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Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension
Nutrition, Metabolism & Cardiovascular Diseases (2012) 22, 871e876
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension F. Fallo a,*, C. Catena b, V. Camozzi c, G. Luisetto c, C. Cosma d, M. Plebani d, M. Lupia e, F. Tona e, L.A. Sechi b a
Clinica Medica 3, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35128 Padova, Italy b Clinica Medica, Department of Experimental and Clinical Medicine, University of Udine, Italy c Division of Endocrinology, University of Padova, Italy d Department of Laboratory Medicine, University Hospital of Padova, Italy e Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Italy Received 28 February 2011; received in revised form 15 June 2011; accepted 20 June 2011
KEYWORDS Vitamin D; Essential hypertension; Left ventricular hypertrophy
Abstract Background and aim: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH). Methods and results: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18e65 years, with grade 1e2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P Z 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r Z e0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r Z 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P Z 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P Z 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found.
* Corresponding author. Tel.: þ39 049 8212654; fax: þ39 049 8213332. E-mail address: [email protected] (F. Fallo). 0939-4753/$ - see front matter ª 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2011.06.001
872
F. Fallo et al. Conclusions: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH. ª 2011 Elsevier B.V. All rights reserved.
Introduction Vitamin D deficiency, as defined by a serum 25hydroxyvitamin D [25(OH)D] concentration of less than 50 nmol/L, or insufficiency is a highly common condition in the general population [1,2]. Serum 25(OH)D level is the best indicator of overall vitamin D status because the measurement reflects total vitamin D from sunlight-induced skin production and dietary intake, as well as the conversion of vitamin D from adipose stores in the liver [2]. Low serum concentrations of 25(OH)D may have an important role in modifying cardiovascular risk [3,4,5], predisposing to hypertension [6,7,8] and myocardial disease [9,10]. Hypertensive cohorts in prospective studies include however patients with cardiovascular risk factors such as old age, diabetes and/or obesity, which are also negatively associated with vitamin D status [1,5] and are potential confounders. Whether 25(OH)D deficiency is the cause or merely the consequence of cardiovascular disease remains unclear. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, as assessed by echocardiography, in a series of patients with essential hypertension (EH).
hypertension. Renal disease was defined as the presence of serum creatinine greater than 133 mmol/L in men and greater than 120 mmol/L in women. Major metabolic abnormalities were ruled out by the following exclusion criteria: 1) diabetes mellitus, i.e., fasting plasma glucose 7.0 mmol/L on two separate occasions; 2) moderate to severe hyperlipidemia, i.e., serum total cholesterol 6.2 mmol/L and/or triglycerides 2.28 mmol/L; 3) obesity, i.e., body mass index (BMI) 30 kg/m2; 4) alcohol intake >20 g/d; 5) smoking habit, defined as at least one cigarette/day for 1 year within the past 5 years. Patients had been weight-stable over the previous six months. During evaluation, they followed a normal sodium and potassium diet, i.e., 100e200 mmol/ d sodium and 50e70 mmol/d potassium. A group of 24 sex-, age- and BMI-matched normotensive individuals, selected according to the same exclusion criteria, were used as controls. These subjects had the same biochemical and hormonal evaluation, and underwent echocardiography. None of hypertensive and normotensive subjects were receiving medications or had medical history and/or conditions affecting bone metabolism, including intestinal malabsorption or lactose intolerance. Informed consent was obtained in all cases. The study was approved by institutional ethics committees.
Methods Echocardiographic examination Patients In this cross-sectional study, 62 Caucasian patients with EH were studied. At the time of the study, patients (32 male, 30 female) were newly diagnosed and had never been treated with antihypertensive agents. They were consecutively selected from a larger hypertensive population of more than 2500 patients seen at our two hospital-based specialized hypertension outpatient clinics over the past 3 years, with time span of evaluation restricted from early spring to mid-autumn. The latitude of Padova is 45 250 000 N and the latitude of Udine is 46 30 4200 N. Patients were first selected according to the following criteria: 1) age 18e65 years; 2) grade 1e2 hypertension, according to the criteria of the European Society of Hypertension-European Society of Cardiology guidelines, with clinic blood pressure 140/ 90 mm Hg measured by mercury sphygmomanometer in a sitting position in at least three separate casual measurements within the past month [11]; 3) no history or clinical evidence of cardiopulmonary, renal or hepatic disease. The estimated duration of hypertension, obtained by careful investigation of the patient’s history and from family practitioner records, was in all patients less than 1 year. After the initial screening visit at our clinics, all subjects underwent as outpatients further selection. Biochemical, hormonal, and instrumental tests excluded those patients with cardiac and renal disease, and those with secondary
