Introduction
Primary aldosteronism (PA) manifests as secondary hypertension and is defined as
excessive autonomous endogenous aldosterone production unresponsive to renin
regulation, further leading to elevated blood pressure and electrolyte imbalance.
PA
has a prevalence of 4.3–9.5% in all patients with hypertension,
13% of those with stage 3 hypertension, and 17–23% of those
with resistant hypertension [1 ]. Higher rates
of long-term mortality and co-morbidities have been reported in PA patients compared
to patients with essential hypertension (EH) [1 ]
[2 ]
[3 ]. Atrial fibrillation (AF) is the most
common arrhythmia in adults, and has a prevalence of 3% in adults aged over
20 years, and more in the elderly and patients with chronic illnesses, and it has
been shown to increase the risk of all-cause mortality and major cardiac and
cerebrovascular complications [4 ]. In patient
with PA, AF is the most common seen arrhythmia with a prevalence of
7.1–7.3% [2 ]
[5 ]. In German Conn’s study, AF
occurred in 7.1%; other atrial or ventricular arrhythmia occurred in
5.2% of the patients [5 ].
The pathogenesis of AF is complex, and involves abnormal cardiac electrical activity
from the atrium and adjacent structures with subsequent cardiac electrical,
structural, neural and autonomic remodeling [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 AF have mostly been
conducted on clinical patients with heart failure and related mineralocorticoid
receptor antagonists (MRAs) treatment as upstream or conjunctional therapy. In
addition, several animal and cell experiments have reported aldosterone-induced
cardiac structural changes or electrophysiological alterations at the pathological
or molecular level [8 ]. The pro-fibrotic and
pro-arrhythmogenic effects of aldosterone and mineralocorticoid receptor (MR)
activation have been proposed in these studies. This implies that excessive
aldosterone in PA patients may be associated with the development of AF, and that
effective treatment 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 with a 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 for the genesis of AF is initiation by ectopic firing
and perpetuation by reentry [6 ]. The
molecular basis for focal ectopic firing from myocyte sleeves within the
pulmonary veins [9 ] and atrial tissue
as the disease progresses [6 ] is
attributed to a diastolic leak of Ca2+ from the
sarcoplasmic reticulum, resulting in Na+ inward current
via Na+ –Ca2+ exchange, and
subsequently spontaneous myocyte depolarization [10 ]. There are two main possible
mechanisms of AF reentry, including reentrant rotors or multiple independent
wavelets [6 ]. Slow conduction
wavefront velocity, indicating structural remodeling, and short effective
refractory periods (ERPs) of the atrium, indicating electrical remodeling,
promote and perpetuate the reentry [6 ]. In addition, fibrotic changes, abnormalities of atrial
cardiomyocytes or interstitial matrix of the atrium all also contribute to
reentry [6 ].
For patients with PA, there are several possible mechanisms for the
development of AF, including arterial hypertension and ventricular
remodeling, hypokalemia, atrial structural and electrical remodeling caused
by excess aldosterone ([Fig. 1 ]).
Fig. 1 Pathogenesis of atrial fibrillation in primary
aldosteronism. Primary aldosteronism (PA) is characteristic of
aldosterone excess, which causes atrial fibrillation (AF) by the
following mechanisms. Aldosterone excess causes arterial
hypertension and hypokalemia, both related to increased risk of AF.
Direct effect of excessive aldosterone working on cardiac structure
favoring could be summarized into two: atrial structural remodeling
and atrial electrical remodeling. Atrial structural remodeling is
caused by increased left ventricle and atrium fibrosis with systemic
inflammation involved, through the emergence of diastolic and
systolic dysfunction; atrial electrical remodeling is caused by
aldosterone-induced atrial fibrosis, altered calcium and potassium
channel function, intra-cellular sodium-calcium dysregulation,
further promotion of reentry and shortening of action potential to
cause AF.
