Atrial fibrillation (AF) is the most commonly encountered arrhythmia in cardiology practice. A diagnosis of AF implies a greater need for hospitalization, a higher risk of stroke and heart failure, and earlier mortality. These complications can be avoided if AF is diagnosed and treated in a timely manner. To achieve this, physicians need to maintain a high index of clinical suspicion, practice cardiovigilance, and screen for AF in appropriate clinical settings. This review describes the vast spectrum of endocrine and metabolic disease that are associated with AF. Through this perspective, it encourages physicians and endocrinologists to play an active role in AF detection, referral and long term management.
Keywords: Arrhythmia, cardiovigilance, diabetes, endovigilance, hyperthyroidism
Atrial fibrillation (AF) is a commonly encountered supraventricular arrhylhmia characterized by lowamplitude baseline oscillations (for fibrillory waves originating from the atria), along with an irregrlarly irregular ventricular rhythm. The f-waves which have variable amplitude, shape and timing, exhibit a frequency of 300-600 beats/minute.
AF is classified according to its natural history, or the predominant autonomic environment that it occurs in.1
Table 1 and 2 list the various types of AF, while Table 3 summarizes the endocrine and metabolic connections of AF.
The ORBIT-AF registry shows that persons with diabetes form a significant (29.5%) proportion of all patients with AF. They are likely to be younger, have hypertension, chronic kidney disease, heart failure, coronary heart disease and stroke. They also have a poorer quality of life, and are more likely to receive anticoagulation. They experience a higher morbidity and mortality risk, including cardiovascular hospitalization, hospitalization, cardiovascular death, sudden cause death, and noncardiovascular death. However, no difference in risk of thromboembolic events, bleeding-related hospitalization, new- on set hear t failure, and AF progression. 2
Thyrotoxicosis is the most common correctable cause of AF with a 5 fold increased risk being documented. AF is more common in hyperthyroidism, in patients with triiodothyronine (T3) toxicosis and in the elderly. 3 Subclinical hyperthyroidism is also associated with a 3 fold rise in AF, and low TSH levels correlate positively with risk of AF. Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a 3x higher risk of AF development within a decade. 4 Some mechanisms by which thyrotoxicosis may cause AF are listed in Table 4.
Thyrotoxicosis exerts a marked chronotropic and dromotropic effect. Elevation of leftatrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation, ischaemia resulting from increased resting heart rate, and increased atrial ectopic activity also predispose to AF. Re-entry is one of the important mechanisms leading to AF. AF is facilitated if effective refractory periods are short and conduction is slow. Hyperthyroidism-associated shortening of action potential durational so contributes to AF. 5,6 Correction of hypothyroidism leads to cure of AF. This has been noted not only in overt thyrotoxicosis, but in subclinical hyperthyroidism as well. A case series described four patients with persistent atrial fibrillation associated with normal plasma to talthyroxine ( T4 ) and triiodothyronine (T3) but an absent plasma thyrotrophin (TSH) response to intravenous thyrotrophin releasing hormone (TRH). Cardioversion failed initially, in three of them. Following antithyroid drug therapy, sinus rhythm was established in all (1 spontaneous, 3 af ter cardioversion).7
Pituitary adenylate cyclase activating polypeptide (PACAP), which is known to activate intracardiac postganglionic parasympathetic nerves, has a profibrillatory effect on the heart. In a dog model, PACAP is shown to shorten effective refractory period (ERP) and conduction time. This may lead to induction of AF. 8 Case reports of AF in patients with pituitary tumours have been published.9,10
Parathyroid and Vitamin-D
Parathyroid hormone (PTH) is found to be elevated in patients with AF. 22 Case reports of AF in parathyroid tumour have been published in literature. 12,13 PTH has cardiotropic effects, which are mediated via PTH receptors that are present in the heart as well as other parts of the cardiovascular system. 14The effects of PTH on the CVS are listed in Table 5. PTH-related peptide levels have been noted to fall after electrical cardioversion in patients with new-onset AF. 11 PTH elevation has been noted in patients with AF, especially in those with AF and hypertension, in those with permanent AF, and in those who were in AF during blood sampling. PTH levels correlate with left atrial size as well. Experts feel that both rhythm and blood pressure play a role in PTH elevation. AF may cause PTH rise by leading to loss of atrial contraction, atrial volume and pressure overload, atrial stretch, and the resultant 10-20% fall in cardiac output. 14 Data regarding the correlation of vitamin D deficiency with AF reveals conflicting evidence. While some authors report a higher incidence of AF in vitamin D deficient persons, others suggest that vitamin D deficiency is unrelated to type of atrial fibrillation, its complications or outcomes.15,16 Higher serum phosphorus levels are associated with greater AF risk; a 1 mg/dl rise in serum phosphorus leads to a hazard ratio of 1.13 (95% confidence interval 1.02- 1.26) of AF, irrespective of gender or race. This association occurs only of eGFR is 90 ml/min/1.72 m2 While total corrected calcium levels are not related to risk of AF, calcium-phosphorus product is associated with greater AF risk. 17 Case reports of symptomatic atrial arrhythmias in haemodialysis patients may be explained by high PTH &/or high phosphorus levels. 18
