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Relationships between Myocardial Injury, All-cause Mortality, Vitamin D, PTH, and Biochemical Bone Turnover Markers in Older Patients with Hip Fractures

Address correspondence to Alexander A. Fisher, M.D., Ph.D., Department of Geriatric Medicine, e Canberra Hospital, Yamba Drive, Garran, ACT 2606, Australia; tel 61 2 6244 2577; fax 61 2 6244 4036; e-mail alex.fisher{at}act.gov.au.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgement References

 
This study examined the relationships between myocardial injury as indicated by serum cardiac troponin I (cTnI) elevation, 25 hydroxyvitamin D [25(OH)D], and PTH status and biochemical markers of bone metabolism in older patients with hip fracture (HF). In 238 consecutive patients (mean age 81.9 ± 7.8 yr; 72% women) with low trauma HF, serum concentrations of cTnI, 25(OH)D, PTH, calcium, phosphorus, magnesium, osteocalcin, bone-specific alkaline phosphatase (BAP), and urine excretion of free deoxypyridinoline (DPD) and N-terminal cross-linked teleopeptide of type I collagen (NTx) were measured and clinical data were collected prospectively. Myocardial injury (cTnI >0.06 µg/L) presented in 29%, 25(OH)D deficiency (<50 nmol/L) in 81.6%, elevated PTH (>6.5 pmol/L) in 53%, and excessive bone resorption (increased DPD and/or NTx excretion) in 93.7%. Multivariate logistic regression showed that elevated serum PTH level is a major predictor of peri-operative myocardial injury (OR = 2.13; 95% CI 1.01–4.51; p = 0.049) and in-hospital all-cause mortality (OR = 18.5; 95% CI 2.0–72.3; p = 0.010), independent of age, sex, 25(OH)D status, and comorbidities. The degree of hyperparathyroidism was associated with the risk of cTnI elevation and the mortality rate. In cTnI positive patients, PTH levels correlated with cTnI concentrations (r = 0.28; p = 0.026) and urine DPD exretion (r = 0.37; p = 0.004). These results suggest for the first time that in older patients with HF, elevated PTH level is associated with peri-operative myocardial injury and in-hospital all-cause mortality, and that elevated PTH level contributes to both disturbed bone metabolism and poor outcomes.

Keywords: cardiac troponin I, vitamin D, PTH, bone turnover markers, hip fracture, mortality

	Introduction

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Cardiovascular diseases and complications are the main causes of morbidity and mortality in older patients undergoing hip fracture (HF) surgery [1,2]. Peri-operative myocardial ischaemia occurs in 35–42% of these patients [3] and cardiovascular events contribute to 50–63% of their in-hospital deaths [4,5].

Osteoporotic fractures, inadequacy in vitamin D and PTH status, and cardiovascular disease are all common in older people and frequently seen in the same patient. However, the understanding of pathophysiological links among these conditions remains incomplete, with conflicting data concerning their clinical significance. Insufficient vitamin D status and hyperparathyroidism contribute not only to impaired bone metabolism but have the potential to affect the cardiovascular system.

There is strong evidence that hyperparathyroidism is causally related to cardiovascular morbidity and mortality in patients with chronic renal disease [6–8]. Although in older patients with osteoporotic HF the association between impaired vitamin D – PTH axis and cardiovascular disease has not been evaluated, several lines of evidence point to a possible relationship. These include associations between osteoporosis and vascular calcification, between low bone mineral density and increased all-cause and cardiovascular mortality as well as nonfatal cardiovascular events [9,10]. Recent studies show that low vitamin D levels and elevated PTH levels are associated with cardiovascular disease [11,12] and mortality [13].

These data taken together raise the possibility that alterations in circulating levels of calciotropic hormones (vitamin D, PTH) may simultaneously affect bone mineralization and cardiovascular function. Thus, it is reasonable to hypothesize that in older patients with HF, altered vitamin D – PTH status could be associated with myocardial damage and mortality, especially in the peri-operative period. There have been no studies of the relationships between myocardial injury, fatal outcome, vitamin D, PTH, and biochemical markers of bone metabolism in this population.

