Posts Tagged ‘BMJ’

Increased Consumption of Dietary Fiber is associated with a significantly Lower Risk of CVD and CHD

Reporter: Aviva Lev-Ari, PhD, RN

LEEDS, UK — Aside from keeping you “regular,” eating fiber also appears to be good for your heart. A new review has shown that increased consumption of dietary fiber is associated with a significantly lower risk of CVD and CHD.

For every 7 g of dietary fiber eaten daily—which can be achieved by eating two to four servings of fruits and vegetables or a serving of whole grains plus a portion of beans or lentils—the risks of CVD and CHD were each lowered by 9%, according to a new meta-analysis published December 19, 2013 in BMJ [1].

“Lower risk of cardiovascular disease was also seen with greater intakes of insoluble, cereal, fruit, and vegetable fiber,” write Diane Threapleton (University of Leeds, UK), a PhD student, and colleagues. “In addition, reduced risk for CHD was associated with greater intake of insoluble fiber and fiber from cereal or vegetable food.”

A cardioprotective effect of dietary fiber was first suggested in the 1970s, and numerous studies have attempted to investigate the link, including the effects of fiber on CV risk factors.

In the present meta-analysis, Threapleton et al analyzed 22 cohort studies that reported total dietary-fiber intake, fiber subtypes, and fiber from food sources and CVD or CHD events. CVD events included CHD along with fatal and incident stroke. Five studies suggested that each 7-g/day increase in insoluble fiber lowered the risk of CVD and CHD by 18%, respectively. Fiber consumption from cereals lowered the risk of CVD and CHD, as did fiber from vegetables. Fiber sourced from fruit lowered the risk of CVD only.

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Putting these results in perspective, Dr Robert Baron(University of California, San Francisco) gets straight to the point in his editorial, “Eat More Fiber”[2]. Although the study is limited by the potential for confounding—there is the possibility of an association between high fiber intake and other healthy behaviors—”clinicians should enthusiastically and skilfully recommend that patients consume more dietary fiber,” writes Baron. This includes a mix of soluble and insoluble fiber and fiber from multiple food sources, he adds.

Although the evidence for recommending higher fiber intake comes from “imperfect evidence,” including observational studies and expert opinion, the updated meta-analysis by Threapleton et al increases confidence in the recommendation, writes Baron.

The study was funded by the UK Department of Health. Threapleton reports that her PhD studentship receives funding from Kellogg’s. Baron reported no relevant financial disclosures.


  1. Threapleton DE, Greenwood DC, Evans CE, et al. Dietary fiber intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 2013; 347:f6879. Available at: http://www.bmj.com.
  2. Baron RB. Eat more fiber. BMJ 2013; 347:f7401. Available at: http://www.bmj.com.




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Curator: Aviva Lev-Ari, PhD. RN

UPDATED on 11/2/2013


Medscape Update on Calcium and Cardiovascular Risk

Curator and Reporter: Larry H. Bernstein, MD, FCAP


Minerals and Cardiovascular Risk

Modern diet contains high sodium to potassium ratio, low omega-3-polyunsaturated acid. (PUFAs) increased omega-6-polyunstaureted, saturated fat and Trans fatty acids these have lead to higher incidence of cardiovascular disease, diabetes mellitus and hyperlipidemia.
Paleolithic diet
Modern diet
More than 10,000 mEq/day (256 Grm)
150mEq/day (6gram)
Less than 50 mmol/day 1.2 Grm
175 mmol/day (4Gram)
Na/K ratio
Less than 0.13 /day
More than 0.67/day
More than 100gram/day
Less than 9 gram/day
Poly saturated to saturated ratio
Increased intake of sodium is associated with hypertension and reduction of salt intake is associated with decrease in BP by 4-6/2-3mmhg in salt sensitive patients. Daily allowance of sodium is not more than 500mg/day.
Cardiovascular events are more common in salt sensitive patients than salt resistance patients, independent of BP reduction. Reduction of BP by salt restriction has benefit apart from BP reduction.
A balance of sodium with other nutrients is important not only for reduction of BP but also for reduction cardiovascular events.
Increased intake of potassium is associated with BP reduction. Recommended daily intake of potassium is 650mEq/day with Na/k ratio of 5:1.
Supplements of 120 mEq/day of potassium reduce BP by 4.4/2.5mmhg in hypertensive patients.
Higher Na/K ratio reduces not only BP but also cardiovascular events.
Intake of 500mg/day to 1000mg/day reduces BP by 5.6/2.8mmhg. Reducing intracellular sodium and calcium and increasing intracellular magnesium and potassium improves BP response.
Insulin sensitivity, LVH and dyslipidemia can be improved with magnesium supplementation.
Oral magnesium acts like natural calcium channel blocker, increases nitric oxide, and improves endothelial dysfunction, and induces vasodilatation.
Studies show link between calcium and hypertension. But trials supplementing calcium do not show benefit. Below we present results of a recent study on Calcium supplementation citing >1400 mg/day been associated with increased cardiovascular risk and mortality.
Low serum zinc levels are associated with hypertension.

