Hypertension: Stowasser M

Sharman JE, Stowasser M. · School of Human Movement Studies, The University of Queensland, St. Lucia, Australia. · J Sci Med Sport. · Pubmed #19147407 No free full text.

Abstract: Hypertension (high blood pressure; BP) is a leading contributor to premature death and disability from cardiovascular disease. Lifestyle modification that includes regular physical activity is often recommended to patients with hypertension as one of the first line treatments for lowering BP, as well as improving overall risk for cardiovascular events. It is recognised that allied health care professionals play an important role in helping patients to achieve BP control by influencing and reinforcing appropriate lifestyle behavior. The minimum amount of exercise that is recommended in patients with hypertension comprises a mix of moderate to vigorous aerobic (endurance) activity (up to 5 days/week) in addition to resistance (strength) training (on 2 or more non-consecutive days/week). However, due to the dose-response relationship between physical activity and health, exercise levels performed beyond the minimum recommendations are expected to confer additional health benefits. Vigorous exercise training is generally safe and well tolerated by most people, including those with hypertension, although some special considerations are required and these are discussed in this review.

Stowasser M, Gordon RD. · No affiliation provided · Hypertension. · Pubmed #17339541 links to  free full text

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Stowasser M. · No affiliation provided · J Hypertens. · Pubmed #11288804 No free full text.

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Campbell DJ, Nussberger J, Stowasser M, Danser AH, Morganti A, Frandsen E, Ménard J. · Department of Medicine, St Vincent's Institute of Medical Research, University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria, Australia. · Clin Chem. · Pubmed #19264850 No free full text.

Abstract: BACKGROUND: Measurement of plasma renin is important for the clinical assessment of hypertensive patients. The most common methods for measuring plasma renin are the plasma renin activity (PRA) assay and the renin immunoassay. The clinical application of renin inhibitor therapy has thrown into focus the differences in information provided by activity assays and immunoassays for renin and prorenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement. CONTENT: Renin activity assays and immunoassays provide related but different information. Whereas activity assays measure only active renin, immunoassays measure both active and inhibited renin. Particular care must be taken in the collection and processing of blood samples and in the performance of these assays to avoid errors in renin measurement. Both activity assays and immunoassays are susceptible to renin overestimation due to prorenin activation. In addition, activity assays performed with peptidase inhibitors may overestimate the degree of inhibition of PRA by renin inhibitor therapy. Moreover, immunoassays may overestimate the reactive increase in plasma renin concentration in response to renin inhibitor therapy, owing to the inhibitor promoting conversion of prorenin to an open conformation that is recognized by renin immunoassays. CONCLUSIONS: The successful application of renin assays to patient care requires that the clinician and the clinical chemist understand the information provided by these assays and of the precautions necessary to ensure their accuracy.

Gordon RD, Stowasser M. · Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Princess Alexandra Hospital, Brisbane, Australia. · Nat Clin Pract Nephrol. · Pubmed #17909546 No free full text.

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Stowasser M, Gordon RD. · Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Australia 4102. · Best Pract Res Clin Endocrinol Metab. · Pubmed #16980202 No free full text.

Abstract: Monogenic mutations leading to excessive activation of the mineralocorticoid pathway result, almost always, in suppressed renin and hypertension in adult life and sometimes in hypokalaemia and alkalosis, which can be severe. In most of these syndromes, precise molecular changes in specific steroidogenic or effector genes have been identified, permitting appreciation of (1) pathophysiology, (2) great diversity of phenotype and (3) possibility of genetic methods of diagnosis. Yet to be achieved elucidation of the genetic basis of familial hyperaldosteronism type II, the most common and clinically significant of them, will enhance detection of primary aldosteronism, currently the commonest specifically treatable and potentially curable form of hypertension. While classic, complete-phenotype presentations of monogenic forms of mineralocorticoid hypertension are rarely recognised, more subtle genetic expression causing less florid manifestations could represent a significant proportion of so-called 'essential hypertension.'

Stowasser M, Gordon RD. · Hypertension Unit, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. · Best Pract Res Clin Endocrinol Metab. · Pubmed #14687591 No free full text.

