Effect of vitamin supplementation in patients of congestive heart failure deficient in vitamin D: A study at a tertiary care center of North India.

Introduction: Heart Failure is a leading cause of mortality worldwide including India. Most cross sectional studies have demonstrated heart failure is associated with deficiency of essential micronutrients including Vitamin D which may play a important role in pathogenesis of ventricular remodelling in heart failure. Aim: Our study performed aimed to determine the effect of supplementation in patients of Heart Failure presenting with Vitamin D deficiency to our institute on severity of Heart Failure. Design and Method: 97 patients of Heart failure coming to our institute were given conventional therapies for Heart Failure along with Vitamin supplementation based on serum Vitamin D levels and followed up for 3 months.
Results: Patient of Heart failure having Vitamin D deficiency had significant reduction in cardiac biomarkers (NT-pro BNP levels), improvement in Left ventricular ejection fraction (LVEF) and more favourable reverse remodelling determined by Left ventricular end diastolic and systolic diameter (LVEDD & LVESD) though quality of life determined by WHODAS 2.0 score did not changed following 12 weeks supplementation of High Dose Vitamin D.
Conclusion: Recognising and treatment of Vitamin D deficiency may determine long term prognosis in patients of Heart Failure.

INTRODUCTION

Congestive heart failure is a condition characterized by failure of the heart to pump adequately as a result of ineffective work done by the cardiac muscles, resulting in high venous filling pressure and systemic venous congestion.[1] Despite new therapy available for the medical management of heart failure, mortality and morbidity associated with heart failure remains high. Possible explanation lies in the fact that pharmacological therapy is unsuccessful in addressing the energy requirement which is often altered in a catabolic state like heart failure. Cardiac myocytes to maintain their contractile function require continuous supply of high-energy substrates including micronutrients. Most of the cross-sectional studies have demonstrated that heart failure is associated with deficiency of essential micronutrients. Thus, the correction of these deficiencies may play an important role in limiting or even possibly reversing the progressive myocyte dysfunction/necrosis or apoptosis which characterize heart failure.[2]

Vitamin D deficiency is common in heart failure patients because poor work capacity results in sun avoidance in these patients. Vitamin-D receptor has been found to have a cardioprotective role through its anti-inflammatory, anti-fibrotic, and anti-apoptotic effect on cardiac myocytes.[3] Cardiac muscle possess Vitamin D receptor and a calcitriol-dependent calcium-binding protein. Furthermore, a voltage-dependent calcium channel which gets activated by calcitriol coexists in these muscles. Experimental studies have found that Vitamin-D receptor suppresses T2-helper cell-mediated inflammation of the heart.[4] Vitamin D receptor activation through calcitriol and paricalcitol causes improvement in capillary deficit and could potentially limit the degree of fibrosis of the heart thus playing a key role in reducing left ventricular hypertrophy.[5] Vitamin D deficiency causes secondary hyperparathyroidism and increased circulating levels of parathyroid hormone (PTH). PTH has been found to activate protein kinase C (PKC) of cardiac myocytes. Activation of this PKC leads to the activation of fetal protein in cardiac myocytes and other hypertrophic growth factors which leads to left ventricular hypertrophy. Furthermore, PTH-related peptide (PTH-rP) is widely expressed in heart cells predominantly in the atria also in ventricles and smooth muscles and plays an important role in cardiac contractile function and adenylate cyclase-mediated vasodilation. Increased PTH level in secondary hyperparathyroidism may attenuate the action of PTH-rP by competing with it for bindings to same receptors due to both being structurally similar thus possible playing a role in cardiac contractile dysfunction.[6] Low level of circulating Vitamin D has thus been found to be directly contributing to the pathogenesis and symptomatology of heart failure.[7] Thus, possible mechanism by which Vitamin D supplementation can reduce disease progression and symptoms severity includes

Negative regulation of activity of the renin- angiotensin-aldosterone system, which has a key role in the pathogenesis of remodeling of the left ventricle following heart failure

Suppression of PTH which in multiple studies has been found to be independently associated with an increased risk of heart failure in the general population[8]

Inflammatory mediators tumor necrosis factor-alpha and interleukin-6 are down regulated. Vitamin-D affects the transcription of COX, NF-Kb, and activates signal cascades such as MAP kinase which are important in inflammation pathway

Directly promotes cardiac myocytes growth and differentiation by means of Vitamin-D receptor

In the endothelium, it regulates the activity of nitric oxide/peroxynitrite and help in normal functioning of the cardiac myocytes.

