European Journal of Cardiovascular Medicine

William Cole introduced the term "stroke" in 1689.¹ A stroke is a neurological injury resulting from a sudden localized interruption in the central nervous system. This interruption can arise from intracerebral bleeding, subarachnoid haemorrhage, or cerebral infarction.² The World Health Organization characterizes a stroke as a rapid onset of clinical symptoms due to a specific disruption in cerebral function. These symptoms must persist for a minimum of 24 hours or lead to death, and there should be no identifiable cause other than a vascular one.³

As reported by the World Health Organization, cerebrovascular accidents rank as the second leading cause of death and the third most common source of disability globally.⁴ Low- and middle-income countries account for 87% of the disability-adjusted life years and fatalities attributed to stroke.⁵

While the incidence of stroke has decreased in high-income countries, it has doubled in low- and middle-income regions.⁶ In 2016, approximately 5.78 million individuals died worldwide due to cerebrovascular diseases.⁷ In industrialized countries, the typical age of stroke onset is 73 years. Conversely, in less developed areas, strokes occur at a lower average age of 65 years. In 2016, stroke resulted in nearly 0.706 million fatalities in India, with 0.334 million females and 0.372 million males among the deceased. The estimated prevalence rate for stroke in rural India varied from 84 to 262 cases per 100,000 individuals, compared to 334 to 424 cases per 100,000 in urban settings.⁸

Vitamin D deficiency (VDD) is a widespread issue across the globe. There has been a common misconception that VDD is rarely found in India. However, despite being a tropical nation with ample sun exposure, India experiences a rate of Vitamin D insufficiency comparable to that of other countries. Research suggests that VDD affects around 74-96 per cent of the Indian population which is generally healthy.⁹

Increasing evidence demonstrates that vitamin D offers additional health benefits, such as reducing the risk of cardiovascular diseases and cognitive impairments.¹⁰ Vitamin D may have neuroprotective effects due to its involvement in regulating neurotrophic factor release and preserving the blood-brain barrier's integrity.^11-14 Since vitamin D deficiencies are treatable, ensuring adequate vitamin D levels could significantly enhance public health by potentially preventing neurological disorders like stroke.

In recent decades, numerous studies have explored the relationship between vitamin D levels and stroke risk, but results have been inconsistent. A new meta-analysis indicated that individuals with the lowest serum levels of 25(OH)D have a 62% increased risk of stroke compared to those with the highest levels.¹⁵ The research included in this analysis employed different threshold values for their assessments. On the other hand, studies that examined more common dichotomous serum level thresholds did not find a significant effect on stroke incidence.^16,17 Additionally, the conflicting results might also stem from differences in the length of follow-up periods. Research conducted over a short duration may not be the best for evaluating the long-term effects of serum vitamin D levels on stroke risk.^18,19 Although the most recent meta-analysis of observational studies identified a link between vitamin D levels and stroke risk, this association was not confirmed in the latest findings from the VITAL trial (Vitamin D and Omega-3 trial).²⁰

AIM:  

To measure the serum 25 hydroxy-vitamin D levels in patients with acute ischaemic stroke and to compare with normal patients without stroke

OBJECTIVES:  

• To find the serum levels of vitamin D in patients with acute stroke and without stroke.
• To find out the association between vitamin D and acute ischaemic stroke.

Study Design:

Observational Case-Control study. 

Study area: 

The study was conducted in a Teaching hospital AIMSR & District headquarters hospital, Chittoor.

Study Period: 1 year.  

Study population:

This study included a total of 120 subjects out of which 60 are cases (acute ischaemic stroke) and 60 are controls.

Sample size:

The study consisted of a total of 120 cases.

Using the hypothesis tests for an odds ratio at a 5% level of significance, power 80%, around 60 patients will be required in each group of cases and controls.

Control selection: A total of 60 age and gender-matched healthy controls were included.

Sampling Technique:  Purposive sampling.   