There are case reports of AF in patients with Cushing's disease, in anabolic steroid users and after intravenous methylprednisolone therapy.19-21 On the other hand, intravenous hydrocor tisone or dexameth ason e administration has been shown to reduce the risk of postoperative AF.22 This may be due to its antiremodeling, 23anti-inflammatory, 24 and anti-emetic action. 22 Animal studies have shown that atrial electrical and structural abnormalities occur if the animal is exposed to corticosteroid in the prenatal period, and develops high blood pressure later on. 25 This may explain the high incidence of AF with hypertension, and offer clues to its pathogenesis. Human studies have shown a higher expression of mineralocorticoid receptors in atria of AF patients. Atrial aldosterone is not increased in AF patients, but the high expression of mineralocorticoid receptors may augment its effects. This can induce atrial ionic remodeling and calcium overload, and thus cause AF. Yoga training has been shown to reduce symptomatic AF episodes, asymptomatic AF episodes, symptomatic non-AF episodes, depression and anxiety in patients with paroxysmal AF. Yoga also improves quality of life, reduces heart rate, and blood pressure. The reduction in arrhythmia burden caused by yoga may be attributed to its effects on adrenal function or stress. 26 The mineralocorticoid receptor is also thought to be involved in the pathogenesis of AF. 27
Gender differences in electrophysiology are well known. Inappropriate sinus tachycardia occurs mostly in women, and is rare in men. Women have a lower prevalence of AF, but higher risk of death once AF occurs. Their risk of experiencing sudden cardiac death is less, though their chances of acquiring long QT syndrome with antiarrhythmic drugs are greater. 28 It is possible that oestrogen receptors, present in atrial myocytes, may modulate these differences. Diminished estrogen receptor occupancy up- regulates the number of functional L-type calcium channels, leads to a shorter sinus length, and may promote arrhythmias. Menstrual cycle changes are also observed in women, with a lower heart rate being documented during menstruation. Supraventricular tachycardia is relatively more common during pregnancy. 28Testosterone deficiency is associated with an increased risk of AF in men aged 55 to 69 years, and men aged 80 years. Estradiol levels are associated with incident AF as well, but dehydroepiandrosterone sulfate (DHEA-S) levels do not exhibit statistically significant correlation with AF. Reduced testosterone is also associated with lone AF in men.29,30 AF has been reported in a case of familial cardiomyopathy, primary testicular failure and collage noma. 31
Atrial fibrillation (AF), the commonest arrhythmia in both outdoor and indoor clinical practice, is associated with higher risk of stroke, all-cause mortality, and heart failure. AF is linked with multiple metabolic and endocrine morbidities. The endocrinologist should play an important role in AF detection and referral. This review encourages cardio vigilance, and especially electro-cardio vigilance, in endocrine practice, by sharing an endo-metabolic perspective of AF.
1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Conti JB, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 ;64:e1-76.
2. Piccini JP, Simon DN, Steinberg BA, Thomas L, Allen LA, Fonarow GC, et al. Differences in clinical and functional outcomes of atrial fibrillation in women and men: two-year results from the ORBITAF registry. JAMA cardiology. 2016 ; 1:282-91.
3. Heeringa J, Hoogendoorn EH, Van der Deure WM, Hofman A, Peeters RP, Hop WC, det al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam study. Arch. Intern.Med.. 2008 ; 168: 2219-24.
4. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum thyrotropin concentrations as a risk factor for atrial
fibrillation in older persons. N Engl J Med.1994 ; 331:1249-52.
5. Bielecka-Dabrowa A, Mikhailidis DP, Rysz J, Banach M. The mechanisms of atrial fibrillation in hyperthyroidism. J Thyroid Res. 2009; 2:4.
6. Sojo L, Corcoy R. Seasonal variation in morbidity and mortality related to atrial fibrillation-could thyroid function contribute? Int J Cardiol. 2006 ;107:281.
7. Forfar JC, Feek CM, Miller HC, Toft AD. Atrial fibrillation and isolated suppression of the pituitary-thyroid axis: response to specific antithyroid therapy. Int J Cardiol. 1981; 1: 43-8.
8. Hirose M, Leatmanoratn Z, Laurita KR, Carlson MD. Mechanism for
Pituitary Adenylate Cyclase?Activating Polypeptide?Induced Atrial Fibrillation.J Cardiovasc Electrophysiol. 2001;12:1381-6.
