Diabetes mellitus, a prevalent metabolic disorder, not only affects organ function but also induces significant metabolic abnormalities, including disturbances in calcium homeostasis¹. These disturbances manifest as both hypo- and hypercalcemia, potentially impacting various internal structures reliant on metabolic products². The resultant dysfunction at the cellular level can ultimately lead to organ dysfunction and mortality³. While hypocalcemia often arises in the presence of renal insufficiency, hypercalcemia in diabetes is associated with mechanisms such as insulin resistance, further exacerbating insulin resistance itself ⁴. And the calcium is the important one for the production of insulin and glucose uptake in the cells. Ionized serum calcium is the active form of calcium⁵.

The heart, a vital organ, is susceptible to damage from various conditions, including hypertension, diabetes, dyslipidemia, and hypercalcemia⁶. Despite historical views not designating hypercalcemia as a cardiac risk factor, recent studies have demonstrated its potential to induce severe cardiac abnormalities, encompassing both systolic and diastolic dysfunction⁷. The term "remodelling" encapsulates morphological changes in the heart post-injury, involving alterations in ventricular cavity diameter, wall thickness, and scarred areas⁸. Myocardial ischemia and various benign cardiac conditions may progress to significant abnormalities, emphasizing the importance of understanding factors contributing to left ventricular hypertrophy (LVH) ⁹.

LVH, identified as a threatening prognostic sign and an independent risk factor for cardiac death, coronary heart disease, ventricular dysrhythmias, and heart failure, is prevalent in type 2 diabetes mellitus (T2DM) ¹⁰. The association between T2DM and LVH persists even in the absence of hypertension and obesity, suggesting additional contributing factors beyond traditional risk factors ¹¹. Despite efforts to control glycemia, blood lipids, urinary albumin excretion rate, and insulin resistance, LVH remains a common occurrence in T2DM patients. This study explores the potential role of altered calcium homeostasis, indexed by serum calcium levels, in contributing to LVH prevalence in T2DM patients.

As serum calcium levels have shown positive correlations with blood lipids and glucose levels in T2DM, irrespective of measured parameters, investigating the link between serum calcium and LVH becomes imperative. This cross-sectional study aims to determine the effect of serum calcium on left ventricular dimension and wall thickness in diabetic patients, shedding light on a potential yet underexplored aspect of cardiac complications in diabetes.

A cross sectional study conducted among Diabetic patients presenting to outpatient department and patients admitted in Medicine department, Government Medical College, Nizamabad, Telangana, India.

All the design, analysis, interpretation of data, drafting and revisions followed the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guidelines and the study was based on Declaration of Helsinki.

 Inclusion Criteria:

• Patients with type 2 diabetes
• Diabetes in this study will be defined by the American Diabetes Association as either
  • Fasting plasma glucose (FBS) of >126 mg/dl or
  • Post prandial blood sugars at 2 hr (PPBS) >200 mg/dl

Exclusion criteria:

• Patients with hypertension
• On treatment with sulfonylureas
• H/O myocardial infarction, coronary artery bypass or angioplasty, atrial fibrillation, moderate to severe valvular heart disease, stroke or occlusive peripheral vascular disease, heart failure
• Serum creatinine > 110 micromoles/ (>1.2 mg/ d L)
• Patients with history of parathyroid disease or vitamin D related
• Medication history including vitamin D, bisphosphonate, estrogen replacement therapy and diuretics
• Uncontrolled thyroid diseases
• Patient with chronic liver diseases

Sampling Procedure: 206 diabetic patients visiting OPD or admitted in General Medicine, Government Medical College, Nizamabad, Telangana, India who met inclusion criteria of study and gave consent were included in the study.

Demographics: Age distribution, gender of study participants was recorded. Height in cms, weight in kgs was recorded.

Lab investigations: CBP (complete blood picture), RFT (renal function tests), LFT (liver function tests), Serum calcium, total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), FBS, PLBS, HBA1C

Clinical examinations: ECG, Chest X-ray, 2D ECHO – echocardiography was done in all patients. In left lateral position ECHO was performed in parasternal long axis, 4 chamber view. M mode was used to assess the septal wall, posterior wall thickness and left ventricular diastolic dimension.

