Parathyroid hormone and left ventricular hypertrophy

F.N Saleha,*, H Schirmerb, J Sundsfjordc and R Jordea

a Department of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
b Institute of Community Medicine, University of Tromsø, Tromsø, Norway
c Department of Clinical Chemistry, University Hospital of North Norway, Tromsø, Norway

* Correspondence to: Farahnaz N. Saleh, Department of Internal Medicine, University Hospital of North Norway, 9038 Tromsø, Norway. Tel: +47 77628090; Fax: +47 77626863
E-mail address: farahnaz.saleh{at}unn.no

Received 20 January 2003; revised 14 August 2003; accepted 11 September 2003

Abstract

Aims A relation between left ventricular hypertrophy and parathyroid hormone (PTH) has been described in patients with end stage renal disease and secondary hyperparathyroidism. In vitro studies indicate a hypertrophic effect of PTH on cardiomyocytes. The purpose of this study was to examine the relation between PTH and left ventricular hypertrophy in a general population.

Methods and results The fourth Tromsø study (1994–1995) included 27 159 subjects. 2700 had serum PTH measurement and left ventricular mass by height (LVMH) estimated with M-mode echocardiography. Among these, 980 males and 1060 females were without known cardiovascular disease or valvular heart disease and did not use blood pressure medication. In this group, using a multiple linear regression model, body mass index (BMI), followed by systolic blood pressure, were found to be the strongest predictors of LVMH. In males older than 59 years and females younger than 60 years, PTH was a significant and positive predictor of LVMH (P<0.05). The relation between PTH and LVMH was not linear. There was a sharp increase in LVMH (both unadjusted and adjusted for age, BMI, and systolic blood pressure) in the upper PTH percentiles with the breaking point being the 95 percentile for men and the 98 percentile for women. Subjects in these upper PTH ranges had 12–17% higher adjusted LVMH than those in the lower 10% of the PTH range. This effect was not related to serum calcium level. If examining separately those with PTH levels within ±2SD from the mean, no relation between PTH and LVMH was found.

Conclusions PTH is an independent predictor of LVMH in males older than 59 years and females younger than 60 years. This effect is only seen when PTH is substantially elevated and may then be involved in cardiac pathophysiology.

Key Words: Echocardiography • Left ventricularhypertrophy • Parathyroid hormone • Blood pressure • Body mass index

1. Introduction

The circulating level of parathyroid hormone (PTH) is regulated by the calcium concentration in the plasma. Thus, a falling plasma calcium level elicits synthesis and release of the hormone whereas an increase in plasma calcium has an inhibitory effect on the PTH secretion.1In turn, PTH raises the plasma calcium level by causing release of calcium from the bones, increases the absorption of calcium from the small intestine, and reduces the renal excretion of calcium.

In addition to these classical PTH target organs, it appears that PTH may have effects on other tissues as well.2Accordingly, PTH receptors have been demonstrated in the heart, and in vitro, PTH induces hypertrophy of cardiomyocytes.3

From clinical studies there are also indications that PTH may contribute to development of left ventricular hypertrophy. Thus, in patients with end-stage renal disease and secondary hyperparathyroidism4as well as in patients with primary hyperparathyroidism,5there is a strong correlation between left ventricular mass and the level of serum PTH.

However, to our knowledge, there are no population based studies where this relation has been examined, nor are there any studies where confounding factors like the effects of age, BMI, and blood pressure have been taken properly into account. In Tromsø, Northern Norway there has been several large health surveys.6In the fourth one in 1994–1995 echocardiography and measurement of serum PTH were performed in a large subgroup, thus enabling us to examine the relation between PTH and left ventricular hypertrophy from an epidemiological point of view.

2. Methods

2.1. Subjects
In 1994–1995 all men and women who were >24 years of age and who lived in the municipality of Tromsø, Northern Norway, were invited to participate in a health survey that was conducted in a manner similar to the previous Tromsø studies.6All subjects aged 55–74 years and random 5–10% samples of the other age groups were invited to a second visit for more extensive screening.

