European Journal of Cardiovascular Medicine

Hypertension is one of the most important modifiable risk factors for cardiovascular morbidity and mortality worldwide, and its prevalence continues to rise in both developed and developing countries, including India. It is a major contributor to the burden of coronary artery disease, stroke, congestive heart failure and chronic kidney disease. Although the majority of cases are labelled as "essential" or primary hypertension, in which no single identifiable cause is found, a multifactorial interplay of genetic, environmental, dietary and endocrine factors is now recognised to underlie the elevation of blood pressure.

Among the various biochemical factors studied in relation to blood pressure regulation, the divalent cations calcium and magnesium have received considerable attention. Magnesium is the second most abundant intracellular cation after potassium and acts as a natural physiological calcium antagonist. It is a cofactor for more than three hundred enzymatic reactions, including those governing ATP-dependent ion transport, and plays a central role in maintaining vascular smooth muscle tone, endothelial function and myocardial excitability.¹ At the cellular level, magnesium regulates the entry of calcium into vascular smooth muscle cells; a fall in intracellular magnesium is associated with an increase in intracellular free calcium, leading to increased vascular tone, vasoconstriction and a consequent rise in peripheral vascular resistance and blood pressure.²

Epidemiological and clinical studies over the past few decades have suggested an inverse relationship between dietary and serum magnesium levels and blood pressure. The landmark Atherosclerosis Risk in Communities (ARIC) study demonstrated that serum and dietary magnesium levels were inversely associated with blood pressure and the prevalence of hypertension in a large American cohort.³ Similarly, earlier population-based surveys had shown that communities with a higher dietary intake of magnesium tended to have a lower prevalence of hypertension.⁴

Indian workers have also examined this relationship in local populations. Gupta et al, in a study conducted on hypertensive patients attending a tertiary care hospital, reported significantly lower serum magnesium levels in hypertensives as compared to normotensive controls and suggested that hypomagnesaemia could be a contributing biochemical abnormality in Indian hypertensive subjects.⁵ In a similar hospital-based study from South India, Reddy and Bindu documented a high prevalence of hypomagnesaemia among newly diagnosed hypertensives and observed a significant negative correlation between serum magnesium and both systolic and diastolic blood pressure.⁶ Rao and Rao, in their biochemical evaluation of hypertensive subjects, further supported these findings and proposed that a fall in serum magnesium correlated with increasing severity of hypertension.⁷ Sharma et al, studying newly diagnosed, untreated hypertensive patients, similarly reported significantly reduced serum magnesium levels and concluded that magnesium estimation may serve as a useful adjunct marker in the biochemical work-up of hypertensive patients.⁸ These Indian observations, made across different regions and settings, are broadly consistent with the western literature and lend support to the hypothesis that magnesium deficiency may be an important, correctable factor in the pathogenesis of essential hypertension in the Indian population as well.

The proposed mechanisms by which magnesium deficiency may raise blood pressure include increased vascular smooth muscle contractility due to elevated intracellular calcium, endothelial dysfunction with reduced nitric-oxide-mediated vasodilation, increased production of vasoconstrictor prostaglandins and thromboxane, activation of the renin-angiotensin-aldosterone system, and enhanced sensitivity to circulating catecholamines and angiotensin II.⁹ Several small clinical trials have also shown a modest but significant reduction in blood pressure with oral magnesium supplementation in hypertensive patients, further strengthening the biological plausibility of this association.¹⁰

Despite this body of evidence, the relationship between serum magnesium and hypertension has not been uniformly consistent across all studies, and the magnitude of the association appears to vary with the population studied, dietary pattern, renal function, and concurrent use of antihypertensive or diuretic therapy. Given the simplicity, low cost and wide availability of serum magnesium estimation, and its potential clinical relevance in the Indian setting where dietary magnesium intake may be inadequate in a proportion of the population, the present study was undertaken to evaluate serum magnesium levels in hypertensive patients as compared with normotensive controls, and to study its correlation with blood pressure and the severity of hypertension.

Aims and Objectives

To estimate and compare serum magnesium levels in hypertensive patients (cases) and normotensive individuals (controls).

Study Design and Setting

This was a hospital-based, cross-sectional, case–control study carried out in the Department of Medicine of a tertiary care teaching hospital, over a period of twelve months, after obtaining approval from the Institutional Ethics Committee. Written informed consent was obtained from all participants prior to enrolment.

Study Population

•        A total of 200 subjects between 30 and 65 years of age were enrolled and divided into two groups of 100 each:

•        Group I (Cases): 100 patients with a confirmed diagnosis of essential hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on at least two separate occasions, as per JNC-8 criteria), attending the medicine outpatient department.

•        Group II (Controls): 100 age- and sex-matched, apparently healthy normotensive individuals with no personal or family history of hypertension, recruited from among attendants and volunteers.

•        Inclusion Criteria

•        Age 30–65 years, of either sex.

•        Newly diagnosed or known cases of essential hypertension, whether treatment-naïve or on regular antihypertensive therapy.

•        Willingness to give written informed consent.

Exclusion Criteria

•        Secondary hypertension (renal, endocrine, or drug-induced).

