TASKS OF COMPLIMENTARY AND FUNCTIONAL TRIO-MINERALS IN HYPERTENSION

Received on 11 February, 2014; received in revised form, 11 March, 2014; accepted, 13 June, 2014; published 01 August, 2014

TASKS OF COMPLIMENTARY AND FUNCTIONAL TRIO-MINERALS IN HYPERTENSION

Kannan Eagappan* and Sasikala Sasikumar

Department of Clinical Nutrition and Dietetics, PSG College of Arts and Science, Coimbatore, Tamil Nadu, India

ABSTRACT: Micronutrient deficiencies such as potassium, magnesium and calcium are very common in the general population and it is more predominantly present in the individuals with hypertension and cardiovascular patients. These deficiencies will have a massive impact on present and future cardiovascular health outcomes such as hypertension, myocardial infarction, stroke, etc. Recent efforts to reduce the prevalence of hypertension have focused on non-pharmacologic means, specifically diet in order to overcome micronutrient deficiencies. From most of the studies it is evident that an increased intake of minerals such as potassium, magnesium, and calcium by dietary means to reduce blood pressure in patients with hypertension.  This article also focuses on how these minerals influence vaso dilation, rennin- angiotension and aldosterone system, natriuresis, sympathetic nervous system nitric oxide production and vascular injury. On the whole, this review will talk about the roles of potassium, magnesium, and calcium in the prevention and treatment of hypertension with specific emphasis on clinical trial evidence, mechanism of action, and recommendations for dietary intake of these minerals.

Hypertension, Trio-minerals, mechanism, Dietary intake, Supplements, Nutrient recommendation

INTRODUCTION: High Blood Pressure also known as the “silent killer’’ affects one billion or one in three adults worldwide, and attributes to about 40% of cardiovascular related deaths; unfortunately more than 50% of hypertensive individuals are unaware of their condition ¹. American heart association defined Hypertension as a systolic blood pressure greater than 140 mmHg and or a diastolic blood pressure greater than 90 mmHg is one of the major risk factors for cardiovascular morbidities including coronary artery disease, myocardial infarction and kidney disease, as well as for mortality ².

Recent reports indicate that nearly 1 billion adults (more than a quarter of the world’s population) had hypertension in 2000, and this is predicted to increase to 1.56 billion by 2025 ³.

Hypertension is reported to be the fourth contributor to premature death in developed countries and the seventh in developing countries ⁴. In India, hypertension is the leading non communicable disease risk and estimated to be attributable for nearly 10 per cent of all deaths ¹⁹.

From the studies of Gupta, 2004 and Reddy, 2005 it is evident that adult hypertension prevalence has risen dramatically over the past three decades from 5 per cent to  20-40 per cent in urban areas and 12-17 per cent in rural area ^{20, 21}. Also, Reddy (2005) reported that the number of hypertensive individuals is anticipated to nearly double from 118 million in 2000 to 213 million by 2025 ²⁵.

FIGURE 1: PATHOGENESIS OF HYPERTENSION

From the study of Mohan et al, 2011, it is understood that 16 per cent of ischemic heart disease, 21 per cent of peripheral vascular disease, 24 per cent of acute myocardial infarctions and 29 per cent of strokes are attributable to hypertension, emphasizing the huge impact of effective hypertension prevention and control in order to reduce the accelerating encumbrance of cardiovascular disease (CVD) ²². There are number of factors that increase blood pressure such as obesity, insulin resistance, high alcohol intake, high salt intake (in salt-sensitive patients), aging and perhaps sedentary lifestyle, stress, low potassium intake, and low calcium intake ^{5, 6}. Observational studies have shown that a diet rich in potassium, magnesium, and calcium, present mainly in fruits and vegetables, is associated with lower incidence and mortality from cardiovascular disease ⁷.

Clinical and population-based studies show that several components of the diet such as sodium, potassium, calcium, magnesium, fiber and fish oil influence blood pressure, and modification of these nutritional factors provide an important strategy to control blood pressure especially in the prehypertensive stage (SBP 120–139mmHg and/or DBP 80–89mmHg) or stage I hypertension (SBP 140–159mmHg and/or DBP 90–99mmHg) ⁸. The role of these dietary factors, singly or in combination in blood pressure regulation and to what extent each contributes has been a subject of research for many decades.

