Accepted Manuscript Relation of vitamin D deficiency and new-onset atrial fibrillation among hypertensive patients Ozgur Ulas Ozcan, MD, Consultant, Adalet Gurlek, MD, Professor of Cardiology, Eren Gursoy, MD, Consultant, Demet Menekse Gerede, MD, Consultant, Cetin Erol, MD, Professor of Cardiology PII:
S1933-1711(15)00014-5
DOI:
10.1016/j.jash.2015.01.009
Reference:
JASH 636
To appear in:
Journal of the American Society of Hypertension
Received Date: 2 December 2014 Revised Date:
8 January 2015
Accepted Date: 13 January 2015
Please cite this article as: Ozcan OU, Gurlek A, Gursoy E, Gerede DM, Erol C, Relation of vitamin D deficiency and new-onset atrial fibrillation among hypertensive patients, Journal of the American Society of Hypertension (2015), doi: 10.1016/j.jash.2015.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Relation of vitamin D deficiency and new-onset atrial fibrillation among hypertensive patients
RI PT
Short title: Vitamin D deficiency and atrial fibrillation Ozgur Ulas Ozcan1, MD, Consultant
Eren Gursoy1, MD, Consultant
M AN U
Demet Menekse Gerede1, MD, Consultant
SC
Adalet Gurlek1, MD, Professor of Cardiology
Cetin Erol1, MD, Professor of Cardiology
1: Ankara University, Cardiology Department, Ankara, Turkey
TE D
Address for correspondence: Ozgur Ulas Ozcan, MD Ankara University, School of Medicine, Cardiology Department
EP
Postal address: Ovecler 1042nd street 45/14. 06460 Cankaya-Ankara/Turkey
Fax:
AC C
Email: [email protected] +90 312 264 78 00
GSM: +90 505 707 76 70
Funding Source: This study is funded by Turkish Society of Cardiology with a grant number X306.
ACCEPTED MANUSCRIPT
ABSTRACT Introduction: Vitamin D deficiency is associated with various cardiovascular disorders including
RI PT
hypertension, coronary artery disease and heart failure. Renin-angiotensin-aldosterone system (RAS) axis is activated in vitamin D deficiency. RAS axis also plays a role in the pathophysiology of AF. We aimed to investigate whether vitamin D deficiency is a risk factor for the development
SC
of new-onset AF in hypertension.
Methods: A total of 227 hypertensive patients were enrolled, of whom 137 had new-onset atrial
M AN U
fibrillation and 90 patients without AF were included in the control group.
Results: Age of the patient, left atrial diameter and vitamin D deficiency increased the probability of new-onset AF independent from confounding factors [(OR: 1.04, 95% CI 1.01-1.08,
TE D
p=0.03 for age), (OR: 1.88, 95% CI 1.15-3.45, p=0.03 for left atrial diameter), (OR: 1.68, 95% CI 1.18-2.64, p=0.03 for vitamin D deficiency)].
EP
Conclusions: Vitamin D deficiency is associated with new-onset AF in hypertension. Keywords: atrial fibrillation, hypertension, renin-angiotensin-aldosterone system, vitamin D
AC C
deficiency.
ACCEPTED MANUSCRIPT
INTRODUCTION Atrial fibrillation (AF), an important cause of cardiac mortality and morbidity is the most
RI PT
common type of cardiac arrhythmia in clinical practice [1]. Hypertensive individuals are at particular risk of development of atrial fibrillation [2, 3]. Renin-angiotensin-aldosterone system (RAS) that is activated in hypertension may be the underlying mechanism of AF among
SC
hypertensive patients [4-6].
