Randomized Trial on the Effect of Oral Potassium Chloride Supplementation on the Thiazide-Sensitive Sodium Chloride Cotransporter in Healthy Adults.

Introduction: The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake. Methods: Healthy adults maintained on a high sodium (∼4.5 g [200 mmol]/d) low potassium (∼2.3 g [60 mmol]/d) diet underwent a 5-day run-in period followed by a crossover study, with 5-day supplementary KCl (active phase, Span-K 3 tablets (potassium 24 mmol) thrice daily) or 5-day placebo administrated in random order and separated by 2-day washout. Ambulatory blood pressure (BP) and biochemistries were assessed, and uEVs were analyzed by western blotting. Results: Among the 18 participants who met analysis criteria, supplementary KCl administration (vs. placebo) was associated with markedly higher levels of plasma potassium and 24-hour urine excretion of potassium, chloride, and aldosterone. KCl supplementation was associated with lower uEV levels of NCC (median fold change (KCl/Placebo) = 0.74 [0.30-1.69], P < 0.01) and pNCC (fold change (KCl/Placebo) = 0.81 [0.19-1.75], P < 0.05). Plasma potassium inversely correlated with uEV NCC (R2 = 0.11, P = 0.05). Conclusions: The lower NCC and pNCC in uEVs in response to oral KCl supplementation provide evidence to support the hypothesis of a functional "renal-K switch" in healthy human subjects.

In Primary Aldosteronism Acute Potassium Chloride Supplementation Suppresses Abundance and Phosphorylation of the Sodium-Chloride Cotransporter.

Background: Elevated abundance of sodium-chloride cotransporter (NCC) and phosphorylated NCC (pNCC) are potential markers of primary aldosteronism (PA), but these effects may be driven by hypokalemia. Methods: We measured plasma potassium in patients with PA. If potassium was <4.0 mmol/L, patients were given sufficient oral potassium chloride (KCl) over 24 hours to achieve as close to 4.0 mmol/L as possible. Clinical chemistries were assessed, and urinary extracellular vesicles (uEVs) were examined to investigate effects on NCC. Results: Among 21 patients with PA who received a median total dose of 6.0 g (2.4-16.8 g) of KCl, increases were observed in plasma potassium (from 3.4 to 4.0 mmol/L; P<0.001), aldosterone (from 305 to 558 pmol/L; P=0.01), and renin (from 1.2 to 2.5 mIU/L; P<0.001), whereas decreases were detected in uEV levels of NCC (median fold change(post/basal) [FC]=0.71 [0.09-1.99]; P=0.02), pT60-NCC (FC=0.84 [0.06-1.66]; P=0.05), and pT55/60-NCC (FC=0.67 [0.08-2.42]; P=0.02). By contrast, in 10 patients with PA who did not receive KCl, there were no apparent changes in plasma potassium, NCC abundance, and phosphorylation status, but increases were observed in plasma aldosterone (from 178 to 418 pmol/L; P=0.006) and renin (from 2.0 to 3.0 mU/L; P=0.009). Plasma potassium correlated inversely with uEV levels of NCC (R 2=0.11; P=0.01), pT60-NCC (R 2=0.11; P=0.01), and pT55/60-NCC (R 2=0.11; P=0.01). Conclusions: Acute oral KCl loading replenished plasma potassium in patients with PA and suppressed NCC abundance and phosphorylation, despite a significant rise in plasma aldosterone. This supports the view that potassium supplementation in humans with PA overrides the aldosterone stimulatory effect on NCC. The increased plasma aldosterone in patients with PA without KCl supplementation may be due to aldosterone response to posture challenge.

Acute Intravenous NaCl and Volume Expansion Reduces Sodium-Chloride Cotransporter Abundance and Phosphorylation in Urinary Extracellular Vesicles.

