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REVIEW
Cardiovascular Research (2012) 94, 10–19
doi:10.1093/cvr/cvs092
Aldosterone and parathyroid hormone: a
precarious couple for cardiovascular disease
Andreas Tomaschitz 1*†, Eberhard Ritz 2, Burkert Pieske 1, Astrid Fahrleitner-Pammer 3,
Katharina Kienreich 3, Jörg H. Horina 4, Christiane Drechsler 5, Winfried März 6,7,8,
Michael Ofner 9, Thomas R. Pieber 3, and Stefan Pilz 3,10†
1
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; 2Division of Nephrology, Department of Medicine,
University Hospital Heidelberg, Heidelberg, Germany; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 4Division of
Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Division of Nephrology, Department of Medicine, University of Würzburg, Würzburg, Germany;
6
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; 7Synlab Academy, Synlab services LLC, Mannheim, Germany; 8Medical Faculty
Mannheim, Mannheim Institute of Public Health, Ruperto Carola University Heidelberg, Mannheim, Germany; 9Frank Stronach Institute of Health, Oberwaltersdorf, Austria; and
10
Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
Received 12 October 2011; revised 2 February 2012; accepted 9 February 2012; online publish-ahead-of-print 13 February 2012
Abstract
Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone
(PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV
system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin–angiotensin system. Upregulation of aldosterone synthesis might contribute to the
higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore,
parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower
renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing
salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The
ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone
excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains
why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with
primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially
ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the
interaction between the two hormones.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Aldosterone † Parathyroid hormone † Cardiovascular disease
1. Introduction
Research in cardiovascular (CV) endocrinology deals with vascular
and myocardial pathology caused by dysregulated endocrine
systems. The search for novel endocrine parameters to assess their
potential role in the pathophysiology of CV complications is a novel
challenge in endocrinology. In the past, dysregulation of aldosterone
as well as of parathyroid hormone (PTH) has been recognized to
play an important role in the development and progression of cardiovascular disease (CVD). Less is known, however, about the recently
recognized reciprocal interaction between these two hormones and
its potential role for target organ damage. Specifically, the mechanisms
involved in the interaction between aldosterone and PTH are poorly
understood and this issue is largely ignored in clinical routine. The
delineation of this bidirectional interaction is hampered by multiple
factors, such as the activity of the sympathetic nervous system,
which impact on both renin –angiotenin–aldosterone system
(RAAS) activation and PTH secretion, respectively.1,2 Due to the
complex regulation of either hormone, it is beyond the scope of
this review to consider all regulatory mechanisms in detail. Rather,
we attempt to provide an overview specifically addressing the physiology and pathophysiology of the interaction between aldosterone
* Corresponding author. Tel: +43 664 1443993; fax: +43 316 385 13733, Email: [email protected]
†
Both authors contributed equally to the manuscript.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected].
11
Aldosterone and parathyroid hormone
and PTH as well as its potential impact on CV health in three different
scenarios: (i) primary hyperparathyroidism; (ii) chronic heart failure;
and (iii) primary aldosteronism.
2. Physiology and pathophysiology
of aldosterone and parathyroid
hormone
Accumulating evidence points to an eminent role of the mineralocorticoid hormone aldosterone, produced with the zona glomerulosa (ZG) of the adrenal gland, in the pathogenesis of CV and
renal diseases.3 The renin –angiotensin system, potassium, and adrenocorticotropic hormone are major regulators of adrenal aldosterone synthesis.