•        Diabetes mellitus, chronic kidney disease, or hepatic disease.

•        Pregnancy.

•        History of magnesium or calcium supplementation, or use of diuretics known to alter magnesium homeostasis, within the preceding four weeks.

•        Chronic alcoholism or malabsorption syndromes.

Sample Collection and Biochemical Analysis

Under aseptic precautions, 5 mL of fasting venous blood was withdrawn from each subject between 8 and 10 a.m. The serum was separated by centrifugation at 3000 rpm for 10 minutes and analysed on the same day. Serum magnesium was estimated by the calmagite dye-binding colorimetric method on a semi-autoanalyser, using a commercially available diagnostic kit, with results expressed in mg/dL. The reference range for serum magnesium in the study laboratory was taken as 1.7–2.6 mg/dL, and hypomagnesaemia was defined as a serum magnesium level below 1.7 mg/dL.

Blood Pressure Measurement

Blood pressure was recorded in the sitting position after at least 10 minutes of rest, using a calibrated mercury sphygmomanometer, on the right arm, and the mean of two readings taken five minutes apart was used for analysis. Hypertension was further sub-classified as Stage 1 (SBP 140–159 mmHg or DBP 90–99 mmHg) and Stage 2 (SBP ≥160 mmHg or DBP ≥100 mmHg).

Statistical Analysis

Data were entered in Microsoft Excel and analysed using SPSS software (version 25.0). Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as frequencies and percentages. Comparison of means between two groups was done using the unpaired Student's t-test, while comparison across more than two groups (severity grades) was done using one-way ANOVA with post-hoc Tukey test. Pearson's correlation coefficient (r) was used to assess the correlation between serum magnesium and blood pressure parameters. A p-value of less than 0.05 was considered statistically significant.

A total of 200 subjects (100 cases and 100 controls) completed the study. The baseline demographic and clinical characteristics of both groups are summarised in Table 1. The two groups were comparable with respect to age and sex distribution (p>0.05), while body mass index and blood pressure parameters were, as expected, significantly higher in the hypertensive group (p<0.001).

Table 1: Baseline demographic and clinical characteristics of study participants

The mean serum magnesium level was significantly lower in cases as compared to controls (Table 2). The mean serum magnesium in hypertensive patients was 1.68 ± 0.29 mg/dL, as against 2.11 ± 0.24 mg/dL in normotensive controls, a difference that was highly statistically significant (p<0.001).

Table 2: Comparison of serum magnesium levels between cases and controls

On classifying subjects according to serum magnesium status, hypomagnesaemia (serum Mg <1.7 mg/dL) was found in 54% of cases as compared to only 9% of controls, a difference that was statistically significant (χ² = 45.2, p<0.001) (Table 3).

Table 3: Distribution of subjects according to serum magnesium status

When cases were further sub-divided according to severity of hypertension, a progressive fall in mean serum magnesium was observed with increasing severity of disease. Patients with Stage 2 hypertension had significantly lower serum magnesium (1.51 ± 0.27 mg/dL) than those with Stage 1 hypertension (1.79 ± 0.23 mg/dL) and controls (2.11 ± 0.24 mg/dL) (p<0.001 by ANOVA) (Table 4).

Table 4: Serum magnesium levels according to severity of hypertension

Pearson's correlation analysis showed a statistically significant negative correlation between serum magnesium and both systolic blood pressure (r = −0.52, p<0.001) and diastolic blood pressure (r = −0.46, p<0.001) among hypertensive patients, indicating that lower serum magnesium levels were associated with higher blood pressure readings (Table 5).

Table 5: Correlation of serum magnesium with blood pressure parameters in cases

No statistically significant difference in serum magnesium levels was observed between male and female hypertensive patients (p = 0.54), suggesting that the fall in serum magnesium in hypertension was independent of sex in this study population (Table 6).

Table 6: Sex-wise comparison of serum magnesium levels among cases

Overall, the results of this study demonstrate a significant reduction in serum magnesium levels among hypertensive patients as compared to normotensive controls, a high prevalence of hypomagnesaemia among hypertensives, a significant negative correlation between serum magnesium and blood pressure, and a progressive decline in serum magnesium with increasing severity of hypertension.

The present case–control study was designed to evaluate serum magnesium levels in hypertensive patients and to correlate them with blood pressure and disease severity. The principal finding of this study was a significant reduction in mean serum magnesium levels among hypertensive patients (1.68 ± 0.29 mg/dL) as compared to normotensive controls (2.11 ± 0.24 mg/dL), along with a significantly higher prevalence of hypomagnesaemia among cases (54%) as compared to controls (9%). These findings are consistent with the hypothesis that magnesium deficiency is associated with, and may contribute to, the pathogenesis of essential hypertension.

