Patients with acute coronary syndrome (ACS) constitute a very heterogeneous population, with great variability in terms of both the form of presentation of the syndrome and the risk of death or ischemia recurrence over the long term.1 The continuous search for new tools offering support for clinicians in assessing the patient prognosis is therefore essential. In addition to purely clinical variables such as cardiovascular history, comorbidities, the electrocardiogram or the presence of heart failure upon admission, biomarkers have become an essential element for diagnosis, patient stratification and management decision making.2 The Global Registry of Acute Coronary Events (GRACE) score is routinely used for the risk stratification of patients with ACS, and has been shown to be a potent tool in this respect. However, while its performance in differentiating poor outcome patients is good, it is not perfect – as suggested by its C statistic in the order of 0.8.3 This observation is of particular importance, since any improvements in the discriminating capacity of this score would be of great value in clinical practice.

Both vitamin D, in the form of calcidiol and calcitriol, and parathyroid hormone (PTH) play a key role in bone homeostasis and in the maintenance of calcium-phosphorus balance. Previous studies have demonstrated a relationship between increased cardiovascular risk and the presence of primary4 or secondary hyperparathyroidism.5 This relationship appears to be largely attributable to an increase in the prevalence of cardiovascular risk factors among patients with asymptomatic primary hyperparathyroidism.6,7 On the other hand, a number of authors have related the presence of high PTH levels to more complex coronary disease8; a suboptimum response to antiplatelet medication9; and even the presence of a greater number of adverse events during follow-up10 in patients diagnosed with stable coronary disease. However, the evidence of a potential prognostic impact of PTH in patients with ACS is practically inexistent, and is based only on a small pilot study involving 22 patients.11 No specific study designed to explore this hypothesis has been carried out to date.

The present study was therefore carried out to determine whether measurement of the circulating PTH levels offers prognostic information following the discharge of patients admitted due to ACS. We have also investigated whether the circulating levels of calcidiol and calcitriol are useful for the differentiation of patients at risk of suffering adverse events, and whether such an association persists after controlling for other more solidly established biomarkers such as the amino-terminal fraction of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) or cystatin C.

A prospective, analytical, observational cohort study was carried out with the recruitment of all patients presenting a main diagnosis of ACS admitted between 1 November 2011 and 31 April 2012 to a General University Hospital in Cartagena (Murcia, Spain; latitude 37° N). Patients not living in Spain and therefore not amenable to follow-up were excluded, as were those who failed to give informed consent to participation in the study. Data collection included: demographic information, cardiovascular risk factors, history of cardiovascular disease and chronic kidney disease (CKD), clinical and laboratory test data (albumin, hemoglobin, creatinine, cystatin C, CRP, NT-proBNP, 25-hidroxivitamina D or calcidiol [25(OH)-D], 1,25(OH) vitamin D or calcitriol [1,25(OH)-D], PTH, fibrinogen, calcium and albumin-corrected calcium) referred to admission, and events during follow-up. The study was approved by the Clinical Research Ethics Committee (CREC) of our center, and complied with the principles of the current version of the Declaration of Helsinki.

Our study offers the following novel findings: (1) patients admitted to hospital due to ACS often present high PTH levels (approximately one out of every four patients); (2) patients with high PTH levels have more cardiovascular risk factors, suffer more extensive infarctions, with greater risk, with more heart failure, and are more often managed on a conservative basis, with greater associated inflammation, and a poorer outcome after discharge; (3) parathyroid hormone nevertheless was not identified as an independent predictor of poor patient outcome after adjustment for the GRACE scale–thus suggesting that most of the contributed information is already included in a stratification scale commonly used in clinical practice; and (4) calcidiol and calcitriol likewise were not found to be useful instruments for the risk stratification of patients with ACS.

At present, many studies support the relationship between cardiovascular disease and hyperparathyroidism. The presence of high PTH levels has been associated to an increased cardiovascular risk–the latter being largely attributed to an increased prevalence of the classical cardiovascular risk factors, including fundamentally hypertension14 and glucose intolerance.15 The proposed mechanisms underlying hypertension in patients with hyperparathyroidism include greater arterial stiffness in long-standing or severe disease, direct stimulation of the renin-aldosterone system through PTH, and endothelial dysfunction, with an increase in sympathetic activity. Likewise, high PTH levels have been associated to a decrease in insulin sensitivity, with associated hyperinsulinemia.15 In this regard, recent observational studies in our setting, such as that published by Garcia-Martin et al. (2014),6 have retrospectively analyzed patients with asymptomatic primary hyperthyroidism, revealing a high prevalence of obesity (59.9%), diabetes mellitus (25%), hypertension (47.2%) and dyslipidemia (44.4%). The prognostic impact of hyperparathyroidism in relation to cardiovascular disease was evidenced in the study of Vestergaard and Mosekilde (2003),16 who recorded a decrease of approximately 40% in the relative risk of myocardial infarction, stroke and death in patients with surgically corrected primary hyperparathyroidism compared with those individuals treated on a conservative basis.

