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Stefania Lucia Magda1,2, Elisa Serban2

1 Department of Cardiology, Discipline of Ambulatory Medicine, „Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
2 Department of Functional Science, Discipline of Medical Informatics and Biostatistics, „Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
3 Department of Internal Medicine, „Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
4 „Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania

Abstract: Introduction – In heart failure (HF) anxiety and depression were relatively ignored by researchers, even if the measurement of quality of life (QoL) in these patients have become important tools to quantify disease severity. The objective of the present study was to quantify psychological stress and QoL in patients with chronic stable HF, and correlate the scores obtained with severity of heart failure and vitamin D levels. Materials and methods – The study included 45 patients with HF who performed clinical evaluation, biochemical analysis, echocardiography, determination of quality of life scores according to the Minnesota Living with Heart Failure questionnaire (MLHFQ) and the Hospital anxiety-depression scale (HAD). Results – It was found a signifi cant correlation between the severity of HF versus vitamin D levels (p <0.001), HAD-A scores (p<0.011), HAD-D scores (p<0.033), also for the MLHFQ (p<0.001). The results of the study demonstrated a significant correlation between the MLHFQ scores and levels of vitamin D (p <0.001). Conclusions – The results obtai-ned in this study showed that vitamin D deficiency in patients with chronic heart failure is significantly correlated with the severity of heart failure and decreased quality of life, anxiety and depression and could be used as a marker of increased risk. Keywords: vitamin D, heart failure, quality of life, anxiety, depression.

INTRODUCTION
Heart failure (HF) is a chronic condition requiring per-manent treatment. Patients with HF are monitored in the ambulatory cardiology departments at regular in-tervals, based on the severity of disease1.
The evolution of HF is usually towards worsening, with decreased quality of life and increased mortality in the medium and long term. Prevention of cardio-vascular diseases (especially myocardial infarction) and modern methods of treatment have led in the last years to an improvement in the survival of HF pati-ents2.
Associations of risk factors (smoking, hypertension, diabetes, dyslipidemia) are consistent for occurrence of heart failure with both preserved and reduced left ventricular ejection fraction (LVEF), the most com-mon sub-phenotypes of these condition3. Heart failure prevention is an important public health purpose. In-creased physical activity and exercise can help prevent HF, as they are associated with reduced HF incidence and potentially act through a variety of mechanisms to slow disease progression.
The severity of heart failure is associated in nume-rous studies with vitamin D defi ciency4, and also with a worse prognosis5; moreover, supplementation of vi-tamin D could reduce the mortality rate and increase quality of life in patients with HF6.
Different questionnaires that measure the quality of life in HF patients have become important assessment tools over the last decades7,8. Among these, one of the most well-known and used is the Minnesota Living with Heart Failure questionnaire (MLHFQ), which has de-monstrated good psychometric properties in numero-us studies, being translated and culturally adapted in at least 34 languages8-11. However, there are some con-cerns about the the homogeneity of its elements and about quantification of anxiety and depression, com-mon comorbidities especially in these patients. Asso-ciations between HF and depression\ anxiety increase mortality17. Therefore, specific scores can be obtained for a comprehensive quantification of psychologic pa-rameters, by using the HAD questionnaire.
The objective of the present study was to quantify psychological stress and quality of life in patients with chronic stable HF, and correlate the scores obtained with severity of heart failure and vitamin D levels.

MATERIAL AND METHODS
In the present study we correlated the echocardio-graphic parameters of cardiac performance and the scores obtained from the Minnesota Living with Heart Failure and HAD Questionnaires with vitamin D levels in 45 selected patients with chronic heart failure of different etiologies. The patients were divided into 3 groups according to ejection fraction: group A with preserved EF (≥50%) (n=15), group B with interme-diate EF (40-49%) (n=15) and group C with low EF (<39%) (n=15), according to European guidelines1. This study conformed to the Declaration of Helsinki, was approved by the local ethics committee and all patients provided written informed consent.