The aim of the present study was to examine the associations between cardiac troponin I (cTnI), a highly specific and sensitive indicator of myocardial injury [14], vitamin D – PTH status, and biochemical markers of bone metabolism in older patients with HF. We also evaluated the relation of PTH and vitamin D to in-hospital all-cause mortality. We hypothesized that secondary hyperparathyroidism and/or vitamin D inadequacy would be related to a higher prevalence of myocardial injury, as well as all-cause mortality.

	Materials and Methods

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Patients.  The study population consisted of 238 consecutive patients with low-trauma HF (age 60 yr, 172 females and 66 males) admitted to e Canberra Hospital, a tertiary teaching hospital, during an 18-mo period (July 2004 to December 2005). The characteristics of the study population are shown in Table 1. The study protocol was reviewed and approved by the local Ethics Committee and written informed consent was obtained from all patients.

Blood and urine sampling.  In each patient blood and second morning urine samples were collected after a 12-hr overnight fast. In all patients the samples were obtained within 72 hr (89% within 48 hr) after arrival at the Emergency Department. In 182 (76.5%) patients, the samples were collected postoperatively. Routine hematological and chemical parameters were analysed immediately. Centrifuged plasma was filtered and serum samples were stored at –70°C for 1.5 yr before analysis for cardiac troponin I (cTnI), osteocalcin (OC), and bone-specific alkaline phosphatase (BAP) (bone formation biomarkers). cTnI is stable in specimens frozen for up to 3 yr [15]. The bone resorption markers, N-terminal cross-linked telopeptide of type 1 collagen (NTx), and free deoxypyridinoline (DPD) were determined in urine samples. Biochemical markers of bone turnover and serum cTnI levels were determined simultaneously.

Biochemical analyses.  Serum cTnI, 25(OH) vitamin D, PTH, and bone metabolism markers in serum and urine were measured using commercially available kits according to the manufacturers’ protocols. Serum cTnI was determined by a 2-step chemiluminescent microparticle immunoassay (Chemiflex, Abbott Labs, Mississauga, Ontario, Canada), 25 (OH)D by a radioimmunoassay kit (Dia Sorin, Stillwater, MN, USA), intact PTH by 2-site chemiluminescent enzyme-linked immunoassay on DPC Immulite 2000 (Diagnostic Products, Los Angeles, CA), serum osteocalcin (OC) by electrochemiluminescent immunoassay (Elecsys 1010, Roche Diagnostics, Indianapolis, IN, USA), serum bone-specific alkaline phosphatase (BAP) by Metra BAP ELISA (Quidel, San Diego, CA, USA), urinary cross-linked N-teleopeptide of type I collagen (NTx) by ELISA (Wampole Labs, Princeton, NJ, USA), and urinary deoxypyridinoline (DPD) by 2-site chemiluminescent enzyme-labeled immunoassay (DPC Immulite 2000, Diagnostic Products, Los Angeles, CA).

According to the manufacturer, the low detection limit for cTnI assay is 0.03 µg/L and the upper limit of reference range is 0.06 µg/L. In this study all values of cTnI above this level were considered elevated, indicating myocardial injury. All results for urinary bone turnover markers were normalized to urinary creatinine (Cr) concentration (mmol/L). Serum total calcium, phosphate, magnesium, albumin, creatinine, urea nitrogen, thyroid stimulating hormone (TSH), and thyroxine (T4) were measured by standard automated laboratory methods. Serum calcium concentrations were corrected for serum albumin: corrected calcium (mmol/L) = measured calcium (mmol/L) + 0.015 x [44 – patient’s albumin (g/L)]. Glomerular filtration rate (GFR) was estimated by the formula developed by Levey et al [16]. All assays were measured blind to any clinical information. For the purpose of analyses, deficiency of vitamin D was defined as 25(OH)D <50nmol/L based on current Australian guidelines [17]. For PTH levels and bone turnover markers, we used the usual (standard) laboratory reference ranges.