In its action, aldosterone binds to the mineralocorticoid receptor
(MR) and regulates gene transcription of the epithelial sodium
channel in endothelial cells and in the renal collecting duct, increasing
vascular stiffness on the one hand and promoting sodium retention on
the other hand.4,5 Given that the MR has also been identified in
non-epithelial tissues, such as vascular smooth muscle cells as well
as cardiomyocytes, the classic view that aldosterone acts exclusively
on transport epithelial cells has been broadened to include cells
other than transport epithelia.6 It is increasingly recognized that,
even in the absence of primary aldosteronism, a relative excess of aldosterone, i.e. in the absence of aldosterone concentrations above
the ‘normal range’—aldosterone may play an important role in the
genesis of arterial hypertension and CV damage.7 – 9
The activated MR –aldosterone complex regulates the transcription of myriads of genes in a tissue-specific pattern.10 Experimental
and clinical studies documented that aldosterone-mediated proinflammatory and profibrotic effects were associated with left ventricular hypertrophy and reduced kidney function.11 – 13 We and
others recently reported a strong and independent association
between plasma aldosterone levels within the ‘normal range’ and
CV mortality, in particular fatal stroke and sudden cardiac
death.14,15
PTH is secreted by the chief cells in the parathyroid gland mainly in
response to a decreased circulating ionized calcium concentration.16
In addition, calcitriol, phosphate, magnesium, the FGF23/klotho
system, and other factors participate in the regulation of PTH synthesis.17 PTH acts via binding to (i) the PTH/PTH-related protein receptor (PTH/PTH-rP receptor ¼ PTH1R), (ii) the NH2-terminal PTH
receptor II (PTHR2), or (iii) the COOH terminal PTH receptor
(C-PTHR).18,19 PTH is a crucial regulator of calcium and phosphate
homeostasis. This goal is achieved by activating osteoclasts and osteoblasts, enhancing intestinal Ca2+ absorption, promoting the synthesis
of active vitamin D in the kidney, and increasing active renal Ca2+ reabsorption. The subsequent elevation of plasma Ca2+ concentration
in turn lowers PTH secretion by activating calcium sensing receptors
located on chief cells. The close control of ionized calcium levels is
essential for the maintenance of a plethora of processes, such as
cell signalling, neuromuscular function, and bone metabolism.
The identification of PTH receptors within the CV system, for
example, in cardiomyocytes, vascular smooth muscle, and endothelial
cells, indicates that PTH excess may have potential effects beyond the
regulation of calcium and phosphate homeostasis.20
3. The interplay between
aldosterone and parathyroid
hormone in primary
hyperparathyroidism
Primary hyperparathyroidism, the third most common endocrine disorder, is characterized by excess PTH secretion, i.e. secretion inappropriate with respect to the prevailing concentration of ionized
calcium. Most patients with primary hyperparathyroidism have no
characteristic symptoms; in the majority of cases, excess PTH concentrations are detected incidentally. In the long term, primary hyperparathyroidism is associated with the development of osteoporosis
and the ensuing fracture risk. Although this had not been realized in
the distant past, patients with primary hyperparathyroidism have a remarkably higher risk to die from CV causes compared with the
general population.21,22 In addition, various observational studies
linked elevated PTH levels to a higher risk of hypertension, left ventricular hypertrophy, arrhythmia, diabetes, hyperlipidaemia, and,
most importantly, CV morbidity and mortality.23 – 26 Furthermore, in
patients with CVD and in elderly men, prospective studies revealed
strong and independent associations between higher PTH levels and
increased CV mortality.27,28 Even a minor asymptomatic PTH
excess is associated with a higher risks of all-cause mortality, fatal,
and non-fatal CVD as well as of renal failure and renal stones.29
The interplay between PTH and aldosterone is increasingly suggested as an important mechanism underlying the increased risk of
CV damage observed in primary hyperparathyroidism.30 Early evidence for a physiological and pathophysiological bidirectional link
between aldosterone and PTH in humans had initially been derived
mainly from case reports.31 To explain the biochemical changes following parathyroid surgery, it has been suggested that hyperaldosteronism might be caused (directly or indirectly) by primary
hyperparathyroidism and vice versa.32,33
Several studies evaluated the RAAS after parathyroidectomy in
animals and in humans with PTH excess. In 5/6 nephrectomized
