P.O. Lim

High prevalence of primary aldosteronism in the Tayside hypertension clinic population.

Primary aldosteronism (PA) was thought to be rare but recent evidence from Australia suggests that it may be more common. As this has important implications in terms of hypertension management, we undertook to screen for this treatable condition in our hypertension clinic. We obtained blood samples in sequential patients referred for assessment in our hypertension clinic in Tayside for plasma renin activity (PRA) and aldosterone. The aldosterone to PRA ratio (ARR) was used as an initial screening test to identify potential patients with PA. Those patients with an elevated ratio (⩾750) were admitted for the salt loading and fludrocortisone suppression test. These patients also underwent adrenal CT scanning, and in selected patients, adrenal scintigraphy. Between May 1995 and January 1997 (21 months), we screened a total of 495 patients. ARR was available in 465 (93.9%) patients. Out of that number, 77 (16.6%) had an elevated ratio of ⩾750, five of whom had an adrenal adenoma (one had previous adrenalectomy). Forty-five of these patients were admitted for the salt loading and fludrocortisone suppression test with 41 positive test results suggesting PA. One patient with a negative salt loading test result however had an adenoma proven on histology. A total of 43 cases of PA were identified, giving a minimum prevalence of 9.2% (43/465). Potentially the prevalence may be up to 15% assuming that the ARR has a sensitivity of 93% (42/45) in predicting PA. In conclusion, about one in 10 patients attending a hypertension clinic may have PA. This suggests that the prevalence of PA in Tayside is as high as that in the Australian hypertensive population, and this is likely to be true elsewhere, with obvious important implications for hypertension management.

Is aldosterone the missing link in refractory hypertension?: aldosterone-to-renin ratio as a marker of inappropriate aldosterone activity.

Use of the random aldosterone-to-renin ratio (ARR) as a reliable marker of inappropriate aldosterone activity has led to primary aldosteronism (PA) being increasingly diagnosed in hypertensive patients. At least 10% of hypertensives have been found to have PA, the majority of whom presumably have bilateral adrenal hyperplasia or idiopathic hyperaldosteronism as an aetiology for PA. Whilst these patients clearly have excess aldosterone activity, they have in common many features that are found in hypertensive patients in general, amongst which include heightened angiotensin II adrenal sensitivity. Whether these individuals belong within the spectrum of ‘essential hypertension’ is being debated, but is probably irrelevant clinically since they appear to respond favourably to spironolactone treatment. In addition, there is recent evidence suggesting that these patients overexpress a key enzyme involved in aldosterone production, the aldosterone synthase, the activity of which appears to relate to its genotypic variation.

Left atrial size and function: assessment using echocardiographic automatic boundary detection.

OBJECTIVE--To evaluate the waveforms of left atrial area changes obtained by automated boundary detection with newly developed acoustic quantification technology. DESIGN--All subjects had measurements of left atrial areas taken in the apical four chamber, parasternal long axis, and parasternal short axis views using both conventional echocardiographic methods and automatic boundary detection on two occasions separated by at least a week. On the second visit measurements were also repeated in healthy volunteers after acute intravenous volume loading with 1 litre of saline over 2-5 minutes. SETTING--A university medical school echocardiographic laboratory. SUBJECTS--12 healthy male volunteers and 8 patients with cardiac disease (5 with congestive heart failure, 1 with mitral stenosis, and 2 with hypertensive left ventricular hypertrophy, and dilated left atria). RESULTS--There was close correlation between conventionally derived left atrial areas and those obtained by automatic boundary detection, particularly in the apical four chamber view (r = 0.98). Both inter and intra observer variabilities (coefficient of variation) for left atrial areas measured by automatic boundary detection were good (4.7-14.2% and 8.1-18.6% respectively). The reproducibility (coefficient of variation) for derived indices of left atrial function, however, was much poorer (10.4-104.8% and 12.5-88% respectively). After acute volume loading significant increases in left atrial area were observed at all stages in the cardiac cycle. CONCLUSIONS--These data demonstrate that although the reproducibility of left atrial functional indices is poor, instantaneous left atrial cavity measurements with automatic boundary detection are reproducible. This suggests that automatic boundary detection may assist in serial non-invasive measurement of left atrial size to assess disease states and treatments.

Aldosterone to renin ratio as a determinant of exercise blood pressure response in hypertensive patients.