Statistical Analyses.  Continuous data are given as means ± SD and discrete variables are given as absolute and/or relative frequencies (%). To test differences between groups (with and without cTnI elevation), the chi-square statistic, Fisher’s exact test, or 2-way analysis of variance (ANOVA) were used for discrete variables and unpaired t-test for continuous, normally distributed variables. A 2-sided p value <0.05 was considered significant. PTH values were normalized by logarithmic transformation. Logistic regression analyses and Pearson’s correlation coefficient were used to assess interrelationships. Unadjusted odds ratios (OR) and 95% confidence intervals (CI) for serum cTnI and PTH concentrations above upper reference limit (>0.06 µg/L and >6.5 pmol/L, respectively) were obtained by logistic regression on clinical and biochemical variables. Because of the interdependence of many of these parameters, to investigate the independent effect of clinical and laboratory variables on cTnI and mortality, a multivariate logistic approach was used. Variables with p <0.20 in the univariate analysis were included in the multivariate models Statistical analyses were performed using Stata software (version 7, Stata Corp, College Station, TX, USA).

	Results

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cTnI elevation and clinical parameters.  Of 238 older patients with low-trauma HF, 69 (29%) had peri-operatively elevated cTnI. The mean cTnI level was 0.63 ± 1.50 µg/L (range 0.07–11.8 µg/L). Only 24 (34.8%) of 69 patients with elevated cTnI had a history of coronary artery disease (CAD). Patients with elevated cTnI were significantly older (85.1 ± 6.5 vs 80.5 ± 8.0 yr; p = 0.001), more often had a history of CAD (34.8% vs 14.3%; p = 0.001), a history of stroke (22.3% vs 8.4%; p = 0.007), an esimtated GFR <60 ml/min (57.6% vs 42.4%; p = 0.02), an ASA score > 3 (88.2% vs 67.2%; p= 0.007), and more often were current smokers (9.1% vs 1.2%; p = 0.008). There were no differences between the two groups in gender, type of HF, types of surgery and anesthesia, other comorbidities, residential status, or medications.

Multivariate logistic regression showed that of all clinical parameters only age was an independent and significant predictor of cTnI elevation: for each 5 yr from age of 60, OR = 1.49 (95% CI 1.21–1.84; p = 0.001). cTnI >1 µg/L was strongly associated with all-cause in-hospital mortality. After adjusting for age, sex, history of CAD, history of stroke, dementia, ASA score, GFR, smoking, medications, and timing of cTnI measurement (pre-or postoperative), patients with cTnI >1 µg/L vs those with cTnI level <1 µg/L had 16-fold higher mortality risk (OR = 15.9; 95% CI 2.6–97.1; p = 0.003).

Multivariate regression analysis also revealed a significant association between peri-operative cTnI elevation and prolonged hospital stay (>20 days) (OR = 2.2; 95% CI 1.01–4.74; p = 0.047) and being discharged to long-term residential care (OR = 2.74; 95% CI 1.24–6.06; p = 0.013).

cTnI and vitamin D – PTH status.  Serum PTH levels in patients with elevated cTnI were significantly increased compared to the rest of the cohort while the difference in mean 25(OH)D concentrations was not statistically significant (Table 2). In the cTnI positive group, serum PTH concentration was elevated (>6.5 pmol/L) in 53% of patients, with levels >15 pmol/L in 15.4%, while in the cTnI negative group these were observed in 34.2% and 4.2% respectively (analysis of variance p = 0.004). Increased PTH levels after adjusting for age and gender accounted for 70.3% of variance in cTnI. No differences were seen between the two groups in the incidence and degree of vitamin D deficiency: 25(OH)D <50 nmol/L presented in 85.9% of cTnI-positive and 80.1% of cTnI-negative patients.

The incidences of abnormal levels of bone turnover markers in patients with and without cTnI elevation did not differ significantly. Excessive bone resorption (increased DPD and/or NTx excretion) presented in 98.4% of cTnI-positive patients and in 91.7% cTnI-negative patients (p = 0.134).