Background: Sodium chloride (NaCl) loading and volume expansion suppress the renin-angiotensin-aldosterone system to reduce renal tubular reabsorption of NaCl and water, but effects on the sodium-chloride cotransporter (NCC) and relevant renal transmembrane proteins that are responsible for this modulation in humans are less well investigated. Methods: We used urinary extracellular vesicles (uEVs) as an indirect readout to assess renal transmembrane proteins involved in NaCl and water homeostasis in 44 patients with hypertension who had repeatedly raised aldosterone/renin ratios undergoing infusion of 2 L of 0.9% saline over 4 hours. Results: When measured by mass spectrometry in 13 patients, significant decreases were observed in NCC (median fold change [FC]=0.70); pendrin (FC=0.84); AQP2 (FC=0.62); and uEV markers, including ALIX (FC=0.65) and TSG101 (FC=0.66). Immunoblotting reproduced the reduction in NCC (FC=0.54), AQP2 (FC=0.42), ALIX (FC=0.52), and TSG101 (FC=0.55) in the remaining 31 patients, and demonstrated a significant decrease in phosphorylated NCC (pNCC; FC=0.49). However, after correction for ALIX, the reductions in NCC (FC=0.90) and pNCC (FC=1.00) were no longer apparent, whereas the significant decrease in AQP2 persisted (FC=0.62). Conclusion: We conclude that (1) decreases in NCC and pNCC, induced by acute NaCl loading and volume expansion, may be due to diluted post-test urines; (2) the lack of change of NCC and pNCC when corrected for ALIX, despite a fall in plasma aldosterone, may be due to the lack of change in plasma K+; and (3) the decrease in AQP2 may be due to a decrease in vasopressin in response to volume expansion.

May Measurement Month 2019: an analysis of blood pressure screening results from Australia.

May Measurement Month (MMM) is an annual global blood pressure (BP) screening campaign aimed at obtaining standardized BP measurements and other relevant health information from members of the community to increase awareness of elevated BP and the associated risks. Adults (≥18 years) were recruited through opportunistic sampling across the various Australian states during May 2019. Three BP readings were recorded in a standardized manner for each participant, and data on lifestyle factors and comorbidities were collected. Hypertension was defined as a systolic BP ≥140 mmHg, or a diastolic BP ≥90 mmHg (according to the MMM protocol) or taking antihypertensive medication. Multiple imputation was used to estimate participants' mean BP where three readings were not available. Of the 2877 participants, 901 (31.3%) had hypertension of whom 455 (50.5%) were aware of their condition, and 366 (40.6%) were on antihypertensive medication. Of those taking antihypertensive medication, 54.3% were controlled to <140/90 mmHg with the remaining 45.7% of participants inadequately treated. Approximately 74% of treated patients were on a single antihypertensive medication. The MMM campaign provides an important platform for standardized compilation of BP data and creation of BP awareness in Australia and other nations worldwide. Data from the 2019 MMM campaign highlight that BP control rates in Australia remain unacceptably low.

May Measurement Month 2018: an analysis of blood pressure screening results from Australia.

May Measurement Month (MMM), originally initiated as a temporary solution to address the lack of blood pressure (BP) screening programs worldwide, emerged as an effective annual campaign to increase the awareness of hypertension. MMM18, a cross-sectional survey of volunteers aged ≥18 years was carried out during May 2018 predominantly in capital cities across Australia following the standard MMM protocol. Blood pressure screening along with additional information including anthropometric data and responses to questionnaires on demographic, lifestyle, and environmental factors were collected from 3 352 individuals across Australia. After multiple imputation, 1 026 (30.6%) adult Australians had hypertension. Of the 2 936 individuals not on antihypertensive treatment, 610 (20.8%) were hypertensive, and 237 (57.1%) of the 416 individuals receiving antihypertensive treatment had uncontrolled BP. In line with MMM17 results and other previous surveys, MMM18 revealed that close to one-third of the screened population (30.6%) had hypertension, 57.1% of individuals treated with BP-lowering medication remained uncontrolled indicating suboptimal management of the condition in the majority of patients. Most importantly, only 49.0% of those with hypertension were aware of their elevated BP, highlighting lack of awareness of elevated BP in nearly half of the affected population. Elevated BP was directly associated with alcohol consumption, overweight, and obesity. Our findings demonstrate the need for (i) continued efforts to increase BP awareness in the population, (ii) optimization of BP management strategies, and (iii) tackling some of the major contributors to BP elevation, including alcohol consumption and obesity.

Effects of Ramipril on the Aldosterone/Renin Ratio and the Aldosterone/Angiotensin II Ratio in Patients With Primary Aldosteronism.

