What is behind the calcium? The relationship between calcium and necrotic core on virtual histology analyses

We read with great interest the investigative paper by Misselet al.¹ We would like to thank the authors for furthering ourknowledge in this field with their continued production of high-quality     

Does calcium supplementation increase cardiovascular risk?

Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium calls this assumption into question, and consideration of vascular event data from other calcium trials does not refute the Auckland findings. Meta‐analyses of these data will be necessary to settle this matter. It is already accepted that calcium supplements increase vascular risk in patients with renal compromise, even in those not yet requiring dialysis. Also, there is substantial epidemiological evidence that serum calcium levels in the upper part of the normal range are a risk factor for vascular disease, and that calcium supplements acutely elevate serum calcium – a combination of findings that lends plausibility to supplementation increasing vascular risk. As there are reasonable grounds for doubting the safety of calcium supplements, and as the evidence for their efficacy in fracture prevention remains marginal, we suggest that there should be a reappraisal of their role in the management of osteoporosis, with a greater emphasis on agents known to prevent fractures.     

Does calcium aggravate and cause hypertension?

Albert Szent-Gyorgyi around 30 years ago proposed that "ions were the powerful tools of life as it developed in oceans". The purpose of this fundamental concept was to divert the attention of investigators towards the basic role of cations such as Na, K, Ca and Mg in muscle contraction. There is now sufficient evidence to support this prediction. Until recently the strongest evidence pointed to a positive relationship between raised Ca and blood pressure. More recent evidence claimed that increased dietary Ca can lower blood pressure and populations taking lowered dietary Ca, have a higher incidence of hypertension. It has been suggested that in susceptible persons, in the presence of high Na intake, Ca accumulation in the arterial cell becomes rapid due to impaired Na-Ca exchange causing an early rise in blood pressure. This is possibly due to abnormal handling of Ca by the smooth muscle cells in most forms of hypertension. Clinical experimental and epidemiologic studies showed that Ca not only mediates arterial smooth muscle contraction but excess of Ca can also cause an increase in peripheral vascular resistance leading to essential hypertension. Ca entry blockers such as verapamil and nifedipine which reduce the influx of Ca into the arterial smooth muscle cell have been successfully used in the management of these patients. The effect of Ca on blood pressure could be independent of other factors. Recent studies strongly favour a significant relationship between raised serum Ca and high blood pressure. Such a relationship has also been described between dietary Ca, 24 urinary Ca and high blood pressure. A large number of studies, particularly from the USA, contradicting the above view, suggest that the rate of Ca flux rather than the absolute quantity that enters the cell, is the deciding factor in arterial smooth muscle contraction. These investigators in the last 6 years have studied a large area of north America and suggested that Ca deficiency rather than an excess is the cause of hypertension. Persons consuming less than 300 mg Ca per day have 11-14% risk of developing hypertension compared to person taking 1200 mg per day of dietary Ca and exposed to only 3-6% risk.(ABSTRACT TRUNCATED AT 400 WORDS)     

Who should receive calcium and vitamin D supplementation?

Combined calcium and vitamin D supplementation is recommended in the prevention and treatment of osteoporosis. Until recently, supplementation was perceived as harmless without adverse effects. However, recent meta-analyses have provided evidence suggesting that calcium supplements, whether or not in combination with vitamin D, may be associated with cardiovascular risks. Although this finding constitutes a safety signal that has to be taken seriously, these data have to be interpreted with some caution. Current data do not allow definite conclusions to be drawn, but require further independent confirmation, since in numerous large studies, combined calcium and vitamin D supplementation did not increase cardiovascular events, even in the most frail and elderly populations. Nevertheless, it seems appropriate to correct calcium deficiency preferably by enhancing dietary intake and to target supplementation on individuals at high risk of fracture or in whom calcium and vitamin D deficiency is highly prevalent. Other trials have shown an increased risk of falls and fractures with annual oral administration of high dose of vitamin D. Therefore, supplementation with more frequent, lower doses is preferred. Yet, the optimal dosing schedule is unknown and needs further study. In order to correct age-associated secondary hyperparathyroidism and to prevent osteoporotic fractures, a daily dose of 1,000-1,200?mg calcium and 800?IU vitamin D is recommended in elderly or institutionalised people, patients with established osteoporosis and individuals on glucocorticoids.     

Antioxidant effects and anti-elastase activity of the calcium antagonist nicardipine on activated human and rabbit neutrophils--a potential antiatherosclerotic property of calcium antagonists?