Authors of the BMJ of 2/13/2013 article reported, below offer the following Possible Explanations and Implications

Calcium levels in serum are under tight homeostatic control, and calcium intake is not normally correlated with calcium serum levels.

  • Diets that are low or very high in calcium can, however, override normal homeostatic control causing changes in blood levels of calcium or calciotropic hormones.52
  • Calcium enriched meals can reduce calcitriol, the active vitamin D metabolite, by inhibition of 1α hydroxylase53and also increase serum levels of fibroblast growth factor 23.54
  • Higher levels of circulating fibroblast growth factor 23 are associated with an increased risk of cardiovascular events and all cause mortality.55 56 57 In addition,
  • fibroblast growth factor 23 downregulates calcitriol levels.58
  • Vitamin D suppression leads to an upregulation of the renin-angiotensin-aldosterone system and hypertension, higher levels of proinflammatory cytokines involved in the pathogenesis of atherosclerosis:

–  increased carotid artery intima medial thickness,

–  decreased endothelial function,

–  hypertrophy of cardiac and vascular muscle cells, and a

–  possible increase in serum triglycerides.59 Finally,

  • high serum calcium levels can increase the risk of cardiovascular mortality60 by induction of a hypercoagulable state.61

Vascular calcification and plaque rupture

There are two types of vascular calcification,  intimal calcification of atherosclerosis and medial calcification. Both are associated with increased incidence of ischemic heart disease. Plaque rupture is manly restricted to intimal plaques fibrous cap calcification. Calcification of this fibrous cap is associated with increased incidence of ischemic heart disease. Below discussion is about controversy associated with fibrous cap calcification.

Whether intimal calcification stabilizes the plaque or makes it prone for rupture is a matter debate. Calcified and fibrotic lesions are more hypo-cellular, they are stiffer than cellular lesions, and further more biomechanical data suggest calcification reduces the “stresses” in a plaque does not cause rupture.  Plaques with heavily calcified are 5 times stiffer that non-calcified lesions.
Calcium crystal have shown to aggravate inflammation
Above observation are contradictory to each other. If calcium induces inflammation than plaque should get destabilize?
Under mechanical stress produced by balloon angioplasty, calcified plaque is more likely to rupture than non-calcified plaque, and the rupture occurs along the interface between the calcium deposit and soft tissue. So this suggest that plaque rupture may occur at these week points
It has been stated that when entire plaque is calcified it protects against rupture unlike focal calcification
The ratio of surface area to volume in calcium deposits may determine whether they are harmful or protective

Lipoprotein a (Lp(a)) genetic variant doubles the causal risk of Aortic valvular calcification.

In the last 15 to 20 years our understanding of aortic valve calcification has changed from just simple degenerative disease to disease secondary to an active process involving endothelial dysfunction, lipid accumulation, an inflammatory infiltrate. With this understanding many potential therapeutic approach have been considered. Statins showed promise in prevention of calcification in retrospective trials but prospective trials did not show benfit. Rennin angiotensin inhibitors have given discordant results in retrospective trials and no randomized control trial is there to prove their efficacy.

Aortic Valvular Calcification

new potential therapeutic  target for prevention aortic valve calcification i.e. Lp(a).Article published in NEJM Feb 7 2013 from Johns Hopkins, Harvard University, McGill University, the University of Iceland and the National Institutes of Health says, there is variant of Lp(a) which is associated with aortic valve calcification. In this publication genomewide association was evaluated for 6942 participants of aortic valvular calcification and 3795 participants of mitral valve calcification, detected by CT scanning.

Previous studies showed association of Lp(a) with calcification of aortic valve. Causal or just marker of calcification was not confirmed, present study shows causal relationship of Lp(a) and aortic valve calcification.
From this causal relationship one may think of targeting Lp(a) for preventing aortic valve calcification. Niacin reduces Lp(a) levels. Although  HPS-2 THRIVE trial (with niacin/laropiprant) which was done for coronary artery disease did not show clinical benfit, still one may keep hope for prevention of aortic valve calcification. Time may tell about us this in future.

Types of Vascular Calcification

  • Artery Medial Calcification (AMC) – Concentric Vessel – Stiffening
  • Atherosclerotic Intimal Calcification (AIC)

Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f228 (Published 13 February 2013)

Cite this as: BMJ 2013;346:f228

  1. Karl Michaëlsson, professor1,
  2. Håkan Melhus, professor2,
  3. Eva Warensjö Lemming, researcher1,
  4. Alicja Wolk, professor3,
  5. Liisa Byberg, associate professor1

Author Affiliations

  1. 1Department of Surgical Sciences, Section of Orthopedics, Uppsala University, SE-751 85 Uppsala, Sweden

  2. 2Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, Sweden

  3. 3Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to: K Michaëlsson karl.michaelsson@surgsci.uu.se
  • Accepted 28 December 2012


Objective To investigate the association between long term intake of dietary and supplemental calcium and death from all causes and cardiovascular disease.

