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Print version ISSN 0066-782X
Arq. Bras. Cardiol. vol.99 no.4 São Paulo Oct. 2012 Epub Sep 13, 2012
Hakan AltayI; Ali ZorluII; Halil Tolga KocumI; Senol DemircanI; Nuryil YilmazIII; Mehmet Birhan YilmazIV
IDepartment of Cardiology, Baskent University Faculty of Medicine, Adana
IIDepartment of Cardiology, Bulanık State Hospital, Mus
IIIDepartment of Psychiatry, Sivas State Hospital
IVDepartment of Cardiology, Cumhuriyet University Faculty of Medicine, Sivas
BACKGROUND: Depression has been found to be a predictor of rehospitalization and mortality in heart failure (HF). Parathyroid hormone (PTH) is a novel promising biomarker that can predict hospitalization, functional status and mortality in HF.
OBJECTIVE: We aimed to investigate the association of depression with serum PTH levels in patients with systolic HF.
METHODS: A total of consecutive 100 outpatients with systolic HF having left ventricular ejection fraction (LVEF) < 40%, were prospectively studied. All patients underwent laboratory tests, including brain natriuretic peptide (BNP) and PTH analyses. The patients were asked to complete the Beck Depression Inventory- II (BDI).
RESULTS: Fifty-one patients (51%) were shown to have poor BDI score (BDIS > 18). Patients with poor BDI score had significantly higher PTH levels compared to those with good BDIS (133 ± 46 pg/ml vs. 71 ± 26 pg/ml, p < 0.001). In multivariable logistic regression model, PTH level (Odds ratio (OR) = 1.035, p = 0.003), LVEF (OR = 0.854, p = 0.004), NYHA functional class III/IV (OR = 28.022, p = 0.005), C-reactive protein (CRP) (OR = 1.088, p = 0.020), and presence of pretibial edema (OR = 12.341, p = 0.033) were found to be independent predictors of moderate to severe depression after adjustment of other potential confounders.
CONCLUSION: Systolic HF patients with moderate to severe depression had higher serum levels of PTH and CRP, poor functional status and lower LVEF. The association of depression with such parameters might explain the contribution of depression to hospitalization and mortality in HF.
Keywords: Parathyroid hormone; depression; heart failure/mortality; C-reactive protein.
Chronic heart failure (HF) is a highly prevalent and costly disease in the world. Depression and depressive symptoms occur in 24% to 42% of HF patients1. Clinically significant depression is more prevalent in advanced HF1. When present, depression and depressive symptoms are associated with poorer functional capacity and survival, decreased compliance and response to treatment and greater use of healthcare services, including hospitalization and outpatient services.
Several factors including hypovitaminosis D, aldosteronism, chronic use of furosemide and impaired renal function have been shown to contribute to the appearance of secondary hyperparathyroidism in HF patients2. The association of serum intact Parathyroid Hormone (PTH) levels with severity and prognosis of HF has been recently reported3. Heart failure and depression share common pathophysiological aspects, both increasing the levels of circulating inflammatory cytokines4.
In view of these findings, we sought to verify the role of PTH in the prediction of clinically significant depression in patients with systolic HF, admitted to a tertiary care hospital for outpatient control visit.
A total of 100 consecutive patients with systolic HF (left ventricular ejection fraction < 40%) were prospectively enrolled between November 2010 and September 2011 in participating centers. Patients with end stage renal disease undergoing dialysis treatment, primary lung disease including moderate to severe chronic obstructive pulmonary disease, musculoskeletal diseases, myocardial infarction or unstable angina within previous 3 months, acute or chronic infection, inflammatory diseases such as sepsis, arthritis or systemic connective tissue disease, symptomatic coronary or peripheral vascular disease, long term alcoholism, valvular cardiomyopathy or artificial heart valve, malignant disease, significant liver, thyroid, parathyroid, suprarenal gland or pituitary disease, patients with impending signs and symptoms of decompensation or those who were hospitalized for a recent decompensation and patients without stable symptoms at least for a month were excluded.