2.2. Measurements
Trained nurses checked a questionnaire that included medical history and past and present medication. The participants were not requested to fast. Height and weight were measured while the subjects wore light clothing and no shoes. Blood pressure was measured with an automatic device (Dinamap Vital Signs Monitor 1846; Critikon Inc, Tampa, FL).6

Echocardiography, using a VingMed CFM 750 (VingMed Sound A/S, Horten, Norway), was performed in a subgroup as previously described in detail regarding method and reproducibility.7In short, the subjects were examined in a supine, left lateral position with a combined 3.25MHz mechanical and 2.5MHz Doppler probe. Left ventricular diastolic dimensions were measured on-line from standard two-dimensional guided M-mode registrations according to the leading edge to leading edge convention, using EchoPAC software. Only one heart cycle was measured per subject. Left ventricular mass by height (LVMH) was calculated using the correction of the cube formula proposed by Devereux et al. for leading edge to leading edge measurements (left ventricular mass=0.832x[interventricular septal thickness+posterior wall thickness+end diastolic diameter]3–[end diastolic diameter]3)+0.6).8

Blood samples were analysed for serum PTH (reference range 1.1–6.8pmol/l for those <50 years and 1.1–7.5pmol/l for those ≥50 years) and serum calcium (reference range2.20–2.60mmol/l) as previously described.9

2.3. Statistical analyses
Normal distribution was evaluated by visual inspection and determination of skewness and kurtosis. To identify main effects and interactions (between PTH and gender, PTH and disease states, PTH and use of blood pressure medication (two-way interaction), and between valvular heart disease, cardiovascular disease and use of blood pressure medication (three-way interaction)), the data were initially evaluated with a factor analysis of variance with LVMH as dependent variable, serum PTH quartiles, gender, presence or absence of valvular heart disease, history of known cardiovascular disease (myocardial infarction, angina, stroke), and use of blood pressure medication as fixed factors, and age, systolic blood pressure, serum calcium and BMI as independent variables. In men and women separately, a subanalysis on the interaction between PTH quartiles and age (divided in two groups as >59 and <60 years) in subjects without known cardiovascular disease or valvular heart disease and no blood pressure medication was performed. A multiple linear regression model was used to control for confounding factors regarding LVMH and included age, BMI, systolic blood pressure, serum PTH and calcium as independent variables. The appropriateness of the model was verified by plotting the residuals against each variable and inspecting the plot for even distribution throughout the variable range.

Subgroup analyses were performed based on the interactions that were found. Where PTH quartiles are used in the analyses, they were calculated specifically for the subgroup in question, except for the initial factor analysis where all subjects were included. LVMH values adjusted for age, BMI and systolic blood pressure were obtained by linear regression (unstandardized predicted values).

Unless otherwise stated, all data are expressed as mean±SD. All tests were done two-sided, and P<0.05 was considered statistically significant. Statistical analyses was performed with SPSS version 10.0 (SPSS Inc, Chicago).

2.4. Ethics
The study complies with the Declaration of Helsinki, was approved by the regional ethics committee, and all subjects gave their written informed consent to participate.

3. Results

3.1. Subjects
A total of 27 159 subjects were included in the fourth Tromsø study. 6891 subjects attended the second visit, and 3287 randomly selected subjects were examined by echocardiography. This examination was successful in 2794, and among these, serum PTH was measured in 2700 (1316 males and 1384 females, age 59.3±10.5 and 60.3±10.6 years, respectively). Among the males, 202 had a history of cardiovascular disease, 63 had valvular heart disease, and 165 used blood pressure medication. The corresponding figures in the females were 135, 87, and 176.

In the following, the subjects are presented in three subgroups: group A: Subjects without known cardiovascular disease or valvular heart disease and not taking blood pressure medication (‘healthy cohort’); group B: Subjects with known cardiovascular disease, but without valvular heart disease or blood pressure medication; and group C: The rest of the cohort.