Design Prospective longitudinal cohort study.

Setting Swedish mammography cohort, a population based cohort established in 1987-90.

Participants 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years.

Main outcome measures Primary outcome measures, identified from registry data, were time to death from all causes (n=11 944) and cause specific cardiovascular disease (n=3862), ischaemic heart disease (n=1932), and stroke (n=1100). Diet was assessed by food frequency questionnaires at baseline and in 1997 for 38 984 women, and intakes of calcium were estimated. Total calcium intake was the sum of dietary and supplemental calcium.

Results The risk patterns with dietary calcium intake were non-linear, with higher rates concentrated around the highest intakes (≥1400 mg/day). Compared with intakes between 600 and 1000 mg/day, intakes above 1400 mg/day were associated with higher death rates from all causes (hazard ratio 1.40, 95% confidence interval 1.17 to 1.67), cardiovascular disease (1 49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09) but not from stroke (0.73, 0.33 to 1.65). After sensitivity analysis including marginal structural models, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average associated with all cause or cause specific mortality but among calcium tablet users with a dietary calcium intake above 1400 mg/day the hazard ratio for all cause mortality was 2.57 (95% confidence interval 1.19 to 5.55).

Conclusion High intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke.


Calcium is one of the most abundant minerals in the human body and plays a pivotal role in human physiology. The serum levels of calcium are strictly regulated and an insufficient calcium intake is met by a more efficient intestinal absorption and renal conservation of calcium. Calcium is also mobilised from the skeleton, which can lead to bone loss1 and subsequent risk of fractures. Consequently, to prevent fractures in elderly people previous and existing guidelines2 recommend avoidance of low calcium intake. Fractures are common, especially in women, and are associated with high disability, healthcare costs, and mortality.3 Insufficient calcium intakes might also lead to secondary hyperparathyroidism, which is associated with higher mortality.1 4 5 Supplemental use of calcium has become common, and more than 60% of middle aged and older women in the United States are regular users of calcium supplements.6 7 Worryingly, three recent reanalyses of randomised trials in women have indicated a higher risk of both ischemic heart disease and stroke with calcium supplements,8 9 10 a pattern not observed in a reanalysis of another randomised trial.11 Few cohort studies in women have examined the association between dietary and supplemental intake of calcium with risk of cardiovascular incidence and mortality; instead,12 13 14 15 16 the focus has been on the incidence of stroke, with both contrary and inconsistent findings.12 13 14 16

We hypothesised that long term intake of low or high calcium increases the risk of cardiovascular mortality. We investigated associations between long term dietary and supplemental intake of calcium with all cause mortality as well as with cardiovascular mortality in a large population based prospective study of Swedish women.


The Swedish mammography cohort

The Swedish mammography cohort was established in 1987-90. All women (n=90 303) residing in two Swedish counties (Uppsala and Västmanland) and born between 1914 and 1948 received a mailed invitation to a routine mammography screening. Enclosed with this invitation was a questionnaire covering diet (food frequency questionnaire) and lifestyle, which was completed by 74% of the women. In 1997, a second, expanded questionnaire was distributed to those who were still living in the study area (response rate 70%). The study sample with exclusions has been described previously.17 18 In all, 61 433 women with baseline data (1987-90) and 38 984 with data from 1997 were available for analysis in the present study (fig 1).

Fig 1 Study samples in Swedish mammography cohort


Follow-up was through the Swedish cause of death registry. Complete linkage with the register is rendered by the personal identity number provided to all Swedish residents. Since 1952 the National Board of Health and Welfare has collected information on the causes of death for all Swedish residents in the cause of death registry. We used the underlying cause of death in the registry to define the outcomes of death from all causes, cardiovascular disease (international classification of diseases, ninth and 10th revisions; ICD-9 codes 390-459 or ICD-10 codes I00-I99), ischaemic heart disease (ICD-9 codes 410-414 or ICD-10 codes I20-I25), and stroke (ICD-9 codes 430-436 or ICD-10 codes I60-I64).

Dietary assessment

The food frequency questionnaires have been described previously.17 19 20 The participants reported their average frequency of consumption of up to 96 foods and beverages during the past year. For most food items, eight categories for frequency of consumption were provided, ranging from never to three or more times daily. For some commonly consumed foods such as milk, sour milk/yogurt, and cheese, participants could fill in the exact number of servings they consumed daily or weekly. We estimated nutrient intakes by multiplying the consumption frequency of each food item by the nutrient content of age specific portion sizes. Nutrient data were obtained from the Swedish National Food Administration database.21 We adjusted nutrient intakes for total energy intake (7.1 MJ or 1700 kcal, mean in the study population) using the residual method.22 To better account for changes in diet during follow-up and to better represent long term dietary intake we treated calcium intake as cumulative average intake.23 In the second questionnaire the lifetime use of dietary supplements and multivitamins was reported. In Sweden one calcium dose contains 500 mg if from calcium supplements and 120 mg if from multivitamins. Total calcium intake included supplemental calcium from any source. Even if supplement use was absent in the first food frequency questionnaire (baseline questionnaire), the frequency of calcium containing supplement use (with or without vitamin D) within the cohort during the first years of follow-up was low (6%),24 and this proportion was similar across the whole range of dietary calcium intake. Calcium intake in the 1997 food frequency questionnaire correlated well with estimates from 14 repeated 24 hour recalls over one year (r=0.77).25 Furthermore, a second validation of calcium intake was carried out with four seven day food records every third month in 104 of the women (r=0.72). Bland-Altman plots revealed only small systematic errors related to intake level between the methods, and the average difference with 95% confidence interval between the 1997 food frequency questionnaire and seven day food record was 56.4 mg/day (95% confidence interval −4.4 to 108.4 mg/day)—that is, as previously reported,25 a tendency of higher estimates for calcium intake with the food frequency method. Similar estimates were achieved for the baseline questionnaire.24