Vitamin D deficiency has been shown to be involved in the pathogenesis of hypertension, heart
M AN U
failure, cardiovascular disease, and obesity, which are conventional risk factors for the development of AF [7-9]. Increased RAS activity is one of the postulated mechanisms by which vitamin D deficiency may trigger the development of hypertension and various cardiovascular diseases [10, 11]. On the basis of these data, we hypothesized that vitamin D deficiency might
TE D
be associated with new-onset AF among patients with hypertension. MATERIALS AND METHODS
EP
A hospital-based case-control study was carried out to assess the relationship between vitamin
AC C
D status and the development of new-onset atrial fibrillation in the hypertensive cohort. We aimed to generate etiological hypothesis that can then be tested in specifically designed prospective cohort studies. Study patients
The study was conducted during the winter and spring months between 2012 and 2014. Incident cases of hypertensive patients presented with new-onset atrial fibrillation at the
ACCEPTED MANUSCRIPT
Ankara University Hospital during study period were identified, and information on their demographic and clinical characteristics was obtained. Controls were selected from age and sex matched hypertensive patients without AF. Hypertension was defined as blood pressure ≥
RI PT
140/90 mmHg or a history of antihypertensive drug use. Atrial fibrillation was diagnosed with an electrocardiogram that demonstrated the absence of P waves and an irregular ventricular rate. New-onset AF was defined as AF identified for the first time by an electrocardiogram or
SC
ambulatory Holter monitoring. Patients were excluded if they had established coronary artery
M AN U
disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, significant heart valve disease, hyperthyroidism, renal failure, any malignancy, acute infection, they had undergone recent thoracic or abdominal surgery or they were under therapy of vitamin D3 in both AF and control groups. Coronary artery disease was defined as the presence of a history of
TE D
myocardial infarction or angiographic evidence of greater than 50% diameter narrowing in any of the major epicardial coronary arteries on coronary angiography. Heart failure was identified by presence of clinical signs or symptoms of heart failure or echocardiography with left
EP
ventricular ejection fraction lower than 50%. Clinical diagnosis of chronic obstructive pulmonary disease was confirmed by spirometry. Diabetes mellitus was defined as fasting blood glucose
AC C
level ≥126 mg/dl or use of hypoglycemic drugs. Significance of heart valve disease was established according to the guideline for valvular heart disease which was contributed by European Society of Cardiology [12]. Hyperthyroidism was defined as clinical symptoms associated with decreased thyroid stimulating hormone levels and elevated serum levels of thyroxine. Renal failure was defined as a serum creatinine level ≥2 mg/dl.
ACCEPTED MANUSCRIPT
A total of 227 hypertensive patients were enrolled, of whom 137 had new-onset atrial fibrillation and 90 patients without AF were included in the control group (figure 1). All patients provided written, informed consent. This study complied with the Declaration of Helsinki and
ClinicalTrials.gov (identifier NCT02298738).
SC
Laboratory tests
RI PT
was approved by the institutional committee on human research and registered at
Blood samples were collected to measure serum levels of creatinine, calcium and 25 hydroxy
M AN U
(OH) vitamin D, following a fasting period of 8 hours. Serum 25(OH) vitamin D levels were measured by chemiluminescent immunoassay using a LIAISON analyzer (DiaSorin Inc., MN, USA). Plasma levels of 25 OH vitamin D, precursor of 1, 25 dihydroxy vitamin D, were measured due to its relatively long half-life. Vitamin D deficiency was defined as serum levels of 25 OH
TE D
vitamin D 30 ng/mL was defined as normal. All plasma samples were assayed
EP
in duplicate, and the mean intra-assay coefficient of variation (CV) was 5.8%. The inter-assay CV from 3 samples assayed in duplicate was 7.4%.
