Diane Cowley

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 >250m/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±7mm 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±1.7dB 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.

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.

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.

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).

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.

Elevated Serum Interleukin 6 Levels in Normotensive Individuals With Familial Hyperaldosteronism Type 1

To the Editor: Experimental and clinical evidence suggests that aldosterone excess is associated with adverse cardiovascular sequelae, including remodeling, fibrosis, left ventricular (LV) dysfunction, stroke, myocardial infarction, and arrhythmias, independent of its effects on blood pressure (BP).1 Although the underlying mechanisms have yet to be fully elucidated, results from animal studies suggest the involvement of inflammatory pathways.1 Familial hyperaldosteronism type 1 (glucocorticoid remediable aldosteronism [FH-1]) is a rare form of primary aldosteronism in which inheritance of a “hybrid” 11β-hydroxylase/aldosterone synthase gene leads to excessive aldosterone production regulated by corticotropin rather than renin-angiotensin.2 Genetic testing has permitted the identification of individuals with FH-1 with biochemical evidence of aldosterone excess but normal BP, providing a unique opportunity to investigate adverse effects of aldosterone excess without the confounding influences of BP elevation. We have reported previously that these individuals have increased echocardiographically measured LV wall thicknesses and reduced LV diastolic function when compared with normotensive controls matched for age, sex, and BP.3 In the current study, we sought evidence in these same individuals of aldosterone-mediated cardiovascular inflammation by comparing their blood levels of 3 markers of inflammation (interleukin 6 [IL-6], osteopontin …

A-001 ALDOSTERONE EXCESS STIMULATES SALT APPETITE IN PATIENTS WITH ALDOSTERONE PRODUCING ADENOMA

Background Salt appetite is a motivated behavioural state that drives animals to seek and ingest foods and fluids that contain sodium. Experimental studies have demonstrated that aldosterone stimulates salt ingestion and some brainstem neurones are specifically aldosterone-sensitive. However, the role of aldosterone in determining salt appetite in humans is unknown. Methods We studied 83 patients with primary aldosteronism (confirmed by positive fludrocortisone suppression test, FST) which lateralized to one adrenal on adrenal venous sampling and who underwent laparoscopic unilateral adrenalectomy (ADX). These patients had repeat FST postoperatively (5.3 ± 3.8 months) to determine biochemical cure of autonomous aldosterone secretion. The very strict FST protocol involves hospital admission, exposure to a high salt diet with additional “Slow Na” (tablets) 30 mmol thrice daily with meals and fludrocortisone 0.1 mg six hourly for four days. We compared pre- and post-operative 24-hour urinary sodium (UNa) collected on the last day (day 4) of FST, using exactly the same protocol, and, in 24 patients, we analyzedUNa collected out of hospital. Results For the 83 patients as a group, systolic and diastolic blood pressure, number of antihypertensive medications, serum sodium, plasma aldosterone concentration and aldosterone/renin ratio decreased while plasma renin and serum potassium and creatinine increased after ADX. Day 4 UNa decreased from 325 ± 77 mmol/day pre-operatively to 273 ± 76 mmol/day (p < 0.0001) postoperatively despite equal salt supplementation. Out of hospital UNa fell from 180 ± 57 to 140 ± 54 mmol/day (p = 0.0022) after ADX. Interestingly, on subgroup analysis, UNa on day 4 FST fell significantly only in patients whose FST after ADX showed biochemical cure of primary aldosteronism (n = 60), but not in those whose FST showed any remaining autonomous aldosterone production (n = 23). Conclusions Aldosterone excess in humans appears to contribute to salt appetite and its correction by ADX seems to reduce salt intake, both on unrestricted and high salt diets. Aldosterone reduction, by adrenalectomy, or aldosterone blockade, by spironolactone, may have the potential effect to reduce salt intake in humans.

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 ± 3.3 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.

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.

OS 33-06 IN PATIENTS WITH PRIMARY ALDOSTERONISM, OBSTRUCTIVE SLEEP APNOEA IMPROVES WITH TREATMENT BY ADRENALECTOMY OR MEDICAL THERAPY.

Objective: Obstructive sleep apnoea (OSA) is known to commonly co-exist with primary aldosteronism (PA), but it is unknown if treatment via mineralocorticoid receptor blockade or adrenalectomy (for aldosterone producing adenoma, APA), improves sleep apnoea parameters in these patients. We therefore aimed to determine if specific medical or surgical treatment of PA improves OSA, as measured by the apnoea hypopnoea index (AHI). Design and Method: Patients undergoing diagnostic workup for PA were recruited if they had symptoms suggestive of OSA. Patients with confirmed PA underwent polysomnography (PSG) at baseline and again at least 3 months after specific treatment for PA. Patients with severe OSA were referred for continuous positive airway pressure (CPAP) and only restudied with PSG if this had not yet commenced at the planned time of restudy. Results: Of 34 patients with PA, 7 (21%) had no evidence of OSA (AHI <5), 9 (26%) had mild (AHI 5 - 15), 8 (24%) moderate (AHI 15 - 30) and 10 (29%) severe OSA (AHI > = 30). Weight, body mass index tertile, and neck circumference correlated with the AHI. 20 patients had repeat PSG performed after treatment for PA (mineralocorticoid receptor antagonists in 13 with bilateral PA and adrenalectomy in 7 with unilateral PA). In this group the median (SD) AHI reduced from 22.5 (14.7) to 12.3 (12.1) (p = 0.018). There was a similar magnitude of fall between surgically and medically treated patients. There was no significant change in patient weight (95.2 kg vs 96.6 kg, p = 0.33; mean change +0.66 kg), however a small but significant reduction in neck circumference occurred (41.6 cm vs 41.2 cm, p = 0.012; mean change −0.56 cm). Conclusions: OSA is common in patients with PA, and improves with specific therapy for this disease. Aldosterone and sodium mediated fluid retention in the upper airways and neck region may be a potential mechanism for this relationship.