• By using wall thickness left ventricular mass is calculated. Adjusting the left ventricular mass with body surface area left ventricular mass index is calculated.

PROCEDURE:

2D Echocardiography Procedure:

Patient Positioning: Patients were placed in the left lateral position to optimize imaging of the heart.

Probe Placement: A suitable echocardiography probe was selected and placed on the chest wall.

Imaging Plane Selection:

Parasternal Long Axis View: The echocardiographer identified the parasternal long axis for imaging, providing a longitudinal view of the left ventricle and its surrounding structures.

4 Chamber View: The imaging plane was adjusted to capture the heart in the 4- chamber view, offering a comprehensive visualization of the four heart chambers.

M-mode Echocardiography: M-mode, or motion mode, was employed to assess specific parameters with high temporal resolution.

Measurement of Septal Wall and Posterior Wall Thickness: Using M-mode, the echocardiographer obtained measurements of the septal wall thickness and posterior wall thickness. These measurements provide information about the structural integrity of the left ventricle.

Left Ventricular Diastolic Dimension Assessment: M-mode was utilized to measure the left ventricular diastolic dimension, offering insights into the chamber size during diastole.

Calculation of Left Ventricular Mass:

Left ventricular mass was calculated using the provided  corrected formula:

LV mass

(g)=0.8{1.04×(LVDD+IVS+PW)3−(LVDD)3}+0.6LV mass (g)

Where LVDD represents left ventricular diastolic dimension, IVS is interventricular septum thickness, and PW is posterior wall thickness.

Comprehensive Recording: All measurements and observations from the echocardiography session were meticulously recorded for subsequent analysis and interpretation.

Statistical Analysis

The collected data was entered into MS Excel and checked for completeness. The collected data was analysed using Statistical Package for Social Sciences version

28.0 (SPSS V 28). Descriptive statistics were obtained as means and standard deviation for continuous variables and frequency and percentage for categorical variables. Chi-square test, Independent T-test, Pearsons correlation test was done. P≤0.05 was considered significant.

TABLE 1: AGE DISTRIBUTION OF STUDY PARTICIPANTS

In Table 1 the age distribution of study participants is presented, revealing a cohort predominantly composed of individuals aged 50 and above. Specifically, 51.9% of the participants fell within the 50-59 age group, representing the largest proportion in the study. Additionally, 23.8% of participants were in the 40- 49 age range, 19.9% in the 60-69 age group, and 4.4% were 70 years or older.

TABLE 2: GENDER DISTRIBUTION OF STUDY PARTICIPANTS

In Table 2 the gender distribution of study participants is presented, demonstrating a relatively balanced representation between male and female individuals. Among the study participants, 58.3% were male, while 41.7% were female.

TABLE 3: DISTRIBUTION OF STUDY PARTICIPANTS BASED ON LVH

Table 3 provides an overview of the distribution of study participants based on the presence or absence of Left Ventricular Hypertrophy (LVH). The data reveals a nearly equal distribution, with 51% of participants exhibiting LVH and 49% showing its absence.

TABLE 4: AGE DISTRIBUTION OF STUDY PARTICIPANTS BASED ON LVH

CHI-SQUARE

P≤0.05 IS STATISTICALLY SIGNIFICANT

Table 4 presents the age distribution of study participants stratified based on the presence or absence of Left Ventricular Hypertrophy (LVH). The results indicate insignificant associations between age groups and the occurrence of LVH (p=0.012). In the 40-49 age category, 23.8% of participants with LVH were observed, compared to 23.8% without LVH. Among individuals aged 50-59, 52.4% with LVH were noted, compared to 51.5% without LVH. Similarly, in the 60-69 age group, 19% had LVH, and 20.8% did not. For those aged 70 and above, 4.8% exhibited LVH, compared to 3.9% without LVH.

