* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Parathyroid hormone level is associated with mortality and
History of invasive and interventional cardiology wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Cardiac surgery wikipedia , lookup
Jatene procedure wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Saturated fat and cardiovascular disease wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
CLINICAL RESEARCH European Heart Journal (2010) 31, 1591–1598 doi:10.1093/eurheartj/ehq109 Coronary heart disease Parathyroid hormone level is associated with mortality and cardiovascular events in patients undergoing coronary angiography Stefan Pilz 1*, Andreas Tomaschitz 1, Christiane Drechsler 2, Eberhard Ritz 3, Bernhard O. Boehm 4, Tanja B. Grammer 5, and Winfried März 5,6,7 Received 19 October 2009; revised 22 January 2010; accepted 22 February 2010; online publish-ahead-of-print 2 May 2010 Aims Elevated parathyroid hormone (PTH) levels have been associated with increased cardiovascular risk in the general population. We aimed to elucidate whether PTH levels are associated with mortality and fatal cardiovascular events in patients referred for coronary angiography. ..................................................................................................................................................................................... Methods Intact PTH was measured in 3232 Caucasian patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, who underwent coronary angiography at baseline (1997–2000). During a median follow-up time and results of 7.7 years, 742 patients died including 467 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs) (with 95% confidence intervals) in the fourth when compared to the first PTH quartile were 2.13 (1.75– 2.60) for all-cause and 2.47 (1.92– 3.17) for cardiovascular mortality. After adjustments for common cardiovascular risk factors, these HRs remained significant with 1.71 (1.39–2.10) for all-cause and 2.02 (1.55– 2.63) for cardiovascular mortality. Among specific cardiovascular events we observed a particularly strong association of PTH with sudden cardiac death (SCD). The adjusted HR for SCD in the first vs. the fourth PTH quartile was 2.68 (1.71– 4.22). ..................................................................................................................................................................................... Conclusion Our results among patients undergoing coronary angiography show that PTH levels are an independent risk factor for mortality and cardiovascular events warranting further studies to evaluate whether PTH modifying treatments reduce cardiovascular risk. ----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords PTH † Vitamin D † Cardiovascular disease † Sudden cardiac death † Mortality † Prospective study Introduction Parathyroid hormone (PTH), which is crucial for the maintenance of calcium homeostasis, has been associated with increased cardiovascular risk.1 Parathyroid hormone is secreted by the parathyroid glands in response to hypocalcaemia which is detected by the calcium sensing receptor (CaSR).2 Classic PTH effects on bone and kidney are important for the control of calcium homeostasis, but PTH receptors are also expressed in the vessel walls and the myocardium suggesting direct effects on the cardiovascular system.1 In this context, PTH levels have been associated with hypertension, myocardial dysfunction, and vascular diseases.1 – 6 Primary hyperparathyroidism, characterized by inadequately high PTH levels with subsequent hypercalcaemia, has been associated with increased cardiovascular risk and mortality, which could be significantly reduced by parathyroidectomy in most but not all studies in this field.1,2,7 Secondary hyperparathyroidism, which is frequently observed in patients with impaired kidney function, is also associated with increased mortality and PTH modifying therapies have been shown to improve the clinical outcome of patients with * Corresponding author. Tel: +43 650 9103667, Fax: +43 316 673216, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected]. Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 1 Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; 2Division of Nephrology, Department of Internal Medicine, University of Würzburg, Würzburg, Germany; 3Division of Nephrology, Department of Internal Medicine, Rupertus Carola University Heidelberg, Heidelberg, Germany; 4Division of Endocrinology and Diabetes, Department of Internal Medicine _, Ulm University, Ulm, Germany; 5Synlab Center of Laboratory Diagnostics, Heidelberg, Germany; 6Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; and 7Mannheim Institute of Public Health, Medical Faculty Mannheim, Rupertus Carola University Heidelberg, Heidelberg, Germany 1592 Methods Participants and study design The LURIC study, a prospective cohort study of patients referred to coronary angiography, was designed to investigate environmental and genetic risk factors for cardiovascular diseases.16 The baseline examination was performed between July 1997 and January 2000 at a tertiary care centre in south-west Germany (Herzzentrum Ludwigshafen) and included 3316 study participants. Inclusion criteria were the availability of a