The dependent variable LVMH had a kurtosis of 3.1 and skewness of 1.3 in the males and 3.5 and 1.2 in the females, respectively. By visual inspection of the distribution curves LVMH was considered to be normally distributed. In the initial factor analysis, PTH (P<0.001), gender (P<0.001), known cardiovascular disease (P<0.001), valvular heart disease (P<0.001), blood pressure medication (P<0.001), age (P<0.05), BMI (P<0.001), and systolic blood pressure (P<0.001) all came out as significant predictors of LVMH. Regarding LVMH, there were significant interactions between PTH and gender (P<0.02), between PTH and known cardiovascular disease (P=0.05), PTH and valvular heart disease (P<0.001), PTH and blood pressure medication (P<0.001), and between known cardiovascular disease, valvular heart disease and blood pressure medication (P<0.001). In group A there was a significant interaction between PTH and age in males (P<0.02).

Serum calcium was not a significant predictor of LVMH, and was excluded from the model. The serum PTH values were slightly higher in the winter than the summer months, but correcting for season did not affect the results.

3.2. Group A
This cohort of ‘healthy’ subjects included 980 males and 1060 females, age 57.5±10.8 and 58.7±11.0 years, respectively. The mean values of LVMH, PTH, BMI, and systolic blood pressure in relation to age and gender in this cohort are given in Table 1, and the mean values of age, PTH, BMI, and systolic blood pressure in relation to LVMH quartiles in Table 2. The frequency distribution of LVMH is shown in Fig. 1.


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Table 1 LVMH, serum PTH, BMI and systolic blood pressure in relation to age and gender in those without known cardiovascular disease or valvular heart disease and not taking blood pressure medication (group A)

 

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Table 2 Age, PTH, BMI and systolic blood pressure in relation to LVMH quartiles in men and women without known cardiovascular disease or valvular heart disease and not taking blood pressure medication (group A)

 


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Fig. 1 Frequency distribution of LVMH in 980 men and 1060 women without known cardiovascular disease or valvular heart disease and not using blood pressure medication (group A).

 
The relation between PTH and these variables is demonstrated in Table 3where the subjects are grouped in PTH quartiles. With increasing PTH quartiles, there was in both sexes a gradual and significant increase in age, unadjusted and adjusted LVMH, BMI, and systolic blood pressure.


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Table 3 Age, unadjusted and adjusted LVMH, BMI, and systolic blood pressure in relation to serum PTH quartiles in men and women without known cardiovascular disease or valvular heart disease and not taking blood pressure medication (group A)

 
By inspection of the scatter plots for the residuals the relations between the independent variables and LVMH were considered adequate for the multiple regression model. In this model, BMI was the strongest predictor of LVMH in both sexes, followed by the systolic blood pressure (Table 4). PTH was a significant predictor of LVMH in males >59 years (P<0.01) and in females <60 years (P<0.05) (Table 4).


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Table 4 Standardized regression coefficient ß and tavalues for the multiple regression model with LVMH as dependent variable in men and women

 
There was a steep increase in adjusted LVMH above the PTH 95 percentile for the males, and above the 98 percentile for the females (Fig. 2). When using multiple linear regression to compare the LVMH for those in the upper 5% of the PTH range in the males and those in the upper 2% in the females, with the rest of the cohort, the differences were statistically significant in both sexes (P<0.05). This was not due to covariation with serum calcium, as the mean serum calcium in the upper 5% of the PTH range was 2.35±0.13mmol/l for the males, and in the upper 2% for the females 2.39±0.20mmol/l vs 2.37±0.10 and 2.38±0.11mmol/l in the rest of the cohort, respectively. Nor could it be explained by inclusion of subjects with incipient primary hyperparathyroidism. Thus, among the 56 males in the upper 5% of the PTH range only three had a serum calcium of 2.50mmol/l or higher, and for the 22 females in the upper 2% range the corresponding figure was only 4.



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Fig. 2 Mean unadjusted LVMH and mean LVMH adjusted for age, BMI and blood pressure in relation to serum PTH percentiles in 980 men and 1060 women (group A). Error bars (adjusted values) represent the SEM.