Studies to determine the level of deficiencies of these micronutrients in patients of heart failure and other cardiovascular diseases and impact of their correction using supplementation on the disease progression are far and few. These could be a potential target for research into the new treatment options and could prove to be an economical and easily accessible therapeutic benefit, especially in a resource-limited country like India with a high degree of prevalence of cardiovascular diseases and lack of facilities for advanced heart care. Our study aims to determine the degree of prevalence of these vitamin deficiencies in patients of heart failure coming to our institute and whether the correction of these deficiencies does have an impact on clinical and laboratory outcomes based on cardiac biomarkers, left ventricular functioning and improvement in the disability level, and quality of life in these patients in a short-term follow-up.

MATERIALS AND METHODS

Participants

Patients from the department of general medicine and cardiology who were age >18 years and diagnosed as congestive heart failure based on Framingham Heart Failure Diagnostic criteria[9] were recruited for the study. The data were collected over a period of 15 months from January 2019 to April 2020. The exclusion criteria included those patients who had underlying malignancy, sarcoidosis, chronic kidney disease, taking Vitamin D supplements, had NYHA class IV symptoms or history of hospitalization in the follow-up period. At the end of the study period, 97 patients were analyzed for the final outcome.

Ethics approval

The study was approved [Annexure 1] by the Institutional Ethical Committee, and informed consent was obtained from all the participants. It should be noted that the present study complied with the declaration of Helsinki.

Disability index

The disability index was assessed using the WHODAS 2.0 12 point questionnaire.

Biochemical measurements

1. NT-pro BNP is measured using Nano-check™ NT-pro BNP test which is an immunochromatography assay, the device used to test is Nano-checker 710 reader. The total circulating serum 25(OH)-D concentration was determined by the electrochemiluminescence immunoassay method in the Department of Biochemistry, AIIMS, Rishikesh, India. The intra-assay and inter-assay coefficients of variations were 4.5% and 8.5%, respectively. Serum calcium and phosphorus were measured by the colorimetric method. PTH was measured using immunoassay (Immulite 1000; Siemens Medical Solutions Diagnostics, Los Angeles, CA) with an average intraassay variability of 3.2%. Patients with 25 (OH)D levels of >30 ng/mL were classified as “normal,” whereas levels of 20–29.9 ng/mL were considered “insufficient,” and levels of <20 ng/mL were “deficient.

Echocardiographic examination

Transthoracic echocardiography was performed in all patients with Philips Epiq 7C Echo-cardiography machine with 2.5-MHz multifrequency phased array transducer. Digital routine gray scale 2-dimensional and tissue Doppler cine loops from three consecutive beats were obtained at end-expiratory apnea from standard apical views at depths of 12–20 cm. Gain settings were adjusted for routine gray scale 2D imaging to optimize endocardial definitions. Routine digital gray scale 2-D and tissue Doppler cine loops were obtained, including mid-LV short axis views at the level of the papillary muscle and standard apical views (4-chamber, 2-chamber, and long-axis). Sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Ejection fractions were obtained with the modified biplane Simpson's method from the apical 2-and 4-chamber images using the biplane Simpson's technique. All measurements were made in >3 consecutive cardiac cycles and in >5 cycles if the patient's rhythm was AF and average values were used for the final analyses.

The pulsed-wave Doppler-derived transmitral flow profile and digital color tissue Doppler-derived mitral annular velocity were obtained from the apical four-chamber view. The mitral flow early diastolic wave velocity (E), late diastolic atrial contraction wave velocity (A), and the E-wave deceleration time (E-DcT) were measured; spectral pulsed-wave tissue Doppler-derived peak systolic velocity (s′), early diastolic velocity (e′), late diastolic velocity (a′), and the E/e′ ratio were calculate to estimate diastolic dysfunction.

Study procedure

All the patients fulfilling the inclusion criteria were informed about the methodology of this study. Informed and written consent was taken in English, Hindi/local language as per patient convenience. Detailed history, physical examination, blood pressure measurement, serum Vitamin D, serum Vitamin B12, intact-PTH, and NT-pro-BNP levels were measured. Echocardiography was performed in all participants to determine left ventricular ejection fraction (LVEF %), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), and baseline WHODAS 2.0 score were calculated. ECHO was performed by single observer to remove bias caused by intraobserver variation. Those who were found to be deficient in Vitamin D (<20 ng/ml) were given Vitamin B12 and Vitamin D supplementation for 12 weeks Vitamin D were given as Vitamin D3 (Cholecalciferol 60000 IU) once a week for 12 weeks. These supplements were adjuvant to conventional therapy for heart failure and not substitution, i.e., depending upon functional status patient received Beta-blockers (Metoprolol/Carvedilol), ACE inhibitors (Ramipril), ± Aldosterone antagonist (Spironolactone), antiplatelets, statins, and other drugs in approved doses. After 12 weeks, NT-pro-BNP (pg/ml), LVEF (%), LVESD (mm), LVEDD (mm) through 2D ECHO, and improvement in disability based on WHODAS 12 questionnaire was determined, and the changes from the baseline were compared in different groups.