rats, a significant increase in aldosterone levels was observed compared with control rats. After combined 5/6 nephrectomy and parathyroidectomy, aldosterone levels were lower, but potentially still
inappropriate, compared with control rats.34 Studies in patients with
primary hyperparathyroidism documented markedly decreased
plasma aldosterone levels and plasma renin activity after parathyroidectomy.35 – 37 Recently, Brunaud et al. 38 reported significantly
decreased aldosterone and blood pressure levels after parathyroidectomy in 134 patients with primary hyperparathyroidism. In the majority of subsequent studies on primary hyperparathyroidism patients,
a significant decline of plasma renin activity, of angiotensin II, and of
aldosterone levels was documented after parathyroidectomy.39 – 42
Unfortunately, firm statements about the change of the RAAS components in the circulation after parathyroid surgery are precluded in
view of the lack of the standardization of laboratory measurement
of the circulating components of the RAAS, of the failure to consider
the impact of blood pressure levels on RAAS activity per se, and in
view of the small sample size of many studies.43
The pathophysiological background of the high prevalence of
arterial hypertension, arterial stiffness, and CVD found in patients
with elevated PTH levels is an important research issue with high
clinical relevance.44 Several cross-sectional and prospective studies
12
documented a strong relationship between aldosterone levels and arterial hypertension as well as increased arterial stiffness.25,26,45 In view
of the interaction between aldosterone and PTH, one might speculate
that the interplay between both hormones aggravates blood pressure
elevation, remodelling of blood vessels, and CVD in patients with elevated PTH.46 This hypothesis would be in line with the observation of
Morfis et al.:25 aldosterone levels were strongly related to 24 h ambulatory blood pressure, but the correlation was less significant when
the confounding effect of PTH was taken into consideration. This is
all the more plausible because in healthy adults, continuous PTH infusion increased urinary tetrahydroaldosterone and blood pressure
values.47 In patients with primary hyperparathyroidism, compared
with healthy controls, blood pressure declined significantly 3
months after parathyroidectomy.48 In 16 patients with primary hyperparathyroidism, the decline in blood pressure after parathyroidectomy
was accompanied by a parallel decrease in aldosterone levels.35 In one
presumably underpowered study, a trend of reduced systolic blood
pressure was noted after parathyroid surgery.37 A recent study
assessed 134 primary hyperparathyroidism patients with arterial
hypertension and/or a positive history of coronary artery disease;
significantly higher aldosterone levels were found compared with
normotensive individuals and probands without known coronary
artery disease.38 Preoperative serum aldosterone levels were significantly higher in patients with PTH . 127 ng/L compared with those
with PTH , 127 ng/L (P ¼ 0.019) independent of ongoing antihypertensive medication. In contrast, 3 months after surgery, no significant
correlation was observed any longer between postoperative PTH and
aldosterone levels. Although causality is not strictly proven, the
current evidence supports the notion that after parathyroid surgery
the lower blood pressure values and the cardio-/vasculoprotective
effects are the result of less RAAS activation following the decrease
in PTH. In our opinion, the above-mentioned evidence for a functional
link between aldosterone and PTH justifies further mechanistic and
interventional studies in order to evaluate the presumed beneficial
effects of the MR-blockade on both CV health and rates of PTH secretion in patients with hyperparathyroidism.
3.1 Mechanisms underlying the functional
interplay between aldosterone and
parathyroid hormone
Several experimental studies aimed to delineate the mechanisms
underlying the effect of PTH on aldosterone secretion from the adrenals. Importantly, PTH stimulates the entry of cytosolic calcium
(Ca2+) into the mitochondrial matrix and this step is essential
for the initiation of steroidogenesis within the mitochondria.49 – 51
L-(high-threshold, long lasting), N-(neural) type, and T-type (lowthreshold, transient) voltage-gated calcium channels are essential for
the control of the cellular calcium messenger system and have been
identified in bovine and human ZG cells.52 – 54 Extracellular potassium
and angiotensin II interact with voltage-gated calcium channels to depolarize the ZG cells causing a sustained calcium influx. After dissecting mitochondrial and cytosolic Ca2+ signals, Wiederkehr et al.55
