Abstract
Objective
PTH influences atrial fibrillation (AF) risk factors and pathways involved in AF. We therefore sought to determine if PTH levels are altered in patients with AF.
Background
In addition to the traditional role of parathyroid hormone (PTH) as a regulator of calcium homeostasis, PTH also acts as a cardiac hormone, vasodilatory substance, and regulator of smooth muscle proliferation.
Methods
We compared plasma PTH levels in subjects with early-onset AF (n=230; 144 with lone AF and 86 with AF and hypertension), and control subjects (n=150). Subjects with structural heart disease were excluded. Plasma PTH levels were determined using a commercially available immunoassay.
Results
PTH levels were higher in subjects with early-onset AF versus controls (56 versus 50 pg/ml, p=0.01), and there was a stepwise increase in PTH levels from controls, to lone AF and AF and hypertension (50, 54 and 59 pg/ml, p=0.03). PTH levels were higher in permanent AF compared to paroxysmal AF (61 versus 55 pg/ml, p=0.03). PTH levels were higher in subjects with AF compared to sinus rhythm at the time of blood draw (64 versus 54 pg/ml, p=0.001). In a multivariable analysis, each mm increase in left atrial size was associated with a 0.005 (±0.002) pg/ml increase in log(PTH) levels (p=0.047).
Conclusions
We demonstrate that PTH levels are higher in AF subjects, most prominently in subjects with hypertension and in AF at blood sampling. These data suggest that both the rhythm itself and hypertension, as a concomitant condition, may influence the relation between PTH and AF.
Keywords: Atrial fibrillation, parathyroid hormone, hypertension, biomarker
Atrial fibrillation (AF) is the most common cardiac arrhythmia, as well as an important cause of cardiovascular morbidity and mortality.(1) Despite an extensive search for contributors of AF risk, a substantial portion of the variability in AF risk remains unexplained. Clinical observations and insights from several animal models have led to the concept that multiple mechanisms, including electrophysiological triggers, altered atrial substrate, and modulating factors are responsible for the induction and maintenance of AF.
Observations suggest that parathyroid hormone (PTH) is associated with risk factors for AF such as hypertension and heart failure, and may be involved in modulation of the renin-angiotensin system.(2) Elevated PTH levels and primary hyperparathyroidism are common in the general population.(3) Classical target organs for PTH are the kidney and bone. However, PTH also has effects on other tissues, including the heart and blood vessels.(4)
PTH receptors are expressed throughout the cardiovascular system, including in the heart.(5) In the cardiovascular system, PTH acts as a cardiac hormone with a diverse array of effects.(6–9) Parathyroid hormone-related protein mRNA expression in the heart of the rat is increased by physiologic maneuvers that increase atrial or ventricular workload and distention.(8) PTH accelerates heart rate, an effect that may be mediated by direct action of PTH on the sinus node and conducting system. PTH also exerts inotropic effects, possibly as a consequence of increased coronary blood flow due to the vasodilatory action of PTH on the coronary circulation.(8) Several experimental and clinical studies reported that PTH is associated with hypertension, disturbances in the renin-angiotensin–aldosterone system, ventricular fibrillation, left-ventricular hypertrophy and heart failure, as well as structural and functional changes in the vascular wall.(2)
Given the associations between PTH and several AF risk factors, we hypothesized that PTH levels are altered in subjects with AF.(10) We therefore assessed the relation between plasma PTH levels and AF in subjects without structural heart disease or inflammatory conditions.
Methods
Study population
Individuals were eligible for enrollment if they had at least one documented electrocardiogram (ECG) with AF and a structurally normal heart on echocardiogram. Two-hunderd-thirty consecutive subjects with AF were prospectively enrolled between July 2001 and October 2005 from referrals to the Cardiac Arrhythmia Service at the Massachusetts General Hospital, Boston, Massachusetts. Subjects were excluded if they had any sign of significant valve disease, a history of rheumatic heart disease, congenital heart disease, cardiomyopathy, or myocarditis. Subjects free of hypertension were considered to have lone AF. Subjects who used any antihypertensive therapy or had a documented blood pressure in a sitting position ≥ 140/90 mmHg on 2 separate occasions before the diagnosis of AF were considered to have AF and hypertension. The final study cohort consisted of 230 subjects with early onset AF (early onset AF group), without any structural heart diseases or inflammatory conditions. This group consisted of 144 subjects with lone AF and 86 subjects with AF and hypertension. One-hunderd-fifty control subjects, with a comparable age and sex distribution, were selected from a healthy primary care population (from the Global Repository, Genomics Collaborative, Inc., Cambridge, Massachusetts). All studies were performed with Institutional Review Board approval at Massachusetts General Hospital and with written informed consent from each subject.