Atrial structural remodeling
Cardiac fibrosis results from excessive activation of cardiac fibroblasts and
myofibroblasts [11 ], and
atrium-specific fibrosis presents with fibrotic atrial cardiomyopathy and
promotes AF with an elevated risk of thromboembolism [7 ]. Excess aldosterone has been shown
to cause cardiac fibrosis in many previous studies [12 ]
[13 ]. Prior to the development of
fibrosis, aldosterone and MR activation facilitate inflammation by inducing
the production of reactive oxygen species (ROS), which activate
proinflammatory transcription factors [14 ] in macrophages [15 ] and
the heart [16 ]. Furthermore,
aldosterone causes cardiac interstitial macrophage infiltration [17 ], and activates the MRs on
macrophages to promote the expressions of profibrotic genes, including
transforming growth factor β1 (TGF-β1) [18 ] and plasminogen activator
inhibitor-1 (PAI‑1) [19 ]. PAI-1
inhibits plasmin-dependent matrix metalloproteinase (MMP) activation to
limit collagen degradation and thus increase fibrosis [20 ]. TGF-β can enhance the
formation of myofibroblasts, which express alpha-smooth muscle actin
(α-SMA), to drive collagen formation [21 ]. Myofibroblasts, which are derived
from fibroblasts, play a particularly crucial role in cardiac fibrosis due
to a nearly two-fold higher capacity of collagen synthesis and higher
capacity of synthesizing many cytokines and chemokines [22 ]. Aldosterone has been shown to
induce the transdifferentiation of neonatal rat cardiac fibroblasts to
myofibroblasts via Keap1/Nrf2 signaling pathways [23 ].
Atrial structural remodeling is a major promoting factor of reentry [6 ]. An excess of aldosterone can cause
increased atrial fibrosis [24 ] and
further conduction interference. Reil et al. found that aldosterone-infused
rats had increased atrial size, fibroblasts and interstitial collagen, but
reduced active MMP-13, a collagen degrading enzyme in both atriums [25 ]. They also found that P-wave
duration, total right atrium activation time, and anisotropy of local
conduction time, as an index of atrial structure remodeling, were all
prolonged in aldosterone-infused rats compared with controls [25 ]. Heterogeneous pathways of slow
conduction and atrial dilatation both provide larger pathways that are more
ready for sustained reentrant circuits [26 ]. The effects of structural atrial remodeling on the
development of AF were most clearly demonstrated in a cardiac
myocyte-specific transgenic mouse model overexpressing
TGF-β1. This model resulted in atrial fibrosis, and the
increase in atrial fibrosis significantly increased
susceptibility to AF [21 ].
Atrial electrical remodeling
Aldosterone-induced atrial fibrosis-related re-entry circuits are another
possible mechanism of AF in PA patient. Fibrotic tissue decreases gap
junction coupling and causes muscle bundle discontinuities which reduce and
promote re-entry circuits [27 ].
Electrophysiological changes have also been documented with
aldosterone-treated cells and animal models. In an aldosterone infusion rat
model, Lammers et al. reported prolonged duration of AF after
transesophageal atrial burst stimulation [28 ]. Interestingly, aldosterone infusion did not affect
ventricular function or atrial pressure in their study, but lengthened
P-wave duration. P-wave duration is a marker of atrial conduction time and
is associated with a higher risk of AF [29 ]
[30 ]. Furthermore, aldosterone
infusion has been associated with a significant shortening of action
potential and increased protein expressions of Kir2.1 and Kv1.5 [28 ]. Inwardly-rectifying potassium
channels (Kir) are characterized by the property of inward-rectification,
which is defined as the ability to allow large inward currents and smaller
outward currents. The activation of Kir would therefore promote the
formation of AF. This implies that electrical condition abnormalities and
hypokalemia may cause AF in patient with PA.