recently demonstrated that matrix Ca2+ participates in the regulation
of energy metabolism and of NAD(P)H concentrations in ZG cells,
thus stimulating aldosterone synthesis. The Ca2+ messenger system
further participates in the initiation of steroidogenesis by enhancing
intramitochondrial cholesterol transfer into the mitochondria.56 In
the setting of secondary hyperparathyroidism, calcium extrusion
A. Tomaschitz et al.
might be impaired causing elevated intracellular calcium levels in ZG
cells.57 This finding is in line with the observation that angiotensin II
maintains intracellular calcium levels by reducing calcium extrusion
through activating the Na+/Ca2+ exchanger in ZG cells.58 In contrast,
under physiological conditions, atrial natriuretic peptide reduces
aldosterone secretion by inhibition of T-type calcium channels.59
It is still under investigation whether PTH stimulates adrenal aldosterone synthesis directly. Activation of both the PTH/PTH-rP receptor and voltage-gated L-type calcium channels mediates
PTH-dependent calcium entry in various cell types.60,61 The PTH/
PTH-rP receptor which has also been identified in human and rat
adrenal cortex binds intact PTH and the biologically active N-terminal
fragment PTH 1–34.62,63 In various cell types, binding to the PTH1R
activates multiple cellular signalling pathways, including cAMP,
phospholipase C, protein kinase C, and, importantly, release of
Ca2+ from intracellular calcium stores. For instance, Klin et al.64
noted that PTH-related calcium entry is receptor-mediated and
involves the G protein-adenylate cyclase-cAMP system, activation of
L-type calcium channels, and protein kinase C. Mazzocchi et al.65
and others demonstrated that in human adrenals, PTH and
PTH-related protein increase aldosterone production by binding to
the PTH/PTH-rP receptor, activating cellular adenylate cyclase/cAMPdependent protein kinase, phospholipase C/protein kinase C- and
cAMP-dependent signalling cascades.66
Mechanistic studies attempted to shed light on the interplay
between aldosterone and PTH by investigating the effects of PTH
on RAAS activity and on aldosterone secretion from adrenal ZG
cells, respectively. Olgaard et al.67 evaluated the effect of PTH on
Ca2+-mediated aldosterone secretion in isolated rat ZG cells. Aldosterone release increased significantly by up to 200% above baseline
values in cells exposed to PTH(1 –84) and PTH(1 –34). The authors
suggested that PTH exerts Ca2+ ionophore-like effects in the ZG
causing increased Ca2+-stimulated aldosterone secretion. One previous investigation had shown that in bovine ZG cells PTH alone
induced only a slight increase in intracellular Ca2+, while the intracellular Ca2+ response was more pronounced after stimulation with
angiotensin II.68 In patients with primary hyperparathyroidism, Fallo
et al.69 compared the response of aldosterone to angiotensin II infusion before and after parathyroidectomy. Plasma aldosterone and
renin activity did not vary significantly before and after the parathyroidectomy. In contrast in the hyperparathyroid patients, the aldosterone response to angiotensin II infusion was significantly greater than in
healthy controls and more pronounced before than after surgery. The
authors concluded that in hyperparathyroid patients, high levels of
extracellular calcium or PTH, or both, play a major role in the exaggerated aldosterone response to angiotensin II. In healthy subjects, as
well continuous (12 days) i.v. PTH infusion increased urinary tetrahydroaldosterone excretion significantly in parallel with the development of hypercalcaemia and hypertension.47 In healthy adults,
Grant et al.70 observed an increase in plasma renin activity after
PTH(1 –34) infusion without any change of ionized serum calcium
concentration. Because, in addition, plasma cortisol levels were elevated after PTH infusion, Hulter et al.47 suggested that a transient
calcium-mediated rise of adrenocorticotropic hormone had increased
the secretion of adrenal steroid hormones. This would be in line with
findings in experimental rat models, indicating that human PTH(1– 34)
directly stimulates adrenal steroidogenesis, presumably by interacting
with the receptor for adrenocorticotropic hormone 1– 39.71 Thus,
currently available evidence derived from these mechanistic studies
Aldosterone and parathyroid hormone
is compatible with the assumption that both in patients with and
without primary hyperparathyroidism, there is an interplay between
aldosterone and PTH. We recently analysed the relation between
PTH and plasma aldosterone concentration in 3296 patients enrolled
in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study
who were referred to coronary angiography. We found a significant
association between plasma aldosterone and plasma PTH levels, particularly in vitamin D insufficient patients.27,72 Considering, however,
that vitamin D may suppress renal renin synthesis, we cannot
exclude the possibility that in patients with vitamin D deficiency, elevated renin levels stimulate aldosterone secretion independent of
PTH. These suggestions could explain the observation of Ozata
et al.73 who found no association between aldosterone and PTH in
male obese subjects; nevertheless in this patient group, upright
plasma renin activity was correlated to PTH.
In summary, the reported experimental and clinical data support
the notion that PTH might stimulate adrenal aldosterone synthesis,
both directly (by facilitating calcium entry into adrenal ZG cells via
binding to PTH/PTH-rP receptor, voltage-gated L-type calcium channels, and adrenocorticotropic hormone-receptors) and indirectly
(by stimulating renal renin release and increasing angiotensin II concentration—thus sensitizing adrenal ZG cells). Such stimulatory
effects of PTH on the RAAS may potentiate the risks of development
and progression of arterial hypertension as well as the risk of CVD in
patients with primary hyperparathyroidism.47 Figure 1 summarizes the
suggested pathways of the interplay between PTH and the RAAS in
the setting of PTH excess.