Abstract: Approaching the fiftieth year since its original description, primary aldosteronism is now thought to be the commonest potentially curable and specifically treatable form of hypertension. Correct identification of patients with primary aldosteronism requires that the effects of time of day, posture, dietary sodium intake, potassium levels and medications on levels of aldosterone and renin be carefully considered. Accurate elucidation of the subtype is essential for optimal treatment, and adrenal venous sampling is the only reliable means of differentiating aldosterone-producing adenoma from bilateral adrenal hyperplasia. With genetic testing already available for one inherited form, making more cumbersome biochemical testing for that subtype virtually obsolete and bringing about improvements in treatment approach, an intense search is underway for genetic mutations causing other, more common familial varieties of primary aldosteronism.

Stowasser M, Gordon RD. · Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Brisbane 4102, Australia. · Trends Endocrinol Metab. · Pubmed #12946873 No free full text.

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Stowasser M, Gunasekera TG, Gordon RD. · Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Queensland, Australia. · Clin Exp Pharmacol Physiol. · Pubmed #11903322 No free full text.

Abstract: 1. Improved approaches to screening and diagnosis have revealed primary aldosteronism (PAL) to be much more common than previously thought, with most patients normokalaemic. The spectrum of this disorder has been further broadened by the study of familial varieties. 2. Familial hyperaldosteronism type I (FH-I) is a glucocorticoid-remediable form of PAL caused by the inheritance of an adrenocorticotrophic hormone (ACTH)- regulated, hybrid CYP11B1/CYP11B2 gene. Diagnosis has been greatly facilitated by the advent of genetic testing. The severity of hypertension varies widely in FH-I, even among members of the same family, and has demonstrated relationships with gender, degree of biochemical disturbance and hybrid gene crossover point position. Hormone "day curve" studies show that the hybrid gene dominates over wild-type CYP11B2 in terms of aldosterone regulation. This may be due, in part, to a defect in wild-type CYP11B2-induced aldosterone production. Control of hypertension in FH-I requires only partial suppression of ACTH and much smaller glucocorticoid doses than previously recommended. 3. Familial hyperaldosteronism type II (FH-II) is not glucocorticoid remediable and is not associated with the hybrid gene mutation. Familial hyperaldosteronism type II is clinically, biochemically and morphologically indistinguishable from apparently non-familial PAL. Linkage studies in one informative family did not show segregation of FH-II with the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL.

Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ. · Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, Australia. · J Renin Angiotensin Aldosterone Syst. · Pubmed #11881117 No free full text.

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Stowasser M, Gordon RD. · Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Qld 4120, Brisbane, Australia. · J Steroid Biochem Mol Biol. · Pubmed #11595502 No free full text.

Abstract: Primary aldosteronism (PAL) may be as much as ten times more common than has been traditionally thought, with most patients normokalemic. The study of familial varieties has facilitated a fuller appreciation of the nature and diversity of its clinical, biochemical, morphological and molecular aspects. In familial hyperaldosteronism type I (FH-I), glucocorticoid-remediable PAL is caused by inheritance of an ACTH-regulated, hybrid CYP11B1/CYP11B2 gene. Genetic testing has greatly facilitated diagnosis. Hypertension severity varies widely, demonstrating relationships with gender, affected parent's gender, urinary kallikrein level, degree of biochemical disturbance and hybrid gene crossover point position. Analyses of aldosterone/PRA/cortisol 'day-curves' have revealed that (1) the hybrid gene dominates over wild type CYP11B2 in terms of aldosterone regulation and (2) correction of hypertension in FH-I requires only partial suppression of ACTH, and much smaller glucocorticoid doses than those previously recommended. Familial hyperaldosteronism type II is not glucocorticoid-remediable, and is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL. In one informative family available for linkage analysis, FH-II does not segregate with either the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL and other curable or specifically treatable forms of hypertension.

Gordon RD, Stowasser M, Rutherford JC. · Endocrine-Hypertension Research Unit, University of Queensland, Department of Medicine, Greenslopes Hospital, Brisbane 4120, Australia. · World J Surg. · Pubmed #11572036 No free full text.