TABLE 5: GENDER DISTRIBUTION OF STUDY PARTICIPANTS BASED ON LVH

CHI-SQUARE

P≤0.05 IS STATISTICALLY SIGNIFICANT

Table 5 outlines the gender distribution of study participants categorized by the presence or absence of Left Ventricular Hypertrophy (LVH). The data reveals that among male participants, 59.1% exhibited LVH, while 57.4% did not. For female participants, 40.9% had LVH, and 42.6% did not. However, in this context, the p- value (0.243) exceeds the threshold, suggesting that there is no statistically significant association between gender and the occurrence of LVH among the study participants.

TABLE 6: SERUM CALCIUM DISTRIBUTION OF STUDY PARTICIPANTS

Table 6 displays the distribution of study participants based on serum calcium levels. The data reveals an equal distribution, with 50% of participants having serum calcium levels exceeding 10.2, and the remaining 50% having levels at or below 10.2.

TABLE 7: SERUM CALCIUM DISTRIBUTION OF STUDY PARTICIPANTS BASED ON LVH

CHI-SQUARE

P≤0.05 IS STATISTICALLY SIGNIFICANT

Table 7 presents the distribution of study participants based on serum calcium levels and their correlation with Left Ventricular Hypertrophy (LVH). The data demonstrates a statistically significant association between serum calcium levels and the presence of LVH (p-value=0.000). Among those with serum calcium levels exceeding 10.2, 98.1% exhibited LVH. In contrast, participants with serum calcium levels at or below 10.2 had a significant association with the absence of LVH, where 100% did not have LVH, and only 1.9% exhibited it in LVH group.

TABLE 8: ECHO MEASUREMENTS DISTRIBUTION OF STUDY PARTICIPANTS BASED ON LVH

INDEPENDENT T TEST

P≤0.05 IS STATISTICALLY SIGNIFICANT

Table 8 presents echocardiographic measurements were comprehensively analyzed to assess their distribution among study participants based on the presence or absence of Left Ventricular Hypertrophy (LVH). individuals with LVH exhibited a higher mean Left Ventricular Diastolic Dimension (LVDD) (51.57 ± 3.73 mm) compared to those without LVH (45.42 ± 2.26 mm) (p = 0.000). Interventricular Septum (IVS) thickness was also notably increased in the LVH group (13.10 ± 1.34 mm) compared to the non-LVH group (10.51 ± 0.69 mm) (p = 0.012). Similarly, Posterior Wall (PW) thickness showed a significant elevation in the LVH group (10.98 ± 1.23 mm) compared to the non-LVH group (8.92 ± 0.65 mm) (p = 0.001). Left Ventricular Mass (LV Mass) was substantially higher in individuals with LVH (232.46 ± 52.37 g) compared to those without LVH (148.19 ± 21.25 g) (p = 0.000). Furthermore, Body Surface Area (BSA) was found to be significantly lower in the LVH group (1.56 ± 0.20 m²) compared to the non-LVH group (1.69 ± 0.36 m²) (p = 0.003). The Left Ventricular Mass Index (LVMI) also demonstrated a substantial increase in the LVH group (174.01 ± 59.08 g/m²) compared to the non-LVH group (91.68 ± 12.49 g/m²) (p = 0.000). These findings underscore the intricate relationships between echocardiographic measurements and the presence of LVH in the studied population, providing valuable insights into the structural alterations associated with cardiac hypertrophy. The statistical significance (p≤0.05) of these observations strengthens the robustness of the results and their potential clinical implications.