In epithelial tissues, activation of the MR by cortisol is mainly
prevented by the cortisol-inactivating enzyme 11b-hydroxysteroid
dehydrogenase-2. In the setting of increased generation of reactive
oxygen species, e.g. in chronic kidney disease and heart failure, cortisol might also activate the MR—in addition to aldosterone—thus
aggravating profibrotic and proinflammatory effects.4,74 To date it is
unclear, however, whether cortisol affects renal handling of calcium
via binding to the MR. One recent study revealed an upregulated
expression of PTH-related peptide in the mice kidney after 4 weeks
treatment with cortisol.75 In the past, only few clinical studies had
addressed the relation between PTH and cortisol. In a small study
of patients with primary hyperparathyroidism, circulating cortisol
levels decreased significantly after parathyroidectomy.41 Conversely,
intravenous infusion of PTH in healthy adults increased plasma cortisol concentration.47 Considering (i) that hypercalcaemia, caused by
PTH excess, results in a transient rise of adrenocorticotropic
hormone secretion; (ii) that PTH stimulates steroid hormone synthesis in part by binding to the adrenocorticotropic hormone receptor;
and (iii) that cortisol upregulates PTH-related peptide, one might
speculate that this sequence impacts on CV health. In view of the
higher CVD risk in patients with hypercortisolism, the conceivable
relationship between glucocorticoids and PTH should be addressed
in further studies.
4. The interplay between
aldosterone and parathyroid
hormone in chronic heart failure
The European Society of Cardiology estimates that the prevalence of
HF in the population is around 4% and even 10–20% in people above
age of 70 years; every second patient suffering from HF will die within
13
4 years.76 Neurohormonal activation is a hallmark of chronic HF.77
Low perfusion pressure due to impaired left ventricular function
results in the activation of the hypothalamic-pituitary-adrenal axis
and of the sympathetic nervous system. Stimulation of adrenal aldosterone synthesis in chronic HF occurs despite sodium and fluid retention. Impaired homeostasis of cations is frequent in patients with HF,
resulting from the combination of a hyperadrenergic state (leading to
translocation of cations into the intracellular compartment) with an
increased aldosterone secretion (stimulating of faecal and urinary
loss of cations), respectively.78 The resulting hypocalcaemia and hypomagnesaemia stimulate PTH secretion which tends to restore extracellular calcium and magnesium homeostasis. On the other hand,
the PTH-promoted mitochondrial Ca2+ excess, e.g. in the myocardium, induces oxidative stress and necrotic cell death which in the
long term causes or amplifies myocardial fibrosis aggravating systolic
and diastolic HF. Importantly, as discussed above, PTH tends to
further stimulate adrenal aldosterone synthesis, thus triggering a
vicious circle of mutually reinforcing aldosteronism and hyperparathyroidisms with the resulting risk of even more target organ
damage. Relative aldosterone excess causes sodium retention and oxidative stress, thus increasing CV morbidity and mortality.79 Conversely, inhibition of the MR improves survival in patients with different
forms of HF: severe HF, HF after myocardial infarction, and even
HF with mild symptoms.80 – 85
Important insight into the relationship between inappropriately elevated aldosterone and PTH levels has been gained by experimental
studies performed by Weber et al.86 – 88 In rats, administration of
aldosterone and 1% NaCl caused increased urinary and faecal Ca2+
and Mg2+ excretion, hypocalcaemia, hypomagnesaemia, and consequently secondary hyperparathyroidism as well as increased tissue
calcium concentration. Moreover, as a result of increased PTH activity, bone mineral density and strength were significantly reduced. The
role of aldosterone is underlined by the finding that urinary and faecal
Ca2+ and Mg2+ excretion was attenuated by spironolactone. Furthermore, MR blockade improved bone mineral density and strength,
reduced the intracellular calcium overload, and improved the redox
status in peripheral blood mononuclear cells.89 Weber et al. suggested
that as a result of the aldosterone-PTH interplay, the disequilibrium
between the pro-oxidant calcium and the antioxidant zinc is a
crucial factor in the pathogenesis of cardiomyocyte necrosis and myocardial fibrosis in chronic HF.90 In various cell types, elevated PTH
further stimulates calcium influx by different pathways.91 The subsequent intracellular and mitochondrial calcium overload causes a
disturbed redox status and increased oxidative stress in various
tissues, i.e. in cardiac myocytes.90,92,93 In particular, when mitochondria are exposed to calcium overload and oxidative stress, sustained
opening of the mitochondrial permeability transition pore is seen.94
This leads to reduction in intra-mitochondrial ATP levels and subsequent necrotic cell death and myocardial fibrosis.95 Presumably,
these mechanisms explain, at least in part, the relationship between
circulating aldosterone and PTH levels as well as the higher risk of
left ventricular hypertrophy and sudden cardiac death.13,79
Increased aldosterone-mediated renal calcium loss might be the key
mechanism for the subsequent development of hyperparathyroidism
in chronic HF. The majority of studies demonstrated calcium
wasting triggered by aldosterone, particularly in the setting of
dietary salt excess, although conflicting results were reported.96 – 99
In an attempt to counteract calcium loss, the resulting hypocalcaemia
and hypomagnesaemia triggers secondary hyperparathyroidism.