 
Within the PTH reference range (2.5–97.5 percentile), PTH was not a significant predictor of LVMH in eithersex.

If defining left ventricular hypertrophy as that above the 97.5 percentile for LVMH (173.7g/m for men and 139.5g/m for women), serum PTH was higher in these subjects when compared with the rest of thecohort (4.01±2.38 vs 2.67±1.26pmol/L for men and 2.91±1.42 vs 2.53±1.18pmol/L for women, P<0.01 and ns, respectively, when evaluated with linear regression with age, BMI and serum calcium as covariates).

3.3. Group B
This group included 119 males and 78 females, age 63.8±7.9 and 66.6±6.8 years, respectively. In the multiple regression model, BMI and PTH were significant predictors of LVMH in the males, whereas for the females, none of the predictors reached statistical significance (Table 4).

3.4. Group C
The remaining subjects (217 males and 246 females, age 64.6±7.4 and 65.4±8.1 years, respectively) could be divided into several subgroups according to presence or absence of cardiovascular disease, valvular heart disease, and blood pressure medication. These subgroups became too small for PTH to reach statistical significance as predictor of LVMH. However, if analysed together, serum PTH was significantly associated with LVMH in the males (P<0.05) (data not shown).

4. Discussion

To our knowledge, the present study is the first to describe PTH as a significant predictor of LVMH in a general population. Regarding PTH levels our population is probably similar to the rest of Europe, and in particular, the frequency of secondary hyperparathyroidism is not higher than in other countries.10

In addition to PTH, we also found BMI, systolic blood pressure, age, gender, a history of known cardiovascular or valvular heart disease, and the use of blood pressure medication to be significantly associated with LVMH. The initial factor analysis disclosed several interactions between these predictors and PTH in their relation to LVMH, and further analysis was therefore performed sex-specific in the relevant subgroups.

In group A (the ‘healthy’ cohort) BMI and systolic blood pressure were, as expected,7the most important predictors of LVMH in the multiple linear regression model. In addition, PTH was a significant predictor in the males older than 59 years and females younger than 60 years. This relation to age may for the males possibly be explained by the higher PTH levels in older than younger subjects.11Furthermore, elevated PTH levels tend to persist,9and accordingly, the older subjects with elevated PTH levels have probably been exposed to the possible harmful effects of PTH over a longer period of time than the younger age groups. However, this can not explain the results in the females where the opposite effect of age was seen. Thus, for the females there was a significant bivariate correlation between PTH and LVMH in both age groups that was only slightly affected by adjusting for age and blood pressure. However, adjusting for BMI abolished the PTH–LVMH relation in the older but not in the young females, which is hard to explain.

There was a strong correlation between age and LVMH that, however, after adjusting for BMI and blood pressure almost disappeared. This must be interpreted with some caution as our study mainly included subjects above the age of 50 years. Furthermore, we measured the left ventricular mass by two-dimensional guided M-mode echocardiography. This technique may give erroneous results in distorted ventricles, and is not as accurate as measurement by magnetic resonance imaging (MRI).12However, because of its simplicity and acceptablereproducibility,7it is generally considered as suited for epidemiological studies.13

The relation between PTH and LVMH was not linear, as shown in.Fig. 2Thus, in relation to increasing PTH levels the adjusted LVMH values appeared to increase only slightly until PTH reached the upper 95 percentile. Furthermore, if excluding the upper and lower 2.5% of the PTH values, and therefore only looking at those included in a general reference range, PTH no longer was a significant predictor of LVMH. Accordingly, if PTH is of causal importance for the development of left ventricular hypertrophy, it must be substantially elevated before the effect can be demonstrated. However, in the upper PTH ranges the LVMH was {approx}14% higher than in the lower PTH ranges, a difference that was significant in both sexes.

Furthermore, in those with left ventricular hypertrophy (defined as LVMH above the 97.5 percentile), eight out of 24 men, but only one out of 26 women had a PTH level in the upper 2.5% range. Thus, if a substantially elevated PTH level is of causal importance for the development of left ventricular hypertrophy it could be of considerable importance, at least in males.

