial dysfunction is mainly related to the subendocardial involvement or subepicardial injury . The presence of such a new technique might allow the recognition of early subendocardial involvement in CKD and to study its relationship with LVH and the best determinants of both. This is the exact goal of this research. Such understanding of those pathogenetic relationships might help to initiate new therapeutic strategies such as early placement of insulin sensitizers for myocardial protection in patients with CKD
This case-control cross-sectional study was conducted from September 2017 to September 2018; it included two groups: Group 1: 40 patients with CKD were enrolled from Nephrology unit in Cairo University Children Hospital. Exclusion criteria included arrhythmia, congenital or acquired heart disease or diabetes mellitus as proved by oral glucose tolerance test (OGTT). Group 2: 40 healthy age and sex matched controls collected from general outpatient clinics in Cairo University Children Hospital among children coming for well child checkup and those who have upper respiratory tract infections
Written and informed consent was obtained from all the study participants legal guardians. The study was approved by the local ethics committee of Cairo University.
For the two study groups the following was performed.
Continuous blood pressure monitoring with average daytime and night time Blood Pressure calculated.
Echocardiographic assessment: Transthoracic echocardiography was performed using General Electric (Vivid-7/9, Horten, Norway) machine with 3- and 5-MH transducers according to the age of the patient and having tissue velocity imaging capabilities [7,8].
Two-dimensional Speckle tracking myocardial layer strain discriminating echocardiography (MLSD-STE or transmural strain) of the left ventricle: (1) The endocardial border of the heart was manually traced at end systole; (2) the software automatically then detected and calculated for each of the 17 segments the longitudinal strain (shortening) of the subepicardial layer of the myocardium alternatively called ‘Epicardial Strain’ (Epi-S) and that of subendocardial layer of the myocardium alternatively known as ‘Endocardial Strain’ (Endo-S) and the average of both known as mid-myocardial strain or simply myocardial strain ; and (3) the average of the 17 segments was then calculated for each of the three longitudinal strain values to calculate the mid-myocardial strain alternatively called global longitudinal strain (GLS) and the subepicardial GLS and subendocardial GLS.
Three-dimensional echocardiography: Full-volume acquisition of the LV was obtained by harmonic imaging from the apical approach. Six ECG-gated consecutive beats were acquired during end-expiratory breath-hold to left ventricular full volume. The software automatically identified the left ventricular cavity endocardial border. The operator performed all the necessary adjustments manually in order to correctly place the endocardial border. After the adjustments software provided the left ventricular volumes, ejection fraction and left ventricular mass, left ventricular mass was subsequently indexed to body surface area to calculate LV mass index (LVMI). Three-dimensional echocardiography was relied upon for calculation of LVMI instead of motion-mode echocardiography having the narrowest reported intermethod variability (<3%) when compared to standard cardiac MRI.
For the Group 1, only additional data were performed as follows.
Biochemical assessment included serum creatinine, urea, cholesterol, triglycerides all in milligram per deciliter (mg/dl). Homeostasis model assessment of insulin resistance (HOMA-IR) will be quantified using the following equation: Fasting insulin (after 12 hours of fasting) (µU/ml) × fasting glucose (mmol/l)/22.5 calculated to determine the severity of insulin resistance in each group of patient; it has as well the advantage of being easily performed unlike OGTT which depends on serial serum glucose measurements .
Table 1 shows the measured demographic, clinical, laboratory and echocardiographic parameters in the two study groups. It clearly shows higher BMI in CKD patients. Moreover, blood pressure was statistically higher in cases compared with controls.
Subendocardial systolic function as expressed by subendocardial GLS was significantly lower in CKD patients while subepicardial GLS was comparable between the two groups.
Table 2 is a multivariate analysis showing that the best predictor of LVH in CKD patients is insulin resistance compared with systemic hypertension.
Figure 1 is a scatter plot confirming the tight relationship between LVMI and subendocardial function with r = −0.69
CKD is an important cause of myocardial dysfunction. Cardiovascular complications are considered the most important causes of death in CKD patients. Whether these complications are related to endothelial dysfunction, pericardial disease, infective endocarditis from catheter related infections and last but not least myocardial dysfunction [10,11].