Abstract: Many cases of potentially curable primary aldosteronism are currently likely to be diagnosed as essential hypertension unless screening tests based on suppression of renin are carried out in all hypertensive patients. More than half of the patients with primary aldosteronism detected in this way have normal circulating potassium levels, so measurement of potassium is not enough to exclude primary aldosteronism. When primary aldosteronism is diagnosed, fewer than one-third of patients are suitable for surgery as initial treatment, but this still represents a significant percentage of hypertensive patients. After excluding glucocorticoid-suppressible primary aldosteronism, adrenal venous sampling is essential to detect unilateral production of aldosterone and diagnose angiotensin-responsive aldosterone-producing adenoma. One cannot rely on the computed tomography scan. If all hypertensive patients are screened for primary aldosteronism and the workup is continued methodically in those with a positive screening test, patients with unilateral overproduction of aldosterone who potentially can be cured surgically are not denied the possibility of cure.

Stowasser M. · Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Clin Exp Pharmacol Physiol. · Pubmed #11553016 No free full text.

Abstract: 1. Evidence from recent experimental and clinical studies suggests that excessive circulating levels of aldosterone can bring about adverse cardiovascular sequelae independent of the effects on blood pressure. Examples of these sequelae are the development of myocardial and vascular fibrosis in uninephrectomized, salt-loaded rats infused with mineralocorticoids and, in humans, an association of aldosterone with left ventricular hypertrophy, impaired diastolic and systolic function, salt and water retention causing aggravation of congestion in patients with established congestive cardiac failure (CCF), reduced vascular compliance and an increased risk of arrhythmias (resulting from intracardiac fibrosis, hypokalaemia, hypomagnesaemia, reduced baroreceptor sensitivity and potentiation of catecholamine effects). 2. These sequelae of aldosterone excess may contribute to the pathogenesis and worsen the prognosis of CCF and hypertension. 3. The heart and blood vessels may be capable of extra-adrenal aldosterone biosynthesis, raising the possibility that aldosterone may have paracrine or autocrine (and not just endocrine) effects on cardiovascular tissues. 4. The high prevalence of CCF, which is associated with secondary aldosteronism, and primary aldosteronism (PAL; recently recognized to be a much more common cause of hypertension than was previously thought) argue for an important role for aldosterone excess as a cause of cardiovascular injury. 5. The recognition of non-blood pressure-dependent adverse sequelae of aldosterone excess raises the question as to whether normotensive individuals with PAL, who have been detected as a result of genetic or biochemical screening among families with inherited forms of PAL, are at excess risk of cardiovascular events. 6. Provided that patients are carefully investigated in order to permit the appropriate selection of specific surgical (laparoscopic adrenalectomy for PAL that lateralizes on adrenal venous sampling) or medical (treatment with aldosterone antagonist medications) management and safety considerations for the use of aldosterone antagonists are kept in mind, the appreciation of a widening role for aldosterone in cardiovascular disease should provide a substantially better outlook for many patients with CCF and hypertension.

Stowasser M. · Hypertension Unit, University Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. · Curr Hypertens Rep. · Pubmed #11353574 No free full text.

Abstract: Wider application of the aldosterone/plasma renin activity ratio among hypertensives has facilitated the detection of primary aldosteronism at earlier stages of evolution (with most patients normokalemic), and found prevalence rates far greater than those previously reported. Reliable detection of patients with PAL requires that 1) the diagnosis is considered in all hypertensives; 2) blood samples are collected under standardized conditions of diet, posture, and time of day; 3) medications known to alter the ratio are avoided or their effects taken into account; 4) aldosterone and plasma renin activity are measured using consistently accurate assay techniques; and 5) reliable methods (such as fludrocortisone suppression testing) are used to confirm primary aldosteronism. Adrenal venous sampling is the only dependable way to differentiate aldosterone-producing adenoma from bilateral adrenal hyperplasia. As has occurred in familial hyperaldosteronism type I, the elucidation of genetic mutations causing other forms of primary aldosteronism should further facilitate detection of this potentially curable or specifically treatable variety of hypertension.

Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. · University of Queensland, Brisbane, Australia. · Circulation. · Pubmed #15277317 links to  free full text

Abstract: BACKGROUND: Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. METHODS AND RESULTS: Thirty medically treated ambulatory hypertensive patients (19 women, age 62+/-6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A <1, E deceleration time >250 m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31+/-5 kg/m2) with reduced treadmill exercise capacity (6.7+/-2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133+/-17/80+/-7 mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57+/-0.46 s(-1) versus 6-months: -1.91+/-0.36 s(-1), P<0.01), peak systolic strain (-20.3+/-5.0% versus -26.9+/-4.3%, P<0.001), and CVIB (7.4+/-1.7 dB versus 8.6+/-1.7 dB, P=0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P=0.05, P=0.02, and P=0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P=0.04) and a trend to reduced left atrial area (P=0.09). CONCLUSIONS: Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Scott I, Stowasser M. · Department of Internal Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Intern Med J. · Pubmed #12823686 No free full text.

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Sukor N, Gordon RD, Ku YK, Jones M, Stowasser M. · Endocrine Hypertension Research Center, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Australia. · J Clin Endocrinol Metab. · Pubmed #19401369 No free full text.

Abstract: OBJECTIVE: The aim of the study was to examine blood pressure and biochemical responses to unilateral adrenalectomy in patients with bilateral primary aldosteronism (PA) and identify predictive parameters. CONTEXT: PA considered due to bilateral autonomous production of aldosterone is usually treated medically. Unilateral adrenalectomy has been considered ineffective. Because quality outcome data are lacking and medical treatment may cause adverse effects or fail to control hypertension, defining the role for unilateral adrenalectomy in bilateral PA is an important clinical issue. DESIGN AND SETTING: Between 1984 and 2004, 51 of 684 patients diagnosed with bilateral PA underwent unilateral adrenalectomy. This report is based on the records of the 40 considered suitable for inclusion, who were followed for at least 12 (median, 56.4) months. RESULTS: Hypertension was cured in 15% of patients and improved in 20%, usually within 1 yr of unilateral adrenalectomy. The proportion with controlled hypertension was significantly (P < 0.001) higher after adrenalectomy (65%) than before (25%). Mean systolic (P < 0.001) and diastolic (P < 0.001) blood pressure, left ventricular mass index (P < 0.05), plasma upright aldosterone (P < 0.05), and aldosterone/renin ratio (P < 0.001) fell. Serum creatinine independently predicted hypertension cure. CONCLUSION: Although this retrospective analysis of patients from a single center does not permit prediction of response rates among patients diagnosed elsewhere, it suggests that unilateral adrenalectomy can be beneficial in some patients with apparent bilateral PA and should not be dismissed as a treatment option.

Taylor PJ, Cooper DP, Gordon RD, Stowasser M. · Endocrine Hypertension Research Centre, University of Queensland, Greenslopes Hospital, Brisbane, Australia. · Clin Chem. · Pubmed #19359537 No free full text.

Abstract: BACKGROUND: Reliable measurement of aldosterone with less interlaboratory variation than RIA would help standardize testing for primary aldosteronism. We set out to validate a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for aldosterone in human plasma. METHODS: We prepared samples (EDTA plasma, lithium heparin plasma, and serum from separator and plain clot tubes) and measured aldosterone using online HPLC-MS/MS with d(7)-aldosterone as internal standard. We also analyzed EDTA plasma samples by immunoassay. We established a reference range for HPLC-MS/MS aldosterone by analyzing blood collected midmorning from 97 normotensive seated subjects. RESULTS: The linear range was 69.4-5548.0 pmol/L (2.5-200 ng/dL) (r(2) > 0.994, n = 14). Inter- and intraday analytical recovery and imprecision for quality control samples of 166.4, 1109.6, and 4161.0 pmol/L (6.0, 40.0, and 150.0 ng/dL) were 92.2%-102.0% and <6.3%, respectively (n = 5). The lower limit of quantification was 69.4 pmol/L (2.5 ng/dL), with inter- and intraday analytical recovery and imprecision of 91.4%-94.5% and <9.5% (n = 5). No interferences were observed in plasma from Addison's disease patients (n = 5). Comparison of collection tubes, using EDTA as the reference, revealed similar aldosterone results. Comparison of HPLC-MS/MS with immunoassay gave an acceptable mean bias (0.83%) but wide range (-44.8% to 39.7%) of differences. HPLC-MS/MS aldosterone concentrations in normotensive subjects ranged from <69.4 to 635.2 pmol/L (<2.5 to 22.9 ng/dL). CONCLUSIONS: This first reported aldosterone method using online HPLC-MS/MS is precise across the clinically relevant range, not influenced by collection tube type, and offers semiautomated sample preparation and high throughput.