Clinical characteristics
Each subject underwent a physical examination and a structured interview using a 28-page data form to elicit a detailed medical history. This included a personal history of AF including symptoms while in AF, potential triggers for AF, medical and procedural treatments for AF, associated cardiovascular and medical conditions, as well as current and past medication use. All subjects had an ECG at the time of enrollment and an echocardiogram within 90 days of enrollment. Echocardiography included a comprehensive two-dimensional, M-mode, and Doppler evaluation. Subjects with AF of > 6 months in duration and ≥ 1 attempted electrical cardioversion on separate occasions to restore normal sinus rhythm were considered to have permanent AF. All other subjects were considered to have paroxysmal AF.
Parathyroid hormoon assay
At enrollment a 7-ml blood sample was obtained from a peripheral vein into EDTA containing tubes. Samples were centrifuged at 2500 rotations per minute, plasma was extracted, aliquoted, and stored at −80 degrees Celsius until analysis. Plasma PTH levels were determined using an enzyme immuno-assay (manufactured by Biomedica Gruppe, Germany) according to manufacturers instructions. All samples were performed in duplicate and values were normalized to a standard curve. The intra- and interassay variabilities for PTH were 3.0% and 5.1%, respectively. The lower limit of detection for this assay is 1.72 pg/ml.
Statistical Analysis
Subject characteristics were compared between lone AF and AF and hypertension groups using the Student’s t-test or Mann-Whitney U test for continuous variables depending on normality of the data, or the Fisher’s exact test for categorical data. Baseline descriptive statistics are presented as the mean ± standard deviation (SD) or median (range) for continuous variables and as numbers with percentages for categorical variables. Since PTH levels were both skewed and kurtotic, they were logarithmically transformed before all analyses. Median values (interquartile range) of PTH are presented. We compared log(PTH) levels between subjects with lone AF, AF and hypertension, and control subjects using one-way ANOVA. In order to determine correlates of log(PTH) levels, all univariate clinical, electrocardiographic, and echocardiographic variables with a univariable p-value < 0.10 were entered into a backward selection linear regression algorithm. A p-value <0.05 was considered statistically significant. Analyses were performed using SPSS 16.0 (SPSS Inc., Chicago).
Results
Baseline characteristics
The study cohort consisted of 380 subjects (230 with early-onset AF and 150 control subjects). The baseline characteristics are shown in Table 1. The mean age at diagnosis of AF was 48 ± 12 years and the mean age at enrollment was 56 ± 11 years. The majority of subjects were male (80%) and had paroxysmal AF (88%). At enrollment, 71% of subjects were in sinus rhythm. The early-onset AF group consisted of 144 subjects with lone AF and 86 with AF and hypertension. As expected, those subjects with AF and hypertension were older than those with lone AF (60±9 versus 53±11 years), had higher blood pressures (systolic 138±19 versus 123±13 mmHg, p<0.001, and diastolic 82±10 versus 76±8 mmHg, p<0.001) body mass index (30±6 versus 27±4 kg/m2, p<0.001), and were more likely to be receiving antihypertensive medications (Table 2). Control subjects had no significant past medical history.
Table 1.