Echocardiography was performed by standardized procedures with SONOS 5500 (Hewlett Packard, HP Co., Palo Alto, CA, USA) or Aplio CV (Toshiba Medical System, Tochigi, Japan). The echocardiographic study protocol recorded at least 10 cycles of two-dimensional parasternal long- and short-axis LV views with optimal orientation of the M-mode cursor beam. The left atrial diameter, LV internal dimensions, inter-ventricular septum, and posterior wall thickness were measured according to the recommendations of the American Society of Echocardiography [12]. End-diastolic relative wall thickness (RWT) (i.e., the ratio of posterior wall thickness to one-half LV internal dimensions) was calculated as index of LV geometric pattern [13]. According to echocardiography recommendations, assessment of LV dimensions was based on the average of five measurements of left ventricular diameters and wall thickness. When optimal orientation of LV M-mode recordings could not be obtained, correctly orientated linear dimension measurements were made using two-dimensional imaging [12]. The LV mass was calculated according to the formula LV mass Z 0.8 [1.04 (inter-ventricular septal thickness þ LV end-diastolic diameter þ posterior wall thickness)3 e (LV end-diastolic diameter)3] þ 0.6 g [12,14]; LV mass index was obtained after normalization of LV mass for height to the 2.7 power (g/m2.7), and LV hypertrophy was defined as a value of LV mass index 51 g/m2.7 in both sexes [15]. In all patients pulsed Doppler recordings at the level of the mitral
Vitamin D and left ventricular hypertrophy valve tips from apical four-chambers two-dimensional views were obtained in order to measure peak early (E-wave) and late diastolic (A wave) flow velocities, their ratio (E/A) and Ewave deceleration time, as measurement of diastolic filling. Diastolic dysfunction was defined by E/A ratio <1 [16] and Ewave deceleration time >220 ms. Two different readers, unaware of the patients’ identity, performed all echocardiographic and Doppler measurements. To test the reproducibility of echocardiography for LV mass and E/A ratio assessment, in 20 subjects the ultrasound study was repeated 2e4 weeks later by each reader. The difference between the two studies averaged for each reader 8.1 4.3 and 7.6 4.0% for LV mass, and 7.1 3.8 and 6.3 3.9% for E/A ratio, respectively.
Laboratory methods In all individuals, blood samples for biochemical and metabolic laboratory measurements were obtained at 08:00 h, after overnight fasting. Serum 25OHD was determined with the DiaSorin LIAISON 25OH total vitamin D kit (Saluggia, Italy), using chemiluminescence technology (CLIA), normal range 76e250 nmol/L (30e100 ng/ml). Serum 1,25-dihydroxyvitamin D [1,25(OH)D] was measured with the RIA IDS kit (Fountain Hills, AZ, USA), normal range 43e148 pmol/l (18e62 pg/ml); serum parathyroid hormone (PTH) was measured using DiaSorin LIAISON N-tactTH PTH kit (Saluggia, Italy), with the CLIA method, normal range 1.8e7.7 pmol/L (17e73 ng/l). For hormone measurements, intra- and inter-assay coefficients of variation were less than 10%. All other biochemical variables were assayed in plasma or serum using standard methods.
Statistical analysis All results are expressed as mean SD for continuous variables and as a percentage for categorical variables. Table 1
873 Continuous data were subjected to the KolmogoroveSmirnov test to determine their distribution. Statistical significance between groups was assessed in normally distributed data by Student t-test for independent samples, and in non-normally distributed data by ManneWhitney U test. Categorical variables were analyzed by the chi-square analysis, or Fisher’s exact test when appropriate. Correlations were assessed by the Pearson’s coefficient or the rank order Spearman’s coefficient. Potential predictors of LV mass were evaluated by univariate linear (when LV mass, the dependent variable, was considered as a continuous variable) regression analysis or logistic (when LV hypertrophy was modeled as categorical variable) regression analysis. Multivariable logistic regression analysis was used to find the independent factors associated with LV hypertrophy, considering only significant predictors of the outcome at univariate analysis. Results were calculated as regression coefficients and values of P associated with Wald test, and odds ratio (OR) and 95% confidence interval (CI) were computed. Statistical significance was assumed if the null hypothesis could be rejected at P < 0.05. Statistical analyses were performed with SPSS 18.0 for Windows software (SPSS Institute Inc., Chicago, Ill., USA).
Results Serum 25(OH)D deficiency, i.e., 25(OH)D levels <50 nmol/ L, was detected in 28 out of 62 hypertensive patients, i.e., in 45.8% of our hypertensive group. Clinical, endocrinemetabolic, and main cardiac parameters of hypertensive patients without and with 25(OH)D deficiency are shown in Table 1. The two groups of patients were similar as to age, sex, systolic and diastolic blood pressure, and heart rate. Between-group comparison analysis showed only two variables to be different in hypertensive patients with 25(OH)D deficiency and in their with 25(OH)D-sufficient counterparts, i.e., LV mass and PTH levels. Left ventricular
Characteristics of hypertensive patients with and without 25-hydroxyvitamin D [25(OH)D] deficiency.