Comorbidity and other additional information

Lifestyle information was obtained from the questionnaires. This information included the use of postmenopausal oestrogen therapy and menopausal status, parity, weight and height, smoking habits, and leisure time physical activity during the past year, with five predefined levels ranging from one hour weekly to more than five hours weekly. Physical activity, collected in the 1997 questionnaire, is valid compared with activity records and accelerometer data.26 We divided educational level into four categories: up to 9 years, 10-12 years, more than 12 years, and other (such as vocational). Diagnosis codes were collated from the national patient registry (ICD codes 8, 9, and 10) to calculate Charlson comorbidity scores.27 28 The Charlson comorbidity index predicts the 10 year mortality for a patient who may have a range of comorbid conditions (up to 22 diseases). Each condition is assigned a score of 1 to 6 depending on the risk of dying associated with this condition.

Statistical analysis

For each participant, follow-up time was accrued from baseline (1987-90) until the first date of death, date of leaving the study regions, or the end of the study period (31 December 2008), whichever occurred first. In secondary analyses we considered time to incidence of cardiovascular disease, ischaemic heart disease, and stroke. To improve the validity of our exposure estimate, we used a calibrated calcium intake obtained by usage of linear regression coefficients between food records (FR) and the food frequency questionnaire (FFQ): (RiFRFR+ βFR* FFQi, (R reported calcium in the food records, i in the individual)).29 Using Cox proportional hazards regression we estimated age adjusted and multivariable adjusted hazard ratios and their 95% confidence intervals for prespecified categories of calcium intake: <600, 600-999, 1000-1399, and ≥1400 mg/day. To facilitate comparisons of the estimates we used the same category cut-offs in the analysis of dietary and total calcium intake. We estimated the risk with use of calcium containing supplements from the date of the second questionnaire survey (from 1 January 1998). The proportional hazard assumptions in the Cox models were confirmed graphically by comparing Nelson-Aalen plots. Non-linear trends of risk were additionally analysed using restricted cubic-spline Cox regression. We used four “knots” placed at centiles 5, 35, 65, and 95 of the cumulative average calcium intake.30 The reference level was set to 800 mg of calcium, which corresponds to the recommended daily intake for Swedish women aged more than 50 years.31

To minimise potential bias we used the directed acyclical graph approach to identify a suitable multivariable model. The model included age, total energy and vitamin D intake, body mass index, height (all continuous), educational level (≤9, 10-12, >12 years, other), living alone (yes or no), use of supplements containing calcium (yes or no), a healthy dietary pattern (fifths), physical activity (five categories), smoking status (never, former, current), and score on the Charlson comorbidity index (continuous, 1-16).27 28 A healthy dietary pattern was defined by using a validated method.3233 Briefly, we used factor analysis to derive the dietary pattern empirically. Factor analysis reduces dietary data to a few composite factors (one being a healthy dietary pattern) that describe the eating pattern in the population. Other potential covariates (such as menopausal status; hormone replacement therapy; intakes of total fat, retinol, alcohol, potassium, phosphorous, and protein; nulliparity; and previous fracture of any type) in the multivariable models only marginally changed the relations and were therefore not included in the models. We treated covariates as cumulative averages.28 The Markov chain Monte Carlo multiple imputation method was used to impute covariates not assessed in the baseline questionnaire in 1987-90 (for example, smoking habits and physical activity). Restriction to non-missing data did not alter our interpretation of the results (data not shown). Moreover, in an attempt to examine whether calcium supplement use modified the association between dietary calcium intake and mortality, we performed stratified analysis by calcium supplement use (no use, use of any type of calcium containing supplements, and specific use of calcium tablets). Additionally, we estimated the synergy index between dietary calcium intake and calcium tablet use.34 We performed sensitivity analysis, limiting the analysis to baseline data using ordinary Cox’s regression without time updated information. In an attempt to validate the robustness of the Cox’s regression model using information updated over time, we used marginal structural modelling.35 The categorical exposure in the marginal structural models was treated as described previously.36 We calculated an additional inverse probability weight for having time varying data, and we gave a weight of zero to those without time varying data.