Pathophysiology of Hypertension: Even though hypertension is the most prevalent chronic medical conditions, the pathophysiology of hypertensive crises is still poorly understood ^9-12. In addition, not like other disorders the hypertension develops due to a single known entity, rather multifaceted etiological factors could synergistically affect blood pressure. From the studies of Smithburger et al (2010) and Varon, (2008), it is clearly implicated that two processes are considered to recklessly induce hypertensive paradigm such as sudden increase in systemic vascular resistance (SVR) and a failure of cerebral blood flow auto regulation, the mechanism that maintains blood flow at an appropriate level during changes in blood pressure ^{10, 11}.

Varon, 2008 reported that hypertensive crisis can also be present without documenting any history of hypertension; the acute nature of these events suggests an underlying hypertensive condition coupled with the presence of an additional seditious factor or event. This was explained by him using an example such as, in the perioperative setting, stimuli such as elevated BP during anesthesia induction, tracheal intubation, and emergence from anesthesia can be the initiating event for the hypertensive crisis ¹³. Anesthesia induction alone can cause an increase of 20 mmHg in normotensive patients, and up to 90 mmHg in patients with a pre-existing hypertensive condition¹⁴.

Studies done by Kuppasani and Reddi, 2010; Smithburger et al., 2010; Vaughan and Delanty, 2000, revealed that Vascular endothelial injury may result from repeated instances of acute hypertension, associated with elevated systemic vascular resistance. As blood pressure increases, vessel walls are subjected to stress, which leads to the release of vasoconstrictors resulting in further endothelial damage ^{9, 10, 15}. Kuppasani and Reddi, 2010 in their study explained that if vascular endothelial injury is not promptly treated, a cycle of clotting cascade activation, arteriole tissue death and accumulation, neurohormonal system upregulation, induction of oxidative stress, and inflammatory cytokines develops ⁹.

Deposition of platelets and fibrin, vasoconstriction, and thrombosis, as a consequence of vascular injury, result in decreased blood flow and supply to and from organs (hypoperfusion and ischemia) ^{9, 10}. If this vicious cycle is not concluded, auto regulatory dysfunction becomes imminent ¹⁶. Autoregulation is crucial to maintenance of adequate perfusion of the kidney, heart, and brain. These organs require specific amounts of oxygen to function, and reduced blood flow can lead to ischemia and organ injury. Autoregulation occurs in many body tissues, but has best been studied in cerebral blood flow. When blood pressure is severely elevated there is a right shift in the autoregulation curve, resulting in cerebral blood flow at higher mean arterial pressures ^{15, 17, and 18}.

In order to avoid hyperperfusion of tissues, blood pressure in these patients must be lowered carefully so that hypoperfusion does not occur ^{17, 18}

In the blood pressure range between 60 mmHg and 140 mmHg, cerebral blood flow is “autoregulated” extremely well. Belsha, 2011 explained in his study that, autoregulation in  hypertensive patients occurs with mean arterial pressure (MAP) up to 180 mmHg (shifted to the right), though the blood flow remains constant. During hypertensive crises, the shift in the autoregulatory curve often fails to occur, putting patients at risk for cerebral hyperperfusion. When the corresponding increase in BP crosses the autoregulatory range, compensatory mechanisms end ¹⁷. Vasodilation and endothelial dysfunction occurs, which may lead to cerebral fluid buildup (edema), ultimately followed by cerebral spasm (eclampsia) and ischemia ⁹.

Continuation of this “vicious” cycle results in the severe, acute elevation in BP.

Impact of Potassium, Magnesium and Calcium on Hypertension:

POTASSIUM: The correlation between potassium and blood pressure has been described in many studies. The mechanism by which potassium intake regulates antihypertensive effects is explained in the table 1.

TABLE 1: THE MECHANISMS BY WHICH POTASSIUM INTAKE REGULATES HYPERTENSION

Potassium intake was found to be inversely related to both DBP and SBP in a population based study including 685 men and women who were principally Caucasian in Southern California, United States of America (USA) ³². Similar result was illustrated in the Rotterdam Study ^{33, 57}, a big population- based study in which 3239 participants older than 55 years old were included.

Patients with an increase in potassium intake of 1000mg/day had a 0.9mmHg lower SBP and a 0.8mmHg lower DBP ³⁴.

Priddle (1931) conducted an experiment by giving low sodium, high potassium diet to a group of 45 hypertensives, including some with impaired renal function, and their study results reported a lowering of blood pressure and an improvement in their general medical condition ³⁵. Similarly, the rice-fruit diet utilized by Kempner for treatment of hypertension resulted in consistent reductions of blood pressure by reducing the levels of Na⁺ intake and the Na⁺/K⁺ diet ratio by 99% ³⁶.