Age (years) Sex (M/F) Body mass index (kg/m2) Systolic BP/diastolic BP (mm Hg) Heart rate (beats/min) Total cholesterol (mmol/L) LDL-cholesterol (mmol/L) HDL-cholesterol (mmol/L) Triglycerides (mmol/L) Glucose (mmol/L) Calcium (mmol/L) Phosphate (mmol/L) 1,25 (OH)D (pmol/L) PTH (pmol/L) LV hypertrophy, n(%) Diastolic dysfunction, n (%)
25(OH)D deficiency(n Z 28)
No 25(OH)D deficiency(n Z 34)
P
46.13 13.6 13/15 25.5 3.0 152.6/93.0 12.5/6.8 77.6 7.4 5.0 0.8 3.0 0.7 1.34 0.3 1.1 0.4 5.0 0.7 2.37 0.07 1.06 0.19 96.9 38.1 10.1 4.79 16(57.1) 14(50.0)
48.4 9.0 19/15 24.3 0.2 150.0/92.5 19.8/9.5 76.8 8.1 5.3 0.9 3.8 0.98 0.8 0.6 0.9 0.4 5.1 0.6 2.25 0.12 1.16 0.12 91.5 35.9 4.45 0.19 6 (17.6) 16 (47.0)
0.44 0.46 0.26 0.48/0.79 0.44 0.48 0.34 0.27 0.42 0.27 0.09 0.30 0.36 <0.0001 0.02 0.89
BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; 1,25 (OH)D, 1,25-hydroxyvitamin D; PTH, parathyroid hormone; LV, left ventricular; LV hypertrophy defined by LV mass 51 g/m2.7; Diastolic dysfunction defined by E/A ratio < 1 and E-wave deceleration time > 220 ms. Mean values SD.
874 Table 2
F. Fallo et al. Echocardiographic features of hypertensive patients with and without 25-hydroxyvitamin D [25(OH)D] deficiency. 25(OH)D deficiency (n Z 28)
Left atrium diameter (mm) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) Inter-ventricular septum thickness (mm) LV posterior wall thickness (mm) Relative wall thickness LV mass (g) LV mass index (g/m2.7) LV ejection fraction (%) E velocity (cm/s) A velocity (cm/s) E/A ratio E-wave deceleration time (ms)
35.0 48.9 29.0 10.5 9.6 0.40 215.1 51.2 72.7 60.8 69.4 0.91 203.1
7.0 5.5 4.6 2.5 2.1 0.12 78.7 17.2 4.8 16.3 15.4 0.32 56.0
No 25(OH)D deficiency (n Z 34) 32.2 47.3 28.5 8.6 8.7 0.36 161.9 37.0 76.8 61.9 64.2 1.01 190.3
4.9 5.7 5.6 1.6 1.6 0.10 54.8 10.9 5.07 15.1 11.7 0.23 52.9
P 0.32 0.10 0.28 0.008 0.01 0.13 0.002 0.0003 0.12 0.03 0.29 0.08 0.18
LV, left ventricular; E, peak early (E-wave) diastolic flow velocity; A, peak late (A wave) diastolic flow velocity. Mean values SD.
hypertrophy was indeed observed in 16 out of 28 patients (57.1%) with 25(OH)D deficiency and in 6 out of 34 patients (17.6%; P Z 0.02) without 25(OH)D deficiency. No difference between the two groups was found in blood pressure levels as well as in other biochemical and hormone parameters. Table 2 summarizes comparisons of single echocardiographic parameters of the two groups of hypertensive patients. Patients with 25(OH)D deficiency had a significantly greater average values of LV mass than patients without, which was also consistent with a greater inter-ventricular septum thickness and LV posterior wall thickness. There was an inverse correlation between LV mass index and 25OHD levels (r Z e0.366, P < 0.003) and a direct correlation between BMI and LV mass index (r Z e0.333, P < 0.006) in the entire hypertensive population (Fig. 1). No additional correlations were found between demographic, clinical, and biochemical parameters and echocardiographic parameters. At univariate logistic regression analysis, serum 25OHD was significantly associated with the presence of LV hypertrophy (OR 1.04, 95% CI 1.01 to 1.07, P < 0.005) and BMI was marginally associated (OR 1.182, 95% CI 0.987 to 1.416, P < 0.07). The two variables were independently associated with LV hypertrophy at multivariable logistic regression analysis (OR 1.05, 95% CI 1.01 to 1.08, P < 0.005 and OR 1.25, 95% CI 1.014 to 1.545. P Z 0.03), respectively. Normotensive controls showed a biochemical profile similar to that observed in the entire EH population. The 25(OH)D, 1,25(OH)D and PTH levels were also similar. Overall prevalence of 25(OH)D deficiency was not different in EH patients and in control cases (28/62, i.e., 45.1% vs 10/ 24, i.e., 41.6%, P Z 0.89), and no correlation between echocardiographic and hormonal variables was found.
present in our hypertensive population. This association was observed in a series of newly diagnosed hypertensive patients without potential confounders, notably without additional cardiovascular risk factors. Furthermore, patients had never been treated with antihypertensive agents excluding possible pharmacological influence on LV mass, and hormone samples were collected within a limited period of the year, in order to avoid seasonal fluctuations of 25(OH)D. Our data confirm previous cross-sectional studies showing that 25(OH)D deficiency is highly prevalent in patients with hypertension [6,7,8], and suggest that this condition might be an underestimated risk factor for cardiovascular disease. A potential explanation for our results would be that vitamin D deficiency is simply one of multiple humoral factors, together with hemodynamic imbalance, “unhealthy” lifestyle and genetic background, which may promote structural hypertrophic remodeling in hypertensive heart disease [17]. Vitamin D seems in fact to have cardiovascular protective effects through modulation of inflammatory cytokines, oxidative stress, and systemic
Discussion This study has provided the first evidence that EH patients with 25(OH)D deficiency have a higher prevalence of LV hypertrophy than their 25(OH)D-sufficient counterparts. An inverse association between serum 25(OH)D and LV mass, an independent cardiovascular risk factor [17], was also
Figure 1 Relationship between 25(OH)D levels and LV mass index in patients with essential hypertension.