Baseline characteristics of control subjects and subjects with early-onset AF.
| Controls (n=150) | Early-onset AF (n=230) | |
|---|---|---|
| Baseline characteristics | ||
| Age at enrollment, years | 53±8 | 56 ± 11 |
| Male sex | 135 (85%) | 185 (80%) |
| Body mass index, kg/m2 | - | 28 ± 5 |
| Systolic Blood Pressure, mmHg | - | 129 ± 17 |
| Diastolic Blood Pressure, mmHg | - | 78 ± 9 |
| Personal history of AF | ||
| Age at AF diagnosis, years | - | 48 ± 12 |
| Over 20 episodes of AF | - | 137 (60%) |
| Over 100 episodes AF | - | 105 (46%) |
| Number of ED visits or admissions for AF | - | 1 (0–25) |
| Paroxysmal AF at initial presentation | - | 203 (88%) |
| Previous electrical cardioversion | - | 87 (38%) |
| Number of cardioversions | - | 0 (0–20) |
| Medications | ||
| Beta-blocker | - | 136 (59%) |
| Digoxin | - | 49 (21%) |
| Calcium channel blocker | - | 46 (20%) |
| Lipid lowering agent | - | 60 (26%) |
| ACE inhibitor or ARB | - | 40 (17%) |
| Warfarin | - | 117 (51%) |
| Laboratory measurement | ||
| Creatinine, mg/dl | - | 1.03 ± 0.21 |
Abbreviations: AF = atrial fibrillation; ARB = angiotensin receptor blocker; ACE = angiotensin-converting enzyme; ED = Emergency department.
Table 2.
Baseline characteristics of subjects with lone AF and AF and hypertension.
| Lone AF (n=144) | AF and hypertension (n=86) | P-value* | |
|---|---|---|---|
| Baseline characteristics | |||
| Age at enrollment, years | 53±11 | 60±9 | <0.001 |
| Male sex | 116 (81%) | 69 (80%) | 1.0 |
| Body mass index, kg/m2 | 27±4 | 30±6 | <0.001 |
| Systolic Blood Pressure, mmHg | 123±13 | 138±19 | <0.001 |
| Diastolic Blood Pressure, mmHg | 76±8 | 82±10 | <0.001 |
| Personal history of AF | |||
| Age at AF diagnosis, years | 45±11 | 52±12 | <0.001 |
| Over 20 episodes of AF | 97 (67%) | 40 (47%) | 0.02 |
| Over 100 episodes AF | 77 (53%) | 28 (33%) | 0.01 |
| Number of ED visits or admissions for AF | 1 (0–22) | 1 (0–25) | 0.90 |
| Paroxysmal AF at initial presentation | 132 (92%) | 71 (83%) | 0.06 |
| Previous electrical cardioversion | 47 (33%) | 40 (47%) | 0.049 |
| Number of cardioversions | 0 (0–20) | 1 (0–12) | 0.009 |
| Medications | |||
| Beta-blocker | 79 (55%) | 57 (68%) | 0.07 |
| Digoxin | 28 (19%) | 21 (25%) | 0.32 |
| Calcium channel blocker | 25 (17%) | 21 (25%) | 0.17 |
| Lipid lowering agent | 19 (13%) | 41 (49%) | <0.001 |
| ACE inhibitor or ARB | 2 (1%) | 38 (46%) | <0.001 |
| Warfarin | 67 (47%) | 50 (58%) | 0.07 |
| Laboratory measurement | |||
| Creatinine, mg/dl | 1.01 ± 0.19 | 1.06 ± 0.23 | 0.14 |
Abbreviations: AF = atrial fibrillation; ARB = angiotensin receptor blocker; ACE = angiotensin-converting enzyme; ED = Emergency department.
Electrocardiographic and echocardiographic characteristics
The electrocardiographic and echocardiographic characteristics of the early onset AF cohort are shown in Table 3. There were no electrocardiographic abnormalities, despite an increased mean PR-interval and mean corrected QT interval, both within normal ranges, in the AF and hypertension group, compared to lone AF (Table 4). The only marked finding with echocardiography was a mean left atrial diameter at the upper limits of normal. The mean values of all other echocardiographic parameters, including chamber dimensions, wall thicknesses, and functional indices, were normal in the study cohort. In subjects with AF and hypertension the mean aortic root diameter and mean intraventricular septum were larger than in subjects with lone AF (Table 4).
Table 3.