Inclusion Criteria:

1. Patients with new onset stroke with an acute infarct on CT brain, admitted in medical wards in AIMSR, DHH Chittoor government hospital, within 7 days of onset of stroke were taken as cases.
2. Patients without stroke, who attended the medical OPD were taken as control
3. 50 to 80 years age group.
4. Sex -Both male and female.

Exclusion criteria:

• History of chronic ischaemic stroke.
• On drugs     that        affect     vitamin  D            metabolism          (Antiepileptics, steroids, Antiretrovirals).
• Calcium or vitamin D supplements.
• Patients who are not willing to participate in the study.
• History of cardiovascular diseases and renal diseases.

Ethical consideration: Institutional Ethical committee permission was taken before the commencement of the study.

Study tools and Data collection procedure:

Written informed consent will be obtained from all the participants. Laboratory investigations including Haemoglobin, TLC, Platelets, Urea, creatinine, Blood sugar, glycosylated haemoglobin, Lipid profile, Liver Function test, Serum Vitamin D and calcium, ECG and CT brain were done for all the participants.

Statistical analysis:

Data was entered into Microsoft Excel and analysis was done using IBM Statistical for the Social Science (SPSS) version 22. Descriptive and frequency analysis was done. Mean and Standard deviation were used for continuous variables. The chi-square test and Mann-Whitney U test were used to find the associations and a p-value less than 0.05 was considered significant.

The mean age of case participants was 64.18 years with a standard deviation (SD) of 9.32, while control participants had a mean age of 62.48 years with an SD of 9.11. The p-value of 0.921 indicates no significant difference in age between the two groups. Among cases, 65% were male and 35% were female, while among controls, 60% were male and 40% were female. The p-value of 0.572 suggests no significant difference in gender distribution between cases and controls.

Table 1: Comorbidities distribution among the study participants

Case participants had higher rates of hypertension (83.3% vs. 20%), diabetes mellitus (55% vs. 13.3%), and other comorbidities compared to controls. The p-values for these comorbidities were all <0.001, indicating significant differences between the groups.

The mean BMI among cases and controls were 23.54 ± 3.08 and 23.92 ± 2.85 respectively. The mean haemoglobin among cases and controls was 10.94 ± 1.71 and 10.95 ± 2.04 respectively.

Table 2: Total leucocyte count in the study participants

Case participants had a lower TLC (8344.67) compared to controls (9491.33), with a p-value of 0.049, indicating a significant difference in TLC between the groups. The mean platelet count among cases and controls were 2.74 ± 0.82 and 2.68 ± 0.86 respectively.

The mean serum creatinine among cases and controls were 1.58 ± 1.26 and 1.3 ± 1.10 respectively. The mean urea among cases and controls were 41.75 ± 24.48 and 30.83 ± 15.76 respectively. Fasting blood sugar (FBS) levels were significantly higher in cases (137.55) compared to controls (122.33), with a p-value of 0.018. The mean post-prandial blood sugar among cases and controls were 217.40 ± 49.88 and 218.67 ± 51.07 respectively.

The mean cholesterol among cases and controls were 183.52 ± 62.76 and 173.07 ± 192.73 respectively. The mean triglycerides among cases and controls were 192.20 ± 139.74 and 156.05 ± 34.66 respectively. The mean HDL among cases and controls were 54.02 ± 29.99 and 62.49 ± 43.53 respectively. The mean LDL among cases and controls were 64.60 ± 36.12 and 58.64 ± 29.57 respectively. The mean calcium among cases and controls were 7.75 ± 1.36 and 7.71 ± 1.82 respectively.

Table 3: ECG findings in the study participants

Among the cases, 6.6% showed left axis deviation, 8.3% had LVH, 3.3% exhibited ST depression, and 51.7% had a normal ECG. Other findings such as P mitral, RVH, diffuse T wave inversions, Q waves in various leads, RBBB, sinus tachycardia, and T wave inversion in lateral leads were also observed but at lower frequencies.

