Emil Hagström

Plasma parathyroid hormone and the risk of cardiovascular mortality in the community

Background— Diseases with elevated levels of parathyroid hormone (PTH) such as primary and secondary hyperparathyroidism are associated with increased incidence of cardiovascular disease and death. However, data on the prospective association between circulating PTH levels and cardiovascular mortality in the community are lacking. Methods and Results— The Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (mean age, 71 years; n=958), was used to investigate the association between plasma PTH and cardiovascular mortality. During follow-up (median, 9.7 years), 117 participants died of cardiovascular causes. In Cox proportional-hazards models adjusted for established cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease), higher plasma PTH was associated with higher risk for cardiovascular mortality (hazard ratio for 1-SD increase in PTH, 1.38; 95% confidence interval, 1.18 to 1.60; P<0.001). This association remained essentially unaltered in participants without previous cardiovascular disease and in participants with normal PTH (<6.8 pmol/L) with no other signs of a disturbed mineral metabolism (normal serum calcium, 2.2 to 2.6 mmol/L; normal glomerular filtration rate, >50 mL · min−1 · 1.73 m−2 and without vitamin D deficiency, plasma 25-OH vitamin D >37.5 nmol/L). Interestingly, elevated plasma PTH (>5.27 pmol/L) accounted for 20% (95% confidence interval, 10 to 26) of the population-attributable risk proportion for cardiovascular mortality. Conclusions— Plasma PTH levels predict cardiovascular mortality in the community, even in individuals with PTH within the normal range. Further studies are warranted to evaluate the clinical implications of measuring PTH in cardiovascular risk prediction and to elucidate whether PTH is a modifiable risk factor.

Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes

CONTEXT Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. MAIN OUTCOME MEASURE Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. RESULTS Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. CONCLUSION Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

Conjoint Effects of Serum Calcium and Phosphate on Risk of Total, Cardiovascular, and Noncardiovascular Mortality in the Community

Objective—Hyperphosphatemia is a cardiovascular risk factor in patients with chronic kidney disease. Relations of circulating calcium (Ca) and phosphorus (Pi) to long-term mortality risk in the community require further investigation. Methods and Results—Associations of serum Ca and Pi to mortality were evaluated in a community-based cohort of 2176 men (mean age, 50.1 years). During follow-up (median, 29.8 years), 1009 men died, and 466 of these deaths resulted from cardiovascular causes. In Cox proportional hazards models, serum Pi and [Ca×Pi] were independent predictors of total mortality (hazard ratio per SD, 1.06; 95% CI, 1.01–1.12; P=0.03; 1.07; 95% CI, 1.01–1.12; P=0.01) and cardiovascular mortality (1.10; 95% CI, 1.02–1.18; P=0.01; 1.10; 95% CI, 1.03–1.19; P=0.008). Serum Ca was associated with risk of total mortality (1.08; 95% CI, 1.01–1.16; P=0.02) and noncardiovascular mortality (1.10; 95% CI, 1.01–1.21; P=0.04). Results were consistent after multivariate adjustments in subsamples of individuals with estimated glomerular filtration rate >90 mL/min and low-to-normal serum Ca and Pi. Conclusion—Circulating Ca and Pi levels are associated with risks of total, cardiovascular, and noncardiovascular mortality in the community, and their conjoint effects are additive. Additional studies are warranted to evaluate whether Ca and Pi are modifiable risk factors in the general population.

Plasma parathyroid hormone and risk of congestive heart failure in the community.

In experimental studies parathyroid hormone (PTH) has been associated with underlying causes of heart failure (HF) such as atherosclerosis, left ventricular hypertrophy, and myocardial fibrosis. Individuals with increased levels of PTH, such as primary or secondary hyperparathyroidism patients, have increased risk of ischaemic heart disease and HF. Moreover, increasing PTH is associated with worse prognosis in patients with overt HF. However, the association between PTH and the development HF in the community has not been reported.

Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago.

Population-based screening showed 2.1% prevalence of primary hyperparathyroidism (pHPT) in postmenopausal women. Individuals with total serum (s)-calcium levels of 2.55 mmol/L or more at screening were diagnosed with pHPT when subsequent analysis supported inappropriately elevated intact parathormone (PTH) levels in relation to even normal s-calcium levels. The arbitrary diagnostic criteria were validated by parathyroidectomy. Herein we reinvestigated biochemical signs of pHPT in women not diagnosed with pHPT due to s-calcium 2.50 to 2.54 mmol/L (group A, n = 160) at screening or due to appropriate PTH levels on two occasions after screening (group B, n = 70). Altogether, 99 women in group A and 47 in group B underwent reinvestigation 8.8 years after screening when they were 65 to 84 years old. The s-calcium levels averaged 2.56 mmol/L and had increased in group A (mean 0.04 mmol/L) and decreased in group B (mean 0.05 mmol/L). A total of 48 and 18 females (48%, 38%), respectively, met the previously validated criteria of pHPT. Altogether 21% of them were hypercalcemic (range 2.60–3.12 mmol/L). Subgroup analysis showed that PTH had not increased with time (n = 47) and that atherogenic blood lipids, but not glucose levels, were similar in pHPT patients and matched controls (n = 37). Assuming the existence of pHPT already at screening, the prevalence of pHPT could be adjusted to 3.4%. Even the most liberal diagnostic criteria utilized at pHPT screening seemed to underdiagnose the disease by inefficient cutoff limits for s-calcium and PTH. Because one-fifth of the women with pHPT progressed to hypercalcemia, long-term follow-up is advocated for those with s-calcium in the upper normal range.

