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    Primary Aldosteronism and Atrial Fibrillation

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    Published online: 2020-04-14 Pie ene Atrial Fibrillation in Primary Aldosteronism Authors CChien-Ting Pan'-2, Cheng-Hsuan Tsal2?, Zheng-Wel Cher Yen-Hung Lin, the TAIPAI Study Group Affiliations 1. Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan 2 Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 3. Department of ternal Medicine, National Taiwan University Hospital jin Shan Branch, New Taipel Gy, Taiwan 4 Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Talpel City, Taiwan 5. Division of Nephrology, Department of internal Medi- ‘ine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 6 Cardiovascular Center, National Taiwan University Hospital, Tapel,Talwan Key words tial fibrillation, primary adosteronism, aldosterone, atrial remodeling received 16.12.2019 accepted 09.03.2020 Bibliography DOI https://dol.org/10.1055/a-1141-5989 Published online: 14.4.2020 Horm Metab Res 2020; 52: 357-265 © Georg Thieme Verlag KG Stuttgart» New York SSN 0018-5043, Correspondence Yen-Hung Lin MD, PhO Department of Internal Medicine, National Taiwan University Hospital No. 7, Chung-Shan South Road 100 Taipel Taiwan Tel: +886 2 23123456, ext.62152, Fox: +886 223515811 austinr34@gmail.com ‘Yi¥ao Chang*, Vin-Cent Wu*, Chi-Sheng Hung *, ABSTRACT Primary aldosteronism (PA) isthe most common cause of sec- ‘ondary hypertension Increasing evidence has demonstrated an increased cardiovascular rik n patients with PA compared to those with essential hypertension (EH), including atl lation (AF), the most prevalent arrhythmia among adults that Is assoclated with an elevated risk of subsequent cerebro-car- diovascular adverse events. The mechanisms of increased prev- ~alence of AF inPA patients are complex. Excessive aldosterone production is regarded to be a key component in the patho- ‘genesis of AF, inaddition to arterial hypertension and electro- Iyte imbalance. In addition, several translational and clinical studies have eeported that structural emodeling with arial fibrosis and electrical remodeling with arthythmogenicity in- ‘duced by an excess of aldosterone also play major roles in AF ‘genesis Clinical studies from several registries and meta-anal~ ysishave reported an increased prevalence and riskof AF in PA, patients compared to EH patients. Recent trials have further ‘demonstrated a reduction inthe risk ofnew-onset atrial bil- lation (NOAF) after adrenalectomy, while the results of medical ‘treatment with mineralocorticoid receptor antagonists (MRAs) have been inconsistent. Ths review outlines the current evi- dence of the relationship between PA and AF, and highlights recent progress in the management of PA with regards tothe development of AF. Introduction Primary aldosteronism (PA) manifests as secondary hypertension andis defined as excessive autonomous endogenous aldosterone Pant eal Ail aon NPA. Horm Metab Res 2020, 52:357-265 production unresponsive to renin regulation, furtherleading to el- ‘evated blood pressure and electrolyte imbalance, PA has a preva- lence of 4.3-8.5% inal patients with hypertension, 13% of those with stage 3 hypertension, and 17-23 % of those with resistant hy- 357 aa ae pertension 1]. Higher rates of long-term mortality and ¢o-mor- bidities have been reported in PA patients compared to patients with essential hypertension (EH) [1~3] Atrial fibrillation (AF) is the ‘most common arthythmiain adults, and has prevalence of 3% in adults aged over 20 years, and more in the elderly and patients with chronic illnesses, and ithas been shown to increase the risk of all- ‘cause mortality and major cardiac and cerebrovascular complica tions [4]. In patient with PA, AF isthe most common seen arthyth- ‘mia with a prevalence of 7.1~7.3% [2,5]. In German Con's study, AF occurred in 7.1 % other atrial or ventricular arrhythmia occurred in5.2% ofthe patients [5] The pathogenesis of AF is complex, and involves abnormal car- diac electrical activity from the atrium and adjacent structures with subsequent cardiac electrical, structural, neural and autonomicre- ‘modeling [6]. The progressive remodeling and degradation with fibrosis of the atrium and other cardiac structure combined with ‘AF has been shown to increase the risk of thromboembolism [7]. Previous studies on the association between aldosterone and ‘AFhave mostly been conducted on clinical patients with heart fil- ure and related mineralocorticoid receptor antagonists (MRAS) treatment as upstream or conjunctional therapy. In addition, sev- eral animal and cell experiments have reported aldosteron: duced cardiac structural changes or electrophysiological altera- tons atthe pathological or molecular level (8. The pro-fibratic and pro-arrhythmogenic effects of aldosterone and mineralocor- ticold receptor (MR) activation have been proposed in these stud les. This implies that excessive aldosterone in PA patients may be associated with the development of AF, and that effective treat- ‘ment of PA may decrease the risk of further occurrences of AF. This review evaluates the current evidence of the relationship between PA and AF, from the pathogenesis of AF witha clinical or basic approach to concurrent clinical trials about PA treatment. Pathophysiology of the occurrence of AF in PA patients AF genesis The leading hypothesis forthe genesis of AFisinitiation by ectopic firing and perpetuation by reentry [6]. The molecular basis for focal ectopic fring from myocyte sleeves within the pulmonary veins [9] and atria tissue asthe disease progresses [6] is atributed toa di- astolicleak of Ca?” from the sarcoplasmic reticulum, resulting in Na* inward current via Na*~Ca?