Despite the above, there is still very weak evidence of the relationship between PTH concentration and the patient prognosis once coronary disease has been established. Recent studies have analyzed the presence of conditioning factors associated to a more adverse clinical profile in patients with stable chronic angina and high PTH levels. For example, it has been seen that the presence of high PTH levels is correlated to more complex coronary disease, with a higher Syntax score and increased calcification (Martín-Reyes et al., 2016),8 or to a suboptimum response to antiplatelet medication secondary to greater platelet reactivity (Verdoia et al., 2016).9 With regard to the prognostic implications in stable patients, high PTH levels have also been related to increased cardiovascular adverse events during follow-up. The study published by Tuñón et al. (2016),10 involving the analysis of patients 6 months after admission due to ACS, found that type 2 diabetics who subsequently suffered more events during follow-up presented higher levels of PTH [71.3 (47.3–106.6) vs. 51.9 (40.8–66.2) pg/ml; p=0.004], fibroblast growth factor-23 [112.0 (59.9–167.6) vs. 68.9 (54.2–93.0) RU/ml; p=0.002] and phosphorus [(3.53±0.71 vs. 3.25±0.50mg/dl; p=0.017)] than diabetics who did not develop adverse events–no significant differences being recorded in non-diabetic patients. In this same line, a small study of 22 patients over 60 years of age admitted due to ACS without ST-segment elevation concluded that the presence of low 25(OH)-D levels and high PTH concentrations identified those individuals with a greater probability of suffering a cardiovascular adverse event (3 patients) during follow-up–the PTH levels being significantly higher in patients with such events.11

In this regard, our study consistently shows that high PTH levels in patients with ACS are associated to a poorer outcome in terms of mortality and readmission due to myocardial infarction or angina, though this association practically disappears on adjusting for the GRACE score–thus suggesting the absence of an independent effect upon the prognosis in this group of patients. The observation of a greater IR of events in patients with elevated PTH levels during follow-up was reasonable, taking into account that these individuals had an increased cardiovascular risk and a larger number of poor prognosis predictive factors than those with normal PTH values upon admission. The patients with high PTH levels presented more cardiovascular risk factors such as hypertension and dyslipidemia, as well as a more frequent history of chronic ischemic heart disease. Our study coincides with previous publications that have analyzed the higher prevalence of such risk factors in this population group,6,7 though with notoriously different prevalences, e.g., in relation to hypertension (80.0% of the population with high PTH levels in our series versus 47.2% in previous registries), diabetes (47.5% of the population with high PTH levels in our series versus 25% in previous registries) or dyslipidemia (71% of the population with high PTH levels in our series versus 44% in previous registries). These findings are probably related to the fact that our population was characterized by greater cardiovascular risk, older age and prior ischemic events, while the patients in the aforementioned studies6,7 were limited to individuals with a diagnosis of asymptomatic primary hyperparathyroidism. From the perspective of renal function, the patients with high PTH levels had a more frequent history of CKD, and presented poorer GFR and higher cystatin C levels. This impairment in renal function has been found to be an important independent prognostic marker in ischemic heart disease–being consistently identified as a risk factor for cardiovascular events and global mortality in high risk populations.17,18 Mention also must be made of the fact that the patients with high PTH levels presented other laboratory test data directly related to an adverse cardiovascular prognosis in the context of ACS, such as a greater presence of anemia, higher NT-proBNP levels, or the presence of greater acute phase reactant concentrations – this being in concordance with the observations of previous studies.19–21

On the other hand, we found that patients with high PTH levels had lower 25(OH)-D concentrations [rho=−0.274; p=0.001]. This observation is interesting, since previous studies have documented the relationship between lowered 25(OH)-D and an adverse outcome in ACS21–24 thereby representing an additional poor prognosis marker in this group of patients. Furthermore, vitamin D deficiency is associated to an increased prevalence of comorbidities in the general population,24 and it has been postulated that vitamin D concentration could reflect the “global health” of an individual.25 This observation is consistent with the results of our study.

There was a high prevalence of elevated PTH levels among the patients admitted due to ACS, and the presence of such elevation was associated to a poorer clinical profile and outcome. However, PTH elevation was not identified as an independent predictor of poor prognosis on adjusting for a commonly used scale (GRACE score). In turn, while low calcidiol and calcitriol levels were associated to an increased risk and to more comorbidity, they were not found to be useful in terms of risk stratification.

All the authors have participated in the research work and in the preparation of the article, and have approved the final version of the manuscript.

The authors declare that they have no conflicts of interest.