Vitamin D and left ventricular hypertrophy renin-angiotensin-aldosterone system [1,18]. Moreover, since in our patients serum 25(OH)D was inversely associated with LV mass, it can be suggested that the inadequate vitamin D status has a direct pathogenic role in LV hypertrophy. Serum 25(OH)D, as well as BMI, were independent determinants of LV mass. While the relationship of BMI with LV mass was not surprising since several EH patients were overweight (although none was obese) [19], the inverse association of 25(OH)D with LV mass needs to be explained. Experimental studies show that vitamin D has direct effects on electrophysiology, contractility and structure of the heart [10]. There are cardiac receptors for 1,25(OH)D, the biologically active vitamin D, in animal models [20], and 1,25(OH)D exerts in vitro anti-hypertrophic effects on cardiomyocytes and reduces the expression of several genes that are up-regulated in myocardial hypertrophy [10,21,22]. Suppression of the cardiac renin-angiotensin system and natriuretic peptides may partially mediate the anti-hypertrophic effects [1,10]. Recently, therapeutic effects of 1,25(OH)D analogs on cardiac hypertrophy have been observed in spontaneously hypertensive rats [23]. In our patients, serum 1,25(OH)D levels were similar in patients with and without LV hypertrophy, and no correlation of 1,25(OH)D with LV mass was observed. This is not surprising, since the pathophysiological basis of extraskeletal action of vitamin D mainly depends on the presence of 25(OH)D-1a-hydroxylase activity that converts 25(OH)D to 1,25(OH)D [20,24] in peripheral tissues. Many non-classical target tissues expressing 1,25(OH)D receptors may thus regulate the biological action of 25(OH)D in an autocrine and/or paracrine fashion [25]. Based on our present findings, we hypothesize that hypertensive individuals lacking the antiproliferative effect locally exerted by 1,25(OH)D on the heart may develop, under environmental and/or genetic influence, LV hypertrophy. Although LV hypertrophy is a major determinant of diastolic abnormalities in hypertension, no significant differences were found as to diastolic function between our hypertensive patients with and without 25(OH)D deficiency. It is however known that other factors influence LV relaxation, such as those regulating energy production in cardiomyocytes [19]. An overactivity of the circulating renin-angiotensinaldosterone system, which was not measured in our patients, also may have a role in the pathogenesis of LV mass increase. Some potential limitations of the present study need to be finally discussed. First, the overall prevalence of vitamin D deficiency in our EH patients was comparable to that found in normotensive controls (29.6%), and similar to that found in healthy women from the same geographical area in Italy [26]. Normotensive subjects however showed no correlation between 25(OH)D levels and LV mass. Beside the absent effect of blood pressure elevation on LV mass per se, lack of LV hypertrophy in normotensive subjects with 25(OH)D deficiency might be ascribed to compensatory mechanisms capable of correcting an initial metabolic imbalance that leads to changes in cardiac structure and/ or function. In this regard, early markers of cardiovascular damage should be tested in future large-scale longitudinal studies. Second, we cannot exclude a contributive effect of PTH on LV mass in our hypertensive group. Several studies have shown that serum/plasma levels of PTH are positively
875 associated with increased blood pressure [4]. The PTH levels rise when serum levels of 25(OH)D fall below 75 nmol/L [27], and this has been linked to hypertension. Recently, an association between low 25(OH)D levels and LV hypertrophy in patients with mild primary hyperparathyroidism has been shown [28]. Our EH group with 25(OH) D deficiency had indeed PTH levels higher than those of patients without such deficiency, although no correlation of PTH with LV mass was observed. Indeed, there are data suggesting that PTH has a trophic effect on cardiomyocytes and vascular smooth muscle cells by increasing intracellular calcium and muscle tone [28], perhaps involving reactive oxygen species at endothelial level [29]. Third, our study design was cross-sectional, exposing to chance of selection bias and serendipity findings, and the size of patient groups was relatively small, potentially introducing a type 2 statistical error for echocardiographic (including LV geometry) variables. Further evaluation of cardiac performance would be important and should be addressed in larger groups of patients by use of more sensitive methods, i.e., strain measurement by speckle tracking ot tissue Doppler echocardiography, that enable detection of subtle changes in LV systolic function. Finally, the impact of blood pressure elevation on cardiac anatomy and function in our hypertensive patients might have been underestimated owing to lack of data on 24-h ambulatory blood pressure values. In conclusion, 25(OH)D deficiency is a frequent finding in EH patients without major cardiovascular risk factors, and is independently associated with increased LV mass. The hypothesis that this metabolic alteration provides substantial contribution to cardiovascular risk in hypertensive patients [30] has to be investigated. Interventional studies will have to determine whether vitamin D supplementation decreases the prevalence of LV hypertrophy in hypertensive patients.
Disclosures The authors have no conflicts of interest.
