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Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease

Andreas Tomaschitz, Eberhard Ritz, Burkert Pieske, Astrid Fahrleitner-Pammer, Katharina Kienreich, Jörg H. Horina, Christiane Drechsler, Winfried März, Michael Ofner, Thomas R. Pieber, Stefan Pilz
DOI: http://dx.doi.org/10.1093/cvr/cvs092 10-19 First published online: 14 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.

  • 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 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.79

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.1113 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 = 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.2326 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.3537 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.3942 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 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 = 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.4951 L-(high-threshold, long lasting), N-(neural) type, and T-type (low-threshold, 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.5254 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 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/cAMP-dependent 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 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.

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.

In epithelial tissues, activation of the MR by cortisol is mainly prevented by the cortisol-inactivating enzyme 11β-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 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.8085

Important insight into the relationship between inappropriately elevated aldosterone and PTH levels has been gained by experimental studies performed by Weber et al.8688 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.9699 In an attempt to counteract calcium loss, the resulting hypocalcaemia and hypomagnesaemia triggers secondary hyperparathyroidism. 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 (low-threshold, 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 α1-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 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.110112

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.113115 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 aldosterone-producing 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.

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.

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.125127 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 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.

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 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).

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.

Footnotes

  • Both authors contributed equally to the manuscript.

References

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