In addition to ultraviolet radiation and genes, vitamin D intake is a determinant of vitamin D status,37 38 39 and vitamin D insufficiency is related to cardiovascular disease mortality and incidence.40 We therefore investigated effect measure modification between dietary calcium and vitamin D intake by including a product interaction term in the multivariable models and performing likelihood ratio tests of its contribution in nested models. We further calculated the relative excess risk that is due to interaction.34 When analysing cause specific mortality, we considered the potential competing risk problem from other causes of mortality41 and cumulative incidence curves.42 The subhazard ratios were similar to the hazard ratios from the ordinary Cox regression, suggesting no major effect of competing risks, which is also the conclusion drawn after analysis of cumulative incidence curves (data not shown).

The statistical analyses were performed with STATA 11 and SAS, version 9.2.


Table 1 lists the characteristics of the study participants by categories of calcium intake. The average total cumulative calcium intake in the lowest category was 572 mg/day and in the highest was 2137 mg/day. With increasing categories of energy standardised calcium intake, the reported intake for most other nutrients also increased, although alcohol intake tended to decrease. There were small differences in calcium supplement use, comorbidity, educational level, smoking status, and physical activity level between categories of calcium intake.

Vitamin D intake did not significantly modify the associations between calcium intake and the rate of deaths from all causes, cardiovascular disease, or ischaemic heart disease (results not shown).


In this study of women in the Swedish mammography cohort, a high calcium intake (>1400 mg/day) was associated with an increased rate of mortality, including death from cardiovascular disease. The increase was moderate with a high dietary calcium intake without supplement use, but the combination of a high dietary calcium intake and calcium tablet use resulted in a more pronounced increase in mortality. For most women with lower intakes we observed only modest differences in risk.

Strengths and weaknesses of the study

Strengths of our study include the population based prospective design, study size, and repeated measurements of calcium intake, as well as a large number of potential covariates. Date and cause of death were traced through national healthcare registries and deterministic record linkage, permitting complete ascertainment of the outcomes. The accuracy of classification of causes of death in the cause of death registry and diagnoses in the national patient registry are high.43 Furthermore, we adjusted for several important covariates (for example, smoking, socioeconomic status, physical activity, nutrients other than calcium, educational level, and comorbidity), but residual confounding remains a possible limitation. The lower age adjusted rates of death from all causes and cardiovascular disease among women with a high total calcium intake were largely explained by their use of dietary supplements (table 2), a variable considered in the multivariable models. Other health related covariates, including a healthy diet and level of physical activity contributed to a lesser degree. People who use dietary supplements have, on average, a healthier lifestyle and a lower risk factor profile for cardiovascular disease44 and not considering this might distort the risk estimates. Moreover, the low proportion of women who took prescription calcium tablets (6%), containing a four times higher dose of calcium than in regular multivitamin dietary supplements, made it difficult to detect modestly strong associations with calcium tablet use specifically. Dietary assessment methods are prone to several limitations, affecting both the precision and accuracy of the measurement. In larger studies, a food frequency questionnaire is used to assess the habitual intake of diet, and a recent review concluded that it was a valid method for assessing dietary mineral intake, particularly for calcium.45 The food frequency questionnaire may, to some extent, overestimate calcium intake,25 which was also indicated by our validation. A further limitation in our study is the use of age standardised portion sizes and not actual individual portion sizes. By use of our calibrated analysis of calcium intake, we none the less tried to avoid some misclassification of study participants. By using repeated measurements on dietary intake we increased the accuracy of the measurement but may also have introduced bias using time dependent Cox regression models. Indeed, after using only baseline data and also after performing the marginal structural model analyses, we no longer observed an increased mortality for women with low calcium intakes or a high total calcium intake. Without being causally linked to death, a low calcium intake could therefore be viewed as a marker of frailty or a less healthy behaviour associated with a higher mortality. There are, however, also theoretical drawbacks of our causal inference model. It is sensitive to correct model specifications and indeed renders estimates with lower precision than ordinary Cox’s regression.46 47 It is worth emphasising that traditionally obtained estimates, such as those from Cox’s regression, would not generally agree with estimates from marginal structural models even when there is no confounding.48 Irrespective of analytical approach, the observational study design precludes conclusions about causality, and cautious interpretations of the results are therefore recommended. The results for women with a high calcium intake are, however, compatible with results from previous randomised studies,8 9 10 and by fitting the marginal structural model we obtained similar risk estimates although with wider confidence intervals. Our results might also not apply to people of different ethnic origins or to men.

Strengths and weaknesses in relation to other studies

Calcium intake in adulthood and all cause mortality in women has not been previously investigated. In an analysis including 387 deaths within the Iowa Women’s Health Study cohort15 a total calcium intake below 700 mg/day but not above 1400 mg/day was associated with higher mortality from ischaemic heart disease. Furthermore, a recent reanalysis of the same cohort showed that use of calcium supplements was inversely related to the total and cardiovascular mortality rate, although the benefit was lost at the highest doses of dietary calcium intake.49In contrast, use of calcium supplements in a Finnish cohort increased the risk of cardiovascular disease.50 Intriguingly, three reanalyses of randomised trials have consistently shown a higher rate of both myocardial infarction and stroke by 25% to 30% and by 15% to 20%, respectively, with calcium supplementation.8 9 10These results were not confirmed in a reanalysis of another randomised trial using a broad composite endpoint of different cardiovascular events.11 Interestingly, the higher risk of cardiovascular events with calcium supplements in a meta-analysis8was only observed in women with a dietary calcium intake higher than 800 mg/day and not in women with lower intake levels.