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journal homepage: www.elsevier.com/locate/nmcd
Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension F. Fallo a,*, C. Catena b, V. Camozzi c, G. Luisetto c, C. Cosma d, M. Plebani d, M. Lupia e, F. Tona e, L.A. Sechi b a
Clinica Medica 3, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35128 Padova, Italy b Clinica Medica, Department of Experimental and Clinical Medicine, University of Udine, Italy c Division of Endocrinology, University of Padova, Italy d Department of Laboratory Medicine, University Hospital of Padova, Italy e Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Italy Received 28 February 2011; received in revised form 15 June 2011; accepted 20 June 2011
KEYWORDS Vitamin D; Essential hypertension; Left ventricular hypertrophy
Abstract Background and aim: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH). Methods and results: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18e65 years, with grade 1e2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P Z 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r Z e0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r Z 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P Z 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P Z 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found.
* Corresponding author. Tel.: þ39 049 8212654; fax: þ39 049 8213332. E-mail address: [email protected] (F. Fallo). 0939-4753/$ - see front matter ª 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2011.06.001
872
F. Fallo et al. Conclusions: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH. ª 2011 Elsevier B.V. All rights reserved.
Introduction Vitamin D deficiency, as defined by a serum 25hydroxyvitamin D [25(OH)D] concentration of less than 50 nmol/L, or insufficiency is a highly common condition in the general population [1,2]. Serum 25(OH)D level is the best indicator of overall vitamin D status because the measurement reflects total vitamin D from sunlight-induced skin production and dietary intake, as well as the conversion of vitamin D from adipose stores in the liver [2]. Low serum concentrations of 25(OH)D may have an important role in modifying cardiovascular risk [3,4,5], predisposing to hypertension [6,7,8] and myocardial disease [9,10]. Hypertensive cohorts in prospective studies include however patients with cardiovascular risk factors such as old age, diabetes and/or obesity, which are also negatively associated with vitamin D status [1,5] and are potential confounders. Whether 25(OH)D deficiency is the cause or merely the consequence of cardiovascular disease remains unclear. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, as assessed by echocardiography, in a series of patients with essential hypertension (EH).
hypertension. Renal disease was defined as the presence of serum creatinine greater than 133 mmol/L in men and greater than 120 mmol/L in women. Major metabolic abnormalities were ruled out by the following exclusion criteria: 1) diabetes mellitus, i.e., fasting plasma glucose 7.0 mmol/L on two separate occasions; 2) moderate to severe hyperlipidemia, i.e., serum total cholesterol 6.2 mmol/L and/or triglycerides 2.28 mmol/L; 3) obesity, i.e., body mass index (BMI) 30 kg/m2; 4) alcohol intake >20 g/d; 5) smoking habit, defined as at least one cigarette/day for 1 year within the past 5 years. Patients had been weight-stable over the previous six months. During evaluation, they followed a normal sodium and potassium diet, i.e., 100e200 mmol/ d sodium and 50e70 mmol/d potassium. A group of 24 sex-, age- and BMI-matched normotensive individuals, selected according to the same exclusion criteria, were used as controls. These subjects had the same biochemical and hormonal evaluation, and underwent echocardiography. None of hypertensive and normotensive subjects were receiving medications or had medical history and/or conditions affecting bone metabolism, including intestinal malabsorption or lactose intolerance. Informed consent was obtained in all cases. The study was approved by institutional ethics committees.
Methods Echocardiographic examination Patients In this cross-sectional study, 62 Caucasian patients with EH were studied. At the time of the study, patients (32 male, 30 female) were newly diagnosed and had never been treated with antihypertensive agents. They were consecutively selected from a larger hypertensive population of more than 2500 patients seen at our two hospital-based specialized hypertension outpatient clinics over the past 3 years, with time span of evaluation restricted from early spring to mid-autumn. The latitude of Padova is 45 250 000 N and the latitude of Udine is 46 30 4200 N. Patients were first selected according to the following criteria: 1) age 18e65 years; 2) grade 1e2 hypertension, according to the criteria of the European Society of Hypertension-European Society of Cardiology guidelines, with clinic blood pressure 140/ 90 mm Hg measured by mercury sphygmomanometer in a sitting position in at least three separate casual measurements within the past month [11]; 3) no history or clinical evidence of cardiopulmonary, renal or hepatic disease. The estimated duration of hypertension, obtained by careful investigation of the patient’s history and from family practitioner records, was in all patients less than 1 year. After the initial screening visit at our clinics, all subjects underwent as outpatients further selection. Biochemical, hormonal, and instrumental tests excluded those patients with cardiac and renal disease, and those with secondary
