Author + information
- Michiel Rienstra, MD, PhD,
- Steven A. Lubitz, MD, MPH,
- Michael L. Zhang, BSc,
- Rebecca R. Cooper, BA and
- Patrick T. Ellinor, MD, PhD⁎ ()
- ↵⁎Cardiac Arrhythmia Service, Massachusetts General Hospital, 55 Fruit Street, GRB 109, Boston, Massachusetts 02114
To the Editor:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, as well as an important cause of cardiovascular morbidity and mortality. Despite an extensive search for contributors to AF risk, a substantial portion of the variability in AF risk remains unexplained.
Parathyroid hormone (PTH) receptors are expressed throughout the cardiovascular system, including in the heart, where PTH acts as a cardiac hormone with a diverse array of effects (1). Parathyroid hormone accelerates heart rate, an effect that may be mediated by direct action of PTH on the sinus node and conducting system; and 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 (2). 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 (1).
Given the associations between PTH and several AF risk factors, we hypothesized that PTH levels are altered in subjects with AF.
Consecutive subjects with AF were prospectively enrolled between 2001 and 2005 from the Cardiac Arrhythmia Service. Inclusion criteria were electrocardiography documented AF, age younger than 66 years, and a structurally normal heart on echocardiography. Subjects were excluded if they had significant valve disease, a history of rheumatic heart disease, congenital heart disease, cardiomyopathy, myocarditis, or thyrotoxicosis. Subjects free of hypertension were considered to have lone AF. Control subjects, with comparable age and sex distribution, were selected from a healthy primary care population (Global Repository, Genomics Collaborative, Inc., Cambridge, Massachusetts). All studies were performed with institutional review board approval and written informed consent from each subject.
All AF subjects underwent a structured interview to elicit a detailed medical history, physical examination, electrocardiography, and echocardiography. Subjects with AF of >6 months in duration and ≥1 attempted electrical cardioversion were considered to have permanent AF. All other subjects were considered to have paroxysmal AF.
Plasma PTH levels were determined using an enzyme immunoassay (Biomedica Gruppe, Vienna, Austria). All samples were performed in duplicate, and values were normalized to a standard curve. The intra-assay and interassay variabilities for PTH were 3.0% and 5.1%, respectively.
The study cohort consisted of 380 subjects (230 with AF and 150 control subjects). The mean age was 56 ± 11 years. Eighty percent were male, 88% had paroxysmal AF. The AF group consisted of 144 subjects with lone AF and 86 with AF and hypertension. Subjects with AF and hypertension were older than subjects with lone AF (60 ± 9 years vs. 53 ± 11 years, respectively), had higher blood pressures (systolic 138 ± 19 mm Hg vs. 123 ± 13 mm Hg, p < 0.001, and diastolic 82 ± 10 mm Hg vs. 76 ± 8 mm Hg, respectively, p < 0.001), and body mass index (30 ± 6 kg/m2 vs. 27 ± 4 kg/m2, respectively, p < 0.001), and were more likely to have received antihypertensive medication. There were no electrocardiographic and echocardiographic abnormalities in either AF group.
The PTH levels were higher in AF subjects compared with those of controls (56 pg/ml [38 to 72 pg/ml] vs. 50 pg/ml [36 to 65 pg/ml], p = 0.01) (Fig. 1). There was a progressive increase in PTH levels among the controls, lone AF, and AF and hypertension (50 pg/ml [36 to 65 pg/ml], 54 pg/ml [39 to 69 pg/ml], and 59 pg/ml [37 to 81 pg/ml], respectively, p = 0.03). At the time of blood sampling, 203 subjects were diagnosed with paroxysmal AF and 27 with permanent AF. The PTH levels were higher in permanent AF subjects as compared with paroxysmal AF subjects (61 pg/ml [52 to 91 pg/ml] vs. 55 pg/ml [37 to 71 pg/ml], p = 0.03), and higher in paroxysmal AF subjects compared with controls (55 pg/ml [37 to 71 pg/ml] vs. 50 pg/ml [36 to 65 pg/ml], p = 0.046). At the time of blood sampling, 164 subjects were in sinus rhythm and 50 were in AF; PTH levels were higher in AF compared to sinus rhythm (64 pg/ml [44 to 87 pg/ml] vs. 54 pg/ml [38 to 70 pg/ml], p = 0.001), and no significant difference between sinus rhythm and controls was found (54 pg/ml [38 to 70 pg/ml] vs. 50 pg/ml [36 to 65 pg/ml], p = 0.08). Multivariable regression modeling of the AF cohort revealed that each millimeter increase in left atrial size was associated with a 0.23 ± 0.01 pg/ml increase per SD of log(PTH) levels (mean 1.72 ± 0.21; p = 0.047).
We observed that PTH levels are higher in subjects with AF. This elevation is most prominent in subjects with AF and hypertension, subjects with permanent AF, and subjects who were in AF during blood sampling. Our data suggest that both the rhythm itself and hypertension may play a role in determining PTH levels.
Our findings are consistent with earlier findings that PTH is reported to be associated with hypertension and left ventricular hypertrophy (1). Whether stimulation of vascular smooth muscle cells by increased intracellular cAMP-levels and reduced influx of calcium, or impaired endothelium-dependent vasodilation, or stiffening of the arteries leading to impaired hemodynamics by chronic hypercalcemia plays a role as a result of PTH is uncertain.
The PTH levels were higher in subjects in AF at the time of blood draw compared to levels in subjects in sinus rhythm, and the highest levels were found in subjects with permanent AF compared to paroxysmal AF. Furthermore, we found an association between left atrial size and PTH. These observations may implicate AF as a causal factor for PTH elevation. Potentially, the hemodynamic consequences of AF, including the loss of atrial contraction, atrial volume, and pressure overload, atrial stretch, and the 10% to 20% decrease of cardiac output, may be the underlying mechanism. Previously, data have been reported that PTH-related protein messenger ribonucleic acid expression increased in the rat heart as result of physiologic maneuvers that increase atrial or ventricular workload and distention (2). Also, a decline in elevated PTH-related peptide levels was observed directly after electrical cardioversion in patients with new-onset AF (3).
Our study is cross-sectional in design, which precludes definite conclusions regarding a cause-effect relationship. Future studies will be necessary to delineate the temporal relation between AF and PTH levels.
Please note: 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, R21DA027021) to Dr. Ellinor.
- American College of Cardiology Foundation