The results from the few prospective cohort studies that have examined the relation between calcium intake and incidence of cardiovascular disease in women are contradictory or not conclusive. In the Nurses’ Health Study cohort there was a higher risk of stroke in women with a calcium intake below 600 mg/day.12 Similarly, in a Japanese setting with a comparably low average calcium intake, women with an intake below about 500 mg/day had a higher rate of stroke but not of coronary heart disease.13 14 None the less, calcium intake was not related to stroke incidence in a previous analysis in our cohort,16 concordant with the results of the present investigation. We have recently shown that calcium intakes above 700 mg/day do not further reduce the risk of fracture and osteoporosis.18

Vitamin D enhances, directly or indirectly, renal conservation and intestinal absorption of calcium.51 Our results suggest that vitamin D intake did not modify the association of calcium intake and mortality rate. In comparison with exposure to ultraviolet radiation and genetic constitution, vitamin D intake contributes only modestly to vitamin D status,37 38 39 which is determined by serum calcidiol levels, a metabolite not measured in the present investigation.

Possible explanations and implications

Calcium levels in serum are under tight homeostatic control, and calcium intake is not normally correlated with calcium serum levels. Diets that are low or very high in calcium can, however, override normal homeostatic control causing changes in blood levels of calcium or calciotropic hormones.52 Calcium enriched meals can reduce calcitriol, the active vitamin D metabolite, by inhibition of 1α hydroxylase53and also increase serum levels of fibroblast growth factor 23.54 Higher levels of circulating fibroblast growth factor 23 are associated with an increased risk of cardiovascular events and all cause mortality.55 56 57 In addition, fibroblast growth factor 23 downregulates calcitriol levels.58 Vitamin D suppression leads to an upregulation of the renin-angiotensin-aldosterone system and hypertension, higher levels of proinflammatory cytokines involved in the pathogenesis of atherosclerosis, increased carotid artery intima medial thickness, decreased endothelial function, hypertrophy of cardiac and vascular muscle cells, and a possible increase in serum triglycerides.59 Finally, high serum calcium levels can increase the risk of cardiovascular mortality60 by induction of a hypercoagulable state.61

Our present data together with previous observations suggest that for the prevention of fractures in elderly people18 and simultaneous avoidance of possible serious adverse events related to a high calcium intake (such as higher risk of hip fracture,18 62 cardiovascular disease,63 renal stones,64 and, as observed in the current study, mortality) emphasis should be placed on people with a low intake of calcium rather than increasing the intake of those already consuming satisfactory amounts.


When looking at the totality of our data, high calcium intakes were associated with higher rates of death from all causes and cardiovascular disease. Mortality was not increased between 600 and 1400 mg/day of total calcium intake, the most customary levels of intake in this setting. The suggestion of an increased risk of mortality by a low calcium intake in our study seemed to be biased by time varying confounding factors.

What is already known on this topic

  • A low calcium intake is associated with higher fracture rates in elderly people and a higher risk of stroke and fatal ischaemic heart disease
  • Meta-analyses of some randomised studies have, however, shown a higher risk of incident ischaemic heart disease and stroke with calcium supplement use
  • In observational studies, use of calcium supplements has been associated with both lower overall and cardiovascular mortality rate, as well as higher incidence of cardiovascular disease

What this study adds

  • In this Swedish cohort study of women, high intakes of calcium (>1400 mg/day) were associated with higher mortality
  • The increase was moderate with a high dietary calcium intake without supplement use, but more pronounced with a high dietary calcium intake with calcium tablet use
  • For most women with lower calcium intakes only modest differences in risk were observed


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Updated Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

Reporter: Aviva Lev-Ari, PhD,RN


UPDATED on 5/27/2014

Survival After TAVI: Longest Follow-up Data Yet Yield Some Surprises

May 23, 2014

PARIS, FRANCE — Some of the longest follow-up for the first transcatheter aortic-valve implantations (TAVI) ever performed confirm earlier observations that the biggest threat to survival in TAVI-implanted patients remains their comorbidities and not problems related to their valves, regardless of valve type. More surprising, some of the procedural issues that preoccupy interventionalists and surgeons today did not emerge as important in this longer-term follow-up.

Presenting three- and five-year data from the UK TAVI registry in a press conference here at EuroPCR 2014 , Dr Neil Moat (Royal Brompton Hospital, London, UK) pointed to what he called “biphasic” survival curves. In the first few months after valve implantation, there is a steep drop in survival, he noted. Thereafter, the curve becomes significantly less steep, mirroring the survival curves typically seen in older patients who have undergone surgical valve replacement.