Plasma 25-Hydroxyvitamin D Levels and Fracture Risk in a Community-Based Cohort of Elderly Men in Sweden

CONTEXT Blood levels of 25-hydroxyvitamin D [25(OH)D] is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE The objective of the study was to determine the threshold at which low plasma 25(OH)D levels are associated with fractures in elderly men and clarify the importance of low levels on total fracture burden. DESIGN AND PARTICIPANTS In the Uppsala Longitudinal Study of Adult Men, a population-based cohort (mean age, 71 yr, n = 1194), we examined the relationship between 25(OH)D and risk for fracture. Plasma 25(OH)D levels were measured with high-pressure liquid chromatography-mass spectrometry. SETTING The study was conducted in the municipality of Uppsala in Sweden, a country with a high fracture incidence. MAIN OUTCOME MEASURE Time to fracture was measured. RESULTS During follow-up (median 11 yr), 309 of the participants (26%) sustained a fracture. 25(OH)D levels below 40 nmol/liter, which corresponded to the fifth percentile of 25(OH)D, were associated with a modestly increased risk for fracture, multivariable-adjusted hazard ratio 1.65 (95% confidence interval 1.09-2.49). No risk difference was detected above this level. Approximately 3% of the fractures were attributable to low 25(OH)D levels in this population. CONCLUSIONS Vitamin D insufficiency is not a major cause of fractures in community-dwelling elderly men in Sweden. Despite the fact that cutaneous synthesis of previtamin D during the winter season is undetectable at this northern latitude of 60 degrees, only one in 20 had 25(OH)D levels below 40 nmol/liter, the threshold at which the risk for fracture started to increase. Genetic adaptations to limited UV light may be an explanation for our findings.

Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population‐based study over five years

objective Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients.

Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women.

Context  In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear.

Secondary prevention and risk factor target achievement in a global, high-risk population with established coronary heart disease: baseline results from the STABILITY study

Aim: There is limited contemporary data on achievement of risk factor goals for secondary prevention of cardiovascular (CV) disease from countries in many regions of the world. This report describes the global and regional prevalence of CV risk factors and use of preventive medications at baseline in participants in the ongoing STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial. Methods and Results: Detailed individual data on CV risk factors were obtained before randomization in 15,828 patients with chronic coronary heart disease (CHD) from 39 countries on five continents. Subjects had a history of myocardial infarction, prior coronary revascularization, or multi-vessel CHD without revascularization and at least one additional CV risk factor. The majority were taking a statin (97%), antiplatelet therapy (96%), beta-blocker (79%), or angiotensin converting enzyme inhibitor/angiotensin receptor blocker (77%). However, a large proportion of patients did not achieve guideline-recommended targets. For instance, in 29% low-density lipoprotein (LDL) cholesterol was >2.5 mmol/l and in 46% blood pressure was ≥140/90 mmHg or ≥130/80 mmHg in those with diabetes or renal impairment. The body mass index was >30 kg/m2 in 36%, waist circumference ≥102 cm for men or ≥88 cm for women in 54%, and 18% were smoking. Regional differences in risk factor prevalence and target achievement were observed and were more marked for LDL cholesterol and obesity. Conclusion: The prevalence of modifiable CV risk factors was generally high in the STABILITY population. Although, most patients were receiving evidence-based secondary preventive therapy many subjects from all regions did not reach recommended secondary prevention goals.

Physical activity in patients with stable coronary heart disease: an international perspective

Aims Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib. Methods and results Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤24MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either ‘not limited’ or ‘limited a little’ walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/½ mile (68%), and <10% were limited ‘a lot’ by dyspnoea or angina. Variables independently associated with both low physical activity and decreasing exercise after diagnosis of CHD included more co-morbid conditions, poorer general health, fewer years of education, race, and country (P < 0.001 for all). Conclusion In this international study, low physical activity was only partly explained by cardiovascular symptoms. Potentially modifiable societal and health system factors are important determinants of physical inactivity in patients with chronic CHD.