14
A. Tomaschitz et al.
Figure 1 Suggested pathways of the interplay between PTH and the renin – angiotensin – aldosterone system in the setting of PTH excess. Abbreviations: BMD, bone mineral density; PTH (rP), parathyroid hormone (related peptide); ACTH, adrenocorticotropic hormone; ANG II, angiotensin II; ZG,
zona glomerulosa; JG, juxtaglomerular; MR, mineralocorticoid receptor; ACE, angiotensin concerting enzymes; AT1-receptor, angiotensin II type 1
receptor. PTH (excess) increases circulating ionized Ca2+ (via increasing Ca2+ release from bone and decreasing renal Ca2+ excretion). PTH is suggested to stimulate renin synthesis by increasing calcium levels in JG cells. Renal renin synthesis is further controlled by tubular sodium concentration,
arterial blood pressure, and the sympathetic nervous system. Extracellular potassium and angiotensin II are major stimulators of aldosterone synthesis
in the adrenal glands. Both factors interact with voltage-gated calcium channels and depolarize the ZG cells which result in elevated intracellular
calcium levels. PTH might also directly stimulate aldosterone synthesis by binding to the PTH/PTH-rP receptor, voltage-gated calcium channels,
and the adrenocorticotropic hormone receptor, which results in increased mitochondrial Ca2+ levels. In addition, PTH is suggested to increase sensitization towards angiotensin II which by itself reduces cellular calcium extrusion through activating Na+/Ca2+ exchangers in ZG cells. PTH contributes to the development of arterial stiffness, arterial hypertension, and cardiac hypertrophy via binding to the PTH/PTH-rP receptor, which is
expressed in vascular smooth muscle cells and cardiomyocytes. In addition, aldosterone, i.e. relative aldosterone excess, exerts genomic (by
binding to the MR), and non-genomic profibrotic and proinflammatory effects on blood vessels and the myocardium.
This may explain that increased levels of PTH, i.e. secondary hyperparathyroidism, are found in many patients with severe chronic
HF.100 Furthermore, salt loading may also increase renal calcium elimination independent of aldosterone. To date, it is unclear whether
relative aldosterone excess causes calcium wasting even in the
absence of dietary salt excess. Weber et al. suggested that decreased
reabsorption of Na+, Mg2+, and Ca2+ in the distal tubule, caused by
salt retention and volume expansion, is responsible for aldosterone
driven excretion of calcium and magnesium.89 Rossi et al.101 demonstrated that the effect of salt loading on renal calcium loss was even
more pronounced in patients with primary aldosteronism compared
with patients with essential hypertension. Aldosterone itself may
cause intracellular calcium excess by upregulating T-type (lowthreshold, transient) calcium channels in various cell types.102 In aldosterone salt-treated rats, Vidal et al. documented an altered
redox state, reflected by decreased levels of a1-antiproteinase.103 Importantly, oxidative stress in this experimental setting is attenuated by
calcium and magnesium supplementation.104
Despite the recent decline in risk-adjusted HF hospitalization and
risk-adjusted 1-year mortality rates between 1998 and 2008 in the
USA, the 1-year overall mortality within heart failure patients
remains unacceptably high.105 Despite a class I recommendation for
15
Aldosterone and parathyroid hormone
their use in heart failure (NYHA class III/IV), MR blockers are still
underused in this patient group.106,107 Given the increasing evidence
that the potential interplay between aldosterone and PTH might contribute to the pathogenesis of HF and CVD, it should be determined
whether more consistent use of MR blockers improves outcomes in
CV risk patients; certainly contraindications must be considered and
regular monitoring for side effects is mandatory.108
5. The interplay between
aldosterone and parathyroid
hormone in primary aldosteronism
Primary aldosteronism, i.e. an absolute excess of aldosterone, is characterized by excessive adrenal aldosterone secretion out of proportion to its principal stimulant renin. The estimated prevalence of
primary aldosteronism is 5–12% in arterial hypertension and
17– 23% in drug-resistant hypertension.109 Absolute aldosterone
excess is strongly associated with a higher risk of development and
progression of left ventricular hypertrophy, coronary artery disease,
sudden cardiac death, chronic kidney disease, and strokes.110 – 112
