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Book ; Online: Role of Genomics in the Management of Hypertension

Mulatero, Paolo / Monticone, Silvia

2020

Keywords	Research & information: general ; Biology, life sciences ; atrial natriuretic peptide ; T2238C variant ; endothelial dysfunction ; smooth muscle cells contraction ; platelet aggregation ; epigenetics ; cardiovascular diseases ; renin ; low-renin ; hypertension ; mineralocorticoid receptor ; genetics ; aldosterone ; essential hypertension ; blood pressure ; genome-wide association studies ; exome microarray ; next-generation sequencing ; rare variants ; rare-variants association testing ; burden test ; sequence kernel association test ; hypokalemia ; low renin hypertension ; monogenic hypertension ; Liddle syndrome ; SCNN1A ; SCNN1B ; SCNN1G ; non-coding RNA ; micro RNA ; primary aldosteronism ; aldosterone-producing adenoma ; transcriptome profiing ; DNA methylation ; histone modifications ; vascular smooth muscle cells ; endothelial cells ; Kruppel-like factor 15 ; left ventricular hypertrophy ; cardiac hypertrophy ; heart failure ; genetics of left ventricular hypertrophy ; fibromuscular dysplasia ; non atherosclerotic vascular stenosis ; PHACTR1 ; genetic association ; cervical artery dissection ; spontaneous coronary arteries dissection ; CRY1 ; CRY2 ; HSD3B1 ; HSD3B2 ; cardio-tonic steroids ; endogenous ouabain ; adducin ; renal damage ; African American ; ARMC5 ; GRK4 ; CACNA1D ; endocrine hypertension
Size	1 electronic resource (200 pages)
Publisher	MDPI - Multidisciplinary Digital Publishing Institute
Publishing place	Basel, Switzerland
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT021044290
ISBN	9783039366286 ; 3039366289
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Resistant or refractory hypertension: it is not just the of number of drugs.

Veglio, Franco / Mulatero, Paolo

Journal of hypertension

2021 Volume 39, Issue 3, Page(s) 589–591

MeSH term(s)	Antihypertensive Agents/pharmacology ; Antihypertensive Agents/therapeutic use ; Blood Pressure ; Humans ; Hypertension/drug therapy ; Pharmaceutical Preparations
Chemical Substances	Antihypertensive Agents ; Pharmaceutical Preparations
Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Editorial
ZDB-ID	605532-1
ISSN	1473-5598 ; 0263-6352 ; 0952-1178
ISSN (online)	1473-5598
ISSN	0263-6352 ; 0952-1178
DOI	10.1097/HJH.0000000000002814
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Article ; Online: Approach to the Patient on Antihypertensive Therapy: Screen for Primary Aldosteronism.

Mulatero, Paolo / Bertello, Chiara / Veglio, Franco / Monticone, Silvia

The Journal of clinical endocrinology and metabolism

2022 Volume 107, Issue 11, Page(s) 3175–3181

Abstract: Primary aldosteronism (PA) is a condition that is still largely overlooked, resulting in a considerable burden of mortality and morbidity. This is despite decades of clinical and translational research on the deleterious effects of aldosterone on the ... ...

Abstract	Primary aldosteronism (PA) is a condition that is still largely overlooked, resulting in a considerable burden of mortality and morbidity. This is despite decades of clinical and translational research on the deleterious effects of aldosterone on the cardiovascular system and the publication of several guidelines and consensuses on its diagnosis and treatment. One of the main reasons for the low rate of testing is the difficulty of screening patients on antihypertensive therapy that potentially interferes with aldosterone and renin levels and thus confound the interpretation of the aldosterone to renin ratio, the accepted and conventionally used screening test. To avoid interference, usually the therapies that affect the renin-angiotensin aldosterone system are withdrawn and substituted with noninterfering medications. However, in many cases the screening test can be confidently interpreted even when such therapies are not discontinued. In this review, we will evaluate the effects of antihypertensive therapies on the screening test for PA and suggest a practical approach for its interpretation.
MeSH term(s)	Humans ; Aldosterone ; Renin ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/drug therapy ; Antihypertensive Agents/therapeutic use ; Renin-Angiotensin System
Chemical Substances	Aldosterone (4964P6T9RB) ; Renin (EC 3.4.23.15) ; Antihypertensive Agents
Language	English
Publishing date	2022-08-12
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgac460
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Article ; Online: Aldosterone as a Mediator of Cardiovascular Damage.