Echocardiography was performed by standardized procedures with SONOS 5500 (Hewlett Packard, HP Co., Palo Alto, CA, USA) or Aplio CV (Toshiba Medical System, Tochigi, Japan). The echocardiographic study protocol recorded at least 10 cycles of two-dimensional parasternal long- and short-axis LV views with optimal orientation of the M-mode cursor beam. The left atrial diameter, LV internal dimensions, inter-ventricular septum, and posterior wall thickness were measured according to the recommendations of the American Society of Echocardiography [12]. End-diastolic relative wall thickness (RWT) (i.e., the ratio of posterior wall thickness to one-half LV internal dimensions) was calculated as index of LV geometric pattern [13]. According to echocardiography recommendations, assessment of LV dimensions was based on the average of five measurements of left ventricular diameters and wall thickness. When optimal orientation of LV M-mode recordings could not be obtained, correctly orientated linear dimension measurements were made using two-dimensional imaging [12]. The LV mass was calculated according to the formula LV mass Z 0.8 [1.04 (inter-ventricular septal thickness þ LV end-diastolic diameter þ posterior wall thickness)3 e (LV end-diastolic diameter)3] þ 0.6 g [12,14]; LV mass index was obtained after normalization of LV mass for height to the 2.7 power (g/m2.7), and LV hypertrophy was defined as a value of LV mass index 51 g/m2.7 in both sexes [15]. In all patients pulsed Doppler recordings at the level of the mitral
Vitamin D and left ventricular hypertrophy valve tips from apical four-chambers two-dimensional views were obtained in order to measure peak early (E-wave) and late diastolic (A wave) flow velocities, their ratio (E/A) and Ewave deceleration time, as measurement of diastolic filling. Diastolic dysfunction was defined by E/A ratio <1 [16] and Ewave deceleration time >220 ms. Two different readers, unaware of the patients’ identity, performed all echocardiographic and Doppler measurements. To test the reproducibility of echocardiography for LV mass and E/A ratio assessment, in 20 subjects the ultrasound study was repeated 2e4 weeks later by each reader. The difference between the two studies averaged for each reader 8.1 4.3 and 7.6 4.0% for LV mass, and 7.1 3.8 and 6.3 3.9% for E/A ratio, respectively.
Laboratory methods In all individuals, blood samples for biochemical and metabolic laboratory measurements were obtained at 08:00 h, after overnight fasting. Serum 25OHD was determined with the DiaSorin LIAISON 25OH total vitamin D kit (Saluggia, Italy), using chemiluminescence technology (CLIA), normal range 76e250 nmol/L (30e100 ng/ml). Serum 1,25-dihydroxyvitamin D [1,25(OH)D] was measured with the RIA IDS kit (Fountain Hills, AZ, USA), normal range 43e148 pmol/l (18e62 pg/ml); serum parathyroid hormone (PTH) was measured using DiaSorin LIAISON N-tactTH PTH kit (Saluggia, Italy), with the CLIA method, normal range 1.8e7.7 pmol/L (17e73 ng/l). For hormone measurements, intra- and inter-assay coefficients of variation were less than 10%. All other biochemical variables were assayed in plasma or serum using standard methods.
Statistical analysis All results are expressed as mean SD for continuous variables and as a percentage for categorical variables. Table 1
873 Continuous data were subjected to the KolmogoroveSmirnov test to determine their distribution. Statistical significance between groups was assessed in normally distributed data by Student t-test for independent samples, and in non-normally distributed data by ManneWhitney U test. Categorical variables were analyzed by the chi-square analysis, or Fisher’s exact test when appropriate. Correlations were assessed by the Pearson’s coefficient or the rank order Spearman’s coefficient. Potential predictors of LV mass were evaluated by univariate linear (when LV mass, the dependent variable, was considered as a continuous variable) regression analysis or logistic (when LV hypertrophy was modeled as categorical variable) regression analysis. Multivariable logistic regression analysis was used to find the independent factors associated with LV hypertrophy, considering only significant predictors of the outcome at univariate analysis. Results were calculated as regression coefficients and values of P associated with Wald test, and odds ratio (OR) and 95% confidence interval (CI) were computed. Statistical significance was assumed if the null hypothesis could be rejected at P < 0.05. Statistical analyses were performed with SPSS 18.0 for Windows software (SPSS Institute Inc., Chicago, Ill., USA).
Results Serum 25(OH)D deficiency, i.e., 25(OH)D levels <50 nmol/ L, was detected in 28 out of 62 hypertensive patients, i.e., in 45.8% of our hypertensive group. Clinical, endocrinemetabolic, and main cardiac parameters of hypertensive patients without and with 25(OH)D deficiency are shown in Table 1. The two groups of patients were similar as to age, sex, systolic and diastolic blood pressure, and heart rate. Between-group comparison analysis showed only two variables to be different in hypertensive patients with 25(OH)D deficiency and in their with 25(OH)D-sufficient counterparts, i.e., LV mass and PTH levels. Left ventricular
Characteristics of hypertensive patients with and without 25-hydroxyvitamin D [25(OH)D] deficiency.