Ouvrard-Pascaud et al. reported that aldosterone increased L-type
Ca2+ channels in neonatal rat atrial mouse cells, and
decreased the activity of the rapidly activating delayed rectifier potassium
current IKr and transient outward K+ current Ito1 [31 ]. Aldosterone has also been shown to
promotes the prolonged release of Ca2+ from the
sarcoplasmic reticulum due to opening of ryanodine receptors, finally
leading to Ca2+ overload and thereby promoting AF [32 ]. Aldosterone has also been shown to
increase ICaT and induce calcium overload [33 ]. This aldosterone-induced calcium overload will produce a
positive feedback vicious cycle of atrial electrical remodeling and leading
to AF.
In a special group of PA patients (familial hyperaldosteronism type III) who
were characterized by having germline mutation of KCNJ5 (potassium
inwardly-rectifying channel, subfamily J, member 5) [34 ], KCNJ5 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 KCNJ5 mutations are also
associated with early-onset lone AF in Caucasians [36 ], while novel molecules targeting
mutant KCNJ5 potassium channels are under development to treat
bradyarrhythmia and AF [37 ].
Arterial hypertension and ventricular remodeling
Chronic hypertension results in left ventricular hypertrophy [38 ] and diastolic dysfunction and
consequently elevation of left ventricular end diastolic pressure [39 ], and it is a major risk factor for
AF [40 ]. Left ventricular diastolic
dysfunction and elevated left ventricular end diastolic pressure result in
elevated left atrial pressure, structural changes, and subsequently an
increased occurrence of AF [41 ]. In
animal models, hypertension has been shown to cause left atrial remodeling,
including atrial dilatation, hypertrophy, inflammatory
infiltrates, interstitial fibrosis, conduction slowing and
heterogeneity [42 ]. In clinical
studies, the Framingham Heart Study revealed that levels of systolic and
pulse pressures were significantly associated with increased left atrial
size [43 ], and an increased left
atrial size has been shown to contribute to the development of AF [44 ]. Furthermore, even after adjusting
for age and sex, hypertension has been reported to remain a significant
predictor of AF [45 ].
Hypokalemia
Hypokalemia is defined as a low serum potassium level, and it has been
reported in cases and series of AF in patients with PA [46 ]
[47 ]. An epidemiological study
reported that a low serum level of potassium was associated with a higher
risk of AF among the general population [48 ] or patients after cardiac surgery [49 ]. The electrophysiological effects
of hypokalemia include resting membrane hyperpolarization,
Na+ –K+ ATPase inhibition,
and suppression of K+ channel conductance, resulting in
action potential duration prolongation, reduced repolarization reserve,
early afterdepolarization, delayed afterdepolarization, and automaticity
[50 ], which may all contribute to
the genesis of AF. Clinically, previous study from 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, Milliez et al. reported a 12.1-fold elevated risk and a
prevalence of 7.3% of AF among 124 PA patients compared to 465
EH controls with a prevalence of 0.6% [2 ]. Their study followed the
patients for 3 years, after which the PA patients also held a 4.2-fold
higher risk of stroke than the EH controls. Although the sample size was
relatively small, the study provided initial and early evidence of the
additional cardiovascular risk of PA over EH after blood pressure had
been matched between the two groups. In 2008, Catena et al. reported an
elevated odds ratio of 4.93 for sustained arrhythmia among 54 PA
patients compared with EH controls, although the definition of sustained
arrhythmia included arrhythmia other than AF [51 ]. In 2009, the German
Conn's Registry reported a prevalence rate of AF of 7.1%
among 553 of 640 PA patients, and atrial arrhythmia was more common in
those with the hypokalemic variant (12.3%) than in those with
normokalemic PA (7.8%) without statistical significance [5 ]. In addition, Savard et al.
reported a significantly higher prevalence of AF of 3.9% with an
adjusted odds ratio of 5.0 among 459 PA patients compared to 1290 EH
controls in whom the prevalence was 1.1% [52 ]. Moreover, Mulatero et al.
reported that sustained arrhythmias (AF, atrial flutter, sustained
ventricular tachycardia, and ventricular fibrillation) were
significantly more common among 270 PA patients after 12 years of
follow-up with an odds ratio of 2.2 compared to EH patients [53 ]. In 2018, the JPAS Study Group
further reported a prevalence of AF of 2.8% in a multi-center,
nationwide, and large cohort of 2582 PA patients over a 10-year period
[54 ]. Furthermore, Monticone
et al. reported a 3.52-fold higher risk of AF in 3838 PA patients
compared to 9284 EH controls in a meta-analysis of 31 studies over a
median period of 8.8 years [3 ].