TABLE 9: CHOLESTROL PROFILE OF STUDY PARTICIPANTS BASED ON LVH

INDEPENDENT T TEST

P≤0.05 IS STATISTICALLY SIGNIFICANT

The cholesterol profile of the study participants was thoroughly examined in relation to the presence or absence of Left Ventricular Hypertrophy (LVH). The mean levels of Total Cholesterol were significantly higher in the LVH group (216.33 ± 36.16) compared to the non-LVH group (187.97 ± 28.93), indicating elevated overall cholesterol levels in individuals with LVH (p = 0.001). Similarly, Triglyceride (TGL) levels showed a significant increase in the LVH group (159.09 ± 29.09) compared to the non-LVH group (135.73 ± 34.92), suggesting higher triglyceride levels in individuals with LVH (p = 0.002). Low-Density Lipoprotein (LDL) cholesterol exhibited a substantial difference between the LVH group (113.85 ± 17.66) and the non-LVH group (97.74 ± 21.43), signifying elevated LDL cholesterol in individuals with LVH (p= 0.001). Conversely, High-Density Lipoprotein (HDL) cholesterol levels were significantly lower in the LVH group (60.02 ± 6.49) compared to the non-LVH group (36.19 ± 0.95), indicating reduced levels of protective HDL cholesterol in individuals with LVH (p = 0.000).

In the present study, it was observed that 51% of the study participants exhibit LVH, a proportion that closely corresponds to the prevalence reported by Venkateswarlu D et al., which is 50.5% ¹². However, this prevalence is comparatively lower than the findings reported by Li J et al., where LVH was identified in 37.8% of the study population ¹³.

In the current research 51.9% of the participants fall within the age range of 50-59 years, aligns with D. Venkateswarlu et al, were 52.4% fall within the same age group ¹⁴. In the present study, no notable distinction was observed in terms of age among participants with LVH and those without LVH. The study highlights that advanced age poses a substantial risk for both diabetes and prediabetes, resulting in a greater prevalence of these health conditions among the elderly when compared to younger and middle-aged individuals. Additionally, the elderly face an elevated likelihood of experiencing complications in their cardiovascular, retinal, and renal systems, emphasizing the importance of addressing these concerns in older populations ¹⁵.

In the present study, it was observed that 58.3% of male participants are affected by diabetes. This finding aligns with the research of Kautzky-Willer A et al., which indicates a global trend where an estimated 17.7 million more men than women are affected by diabetes mellitus ¹⁶. In the present study, no notable distinction was observed in terms of gender among participants with LVH and those without LVH. Firstly, it may suggest that the development of LVH is not strongly influenced by gender in this particular study population. Alternatively, it could imply that other factors, such as age, comorbidities, or lifestyle factors, play a more predominant role in the occurrence of LVH within this cohort.

In diabetic patients within the current study, a notable distinction in hypercalcemia was observed between those with left ventricular hypertrophy (LVH) and those without LVH. Specifically, 98.1% of individuals with LVH exhibited hypercalcemia, while none in the group without LVH displayed hypercalcemia this finding aligns with previous studies ¹⁷. Supporting this, Jensen et al. conducted a study involving 2729 chronic heart failure patients identified from Danish National Registries. Their analysis of serum calcium values revealed that the highest mortality risk was associated with early deaths (≤30 days). Hypocalcemic patients had a hazard ratio (HR) of 2.22 (95% CI; 1.74-2.82), while hypercalcemic patients had an HR of 1.67 (95% CI; 0.96-2.90) compared to normocalcemic patients. The conclusion drawn was that altered calcium homeostasis was linked to an increased short-term mortality risk. Notably, almost one-third of all heart failure patients suffered from hypocalcemia, which was associated with a poor prognosis ¹⁸.

Historically, the evaluation of left ventricular (LV) remodelling has predominantly relied on echocardiography. In the present study, LV remodelling was assessed using echocardiography, revealing a statistically significant difference in echocardiographic measurements between the groups with and without LVH ¹⁹. Notably, diabetic patients with LVH exhibited the highest values in alignment with previous research, specifically studies ²⁰. This alignment underscores the consistent observation that key influencing factors contributing to left ventricular hypertrophy include parameters such as left ventricular end-diastolic dimension, posterior wall thickness, and interventricular septal thickness. The statistical significance of these differences in echocardiographic measurements implies that these specific structural dimensions play a crucial role in the development of left ventricular hypertrophy in diabetic patients. The reliance on echocardiography for this assessment reinforces its established utility as a non-invasive and widely used diagnostic tool for evaluating cardiac structure and function.