Buffolo, Fabrizio / Tetti, Martina / Mulatero, Paolo / Monticone, Silvia

Hypertension (Dallas, Tex. : 1979)

2022 Volume 79, Issue 9, Page(s) 1899–1911

Abstract: Besides the physiological regulation of water, sodium, and potassium homeostasis, aldosterone modulates several physiological and pathological processes in the cardiovascular system. At the vascular level, aldosterone excess stimulates endothelial ... ...

Abstract	Besides the physiological regulation of water, sodium, and potassium homeostasis, aldosterone modulates several physiological and pathological processes in the cardiovascular system. At the vascular level, aldosterone excess stimulates endothelial dysfunction and infiltration of inflammatory cells, enhances the development of the atherosclerotic plaque, and favors plaque instability, arterial stiffness, and calcification. At the cardiac level, aldosterone increases cardiac inflammation, fibrosis, and myocardial hypertrophy. As a clinical consequence, high aldosterone levels are associated with enhanced risk of cardiovascular events and mortality, especially when aldosterone secretion is inappropriate for renin levels and sodium intake, as in primary aldosteronism. Several clinical trials showed that mineralocorticoid receptor antagonists reduce cardiovascular mortality in patients with heart failure and reduced ejection fraction, but inconclusive results were reported for other cardiovascular conditions, such as heart failure with preserved ejection fraction, myocardial infarction, and atrial fibrillation. In patients with primary aldosteronism, adrenalectomy or treatment with mineralocorticoid receptor antagonists significantly mitigate adverse aldosterone effects, reducing the risk of cardiovascular events, mortality, and incident atrial fibrillation. In this review, we will summarize the major preclinical and clinical studies investigating the cardiovascular damage mediated by aldosterone and the protective effect of mineralocorticoid receptor antagonists for the reduction of cardiovascular risk in patients with cardiovascular diseases and primary aldosteronism.
MeSH term(s)	Aldosterone ; Atrial Fibrillation/complications ; Cardiovascular System ; Heart Failure ; Humans ; Hyperaldosteronism/complications ; Hyperaldosteronism/drug therapy ; Mineralocorticoid Receptor Antagonists/pharmacology ; Mineralocorticoid Receptor Antagonists/therapeutic use
Chemical Substances	Mineralocorticoid Receptor Antagonists ; Aldosterone (4964P6T9RB)
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.122.17964
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Article ; Online: Primary aldosteronism in pregnancy.

Forestiero, Vittorio / Sconfienza, Elisa / Mulatero, Paolo / Monticone, Silvia

Reviews in endocrine & metabolic disorders

2022 Volume 24, Issue 1, Page(s) 39–48

Abstract: Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In ... ...

Abstract	Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In this review we discuss about current knowledge on pathophysiology, natural history, diagnosis and treatment of PA in pregnancy. Because of the physiologic changes in the renin-angiotensin-aldosterone system (RAAS) and the contraindication to both confirmatory test and subtype differentiation, diagnosis of PA during pregnancy is challenging and relies mostly on detection of low/suppressed renin and high aldosterone levels. The course of pregnancy in patients with PA is highly variable, ranging from progesterone-induced amelioration of blood pressure (BP) control to severe and resistant hypertension with potential maternal and fetal complications. Mineralcorticoid receptor antagonists (MRA) are the recommended and most effective drugs for treatment of PA. As the anti-androgenic effect of spironolactone can potentially interfere with sexual development, their prescription is not recommended during pregnancy. On the other side, eplerenone, has proven to be safe and effective in 6 pregnant women and may be added to conventional first line drug regimen in presence of resistant hypertension or persistent hypokalemia. Ideally, patients with unilateral forms of PA should undergo adrenalectomy prior to conception, however, when PA is diagnosed during pregnancy and medical therapy fails to adequately control hypertension or its complications, adrenalectomy can be considered during the second trimester in case of unilateral adrenal mass at MRI-scan.
MeSH term(s)	Humans ; Female ; Pregnancy ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/therapy ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Spironolactone/therapeutic use ; Hypertension/drug therapy ; Eplerenone/therapeutic use
Chemical Substances	Mineralocorticoid Receptor Antagonists ; Spironolactone (27O7W4T232) ; Eplerenone (6995V82D0B)
Language	English
Publishing date	2022-05-10
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2185718-0
ISSN	1573-2606 ; 1389-9155
ISSN (online)	1573-2606
ISSN	1389-9155
DOI	10.1007/s11154-022-09729-6
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Article ; Online: Response to Letter to the Editor from Rossi and Rossitto: "Mineralocorticoid Receptor Antagonist Effect on Aldosterone to Renin Ratio in Patients With Primary Aldosteronism".