Aldosterone to renin ratio (ARR) is a marker of inappropriate aldosterone activity in hypertension. Since aldosterone may adversely affect vascular compliance, we hypothesised that the ARR would relate to exercise blood pressure (BP) responses in hypertension. Blood sampling was done in untreated hypertensives for plasma renin activity (PRA, ng/mL/hr) and plasma aldosterone (PA, pmol/L). ARR was derived by dividing the PA value by the PRA value, and this index was normalised by natural logarithm (lnARR) for further analyses. Each patient underwent 24-h ambulatory BP (ABP), and a 3-min submaximal exercise test using the Dundee Step Test. The Spearman rank correlation coefficients between lnARR and office BP (OBP), ABP and exercise BPs and BP changes estimated during exercise were assessed. A total of 119 (66 males) hypertensive subjects aged 48 (s.d. 12) years were studied. The respective OBP, ABP, exercise BP and the change in exercise BP were 167(23)/105(11), 140(15)/87(10), 189(26)/107(12) and 25(15)/2(9)u2009mmHg. lnARR was significantly correlated with exercise systolic BP (r = 0.24, P < 0.001), exercise diastolic bp (r = 0.23, P < 0.05), systolic abp (r = 0.22, P < 0.05) and systolic obp (r = 0.19, P < 0.05). in a multiple regressional analysis controlling for age and sex and all other bp measurements to assess the relative strengths of correlation between all the bp indices with lnarr, only exercise systolic bp (P = 0.012) and the change in systolic BP during exercise (negatively, P = 0.013) emerged as significant independent predictors of lnARR. In conclusion, there was an independent and significant correlation between ARR and exercise systolic BP.

Blood pressure determinants of left ventricular wall thickness and mass index in hypertension: comparing office, ambulatory and exercise blood pressures

Left ventricular (LV) mass relates positively and continuously to cardiac mortality and thus its regression is a rational therapeutic aim. Whilst the office blood pressure (BP) relates poorly to LV mass, it was unclear whether the 24-h ambulatory BP or the exercise systolic BP (ExSBP) was the stronger correlate of LV structural indices. We studied 49 hypertensive patients with a mean age of 45 (s.d. 12) years with a mean body mass index of 27.1(3.9) kg/m2. The mean (s.d.) of office BP, ambulatory BP and ExSBP measured at the end of the first three stages of Bruce protocol treadmill exercise I, II and III were 161(20)/99(10), 140(13)/89(10), 190(30), 198(30) and 201(33) mmu2009Hg respectively. The LV indices measured echocardiographically were LV septal thickness (IVSd) (1.1(0.2) cm), LV posterior wall thickness (LVPWd) (1.0(0.1) cm) and LV mass indexed to body surface area (LVMI) (123(30) g/m2). Age and gender (male) had the highest correlations with the LV indices. Of the BP measures, the stage II ExSBP’s correlation with the LV indices was consistently higher than all other ExSBP, office systolic BP and 24-h systolic ambulatory BP. In a stepwise multiple regression analysis on IVSd, after adjusting for age and gender, the stage II ExSBP was independently associated with IVSd (β= 0.018 (s.e. 0.008), P = 0.024). When only BP measures were considered as explanatory variables only stage II ExSBP was a significant predictor (P = 0.0001) of IVSd as was the case with LVPWd (P = 0.006) and LVMI (P = 0.0008). Submaximal exercise BP measured at a workload comparable to physical activity encountered in daily life correlated more closely with the left ventricular wall thickness and mass. The exercise BP should perhaps be normalised in hypertension management to optimise regression of LV hypertrophy.

Is there a role for renin profiling in selecting chronic heart failure patients for ACE inhibitor treatment

BACKGROUND It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation. OBJECTIVE To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin. DESIGN Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59–82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA ⩽u20091.5 ng/ml/h, nu2009=u200911); normal (1.5u2009<u2009PRAu2009<u20095, nu2009=u200914); and high (PRA >u20095, nu2009=u200913). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status. RESULTS There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66.3 (18.9) mmol/l; pu2009=u20090.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (pu2009=u20090.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (−9.6%, pu2009=u20090.335) following ACE inhibition in this subgroup of patients. CONCLUSIONS About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn.

Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction.

The vascular endothelium maintains a relatively vasodilated state via the release of nitric oxide (NO), a process that could be disrupted by hyperhomocysteinaemia. Since endothelial dysfunction is associated with increased systemic vascular resistance that is the hallmark of sustained arterial hypertension, we hypothesised that in patients with both hypertension and coeliac disease with hyperhomocysteinaemia (via malabsorption of essential cofactors), treatment of the latter disease could improve blood pressure (BP) control. A single patient with proven sustained hypertension and newly-diagnosed coeliac disease had baseline and post-treatment BP and endothelial function assessed by ambulatory BP monitoring (ABPM) and brachial artery forearm occlusion plethysmography respectively. This 49 year-old woman had uncomplicated sustained hypertension proven on repeated ABPM carried out 6 weeks apart (daytime mean 151/92 mmu2009Hg and 155/95 mmu2009Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments revealed raised homocysteine levels with low normal vitamin B12 level. It was likely that she had impaired absorption of essential cofactors for normal homocysteine metabolism. She adhered to a gluten-free diet and was give oral iron, folate and B6 supplementations as well as B12 injections for 3 months. Her BP had improved by 6 months and normalised by 15 months (daytime ABPM mean 128/80 mmu2009Hg). There was parallel restoration of normal endothelial function with normalisation of her homocysteine levels. These observations suggest that sub-clinical coeliac disease related hyperhomocysteinaemia might cause endothelial dysfunction, potentially giving rise to a reversible form of hypertension. In addition, this case study supports the notion that irrespective of aetiology, endothelial dysfunction may be the precursor of hypertension. This highlights the need to resolve co-existing vascular risk factors in patients with hypertension.