AC C
Statistical analysis
Data are expressed as frequencies for discrete variables and as means ± standard deviation for continuous variables. Shapiro-Wilk test assessed distribution of data. Continuous variables were compared by Student’s unpaired t-test or Mann–Whitney U-test according to the distribution of data. The chi-square analysis or Fisher exact test was used to assess the significance of differences between dichotomous variables. In univariate logistic regression analysis; age, sex,
ACCEPTED MANUSCRIPT
body mass index, smoking status, hyperlipidemia, use of statins, beta-blockers, angiotensinconverting enzyme inhibitor or calcium channel blockers, serum levels of creatinine, calcium and 25 OH vitamin D, left atrial diameter, left ventricular ejection fraction, pulmonary arterial
RI PT
systolic pressure, and presence of vitamin D deficiency were assessed. Univariate correlates of new-onset atrial fibrillation with a p value
S1933-1711(15)00014-5
DOI:
10.1016/j.jash.2015.01.009
Reference:
JASH 636
To appear in:
Journal of the American Society of Hypertension
Received Date: 2 December 2014 Revised Date:
8 January 2015
Accepted Date: 13 January 2015
Please cite this article as: Ozcan OU, Gurlek A, Gursoy E, Gerede DM, Erol C, Relation of vitamin D deficiency and new-onset atrial fibrillation among hypertensive patients, Journal of the American Society of Hypertension (2015), doi: 10.1016/j.jash.2015.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Relation of vitamin D deficiency and new-onset atrial fibrillation among hypertensive patients
RI PT
Short title: Vitamin D deficiency and atrial fibrillation Ozgur Ulas Ozcan1, MD, Consultant
Eren Gursoy1, MD, Consultant
M AN U
Demet Menekse Gerede1, MD, Consultant
SC
Adalet Gurlek1, MD, Professor of Cardiology
Cetin Erol1, MD, Professor of Cardiology
1: Ankara University, Cardiology Department, Ankara, Turkey
TE D
Address for correspondence: Ozgur Ulas Ozcan, MD Ankara University, School of Medicine, Cardiology Department
EP
Postal address: Ovecler 1042nd street 45/14. 06460 Cankaya-Ankara/Turkey
Fax:
AC C
Email: [email protected] +90 312 264 78 00
GSM: +90 505 707 76 70
Funding Source: This study is funded by Turkish Society of Cardiology with a grant number X306.
ACCEPTED MANUSCRIPT
ABSTRACT Introduction: Vitamin D deficiency is associated with various cardiovascular disorders including
RI PT
hypertension, coronary artery disease and heart failure. Renin-angiotensin-aldosterone system (RAS) axis is activated in vitamin D deficiency. RAS axis also plays a role in the pathophysiology of AF. We aimed to investigate whether vitamin D deficiency is a risk factor for the development
SC
of new-onset AF in hypertension.
Methods: A total of 227 hypertensive patients were enrolled, of whom 137 had new-onset atrial
M AN U
fibrillation and 90 patients without AF were included in the control group.
Results: Age of the patient, left atrial diameter and vitamin D deficiency increased the probability of new-onset AF independent from confounding factors [(OR: 1.04, 95% CI 1.01-1.08,
TE D
p=0.03 for age), (OR: 1.88, 95% CI 1.15-3.45, p=0.03 for left atrial diameter), (OR: 1.68, 95% CI 1.18-2.64, p=0.03 for vitamin D deficiency)].
EP
Conclusions: Vitamin D deficiency is associated with new-onset AF in hypertension. Keywords: atrial fibrillation, hypertension, renin-angiotensin-aldosterone system, vitamin D
AC C
deficiency.
ACCEPTED MANUSCRIPT
INTRODUCTION Atrial fibrillation (AF), an important cause of cardiac mortality and morbidity is the most
RI PT
common type of cardiac arrhythmia in clinical practice [1]. Hypertensive individuals are at particular risk of development of atrial fibrillation [2, 3]. Renin-angiotensin-aldosterone system (RAS) that is activated in hypertension may be the underlying mechanism of AF among
SC
hypertensive patients [4-6].