Correlation between cTnI, PTH, 25(OH)D, and parameters of bone and mineral metabolism.  There was significant positive correlation between serum cTnI and PTH concentrations in the total study population (r = 0.25; p = 0.001) (Table 4). A subgroup analysis of cTnI positive patients showed a similar relationship between cTnI and PTH levels (r = 0.28; p = 0.026). In this group serum PTH levels correlated significantly with values of urine DPD excretion (r = 0.37; p = 0.004) and negatively with serum calcium corrected for albumin concentration (r = –0.29; p = 0.018). We found no statistically significant correlations between cTnI levels and 25(OH)D values, nor any bone turnover marker or serum calcium, phosphorus, and magnesium concentrations in the whole study population (Table 4) nor in the group with cTnI elevation (not shown).

Multivariate analysis of predictors of cTnI elevation.  Univariate analysis revealed that of all clinical and biochemical parameters analysed only the following 6 variables were significantly associated with cTnI elevation: PTH >6.5 nmol/L, older age, ASA score >3, history of CAD, history of stroke, and current smoking (Table 5). When multiple linear regression analysis was performed using cTnI elevation as dependent variable and all parameters with p <0.20 in the univariate analysis as independent variables, only older age and elevated PTH level were significant independent predictors of peri-operative myocardial injury (Table 5). Multivariate analysis showed that risk of myocardial injury, as reflected in cTnI elevation, increased 113% in persons with serum PTH levels >6.5 pmol/L, and by 54% for every 5 yr of age (from age 60 yr). There was a synergistic effect when two factors presented simultaneously. For example, in patients with elevated PTH levels, every 5 yr of age (starting from 60 yr) carried an excess risk of myocardial injury of 228% (OR = 3.28; 95% CT 1.46–7.36; p = 0.004); co-existing ASA score >3 had a 267% excess risk (OR = 3.67; 95% CT 1.06–12.68; p = 0.040); and co-existing history of CAD had a 231% excess risk (OR = 3.31; 95% CT 1.08–10.11; p = 0.035).

The risk of fatal in-hospital outcome was about 10-times higher in patients with PTH level >5.4 pmol/L (median value) (OR = 9.91; 95% CI 1.24–79.48; p = 0.031) and 16 times higher in patients with PTH level >6.5 pmol/L (OR = 15.83; 95% CI 1.97–127.16; p = 0.009) compared to subjects with serum PTH concentrations <5.4 pmol/L and 6.5 pmol/L, respectively. After adjusting for age, sex, ASA score, history of CAD, history of stroke, cTnI elevation, 25(OH)D status (<50 nmol/L), and estimated glomerular filtration rate (<60 ml/min), patients with PTH >6.5 pmol/L vs those with PTH 6.5 pmol/L had a 18.5-fold increase in mortality risk from any cause (OR = 18.5; 95% CI 2.0–172.3; p = 0.010). A cut-off value of PTH >6.5 pmol/L for predicting in-hospital mortality has 90% sensitivity, 63.8% specificity, and 99.3% negative predictive value.

	Discussion

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The most striking finding of our study is that in older patients with osteoporotic HF, elevated serum PTH level is a major independent predictor of peri-operative myocardial injury and in-hospital all-cause mortality. Hyperparathyroidism may be the common pathophysiological mechanism contributing to both poorer outcome and increased bone resorption.

In our cohort of 238 consecutive older HF patients, elevated PTH levels were present in 53%, which is in accordance with many previous studies [18–20], but not all [21,22]. The 29% prevalence of peri-operative myocardial injury defined as serum cTnI >0.06 µg/L in our study agrees with previous observations [23]. However, only 35% of our patients with this complication had been diagnosed with CAD pre-operatively. It is intriguing that multivariate analyses demonstrated that elevated serum PTH level is an independent factor in myocardial injury and all-cause mortality and is more important than the usual risk factors for cardiovascular disease. Loss of integrity of cardiac myocyte membranes causes release into the circulation of cTnI, a low-molecular-weight protein that is part of the troponin complex and an integral component of the myofibrillar contractile apparatus. Increased serum cTnI concentrations occur in acute coronary syndrome and in a wide range of other clinical settings [15,24,25]. PTH has many effects on the cardiovascular system [26] and hyperparathyroidism could cause and/or predispose to myocardial damage even in the absence of overt CAD [27,28].