Electrocardiographic and echocardiographic findings of subjects with early-onset AF.
| Electrocardiogram | Early-onset AF (n=230) |
|---|---|
| Sinus rhythm or sinus bradycardia | 164 (71%) |
| Atrial fibrillation | 42 (18%) |
| Atrial flutter | 8 (4%) |
| Paced or other rhythm | 16 (7%) |
| Mean ventricular rate | 68 ± 19 |
| PR interval | 178 ± 34 |
| QRS interval | 94 ± 15 |
| Corrected QT interval | 413 ±40 |
| Echocardiogram | |
| Left-ventricular ejection fraction, % | 62 ± 7 |
| Left atrial size, mm | 39 ± 6 |
| Left ventricular end-diastolic diameter, mm | 49 ± 5 |
| Aortic root, mm | 34 ± 5 |
| Posterior wall thickness, mm | 10 ± 1 |
| Intraventricular septum, mm | 10 ± 2 |
Table 4.
Electrocardiographic and echocardiographic findings of subjects with lone AF and AF and hypertension.
| Electrocardiogram | Lone AF (n=144) | AF and hypertension (n=86) | P-value |
|---|---|---|---|
| Sinus rhythm or sinus bradycardia | 108 (75%) | 56 (65%) | 0.10 |
| Atrial fibrillation | 19 (13%) | 23 (27%) | |
| Atrial flutter | 7 (5%) | 1 (1%) | |
| Paced or other rhythm | 10 (7%) | 6 (7%) | |
| Mean ventricular rate | 68 ± 18 | 69 ± 20 | 0.68 |
| PR interval | 174 ± 33 | 186 ± 36 | 0.03 |
| QRS interval | 92 ± 15 | 95 ± 15 | 0.17 |
| Corrected QT interval | 406 ± 41 | 425 ± 36 | <0.001 |
| Echocardiogram | |||
| Left-ventricular ejection fraction, % | 62 ± 6 | 63 ± 8 | 0.23 |
| Left atrial size, mm | 39 ± 7 | 41 ± 6 | 0.07 |
| LVEDD, mm | 50 ± 5 | 49 ± 5 | 0.72 |
| Aortic root, mm | 34 ± 5 | 36 ± 5 | 0.006 |
| Posterior wall thickness, mm | 10 ± 1 | 10 ± 2 | 0.11 |
| Intraventricular septum, mm | 10 ± 2 | 11 ± 2 | 0.04 |
Abbreviation: LVEDD = left ventricular end-diastolic diameter.
Parathyroid hormone levels
PTH levels were significantly higher in subjects with early-onset AF versus control subjects (56 [38–72] versus 50 [36–65] pg/ml, p=0.01, Figure 1A). There was a progressive increase in PTH levels among the control subjects, those with lone AF, and those with AF and hypertension (50 [36–65] versus 54 [39–69] versus 59 [37–81] pg/ml, p=0.03, Figure 1B). At the time of blood sampling, 203 subjects were in paroxysmal AF and 27 in permanent AF. PTH levels were higher in subjects with permanent as compared to paroxysmal AF (61 [52–91] versus 55 [37–71] pg/ml, p=0.03, Figure 2A), and higher in paroxysmal AF compared to control subjects (55 [37–71] versus 50 [36–65] pg/ml, p=0.046). One-hunderd-sixty-four subjects were in sinus rhythm or sinus bradycardia and 50 in AF at time of blood sampling AF; PTH levels were higher in subjects with AF compared to sinus rhythm (64 [44–87] versus 54 [38–70] pg/ml, p=0.001, Figure 2B), and no significant difference between sinus rhythm or sinus bradycardia subjects and control subjects was found (54 [38–70] versus 50 [36–65] pg/ml, p=0.08). No gender-based differences in PTH levels were present.
Figure 1.
Box plots illustrating the PTH levels in healthy controls and in subjects with early-onset AF (A), and lone AF, and AF and hypertension (B). Boxes show interquartile ranges, and bars represent the 90th and 10th percentile.
Figure 2.
Box plots illustrating PTH levels in subjects with AF stratified based on paroxysmal versus permanent AF (A), and rhythm at the time of blood sampling (B). Boxes show interquartile ranges, and bars represent the 90th and 10th percentile.