Several interventional studies have shown the positive effects of potassium supplementation on blood pressure reduction. Cappuccio and MacGregor reviewed 19 clinical trials in which oral potassium supplements significantly lowered SBP (mean of −5.9mmHg, 95% confidence interval (CI), −6.6 to −5.2mmHg) and DBP (mean of −3.4mmHg, 95% CI, −4.0 to 2.8mmHg) ³⁷ . A meta-analysis consisting of 27 potassium trials in adults with a minimum of 2 weeks duration also demonstrated a reduction in blood pressure with increased potassium intake: a mean of −2.42mmHg (95% CI, −3.75 to −1.08mmHg) in SBP and −1.57mmHg (95% CI, −2.65 to −0.50mmHg) in DBP pressure ³⁸.

There are few Japanese studies examining the role of potassium in the regulation of blood pressure^{42, 43}. The traditional diet of the Japanese is high in salt (up to 400 mmoles/day in some regions) and this is considered to be causal in the higher mortality from stroke observed in Japan compared to that of Western cultures. In a large epidemiological study,  a population from Shimano region where the traditional lifestyle and diet were potted, blood pressure was inversely correlated with urinary potassium excretion and positively correlated with the urinary Na+/K+ ratio, especially in the older age groups ⁴³.

Thus, this study is implicative that the traditional diet comprising of more potassium sources and deprived of novel processed foods containing more sodium helps in the less prevalence of hypertension. A similar relationship was found when two neighbouring regions with markedly different prevalence of hypertension were compared. Individuals from the region with the lower prevalence of hypertension had higher urinary potassium excretions, presumably because of increased consumption of potassium in the form of apples, since the area studied is a region of major apple production ⁴³.

Two recent studies have also assessed the effect of approximately doubling of normal potassium intake (from approximately 60 or 75 mM/day to 120 or 160 mM/day, respectively) on blood pressure in essential hypertensive who maintained normal intakes of sodium during the period of K+ supplementation. Both studies reported significant reductions of arterial pressure of 10% ⁴⁴ and which were insufficient to normalize blood pressure in these hypertensive patients.

It has also been stated that apart from K⁺ supplementation racism too plays a considerable role in modulating hypertension even with K⁺ supplementation. A meta-analysis of all K⁺ supplementation clinical trials in the treatment of hypertension demonstrated a racial difference—with black subjects having a more substantial reduction in BP compared with white subjects. A high K intake is most effective in reducing BP in patients with diuretic-induced hypokalemia, in those with a high Na⁺ intake ^45-47, in patients with salt-sensitive hypertension ⁴⁷, severe hypertension, or a positive family history ⁴⁷, as well as in African Americans ⁴⁷ and Chinese ⁴⁶. Alteration of the K⁺/Na⁺ ratio to a higher level is important for antihypertensive as well as cardiovascular and cerebrovascular effects ^{46, 48}. High K intake reduces the incidence of cardiovascular and CVAs independent of BP reduction ^49-51.

Gu et al ⁴⁶  recently demonstrated for the first time that K supplementation at 60 mmol of KCI per day for 12 weeks significantly reduced SBP _5.0 mm Hg (range, _2.13 to _7.88 mm Hg) ( P b .001) in 150 Chinese men and women aged 35 to 64 years. This study confirmed that the higher the initial BP, the greater the response. Finally, it showed that the urinary Na/K ratio correlates best with BP reduction as does the dietary Na/K ratio⁴⁸ compared with either urinary Na or K individually ⁴⁶.

Based on existing data, the Institute of Medicine has recommended a potassium intake of 4700mg (120mmol) a day as adequate intake for all adults ⁵². A similar amount of daily potassium consumption was also suggested by the American Heart Association (AHA) in 2006 to achieve the potential benefit of blood pressure reduction ⁵³.

The 2003 WHO/International Society of   Hypertension statement on management of hypertension supported an increased dietary potassium intake although a threshold was not specified ⁵⁴. However, the suggested daily intake of potassium might be lower in patients who are prone to develop hyperkalemia such as those with impaired renal excretion of potassium from CKD, CHF, adrenal insufficiency, and medications use (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), potassium sparing diuretics, trimethoprim, cyclosporine, heparin, etc.)

Apart from drugs influencing the body concentrations of potassium, certain foods may also increase the levels of potassium; table 2 displays the good natural sources of potassium.

TABLE 2: FOODS HIGH IN POTASSIUM

Source: Values were obtained from the USDA Nutrient Database for Standard References, Release 15 for Potassium, K (mg) content of selected foods per common measure.