Age (years) Sex (M/F) Body mass index (kg/m2) Systolic BP/diastolic BP (mm Hg) Heart rate (beats/min) Total cholesterol (mmol/L) LDL-cholesterol (mmol/L) HDL-cholesterol (mmol/L) Triglycerides (mmol/L) Glucose (mmol/L) Calcium (mmol/L) Phosphate (mmol/L) 1,25 (OH)D (pmol/L) PTH (pmol/L) LV hypertrophy, n(%) Diastolic dysfunction, n (%)
25(OH)D deficiency(n Z 28)
No 25(OH)D deficiency(n Z 34)
P
46.13 13.6 13/15 25.5 3.0 152.6/93.0 12.5/6.8 77.6 7.4 5.0 0.8 3.0 0.7 1.34 0.3 1.1 0.4 5.0 0.7 2.37 0.07 1.06 0.19 96.9 38.1 10.1 4.79 16(57.1) 14(50.0)
48.4 9.0 19/15 24.3 0.2 150.0/92.5 19.8/9.5 76.8 8.1 5.3 0.9 3.8 0.98 0.8 0.6 0.9 0.4 5.1 0.6 2.25 0.12 1.16 0.12 91.5 35.9 4.45 0.19 6 (17.6) 16 (47.0)
0.44 0.46 0.26 0.48/0.79 0.44 0.48 0.34 0.27 0.42 0.27 0.09 0.30 0.36 <0.0001 0.02 0.89
BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; 1,25 (OH)D, 1,25-hydroxyvitamin D; PTH, parathyroid hormone; LV, left ventricular; LV hypertrophy defined by LV mass 51 g/m2.7; Diastolic dysfunction defined by E/A ratio < 1 and E-wave deceleration time > 220 ms. Mean values SD.
874 Table 2
F. Fallo et al. Echocardiographic features of hypertensive patients with and without 25-hydroxyvitamin D [25(OH)D] deficiency. 25(OH)D deficiency (n Z 28)
Left atrium diameter (mm) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) Inter-ventricular septum thickness (mm) LV posterior wall thickness (mm) Relative wall thickness LV mass (g) LV mass index (g/m2.7) LV ejection fraction (%) E velocity (cm/s) A velocity (cm/s) E/A ratio E-wave deceleration time (ms)
35.0 48.9 29.0 10.5 9.6 0.40 215.1 51.2 72.7 60.8 69.4 0.91 203.1
7.0 5.5 4.6 2.5 2.1 0.12 78.7 17.2 4.8 16.3 15.4 0.32 56.0
No 25(OH)D deficiency (n Z 34) 32.2 47.3 28.5 8.6 8.7 0.36 161.9 37.0 76.8 61.9 64.2 1.01 190.3
4.9 5.7 5.6 1.6 1.6 0.10 54.8 10.9 5.07 15.1 11.7 0.23 52.9
P 0.32 0.10 0.28 0.008 0.01 0.13 0.002 0.0003 0.12 0.03 0.29 0.08 0.18
LV, left ventricular; E, peak early (E-wave) diastolic flow velocity; A, peak late (A wave) diastolic flow velocity. Mean values SD.
hypertrophy was indeed observed in 16 out of 28 patients (57.1%) with 25(OH)D deficiency and in 6 out of 34 patients (17.6%; P Z 0.02) without 25(OH)D deficiency. No difference between the two groups was found in blood pressure levels as well as in other biochemical and hormone parameters. Table 2 summarizes comparisons of single echocardiographic parameters of the two groups of hypertensive patients. Patients with 25(OH)D deficiency had a significantly greater average values of LV mass than patients without, which was also consistent with a greater inter-ventricular septum thickness and LV posterior wall thickness. There was an inverse correlation between LV mass index and 25OHD levels (r Z e0.366, P < 0.003) and a direct correlation between BMI and LV mass index (r Z e0.333, P < 0.006) in the entire hypertensive population (Fig. 1). No additional correlations were found between demographic, clinical, and biochemical parameters and echocardiographic parameters. At univariate logistic regression analysis, serum 25OHD was significantly associated with the presence of LV hypertrophy (OR 1.04, 95% CI 1.01 to 1.07, P < 0.005) and BMI was marginally associated (OR 1.182, 95% CI 0.987 to 1.416, P < 0.07). The two variables were independently associated with LV hypertrophy at multivariable logistic regression analysis (OR 1.05, 95% CI 1.01 to 1.08, P < 0.005 and OR 1.25, 95% CI 1.014 to 1.545. P Z 0.03), respectively. Normotensive controls showed a biochemical profile similar to that observed in the entire EH population. The 25(OH)D, 1,25(OH)D and PTH levels were also similar. Overall prevalence of 25(OH)D deficiency was not different in EH patients and in control cases (28/62, i.e., 45.1% vs 10/ 24, i.e., 41.6%, P Z 0.89), and no correlation between echocardiographic and hormonal variables was found.
present in our hypertensive population. This association was observed in a series of newly diagnosed hypertensive patients without potential confounders, notably without additional cardiovascular risk factors. Furthermore, patients had never been treated with antihypertensive agents excluding possible pharmacological influence on LV mass, and hormone samples were collected within a limited period of the year, in order to avoid seasonal fluctuations of 25(OH)D. Our data confirm previous cross-sectional studies showing that 25(OH)D deficiency is highly prevalent in patients with hypertension [6,7,8], and suggest that this condition might be an underestimated risk factor for cardiovascular disease. A potential explanation for our results would be that vitamin D deficiency is simply one of multiple humoral factors, together with hemodynamic imbalance, “unhealthy” lifestyle and genetic background, which may promote structural hypertrophic remodeling in hypertensive heart disease [17]. Vitamin D seems in fact to have cardiovascular protective effects through modulation of inflammatory cytokines, oxidative stress, and systemic
Discussion This study has provided the first evidence that EH patients with 25(OH)D deficiency have a higher prevalence of LV hypertrophy than their 25(OH)D-sufficient counterparts. An inverse association between serum 25(OH)D and LV mass, an independent cardiovascular risk factor [17], was also
Figure 1 Relationship between 25(OH)D levels and LV mass index in patients with essential hypertension.