coronary angiogram, clinical stability with the exception of acute coronary syndromes (ACSs), and Caucasian origin, in order to limit genetic heterogeneity. Indications for coronary angiography were commonly chest pain or non-invasive tests in which myocardial ischaemia was suspected. Patients with any acute illness other than ACS, with a history of malignancy within the past 5 years and with any predominant non-cardiac disease were excluded from the study. Informed written consent was obtained from all study participants and approval for the study was obtained from the ethics committee at the ‘Ärztekammer Rheinland-Pfalz’ (Mainz, Germany). The LURIC study complies with the Declaration of Helsinki. Baseline examination Detailed descriptions of the baseline examination in LURIC have been published previously.16 Angiographic coronary artery disease (CAD) was diagnosed in patients with at least one stenosis ≥50% of at least one out of 15 coronary segments, using the maximal luminal narrowing estimated by visual analysis. Diabetes mellitus was diagnosed if the fasting glucose was .7.0 mmol/L or the 2 h value in an oral glucose tolerance test was .11.1 mmol/L and in patients already receiving antidiabetic medication. Arterial hypertension was diagnosed if the mean systolic and diastolic blood pressures out of five measurements exceeded 140 and/or 90 mmHg or if patients were already on antihypertensive treatment. Biochemical analyses Routine laboratory measurements were performed as previously described.16 In brief, venous blood sampling was performed in the morning before coronary angiography and routine laboratory parameters were immediately determined, whereas remaining blood samples were snap frozen for further determinations and stored at 2808C until analysis. Intact PTH was determined in serum by ElectroChemiLuminescence Immunoassay (ECLIA) on an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany), with a normal range of 15 – 65 pg/mL and an inter-assay coefficient of variation of 5.7– 6.3%. Serum concentrations of 25(OH)D were measured by a radioimmunoassay (DiaSorin Antony, France; Stillwater, USA) with an intra- and inter-assay coefficient of variation of 8.6 and 9.2%, respectively.17 Levels of 1,25-dihydroxyvitamin D were also measured by radioimmunoassay (Nichols Institute Diagnostika GmbH, Bad Nauheim, Germany) on a multicrystal counter (Berthold LB2014, DiaSorin, SA, USA). N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) was determined by ElectroChemiLuminescence (ECL) on an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). C-reactive protein was measured by immunonephelometry (N High Sensitivity CRP, Dade Behring, Marburg, Germany). Plasma aldosterone was determined by radioimmunoassay (Active aldosterone, Diagnostic Systems Laboratories, Sinsheim, Germany) and glomerular filtration rate (GFR) was calculated according to the abbreviated MDRD study equation.18 Follow-up Information on vital status was obtained from local person registries. Hospital records and death certificates were reviewed to classify the causes of death. Cardiovascular deaths included SCD, fatal myocardial infarction, deaths due to heart failure, deaths after intervention to treat CAD, stroke, and other deaths due to heart disease. Sudden cardiac death was defined as a sudden unexpected death either within 1 h of symptom onset or within 24 h of having been observed alive and symptom free.19,20 Persons whose sudden death was most likely attributable to a non-cardiac disease and patients who suffered from any predominant non-cardiac and terminal disease (e.g. cancer) so that their death was not unexpected were not classified as having died due to SCD. Three experienced clinicians who were blinded to PTH values and baseline characteristics of the study probands classified the causes of death. Statistics Parathyroid hormone quartiles were calculated according to the values of the entire study cohort. All skewed continuous parameters were logarithmically transformed before use in parametric procedures. Baseline characteristics were stratified by PTH quartiles. Depending on their distribution, continuous parameters are either presented as means + standard deviation (normally distributed variables) or as medians with interquartile range (skewed variables). Categorical data are shown as proportions. Comparisons across PTH quartiles were calculated by analysis of variance (ANOVA) with P for trend for continuous parameters and by x2 test with P for liner-by-linear test for categorical variables. For all-cause and cardiovascular mortality, Kaplan– Meier curves followed by a log-rank test were graphed to show the differences in event-free survival between PTH quartiles. Hazard ratios (HRs) with 95% confidence intervals (95% CI) for all-cause and cardiovascular mortality were calculated with Cox proportional hazard models using the first PTH quartile as the reference. We present data from these analyses of a crude (unadjusted) model, of an age- and sex-adjusted model (Model 1) and of a model adjusted for common cardiovascular risk factors (Model 2). The latter model includes variables for BMI (kg/m2), haemoglobin A1c (HbA1c) (%), systolic blood pressure (mmHg), GFR (mL/min/1.73 m2), LDL- and HDL-cholesterol (mg/dL), triglycerides (mg/dL), C-reactive protein (mg/L), ex- and active smokers (yes/no), and number of diseased vessels (0 – 3 vessels). In addition to the covariates of Model 2, we adjusted for the use of medication (ACE-inhibitors, beta-blockers, Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 renal failure.2,8 Only a few studies addressed the clinical significance of PTH levels for mortality and cardiovascular diseases in persons without significant renal disease.2,7 Currently available studies in this field have shown an association of PTH levels and mortality in the elderly.2,9 – 15 Importantly, a recent study among a community-based cohort of 958 elderly men has shown that PTH levels within the normal range are predictive for fatal cardiovascular events.13 Whether this applies for both genders and for patients at higher cardiovascular risk remains largely unknown. Given that PTH modifying therapies such as vitamin D and calcium supplementation can be easily and relatively safely performed, there exists a great public health interest to elucidate whether PTH is a promising target for the treatment to reduce cardiovascular risk.1,2 Hence, we aimed to prospectively evaluate whether PTH levels are a risk factor for mortality and fatal cardiovascular events [e.g. sudden cardiac death (SCD)] in a large cohort of patients referred for coronary angiography. S. Pilz et al. 1593 Continued ............................................................................................................................................................................................................................................. ,0.001 ,0.001 ,0.001 141 + 23 81 + 11 63.7 138 + 23 79 + 11 69.0 Blood pressure (mmHg) Systolic Diastolic Ex- and active smokers (%) 142 + 23 82 + 11 62.8 145 + 24 82 + 12 59.2 ............................................................................................................................................................................................................................................. ,0.001 ,0.001 0.002 0.067 0.088 ,0.001 P-value .40 758 67.8 (60.2– 72.8) 34.7 27.4 (24.8– 30.1) 35.2 6.1 (5.6– 6.8) 79.4 23– 29 742 62.5 (55.8– 69.3) 29.8 27.1 (24.9– 29.4) 31.4 6.0 (5.5– 6.5) 70.6 ,23 885 59.9 (52.4 – 67.3) 26.1 26.6 (24.7 – 29.2) 30.5 6.0 (5.6–6.6) 67.9 PTH (pg/mL) Numbers Age (years) Female (%) Body mass index (kg/m2) Diabetes mellitus (%) HbA1c (%) Arterial hypertension (%) 30 –40 847 64.7 (58.2– 71.0) 31.8 27.2 (24.5– 29.9) 31.1 6.0 (5.6– 6.6) 73.8 4th quartile 3rd quartile 2nd quartile 1st quartile Eighteen patients were lost during a median follow-up time of 7.7 years (interquartile range: 7.2 –8.5 years) and in 24 study participants we did not obtain sufficient information to classify their causes of death. These latter patients were included in the analyses for all-cause mortality but excluded from analyses for cardiovascular mortality and specific cardiovascular events. Among 3232 patients with available PTH levels, 742 died during follow-up, of whom 467 died due to cardiovascular causes. Among specific cardiovascular events we recorded 187 SCDs, 84 fatal myocardial infarctions, 112 deaths due to heart failure, and 84 deaths due to other cardiovascular causes. Kaplan –Meier curves followed by a log-rank test showed that all-cause and cardiovascular mortality significantly increased in the highest two PTH quartiles (P , 0.001 for both; Figure 1A and B). In detail, there was a J-shaped ................................................................................................................................................... Parathyroid hormone, mortality, and fatal cardiovascular events PTH quartiles Parathyroid hormone levels were available in 3232 study participants and elevated PTH levels above 65 pg/mL which are indicative for hyperparathyroidism were observed in 174 patients (5.4%). Only three patients with hyperparathyroidism displayed hypercalcaemia, defined as serum calcium levels above 2.65 mmol/L, indicative for primary hyperparathyroidism. Clinical and laboratory baseline characteristics according to PTH quartiles are shown in Table 1. Coronary artery disease was ruled out in approximately one-third (31.9%) of the study population. Age, BMI, blood pressure, C-reactive protein, aldosterone, and NT-pro-BNP were significantly increased and triglycerides, GFR, haemoglobin, albumin, 25(OH)D, 1,25 (OH)2D, serum calcium, and serum phosphate were significantly decreased in higher PTH quartiles. Proportion of ex- and active smokers, patients with ACS, and use of beta-blockers were significantly reduced and females, higher NYHA classes, frequency of atrial fibrillation and ACS, and the use of ACE-inhibitors and diuretics were significantly increased in patients with higher PTH quartiles. Table 1 Baseline characteristics stratified by parathyroid hormone quartiles Results Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 diuretics, aspirin/other antiplatelet agent, and statins), ventricular dysfunction (NT-pro-BNP) (ng/mL), markers of malnutrition (haemoglobin in g/dL and albumin in g/dL), serum calcium (mmol/L), or 25(OH)D (ng/mL). A further model (Model 3) included all covariates of Model 2 plus various parameters of mineral metabolism (serum calcium, serum phosphate, 