MAGNESIUM: A high dietary intake of magnesium of at least 500 - 1000mg per day reduces blood pressure in most of the reported epidemiologic, observational and clinical trial ^55-64. A study done by Ahsan (1998), in which 60 essential hypotensive subjects were given magnesium supplements showed a significant reduction in blood pressure over an 8- week period consecutively documented by 24-hr ambulatory blood pressure, home and office blood pressure assessments. From the same study it is well understood that magnesium competes with Na⁺ for binding sites on vascular smooth muscles and acts like a calcium channel blocker, it increases PGE, and binds in a necessary cooperative manner with K⁺, inducing endothelial vasodilation and thus reducing blood pressure ⁵⁸.

It is also stated that, magnesium influences blood pressure regulation by modulating vascular tone and reactivity. Vascular effect of magnesium was first suggested in the early 1900s when it was observed in clinical studies that magnesium salt infusion lowers blood pressure via a reduction in peripheral vascular resistance ⁶⁵ in spite of a slight increase in myocardial contractility ⁶⁶. The direct Experimental studies support these clinical observations and confirm that acute magnesium administration induces hypotension through vasodilatory actions ^{67, 68}.

Increased concentrations of extracellular magnesium cause vasodilation, improve blood flow, decrease vascular resistance, increase capacitance function of peripheral, coronary, renal, and cerebral arteries, and attenuate agonist-induced vasoconstriction, whereas, decreased concentrations cause contraction, potentiate agonist evoked vasoconstriction, and increase vascular tone and thus increased blood pressure is possible ^69-72.

The relationship between dietary magnesium intake and blood pressure in humans were first demonstrated in the Honolulu Heart study ⁷³ and later by many epidemiological and clinical investigations that supported the hypothesis that increased magnesium intake contributes to prevention of hypertension and cardiovascular disease ^73-76. Data that were obtained from large, prospective studies on nutrition and blood pressure in US and Dutch populations, reported that magnesium-rich diets may reduce blood pressure levels, especially in older individuals ^{77, 78}. However, there are seldom studies done in India, on the relationship between these minerals and blood pressure.

Perhaps, some studies worldwide have shown blood pressure lowering after magnesium supplementation. According to Kawano (1998), the administration of magnesium oxide (400 mg daily) for eight weeks in patients with hypertension can reduce blood pressure levels, and this reduction has already been detected in office measurements and by ambulatory blood pressure monitoring ⁷⁹. Hatzistavri, (2009), in his study  demonstrated that 600 mg of magnesium pidolate per day  which was given to  48 subjects was found  to reduce blood pressure levels in the supplemented patients when compared to the group with no supplementation ⁸⁰.

Haenni and colleagues (2002), highlighted positive effects of magnesium supplementation in order to confirm the relationship between the metabolism of this mineral and alteration of endothelial function by showing increased endothelium dependent vasodilatation after magnesium infusion ⁸¹. In this context, Shechter (2000), also showed that chronic magnesium supplementation was able to improve endothelial function in patients with coronary artery disease ⁸².

In contrary to above mentioned human study, magnesium supplementation had little antihypertensive effect in adult spontaneously hypertensive rat (SHR) with well-established hypertension. In fact, the effect of supplementation was only positive in younger animals, when started in the prehypertensive phase, preventing or at least attenuating the development of hypertension⁸³. This finding is highly suggestive of a more protective effect of supplemental magnesium, which may prevent or slow the rise in blood pressure at an early stage of hypertension.

With reference to RAAS, a relationship has also been reported between the rennin-angiotensin system, magnesium, and blood pressure. Hypertensive patients with high renin activity have significantly lower serum magnesium levels than normotensive subjects, and plasma renin activity is inversely associated with serum magnesium ⁸⁴.

This has been correlated with a finding that hypertensive patients without blood pressure control may have hypomagnesaemia.

When a question of whether acute one day supplementation does it modulate BP,  Hatzistavri and colleagues (2009) have shown that magnesium supplementation was associated with slight reduction of 24 h blood pressure levels in patients with mild hypertension ⁸⁰, which can be evaluated by ambulatory blood pressure monitoring ⁸⁵. In connection with the supplementation of magnesium containing foods, the following table 3 depicts the magnesium content of various food stuffs.

TABLE 3: FOODS HIGH IN MAGNESIUM

Source: Values were obtained from the USDA Nutrient Database for Standard References, Release 15 for Magnesium, Mg (mg) content of selected foods per common measure.

CALCIUM: Over the years, a great number of observational and interventional studies indicated that chronic calcium malnutrition is associated with various diseases and pathologic conditions of unrelated etiology.  A proposed mechanism by which calcium intake regulates blood pressure is described in table 4.