These data provide evidence of the strong association between
aldosterone and AF in addition to the results reported in the
aforementioned basic studies.
Incidence of PA in AF
An elevated risk of AF in patients with PA has been reported in numerous
clinical studies as discussed above, however, the risk and prevalence of
PA among patients with AF has been less studied. Mourtzinis et al.
reported that screening for PA using the aldosterone to renin ratio
resulted in the diagnosis of four cases of PA in 149 AF patients
(2.6%) in 2017 [55 ]. In
2018, the same group reported a prevalence of PA of 0.056% among
713 569 AF patients, compared with 0.024% in AF-naive controls
using a Swedish national registry [56 ]. A multicenter prospective study (PAPPHY) further
reported increased prevalence of PA among hypertensive patients with
unexplained AF [57 ].
Clinical evidence associated with the occurrence of AF in PA
Left atrium structure and function
Since electrical abnormalities often originate from the left atrium, AF is
associated with left atrial function [7 ]
[58 ]. Left atrium function is
evaluated using echocardiographic studies, from left atrium diameter, left
atrial volume index (LAVI), or left atrial strain analysis [59 ]. Dilatation of the left atrium and
an increase in volume has been positively correlated with the pathogenesis
of AF [58 ]. In 2017, Yang et al.
reported a higher LAVI among 100 PA patients compared to 100 EH controls
[60 ]. Our previous investigation
of left ventricular subclinical systolic dysfunction using strain analysis
also showed a higher left atrial diameter and LAVI among PA patients
compared to those among matched EH controls, although the difference did not
reach statistical significance [61 ].
Wang et al. recently reported increased left atrial stiffness in 107 PA
patients with lower left atrial velocity, strain, and strain rate, and
higher left atrial stiffness index compared to 50 EH controls [62 ].
Left ventricular structure and function
Left ventricular hypertrophy (LVH) with increased left ventricular mass is a
key indicator of diastolic dysfunction[38 ], and diastolic dysfunction is currently considered to be a
potential risk factor for the pathogenesis of AF[41 ]. Numerous previous clinical studies
have reported more LVH and increased left ventricular mass index (LVMI)
among PA patients compared to EH controls.
In 1996, Rossi et al. reported significantly increased left ventricular wall
thickness and LVMI among 34 patients with PA matched to 34 EH controls with
a higher percentage of LVH and concentric remodeling [12 ]. In 2005, Stowasser et al. reported
increased left ventricular wall thicknesses and reduced diastolic function
using Doppler studies among patients with familial hyperaldosteronism type I
[63 ]. In 2007, Catena et al.
reported greater left ventricular mass and more LVH among 54 PA patients
compared with 274 EH controls [64 ]. In
2008, Muiessan et al. investigated left ventricular geometry with more
inappropriate left ventricular mass derived from the difference between
measured LVMI and predicted LVMI in 125 PA patients compared to 125 EH
patients [65 ]. In 2016, Cesari et al.
reported increased left ventricular enlargement and high prevalence of LVH
and diastolic dysfunction using Doppler and tissue Doppler studies among 262
PA patients [66 ]. In our previous
study of 30 adrenal adenoma patients, we found a significantly decreased
LVMI in patients with LVH after adrenalectomy [67 ]. We also reported the significant
positive predictive ability of 24-hour urinary aldosterone to LVMI and
inappropriate LVMI among PA patients, as well as tissue-Doppler studies
measuring diastolic dysfunction [68 ]
[69 ].