Biochemical analysis
Venous blood sampling was performed during hospi-talization. After centrifugation, blood samples were quickly frozen and stored at-80 °C until analysis. 25-OH vitamin D₃ was performed immediately after plasma decompression.The 25-OH vitamin D₃ levels obtained were interpreted according to Table 1.
The glycaemiawas determinedby using a Siemens Dimension RLX-MAX, Dade Behring device.
To determine total cholesterol (TC), triglyceri-des (TG) and HDL-cholesterol (HDL-c) photometric methods (Dimension RLX-MAX automatic analyzer, Dade Behring) were used. LDL-cholesterol fraction was calculated using the Friedewald’s formula:
LDL- C (mg/dL) = CT (mg/dL) – 0,2 x TG (mg/dL)– HDL-C (mg/dL)

Determination of echocardiographic parameters
Transthoracic echocardiography was performed in all patients enrolled in the study on the GE Vivid 9 ultrasound system. M-mode ultrasound was used to accurately measure heart structures. Two-dimensio-nal ultrasound provided morphological and functional information about dimensions, cavities, cardiac wall, valvular lesions, ejection fraction and systolic per-formance. Doppler with two variants – spectral (for quantitative applications) and color (for qualitative applications) evaluated and quantified valvular regur-gitation, left systolic and diastolic ventricular function and pulmonary pressures. Diastolic dysfunction was determined by the E/A ratio, and the left ventricular systolic function by measuring the ejection fraction.

The Minnesota Living with Heart Failure Questionnaire (MLHFQ)
The MLHFQ, a self-administered disease-specific qu-estionnaire for patients with heart failure comprising 21 items representing the impact of HF on quality of life over the last 4 weeks, from 0 to 5, was applied to all patients. It provides a total score ranging from best to worst (0–105). Scores for emotional wellbeing (5 items, ranging between 0 to 25) and physical perfor-mance (8 items, range between 0 to 40) are evalua-ted. The other eight items are only considered for the calculation of the total score. The questions highlight how much the life of the patients with heart failure is affected regarding sleep, diet, physical condition (tired, exhausted), physical activity (entertainment, sports), sexual activity, or emotional life (restlessness, relating with family/friends, feeling a burden for the family).The severity of quality of life impairment in these patients is interpreted according to the score obtained after applying the MLWHF questionnaire (Table 2).

The Hospital anxiety and depression scale (HAD)
HAD scale consists of 14 items and contains two sub-scales, one for anxiety another for depression. Each item is quantified on a 4-point Likert scale from 0 (no symptoms) to 3 (highest level of symptoms). The maximum score is 21 for each subscale, scores like 0-7 are considered normal, whereas scores above 11 mean a considerable psychological morbidity either in the field of anxiety or depression. Scores like 8-10 indicate a borderline status. Scores were considered if at least five answers were given on each subscale. Missing responses in patients who completed only 5 or 6 items were replaced based on the sum of items filled multiplied by 7/5 respectively 7/6.

STATISTICAL ANALYSIS
The statistical analysis was done using SPSS v.17 software and included descriptive statistics results (mean, standard deviation, standard error, confidence intervals). The differences between the independent groups were obtained by the Mann-Whitney test, the correlations between numerical variables were made using the multivariate regression model and the stren-gth of correlation was obtained with the Spearman’s correlation coefficient. Nominal variables were com-pared and associated with the Pearson’s chi-squared test, p<0.05 being considered statistically significant.

Figure 1. Distribution of mean EF % values in the 3 groups (n=45).

Figure 2. Distribution of mean values of 25-OH vitamin D3 levels in the 3 groups (n=45).

Figure 3. Boxplots representing the MLHFQ scores comparison between groups (n=45).

Figure 4. Linear regression plot. Correlation between the MLHFQ scores and 25-OH vitamin D3 (r = -0.493, p <0.001) in the 45 HF patients.

RESULTS
The characteristics of the 3 groups are represented in Table 3.
In Table 4 are represented the results of the Kruskal-Wallis test (comparisons between the three groups, for each variable).
The mean values of age, glycaemia, creatinine, systolic blood pressure, diastolic blood pressure and heart rate showed no statistically signifi cant difference between the 3 groups.
LVEF values were between 15 and 60%. The mean LVEF values in the three groups were as follows: in group A 53.50±2.90%, in group B 43.77±3.09% and in group C 27.60±6.26%. The LVEF was significantly higher in group A compared to the other two groups (p <0.001).
The 25-OH vitamin D₃ values were between 10.1 and 36.1 ng/ml. The mean values in the 3 groups were as follows: in group A 27.19±4.46 ng/ml, in group B 24.65±4.55 ng/ml and in group C 17.24±4.40 ng/ml. The 25-OH vitamin D₃ values were significantly decreased in group C versus A (p <0.001) and group B (p <0.001) (Figure 2).
The MLHFQ scores ranged between 21 and 105. The mean values in the three groups were: in group A 52.40±15.92, in group B 70.07±18.98 and in group C83.73±17.02. The MLHFQ scores were significantly lower in group A vs. group B (p = 0.001) and group C (p <0.001) and in group B vs. group C (p = 0.012) (Figure 3).
A significant negative correlation was found betwe-en the MLHFQ scores and LVEF (r = -0.832, p<0.001) and also 25-OH vitamin D₃ (r=-0.493, p <0.001) (Fi-gure 4).
There was a significant correlation between seve-rity of HF and anxiety-depression overall batch scores (Table 5): for HAD A score (p<0.011) and for HAD D score (p<0.033).
The analysis of correlations between HAD A and HAD D scores with severity of heart failure and risk factors (lipid parameters TC, HDL-C, LDL-C and TGL and mean values of SBP and DBP) revealed a significant positive correlation between HAD A scores and LDL cholesterol values (r=0.133, p=0.025) (Table 6).