Following obtaining informed consent for the study, all patients underwent laboratory tests, including Brain Natriuretic Peptide (BNP) and PTH. Serum intact PTH levels were measured by using an Immulite intact PTH assay (Diagnostics Product Corporation, 2000, Los Angeles, California). The established normal range for this assay was 10 to 65 pg/ml.
All patients underwent depression assessment using the Beck Depression Inventory- II (BDI) scale. In this scale, the patients were classified as follows:
- From 0 to 9 points, none or minimally depressed;
- From 10 to 18 points, patients with mild depression;
- From 19 to 29 points, moderate depression;
- From 30 to 63 points, severe depression.
According to the result of the assessment of BDI-II, the patients were classified into two groups: group 1 - comprising patients with less than or equal to 18 points in the BDI-II scale (none or minimal depression or mild depression, good BDIS), and group 2 - comprising patients with a score higher than 18 (moderate or severe depression, poor BDIS)5. Patients were classified into 4 groups based on New York Heart Association (NYHA) functional class. Consensus of 2 experienced clinicians blinded to each other was required for classification of functional classes. In case of disagreement, a third opinion was obtained from an expert physician.
Hypertension was defined as blood pressure >140/90 mm Hg on >2 occasions during office measurements or having antihypertensive treatment. Diabetes mellitus was defined as fasting blood glucose >126 mg/dl or use of antidiabetic treatment. Ischemia as etiology of HF was recorded if there was a history of myocardial infarction or coronary intervention or documented coronary stenosis >50%. Those who continued smoking during the index admission were considered current smokers. Body mass index was calculated via dividing weight in kilograms by squared height in meters. Estimated creatinine clearance was calculated from serum creatinine values using the Cockroft-Gault Formula6. Rhythm, medications, and hemodynamic findings such as heart rate and systolic and diastolic blood pressures were evaluated. Presence of HF related hospitalization within the previous six months was carefully considered.
All patients underwent two-dimensional transthoracic echocardiography during index visit. Echocardiographic examinations were performed with the Vivid 7 system (GE Healthcare, Wauwatosa, Wisconsin) with 2.5- to 5-MHz probes in all participating centers. Left ventricular ejection fraction (LVEF) was calculated by the modified Simpson method. Chamber sizes were defined according to recent guidelines7. Transmitral diastolic flow was obtained by pulsed-wave Doppler from an apical four-chamber view, with the pulsed Doppler sample volume placed perpendicular to the inflow jet previously identified with the use of color Doppler. Mitral early and late diastolic inflow velocities were designated as E and A, respectively. Two-dimensionally guided pulsed-tissue Doppler imaging sample volume was placed at the level of the lateral mitral valve annulus, measuring the mitral annular early diastolic velocity, designated as E'. Left ventricle filling pressure was estimated using the ratio of E to E', designated as E/ E' 8. Tricuspid annular plane systolic excursion (TAPSE) was measured using 2-dimensional echocardiographically guided M-mode recordings from the apical 4-chamber view with the cursor placed at the free wall of the tricuspid annulus9.
Continuous variables were expressed as mean ± SD or median (interquartile range) in the presence of abnormal distribution, and categorical variables as percentages. Receiver operator characteristic curve analysis was performed to identify the optimal cut-off point of PTH (at which sensitivity and specificity would be maximal) for the prediction of poor BDI score. Areas under the curve (AUC) were calculated as measures of the accuracy of the tests. We compared the AUC with use of the Z test. Patients were categorized into two as poor (Group I) or good (Group II) BDI score. Comparisons between groups of patients were made by use of a χ2 test for categorical variables, independent samples t test for normally distributed continuous variables, and Mann-Whitney U test when the distribution was skewed. Correlations were evaluated either via Pearson or Spearman correlation tests. We used univariate cox proportional-hazards analysis to quantify the association of variables with moderate to severe depression. Variables found to be statistically significant in univariate analysis and other potential confounders were used in a multivariable logistic regression model with forward stepwise method in order to determine the independent predictors of moderate to severe depression. All statistical procedures were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL). A p value of 0.05 was considered statistically significant.