The aldosterone/renin ratio (ARR) is currently considered the most reliable approach for case detection of primary aldosteronism (PA). ACE (Angiotensin-converting enzyme) inhibitors are known to raise renin and lower aldosterone levels, thereby causing false-negative ARR results. Because ACE inhibitors lower angiotensin II levels, we hypothesized that the aldosterone/equilibrium angiotensin II (eqAngII) ratio (AA2R) would remain elevated in PA. Receiver operating characteristic curve analysis involving 60 patients with PA and 40 patients without PA revealed that the AA2R was not inferior to the ARR in screening for PA. When using liquid chromatography-tandem mass spectrometry to measure plasma aldosterone concentration, the predicted optimal AA2R cutoff for PA screening was 8.3 (pmol/L)/(pmol/L). We then compared the diagnostic performance of the AA2R with the ARR among 25 patients with PA administered ramipril (5 mg/day) for 2 weeks. Compared with basally, plasma levels of equilibrium angiotensin I (eqAngI) and direct renin concentration increased significantly (P<0.01 or P<0.05) after ramipril treatment, whereas eqAngII and ACE activity (eqAngII/eqAngI) decreased significantly (P<0.01). The changes of plasma renin activity and plasma aldosterone concentration in the current study were not significant. On day 14, 4 patients displayed false-negative results using ARR_direct renin concentration (plasma aldosterone concentration/direct renin concentration), 3 of whom also showed false-negative ARR_plasma renin activity (plasma aldosterone concentration/plasma renin activity). On day 15, 2 patients still demonstrated false-negative ARR_plasma renin activity, one of whom also showed a false-negative ARR_direct renin concentration. No false-negative AA2R results were observed on either day 14 or 15. In conclusion, compared with ARR which can be affected by ACE inhibitors causing false-negative screening results, the AA2R seems to be superior in detecting PA among subjects receiving ACE inhibitors.

Comparison of Seated With Recumbent Saline Suppression Testing for the Diagnosis of Primary Aldosteronism.

Context: Failure of plasma aldosterone suppression during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). Aldosterone is often higher upright than recumbent in PA; upright levels are used during FST. In a pilot study (24 patients with PA), seated saline suppression testing (SSST) was more sensitive than recumbent saline suppression testing (RSST). Objective, Design, and Patients: The current validation study involved 100 patients who underwent FST, RSST, and SSST, eight before and after unilateral adrenalectomy. Of the 108 FSTs, 73 confirmed and 18 excluded PA. Four patients with inconclusive FST lateralized on adrenal venous sampling, making a total of 77 with PA. Results: The area under the receiver operating characteristic (ROC) curve was greater for SSST than RSST (0.96 vs. 0.80; P < 0.01). ROC analysis predicted optimal cutoff aldosterone levels of 162 pmol/L for SSST and 106 pmol/L for RSST. At these cutoffs, SSST showed high sensitivity for PA (87%) that markedly exceeded that for RSST (38%; P < 0.001) but similar specificity (94 vs. 94%; not significant). SSST was more sensitive than RSST in detecting both unilateral (n = 28, 93% vs. 68%, P < 0.05) and bilateral (n = 40, 85% vs. 20%, P < 0.001) forms of PA. Only three SSST (vs. 9 RSST and 17 FST) results were inconclusive. Conclusions: SSST is highly sensitive and superior to RSST in identifying both unilateral and bilateral forms of PA and has a low rate of false positives and inconclusive results. It therefore offers a reliable and much less complicated and expensive alternative to FST for confirming PA.

Guideline for the diagnosis and management of hypertension in adults - 2016.

The National Heart Foundation of Australia has updated the Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults (updated December 2010). Main recommendations For patients at low absolute cardiovascular disease risk with persistent blood pressure (BP) ≥ 160/100 mmHg, start antihypertensive therapy. The decision to treat at lower BP levels should consider absolute cardiovascular disease risk and/or evidence of end-organ damage, together with accurate BP assessment. For patients at moderate absolute cardiovascular disease risk with persistent systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, start antihypertensive therapy. Treat patients with uncomplicated hypertension to a target BP of < 140/90 mmHg or lower if tolerated. Changes in management as a result of the guideline Ambulatory and/or home BP monitoring should be offered if clinic BP is ≥ 140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome. In selected high cardiovascular risk populations, aiming for a target of < 120 mmHg systolic can improve cardiovascular outcomes. If targeting < 120 mmHg, close follow-up is recommended to identify treatment-related adverse effects including hypotension, syncope, electrolyte abnormalities and acute kidney injury. Why the changes have been made A 2015 meta-analysis of patients with uncomplicated mild hypertension (systolic BP range, 140-169 mmHg) demonstrated that BP-lowering therapy is beneficial (reduced stroke, cardiovascular death and all-cause mortality). A 2015 trial comparing lower with higher blood pressure targets in selected high cardiovascular risk populations found improved cardiovascular outcomes and reduced mortality, with an increase in some treatment-related adverse events.

The utility of renal venous renin studies in selection of patients with renal artery stenosis for angioplasty: a retrospective study.