Monticone, Silvia / Veglio, Franco / Mulatero, Paolo

The Journal of clinical endocrinology and metabolism

2021 Volume 107, Issue 2, Page(s) e896–e897

MeSH term(s)	Adrenalectomy ; Aldosterone ; Humans ; Hyperaldosteronism/drug therapy ; Hyperaldosteronism/surgery ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Renin
Chemical Substances	Mineralocorticoid Receptor Antagonists ; Aldosterone (4964P6T9RB) ; Renin (EC 3.4.23.15)
Language	English
Publishing date	2021-10-05
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgab719
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Article ; Online: Prevalence of Functioning Adrenal Incidentalomas: A Systematic Review and Meta-analysis.

Sconfienza, Elisa / Tetti, Martina / Forestiero, Vittorio / Veglio, Franco / Mulatero, Paolo / Monticone, Silvia

The Journal of clinical endocrinology and metabolism

2023 Volume 108, Issue 7, Page(s) 1813–1823

Abstract: Context: Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of functioning AIs are important to direct resources allocations.: ... ...

Abstract	Context: Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of functioning AIs are important to direct resources allocations. Objective: To assess the prevalence of autonomous/possible autonomous cortisol secretion (ACS), primary aldosteronism (PA), pheochromocytoma (PHEO), and Cushing syndrome (CS) in patients with AI. Methods: We performed a comprehensive search of multiple databases (PubMed, Ovid MEDLINE, Web of Science) for potentially relevant studies without language restriction, up to February 2022. Of the 1661 publications evaluated at title and abstract levels, 161 were examined as full text and 36 were included. Study level clinical data were extracted by 3 independent reviewers. Results: The overall prevalence of functioning AIs was 27.5% (95% CI 23.0, 32.5). ACS/possible ACS, with a prevalence of 11.7% (95% CI 8.6, 15.7), was the most frequent hormonal alteration, while PA occurred in 4.4% of the patients (95% CI 3.1, 6.2). Subgroup analysis showed that PA was more prevalent in patients from Asia than in patients from Europe/America; in contrast, ACS/possible ACS had a lower prevalence in Asian countries. At meta-regression analysis, the prevalence of ACS/possible ACS was influenced by the proportion of female patients, while the prevalence of PA was positively associated with the proportion of patients with hypertension and the publication year. Finally, PHEO and CS prevalence were 3.8% (95% CI 2.8, 5.0) and 3.1% (95% CI 2.3, 4.3) respectively. Conclusion: This meta-analysis provides extensive data on the prevalence of functioning AIs and the factors affecting heterogeneity in prevalence estimates.
MeSH term(s)	Humans ; Female ; Adrenal Gland Neoplasms/epidemiology ; Adrenal Gland Neoplasms/complications ; Prevalence ; Cushing Syndrome/epidemiology ; Cushing Syndrome/complications ; Hypertension/epidemiology ; Hypertension/complications ; Pheochromocytoma/complications ; Hydrocortisone
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2023-01-31
Publishing country	United States
Document type	Meta-Analysis ; Systematic Review ; Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgad044
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Article ; Online: Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline.

Mulatero, Paolo / Scholl, Ute I / Fardella, Carlos E / Charmandari, Evangelia / Januszewicz, Andrzej / Reincke, Martin / Gomez-Sanchez, Celso E / Stowasser, Michael / Dekkers, Olaf M

European journal of endocrinology

2024 Volume 190, Issue 4, Page(s) G1–G14

Abstract: We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, ... ...

Abstract	We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, endocrine hypertension, paediatric endocrinology, and cardiology as well as a methodologist. A systematic literature search was conducted, and because of the rarity of the condition, most recommendations were based on expert opinion and small patient series. The guideline includes a brief description of the genetics and molecular pathophysiology associated with each condition, the patients to be screened, and how to screen. Diagnostic and treatment approaches for patients with genetically determined diagnosis are presented. The recommendations apply to patients with genetically proven familial hyperaldosteronism and not to families with more than one case of primary aldosteronism without demonstration of a responsible pathogenic variant.
MeSH term(s)	Child ; Humans ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/genetics ; Hyperaldosteronism/therapy ; Hypertension/diagnosis ; Hypertension/genetics ; Hypertension/therapy ; Endocrinology
Language	English
Publishing date	2024-03-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1093/ejendo/lvae041
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Article ; Online: CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone-to-renin ratio, an indicator of sodium retention, in healthy volunteers.

