Download Parathyroid hormone level is associated with mortality and

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].
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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,
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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
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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.
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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
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...............................................................................................................................................................................
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.
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