Autonomic dysfunction
Autonomic dysfunction has been reported in PA patients with reversible
sympathetic overactivity before and after adrenalectomy [70 ]. Heart rate variability (HRV) has
been shown to be a valid tool to evaluate autonomic nerve system [71 ], and to be a potential predictor of
AF in middle-aged individuals [72 ].
Left atrium dilatation has been correlated with decreased HRV [73 ]. A recent study further reported an
association between decreased HRV and a higher incidence of AF in a large
cohort with long-term follow-up, as a presentation of cardiac autonomic
dysfunction [74 ]. In 1995, Veglio et
al. reported impaired heart rate and blood pressure variability when
responding to tilt in 17 PA patients compared to 11 EH controls[75 ]. We previously reported comparable
conventional HRV parameters but decreased heart rhythm complexity among 20
PA patients compared to 25 EH controls, and partial reversal of heart rhythm
complexity impairment after adrenalectomy in PA patients [76 ]. Impairment of HRV or heart rhythm
complexity may contribute AF genesis. However, the relations between HRV and
AF in PA patients are still unclear and need further studies.
Treatment of PA and the effect on AF
Correction of hypertension and hypokalemia and targeted treatment for
excessive aldosterone
Treatment with antihypertensive agents for elevated blood pressure and
potassium supplements has been shown to reduce the risk of AF in several
hypertension trials [77 ]. PA has been
shown to be associated with a much higher cardiovascular risk than age-,
sex-, and BP-matched EH patients in a clinical study and meta-analysis [2 ]
[3 ], and other clinical studies have
shown that targeted treatment is beneficial for hypertensive patients [51 ]
[78 ]
[79 ].
The targeted treatment for PA recommended in current guidelines is unilateral
laparoscopic adrenalectomy for patients with documented unilateral PA to
cure hyperaldosteronism and hypokalemia and cure or substantially reduce
elevated blood pressure. For those with bilateral PA and unilateral PA not
receiving surgery, medical treatment with an MRA is suggested to lower both
blood pressure and the deleterious effects of aldosterone hypersecretion
[1 ].
Surgical adrenalectomy
With regards to the occurrence of AF in PA, the results of the PAPY study, a
large prospective registry of 107 PA patient and 894 EH patients with a
median 11.8 years of follow-up reported in 2018 by Rossi et al.,
demonstrated a trend of a higher risk of NOAF among the PA patients
receiving treatment than the EH patients. In addition, the surgically
treated PA patients had a similar AF-free survival rate compared to the
optimally treated EH patients, while the medically treated PA patients still
had a higher risk of AF [80 ]. Hundemer
et al. performed a retrospective chart review study of 396 PA patients, of
whom 201 received adrenalectomy, and 40092 EH patients, and found no
significant difference in the risk of NOAF between the PA patients treated
with surgical adrenalectomy and the patients with EH [81 ]. In our recent publication using
the large nationwide National Health Insurance Research Database (NHIRD) of
Taiwan, we found a lower risk of NOAF in 534 PA patients receiving surgical
adrenalectomy compared to matched EH patients [82 ].
Mineralocorticoid receptor antagonists
PA patients receiving MRA treatment in the PAPY study had a higher risk of AF
and decreased AF-free survival [80 ].
In the retrospective study of Hundemer et al. consisting of 396 PA and 40092
EH patients, 195 of the PA patients received MRAs and had different outcomes
with regards to NOAF according to post-treatment plasma renin activity
level, with a cut-off point of 1 ng/ml/h as a proxy
for insufficient or sufficient MR blockade. In addition, the PA patients
treated with MRAs with suppressed renin activity and insufficient MR
blockade had a higher risk of NOAF than the EH patients, with an adjusted
hazard ratio of 2.55. In comparison, the PA patients treated with MRAs with
increased renin activity and sufficient MR blockade did not have a
statistically significant difference in the risk of NOAF compared to the EH
patients [81 ]. Another larger
retrospective study reported by Hundemer et al. with 602 MRA-treated PA
patients and 41 853 age-matched EH patients showed a hazard ratio of
AF of 1.93 compared with the EH patients, and the PA patients with
insufficient MR blockade had a higher risk of cardiovascular events and
mortality compared to the PA patients with sufficient blockade [83 ]. Post-treatment renin activity may
reflect the adequacy of MR blockade and further guide the dosage of MRAs to
improve cardiovascular outcomes and the risk of NOAF.