“In the first six months, you have quite a dramatic attrition of patients, then mortality falls to about 6% of patients per year,” he said. “What this is telling us is that patients undergoing TAVI are not dying of TAVI-related factors.”

The UK TAVI registry contains prospectively collected data from 100% of all consecutive transcatheter aortic-valve replacement (TAVR) patients treated since January 1, 2007. The current analysis includes 870 early patients whose mortality status was ascertained in July 2013.

In all, 62% of TAVR-treated patients were alive at three years, while just under half—48.4%—were still alive at five years.

Dr Neil Moat [Source: EuroPCR]

In multivariable analyses, the strongest baseline predictor of mortality at three years was

  • creatinine >200 µg/mmol, followed by
  • presence of atrial fibrillation,
  • chronic obstructive pulmonary disease (COPD), or a
  • high EuroSCORE (>18.5).

Of note, device- or procedure-related characteristics that typically get a lot of attention at interventional meetings were not significant predictors of late survival. For example,

  • 12.7% of patients still alive at three years had had moderate/severe aortic regurgitation at the time of their procedure, compared with
  • 14.9% of patients who’d died, but the difference was not statistically significant. Likewise,
  • permanent pacemaker implantation had been performed in 16.2% of patients still alive at follow-up and in
  • 19.3% of patients who died, again a nonsignificant difference.

Not surprisingly,

  • more transfemorally treated patients were alive at three years than
  • patients treated via a nontransfemoral procedure (64.3% vs 55.7%, p=0.017).

Roughly the same number of patients received the

  • Edwards Sapien device in the early days of the TAVI registry (410) as received the
  • Medtronic CoreValve (452).

By three years,

  • 40.7% of Sapien-treated patients had died, compared with
  • 35.4% of CoreValve-treated patients (p=0.078).
“CoreValve had a trend toward better survival, but I wouldn’t want to overinterpret that,” Moat cautioned. These are preliminary data, he stressed, but added, “There is a trend there that needs looking at” when the registry has more patients, with more follow-up.

One of the theories put forward in other sessions at EuroPCR is that the higher pacemaker-implantation rate with CoreValve might, in fact, help bump up survival rates with this device.

“It’s an interesting hypothesis,” Moat said. “But I don’t think we have any data to support that hypothesis, either here or in any other study. I think if there were an effect of early pacemaker implantation it would be in this first [six-month] phase. Some people are concerned that the early attrition is sudden death because of late heart block occurring two, three, or four months after the procedure. So if you are having pacemakers implanted more frequently, you are being protected from that, but I think our data strongly suggest that pacemaker implant does not affect long-term survival.”

Moat disclosed being a consultant for Medtronic.


UPDATED on 2/9/2014

Transcatheter Technologies Completes Durability Testing of Its Prosthetic Aortic Heart Valve, Intrinsic to World’s First ‘Truly Repositionable’ TAVI Device, TRINITY

January 28, 2014 6:29 AM 

Business Wire

“This 3rd-generation TRINITY technology could be a game-changer for TAVI.” Prof. Dr. Christian Hengstenberg, MD, German Heart Center, Munich (Note: Prof. Dr. med Hengstenberg has no financial ties to Transcatheter Technologies.)

REGENSBURG, Germany–(BUSINESS WIRE)–January 28, 2014–

Transcatheter Technologies GmbH, an emerging medical device company that is developing a third-generation transcatheter aortic valve implantation (TAVI) system-TRINITY-announced today that an independent laboratory has completed ‘advanced wear testing’ (AWT) of the company’s TRINITY valve prosthesis, far exceeding minimum testing standards. Indeed, AWT of the TRINITY heart valve has already completed 600 million cycles, or an estimated 15 years of durability testing.

Transcatheter Technologies has previously announced the successful 30-day follow-up results of a pilot study of its TRINITY TAVI system that is designed to be the world’s first ‘truly repositionable’ and, therefore, best TAVI system.

“Unlike second-generation TAVI systems, the Trinity aortic valve is designed to be positioned precisely or repositioned, even after full implantation, in a safe and simple manner,” said principal investigator Prof. Dr. Christian Hengstenberg, a cardiologist at the German Heart Center, Munich, Germany, with no financial interest or arrangement or affiliation with Transcatheter Technologies. “In our study, Trinity’s novel sealing cuff continues to provide outstanding follow-up results without PVL (paravalvular leak), a frequent complication of TAVI. Equally important, the TRINITY aortic valve is designed to reduce the risk of atrio-ventricular (AV) block significantly through supra-annular positioning of the TRINITY valve.”

“We are extremely pleased that our TRINITY valve has already demonstrated three times the minimum standard for advanced wear testing of a tissue heart valve,” said Wolfgang Goetz, M.D., Ph.D., CEO, a cardiac surgeon by training. We also are extremely pleased with the continuing excellent results of our third-generation TRINITY System in the follow-up of our first patient.