Vitamin D deficiency has been shown to be involved in the pathogenesis of hypertension, heart
M AN U
failure, cardiovascular disease, and obesity, which are conventional risk factors for the development of AF [7-9]. Increased RAS activity is one of the postulated mechanisms by which vitamin D deficiency may trigger the development of hypertension and various cardiovascular diseases [10, 11]. On the basis of these data, we hypothesized that vitamin D deficiency might
TE D
be associated with new-onset AF among patients with hypertension. MATERIALS AND METHODS
EP
A hospital-based case-control study was carried out to assess the relationship between vitamin
AC C
D status and the development of new-onset atrial fibrillation in the hypertensive cohort. We aimed to generate etiological hypothesis that can then be tested in specifically designed prospective cohort studies. Study patients
The study was conducted during the winter and spring months between 2012 and 2014. Incident cases of hypertensive patients presented with new-onset atrial fibrillation at the
ACCEPTED MANUSCRIPT
Ankara University Hospital during study period were identified, and information on their demographic and clinical characteristics was obtained. Controls were selected from age and sex matched hypertensive patients without AF. Hypertension was defined as blood pressure ≥
RI PT
140/90 mmHg or a history of antihypertensive drug use. Atrial fibrillation was diagnosed with an electrocardiogram that demonstrated the absence of P waves and an irregular ventricular rate. New-onset AF was defined as AF identified for the first time by an electrocardiogram or
SC
ambulatory Holter monitoring. Patients were excluded if they had established coronary artery
M AN U
disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, significant heart valve disease, hyperthyroidism, renal failure, any malignancy, acute infection, they had undergone recent thoracic or abdominal surgery or they were under therapy of vitamin D3 in both AF and control groups. Coronary artery disease was defined as the presence of a history of
TE D
myocardial infarction or angiographic evidence of greater than 50% diameter narrowing in any of the major epicardial coronary arteries on coronary angiography. Heart failure was identified by presence of clinical signs or symptoms of heart failure or echocardiography with left
EP
ventricular ejection fraction lower than 50%. Clinical diagnosis of chronic obstructive pulmonary disease was confirmed by spirometry. Diabetes mellitus was defined as fasting blood glucose
AC C
level ≥126 mg/dl or use of hypoglycemic drugs. Significance of heart valve disease was established according to the guideline for valvular heart disease which was contributed by European Society of Cardiology [12]. Hyperthyroidism was defined as clinical symptoms associated with decreased thyroid stimulating hormone levels and elevated serum levels of thyroxine. Renal failure was defined as a serum creatinine level ≥2 mg/dl.
ACCEPTED MANUSCRIPT
A total of 227 hypertensive patients were enrolled, of whom 137 had new-onset atrial fibrillation and 90 patients without AF were included in the control group (figure 1). All patients provided written, informed consent. This study complied with the Declaration of Helsinki and
ClinicalTrials.gov (identifier NCT02298738).
SC
Laboratory tests
RI PT
was approved by the institutional committee on human research and registered at
Blood samples were collected to measure serum levels of creatinine, calcium and 25 hydroxy
M AN U
(OH) vitamin D, following a fasting period of 8 hours. Serum 25(OH) vitamin D levels were measured by chemiluminescent immunoassay using a LIAISON analyzer (DiaSorin Inc., MN, USA). Plasma levels of 25 OH vitamin D, precursor of 1, 25 dihydroxy vitamin D, were measured due to its relatively long half-life. Vitamin D deficiency was defined as serum levels of 25 OH
TE D
vitamin D 30 ng/mL was defined as normal. All plasma samples were assayed
EP
in duplicate, and the mean intra-assay coefficient of variation (CV) was 5.8%. The inter-assay CV from 3 samples assayed in duplicate was 7.4%.
AC C
Statistical analysis
Data are expressed as frequencies for discrete variables and as means ± standard deviation for continuous variables. Shapiro-Wilk test assessed distribution of data. Continuous variables were compared by Student’s unpaired t-test or Mann–Whitney U-test according to the distribution of data. The chi-square analysis or Fisher exact test was used to assess the significance of differences between dichotomous variables. In univariate logistic regression analysis; age, sex,
ACCEPTED MANUSCRIPT
body mass index, smoking status, hyperlipidemia, use of statins, beta-blockers, angiotensinconverting enzyme inhibitor or calcium channel blockers, serum levels of creatinine, calcium and 25 OH vitamin D, left atrial diameter, left ventricular ejection fraction, pulmonary arterial
RI PT
systolic pressure, and presence of vitamin D deficiency were assessed. Univariate correlates of new-onset atrial fibrillation with a p value