OBJECTIVES: Recent studies of renal artery stenosis (RAS) failed to demonstrate greater benefit from angioplasty in terms of blood pressure (BP) lowering than medical treatment. Not all RAS are haemodynamically significant and identification of patients likely to benefit from angioplasty remains essential. METHODS: We examined whether performing renal venous renin studies under stringent conditions might predict BP improvement. Patients with at least 60% RAS who underwent renal venous renin measurements in 2008-2013 were identified. Renal venous renin lateralization ratios (RVRRs) were calculated by dividing venous renin from the stenotic kidney with contralateral levels before and after stimulation with enalaprilat or captopril. Benefit was defined as BP less than 140/90  mmHg without medication, 10% decreased mean BP without increased daily defined doses (DDDs) or decreased DDD without a significant increase of mean BP. RESULTS: Twenty-eight patients were treated medically and 42 with angioplasty (median age 60.1 years, 41% male, 29% chronic kidney disease, 50% resistant hypertension). At 11.4 ±â€Š3.3 months, 69% of patients treated with angioplasty had BP benefit compared with 25% with medical treatment (P < 0.001). Logistic regression identified resistant hypertension [odds ratio (OR) 0.18, 95% confidence interval (95% CI) 0.04-0.82, P = 0.03] and baseline DDD (OR 0.69, 95% CI 0.48-0.98, P = 0.04) as being negatively associated, and positive stimulated RVRR (OR 21.6, 95% CI 3.50-133.3, P = 0.001) positively associated with benefit from angioplasty. On multivariate logistic regression, only stimulated RVRR positivity predicted BP benefit (OR 20.5, 95% CI 2.9-145.0, P = 0.003). CONCLUSION: These findings suggest that a positive stimulated RVRR measured under optimal conditions may help to identify patients with RAS likely to improve from angioplasty.

Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study.

CONTEXT: Failure of aldosterone suppression by sodium loading during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). We previously found recumbent SST (RSST) to lack sensitivity. Aldosterone levels can be higher upright (e.g. seated) than recumbent in patients with PA and upright levels are used during FST. We therefore hypothesized that seated SST (SSST) is more sensitive than RSST, especially for posture-responsive PA. SETTING AND DESIGN: Of 66 patients who underwent FST (upright plasma aldosterone levels measured at 10am basally and after 4 days fludrocortisone 0.1 mg 6-hourly and oral salt loading), 31 underwent SST (aldosterone levels measured basally at 8am and after infusion of 2 L normal saline over 4h) both recumbent and seated in randomized order and at least 2 weeks apart. RESULTS: FST confirmed PA in 23 of 31 patients (day 4 upright aldosterone level >165 pmol/L), excluded PA in three and was originally "inconclusive" in five. However, one with "inconclusive" FST had PA confirmed by lateralizing AVS and was reclassified "unilateral PA". Of 24 with confirmed PA (eight unilateral, 11 bilateral, and five undetermined subtype), 23 (96%) tested positive by SSST (4-h aldosterone level >165 pmol/L) compared with 8 (33%) by RSST (4-h plasma aldosterone level >140 pmol/L) (P < .001). RSST missed one unilateral, all bilateral, and four with as-yet undetermined subtype. RSST was positive in 7 of 10 (70%) posture-unresponsive vs one of 14 (7.1%) posture-responsive patients (P < .005). CONCLUSION: These preliminary results suggest that seated SST may be superior to recumbent SST in terms of sensitivity for detecting PA, especially posture-responsive forms, and may represent a reliable alternative to FST.

Ambulatory blood pressure monitoring in Australia: 2011 consensus position statement.

OBJECTIVE: Although most national guidelines for the diagnosis and management of hypertension emphasize that the initiation and modification of blood pressure (BP)-lowering treatment should be related to absolute cardiovascular disease (CVD) risk, there is only limited information on how to incorporate ambulatory BP (ABP) monitoring into this framework. The objective of this initiative is to provide ABP equivalents for BP cut-points for treatment initiation and targets to be included into guidelines. METHODS: A critical analysis of the best available evidence from clinical trials and observational studies was undertaken to develop a new consensus statement for ABP monitoring. RESULTS: ABP monitoring has an important place in defining abnormal patterns of BP, particularly white-coat hypertension (including in pregnancy), episodic hypertension, masked hypertension, labile BP and nocturnal or morning hypertension. This consensus statement provides a framework for appropriate inclusion of ABP equivalents for low, moderate and high CVD risk patients. The wider use of ABP monitoring, although justified, is limited by its availability and cost due to the lack of medical subsidy in Australia. However, cost-benefit analysis does suggest a cost-saving in reduced numbers of inappropriate antihypertensive treatments. CONCLUSION: Although clinic measurement of BP will continue to be useful for screening and management of suspected and true hypertension, ABP monitoring provides considerable added value toward accurate diagnosis and the provision of optimal care in uncomplicated hypertension, as well as for patients with moderate or severe CVD risk.

Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: results of a case-control study.

CONTEXT: Animal studies have demonstrated that dietary sodium intake is a major influence in the pathogenesis of aldosterone-induced effects in the heart such as left ventricular (LV) hypertrophy and fibrosis. LV hypertrophy is an important predictor for cardiovascular morbidity and mortality. OBJECTIVE: We aimed to investigate the relationships between aldosterone and dietary salt and LV dimensions in patients with primary aldosteronism (PA). DESIGN AND PARTICIPANTS: This case-control study included 21 patients with confirmed PA and 21 control patients with essential hypertension matched for age, gender, duration of hypertension, and 24-h systolic and diastolic blood pressure. MAIN OUTCOME MEASURES: Patients were evaluated by echocardiography and 24-h urinary sodium (UNa) excretion while consuming their usual diets. RESULTS: Patients with PA had significantly greater mean LV end-diastolic diameter, interventricular septum and posterior wall thicknesses, LV mass (LVM) and LV mass index, and end systolic and diastolic volumes than control patients. UNa significantly positively correlated with interventricular septum, posterior wall thicknesses, and LVM in the patients with PA but not in control patients. In a multivariate analysis, UNa was an independent predictor for LV wall thickness and LV mass among the patients with PA but not in patients with essential hypertension. CONCLUSIONS: These findings emphasize the importance of dietary sodium in determining the degree of cardiac damage in those patients with PA, and we suggest that aldosterone excess may play a permissive role. In patients with PA, because a high-salt diet is associated with greater LVM, dietary salt restriction might reduce cardiovascular risk.

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study.

BACKGROUND: Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. METHODS: We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). RESULTS: Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. CONCLUSIONS: Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.

Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I.

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.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure.

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.

High rate of detection of primary aldosteronism, including surgically treatable forms, after 'non-selective' screening of hypertensive patients.

BACKGROUND: Wide testing of the aldosterone : renin ratio among hypertensive individuals has revealed primary aldosteronism to be common, with most patients normokalaemic. Some investigators, however, have reported aldosterone-producing adenoma to be rare among patients so detected. OBJECTIVE: To test the hypothesis that differences among reported studies in the rate of detection of aldosterone-producing adenoma (as opposed to bilateral adrenal hyperplasia) reflect differences in the procedures used for diagnosis of primary aldosteronism, and the methods used to identify aldosterone-producing adenomas. METHODS: In the newly established Princess Alexandra Hospital Hypertension Unit (PAHHU), we used procedures developed by Greenslopes Hospital Hypertension Unit (which reports that more than 30% of patients with primary aldosteronism have aldosterone-producing adenomas) to diagnose primary aldosteronism and determine the subtype. All patients with an increased aldosterone : renin ratio (measured after correction for hypokalaemia and while the patient was not receiving interfering medications) underwent fludrocortisone suppression testing to confirm or exclude primary aldosteronism; if they were positive, they underwent genetic testing to exclude glucocorticoid-remediable aldosteronism before adrenal venous sampling was used to differentiate lateralizing from bilateral primary aldosteronism. RESULTS: This approach allowed PAHHU to diagnose, within 2 years, 54 patients [only seven (13%) hypokalaemic] with primary aldosteronism. All tested negative for glucocorticoid-remediable aldosteronism. Aldosterone production was lateralized to one adrenal in 15 patients (31%; only six hypokalaemic) and was bilateral in 34 (69%; all normokalaemic) of 49 patients who underwent adrenal venous sampling. Among patients with lateralizing adrenal hyperplasia, computed tomography revealed an ipsilateral mass in only six and a contralateral lesion in one. Fourteen patients underwent unilateral adrenalectomy, which cured the hypertension in seven and improved it in the remainder. In patients with bilateral primary aldosteronism, hypertension responded to spironolactone (12.5-50 mg/day) or amiloride (2.5-10 mg/day). CONCLUSION: When performed with careful regard to confounding factors, measurement of the aldosterone : renin ratio in all hypertensive individuals, followed by fludrocortisone suppression testing to confirm or exclude primary aldosteronism and adrenal venous sampling to determine the subtype, can result in the detection of significant numbers of patients with specifically treatable or potentially curable hypertension.