In contrast, among the controls, there were no instances of left axis deviation, and LVH was present in 3.3% of cases. The normal ECG rate was notably higher among controls at 80.0%. Other abnormalities like ST depression, P mitral, RVH, diffuse T wave inversions, Q waves in various leads, RBBB, sinus tachycardia, and T wave inversion in lateral leads were present but at lower frequencies compared to cases.

The p-value associated with left axis deviation was less than 0.001, indicating a significant difference in its prevalence between cases and controls.

Table 4: Serum Vitamin D in the study participants

Among the cases, 28 participants (46.7%) were classified as deficient in vitamin D, 27 participants (45%) were classified as insufficient, and 5 participants (8.3%) were classified as having sufficient levels of vitamin D. In comparison, among the controls,

6 participants (10%) were deficient, 35 participants (58.3%) were insufficient, and 19 participants (31.7%) had sufficient levels of vitamin D.

The p-value associated with serum vitamin D levels was less than 0.001, indicating a significant difference in the distribution of vitamin D levels between cases and controls.

Table 5: Mean Vitamin D level in the study participants

For cases, the mean vitamin D level was 14.12 ng/mL with a standard deviation of 7.71 ng/mL. In contrast, for controls, the mean vitamin D level was 25.43 ng/mL with a standard deviation of 8.96 ng/mL. The p-value associated with mean vitamin D levels was less than 0.001, indicating a significant difference in the mean vitamin D levels between cases and controls.

This case-control observational study was carried out at AIMSR Teaching Hospital and the District Headquarters Hospital in Chittoor over a year, after receiving approval from the institutional scientific and ethical committee. The study comprised 120 participants, consisting of 60 individuals with acute ischemic stroke and 60 healthy controls matched by age and gender, selected through purposive sampling. The inclusion criteria included patients experiencing a new onset stroke with an acute infarct visible on a CT scan of the brain, admitted within 7 days of symptom onset, and non-stroke patients visiting the medical outpatient department, aged between 50 to 80 years, of both genders. The exclusion criteria comprised individuals with a history of chronic ischemic stroke, those taking medications that impact vitamin D metabolism, users of calcium or vitamin D supplements, individuals unwilling to participate, and those with a history of cardiovascular or renal diseases. Data collection entailed obtaining written informed consent and performing a range of laboratory tests, including haemoglobin, total leukocyte count, platelets, urea, creatinine, blood glucose, glycosylated haemoglobin, lipid profile, liver function tests, as well as serum vitamin D and calcium levels, an ECG, and CT scans of the brain for all participants. The objective of this research was to assess the serum levels of 25 hydroxy-vitamin D in individuals with acute ischemic stroke and to make comparisons with normal individuals without stroke.

The mean age of case participants was 64.18 years with a standard deviation (SD) of 9.32, while control participants had a mean age of 62.48 years with an SD of 9.11. The p-value of 0.921 indicates no significant difference in age between the two groups. In a study done by Park KY et al.²¹, it was shown that the mean age of the study participants was 66.12. Similarly, in a study done by Alharbi AR et al.²², it was shown that the mean age of the study participants was 68.2. Jha V, Kumar V, and Anand A²³ conducted a study to check for any potentially significant connections between the level of vitamin D and acute ischemic stroke patients. It was shown that the mean age of the patients with cerebrovascular accidents was 59.50 years.

The strongest non-modifiable risk factor for incident stroke is ageing; at the age of 55, the risk doubles every ten years. People 65 years of age or older account for around 75% of stroke cases. The frequency of stroke incidents in older persons is anticipated to increase shortly due to the predicted growth in the population of those 65 and older. This will pose significant difficulties to healthcare professionals and policymakers. About 370 miles make up the intricate network of adult brain vasculature, which exchanges 20% of total blood glucose and oxygen and receives 20% of cardiac output.²⁴

Among cases, 65% were male and 35% were female, while among controls, 60% were male and 40% were female. The p-value of 0.572 suggests no significant difference in gender distribution between cases and controls. In a study done by Park KY et al.²¹, it was shown that 59.5% and 40.5% had males and females respectively. Alharbi AR et al.²⁵ showed that 49.3% of the stroke patients were females. Kim KS et al.²⁶ have shown that 59.4% and 40.6% were males and females respectively.