25[OH]D, and use of diuretics). We also calculated HRs for patients within the reference range of PTH (≤65 pg/mL) to test whether our findings also apply for individuals without hyperparathyroidism. In addition, we tested for interactions by adding product terms to the multivariable adjusted models (Model 2) in order to examine whether the association of PTH quartiles with mortality differs according to sex and the presence or absence of ACS, CAD, significant renal failure (defined as GFR ≤ 60 mL/min/1.73 m2), or vitamin D deficiency (defined as 25[OH]D below 20 ng/mL). Finally, we calculated the C statistic (equivalent to the area under the receiver operating characteristic curve) to assess the discriminative power of the multivariate adjusted model (Model 2) with and without PTH. A P-value , 0.05 was considered statistically significant and all statistical tests were two-sided. Data were analysed using SPSS 15.0 statistical package (SPSS Inc., Chicago, IL, USA). ............................................................................................................................................................................................................................................. Association of PTH level with increased cardiovascular research 1594 Table 1 Continued PTH quartiles ................................................................................................................................................... P-value 1st quartile 2nd quartile 3rd quartile 4th quartile Blood lipids (mg/dL) LDL-cholesterol HDL-cholesterol Trigylycerides GFR (mL/min per 1.73 m2) C-reactive protein (mg/L) Aldosterone (pg/mL) Coronary artery disease (%) 114 (95– 137) 37 (31 –44) 154 (112–217) 84.5 (73.2 – 95.0) 3.3 (1.2–8.1) 73 (45 –117) 67.7 115 (95– 138) 37 (32 –45) 141 (108– 197) 81.9 (71.6 – 93.5) 3.0 (1.2– 7.9) 75 (46 –119) 69.0 113 (93 –137) 38 (32 – 45) 145 (105– 191) 81.1 (70.7– 91.7) 3.2 (1.3– 8.5) 79 (46 – 121) 67.2 115 (93 –138) 37 (30– 45) 141 (108– 196) 76.1 (60.6– 89.0) 4.1 (1.5– 9.4) 86 (56– 143) 68.4 0.360 0.970 ,0.001 ,0.001 0.005 ,0.001 0.880 Number of vessels disease (%) No stenosis Single-vessel disease Two-vessel disease Three-vessel disease Acute coronary syndrome (%) History of MI (%) NT-pro-BNP (ng/mL) 32.3 19.5 17.9 30.3 33.6 42.1 213 (87– 559) 31.0 19.5 21.4 28.1 31.4 41.1 257 (97– 733) 32.8 18.7 18.5 30.0 30.7 38.5 312 (111– 847) 31.6 18.2 18.8 31.4 28.1 41.8 501 (177– 1888) 0.609 NYHA class (%) NYHA 1 NYHA 2 NYHA 3 NYHA 4 Atrial fibrillation (%) 59.1 25.9 12.8 2.3 7.4 56.2 26.3 14.8 2.7 8.4 49.6 32.5 15.2 2.7 15.0 42.2 32.2 21.4 4.2 18.1 ,0.001 Medication use (%) ACE-inhibitor Beta-blocker Aspirin/other platelet agent Statin Diuretics Haemoglobin (g/dL) Albumin (g/dL) 25(OH)D (ng/mL) 1,25(OH)2 D (pg/mL) Serum calcium (mmol/L) Serum phosphate (mg/dL) 49.6 65.6 71.0 49.0 21.4 14.0 + 1.5 4.4 (4.1–4.8) 19.0 (12.2 – 26.1) 33.4 (25.7 – 42.9) 2.35 (2.28 – 2.41) 3.6 (3.2–4.0) 53.5 64.3 74.5 48.1 24.3 13.9 + 1.4 4.3 (4.0– 4.7) 16.9 (11.5 – 23.6) 34.5 (26.4 – 44.0) 2.33 (2.26 – 2.40) 3.5 (3.2– 3.9) 51.7 65.5 72.0 45.3 26.2 13.8 + 1.5 4.3 (4.0– 4.8) 14.8 (9.8–21.7) 33.4 (25.5– 42.6) 2.32 (2.25– 2.38) 3.5 (3.1– 3.8) 58.6 57.1 66.9 45.1 43.8 13.6 + 1.5 4.3 (4.0– 4.7) 12.2 (7.7–18.4) 31.7 (23.5– 42.1) 2.31 (2.24– 2.38) 3.4 (3.0– 3.8) 0.001 0.002 0.058 0.061 ,0.001 ,0.001 0.030 ,0.001 0.001 ,0.001 ,0.001 ............................................................................................................................................................................................................................................. ............................................................................................................................................................................................................................................. 0.019 0.587 ,0.001 ............................................................................................................................................................................................................................................. ,0.001 ............................................................................................................................................................................................................................................. S. Pilz et al. Continuous data are presented as means + standard deviation and as medians with interquartile range and categorical data are shown as percentages. ANOVA with P for trend and x2 test were used. GFR, glomerular filtration rate; MI, myocardial infarction; NT-pro-BNP, N-terminal-pro-B-type natriuretic peptide; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D. Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 1595 Association of PTH level with increased cardiovascular research Figure 1 (A) Kaplan– Meier curves for all-cause mortality according to PTH quartiles. (B) Kaplan– Meier curve for cardiovascular mortality according to PTH quartiles. association with the lowest mortality risk in the second PTH quartile and a significantly increased mortality risk in the third PTH quartile and even more pronounced in the fourth PTH quartile. Unadjusted HRs (with 95% CI) for all-cause and cardiovascular mortality in the fourth (highest) PTH quartile when compared with the first (lowest) PTH quartile were 2.13 (1.75–2.60) and 2.47 (1.92– 3.17), respectively (Table 2). After adjustments for common cardiovascular risk factors, these HRs were attenuated to 1.71 (1.39–2.10) for all-cause mortality and 2.02 (1.55–2.63) for cardiovascular mortality. These HRs remained significant even after further adjustments for the use of medication, NT-pro-BNP, albumin and haemoglobin, serum calcium, 25(OH)D, or a combination of various parameters of mineral metabolism (Table 2). Adjustments for albumin-corrected serum calcium or aldosterone did also not materially change our results (data not shown). For allcause mortality, the C statistic for Model 2 was 0.759 (95% CI: 0.739–0.778) without PTH and 0.765 (0.746–0.785) with PTH. For cardiovascular mortality, the C statistic was 0.748 (0.724 – 0.771) without PTH and 0.758 (0.734–0.782) with PTH. After exclusion of patients with hyperparathyroidism defined as PTH levels above 65 pg/mL, the HRs in the fourth vs. the first PTH quartile remained significant for all-cause [1.49 (1.19–1.86)] and for cardiovascular mortality [1.74 (1.31–2.31)] after adjustments Discussion In patients referred to coronary angiography, PTH levels were significantly associated with all-cause and cardiovascular mortality. These results remained significant after adjustments for common cardiovascular risk factors and other possible confounders including parameters of mineral metabolism. Our findings were materially unchanged after excluding patients with hyperparathyroidism and the association of PTH with mortality was not significantly different in patients with or without CAD, ACS, significant renal disease, or vitamin D deficiency. Among specific cardiovascular events, we observed a particularly strong association of PTH with SCD. Our findings are in line with other studies which found an association of PTH and increased mortality.2,8 – 15 However, we are, to the best of our knowledge, the first to show (i) that PTH is associated with all-cause and cardiovascular mortality in a large cohort of patients referred to coronary angiography and (ii) that PTH is an independent risk factor for SCD.2,8 – 15 Given this strong association of PTH and cardiovascular risk in epidemiological studies, it could be hypothesized that PTH itself contributes to vascular and myocardial diseases. This notion is supported by the fact that vascular smooth muscle cells, endothelial cells, and cardiomyocytes are all target cells for PTH.1,21 Clinical studies showing associations of PTH levels or primary hyperparathyroidism with endothelial dysfunction, coronary heart disease, and carotid-intima media thickness suggest Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 for common cardiovascular risk factors (same adjustments as in Model 2 in Table 2). In analyses for all-cause mortality, there were no significant interactions of PTH quartiles with ACS (P ¼ 0.408), CAD (P ¼ 0.597), significant renal disease (P ¼ 0.259), and vitamin D deficiency (P ¼ 0.289). In subgroup analyses, adjusted HRs for allcause mortality (according to Model 2 in Table 2) in the fourth vs. the first PTH quartile were 1.87 (1.30–2.67) for patients with ACS (n ¼ 1003), 1.61 (1.25–2.08) for patients without ACS (n ¼ 2229), and 1.69 (1.25–2.29) for patients with stable CAD (no ACS but CAD; n ¼ 1248). For further adjusted HRs of the respective subgroup analyses see Figure 2A. In analyses for cardiovascular mortality, there were also no significant interactions of PTH quartiles with ACS (P ¼ 0.990), CAD (P ¼ 0.622), significant renal disease (P ¼ 0.304), and vitamin D deficiency (P ¼ 0.460). In subgroup analyses, adjusted HRs for cardiovascular mortality in the fourth vs. the first PTH quartile were 2.04 (1.48–2.81) for patients with ACS, 1.91 (1.20–3.06) for patients without ACS, and 2.01 (1.39– 2.90) for patients with stable CAD. For further adjusted HRs of the respective subgroup analyses see Figure 2B. In analyses of the entire study cohort for specific cardiovascular events, the HR adjusted (Model 2 in Table 2) for common cardiovascular risk factors in the fourth vs. the first PTH quartile was 2.68 (1.71– 4.22) for SCD, 1.85 (1.02–3.35) for fatal myocardial infarction, and 1.94 (1.15–3.25) for deaths due to heart failure. All of our results did not materially change, when males and females were analysed separately and there was no significant interaction by sex for the association of PTH quartiles with all-cause mortality (P ¼ 0.842) and cardiovascular mortality (P ¼ 0.965). 