Statistical analysis

All analyses were conducted by the Statistical Package for the Social Sciences software, version 21 (SPSS Inc., Chicago, IL, USA). Quantitative variables were compared using the Independent t-test/Wilcoxon–Mann–Whitney test (when the data sets were not normally distributed) between the two groups. Qualitative variables were correlated using the Chi-square test/Fisher's exact test. Relationships were assessed using the Pearson or Spearman tests depending upon distribution. P < 0.05 was considered statistically significant.

RESULTS

Patient characteristics

In our study, 51.5% of the participants were male and 48.5% of the participants were female. The mean age (years) was 53.77 ± 13.02 and ranged from 21 to 81. The most common cause for heart failure in our study was found to be Coronary Artery Disease which accounted for 52.5% of the cases, followed by dilated cardiomyopathy which accounted for 31.2% of the cases. The most common comorbidity was found to be hypertension which was present in 47.4%, followed by COPD which was found in 35.1% of the patients and diabetes in 21.6%. The demographics of the cohort involved in the study is given in Table 1.

Table 1

Demographics of the study population

Characteristics	Mean/No of Patients
Age (years)	54.18±13.71
BMI (kg/m2)	22.73±3.44
Gender, n (%)
Male	47 (48.5)
Female	50 (51.5)
Location, n (%)
Rural	72 (74.2)
Urban	25 (25.8)
Comorbidities, n (%)
HTN	46 (47.4)
Diabetes	21 (21.6)
Dyslipidemia	12 (12.4)
COPD	34 (35.1)
Obesity	6 (6.2)
Hypothyroidism	9 (9.3)
Systolic BP	131.28±20.81
Diastolic BP	81.84±16.48
Etiology of heart failure, n (%)
CAD	51 (52.5)
DCMP	31 (32)
Arrythmia	4 (4.1)
Cor pulmonale	7 (7.2)
RHD	3 (3.1)
Postpartum cardiomyopathy	3 (3.1)
NYHA class, n (%)
Class 1	3 (3.1)
Class 2	74 (74.2)
Class 3	22 (22.)
Heart failure pharmacotherapy, n (%)
Beta blockers	92 (92.4)
ACE-I inhibitors	95 (95.7)
Spironolactone	77 (79.4)
Antiplatelets	55 (56.7)
Statins	68 (70.15)
Diuretics	97 (100)
Digoxin	3 (3.09)

BMI=Body mass index, HTN=Hypertension, COPD=Chronic obstructive pulmonary disease, CAD=Coronary artery disease, DCMP=Dilated cardiomyopathy, RHD=Rheumatic heart disease, NYHA=New York Heart Association, ACE=Angiotensin-converting enzyme, BP=Blood pressure

Biochemical characteristics

Among 97 CHF patients, 17.5% had Vitamin D insufficiency, 55.7% had deficiency at the time of enrolment. 26.8% of the participants in the study had a sufficient serum concentration of 25 (OH) D > 30 nmol/L [Table 2]. Serum i-PTH was significantly correlated with 25 (OH) D (r = −0.820, P < 0.001) [Figure 1].

Table 2

Distribution of the participants in terms of serum Vitamin-D (n=97)

Serum Vitamin-D	Frequency (%)
<20 ng/mL (deficient)	54 (55.7)
20-30 ng/mL (insufficient)	17 (17.5)
>30 ng/mL (sufficient)	26 (26.8)
Total	97 (100.0)

Figure 1

Scatterplot showing correlation between i-PTH and 25-(OH) Vitamin D levels

Comparison of cardiac markers, Left Ventricular Function (LVEF, LVEDD, LVESD) and WHODAS 2.0 score at baseline and after 12 weeks

Table 3 shows Cardiac biomarkers, left ventricular ejection fraction left ventricular end diastolic diameter, left ventricular end systolic diameter, WHODAS score of the two groups (Vitamin D deficient n=54 vs Vitamin D not received n=43) at baseline and after 12 weeks.