Multivariable correlates of parathyroid hormone levels
Multivariable regression modelling revealed that each mm increase in left atrial size was associated with a 0.005 (±0.002) pg/ml increase in log(PTH) levels (p=0.047). The presence of AF at time of blood sampling was associated with an increase in log(PTH) levels of borderline significance (0.071 (±0.036) pg/ml increase in log(PTH) levels (p=0.05; Table 5).
Table 5.
Predictors of Log(PTH) from linear regression.
| Univariable analysis* | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| β | SE | P value | β | SE | P value | |
| Age, years | 0.002 | 0.001 | 0.04 | |||
| Body mass index, kg/m2 | 0.006 | 0.003 | 0.03 | |||
| Paroxysmal AF vs. permanent AF | 0.058 | 0.018 | 0.001 | |||
| AF vs. sinus rhythm, at blood sampling | 0.085 | 0.033 | 0.01 | 0.071 | 0.036 | 0.051 |
| Heart rate, bpm | 0.001 | 0.001 | 0.09 | |||
| Left atrial size, mm | 0.006 | 0.002 | 0.009 | 0.005 | 0.002 | 0.047 |
| ACE inhibitor or ARB | 0.091 | 0.036 | 0.01 | |||
Variables listed are those with p<0.1 in univariable analyses.
Abbreviations: ARB = angiotensin receptor blocker; ACE = angiotensin-converting enzyme.
Discussion
We observed that PTH levels are significantly higher in subjects with early-onset AF. This elevation is most prominent in subjects with AF and hypertension, subjects with permanent AF, and subjects that were in AF during blood sampling. Multivariable analysis revealed that only left atrial size is associated with PTH levels.
To avoid the confounding effects of underlying structural heart disease, we rigorously excluded structural heart diseases and inflammatory conditions and studied well-defined subjects with early-onset AF, consisting of lone AF and AF and hypertension subjects. Our data suggests that both the rhythm itself and hypertension may play a role in determining PTH levels.
Hypertension as possible cause of elevated PTH levels in AF
Our findings are consistent with earlier findings that PTH is reported to be associated with hypertension, and left-ventricular hypertrophy.(2,11) This effect may be due to the vasodilatory effects of PTH.(2) PTH stimulates the vascular smooth muscle cell by binding to the PTH/PTH-related peptide receptor and, increases the intracellular cAMP-levels and reduces the influx of calcium.(12–14) However, in human, PTH-infusion studies reported contradictory results regarding blood pressure response. A blood pressure decrease was observed in essential hypertensives and an increased or unaffected blood pressure in normotensive subjects.(15,16) These differences may be caused by differences in PTH levels and the different cohorts studied. Other mechanisms which may play a role are functional and structural changes of the vascular wall.(2) But again conflicting data exist. Regarding functional changes of the vascular wall due to PTH, some point to an impaired endothelium-dependent vasodilation in primary hyperparathyroidism-patients, which is reversed by parathyroidectomy.(17–19) However, others have observed a decrease of vascular smooth muscle-dependent vasodilation.(20) Regarding structural changes of the vascular wall due to PTH, Nuzzo et al. found an increased intima-media thickness in the carotid artery wall,(21) but others have failed to confirm this.(17,18,22) Finally, in autopsy studies of patients suffering from chronic hypercalcemia is known that there is an increased deposition of calcium in the intima and media of coronary arteries of these patients. As a result, stiffening of the arteries occurs, which may cause systolic hypertension, increase pulse pressure and increase the central artery pressure and subsequently increasing the afterload of the heart, leading to impaired hemodynamics.(23,24)
AF itself as possible cause of elevated PTH levels
The observation that PTH levels were higher in subjects in AF than in those in sinus rhythm at the time of blood draw may implicate AF as a causal factor for PTH elevation. Potential mechanisms by which AF may increase PTH levels include direct hemodynamic consequences of AF. Loss of atrial contraction during AF, causing atrial volume and pressure overload, leading to atrial stretch, and may result in a decrease in cardiac output of 10–20%. We found that left atrial size was associated with PTH levels, which is consisted with the above. Our observations are complementary to previous data. Ogino et al. found an increased PTH-related protein messenger RNA expression in the rat heart as result of physiologic maneuvers that increase atrial or ventricular workload and distention.(8) Recently, Shor et al. observed increased PTH-related peptide levels in 12 subjects with new-onset AF, declining after electrical cardioversion to sinus rhythm.(25) Furthermore, we found elevated PTH levels in both paroxysmal as permanent AF subjects, with the highest levels in permanent AF subjects. This, in accordance with the finding that left atrial size was associated with PTH levels in multivariable analysis, suggests that the progression of AF itself may play a role in the found association between AF and PTH. Further prospective studies are warrentd to clarify this possible reverse causality between AF and PTH.