Case participants had higher rates of hypertension (83.3% vs. 20%), diabetes mellitus (55% vs. 13.3%), and other comorbidities compared to controls. The p-values for these comorbidities were all <0.001, indicating significant differences between the groups. Comparably, Sheng X et al.²⁷ conducted a study in which they found that hypertension was present in 67% of the patients who were suffering from acute ischemic stroke. On the other hand, the prevalence of diabetes mellitus was shown to be lower in a study that was carried out by Ouyang Q et al.²⁸. It is estimated that one-third of all diabetic individuals have diabetes that has not been discovered, which indicates that their physician did not notice it. Patients who are diagnosed with complications, such as a stroke, myocardial infarction, or diabetic foot, generally present with these conditions. In a similar vein, arterial hypertension is the most prevalent risk factor for stroke. As a result of the variability of stroke aetiology and hemodynamic effects, it is difficult to maintain blood pressure in stroke patients. This needs a careful diagnosis as well as the design of therapy goals.

The mean BMI among cases and controls were 23.54 ± 3.08 and 23.92 ± 2.85 respectively. Similarly, in a study done by Ouyang Q et al.²⁸, the mean BMI was 24.47 among the patients with acute ischaemic stroke. The mean calcium among cases and controls were 7.75 ± 1.36 and 7.71 ± 1.82 respectively. In a study done by Jha V, Kumar V, and Anand A²³, it was shown that the mean calcium level was 8.35 mg/dl. Similarly, in a study done by Chung JW et al, it was shown that the mean calcium level was 8.97mg/dl.

The influx of calcium ions into neuronal cells is a mechanism of ischemia cell death, as established by experimental experiments. Ca2+ that has been activated by glutamate has been observed to enter cultured neurons, and higher Ca2+ levels have been found after NMDA receptor stimulation. This phenomenon has been observed multiple times using fluorescent probes. In addition, it has been demonstrated that neuronal nitric oxide synthase, calmodulin, and calcineurin are all examples of effectors of Ca2+ toxicity that can be inhibited to protect neurons from the harmful effects of excitatory amino acids. According to the findings of this research, an increase in the levels of extracellular Ca2+ is associated with an increased risk of early neuronal death brought on by NMDA receptor-mediated Ca2+ intracellular influx.²⁹

Among the cases, 28 participants (46.7%) were classified as deficient in vitamin D, 27 participants (45%) were classified as insufficient, and 5 participants (8.3%) were classified as having sufficient levels of vitamin D. In comparison, among the controls, 6 participants (10%) were deficient, 35 participants (58.3%) were insufficient, and 19 participants (31.7%) had sufficient levels of vitamin D. The p-value associated with serum vitamin D levels was less than 0.001, indicating a significant difference in the distribution of vitamin D levels between cases and controls.

For cases, the mean vitamin D level was 14.12 ng/mL with a standard deviation of 7.71 ng/mL. In contrast, for controls, the mean vitamin D level was 25.43 ng/mL with a standard deviation of 8.96 ng/mL. The p-value associated with mean vitamin D levels was less than 0.001, indicating a significant difference in the mean vitamin D levels between cases and controls. A study done by Park KY et al.²¹, has shown that the average 25(OH)D level was 47.2 ± 31.7 nmol/l, and most patients had vitamin D deficiency (<50 nmol/l; 68.8%). Only 13.6% of patients had an adequate vitamin D level (≥75 nmol/l). 

To investigate any possible connections between vitamin D levels during the acute phase of short-term ischemic stroke and cognitive impairment after one month, Chen H et al³⁰. conducted research. It showed that the mean Vitamin D among the post-stroke patients was 41.47. 30.37%, 29.8% and 39.5% had Vitamin D deficiency, insufficiency and sufficiency respectively.