These three studies demonstrated a higher risk of NOAF among PA patients
receiving MRAs. In our recent publication using the NHIRD, we also found
increased risks of NOAF and major adverse cardiovascular and
cerebro-cardiovascular events in 1668 PA patients receiving MRAs compared
with matched EH patients [82 ].
Reversal of left ventricular mass/echocardiographic
parameters
Rossi et al. found that patients with hyperaldosteronism had increased left
ventricular wall thickness and mass and impaired early diastolic left
ventricular filling indexes compared with EH patients, and that these
effects could be reversed 1 year after adrenalectomy with maintenance
therapy after 5 or 10 years of follow-up [84 ]
[85 ]. In addition, Cetena et al. found
that both adrenalectomy and spironolactone in PA patients had a comparable
effect on reducing left ventricular mass after a mean follow-up period of
6.4 years [64 ]. Indra et al. showed
that adrenalectomy was more effective in reducing left ventricular mass
reduction and left ventricular wall thickening and reversing left
ventricular cavity enlargement, while spironolactone only reduced left
ventricular cavity size [86 ]. Our
group also previously demonstrated the regression of left ventricular mass
in patients receiving adrenalectomy [87 ]. In addition, the improvement after adrenalectomy was seen in
both reversal of left ventricular geometry and also alterations in
myocardial texture, as shown by increased cyclic variation of integrated
backscatter (CVIBS) and decreased plasma carboxy-terminal propeptide of
procollagen type I (PICP) level [88 ].
We also previously reported that aldosterone-induced left ventricular
diastolic dysfunction could be reversed after adrenalectomy [89 ]. Because of the close relation
between left ventricular structure/function and AF genesis,
improvement of left ventricular structure/function after PA target
treatment may further decrease AF burden.
Future perspectives and other hot topics associated with AF in PA
KCNJ5 somatic mutations, primary aldosteronism, and atrial
fibrillation
Several somatic mutations have been found to be highly correlated or
causative for PA [34 ]. Of notice,
KCNJ5 gene mutations, largely seen in aldosterone-producing
adrenal adenomas [90 ]
[91 ], are considered to be the most
common somatic mutations in PA [34 ]
[92 ]. KCNJ5 mutations have been
reported to result in the loss of ion selectivity to cause cell membrane
depolarization and increased Ca2+ entry in adrenal
glomerulosa cells and to increase aldosterone synthesis, and KCNJ5
mutation-related potassium channelopathy is considered to be an important
contributor to the pathogenesis of PA [91 ]. Among PA patients with somatic KCNJ5 mutations,
higher plasma aldosterone level and LVMI [93 ], younger age, and more female gender were reported over PA
patients without somatic KCNJ5 mutations [94 ], with higher rate of cure of
hypertension after adrenalectomy [95 ].
However, the relations between somatic KCNJ5 mutation and AF are not
clear and further studies are warranted.