Limitations
These cohorts are based in a tertiary care arrhythmia clinic, and may represent a selected subset of patients with AF. Our study is cross-sectional in design, which precludes definite conclusions regarding cause-effect relationship. Future studies in cohorts with incident AF will be necessary to delineate the temporal relation between AF and PTH levels.
Conclusion
PTH levels are higher in subjects with AF, most prominently in subjects with AF and hypertension, subjects with permanent AF subjects and subjects with actual AF during blood sampling. Multivariable analysis revealed that only left atrial size is associated with PTH levels. Although these findings merit further studies, our data suggest that both the rhythm itself and hypertension as concomitant condition may play a role in the elevation of PTH in AF.
Acknowledgments
Sources of funding:
Dr. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Rubicon grant 825.09.020). This work was supported by grants from the National Institutes of Health (R01HL092577, R01HL104156, R21DA027021) to Dr. Ellinor. There is no relationship with industry.
Abbreviations list
- ACE
Angiotension-converting enzyme
- AF
Atrial fibrillation
- ARB
Angiotensin receptor blocker
- ECG
Electrocardiogram
- PTH
Parathyroid hormone
Footnotes
The paper is not under consideration elsewhere, and none of the paper’s contents have been previously published. All authors have read and approved the manuscript.
References
- 1.Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N–9N. doi: 10.1016/s0002-9149(98)00583-9. [DOI] [PubMed] [Google Scholar]
- 2.Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease--a review. Eur Heart J. 2004;25:1776–87. doi: 10.1016/j.ehj.2004.07.010. [DOI] [PubMed] [Google Scholar]
- 3.Heath H, 3rd, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med. 1980;302:189–93. doi: 10.1056/NEJM198001243020402. [DOI] [PubMed] [Google Scholar]
- 4.Bro S, Olgaard K. Effects of excess PTH on nonclassical target organs. Am J Kidney Dis. 1997;30:606–20. doi: 10.1016/s0272-6386(97)90484-4. [DOI] [PubMed] [Google Scholar]
- 5.Urena P, Kong XF, Abou-Samra AB, et al. Parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acids are widely distributed in rat tissues. Endocrinology. 1993;133:617–23. doi: 10.1210/endo.133.2.8393771. [DOI] [PubMed] [Google Scholar]
- 6.Wysolmerski JJ, Stewart AF. The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol. 1998;60:431–60. doi: 10.1146/annurev.physiol.60.1.431. [DOI] [PubMed] [Google Scholar]
- 7.Deftos LJ, Burton DW, Brandt DW. Parathyroid hormone-like protein is a secretory product of atrial myocytes. J Clin Invest. 1993;92:727–35. doi: 10.1172/JCI116643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ogino K, Burkhoff D, Bilezikian JP. The hemodynamic basis for the cardiac effects of parathyroid hormone (PTH) and PTH-related protein. Endocrinology. 1995;136:3024–30. doi: 10.1210/endo.136.7.7789328. [DOI] [PubMed] [Google Scholar]
- 9.Hara M, Liu YM, Zhen L, et al. Positive chronotropic actions of parathyroid hormone and parathyroid hormone-related peptide are associated with increases in the current, I(f), and the slope of the pacemaker potential. Circulation. 1997;96:3704–9. doi: 10.1161/01.cir.96.10.3704. [DOI] [PubMed] [Google Scholar]
- 10.Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994;271:840–844. [PubMed] [Google Scholar]