Likewise in chronic HF hypercalciuria, hypocalcaemia and secondary hyperparathyroidism with subsequent intracellular calcium overload is frequently found in patients with low-renin hypertension and
primary aldosteronism.113 – 115 Resnick et al.113 suggested that the
interplay between the hormones regulating calcium homeostasis
and the RAAS might contribute to the pathogenesis of arterial hypertension, particularly salt-sensitive hypertension. They also noted remarkable elevation of PTH levels in the majority of patients with
primary aldosteronism.116 After adrenalectomy, a marked increase
in ionized calcium concentration was observed. Furthermore, it has
been suspected that patients with primary aldosteronism are at
higher risk of developing renal calculi as a result of increased
calcium excretion due to the calciuretic effect of aldosterone
excess.117 In addition, in this setting, hypocitraturia was caused by aldosterone.118 These data led to the hypothesis that calcium intake and
blockade of calcium channels might attenuate the aldosterone-PTH
driven cascade of intracellular calcium overload and the resulting
organ damage.119 This concept is in line with the finding of preserved
bone integrity by co-treatment of hydrochlorothiazide plus spironolactone in aldosterone-salt-treated rats.86
So far, only few studies indicated that hyperparathyroidism is a
common feature in primary aldosteronism. Nevertheless, Rossi
et al.120 observed significantly higher serum concentrations of intact
PTH in patients with PA compared with patients with essential hypertension. After 1 month of MR blockade with 100 mg spironolactone
daily, an increase in serum-ionized calcium and a decrease in PTH
level was observed. Recently, we compared the effects of MR blockade and adrenalectomy on PTH levels in patients with primary aldosteronism enrolled in the Graz Endocrine Causes of Hypertension
(GECOH) study.121 In participants with primary aldosteronism, significantly higher PTH levels were found compared with those participants with essential hypertension.122 A non-significant trend of
higher calcium-creatinine ratios was found in patients with primary aldosteronism. These patients also had significantly lower serum
calcium levels compared with patients with essential hypertension.
This finding supports the results of animal studies documenting
increased aldosterone driven renal calcium loss and ensuing secondary hyperparathyroidism. Both regimens, i.e. adrenal surgery and
treatment with MR blockers, were associated with a decline of PTH
and arterial blood pressure during follow-up; this finding was not
explained by changes in vitamin D status. A recent report supports
our findings: compared with patients with essential hypertension, significantly higher PTH levels were found in patients with aldosteroneproducing adenomas, and again no difference in vitamin D status was
seen.123 Importantly, adrenalectomy was followed by a non-significant
decrease in the urinary calcium excretion. More studies are needed to
confirm that lower serum calcium levels in patients with primary aldosteronism are mainly due to aldosterone-induced renal calcium
loss. After adrenalectomy, however, normalization of PTH levels as
well as an increase in serum-ionized calcium concentration was
observed. Interestingly, the authors measured the expression of
PTH/PTH-rP receptor on aldosterone-producing adenoma cells,
underlining PTH-mediated effects on aldosterone-producing cells.
Finally, whether PTH/PTH-rP receptor activation enhances tumour
growth of aldosterone-producing adenomas, as shown in H295R
adrenocortical tumour cells, remains to be determined.124
Collectively, these observations support the possibility of a clinically
relevant interaction between aldosterone and PTH, presumably potentiating the CV risk in patients with primary aldosteronism. The
mechanisms behind this link remain elusive. Such mechanisms are
not necessarily similar to those which increase PTH in secondary
hyperaldosteronism, e.g. in patients with chronic HF. A future task
is the evaluation whether the measurement of PTH and the inhibition
of PTH-mediated effects have implications for the diagnostic work-up
and outcome of patients with aldosterone excess. Figure 2 gives an
overview of the CV impact caused by the interaction of aldosterone
and PTH in patients with chronic HF and aldosterone excess.