Fahmy E et al.³¹ have shown that the mean Vitamin D in stroke patients was 21.26. Among those with ischaemic stroke 31.3%, 41.7% and 27.1% had Vitamin D deficiency, insufficient and sufficient levels respectively. Wajda J evaluated the hypothesis that patients with IS who had lower levels of 25-hydroxyvitamin D (25-OH-D) have a higher chance of dying. The blood 25-OH-D level in the study group was found to be considerably lower than the level in the control group (9.9 ± 7.1 ng/mL versus 21.0 ± 8.7 ng/mL; p for comparison is less than 0.001). 163 individuals had mildly reduced (insufficient) levels, 217 individuals had moderate insufficiency, and only 29 individuals had severe deficiency.

To determine the link between blood vitamin D levels and the clinical severity of stroke at admission as well as functional independence and impairment at discharge, Alharbi AR et al²². conducted research. 11.9% of the patients who participated in the research had adequate levels of vitamin D, while 66% of the subjects failed to meet the recommended daily allowance for vitamin D. To check for any potentially significant connections between the level of vitamin D and acute ischemic stroke patients, Jha V, Kumar V, and Anand A²³ conducted a study. The mean Vitamin D in stroke patients was 25.37. According to the research, the population was separated into three groups: vitamin D sufficient (>30ng/ml), vitamin D inadequate (20-30 ng/ml), and vitamin D deficient (<20ng/ml). It was found that around 72% of the study population did not have enough levels of vitamin D. Only sixteen (30.77%) of patients with CVA had adequate levels of vitamin D, while eighteen (34.62%) had inadequate levels, and the remaining eighteen (34.62%) had vitamin D deficiencies.

To determine if blood vitamin D levels and short-term functional outcomes in individuals suffering from acute ischemic stroke are related, Kim MS et al.²⁶ conducted research. The median serum 25-OHD level was 17.1 ng/mL. Out of 192 patients, 28, 49 and 115 had sufficient, insufficient and deficient Vitamin D.

The mechanisms underlying the relationship between vitamin D and stroke are multifaceted. Vitamin D receptors (VDRs) are widely distributed in the brain, including regions involved in cerebrovascular regulation and neuroprotection. Experimental studies suggest that vitamin D may exert neuroprotective effects through anti-inflammatory, antioxidant, and anti-apoptotic pathways, which could mitigate neuronal damage and improve stroke outcomes.

Furthermore, vitamin D plays a role in regulating calcium homeostasis, endothelial function, and vascular tone, factors that are crucial in maintaining cerebrovascular health. Vitamin D deficiency has been associated with endothelial dysfunction, arterial stiffness, and increased risk of hypertension and atherosclerosis, all of which are risk factors for stroke. The clinical implications of vitamin D in stroke extend beyond risk assessment to potential therapeutic interventions. Several studies have investigated the impact of vitamin D supplementation on stroke outcomes, albeit with varying results. While some studies suggest a potential benefit in terms of improved functional outcomes, reduced inflammation, and neuroprotection, others report conflicting findings or limited efficacy.

Moreover, the timing, dosage, and duration of vitamin D supplementation remain areas of debate, necessitating well-designed clinical trials to elucidate its optimal use in stroke management. Additionally, the identification of biomarkers or genetic markers related to vitamin D metabolism may help personalize treatment strategies for stroke patients.

In conclusion, this study found significant differences in serum vitamin D levels and other risk factors, such as hypertension, diabetes, TLC, and FBS, between acute ischemic stroke patients and healthy controls. Lower vitamin D levels in stroke cases suggest a potential link between vitamin D deficiency and increased stroke risk, highlighting its role as a modifiable risk factor. However, the study's observational design and small sample size limit definitive conclusions. Further research with larger cohorts and long-term follow-up is needed to establish causality and explore preventive or therapeutic implications. These findings emphasize the importance of considering vitamin D status in stroke risk assessment and management.

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