Previous studies demonstrated that osteoporosis is associated with increased risk for acute cardiovascular events and poorer short and long-term outcomes [9,10]. However, one study reported that in postmenopausal women with known CAD, the risk of coronary events was lower in those who had postmenopausal fractures [29]. The underlying mechanisms by which osteoporosis and cardiovascular disease may be linked are unclear. Common risk factors for cardiovascular disease (age, hypertension, smoking, diabetes, dyslipidemia, family history), which are also associated with increased fracture risk [30], estrogen deficiency, low-grade inflammation, or hyperhomocysteinemia, have each been suspected as a pathogenic factor linking osteoporosis and cardiovascular disease, but could not explain the complex relationship of these two diseases.

There is growing evidence that inadequate vitamin D – PTH status, which is common in patients with osteoporotic fractures, may contribute to cardiovascular disease and subsequent mortality. However, it is unknown whether altered vitamin D status or secondary hyperparathyroidism, both of which may influence cardiac and vascular function, contribute to an increased prevalence of cardiovascular morbidity and mortality. No study had investigated the association of PTH, vitamin D, and peri-operative myocardial injury and inhospital mortality in HF patients. We found that patients with serum PTH >6.5 pmol/L have a 113% greater risk of peri-operative myocardial injury (manifested by elevated cTnI) and 18.5-fold increased risk of in-hospital death compared to patients with PTH 6.5 pmol/L after adjusting for confounding factors. In the multivariate model of cTnI elevation, the only significant predictor other than PTH was age. When elevated PTH presented simultaneously with higher age, ASA score >3, or history of CAD, the risk of myocardial injury increased about 3-times (synergistic effect). In common with previous studies [31], we found a significant relationship between PTH and age. However, elevated PTH remained an independent predictor of both myocardial injury and in-hospital mortality after controlling for age. Moreover, there was positive correlation between serum PTH and cTnI concentrations, as well as association between the degree of hyperparathyroidism, the risk of cTnI elevation, and the mortality rate. From a clinical perspective, elevated PTH level has moderate sensitivity (78%) and positive predictive value (65.9%) for myocardial injury and high sensitivity (90%) and high negative predictive value (99.3%) for in-hospital all-cause mortality.

These results collectively suggest that increases in PTH, but not low 25(OH)D levels per se, have an important impact on peri-operative myocardial injury in older HF patients and may precipitate fatal outcome. Some [32,33] but not all [34] previous studies found raised serum PTH levels in acute myocardial infarction. Increased serum PTH levels have been associated with poor outcome in critically ill patients [35,36]. Our findings are consistent with these observations and with a recent study, which found that in frail older people living in residential care facilities, mild secondary hyperparathyroidism was a significant predictor of all-cause mortality independent of vitamin D status and renal function, two main determinants of elevated PTH in this population [13].

The precise mechanism(s) through which elevated PTH affects myocardium and precipitates fatal events remain(s) unknown. In animal studies, PTH and structurally related peptide (PTH-rP) have been shown to influence cardiomyocyte and vascular smooth muscle cell physiology [26,37,38]. Elevated PTH levels have been implicated in development of vascular calcification, which may explain the accelerated atherosclerosis observed in osteoporotic patients. There is good evidence that primary hyperparathyroidism [27] and secondary hyperparathyroidism in patients with end stage renal failure [6,8,28] are both associated with structural and functional alterations in myocardium and vascular wall, hypertension, arrhythmias, and disturbances in the renin-angiotension-aldosterone system and that these contribute to the high cardiovascular morbidity and mortality. However, the increases in serum PTH levels secondary to vitamin D deficiency in older persons with osteoporotic fractures are not as high as in chronic renal disease and usually there is no significant disturbance in mineral metabolism, as has been shown in the present and previous studies.