DISCUSSION
The Minnesota Living with Heart Failure Questionna-ire was designed by Rector, Kubo, & Cohn in 1987 as a specifi c tool for use in clinical and community trials for quality of life assessment in HF12. The MLHFQ is a very useful tool because it is cost-free, self-administe-red and easy to understand even by elderly patients, being validated by clinicians.
In the present study we observed that the MLHFQ scores are signifi cantly increased in HF patients accor-ding to severity of disease. Numerous recent studies have demonstrated a relationship between LVEF va-lues and the MLHFQ scores9,13 or between LVEF and 25-OH vitamin D₃ levels14,15, but no study has asso-ciated this marker with quality of life in heart failure patients.
A transversal multicenter study, conducted by Fo-tos et al., included 199 patients with HF who were hospitalized at the Department of Cardiology of three general hospitals in Greece over a 1 year period. Clini-cal data were obtained from the reviewed medical files and the quality of life of patients was assessed using the Minnesota Living with Heart Failure Questionnai-re. The results of this study have shown that patients with associated diabetes had a significantly lower qua-lity of life16.
The MLHFQ score in our study was 68.73±21.47, higher than reported by the Fotos et al. study, indi-cating poor health status perceived by patients in our country. This is a matter of concern, given that the mean age of the subjects included in our study, 68.94±9.19, was lower compared to 69.97±9.87 years in Fotos et al. study. The patients completed the ques-tionnaire during hospitalization, not at admission like our patients, when most of them are anxious, a situa-tion generally accompanied by lower scores.
In a recent article Bilbao et al., analyze the constitu-ent parts of the questionnaire, noting that the largest discrepancies are related to the items referring to phy-sical health factors. Although the two initial subscales: physical health (items 2,3,4,5,6,7,12,13) and emotional health (items 17,18,19,20,21) have been validated and applied in many countries (China, Korea, Greece), the authors consider that it is also necessary to validate the social subscale due to the different social situation of HF patients in the world9. Heo et al., proposed that this subscale be analyzed separately17.
Improvement of the MLWHFQ score occurs in all these studies through educational and pharmacologi-cal interventions. The results of our study should be interpreted with caution because of the limitations im-posed by the small number of patients, but compared with other studies the fact that we included the same number of patients in every group increases the power of comparisons. The validity of the results of this study could have been improved by comparing them with other quality of life questionnaires and by correlation with other objective tests (eg. 6 minutes walk test). The better scores in other studies are correlated with the obedience to complete the questionnaire.
In our study, mean serum 25-OH vitamin D₃ levels were significantly correlated with LVEF (p<0.001). These results are in line with similar published findings as confirmed in previous studies18,19. Quality of life and vitamin D₃ defi cit in heart failure patients are closely linked and can cause HF aggravation20. In terms of car-diovascular risk assessment, vitamin D is a marker of increased arterial stiffness, as shown in numerous stu-dies21. Vitamin D deficit is also being suggested to play a key role in depression onset in HF patients22.
These results demonstrate a strong connection between vitamin D deficit and quality of life measured by the MLHFQ, and anxiety and depression measured by HAD scale, suggesting that correction of vitamin D deficit could improve parameters of vascular rigidity, depression and prognosis in heart failure patients.

LIMITATIONS OF THE STUDY
This study had a relatively small sample size. Large multicentre clinical studies are required to confirm our findings.
In conclusion, this study demonstrated that vitamin D defi ciency in patients with chronic heart failure is significantly correlated with the severity of heart fai-lure and decreased quality of life, anxiety and depres-sion and could be used as a marker of increased risk. Further studies are needed to confirm the utility of vitamin D supplementation for clinical and functional improvement of these patients.
Conflict of interests: none declared.
Financial support: This paper was published under the frame of European Social Fund, Human Resources Development Operational Programme, project no. POSDRU 159/1.5/S/136893: “Strategic partnership for the increase of the scientific research quality in me-dical universities through the award of doctoral and postdoctoral fellowships – DocMed.Net_2.0”.

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