Our results are in agreement with earlier Indian studies. Gupta et al reported significantly lower serum magnesium levels in hypertensive subjects as compared to controls in a north Indian tertiary-care population, with a mean difference broadly similar to that observed in the present study.⁵ Reddy and Bindu, in a South Indian cohort, similarly found a high prevalence of hypomagnesaemia among newly diagnosed hypertensives, and a significant inverse correlation between serum magnesium and blood pressure, closely mirroring the correlation coefficients obtained in our study.⁶ Rao and Rao also documented a stepwise fall in serum magnesium with increasing severity of hypertension, a trend that was replicated in our Stage 1 versus Stage 2 comparison.⁷ Sharma et al, studying treatment-naïve hypertensives, likewise reported significantly reduced serum magnesium and recommended its inclusion as a routine biochemical parameter in the work-up of hypertensive patients, a conclusion supported by our own findings.⁸ The consistency of these observations across different Indian regions, laboratory methods and patient populations lends considerable support to a genuine biological association between hypomagnesaemia and essential hypertension in the Indian setting, rather than a chance or population-specific finding.

These Indian findings are also concordant with the larger body of international literature. The ARIC study by Ma et al, involving over 15,000 subjects, found an inverse association between serum and dietary magnesium and both blood pressure and the prevalence of hypertension.³ Kesteloot and Joossens, in an earlier population survey, similarly demonstrated an inverse relationship between dietary magnesium intake and blood pressure across several international cohorts.⁴ The magnitude of the negative correlation observed in the present study (r = −0.52 for systolic and r = −0.46 for diastolic blood pressure) is comparable to that reported in several of these earlier studies, reinforcing the reproducibility of this association across different populations and settings.

The biological plausibility of these findings is supported by several proposed mechanisms. Magnesium acts as a natural calcium-channel blocker; a reduction in intracellular magnesium leads to an increase in intracellular free calcium in vascular smooth muscle cells, resulting in enhanced vascular tone and peripheral resistance.² Magnesium deficiency has also been shown to impair endothelial nitric oxide synthesis, reduce endothelium-dependent vasodilation, and increase the synthesis of vasoconstrictor prostaglandins and thromboxane A2, all of which would tend to raise blood pressure.⁹ In addition, hypomagnesaemia has been linked to increased activity of the renin-angiotensin-aldosterone system and heightened vascular sensitivity to circulating catecholamines and angiotensin II, providing further mechanistic support for the observed inverse relationship between serum magnesium and blood pressure.⁹ Small interventional trials of oral magnesium supplementation have shown modest reductions in both systolic and diastolic blood pressure in hypertensive subjects, indicating that the relationship may, at least in part, be causal rather than purely associative.¹⁰

The progressive fall in serum magnesium with increasing severity of hypertension observed in our study (Stage 1: 1.79 ± 0.23 mg/dL versus Stage 2: 1.51 ± 0.27 mg/dL) suggests that magnesium depletion may not merely be a marker of hypertension but could also parallel disease severity, possibly through a self-perpetuating cycle in which hypomagnesaemia promotes vasoconstriction and elevated blood pressure, which in turn may further worsen renal magnesium handling. This observation is in keeping with the findings of Rao and Rao in their Indian cohort.⁷ Interestingly, no significant sex-based difference in serum magnesium was observed among cases in our study, suggesting that the association between magnesium and hypertension operates similarly in both men and women, at least in the age group studied.

The exact reasons for lower serum magnesium levels in the Indian hypertensive population, as reflected both in our study and in earlier Indian reports, may include inadequate dietary intake of magnesium-rich foods such as green leafy vegetables, whole grains, nuts and legumes, increased consumption of refined and processed foods, use of diuretic antihypertensive agents that increase renal magnesium excretion, and possibly genetic or renal-tubular factors affecting magnesium reabsorption. Given the low cost, wide availability and technical simplicity of serum magnesium estimation, its routine inclusion in the biochemical evaluation of hypertensive patients, particularly in resource-limited settings, could help identify a subgroup of patients who might benefit from dietary correction or magnesium supplementation as an adjunct to standard antihypertensive therapy.

Limitations

This study has certain limitations that merit consideration. First, being a cross-sectional case–control study, it establishes association rather than causation, and a longitudinal or interventional design would be required to confirm a causal relationship between hypomagnesaemia and hypertension. Second, dietary magnesium intake, urinary magnesium excretion and intracellular (erythrocyte or mononuclear cell) magnesium levels, which may more accurately reflect total body magnesium status than serum levels, were not assessed. Third, the relatively modest sample size and single-centre hospital-based design may limit the generalisability of the findings to the wider community. Larger, multicentric, prospective studies incorporating dietary assessment and intracellular magnesium estimation are recommended to further elucidate this relationship.

The present study demonstrates that serum magnesium levels are significantly lower in patients with essential hypertension as compared to normotensive controls, with a high prevalence of hypomagnesaemia among hypertensives. A significant negative correlation was observed between serum magnesium and both systolic and diastolic blood pressure, and serum magnesium levels declined progressively with increasing severity of hypertension. These findings support a possible contributory role of magnesium deficiency in the pathogenesis and severity of essential hypertension. Serum magnesium estimation is a simple, inexpensive and widely available biochemical test that may serve as a useful adjunct in the evaluation of hypertensive patients, and correction of hypomagnesaemia through dietary modification or supplementation may represent a low-cost, complementary strategy in the overall management of hypertension. Further large-scale, prospective and interventional studies are warranted to confirm a causal role for magnesium and to define its place in routine clinical practice.

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