Activated neutrophils which produce certain proteases, such as elastase and reactive oxygen species (ROS) are involved in oxidative stress and inflammation. In the present study, we have shown that nicardipine, a calcium channel blocker, affects the release of elastase and superoxide anion radicals (O₂ ^–) in vitro during human and rabbit neutrophil respiratory bursts. The drug inhibited the release of elastase and O₂ ^– by fMLP (N-formyl-methionylleucin-phenylalaninin), calcium ionophore (A23187) and PMA (phorbol-myristate-acetate)-stimulated human and rabbit neutrophils. Besides the release of elastase, strongly inhibited in the fMLP and A23187 stimulated systems, nicardipine affected elastase and O₂ ^– in a dose-dependent manner. The corresponding 50% inhibitory concentration (IC₅₀) of nicardipine for elastase, released in PMA-stimulated human and rabbit neutrophils, was 15.95 ± 0.17 M and 18.06 ± 0.08 M, respectively, whereas for O₂ ^–, the IC₅₀ of nicardipine in PMA, fMLP and A23187-stimulated human and rabbit neutrophils was 55.41 ± 0.09 M and 58.43 ± 0.03 M, 45.21 ± 0.13 M and 37.19 ± 0.53 M, 33.54 ± 0.09 M and 30.54 ± 0.29, respectively. The mechanisms underlying the inhibition of elastase and superoxide anion radicals by nicardipine appear related to an inhibiting effect on the mobilisation of cytosolic calcium and on activation of protein kinase C (PKC). These antioxidant and anti-elastasic activities contribute to the properties of nicardipine, as positive side effects of its antihypertensive activity and may be useful to prevent inflammatory disorders (tissue damage, oxidative injury) involved in the pathogenesis of hypertension.     

Familial calcium crystal diseases: what have we learned?

The spectrum of heterotopic calcification or ossification is expanding because of the reports of several kindreds with calcium pyrophosphate deposition disease, apatite deposition disease, and others with less common syndromes associated with extracellular matrix calcification, such as fibrodysplasia ossificans progressiva and related syndromes. Genomic DNA studies in both humans and mice provide a shortcut to understanding the genetic basis of promotion and prevention of ECM calcification. Mutation in the COL2A1 gene has been identified in one family with spondyloepiphyseal dysplasia and calcium pyrophosphate and apatite crystalline deposits. In another kindred with precocious osteoarthritis without spondyloepiphyseal dysplasia, the phenotype was linked to markers of chromosome 8. In four other kindreds, the phenotypes were linked to an area of chromosome 5p. Two genes located in this region, which are expressed in articular cartilage, are being investigated as possible calcium pyrophosphate deposition disease genes. The results of linkage studies in three kindreds with articular/periarticular ADD with the COL2A1 gene were noninformative. Two different mouse mutations, the ank/ank and the ttw/ttw mice, are associated with intra-articular and ligament apatite deposits caused by a decrease in extracellular pyrophosphate concentrations, mimicking human arthritis caused by apatite deposition disease. Mutations in the matrix GLA protein, both in mice and in humans, are also associated with vascular and articular calcification. These mouse mutations provide cutting-edge information in the investigation of the mechanisms of apatite deposition in humans.     

Tissue protection by adrenergic blockade in the calcium paradox?

Summary In a graded model of the calcium paradox phenomenon (minimal and total) the presence of the -blocker propranolol (5·10^–6M) in the perfusion media (10 min prior to, during and 5 min following calcium-free perfusion) has no effect upon tissue injury. Propranolol pretreatment (three days prior to the experiments) significantly reduced the myocardial enzyme release during calcium repletion in the minimal calcium paradox. The presence of the ₁ prazosin (1·10^–7M) in the perfusion media (10 min prior to, during and 5 min following calcium-free perfusion) afforded no protective effects. It is concluded that the release of endogenous catecholamines may not be an important factor contributing to myocardial injury in the calcium paradox, and that consequently - or ₁-adrenergic blockade has little if any protective properties in this form of myocardial injury.     

Are calcium antagonists beneficial in diabetic patients with hypertension?

PURPOSE: We analyzed the available data to assess the effects of calcium antagonists in hypertensive patients with diabetes mellitus. METHODS: We performed a MEDLINE search of English-language articles published until April 2003, using the terms diabetes mellitus, hypertension or blood pressure, and therapy. Pertinent articles cited in the identified papers were also reviewed. We included prospective randomized studies of more than 12 months' duration that evaluated the effect of drug treatment on morbidity and mortality in diabetic patients with hypertension. We estimated the effect of treatment with calcium antagonists on morbidity and mortality in comparison with placebo, conventional therapy, and therapy that blocks the renin-angiotensin system. RESULTS: We identified 14 studies that reported outcomes in diabetic hypertensive patients. Compared with placebo, calcium antagonists reduced cardiovascular morbidity and mortality. Compared with conventional therapy, calcium antagonists had similar effects on coronary heart disease and total mortality, but may have reduced the risk of stroke (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.74 to 1.02; P = 0.08). However, they resulted in a lesser reduction of the risk of heart failure (OR = 1.33; 95% CI: 1.17 to 1.50). Calcium antagonists were less effective than blockers of the renin-angiotensin system in preventing heart failure (OR = 1.43; 95% CI: 1.10 to 1.84), but had similar effects on stroke, coronary heart disease, and total mortality. CONCLUSION: Calcium antagonists are safe and effective in reducing most types of cardiovascular morbidity and mortality in diabetic hypertensive patients, although their use is associated with a lesser reduction of risk of heart failure as compared with other treatments for hypertension.