One of the most important strategies followed to alleviate the risk of myocardial dysfunction in CKD was the strict control of blood pressure. This strategy was based as mentioned before on a nearly false fixed belief that myocardial remodeling occurring in CKD is induced directly and only by systemic hypertension; the latter was regarded as the only risk factor for progressive LVH seen in those cases .
Recently, more focus has been given to the metabolic syndrome occurring in patients with CKD, most patients with CKD develop obesity. This is due to several risk factors, some related to the state of disease they are suffering from such as stagnation, long dialysis hours while some others are related to obesity epidemic the world is facing in the previous few years; this obesity epidemic has been mainly linked to long screen times and lack of physical activities, especially among children. This prevalence of obesity has been confirmed in our series; the BMI of cases was markedly higher than the BMI of age matched controls. This state of obesity in CKD patients induces a cascade of metabolic abnormalities that might also be aggravated by the renal insufficiency in such patients. Our study subjects displayed dyslipidemia in the form of mainly high Triglycerides. This finding goes in agreement with previous analyses of lipid abnormalities in obese patients in which hypertriglyceridemia prevails over hypercholesterolemia [13–15].
Insulin resistance and subsequent hyperinsulinemia are two common sequelae of obesity. Insulin resistance has been as well linked to molecular mechanisms in skeletal muscles that are directly related to CKD state and not only to the observed obesity in such patients. Moreover, CKD reduces insulin clearance, therefore, exacerbating hyperinsulinemia. Insulin resistance has been confirmed to aggravate CKD by altering renal hemodynamics, filtration pressure and aggravating sodium retention and therefore hypertension. The role hyperinsulinemia plays in myocardial remodeling is well known in the recent literature [16,17]. Insulin causes myocardial hypertrophy, impairs diastolic function and aggravates systemic hypertension by impairing endothelia function.
In our series insulin resistance was assessed by HOMA-IR, being less invasive, inexpensive and less labor-intensive method to measure insulin resistance. However, HOMA-IR validity should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects.
In our study subjects, hyperinsulinemia reached a level far beyond the cutoff (3.5) by HOMA-IR.
Moreover, among all assessed numerical parameters, insulin resistance proved itself the best predictor of LVH as measured by LVMI. BMI did not achieve enough statistical significance in determining or predicting LVH in CKD patients. The latter finding disagrees with Buono et al.  series which reportedly shows a high correlation between BMI and LVH in hypertensive patients. This is not the first study to implement myocardial strain analysis in CKD patients, and Ravera et al.  and his team are the last to publish a series about GLS involvement in CKD. GLS has the advantage over conventional fractional shortening in taking into account the segmental myocardial involvement.
Despite the extensive studies pointing at the early reduction of GLS in CKD patients, none have used the technique implemented in this study. The relatively new echocardiographic modality termed transmural strain made it possible to understand whether LV systolic dysfunction seen in any systemic disease is mainly related to the subendocardium or subepicardium. The subepicardium is more vulnerable when it comes to deposition disorders such as iron load while the subendocardium  is more commonly involved when the systemic disease in question operates by ischemia. This new aspect has many advantages as it might detect myocardial dysfunction involving a certain layer earlier than GLS and it might uncover the mechanism underlying myocardial involvement. In our series, there was definite reduction of subendocardial GLS in cases compared with controls, while subepicardial strain was preserved. Nevertheless, subendocardial GLS has been negatively correlated with LVMI, as the thickness of the myocardium increases there is gradual distancing of supplying microvasculature from the relatively ischemic subendocardium leading to aggravation of its ischemic state. There is also increasing body of evidence that insulin resistance by itself operates by inducing endothelial dysfunction and this might as well cause the observed subendocardial dysfunction .
This study examines the role of insulin resistance in induction of myocardial remodeling in CKD; the findings identified in this study might represent a new hope for reverse remodeling of the myocardium in such patients. It highlights the fact that insulin resistance is by far given the factors studied is the most important triggering factor of LVH in CKD, and this impacts myocardial function, especially the subendocardium probably by impairing its perfusion. This near to be the fact need more studies to examine the role of insulin sensitizers in reversing the observed remodeling in CKD patients even in the absence of diabetes.
We want to thank our patients for being our source of knowledge but also we want to thank our students, interns and residents for being our source of passion, we wake up everyday with the negative thoughts of giving up; yet meeting these passionate young colleagues, teaching them and working hand in hand with them help to regenerate our positive vibes.
Conflicts of interest
There are no conflicts of interest.
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