Table 3

Cardiac biomarkers, left ventricular ejection fraction left ventricular end diastolic diameter, left ventricular end systolic diameter, WHODAS score of the two groups at baseline and after 12 weeks

Parameters	At baseline		At 12 weeks
	Vitamin D received (n=54)	Vitamin D not received (n=43)	Vitamin D received (n=54)	Vitamin D not received (n=43)
NT-pro BNP (pg/mL)	5236.83 (2777.60)	4218.98 (2507.18)	1386.50 (689.86)	1810.57 (862.46)
LVEF (%)	38.06 (9.54)	36.28 (8.87)	39.26 (9.97)	35.00 (9.51)
LVEDD (mm)	55.89 (5.46)	57.35 (7.11)	55.19 (5.54)	57.33 (7.41)
LVESD (mm)	44.52 (5.72)	45.53 (7.43)	43.83 (5.74)	45.56 (7.62)
WHODAS score	28.54 (7.27)	31.88 (6.61)	27.28 (7.70)	30.91 (6.89)

LVEF=Left ventricular ejection fraction, LVEDD=Left ventricular end diastolic diameter, LVESD=Left ventricular end systolic diameter

Vitamin D correlation with echocardiographic findings

There was no significant difference between the various groups in terms of distribution of diastolic dysfunction (X^2 = 0.080, P = 0.936) [Table 4].

Table 4

Differences between group in terms of serum 25-(OH) Vitamin-D levels and diastolic dysfunction

Diastolic dysfunction	Serum Vitamin-D, n (%)				Fisher’s exact test
	<20 (ng/mL)	20-30 (ng/mL)	>30 (ng/mL)	Total	χ 2	P
Present	45 (83.3)	14 (82.4)	21 (80.8)	80 (82.5)	0.080	0.936
Absent	9 (16.7)	3 (17.6)	5 (19.2)	17 (17.5)
Total	54 (100.0)	17 (100.0)	26 (100.0)	97 (100.0)

Effect of vitamin supplementation

After supplementation, there was a significant decrease in NT-pro BNP (3850.33 vs. 2408.41), and this difference was statistically significant (P < 0.001) Table 5]. Furthermore, those who had Vitamin D deficiency and received supplementation showed improvement in LVEF (%) (1.02 vs. −0.58, P = 0.018), decreased in LVEDD (−0.70 vs. −0.02, P = 0.001), and LVESD (−0.69 vs. 0.02, P < 0.001). However, there was no significant difference between the groups in terms of decrease in WHODAS 2.0 Score (P = 0.281).

Table 5

Comparison of the two groups in follow up

Parameters	Vitamin D supplementation, mean±SD		P
	Received (n=54)	Not received (n=43)
Change in NT pro BNP levels from baseline***	3850.33±2284.89	2408.41±1792.72	0.001a
Decrease in NT-pro BNP levels in %***	70.76±10.44	51.18±16.25	<0.001a
Change in LVEF (%)***	1.02±2.61	−0.58±2.21	0.018a
Change in LVEDD (mm)***	−0.70±0.84	−0.02±0.86	0.001a
Change in LVESD (mm)***	−0.69±0.77	0.02±0.83	<0.001a
Change in WHODAS 2.0 score	−1.26±2.27	−0.98±1.47	0.281a

LVEF=Left ventricular ejection fraction, LVEDD=Left ventricular end diastolic diameter, LVESD=Left ventricular end systolic diameter, SD=Standard deviation, *** Significant at p<0.05, a Wilcoxon Tes

DISCUSSION

Ours was one of the few studies that identified the prevalence of Vitamin D deficiency in heart failure patients, correlated their levels with cardiac biomarkers and left ventricular functioning and identified whether correction of these deficiencies using supplementation had a significant effect and explored its potential therapeutic benefits. The strength of our study lied in the fact that >90% of the patient received the standard therapy for heart failure (beta blockers and ACE-inhibitors) and Vitamin Supplements were used only as an adjuvant in the intervening groups thus minimizing the bias associated with the treatment.

Our study showed there was a strong negative correlation between baseline LVEF (%) and NT-pro BNP (pg/mL), and this correlation was statistically significant. The findings concurs with those done by Dong et al.[10] who had concluded that NT-pro BNP levels correlated negatively with LVEF.

