Calcium Effects on Vascular Endpoints
Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.
Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, it is now recognized as a key aspect of many physiologic pathways necessary for optimum health including the cardiovascular, neurological, hormonal, renal, and gastrointestinal systems. Calcium serves as a cofactor for many extracellular enzymes, most notably the enzymes of the coagulation cascade, and as a source of calcium ions that function as signaling molecules for a great diversity of intracellular processes. These processes include automaticity of nerve and muscle; contraction of cardiac, skeletal, and smooth muscle; neurotransmitter release; and various forms of endocrine and exocrine secretion. Our review will describe the biology and basic physiology of calcium metabolism in humans, the present status of recommendations for intake and supplementation, the traditional role of calcium for optimum maintenance of the skeletal system, and then discuss in detail the relevance of calcium in cardiovascular health as well as several cardiac and vascular disease states.
The body of the average adult contains about 1000 gram of calcium of which 99% is located in the mineral phase of bone as hydroxyapatite crystals [Ca10 (PO4)6(OH)2]. These crystals play a key role in the mechanical weight-bearing properties of bone, serves as a source of calcium to support a number of calcium-dependent biological systems and to maintain blood ionized calcium within normal range. The remaining 1% of total body calcium is located in the blood, extracellular fluid and soft tissues. Of the total calcium in blood, the ionized fraction (45%) is the biologically functional portion and can be measured clinically. Most clinical laboratories report total serum concentrations. Forty-five percent of the total calcium in blood is bound to plasma, proteins notably albumin and up to 10% is bound to anions such as phosphate and citrate. Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/dl (2.12–2.62 mM).
The skeleton, gut and the kidney play a major role in assuring calcium homeostasis. Overall in a typical individual, if 1000 mg of calcium is ingested per day, about 200 mg will be absorbed. Approximately 10 gram of calcium will be filtered daily through the kidney and most will be reabsorbed, with about 200 mg being excreted in the urine. The skeleton, a storage site of approximately 1 kg of calcium, is the major calcium reservoir in the body. Ordinarily as a result of normal bone turnover, approximately 500 mg of calcium is released from bone per day, and the equivalent amount is deposited per day. Parathyroid hormone (PTH) enhances bone resorption and liberates both calcium and phosphate from the skeleton. PTH also enhances calcium re-absorption in the kidney while at the same time inhibiting phosphate re-absorption producing phosphaturia. Hypocalcemia and PTH itself can both stimulate the conversion of the inert metabolite of Vitamin D, 25-OH Vitamin D3 to the active moiety 1, 25-dihydroxy Vitamin D3 which in turn enhances intestinal calcium absorption (see Figure 1).
(Enlarge Image)
Figure 1.
Parathyroid hormone (PTH)-calcium feedback loop that controls calcium homeostasis. Four organs-the parathyroid glands, intestine, kidney, and bone-together determine the parameters of calcium homeostasis. +, positive effect; -, negative effect; 1,25 D, 1,25-dihydroxyvitamin D3; ECF, extracellular fluid.
Abstract and Introduction
Abstract
Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.
Introduction
Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, it is now recognized as a key aspect of many physiologic pathways necessary for optimum health including the cardiovascular, neurological, hormonal, renal, and gastrointestinal systems. Calcium serves as a cofactor for many extracellular enzymes, most notably the enzymes of the coagulation cascade, and as a source of calcium ions that function as signaling molecules for a great diversity of intracellular processes. These processes include automaticity of nerve and muscle; contraction of cardiac, skeletal, and smooth muscle; neurotransmitter release; and various forms of endocrine and exocrine secretion. Our review will describe the biology and basic physiology of calcium metabolism in humans, the present status of recommendations for intake and supplementation, the traditional role of calcium for optimum maintenance of the skeletal system, and then discuss in detail the relevance of calcium in cardiovascular health as well as several cardiac and vascular disease states.
Current Status of Knowledge
The body of the average adult contains about 1000 gram of calcium of which 99% is located in the mineral phase of bone as hydroxyapatite crystals [Ca10 (PO4)6(OH)2]. These crystals play a key role in the mechanical weight-bearing properties of bone, serves as a source of calcium to support a number of calcium-dependent biological systems and to maintain blood ionized calcium within normal range. The remaining 1% of total body calcium is located in the blood, extracellular fluid and soft tissues. Of the total calcium in blood, the ionized fraction (45%) is the biologically functional portion and can be measured clinically. Most clinical laboratories report total serum concentrations. Forty-five percent of the total calcium in blood is bound to plasma, proteins notably albumin and up to 10% is bound to anions such as phosphate and citrate. Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/dl (2.12–2.62 mM).
Mineral Homeostasis
The skeleton, gut and the kidney play a major role in assuring calcium homeostasis. Overall in a typical individual, if 1000 mg of calcium is ingested per day, about 200 mg will be absorbed. Approximately 10 gram of calcium will be filtered daily through the kidney and most will be reabsorbed, with about 200 mg being excreted in the urine. The skeleton, a storage site of approximately 1 kg of calcium, is the major calcium reservoir in the body. Ordinarily as a result of normal bone turnover, approximately 500 mg of calcium is released from bone per day, and the equivalent amount is deposited per day. Parathyroid hormone (PTH) enhances bone resorption and liberates both calcium and phosphate from the skeleton. PTH also enhances calcium re-absorption in the kidney while at the same time inhibiting phosphate re-absorption producing phosphaturia. Hypocalcemia and PTH itself can both stimulate the conversion of the inert metabolite of Vitamin D, 25-OH Vitamin D3 to the active moiety 1, 25-dihydroxy Vitamin D3 which in turn enhances intestinal calcium absorption (see Figure 1).
(Enlarge Image)
Figure 1.
Parathyroid hormone (PTH)-calcium feedback loop that controls calcium homeostasis. Four organs-the parathyroid glands, intestine, kidney, and bone-together determine the parameters of calcium homeostasis. +, positive effect; -, negative effect; 1,25 D, 1,25-dihydroxyvitamin D3; ECF, extracellular fluid.
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