Vitamin D and left ventricular hypertrophy renin-angiotensin-aldosterone system [1,18]. Moreover, since in our patients serum 25(OH)D was inversely associated with LV mass, it can be suggested that the inadequate vitamin D status has a direct pathogenic role in LV hypertrophy. Serum 25(OH)D, as well as BMI, were independent determinants of LV mass. While the relationship of BMI with LV mass was not surprising since several EH patients were overweight (although none was obese) [19], the inverse association of 25(OH)D with LV mass needs to be explained. Experimental studies show that vitamin D has direct effects on electrophysiology, contractility and structure of the heart [10]. There are cardiac receptors for 1,25(OH)D, the biologically active vitamin D, in animal models [20], and 1,25(OH)D exerts in vitro anti-hypertrophic effects on cardiomyocytes and reduces the expression of several genes that are up-regulated in myocardial hypertrophy [10,21,22]. Suppression of the cardiac renin-angiotensin system and natriuretic peptides may partially mediate the anti-hypertrophic effects [1,10]. Recently, therapeutic effects of 1,25(OH)D analogs on cardiac hypertrophy have been observed in spontaneously hypertensive rats [23]. In our patients, serum 1,25(OH)D levels were similar in patients with and without LV hypertrophy, and no correlation of 1,25(OH)D with LV mass was observed. This is not surprising, since the pathophysiological basis of extraskeletal action of vitamin D mainly depends on the presence of 25(OH)D-1a-hydroxylase activity that converts 25(OH)D to 1,25(OH)D [20,24] in peripheral tissues. Many non-classical target tissues expressing 1,25(OH)D receptors may thus regulate the biological action of 25(OH)D in an autocrine and/or paracrine fashion [25]. Based on our present findings, we hypothesize that hypertensive individuals lacking the antiproliferative effect locally exerted by 1,25(OH)D on the heart may develop, under environmental and/or genetic influence, LV hypertrophy. Although LV hypertrophy is a major determinant of diastolic abnormalities in hypertension, no significant differences were found as to diastolic function between our hypertensive patients with and without 25(OH)D deficiency. It is however known that other factors influence LV relaxation, such as those regulating energy production in cardiomyocytes [19]. An overactivity of the circulating renin-angiotensinaldosterone system, which was not measured in our patients, also may have a role in the pathogenesis of LV mass increase. Some potential limitations of the present study need to be finally discussed. First, the overall prevalence of vitamin D deficiency in our EH patients was comparable to that found in normotensive controls (29.6%), and similar to that found in healthy women from the same geographical area in Italy [26]. Normotensive subjects however showed no correlation between 25(OH)D levels and LV mass. Beside the absent effect of blood pressure elevation on LV mass per se, lack of LV hypertrophy in normotensive subjects with 25(OH)D deficiency might be ascribed to compensatory mechanisms capable of correcting an initial metabolic imbalance that leads to changes in cardiac structure and/ or function. In this regard, early markers of cardiovascular damage should be tested in future large-scale longitudinal studies. Second, we cannot exclude a contributive effect of PTH on LV mass in our hypertensive group. Several studies have shown that serum/plasma levels of PTH are positively
875 associated with increased blood pressure [4]. The PTH levels rise when serum levels of 25(OH)D fall below 75 nmol/L [27], and this has been linked to hypertension. Recently, an association between low 25(OH)D levels and LV hypertrophy in patients with mild primary hyperparathyroidism has been shown [28]. Our EH group with 25(OH) D deficiency had indeed PTH levels higher than those of patients without such deficiency, although no correlation of PTH with LV mass was observed. Indeed, there are data suggesting that PTH has a trophic effect on cardiomyocytes and vascular smooth muscle cells by increasing intracellular calcium and muscle tone [28], perhaps involving reactive oxygen species at endothelial level [29]. Third, our study design was cross-sectional, exposing to chance of selection bias and serendipity findings, and the size of patient groups was relatively small, potentially introducing a type 2 statistical error for echocardiographic (including LV geometry) variables. Further evaluation of cardiac performance would be important and should be addressed in larger groups of patients by use of more sensitive methods, i.e., strain measurement by speckle tracking ot tissue Doppler echocardiography, that enable detection of subtle changes in LV systolic function. Finally, the impact of blood pressure elevation on cardiac anatomy and function in our hypertensive patients might have been underestimated owing to lack of data on 24-h ambulatory blood pressure values. In conclusion, 25(OH)D deficiency is a frequent finding in EH patients without major cardiovascular risk factors, and is independently associated with increased LV mass. The hypothesis that this metabolic alteration provides substantial contribution to cardiovascular risk in hypertensive patients [30] has to be investigated. Interventional studies will have to determine whether vitamin D supplementation decreases the prevalence of LV hypertrophy in hypertensive patients.
Disclosures The authors have no conflicts of interest.
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