The study was performed in accordance with the Declaration of Helsinki for human research and was approved by the institutional ethics committee as part of a large study.
Considering the whole cohort, the mean age of the patients was 64 ± 12 years (54% men). The mean PTH level was 101 ± 48 pg/ml. The demographic, clinical and echocardiographic characteristics of the study patients according to BDI score are listed in Table 1. A total of 51 patients (51%) were shown to have moderate to severe depression (BDIS > 18). Patients with clinically significant depression (BDIS > 18) had significantly higher PTH levels compared to those with mild or minimal or no depression (BDIS < 18) (133 ± 46 pg/ml vs. 71 ± 26 pg/ml, p < 0.001). Mean levels of PTH increased as BDIS increased (Figure 1). Patients with poor BDIS had significantly higher CRP and BNP levels and lower sodium and creatinine clearance. These patients also had lower LVEF and higher LA size and E/E' ratio compared to patients with mild or minimal or no depression (BDIS < 18). Women were more frequent in those with poor BDIS (Table 1). Beck depression score index was correlated with NYHA functional class (r = 0.862, p < 0.001), BNP levels (r = 0.625, p < 0.001), PTH levels (r = 0. 753, p < 0.001), E/E' ratio (r = 0.374, p < 0.001), LVEF (r = -0.572, p < 0.001), CC (r = -0.404, p < 0.001), and CRP levels (r = 0.336, p = 0.001).
Furthermore, serum PTH levels were correlated with NYHA functional class (p < 0.001), BNP levels (p < 0.001), E/E' ratio (p < 0.001), TAPSE (p < 0.001), LVEF (p < 0.001), CC (p < 0.001), presence of pretibial edema (p < 0.001), HF related rehospitalization (p < 0.001), and CRP levels (p = 0.002) (Table 2).
Parathyroid hormone, LVEF, NYHA functional class III/IV, CRP, pretibial edema, HF related rehospitalization, E/E' ratio, TAPSE, BNP, disease duration, serum sodium, LA size, CC, left ventricular systolic diameter, and female gender were associated with poor BDIS in univariate analysis. In multivariable logistic regression model, PTH level (Odds ratio (OR) = 1.035, p = 0.003), LVEF (OR = 0.854, p = 0.004), NYHA Functional Class III/IV (OR = 28.022, p = 0.005), CRP (OR = 1.088, p = 0.020), and presence of pretibial edema (OR = 12.341, p = 0.033) were found to be independent predictors of poor BDIS after adjustment of other potential confounders (Table 3).
In face of the difference in PTH levels between the patients with clinically significant depression, i.e moderate or severe depression (BDIS > 18) and no or minimal or mild depression (BDIS < 18), a ROC curve was constructed which identified the PTH level of 99 pg/ml as the best cut off point with 76.5% sensitivity and 87.8% specificity (area under the curve 0.871, 95% confidence interval 0.789 to 0.929; Figure 2).
Not only does the incidence of depression increase with the presence of HF, but it is also related to its severity, being more frequent in advanced HF10. This study demonstrated that depression was associated with clinical, echocardiographic and laboratory parameters all of which have been proven to be well established predictors of advanced HF. It also demonstrated that relationship between serum PTH and clinically significant depression was independent of clinical features and pertinent demographic characteristics, such as LVEF, NYHA functional class, CRP, HF related rehospitalization, disease duration and female gender.
A recent study demonstrated that high serum PTH levels were strongly associated with advanced HF11. This association has been explained by the fact that secondary hyperparathyroidism may contribute to the systemic illness that accompanies advanced HF12. This systemic illness and chronic nature of HF may contribute to depression. The association of depressive disorders and primary hyperparathyroidism has been shown before13 where the resultant hypercalcemia was thought to be the mechanism responsible for the production of depressive symptoms. High serum PTH levels are thought to be related to the systemic induction of oxidative stress that leads to tissue injury and contributes to the pathophysiology of HF14. Increased oxidative stress may also play a critical role in the pathophysiology of depression in chronic HF15. Whether or not there is a cause-and-effect relationship, it is very obvious that high levels of circulating PTH and depression are highly associated especially in patients with advanced systolic HF.