TABLE 4: THE MECHANISMS BY WHICH CALCIUM INTAKE REGULATES HYPERTENSION

From the studies of Hamet et al (1991 and 1992) and Gruchow et al (1988), it is evident that people consuming low levels of calcium in their diets, high salt intake is associated with higher blood pressure levels ^93-95 and based on this there are studies suggesting that the hypertensive effect of a high sodium intake which can be mitigated by increasing dietary calcium ^{96, 92, 97, 98}. Resnick also published extensively on the interlinking of the rennin aldosterone system, calcium regulation, and salt sensitivity in modulating blood pressure responses to salt loading, calcium supplementation, and calcium channel blockers ^{99- 104} . He suggested that these models may provide a targeted approach to identifying and treating hypertensives with calcium supplementation or calcium channel blockers based on their serum renin level and salt sensitivity ^105-107.

Despite the above findings, few systemic reviews express that supplementation of Ca²⁺ have modest effect in reducing BP ^{108, 109}.  From the studies of McCarron (1999) and Witteman (1989) it is clearly understood that, individuals receiving >800 mg/d of calcium compared with 400 mg/d achieved a 23% reduction in risk of developing   hypertension. ¹¹⁰.

Ascherio and co-workersalso demonstrated in more than 30,000 normotensive male health professionals aged 40 to 75 years that men consuming <250 mg/d of calcium had a 50% greater chance of developing hypertension than those who consumed ≥400 mg/d ¹¹¹.

In a prospective cohort of 28,886 US women older than 45 years, dietary intake of calcium was inversely associated with risk of hypertension; however, no change in BP was observed with calcium supplementation ¹¹².

A review of calcium supplementation during pregnancy for preventing hypertensive disorders concluded that calcium supplementation appears to approximately bisect the risk of preeclampsia and reduces the risk of preterm birth and the rare occurrence of the composite outcome “death or serious morbidity”. It is notable that, most women in these trials had a low-calcium diet ¹¹³.

Calcium appears to be particularly effective in reducing the age-related increase in blood pressure. Dobnig et al (2005)  conducted a randomized, double-blind, multi-center study on the effect of daily high-dose calcium supplements in healthy, elderly adults and observed a substantial reduction of systolic and diastolic blood pressure after one year of treatment in individuals who were in the upper third of pre-study blood pressure values ¹¹⁴.

Different intake levels for calcium are recommended by FAO/WHO experts for infants, children and adults ¹¹⁵ to assure optimal whole body calcium retention and consequently adequate development and maintenance of bone mass and mineral density. For children and adolescents between 10–18 years of age, consumption of 1,300 mg per day is recommended, while 1,000 mg per day apply for men between 25–50 years of age and also for women in the same age group, except when higher intake is necessary during pregnancy or after menopause.

Recommended calcium allowance per day for males over 65 years and postmenopausal women is 1,300 mg ¹¹⁵. Based on existing data, the Indian Council of Medical Research has recommended a calcium intake of 600mg a day as adequate intake for all adults ¹¹⁶.

Table 5 below portrays the calcium content of various foods. However, though we suggest excellent sources of calcium containing foods we should also advise them to be cautious about antinutritional factors such as phytic acids, oxalic acid, EDTA, high amount of fiber etc., which would interfere in their absorption.

TABLE 5: FOODS HIGH IN CALCIUM

Source: Values were obtained from the USDA Nutrient Database for Standard References, Release 15 for Calcium, Ca (mg) content of selected foods per common measure.

SUMMARY AND CONCLUSION: Considering the magnitude of the health and financial consequences of HTN, scientific search for more effective and at the same time more affordable means of tackling HTN has become more than a necessity. Dietary modification has important therapeutic roles in blood pressure control. Increasing evidence indicates that low magnesium, potassium and calcium may play a pathophysiological role in the development of hypertension. The modalities by which these trio-minerals are able to mitigate blood pressure have also been described in this review. Indeed, there are accumulating evidences which show the efficiency of controlling both systolic and diastolic blood pressures but on the other hand there are few studies which claim that non dietary supplements are not effective in controlling BP.

Hence, further constructive studies are needed to rule out that synthetic or organic supplements are not able to attenuate high BP. However, as long as hypertensives and even normotensives who have the risk factor of developing hypertension, If they increase their dietary sources of these trio-minerals, are also benefitted by increased intake of other  nutrients too ¹¹⁷. Similarly, as these minerals are certainly favourable in bringing out a good prognosis, yet much care has to be taken in order to avoid the agents which may be found naturally in food sources or as additives ( for e.g. EDTA) from processed foods which may hinder the absorption by binding.  Hence dissemination of knowledge on the positive effect of dietary or organic supplements of these minerals in alleviating the development or control of the “silent killer” hypertension is the need of the hour.

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