™ exchange, and subsequently spontaneous myocyte depolarization [10] There are two main pos- sible mechanisms of AF reentry, including reentrantrotors or mul- tiple independent wavelets [6]. Slow conduction wavefront veloc- ity. indicating structural remodeling, and short effective refractory periods (ERPs) of the atrium, indicating electrical remodeling, pro- ‘mote and perpetuate the reentry 6]. In dition fibrotic changes, abnormalities of atrial cardiomyocytes or interstitial matrixof the atrium al aso contribute to reentry (6). Forpatients with PA there are several possible mechanisms for the development of AF, including arterial hypertension and ven- tricular remodeling, hypokalemia, atrial structural and electrical remodeling caused by excess aldosterone (> Fig. 1) Atrial structural remodeling Cardiac fibrosis sults from excessive activation of cardiac fbro- blasts and myofibroblasts [11], and atrium-specific fibrosis presents with fisatc atrial cardiomyopathy and promotes AF with an ee- vated rk of thromboembolism [7] Excess aldosterone has been ‘shown to cause cardiac fibrosis in many previous studies [12, 13]. Prior tothe development of fibrosis, aldosterone and MR activation fall tateinfammatonbyinducing the production ofeactve oxygenspe- ‘cies (ROS), which activate proinflammatory transcription factors [14] in macrophages [15] and the hear (16), Furthermore, aldosterone ‘Fig. 1 Pathogenesis of tral ibilatin in primar aldosteronism. Primary aldosteronism PA) is characteristic of aldosterone excess, which causes atrial illation (AF) by the folowing mechanisms. Aldosterone excess causes arterial hypertension and hypokalemia, both lated to Increased rik Of AF Direct effect of excesive aldosterone working on cardiac structure favoring could be summarized into two: ta structuralremodeing and ‘tal electrical remodeling. tral structural remodeling is caused by increaed lft ventricle and atrium fbrosis with systemic inflammation involved, ‘through the emergence of diastolic and systolic dysfunction; trial electrical remodeling caused by aldosterone-induced ara boss, altered ‘calcium and potassium channel function, itra-cellularsodlum-cacium dysregulation, further promotion of rentry and shortening of action poten- tialto cause A. 358 Panel Aal ila PA. Hon Metab es 2090, 52:357-355 EESHE PDS a ee sr en gE ye gues Uegues as gapH ea eE men Sn Pern ERENT ‘causes cardiac interstitial macrophage infitration {17}, and activates the Ms on macrophages to promote the expressions of profibrotic genes, including transforming growth factor B1 (TGF-B1) [18] and plasminogen activator inhibitor-1 (PAI-1) [19]. PAl-1 inhibits plasmin-dependent matrix metalloproteinase (MMP) activation to limit collagen degradation and thus increase fibrosis [20]. TGF-B ‘ean enhance the formation of myofibroblasts, which express a: ppha-smooth muscle actin (0-SMA), to drive collagen formation [21 ‘Myofibrobasts, which are derived from fibroblasts, playa particularly ‘rudalrolein cardiac fibrosis due toa nearly two-fold higher capacity (of collagen synthesis and higher capacity of synthesizing many ‘eytokines and chemokines [22]. Aldosterone has been shown to induce the transdiferentation of neonatal rat cardiac fibroblasts to myofibroblasts via Keap 1/Nf2 signaling pathways [23] ‘Arial structural remodeling isa major promating factor of reen tuy[6]. An excess of aldosterone can cause increased atrial fibrosis [24] and further conduction interference. Rell tal. found that al dosterone-infused rats had increased atrial size, fibroblasts andi terstitial collagen, but reduced active MMP-13, acollagen degrad- Ing enzyme in both atrium [25]. They also found that P-wave du ‘ation, total right atrium activation time, and anisotropy of local conduction time, a an index of atrial structure remodeling, were all prolonged in aldosterone-infused rats compared with controls [25]. Heterogeneous pathwvays of slow conduction and atrial dila- tation both provide larger pathways that are more ready for sus- tained reentrant circuits [26]. The effect of structural atrial emod- cling on the development of AF were most clearly demonstrated ina cardiac myocyte-specfic transgenic mouse model overexpress- Ing TGF-B1. This model resulted in atral fibrosis, and the increase Inatrial fibrosis significantly increased susceptibility to AF [21]. Arial electrical remodeling ‘Aldosterone induced atrial frosis-elated re-entry crits are an- «other possible mechanism ofAFin