Our study reports for the first time a strong association between serum PTH levels and outcomes in older HF patients independent of age, gender, vitamin D status, and clinical variables including renal impairment. This provides further evidence that even mildly elevated PTH plays an important role in the pathogenesis of cardiovascular dysfunction, including peri-operative myocardial injury and all-cause mortality. Our data are consistent with epidemiological observations that increased serum PTH levels are associated with hypertension, CAD, and left ventricular hypertrophy in the general population [39], as well as serious clinical consequences and poor outcomes in patients with chronic renal disease [6,8,28].

Circulating 25(OH)D levels, the hallmark for determining the vitamin D status, were insufficient in the majority of our patients (86%) as in other studies [19,31,40,41]. Given the multiple biological calcemic and noncalcemic (immunomodulation, antiproliferative, and anti-inflammatory) effects of vitamin D and results of observational studies that demonstrate that vitamin D deficiency is associated with high morbidity (cardiovascular, autoimmune, malignant) and mortality [42], it is difficult to completely separate the pathophysiological role of low serum 25(OH)D and elevated PTH. Our data suggest that in older HF patients in whom vitamin D insufficiency is almost universal, the peri-operative myocardial injuries as well as the inhospital all-cause mortality are mediated through increased PTH concentrations. We did not find an independent relationship between serum 25(OH)D levels and clinical outcomes in out cohort.

In this study as in some others [41], there was no correlation between serum PTH and 25(OH)D levels, an observation at variance with the known effect of chronic 25(OH)D deficiency to cause compensatory hyperparathyroidism. In general, the negative correlation between serum 25(OH)D and PTH concentrations reported in the literature, although significant, is weak (usually r = <–0.3). The threshold of serum 25(OH)D where serum PTH starts to rise is about 75 nmol/L according to most surveys. However, not all older patients with hypovitaminosis D have the same risk of developing secondary hyperparathyroidism. In older HF patients with hypovitaminosis D, elevated PTH levels have been reported only in 20% [41] to 50% [19], indicating significant heterogeneity of the HF population in regard to the complex and still not fully understood vitamin D – PTH relationship. The mechanism underlying the absence of PTH response to vitamin D deficiency is unclear. It may be related to an abnormality in the calcium-sensing receptor, which plays a central role in regulating PTH gene expression, PTH synthesis and secretion, and/or dysregulation in PTH gene transcription, or possibly a post-transcriptional effect [43]. Magnesium deficiency (shown by a magnesium-loading test) has been recently shown as an important factor contributing to blunted PTH response to vitamin D deficiency in osteoporotic patients [44]. Other factors that may affect the calcium homeostasis, calcium – PTH axis and explain the elevated serum PTH levels in this population include low calcium intake and a decrease in calcium absorption, immobilisation [45], impaired renal function, lack of suppressive effect of estrogens on PTH secretion [46], and ethnic differences [47].

We found excessive bone resorption (urinary excretion of DPD and/or NTx above the upper limit of the reference ranges) in 98.4% of cTnI-positive patients and in 91.7% of cTnI-negative patients; serum OC levels were below the reference range in 43.5% and 56.8%, respectively. These results are consistent with previous studies [22,45,48,49] and demonstrate that HF patients have a significant imbalance in bone remodelling with excessive osteoclastic activity.

There was no association between serum cTnI and any of 4 bone formation or resorption markers, indicating that bone status per se was not related to the mechanism(s) responsible for myocardial injury in HF patients. However, although serum and urine bone turnover markers did not differ significantly between the 2 groups, in cTnI-positive patients serum PTH values were significantly higher and positively correlated with DPD excretion. This novel finding suggests that elevated PTH levels may be the common pathophysiological factor contributing to both myocardial injury and increased bone resorption activity in older HF patients. Notably, increased resorptive activity is unrelated to trauma and subsequent HF surgery as urinary DPD excretion remained unchanged in the early phase after HF and did not change after fracture [50]. It has also been shown that hyperparathyroidism affects mainly markers of bone resorption [45]. Our data are in agreement with the current understanding that sustained hyperparathyroidism, caused by vitamin D insufficiency, is prejudicial to the skeleton, particularly cortical bone [51]. Our study expands this concept and shows that elevated serum PTH levels (because of extra-skeletal PTH effects) are also a major risk factor for poor outcomes in HF patients and stresses the importance of evaluating and correcting vitamin D and PTH status in older patients.