Sukor N, Mulatero P, Gordon RD, So A, Duffy D, Bertello C, Kelemen L, Jeske Y, Veglio F, Stowasser M. · Endocrine Hypertension Research Center, University of Queensland School of Medicine, Greenslopes Hospital, Brisbane, Australia. · J Hypertens. · Pubmed #18622235 No free full text.

Abstract: BACKGROUND: Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. OBJECTIVE: To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). METHODS: Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. RESULTS: All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (theta = 0) for markers D7S462 and D7S517. CONCLUSION: Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.

Sharman J, Stowasser M, Fassett R, Marwick T, Franklin S. · Department of Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia. · J Hum Hypertens. · Pubmed #18596719 No free full text.

Abstract: Central systolic blood pressure (SBP) may differ between individuals with similar brachial SBP, which may have implications for risk assessment. This study aimed to determine the variation and potential clinical value of central SBP between patients with similar brachial SBP. Brachial SBP was measured by sphygmomanometer and central SBP by radial tonometry in 675 people (430 men), comprising healthy individuals (n = 222), patients with known or suspected coronary artery disease (n = 229) and diabetes (n = 224). Individuals were stratified by brachial SBP in accordance with European Society of Hypertension guidelines (optimal, normal, high-normal, grades 1, 2 and 3 hypertension). The potential clinical value of central SBP was determined from the percentage of patients re-classified into different brachial SBP groups due to the difference between brachial and aortic SBP (defined as brachial SBP-central SBP). Central SBP increased with each brachial SBP level (optimal to grade 3 hypertension; P < 0.001 for all). However, large variation in brachial-aortic SBP difference occurred within each brachial SBP group (range 2-33 mm Hg), resulting in sizeable overlap of central SBP between brachial SBP groups. For patients with normal brachial SBP, 96% had central SBP within the range of patients with high-normal brachial SBP, as well as 64% within the range of patients with grade 1 hypertension. We conclude that wide variation in brachial-aortic SBP difference occurs between patients with similar brachial SBP. This results in a significant overlap of central SBP scores between brachial SBP risk groups. This is likely to have treatment implications but remains to be tested.

Jeske YW, So A, Kelemen L, Sukor N, Willys C, Bulmer B, Gordon RD, Duffy D, Stowasser M. · Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes Hospital, Brisbane, Queensland, Australia. · Clin Exp Pharmacol Physiol. · Pubmed #18307725 No free full text.