Together with BMI, PTH was a highly significant predictor of LVMH in males with known cardiovascular disease (group B). Cardiovascular disease is by itself a strong predictor of LVMH and in these subjects one could assume that other predictors would be of less importance. In line with this, the systolic blood pressure was not a predictor of LVMH, and therefore, the significance of PTH in this group was remarkable. As evaluated from the standardised ß values from the multiple regression model, the magnitude of the relation between PTH and LVMH in this group was similar to that seen in the healthy cohort (group A). However, due to the small number of subjects in group B it was not possible to disclose a ‘breaking point’ or ‘threshold’ in this relation.

There are previous reports on a relation between PTH and left ventricular hypertrophy, but in disease states only. Thus, Bauwens et al.14in a study on 36 subjects with hypertension, found a highly significant correlation between left ventricular mass index and PTH that persisted after adjustment for 24-h systolic and diastolic blood pressure. However, in that study, the most important confounder, BMI, was not included in the analysis. There are several studies on the association between PTH and left ventricular hypertrophy in patients with end stage renal disease and secondary hyperparathyroidism. In most of these,15,16but not all,17a significant association has been found. Furthermore, in a study by Hara et al.18there was a regression of ventricular hypertrophy and improvement in cardiac contraction after parathyroidectomy in 10 patients on maintenance haemodialysis, and in a study by Park et al.19intravenous calcitriol had a similar effect. Similarly, there are conflicting reports on the relation between PTH and left ventricular hypertrophy in patients with primary hyperparathyroidism,20,21as well as on the cardiac effects of parathyroidectomy in these patients.5,22,23Thus, in the study by Stefenelli et al.20left ventricular hypertrophy was found significantly more often in patients with primary hyperparathyroidism than in matched controls, whereas no such difference was found by Barletta et al.21This may possibly be explained by the more severe disease and higher serum calcium levels in the patients in Stefenelli's study.20Although serum calcium had no significant effect in our model, it may still be a harmful mediator in the patients with primary hyperparathyroidism. However, when considering all these studies on patients with primary or secondary hyperparathyroidism together with our present findings, it is fair to say that there appears to be an association between substantially increased PTH levels and increased left ventricular mass. On the other hand, this association is of course not a proof of a causal relationship.

The possibility of a causal relationship is, however, strengthened by in vitro studies where PTH appears to have chronotropic, inotropic as well as hypertrophiceffects on cardiomyocytes. Thus, in rat heart cells grown in culture, Bogin et al. found PTH to cause a rise in beat per minute,24and in a study on the isolated papillary muscle of the rat heart Katoh et al.25found a positive ionotropic action by PTH. PTH also appears to have effects on the energy production in the cardiomyocytes,26and finally, there is direct evidence of an hypertrophic effect of PTH on isolated cardiomyocytes from adult rats.27

Most of our subjects with elevated PTH levels had secondary hyperparathyroidism, which is generally caused by lack of sun exposure or inadequate intake of vitamin D or calcium. In light of our findings and the above in vitro studies we feel that an intervention study with vitamin D or calcium to subjects with left ventricular hypertrophy and secondary hyperparathyroidism would be justified. Furthermore, in subjects with unexplained left ventricular hypertrophy serum PTH should be measured irrespective of serum calcium levels, and secondary hyperparathyroidism corrected if found.

In conclusion, we have found an association between elevated PTH levels and LVMH in healthy subjects as well as in subjects with known cardiovascular disease. This is in accordance with findings in patients with end stage renal disease and patients with hyperparathyroidism, as well as reported effects of PTH on cardiomyocytes from in vitro studies. Accordingly, substantially elevated PTH levels may be involved in cardiac pathophysiology, and intervention studies with vitamin D or calcium in relevant patient groups should be undertaken.

Acknowledgments

The present study was supported by a grant from The Norwegian Research Council. The superb technical assistance by Astrid Lindvall and Inger Myrnes is gratefully acknowledged.

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