- 11.Dluhy RG. Uncommon forms of secondary hypertension in older patients. Am J Hypertens. 1998;11:52S–56S. doi: 10.1016/s0895-7061(98)00011-9. [DOI] [PubMed] [Google Scholar]
- 12.Hanson AS, Linas SL. Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells. Hypertension. 1994;23:468–75. doi: 10.1161/01.hyp.23.4.468. [DOI] [PubMed] [Google Scholar]
- 13.Bergmann C, Schoeffter P, Stoclet JC, Gairard A. Effect of parathyroid hormone and antagonist on aortic cAMP levels. Can J Physiol Pharmacol. 1987;65:2349–53. doi: 10.1139/y87-372. [DOI] [PubMed] [Google Scholar]
- 14.Pang PK, Yang MC, Tenner TE, Jr, Kenny AD, Cooper CW. Cyclic AMP and the vascular action of parathyroid hormone. Can J Physiol Pharmacol. 1986;64:1543–7. doi: 10.1139/y86-259. [DOI] [PubMed] [Google Scholar]
- 15.Jespersen B, Randlov A, Abrahamsen J, Fogh-Andersen N, Kanstrup IL. Effects of PTH(1-34) on blood pressure, renal function, and hormones in essential hypertension: the altered pattern of reactivity may counteract raised blood pressure. Am J Hypertens. 1997;10:1356–67. doi: 10.1016/s0895-7061(97)00275-6. [DOI] [PubMed] [Google Scholar]
- 16.Fliser D, Franek E, Fode P, et al. Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans. Nephrol Dial Transplant. 1997;12:933–8. doi: 10.1093/ndt/12.5.933. [DOI] [PubMed] [Google Scholar]
- 17.Kosch M, Hausberg M, Vormbrock K, Kisters K, Rahn KH, Barenbrock M. Studies on flow-mediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism. Am J Hypertens. 2000;13:759–64. doi: 10.1016/s0895-7061(00)00248-x. [DOI] [PubMed] [Google Scholar]
- 18.Nilsson IL, Aberg J, Rastad J, Lind L. Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed after parathyroidectomy. Surgery. 1999;126:1049–55. doi: 10.1067/msy.2099.101422. [DOI] [PubMed] [Google Scholar]
- 19.Kosch M, Hausberg M, Vormbrock K, et al. Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy. Cardiovasc Res. 2000;47:813–8. doi: 10.1016/s0008-6363(00)00130-9. [DOI] [PubMed] [Google Scholar]
- 20.Neunteufl T, Katzenschlager R, Abela C, et al. Impairment of endothelium-independent vasodilation in patients with hypercalcemia. Cardiovasc Res. 1998;40:396–401. doi: 10.1016/s0008-6363(98)00177-1. [DOI] [PubMed] [Google Scholar]
- 21.Nuzzo V, Tauchmanova L, Fonderico F, et al. Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism. Eur J Endocrinol. 2002;147:453–9. doi: 10.1530/eje.0.1470453. [DOI] [PubMed] [Google Scholar]
- 22.Kosch M, Hausberg M, Barenbrock M, Posadzy-Malaczynska A, Kisters K, Rahn KH. Arterial distensibility and pulse wave velocity in patients with primary hyperparathyroidism before and after parathyroidectomy. Clin Nephrol. 2001;55:303–8. [PubMed] [Google Scholar]
- 23.O’Rourke MF, Kelly RP. Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens. 1993;11:327–37. doi: 10.1097/00004872-199304000-00001. [DOI] [PubMed] [Google Scholar]
- 24.Smith JC, Page MD, John R, et al. Augmentation of central arterial pressure in mild primary hyperparathyroidism. J Clin Endocrinol Metab. 2000;85:3515–9. doi: 10.1210/jcem.85.10.6880. [DOI] [PubMed] [Google Scholar]
- 25.Shor R, Tilis Y, Halabe A, Boaz M, Matas Z, Fux A. Serum parathyroid hormone-related protein levels before and after paroxysmal atrial fibrillation. Am J Emerg Med. 2008;26:361–3. doi: 10.1016/j.ajem.2007.08.005. [DOI] [PubMed] [Google Scholar]