1596 S. Pilz et al. Table 2 Hazard ratios with 95% confidence intervals for all-cause and cardiovascular mortality according to parathyroid hormone quartiles PTH quartiles 1st quartile 2nd quartile 3rd quartile 4th quartile Range of values (pg/mL) ,23 23–29 30– 40 .40 Study participants at risk 877 738 843 756 Number of deaths Mean survival in years (+SE) 158 (18.0%) 8.46 + 0.08 125 (16.9%) 8.61 + 0.08 200 (23.7%) 8.13 + 0.09 259 (34.3%) 7.43 + 0.12 Crude model 1.0 reference 0.92 (0.73–1.17) 1.36 (1.11–1.68) 2.13 (1.75– 2.60) Model 1a Model 2b 1.0 reference 1.0 reference 0.82 (0.65–1.04) 0.94 (0.74–1.19) 1.07 (0.87–1.32) 1.24 (1.00–1.54) 1.54 (1.26– 1.88) 1.71 (1.39– 2.10) Model 2 plus medication usec 1.0 reference 0.95 (0.75–1.21) 1.27 (1.03–1.58) 1.48 (1.20– 1.83) Model 2 plus NT-pro-BNP Model 2 plus albumin and haemoglobin 1.0 reference 1.0 reference 0.92 (0.73–1.16) 1.01 (0.78–1.30) 1.21 (0.97–1.50) 1.23 (0.98–1.56) 1.51 (1.22– 1.86) 1.76 (1.40– 2.20) Model 2 plus serum calcium 1.0 reference 0.95 (0.75–1.21) 1.26 (1.02–1.57) 1.74 (1.41– 2.15) Model 2 plus 25-hydroxyvitamin D Model 3d 1.0 reference 1.0 reference 0.90 (0.71–1.14) 0.93 (0.73–1.18) 1.14 (0.92–1.41) 1.19 (0.96–1.48) 1.38 (1.12– 1.71) 1.36 (1.09– 1.69) ............................................................................................................................................................................... ............................................................................................................................................................................... All-cause mortality Cardiovascular mortality Study participants at risk 873 734 835 748 Number of deaths Mean survival in years (+SE) 94 (10.8%) 8.86 + 0.07 70 (9.5%) 8.98 + 0.06 124 (14.9%) 8.54 + 0.08 179 (23.9%) 7.93 + 0.11 Crude model 1.0 reference 0.87 (0.64–1.19) 1.42 (1.09–1.86) 2.47 (1.92– 3.17) Model 1a Model 2b 1.0 reference 1.0 reference 0.78 (0.57–1.07) 0.91 (0.67–1.25) 1.14 (0.87–1.49) 1.35 (1.03–1.78) 1.81 (1.41– 2.34) 2.02 (1.55– 2.63) Model 2 plus medication usec 1.0 reference 0.93 (0.68–1.28) 1.40 (1.06–1.84) 1.76 (1.35– 2.29) Model 2 plus NT-pro-BNP Model 2 plus albumin and haemoglobin 1.0 reference 1.0 reference 0.89 (0.65–1.21) 0.98 (0.70–1.37) 1.31 (0.99–1.73) 1.36 (1.01–1.84) 1.77 (1.35– 2.31) 2.09 (1.57– 2.78) Model 2 plus serum calcium 1.0 reference 0.93 (0.68–1.28) 1.39 (1.06–1.84) 2.10 (1.61– 2.74) Model 2 plus 25-hydroxyvitamin D Model 3d 1.0 reference 1.0 reference 0.88 (0.64–1.20) 0.91 (0.66–1.24) 1.26 (0.95–1.66) 1.32 (1.00–1.75) 1.66 (1.27– 2.17) 1.65 (1.25– 2.17) a Adjusted for age and sex. Additionally adjusted for body mass index, ex- and active smokers, HbA1c, systolic blood pressure, glomerular filtration rate (GFR), LDL- and HDL-cholesterol, triglycerides, C-reactive protein, number of diseased vessels. c Use of ACE-inhibitors, beta-blockers, diuretics, aspirin/other antiplatelet agent, and statins. d Model 3 includes all covariates of Model 2 plus serum calcium, serum phosphate, 25-hydroxyvitamin D, and use of diuretics. b pro-atherosclerotic properties of PTH.1,2,5 – 7,21,22 It should, however, be acknowledged that the underlying mechanism for these pro-atherosclerotic effects of PTH remain largely unknown. An association of PTH levels with atherosclerosis was not consistently observed in all studies,1,2,22 including our study which failed to show a significant association of PTH levels and angiographic CAD (Table 1). Another proposed mechanism linking PTH to cardiovascular diseases may be arterial hypertension because PTH infusions increased blood pressure in healthy volunteers and PTH was an independent determinant of blood pressure in a population-based study.1,3,23 We also observed an association of PTH levels with elevated blood pressure in the LURIC study. After controlling for blood pressure and use of antihypertensive medication, the association of PTH with increased cardiovascular risk remained significant suggesting other mechanisms than hypertension mediating the relationship of PTH levels and fatal cardiovascular events. Direct effects of PTH on cardiomyocytes may be mechanistically relevant for our mortality results because PTH induces myocardial hypertrophy, increases heart rate and automaticity, and may thus increase the risk of cardiac arrhythmias and fatal cardiovascular events.24,25 In line with this, McCarty et al.24 hypothesized that PTH-induced activation of phospholipase C (PLC) may increase arrhythmias by generation of inositol-1,4,5-triphosphate, which has been associated with reperfusion arrhythmias, likewise by increasing calcium release from the sarcoplasmatic reticulum. The association of PTH with atrial fibrillation and SCD in the LURIC study fits well to the concept that PTH increases the risk for arrhythmias. Apart from this, we observed an association of PTH with NT-pro-BNP and higher NYHA class suggesting a link between PTH and heart failure. This is consistent with studies showing that PTH levels are increased in patients with heart failure and are an independent predictor of hospitalization for heart failure.26,27 Assuming a causal relationship of PTH and Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 ............................................................................................................................................................................... 