This study contributes valuable insights into the complex pathophysiology of cardiac complications in T2DM, emphasizing the importance of comprehensive cardiovascular risk assessment that includes serum calcium evaluation. Future research exploring mechanisms underlying the association between calcium dysregulation and LVH could potentially lead to novel therapeutic strategies aimed at reducing cardiovascular morbidity and mortality in diabetic populations.

1. Levy J. Abnormal cell calcium homeostasis in type 2 diabetes mellitus: a new look on an old disease. Endocrine, 1999; 10(1): 1–6.
2. Arya Satheesh, Kadappa Jaligidad. A Study of High Serum Calcium Level In Diabetes Mellitus And Its Association With Left Ventricular Hypertrophy. IOSR Journal of Dental and Medical Sciences. 2023; 22(8):7-11
3. Venkateswarlu D, Kumar MP. A study of high serum calcium level in diabetes mellitus and its association with left ventricular remodelling. International Archives of Integrated Medicine. 2019 Sep 1;6(9).
4. Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. Calcium and phosphate concentrations and future development of type 2 diabetes: The Insulin Resistance Atherosclerosis Study. Diabetologia, 2014; 57(7): 1366–74.
5. De Bacquer D, De Henauw S, De Backer G, Kornitzer M. Epidemiological evidence for an association between serum calcium and serum lipids. Atherosclerosis, 1994; 108: 193–200.
6. Münch G, Bölck B, Karczewski P, Schwinger RH. Evidence for calcineurin- mediated regulation of SERCA 2a activity in human myocardium. J Mol Cell Cardiol., 2002; 34: 321–334.
7. Frohlich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau V, Fauad-Tarazi F, Horan MJ, Marcus M, Massie B, Pfeffer MA. The heart in hypertension. New England Journal of Medicine. 1992 Oct 1;327(14):998-
8. Li J, Wu N, Li Y, Ye K, He M, Hu R. Cross-sectional analysis of serum calcium levels for associations with left ventricular hypertrophy in normocalcemia individuals with type 2 diabetes. Cardiovascular diabetology. 2015 Dec;14(1):1-1.
9. Becerra-Tomas N, Estruch R, Bullo M, Casas R, Diaz-Lopez A, Basora J, et Increased serum calcium levels and risk of type 2 diabetes in individuals at high cardiovascular risk. Diabetes Care. 2014;37(11):3084– 91.
10. Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetologia. 2014;57(7):1366–74.
11. Karanja, N., Morris, C. D., Illingworth, D. R. & McCarron, D. A. (1987) Plasma lipids and hypertension: response to calcium supplementation. Am. J. Clin. Nutr. 45: 60–65.
12. Stevenson JC, Crook D, Godsland IF. Influence of age and menopause onserum lipids and lipoproteins in healthy women. Atherosclerosis. 1993; 98:83–90
13. Münch G, Bölck B, Karczewski P, Schwinger RH. Evidence for calcineurin- mediated regulation of SERCA 2a activity in human myocardium. J Mol Cell Cardiol. 2002; 34:321–334`
14. Gunther S, Grossman W. Determinants of ventricular function in pressure- overload hypertrophy in man. Circulation. 1979; 59:679–688.
15. Imamura T, McDermott PJ, Kent RL, et al. Acute changes in myosin heavy chain synthesis rate in pressure versus volume overload. Circ Res. 1994; 75:418–425.
16. Matsuo T, Carabello BA, Nagatomo Y, et al. Mechanisms of cardiac hypertrophy in canine volume overload. Am J Physiol. 1998;275: H65– H7.
17. Pfeffer MA. Left ventricular remodelling after acute myocardial

          Annu Rev Med. 1995; 46:455– 466.

18. Borg TK, Burgess ML. Holding it all together: organization and functions of the extracellular matrix of the heart. Heart Failure. 1993; 8:230 –238
19. Kuppuswamy D, Kerr C, Narishige T, et al. Fourth association of tyrosine- phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium. J Biol Chem. 1997; 272:4500–4508.
20. McGill G, Shimamura A, Bates RCM, et al. Loss of matrix adhesion triggers rapid transformation-selective apoptosis in fibroblast. J Cell Biol. 1997; 138:901–911.