Our study showed a statistically significant negative correlation between Vitamin D and i-PTH levels. These findings were similar to the findings of the study done by Zittermann et al.[7] Since i-PTH plays an important role in ventricular remodeling in heart failure through PTH-receptors and increased PTH levels are associated with increased hospitalization[11] those having Vitamin D deficiency with increased baseline i-PTH due to secondary hyperparathyroidism may have increased morbidity and worse survival outcome. Hence, prompt determination and treatment of Vitamin-D deficiency may be required in these individuals to alter the pathological ventricular remodeling associated with heart failure.

A study done by Palazzuoli et al. had shown that there is a significant association between baseline NT-pro BNP and Vitamin-D levels with NT-pro BNP tends to be higher in those having low serum level of 25-(OH) Vitamin D.[12] However, in our study, there was no significant correlation between either serum Vitamin-D or Vitamin B12 levels with NT-pro BNP levels.

Akin et al. in a longitudinal study had demonstrated lower 25(OH) level were associated with higher isovolumic relaxation time, and E/E′ ratio (diastolic dysfunction).[13] However, our study found no correlation between baseline Vitamin D levels and diastolic dysfunction. In our study, no correlation was found between baseline Vitamin-D level and LVEF, LVEDD, LVESD which was in contrast to the findings Polat et al. who had concluded that serum Vitamin-D level significantly correlated with Left ventricular parameters (LVEF, LVESD, and LVEDD).[14]

Our study found that the decrease in NT-pro BNP from baseline was higher among the Vitamin D deficiency participants who received Vitamin D supplementation for 12 weeks compared to those who did not receive supplementation this difference was statistically significant. These findings concur with previous study by Witham et al.[15] who had revealed a substantial fall in BNP levels after 10 weeks of Vitamin D2 therapy. However, Schleithoff et al. believed that Vitamin D supplementation did not significantly affected the concentrations of the natriuretic factors.[16] NT-pro BNP levels are prognostic markers in patients of heart failure.[17] The percentage reduction in NT-pro BNP predicts long-term cardiovascular mortality.[18] Thus, recognizing and correcting Vitamin-D deficiency with long-term supplementation may cause significant reduction in NT–pro BNP levels in heart failure patient and may lead to long-term favorable survival outcomes in these patients.

Similarly those who received Vitamin D supplementation versus those who did not showed a small but significant change in LVEF. Furthermore, significant differences were noted in the change in LVEDD, LVESD in group receiving Vitamin D. This decrease in the left ventricular parameters favors the reverse ventricular remodeling in those patients who received Vitamin-D supplementation. Similar results were found in the Vindicate trial[19] where the follow-up period was for 1 year, and the degree of reverse modeling was more evident.

Following initiation of therapy for heart failure, participants in all the groups showed improvement in degree of disability and quality of life in follow-up as evident by decrease in WHODAS 2.0 score in follow-up. However, no significant differences were found between the group of participants.

CONCLUSION

Heart failure continues to be a major problem in the Indian setting. Despite major advances in the treatment strategies outcomes always does not seem favorable. Due to limited availability of centers with advanced heart care, there is a need to review the current treatment strategies and search for other minor aspects associated with the disease which play a crucial role in determining long-term outcomes. This study showed that addressing the nutritional deficiencies in heart failure could be one of the areas of interest. Our studied showed that Vitamin D being an important regulator of the cardiac function, those having low circulating levels of 25-(OH)-Vitamin D may have depressed myocardial function and thus addressing its deficiency had a significant impact on the cardiac stretch biomarkers and ventricular remodeling determined by LVEDD, LVESD, and ventricular functioning based on LVEF. Our study provides sufficient data to conduct large scale clinical trials with high dose of Vitamin D in heart failure patients.

Learning points

What is already known?

High degree of prevalence of Vitamin D deficiency in heart failure patients.

What this study adds?

No significant association was noted between baseline Vitamin D with cardiac biomarkers (NT-pro BNP) and left ventricular function (LVEF, LVESD, LVEDD, and diastolic dysfunction

High-dose Vitamin D supplementation in deficient participants significantly reduced the cardiac stretch biomarkers (NT-pro BNP). Hence, by influencing the circulating cardiac markers level, Vitamin D could influence long-term prognosis of patients with heart failure with underlying Vitamin D deficiency

Vitamin D supplementation causes slight but significant improvement in LVEF. However, also its effect on the left ventricular dimensions (LVEDD and LVESD) warrants the need of further large scale trials with advance techniques like CMR to correlate better with the degree of improvement and longer duration of follow-up evaluate true favored effect toward degree of reverse modeling.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.