Abstract: 1. There are two types of familial hyperaldosteronism (FH): FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We previously reported linkage of FH-II to a approximately 5 Mb region on chromosome 7p22. We subsequently reported finding no causative mutations in the retinoblastoma-associated Kruppel-associated box gene (RBaK), a candidate at 7p22 involved in tumorigenesis and cell cycle control. 2. In the current study we investigated RBaK regulatory regions and two other candidate genes: postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide-binding protein alpha-12 (GNA12, a transforming oncogene). 3. The GNA12 and PMS2 genes were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from a large 7p22-linked FH-II family (family 1). No mutations were found. 4. The RBaK and PMS2 distal promoters were sequenced to -2150 bp from the transcription start site for RBaK and-2800 bp for PMS2. Five unreported single nucleotide polymorphisms (SNPs) were found in subjects A1, A2 but not in U1 or U2; A(-2031 bp)T, T(-2030 bp)G, G(-834 bp)C, C(-821 bp)G in RBaK and A(-876 bp)G in PMS2. Additional affected and unaffected subjects from family 1 and from two other 7p22-linked FH-II families and 58 unrelated normotensive control subjects were genotyped for these SNPs. 5. The five novel SNPs were found to be present in a significant proportion of normotensive controls. The four RBaK promoter SNPs were found to be in linkage disequilibrium in the normal population. The RBaK promoter (-)2031T/2030G/834C/821T allele was found to be in linkage disequilibrium with the causative mutation in FH-II family 1, but not in families 2 and 3. The PMS2 promoter (-)876G allele was also found to be linked to affected phenotypes in family 1. 6. The RBaK and PMS2 promoter SNPs alter the binding sites for several transcription factors. Although present in the normal population, it is possible that the RBaK (-)2031T/2030G/834C/821T and PMS2 (-)876G alleles may have functional roles contributing to the FH-II phenotype in family 1.

So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, New MI, Stowasser M. · Endocrine Hypertension Research Centre, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia. · J Hypertens. · Pubmed #16003173 No free full text.

Abstract: BACKGROUND: Familial hyperaldosteronism type II (FH-II) is characterized by the familial occurrence of primary aldosteronism; unlike FH-I, it is not glucocorticoid-remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Linkage to a 5-Mbp region of chromosome 7p22 was previously reported in an Australian family with eight affected members. Mutations in the exons or intron-exon boundaries of PRKAR1B (7p22, closely related to PRKAR1A, which is mutated in Carney complex) have been excluded in this family. OBJECTIVE: To refine the region of linkage, and to seek evidence of linkage in a South American family and in three other Australian families with FH-II, using seven closely spaced markers at 7p22. METHODS: To establish phenotypes (affected, uncertain or unaffected), blood pressure, plasma aldosterone and plasma renin (activity or concentration) were measured and the aldosterone: renin ratio (ARR) calculated. Individuals with consistently increased ARR underwent fludrocortisone suppression testing. The genotypes of the five pedigrees were analysed using seven closely spaced microsatellite markers at 7p22, and two-point and multipoint logarithm of odds (LOD) scores were calculated to assess linkage with FH-II. RESULTS: The combined multipoint LOD score for three families (the original Australian, the South American and a new Australian family) showing linkage at 7p22 was highly significant at 4.61 (theta = 0) for markers D7S462 and D7S517. A newly found recombination event in the first Australian family narrowed the area of linkage by 1.8 Mbp, permitting exclusion of approximately half the candidate genes in the originally reported locus. It was not possible to demonstrate linkage at the 7p22 region in the remaining two Australian families. CONCLUSION: This study provides further evidence for linkage of FH-II to 7p22, refines the locus, and supports the notion that FH-II may be genetically heterogeneous.

Stowasser M, Sharman J, Leano R, Gordon RD, Ward G, Cowley D, Marwick TH. · Hypertension Unit, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. · J Clin Endocrinol Metab. · Pubmed #15941863 links to  free full text