“The big issue with the second-generation TAVI systems is that they cannot be truly repositioned once fully implanted. TRINITY, however, is designed to solve this critically important issue and thereby potentially reduce the undesirable side consequences of PVL,” added Dr. Goetz. “With TRINITY, once our valve is completely expanded and anchored above the annulus, a cardiologist can fully evaluate the valve’s function to determine whether it needs to be repositioned, retrieved, or kept in the same position. This feature and its supra-annular anchoring are absolutely unique to TRINITY, which is why we have positioned TRINITY as a Third-Generation TAVI System.”

CAUTION: TRINITY is not approved for use in the United States

Ronald Trahan Associates Inc.
Ronald Trahan, APR, +1-508-359-4005, x108


Transcatheter aortic valve implantation (TAVI): risk for stroke and suitability for surgery

For additional discussion go to 

Transcatheter Aortic Valve Implantation (TAVI): Risky and Costly


BMJ 2012; 345 doi: 10.1136/bmj.e4710 (Published 31 July 2012) Cite this as: BMJ 2012;345:e4710

Evidence for TAVI Questioned

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: July 31, 2012

The tens of thousands of transcatheter aortic valve implantations (TAVI) performed worldwide may not have solid evidence behind them, European researchers suggested.

To begin with, a health technology assessment commissioned by the Belgian government suggested that only patients who are “deemed inoperable for technical reasons such as a series of previous operations or irradiation of the chest wall” be reimbursed for TAVI, according to Mattias Neyt, PhD, of the Belgian Health Care Knowledge Centre in Brussels, and colleagues.

That’s about 10% of patients currently being considered for the procedure, they wrote online in an analysis article in BMJ.

Why is there such a big disconnect between the growing number of patients undergoing TAVI and the findings of the Belgian technology assessment? Neyt and colleagues said there are several factors that have resulted in more enthusiasm than evidence for TAVI.

One of those factors is the process by which medical devices receive marketing approval in the E.U., which, they said, puts medical devices “on the same footing as domestic appliances such as toasters.”

As a consequence of what the authors referred to as “Europe’s lax licensing laws,” the two TAVI devices in common use today – Medtronic’s CoreValve and Edward Lifescience’s Sapien – were approved in 2007, “long before any substantial clinical trial evidence was available.”

Even the U.K.’s National Institute for Health and Clinical Excellence (NICE) concluded that the evidence was “adequate from a clinical point of view” for the use of TAVI in those unsuitable for surgery, but when surgery is an option — even a high-risk one — the evidence for TAVI was inadequate.

However, the British analysis did not consider costs associated with the procedure, Neyt and colleagues pointed out.

In the U.S., the FDA approval process is more rigorous than that of the E.U., but Neyt and colleagues were “far from convinced” that the results from the PARTNER trials (Cohort A andCohort B) were adequate to justify approval of the Sapien valve.

Although the cost-effectiveness of TAVI for inoperable patients (cohort B) is “equivocal,” they wrote, the clinical evidence seems to suggest that TAVI can be justified. However, they pointed out some problems that they said were not considered within the overall evidence, such as a higher rate of comorbidities and a higher rate of previous MIs among the inoperable control patients.

In PARTNER cohort A, where TAVI was compared with high-risk surgical patients, the authors noted a concern for a higher rate of stroke or transient ischemic attack among the TAVI patients.

Nevertheless, an FDA panel in June recommended expanding the indication for the Sapien valve to include high-risk surgical candidates. One of the panelists said that stroke is “just an accepted risk of the procedure.”

But Neyt and colleagues don’t accept that. They concluded that based on the evidence, as well as the concern for efficient use of limited resources, “it is difficult to see how healthcare payers can justify reimbursing TAVI for patients suitable for surgery, given that the risk of stroke is twice as high after TAVI.”

Another issue that could undermine the integrity of the evidence, Neyt and colleagues said, was the absence of full disclosure on the part of principal investigator Martin B. Leon, MD, from Columbia University.

According to the Belgian researchers, part of the deal involving the sale of Leon’s valve company to Edwards included future payments from Edwards “on the achievement of three milestones: successful treatment of 50 patients, regulatory approval in Europe, and limited approval in the U.S.”

These three milestones were not disclosed in the original paper published in the New England Journal of Medicinethey said.

Neyt and colleagues also complained that the FDA and Edwards Lifesciences are holding on to negative findings from an FDA-authorized follow-on study of 90 inoperable patients. Some of the data released at an FDA meeting in 2011 showed a higher 1-year mortality rate among those receiving TAVI (34.3% versus 21.6%), they said, but efforts to obtain any of those data have been rebuffed by both the FDA and Edwards.

They brought this concern to the editors of the NEJM, but the editors didn’t think the concern invalidated the overall PARTNER findings.

Tying all this together, Neyt and colleagues called for “a major improvement in transparency of information” that would “allow clinicians to practice evidence-based medicine, patients to make informed decisions, and health technology assessment agencies to make the right judgments.”

The authors reported they had no relationships to disclose.

Primary source: BMJ

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