6. Summary and perspectives
The majority of experimental animal studies and studies in humans
support a clinically relevant interplay between aldosterone and PTH
levels. It has been suggested that treatment of either disease, aldosterone excess, or hyperparathyroidism might positively affect the CV
system by decreasing the activity of either hormone. The reduction
in circulating aldosterone concentrations and in parallel of systolic/diastolic blood pressure values observed after parathyroidectomy suggests that the protective effect of surgery may be mediated, at least
in part by reduction in RAS activity and aldosterone synthesis. Conversely, adrenalectomy or MR blockers, both decrease PTH secretion,
arterial blood pressure as well as bone resorption.
The novel perception of a functional link between aldosterone and
PTH might be one more pathway of RAAS-mediated organ damage.
This finding should encourage the development of novel treatment
strategies to prevent CV disease.125 – 127 The emergence of novel
CV risk factor constellations, e.g. the interactions between PTH, aldosterone, and renin, provide encouraging perspectives for the diagnosis and for the individually tailored treatment of patients at
risk.27,79,128,129 Considering the fact that suboptimal blood pressure
control globally accounted for tremendous health costs, it would be
valuable both economically and for understanding the pathophysiology to measure circulating levels of aldosterone, renin, and PTH
in patient of CV risk.130
Much must be learned about hormone synthesis, secretion, and
elimination rates and about the interaction between hormones and
receptors in target tissues. For example, recent evidence points to
an important role of central haemodynamic effects of
16
A. Tomaschitz et al.
Figure 2 Overview of the CV impact caused by the interaction of aldosterone and PTH in patients with chronic HF and aldosterone excess. BMD,
bone mineral density; PTH (rP), parathyroid hormone (related peptide); Ang II, angiotensin II; MR, mineralocorticoid receptor. Activation of the
renin – angiotensin – aldosterone system in the setting of heart failure results in salt/water retention and urinary loss of cations. Elevated PTH stimulate
renal renin and adrenal aldosterone synthesis. Elevated aldosterone levels in primary and secondary hyperaldosteronism are paralleled by increased
urinary and faecal loss of magnesium and calcium. The resulting lowering of serum calcium concentration further stimulates production of PTH which
in turn amplifies adrenal aldosterone synthesis. PTH excess in turn induces calcium overload and oxidative stress in cardiomyocytes and aggravates the
reduction in intra-mitochondrial ATP levels resulting in subsequent necrotic cell death and myocardial fibrosis. Finally, the vicious circle between aldosterone and PTH might potentiate CV damage.
mineralocorticoids in mediating salt-dependent blood pressure elevation. Activation of the MRs, which are expressed in the circumventricular organs and amygdale, increases salt appetite, endogenous
ouabain release, arginine vasopressin release, and sympathetic
nervous system activity.131,132 Apart from the central nervous
system, the functional link between aldosterone and PTH might be
modified by molecular defects of hormone synthesis, signalling, e.g.
receptor abnormalities and responsiveness.133 Genetic and epigenetic
approaches are warranted to evaluate the biological pathways underlying inter-individual variation in blood pressure and CV risk and the
responsiveness of complex endocrine systems on environmental
stimuli.134,135 It remains to be determined whether blocking
aldosterone-induced MR activation is organ protective by inhibiting
the calcium wasting properties of aldosterone and subsequent PTH
secretion. In addition, novel insight into the functional link between
aldosterone and PTH in primary and secondary aldosteronism might
be generated by the upcoming PTHR blockers.136 Further studies
should therefore evaluate (i) the mechanisms behind the interplay
between aldosterone and PTH, (ii) whether this interplay potentiates
CV damage, and (iii) whether MR blockade breaks the vicious circle of
the interdependence of aldosterone and PTH in various CV risk
groups.
Acknowledgements
The authors thank Ms Tanja Traussnigg (www.mika-design.at) and Ms
Dunja Bacinger Tomaschitz for providing the artwork of this
manuscript.
Conflict of interest: none declared.
Funding
K.K. is supported by funding from the Austrian National Bank (Jubilaeumsfond: project numbers: 13905 and 13878). This work was supported by
the EU Project “MASCARA” (“Markers for Sub-Clinical Cardiovascular
Risk Assessment”; THEME HEALTH.2011.2.4.2-2; Grant agreement no:
278249, BioPersMed (COMET K-project 825329), which is funded by
Aldosterone and parathyroid hormone
the Federal Ministry of Transport, Innovation and Technology (BMVIT),
the Federal Ministry of Economics and Labour/the Federal Ministry of
Economy, Family and Youth (BMWA/BMWFJ), and the Styrian Business
Promotion Agency (SFG).
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