Subclinical Cushing syndrome, primary aldosteronism, and atrial
fibrillation
Subclinical Cushing syndrome has been found to co-exist with certain types of
PA [96 ], and adrenal-cortical tumors
have been shown to have great heterogeneity and complexity in clinical,
morphological, and molecular presentation [97 ]. Tang et al. reported 22 patients with aldosterone- and
cortisol-coproducing adrenal adenomas among 555 PA patients, and found a
higher risk of heart disease including AF compared with 392 adrenal adenoma
patients [98 ]. It is not currently
known whether Cushing syndrome is correlated with AF. A previous
echocardiographic study showed that patients with Cushing syndrome had a
greater reduction in left atrial ejection fraction and increased left
ventricular mass and wall thickness compared with EH controls, which were
corrected after treatment [99 ]. In
addition, iatrogenic Cushing syndrome with exogenous steroid use has been
positively associated with the incidence of AF [100 ]. Further studies are warranted to
investigate the relationships among subclinical Cushing syndrome, PA, and
AF.
New treatment targeting aldosterone excess
Newer potential alternatives for surgical adrenalectomy with CT-guided
radiofrequency ablation have shown promising results [101 ], however further long-term
outcomes and effects on AF need to be confirmed. The investigational new
drug LCI699 has been shown to inhibit aldosterone synthase and to provide a
fair short-term effect, however long-term data are lacking [102 ]. Newer generations of novel
non-steroidal MRAs including finerenone (BAY 94–8862) and
esaxerenone (CS-3150) have been evaluated in preclinical and clinical trials
and have shown the potential to treat PA, however their effects on AF and
long-term mortality have not been well studied [103 ]. In addition, for concurrent MRA
treatment with spironolactone and eplerenone, the optimal dosage has not
definitively been established. The current guidelines for spironolactone
recommend from 12.5 mg per day with slow titration to a maximum dose of
daily 100 mg, and for eplerenone 25 mg twice daily with the goals of
normalizing serum potassium, reduce blood pressure, and eliminating the
vascular, cardiac, and renal effects of aldosterone with a minimum number of
drugs and side effects [1 ]. Further
studies to investigate the optimal dosage of MRAs to prevent AF are also
needed. Further studies are also need to elucidate whether surgical
adrenalectomy can convert pre-existing AF among PA patients. For PA patients
with sinus rhythm, the risk factors for developing AF also need to be
identified.
Conclusion
PA with excessive aldosterone poses an additional risk of AF as evidenced in clinical
trials and basic studies. Further studies are still needed to elucidate the
relationship between PA and AF. In-depth investigations are also needed to study the
unique pathogenesis of AF in PA patients with a genetic preference or late disease
progression and related complications. Further clinical trials are required to
evaluate the risk of NOAF with different PA treatments and the long-term outcomes
in
patients with different subtypes of PA. With a higher level of suspicion and prompt
surveys for PA in specific clinical scenarios, more precise therapeutic strategies
to improve the management and outcomes of patients with PA can be anticipated.
Appendix [the TAIPAI Study Group]
Membership of the Taiwan Primary Aldosteronism Investigation (TAIPAI) Study
Group: Che-Hsiung Wu, MD (Chi-Taz hospital, PI of Committee); Vin-Cent Wu, MD,
PhD (NTUH, PI of Committee); Yen-Hung Lin, MD, PhD (NTUH, PI of Committee);
Yi-Luwn Ho, MD, PhD (NTUH, PI of Committee); Hung-Wei Chang, MD, PhD (Far
Eastern Hospital, PI of Committee); Lian-Yu Lin MD, PhD (NTUH, PI of Committee);
Fu-Chang Hu, MS, ScD, (Harvard Statistics, Site Investigator); Kao-Lang Liu, MD
(NTUH, PI of Committee); Shuo-Meng Wang, MD (NTUH, PI of Committee); Kuo-How
Huang, MD, PhD (NTUH, PI of Committee); Yung-Ming Chen, MD (NTUH, PI of
Committee); Chin-Chi Kuo; MD (Yun-Lin, PI of Committee), Chin-Chen Chang, MD
(NTUH, PI of Committee); Shih-Cheng Liao, MD, PhD (NTUH, PI of Committee);
Ruoh-Fang Yen, MD, PhD (NTUH, PI of Committee); and Kwan-Dun Wu, MD, PhD (NTUH,
Director of Coordinating Center).