Abstract: OBJECTIVES: To explore whether aldosterone excess can induce adverse cardiovascular effects independently of effects on blood pressure (BP), we sought evidence of disturbed cardiovascular structure or function in normotensive individuals with primary aldosteronism. METHODS: Eight normotensive subjects with genetically proven familial hyperaldosteronism type I (FH-I) were compared with 24 age- and sex-matched normotensive controls in terms of BP, biochemical parameters, pulse wave velocity, and echocardiographic characteristics. RESULTS: Subjects with FH-I demonstrated higher serum aldosterone levels and aldosterone/renin ratios than controls, as expected. Despite having similar 24-h ambulatory BPs, subjects with FH-I demonstrated evidence of concentric remodeling with greater septal (mean +/- sd, 9.4 +/- 1.1 vs. 7.9 +/- 0.9 mm; P < 0.001), posterior wall (9.2 +/- 1.7 vs. 7.7 +/- 1.0 mm; P < 0.01), and relative wall (0.29 +/- 0.03 vs. 0.24 +/- 0.02; P < 0.001) thicknesses, and lower mitral early peak velocities (0.74 +/- 0.10 vs. 0.90 +/- 0.16 m/sec; P < 0.05), ratios of early to late peak diastolic transmitral flow velocity (1.56 +/- 0.24 vs. 2.06 +/- 0.41; P < 0.01), and myocardial early peak velocities (8.3 +/- 1.8 vs. 10.3 +/- 2.6 cm/sec; P < 0.05). There were no significant differences in pulse wave velocity or left ventricular ejection fraction, long axis strain rate, peak systolic strain, cyclic variation of integrated backscatter, or posterior wall calibrated integrated backscatter. CONCLUSIONS: Aldosterone excess is associated with increased left ventricular wall thicknesses and reduced diastolic function, even in the absence of hypertension.

Elphinstone MS, Gordon RD, So A, Jeske YW, Stratakis CA, Stowasser M. · Hypertension Units, University of Queensland Department of Medicine, Princess Alexandra and Greenslopes Hospitals, Brisbane 4102, Australia. · Clin Endocrinol (Oxf). · Pubmed #15579186 No free full text.

Abstract: OBJECTIVE: Familial hyperaldosteronism type II (FH-II) is characterized by inheritance of primary aldosteronism (PAL) but, unlike FH-I, is not glucocorticoid remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Analysis of two pedigrees previously demonstrated linkage of FH-II with a locus at chromosome 7p22. We sought to determine whether mutations in the exons or intron/exon boundaries in PRKAR1B (encoding protein kinase A regulatory subunit R1-beta), which resides within the linked locus, are associated with FH-II. METHODS: Primers enabling sequencing of all exons and intron/exon boundaries were designed by BLAT search using known mRNA sequence, and comparison with an orthologous mouse gene. Sequences from four affected and two unaffected subjects from an Australian family with FH-II demonstrating linkage at 7p22 were compared with published sequences. RESULTS: A probable two-nucleotide GenBank sequence error, resulting in an amino acid change, was detected. Two of seven single nucleotide polymorphisms (SNPs) identified were in exons and five in introns. Neither exon-localized SNP resulted in an amino acid change. All intron-localized SNPs were at least 16 nucleotides from the closest intron/exon boundary and therefore unlikely to interfere with gene splicing. Importantly, none of the identified SNPs was exclusively associated with affectation status. CONCLUSIONS: Mutations in the exons or intron/exon boundaries of PRKAR1B do not appear to be responsible for FH-II in this family, but a mutation in the promoter or remaining intronic or 5' or 3' untranslated regions could be. Alternatively, a mutation within another gene residing at the 7p22 locus may be responsible.

Stowasser M, Gordon RD. · Hypertension Unit, University of Queensland, Department of Medicine, Princvess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. · Mol Cell Endocrinol. · Pubmed #15134798 No free full text.

Abstract: Once considered rare, primary aldosteronism (PAL) is now regarded as the commonest potentially curable and specifically treatable form of hypertension. At Greenslopes Hospital Hypertension Unit (GHHU), the decision in 1991 to screen all (and not just hypokalemic or resistant) hypertensives by aldosterone/renin ratio (ARR) testing led to a 10-fold increase in detection rate of PAL and four-fold increase in removal rate of aldosterone-producing adenomas (APAs). The GHHU/Princess Alexandra Hospital Hypertension Unit PAL series stands at 977 patients and 250 APAs removed with hypertension cured in 50-60% (remainder improved). Reliable detection requires that interfering medications are withdrawn (or their effects considered) before ARR measurement, and reliable methods (such as fludrocortisone suppression testing) to confirm PAL. Adrenal venous sampling is the only dependable way to differentiate APA from bilateral adrenal hyperplasia. Genetic testing has facilitated detection of glucocorticoid-remediable, familial PAL. Identification of mutations causing the more common familial variety described by GHHU in 1991 should further aid in detection of PAL.