9. Reschini E, Giustina G, Cantalamessa L, Peracchi M. Hyperthyroidism with elevated plasma TSH levels and pituitary tumor: study with somatostatin. J Clin Endocrinol Metab 1976; 43:924-7.
10. George JT, Thow JC, Matthews B, Pye MP, Jayagopal V. Atrial fibrillation associated with a thyroid stimulating hormone-secreting adenoma of the pituitary gland leading to a presentation of acute cardiac decompensation: A case report. J Med Case Rep. 2008; 2:67.
11. Rienstra M, Lubitz SA, Zhang ML, Cooper RR, Ellinor PT. Elevation of parathyroid hormone levels in atrial fibrillation. J Am Coll Cardiol 2011; 57:2542-3.
12. Russell CF, Edis AJ, Scholz DA, Sheedy PF, Van Heerden JA. Mediastinal parathyroid tumors: experience with 38 tumors requiring mediastinotomy for removal. Ann Surg.1981;193:805.
13. Voss DM, Drake EH. Cardiac manifestations of hyperparathyroidism, with presentation of a previously unreported arrhythmia.Am Heart J.1967 ;73:235-9.
14. Demir M, Uyan U, Melek M. The effects of vitamin D deficiency on atrial fibrillation. Clin Appl Thromb Hemost. 2014; 20:98-103.
15. Chen WR, Liu ZY, Shi Y, Yin DW, Wang H, Sha Y, Chen YD. Relation of low vitamin D to nonvalvular persistent atrial fibrillation in Chinese patients. Ann Noninvasive Electrocardiol. 2014; 19: 166-73.
16. Qayyum F, Landex NL, Agner BR, Rasmussen M, Jøns C, Dixen U. Vitamin D deficiency is unrelated to type of atrial fibrillation and its complications. Dan Med J. 2012 ;59:A4505.
17. Lopez FL, Agarwal SK, Grams ME, Loehr LR, Soliman EZ, Lutsey PL, Chen LY, Huxley RR, Alonso A. Relation of serum phosphorus levels to the incidence of atrial fibrillation (from the Atherosclerosis Risk in Communities [ARIC] Study). J Am Coll Cardiol. 2013;111:857-62.
18. Ansari N, Manis T, Feinfeld DA. Symptomatic atrial arrhythmias in hemo dialysis patients. Renal failure. 2001; 23:71-6.
19. Ronald DB, Van Loon GR, Orth DN, Liddle GW. Cushing's disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J Clin Endocrinol Metab.1973; 36: 445-51.
20. Sullivan ML, Martinez CM, Gallagher EJ. Atrial fibrillation and Anabolic steroids 1. J. Emerg. Med. 1999; 17 : 851-7.
21. Ueda N, Yoshikawa T, Chihara M, Kawaguchi S, Niinomi Y, Yasaki T. Atrial fibrillation following methylprednisolone pulse therapy. Pediatr Nephrol . 1988;2:29-31.
22. Halonen J, Halonen P, Järvinen O, Taskinen P, Auvinen T, Tarkka M,
et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA. 2007;297: 1562-7.
23. Shiroshita-Takeshita A, Brundel BJ, Lavoie J, Nattel S. Prednisone prevents atrial fibrillation promotion by atrial tachycardia remode ling in d ogs. Card iovasc Res. 2 006 ;69 :86 5-7 5.
24. Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatory disorder? Eur Heart J. 2005; 27:136-49.
25. Kistler PM, Sanders P, Dodic M, Spence SJ, Samuel CS, Zhao C, et al. Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation. Eur Heart J. 2006 10; 27:3045-56.
26. Lakkireddy D, Atkins D, Pillarisetti J, Ryschon K, Bommana S, Drisko
J, et al. Effect of yoga on arrhythmia burden, anxiety, depression, and quality of life in paroxysmal atrial fibrillation: the YOGA My Heart Study. J Am Coll Cardiol. 2013; 61:1177-82.
27. Tsai CT, Chiang FT, Tseng CD, Hwang JJ, Kuo KT, Wu CK, et al. Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation. J Am Coll Cardiol
28. Bailey MS, Curtis AB. The effects of hormones on arrhythmias in women. Curr Womens Health Rep. 2002;2:83-8.
29. Magnani JW, Moser CB, Murabito JM, Sullivan LM, Wang N, Ellinor PT, et al. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circ Arrhythm Electrophysiol. 2014; 7:307-12.
30. Jiangtao L, Dongchen Z, Shudong X, Yunpeng S, Lihong W, Liangrong Z, et al. Reduced testosterone levels in males with lone atrial fibrillation.Int J Clin Cardiol 2009; 32:43-6.
31. Sacks HN, Crawley IS, Ward JA, Fine RM. Familial cardiomyopathy, hypogonadism, and collagenoma. Ann Intern Med.1980; 93: 813-7.