PApatient. Fibrotctsue decreas ¢ gap junction coupling and causes muscle bundle discontinuities which reduce and promote re-entry ccuts [27]. Electrophysiolog- ical changes have also been documented with aldosterone-treated cellsand animal models. nan aldosterone infusion rat mode, Lar- ‘mers etal. reported prolonged duration of AF aftr transesophage al atrial burst stimulation [28]. Interestingly, aldosterone infusion didnot affect ventricular function or atrial pressure in thle study, butengthened Pawave duration, Pave duration sa marker of tral conduction time ands associated with a higher isk of A [29,30 Furthermore, aldosterone infusion has been associated with asi nificant shortening of action potential and increased protein expres sions of Kr2.1 and Kv 5 [28]. Inwardly-rectfying potassium chan fel (Kir) are characterized by the property of invard-ectfication, which is defined asthe ability to allow lage inward currents and smaller outward currents. The activation of Kir would therefore promote the formation of AF Ths implies that electrical condition abnormalities and hypokalemia may cause AF in patient with PA Ouvrard-Pascaud etal reported that aldosterone increased L-type Ca?* channels in neonatal rat atrial mouse cells, and de creased the activity ofthe rapidly activating delayed rectifier po- tassium current krand transient outward K" current! [31]. Al: dosterone has also been shown to promotes the prolonged release (oF Ca?* from the sarcoplasmic reticulum due to opening ofryano- Pant eal Ail aon NPA. Horm Metab Res 2020, 52:357-265 dine receptors, finally leading to Ca®* overload and thereby pro~ moting AF [32]. Aldosterone has also been shown to increase ICaT ~and induce calcium overload [33] This aldosterone-induced caci- tum overload will produce a positive feedback vicious cycle of atvial electrical remodeling and leading to AF. Ina special group of PA patients (familial hyperaldosteronism ‘type Il) who were characterized by having germline mutation of CNS (potassium inwardly-rectfying channel, subfamily J, mem- ber 5) [34], KCN5 mutation is also a possible cause of AF genesis Loss of function of KCNJ5 may result in long QT syndrome and AF [35].A previous study revealed that germline KCN/5 mutations are ‘also associated with early-onset lone AF in Caucasians [36], while novel molecules targeting mutant KCI)5 potassium channels are Under development to treat bradyarrhythmia and AF [37]. Arterial hypertension and ventricular remodeling ‘Chronic hypertension results in eft ventricular hypertrophy [38] ‘and diastolic dysfunction and consequently elevation of let ven- ‘ticular end diastolic pressure [39], and tis a major risk factor for AF [40]. Left ventricular diastolic dysfunction and elevated left ventricu- larend diastolic pressure result elevate lft arial pressure, struc ‘tural changes, and subsequently an increased occurrence of AF [41]- Inanimal models, hypertension has been shown to causeleft atrial r- modeling. including tal dilatation, hypertrophy, inflammatory infl- ‘rates, interstitial fbross, conduction slowing andheterogeneity[42]- Incinical studies, the Framingham Heart Study revealed that eves of systolic and pulse pressures were significantly associated with in- ‘creased lft atrial size [43], and an increased left atrial size has been shownto contributeto the development of AF [44]-Furtherore, even after adjusting for age and sex, hypertensionhas been reportedtore- main a significant predictor of AF [45]. Hypokalemia Hypokalemia is defined as alow serum potassium level, and ithas been reported in cases and series of AF inpatients with PA [46,47]. Anepidemiological study reported that alow serumlevel of potas- sium was associated with a higher risk of AF among the general population (48) or patients after cardiac surgery [49]. Theelectro- physiological effects of hypokalemia include resting membrane hy- Perpolarization, Na*-K* ATPase inhibition, and suppression of K” channel conductance, resulting in action potential duration pro~ longation, reduced repolarization reserve, early afterdepolariza- tion, delayed afterdepolarization, and automaticity [50], which may all contribute to the genesis of AF. Clinically, previous study {rom the German Conn's Registry reported that atrial arrhythmia ‘was found more common in those with the hypokalemic variant (12.3%) than in those with normokalemic PA 7.8%), although the difference was not statistically significant [5] PA and AF: Clinical studies and implications Epidemiology Incidence of AF in PA In 2005, Miliez etal. reported a 12.1-fld elevated risk and a prev- | = 60 years od (rom the Framingham Heart Study), Am] Cardiol 2011; 107: 917-821 on Pant eal Ail aon NPA. Horm Metab Res 2020, 52:357-265 [31] Ouwar-Posaud ,Stnte- Marie Berta P tal: Conditional Iineralocoticoid receptor expresion inthe heat leads 0 ieshesteningathythmiss. Creultlon 2005; 111: 3025-3033 [32] Gomez AM, Rued A, Sainte-Marie Vet a Mineralcorticoid modulation of eardac nano receptor activity is sociated with downregulation of A506-bining proteins. 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