Mulatero, Paolo / Groessl, Michael / Vogt, Bruno / Schumacher, Christoph / Steele, Ronald Edward / Brooks, Ashley / Hossack, Stuart / Brunner, Hans-Rudolf

British journal of clinical pharmacology

2023 Volume 89, Issue 8, Page(s) 2483–2496

Abstract: Aims: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.: Methods: This ... ...

Abstract	Aims: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. Methods: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing. Results: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-h aldosterone suppression after 8 days of treatment, unlike the 8- and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge). Conclusions: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.
MeSH term(s)	Humans ; Aldosterone/therapeutic use ; Renin/therapeutic use ; Cytochrome P-450 CYP11B2 ; Healthy Volunteers ; Phosphates/therapeutic use ; Hypertension/complications ; Sodium ; Adrenocorticotropic Hormone ; Potassium
Chemical Substances	Aldosterone (4964P6T9RB) ; Renin (EC 3.4.23.15) ; Cytochrome P-450 CYP11B2 (EC 1.14.15.4) ; Phosphates ; Sodium (9NEZ333N27) ; Adrenocorticotropic Hormone (9002-60-2) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2023-04-10
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.15713
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Article ; Online: 10 good reasons why adrenal vein sampling is the preferred method for referring primary aldosteronism patients for adrenalectomy.

Rossi, Gian Paolo / Mulatero, Paolo / Satoh, Fumitoshi

Journal of hypertension

2018 Volume 37, Issue 3, Page(s) 603–611

Abstract: Nowadays most patients diagnosed with surgically curable primary aldosteronism have small or micro aldosterone-producing adenoma or unilateral micronodular hyperplasia, which are undetectable with available imaging technologies. Therefore, a negative ... ...

Abstract	: Nowadays most patients diagnosed with surgically curable primary aldosteronism have small or micro aldosterone-producing adenoma or unilateral micronodular hyperplasia, which are undetectable with available imaging technologies. Therefore, a negative imaging test by no means excludes unilateral primary aldosteronism. Moreover, about 10% of the subjects above the age of 35 years have nonfunctioning adrenal tumors, regardless of being hypertensive or not, with a prevalence that raises with aging. Hence, the finding of an adrenal mass at imaging does not reliably detect the culprit of primary aldosteronism. On the other hand, when primary aldosteronism patients are selected for adrenalectomy on the basis of demonstration of lateralized aldosterone excess at adrenal vein sampling (AVS), close to 100% are biochemically cured from the hyperaldosteronism, about 45% are cured of arterial hypertension and an additional 52% are markedly improved in terms of blood pressure control. By contrast, patients referred for surgery based on imaging alone often fail to reach these successful outcomes, indicating that surgery was unnecessary or, even worse, performed on the wrong side. For these reasons, and because of the lack of accurate and widely available alternative methods, all current guidelines recommend that AVS be offered to all primary aldosteronism patients with only few exceptions, mainly in patients unable or unwilling to undergo surgery and those with germ-line mutations causing familial primary aldosteronism. The main argument against systematic use of AVS entails its suboptimal performance, partly justified by its intrinsic technical difficulty, and its limited availability. This led to propose skipping AVS strategies for predicting surgically curable primary aldosteronism, but success has been inconsistent. The most urgent standing issue is, therefore, not to find loopholes to avoid AVS, but rather to improve its use, which means improving the rate of AVS success, through formal training of interventionists, selection of appropriate cutoffs and exploitation of a standardized procedure.
MeSH term(s)	Adrenal Glands/blood supply ; Adrenalectomy ; Blood Specimen Collection/methods ; Humans ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/surgery ; Referral and Consultation
Language	English
Publishing date	2018-11-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605532-1
ISSN	1473-5598 ; 0263-6352 ; 0952-1178
ISSN (online)	1473-5598
ISSN	0263-6352 ; 0952-1178
DOI	10.1097/HJH.0000000000001939
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