Dundee step test: a simple method of measuring the blood pressure response to exercise.

The exercise systolic blood pressure (BP) response provides prognostic information over and above that of resting clinic BP in both normotensive and hypertensive individuals. We have developed a 3-min step test as a method of measuring the exercise systolic BP. Healthy volunteers and patients referred for assessment of hypertension took part in validating this exercise test. We assessed the reproducibility of the exercise systolic BP response, and this was compared with that obtained using the cycle ergometry at an equivalent workload. We also compared the baseline characteristics, BP profiles and exercise systolic BP responses in different subject groups. The intra-observer coefficient of variation assessed in 25 subjects was 5.9% with a mean difference of 1.8 mmu2009Hg. The values for between observer were 8.3% and 2.5 mmu2009Hg respectively. Exercise systolic BP measured with the step test correlated with that of cycle ergometer (n = 37, r = 0.93, P < 0.01). exercise systolic bp data from healthy volunteers (n = 107) showed a normal distribution. An exercise systolic BP of ⩾180 mmu2009Hg was greater than 2 standard deviations from the mean and was taken as an abnormally high BP during exercise. There was a positive correlation between exercise BP and increasing age in healthy volunteers (r = 0.57, P < 0.01). this was also present in hypertensive subjects (n = 46, r = 0.48, P = 0.001), however the slope of this relationship was twice as steep as in the normal subjects. Hypertensive subjects with high exercise systolic BP had significantly higher clinic BP, ABPM and a greater BP rise during exercise. The Dundee step test is quick, reproducible and may be prognostically useful.

How well do office and exercise blood pressures predict sustained hypertension? A Dundee Step Test Study.

Exercise systolic blood pressure (BP) appears to be a better predictor of cardiac mortality than casual office BP. We tested whether this could be explained by exercise systolic BP being a better predictor of sustained hypertension than casual office BP. Exercise systolic BP was measured using the lightweight 3-min single stage, submaximal Dundee Step Test in 191 consecutive subjects (102 male, age 52 (s.d. 13) years) who were referred to a specialist hypertension clinic for assessment. Exercise systolic BP was compared with office BP and daytime ambulatory BP (ABP). Sustained hypertension was defined as a mean daytime systolic and/or diastolic ABP of ⩾140/90 mmu2009Hg. Receiver operating characteristic (ROC) curves of exercise systolic BP and office BP in predicting sustained hypertension were compared. The positive predictive value of office diastolic BP ⩾90 mmu2009Hg and office systolic BP ⩾140 mmu2009Hg for sustained hypertension were 64% and 67% respectively. However, exercise systolic BP ⩾180 mmu2009Hg had a positive predictive value of 76%. Twenty-two percent (42/191) of subjects had an exercise systolic BP rise to ⩾210 mmu2009Hg, and 93% of this group had sustained hypertension on ABP. Whilst exercise systolic BP was a better predictor of sustained hypertension using currently recommended office BP treatment thresholds, the ROC curves of these indices were not different. In a multiple regression analysis, exercise systolic BP was an independent predictor of sustained hypertension, accounting for 36% of the variance of daytime systolic ABP after adjusting for age, gender and antihypertensive drug treatment. In conclusion, exercise systolic BP was a marginally better predictor of sustained hypertension than office BP. This may partly explain why exercise systolic BP is a potent predictor of cardiac mortality.

Exercise blood pressure correlates with the maximum heart rate corrected QT interval in hypertension.

Submaximal exercise systolic blood pressure (ExSBP) is a recognised predictor of cardiac mortality. This study examined the possibility that this might be related to increased QT dispersion or prolonged maximum QTc interval (QTcmax). Twenty-nine untreated hypertensive subjects were assessed. Each subject underwent an echocardiographic examination and a 24-h ambulatory blood pressure (ABP). ExSBP was measured during a 3-min lightweight submaximal Dundee step test. In multiple regressional analyses, only left ventricular mass index significantly predicted QT dispersion (R2 = 22.4%, P = 0.018) and QTc dispersion (R2 = 25.3%, P = 0.012). However, with respect to QTcmax, ExSBP (R2 = 21.6%, P = 0.02) emerged as the sole significant predictor of this index. Five (17.2%) out of the 29 subjects had prolonged QTcmax ⩾ 430u2009ms and these subjects were not differentiated by 24-h ABP (146 (s.d. 21)/83 (16) vs 140 (14)/88 (11) mmu2009Hg, P = Ns) but by ExSBP (226 (15) vs 188 (24) mmu2009Hg, P = 0.002). In conclusion, systolic blood pressure measured during exercise correlated with QTc max in hypertension. This finding may partly explain the prognostic value of exercise blood pressure.