1597 Association of PTH level with increased cardiovascular research heart failure, it was speculated that elevated PTH levels contribute to a systemic illness that accompanies heart failure and is characterized by increased oxidative stress, a pro-inflammatory state with elevated IL-6 and TNF-a levels and a catabolic state.26,28 It should, however, be noted that increases in PTH in patients with heart failure are often simply a consequence of increased urinary calcium loss due to both the use of diuretics and secondary hyperaldosteronism.28 Furthermore, there is evidence that PTH exerts Acknowledgements We thank the LURIC study team either temporarily or permanently involved in patient recruitment and sample and data handling and the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg, Ulm and Graz and the German registration offices and local public health departments for their assistance. Funding The LURIC study was funded by grants from the Deutsche Forschungsgemeinschaft (GRK 1041 and SFB 518) and Exzellenzzentrum Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 Figure 2 (A) Forest plots of Cox proportional hazard ratios with 95% CI (adjusted for cardiovascular risk factors) for all-cause mortality in the fourth vs. the first PTH quartile. Results are shown for all study participants and for subgroups stratified by the presence of coronary artery disease, acute coronary syndrome, significant renal disease (defined as GFR ≤60 mL/min/ 1.73 m2) and vitamin D deficiency (defined as 25[OH]D levels ,20 ng/mL). (B) Forest plots of Cox proportional hazard ratios with 95% CI (adjusted for cardiovascular risk factors) for cardiovascular mortality in the fourth vs. the first PTH quartile. Results are shown for all study participants and for subgroups stratified by the presence of coronary artery disease, acute coronary syndrome, significant renal disease (defined as GFR ≤60 mL/min/ 1.73 m2) and vitamin D deficiency (defined as 25[OH]D levels ,20 ng/mL). inotropic effects and improves contractile performance of cardiomyocytes.1,29 Hence, the association of PTH with heart failure is a complex interplay of various harmful and beneficial PTH effects on myocardial structure and function that need to be further clarified in detail. Given the relatively strong and independent association of PTH with increased risk of mortality and fatal cardiovascular events, we believe that further studies are needed to elucidate whether PTH modifying therapies such as vitamin D supplementation, calcium intake, or treatment with calcimimetics (CaSR agonists) improve the clinical outcome of patients at high cardiovascular risk and with elevated or high normal PTH levels. In our opinion, in particular, vitamin D supplementation is a promising therapeutic approach. Apart from lowering PTH levels, vitamin D is suggested to exert numerous beneficial effects on the cardiovascular system, prevents fractures and falls, and may reduce other diseases such as infections and cancer.17,30 – 33 Importantly, treatment of secondary hyperparathyroidism has already been shown to improve the clinical outcome of patients with renal failure.2 We are aware that in the LURIC study, GFR decreased with higher PTH quartiles suggesting beginning (renal) secondary hyperparathyroidism, but our results remained materially unchanged after adjustment for GFR. Importantly, our data suggest that PTH is a risk factor for cardiovascular diseases in both patients with and without significant renal disease (Figure 2A and B). A limitation of the present work is that our results apply only to carefully selected patients undergoing coronary angiography and without predominant non-cardiac disease or malignancy. Our findings may therefore not be generalizable. Furthermore, despite careful adjustments for several possible confounders we cannot rule out residual confounding. On the other hand, our statistical models may also be over-adjusted because some covariates might lie in the causal pathway of deleterious PTH effects. Another drawback of our work is that we did not measure both parathyroid hormone-related peptide (PTH-rP),21 a structuralrelated peptide which shares some effects with PTH, as well as fibroblast growth factor-23 (FGF-23), which predicts mortality and prevents hyperphosphataemia by suppressing PTH and 1,25-dihydroxyvitamin D.34,35 In summary, we have shown that PTH even within the normal range is associated with mortality and fatal cardiovascular events in patients undergoing coronary angiography. Further studies are needed to elucidate the underlying mechanisms for our results and to evaluate whether PTH modifying therapies reduce cardiovascular risk. 1598 ‘Stoffwechselkrankheiten’ Baden-Württemberg to B.O.B. The LURIC study was also supported by unrestricted grants from Sanovi-Aventis, Roche, Dade Behring and AstraZeneca. S. Pilz et al. 19. Conflict of interest: Roche Diagnostics provided reagents for the measurement of PTH, but did not assume any other role in the design, conduct, or interpretation of this study. References 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Downloaded from eurheartj.oxfordjournals.org at UNIVERSITAT DE LLEIDA on July 20, 2010 1. Fitzpatrick LA, Bilezikian JP, Siverberg SJ. Parathyroid hormone and the cardiovascular system. Curr Osteoporos Rep 2008;6:77– 83. 2. Fraser WD. Hyperparathyroidism. Lancet 2009;374:145 –158. 3. Snijder MB, Lips P, Seidell JC, Visser M, Deeg DJ, Dekker JM, van Dam RM. Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med 2007;261: 558 –565. 4. Saleh FN, Schirmer H, Sundsfjord J, Jorde R. Parathyroid hormone and left ventricular hypertrophy. Eur Heart J 2003;24:2054 –2060. 5. Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromso Study. Eur J Cardiovasc Prev Rehabil 2004; 11:69 –74. 6. Choi HS, Kim SH, Rhee Y, Cho MA, Lee EJ, Lim SK. Serum parathyroid hormone is associated with carotid intima-media thickness in postmenopausal women. Int J Clin Pract 2008;62:1352 –1357. 