Our findings have clinical implications both for predicting peri-operative myocardial injury and mortality and preventing such outcomes. Although vitamin D inadequacy is recognised as a global problem, especially among elderly patients and patients with osteoporosis, the PTH status is often unknown and ignored. Our findings support the hypothesis that vigorous control of vitamin D-PTH axis in older persons is important not only for musculoskeletal health but also for other disorders, including cardiovascular disease. Peri-operative measurements of PTH and cTnI are not routine practice. Our data convincingly demonstrate that in patients with HF both hyperparathyroidism and myocardial injury are frequent, interrelated, often unrecognised, and prognostically important. We believe that our results may have broad implications for all older people, especially those undergoing surgery. Routine PTH and cTnI assessment may be helpful in clinical prognostic decision as well as in preventive therapy. The pathophysiological and biological relevance of PTH-related mechanisms responsible for poorer outcomes warrant further evaluation. Improved understanding of hyperparathyroidism as a significant risk factor for peri-operative myocardial injury and all-cause mortality in HF patients may lead to novel prophylactic and therapeutic strategies.

Several limitations of this study should be noted. We performed a single measurement of serum cTnI, intact PTH, 25(OH)D, parameters of mineral metabolism, and bone turnover markers shortly after arrival at the Emergency Department (within 48 hr in 89%). Because serum cTnI level remains elevated for 7 to 10 days after release into circulation, one sample allows identification of patients with myocardial injury, but the maximum elevation, time course, and kinetics of cTnI, which might provide additional diagnostic and prognostic information, are unknown. The sampling time is important in assessment of any metabolic status as it may be affected by trauma and surgery. It has been shown that in HF patients 25(OH)D levels are not influenced by hospitalisation [52], while PTH levels fell at 2 wk after surgery in one study [52] but did not change during in-patient care and the recovery period (2 mo) in another report [53]. In the current study sampling time after fracture was short and therefore the possible confounding effects of trauma and surgery are likely to be minimal. We defined secondary hyperparathyroidism as the upper range of reference level for serum PTH (arbitrary threshold). Because of the cross-sectional design of the study, our findings represent associations but not causal relationships. A longitudinal study might reveal significant associations between vitamin D deficiency and serum PTH levels, as well as bone turnover markers. The lack of such associations in our study may be due at least partially to the cross-sectional analyses. Our results regarding fatal HF outcome should be viewed cautiously given the small number of deaths. Finally, it may not be possible to generalize findings from a predominantly Caucasian cohort to other populations. Despite these limitations, the study expands knowledge on the role of secondary hyperparathyroidism in HF patients and indicates that this treatable condition is an important risk factor for poorer outcomes.

In conclusion, our findings provide for the first time evidence that in older HF patients elevated PTH level is associated with peri-operative myocardial injury and in-hospital all-cause mortality independent of age, sex, vitamin D status, and comorbidities. Secondary hyperparathyroidism is possibly the common mechanism responsible for disturbed bone metabolism, cardiovascular morbidity, and total mortality in this population in which vitamin D insufficiency and excessive bone resorption is nearly universal. If confirmed in other studies, our results suggest that intensive targeted interventions to normalise vitamin D and PTH status could potentially reduce HF and increase survival. Future investigations should elucidate the precise biological mechanisms of these associations and the impact on clinical outcomes of treating these abnormalities.

	Acknowledgement

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The authors are grateful to Robyn Muscat-Presti for secretarial assistance.

	References

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgement References

 

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