The association of low Vitamin D and mortality in HF has recently been shown16. This association may occur directly or through activation of renin-angiotensin-aldosterone system (RAAS)17. The association of Vitamin D deficiency and depression has been shown both in general population18 and HF population19. Vitamin D receptors are present in the brain, and the central nervous system contains enzymes necessary for vitamin D hydroxylation, making it biologically plausible for vitamin D to be associated with brain activity and thus depression20. Immobilization and antisocial behavior of HF patients, especially more prominent when they are depressive, may lead to inadequate exposure to sunlight and hence Vitamin D deficiency. Low serum Vitamin D levels or more accurately, inadequate biologic Vitamin D activity causes serum PTH excess. Because of this, one can hypothesize that the associations of lower Vitamin D activity concentrations with cardiovascular outcomes and depression could be indirectly demonstrated by the presence of serum PTH excess.
CRP was also found to be a strong independent predictor of clinically significant depression in our study. A vicious circle between HF and inflammation is present because inflammatory markers, such as IL-6 and CRP, have been found to be associated with worsening of cardiac function and advanced systolic HF21. Besides, higher levels of inflammatory markers are also found in patients with depression but without HF22.
Further investigation is needed to understand the potential interaction of depression, increased PTH and CRP levels in the pathophysiology of systolic HF, all of which may simply be a marker or drive causality. It is well known that depression is under-recognized and undertreated in HF patients23. Our data shows that high PTH and CRP levels may aid early recognition of clinically significant depression in outpatients with HF who have concomitant low EF and high NYHA functional class.
BNP has been widely used as a biomarker to define the diagnosis and prognosis in patients with HF24. In our study, we demonstrated that patients with clinically significant depression had significantly higher BNP levels. However, when other potential confounders were included, high BNP levels did not predict poor BDI score. This result was different from the recently conducted study which reported that BNP predicted severe depression in HF patients25. The change in the loading (volume) status of the ventricles is known to affect its level in the blood. However, PTH seems to be secreted after a long chain of reactions in the body and not affected by the volume status26.
Other independent predictors of clinically significant depression were low LVEF and high NYHA functional class both of which had been shown to have well established association with depression in patients with HF in the previous studies1. Consistent with previous studies, female gender was associated with clinically significant depression in this study1. Heart failure related rehospitalization were found to be significantly more common in patients with clinically significant depression (Table 1). This result is same as in the literature which reported that depressed patients were hospitalized approximately three times more frequently than non-depressed patients, and depression increased the costs of HF treatment by 25%-40%9.
There are some limitations of the current study worthwhile mentioning. Sample size, though calculated before the study, is not enough to draw definitive conclusions. Furthermore, the behavior and serum level of PTH in patients with RAAS blockade is unpredictable, particularly among those having aldosterone-blocking agent. However, it is of note that this study was not designed to test the temporal behavior of PTH with the therapy, and all patients were clinically stable and under chronic stable HF therapy with stable doses. Hence, we think that the discussion of interaction between confounders and PTH cannot go beyond simple hypothetical link. However, the association of PTH to depression (poor BDIS) presented herein is strong, and independent and the univariate interaction between aldosterone blockade and poor BDIS was lost in the multivariate testing.
In conclusion, the prevalence of depression in advanced HF is high; patients with depression present higher PTH and CRP levels than non-depressed patients; and the higher the NYHA of the patient, the higher their chance of having clinically significant depression. High PTH and CRP levels in a stable systolic HF outpatient should suggest the possibility of clinically significant depression particularly in the presence of high NYHA functional class.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Sources of Funding
There were no external funding sources for this study.
This study is not associated with any post-graduation program.
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Manuscript received April 22, 2012; manuscript revised April 30, 2012; accepted July 31, 2012.
Manuscript received April 22, 2012; manuscript revised April 30, 2012; accepted July 31, 2012.