7. Walker MD, Silverberg SJ. Cardiovascular aspects of primary hyperparathyroidism. J Endocrinol Invest 2008;31:925 –931. 8. Drechsler C, Krane V, Grootendorst DC, Ritz E, Winkler K, März W, Dekker F, Wanner C, German Diabetes and Dialysis Study Investigators. The association between parathyroid hormone and mortality in dialysis patients is modified by wasting. Nephrol Dial Transplant 2009;24:3151 –3157. 9. Sambrook PN, Chen JS, March LM, Cameron ID, Cumming RG, Lord SR, Schwarz J, Seibel MJ. Serum parathyroid hormone is associated with increased mortality independent of 25-hydroxyvitamin D status, bone mass, and renal function in the frail and very old: a cohort study. J Clin Endocrinol Metab 2004;89: 5477 –5481. 10. Björkman MP, Sorva AJ, Tilvis RS. Elevated serum parathyroid hormone predicts impaired survival prognosis in a general aged population. Eur J Endocrinol 2008; 158:749–753. 11. Chen JS, Sambrook PN, March L, Cameron ID, Cumming RG, Simpson JM, Seibel MJ. Hypovitaminosis D and parathyroid hormone response in the elderly: effects on bone turnover and mortality. Clin Endocrinol 2008;68:290 –298. 12. Premaor MO, Scalco R, da Silva MJ, Furlanetto TW. Secondary hyperparathyroidism is associated with increased risk of hospitalization or death in elderly adults living in a geriatric institution. Gerontology 2009;55:405 –410. 13. Hagström E, Hellman P, Larsson TE, Ingelsson E, Berglund L, Sundström J, Melhus H, Held C, Lind L, Michaelsson K, Ärnlöv J. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation 2009;119:2765 – 2771. 14. Fisher A, Goh S, Srikusalanukul W, Davis M. Elevated serum PTH is independently associated with poor outcomes in older patients with hip fracture and vitamin D inadequacy. Calcif Tissue Int 2009;85:301–309. 15. Björkman M, Sorva A, Tilvis R. Parathyroid hormone as a mortality predictor in frail aged inpatients. Gerontology 2009;55:601 –606. 16. Winkelmann BR, März W, Boehm BO, Zotz R, Hager J, Hellstern P, Senges J, LURIC Study Group (LUdwigshafen RIsk, Cardiovascular Health). Rationale and design of the LURIC study: a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001;2:1 –73. 17. Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 2008;93:3927 – 3935. 18. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G, National Kidney Foundation. National kidney foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137 – 147. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association, the Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—executive summary: a report of the American College of cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J 2006;27:2099 – 2140. Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, Ilias N, Vickers C, Dogra V, Daya M, Kron J, Zheng ZJ, Mensah G, McAnulty J. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol 2004;44: 1268 –1275. Schlüter KD, Piper HM. Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide. Cardiovasc Res 1998;37:34 –41. Reis JP, von Mühlen D, Michos ED, Miller ER 3rd, Appel LJ, Araneta MR, Barrett-Connor E. Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis 2009;207:585–590. Hulter HN, Melby JC, Peterson JC, Cooke CR. Chronic continuous PTH infusion results in hypertension in normal subjects. J Clin Hypertens 1986;2:360 –370. McCarty MF, Barroso-Aranda J, Contreras F. Can moderate elevations of parathyroid hormone acutely increase risk for ischemic cardiac arrhythmias? Med Hypotheses 2009;72:581–583. Hara M, Liu YM, Zhen L, Cohen IS, Yu H, Danilo P Jr, Ogino K, Bilezikian JP, Rosen MR. Positive chronotropic actions of parathyroid hormone and parathyroid-hormone-related peptide are associated with increases in the current, I(f), and the slope of the pacemaker potential. Circulation 1997;96: 3704 –3709. Khouzam RN, Dishom DA, Farah V, Flax SD, Carbone LD, Weber KT. Secondary hyperparathyroidism in patients with untreated and treated congestive heart failure. Am J Med Sci 2006;331:30– 34. Sugimoto T, Tanigawa T, Onishi K, Fujimoto N, Matsuda A, Nakamori S, Matsuoka K, Nakamura T, Koji T, Ito M. Serum intact parathyroid hormone levels predict hospitalisation for heart failure. Heart 2009;95:395 –398. Weber KT. The proinflammatory heart failure phenotype: a case of integrative physiology. Am J Med Sci 2005;330:219 –226. Tastan I, Schreckenberg R, Mufti S, Abdallah Y, Piper HM, Schlüter KD. Parathyroid hormone improves contractile performance of adult rat ventricular cardiomyocytes at low concentrations in a non-acute way. Cardiovasc Res 2009;82: 77 –83. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol 2008;52:1949 –1956. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol 2009;6:621 – 630. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266 –281. Bikle DD. Vitamin D and the immune system: role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008;17:348 –352. Karjisnik T, Björklund P, Marsell R, Ljunggren Ö, Akerström G, Jonsson KB, Westin G, Larsson TE. Fibroblast growth factor-23 regulates parathyroid hormone and 1a-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007;195:125 –131. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shan A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584 –592.