Chiara Lonati

Aliskiren: the first direct renin inhibitor available for clinical use.

The idea of blocking the renin-angiotensin system (RAS) with the inhibition of the enzymatic activity of renin has been pursued for half a century, but it became a reality only recently, with the synthesis of aliskiren, the first direct renin inhibitor available for clinical use. The upstream blockade of the system induced by aliskiren, in combination with its unique pharmacological properties (inhibiting potency, high plasma concentration, long half-life and preferential partitioning in the kidney) makes this compound the ideal tool to achieve a complete blockade of the RAS. Consistent with expectations, present evidence indicates that aliskiren, at the licensed dosages of 150-300 mg/day, lowers blood pressure to the same extent as other first-line antihypertensive agents, with the additional advantage of a longer duration of action which persists for several days after the cessation of treatment. Moreover, aliskiren was found to act synergically not only with diuretics but also with other drug classes, including angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. In addition, results of recent clinical trials have shown that aliskiren possesses cardiovascular and renal protective properties which may contribute to the beneficial effects of this drug beyond the reduction of blood pressure. Finally, aliskiren has an excellent, placebo-like tolerability profile, a feature which is very relevant for improving compliance of patients.

Prevalence of type 2 diabetes among patients with hypertension under the care of 30 Italian clinics of hypertension: results of the (Iper)tensione and (dia)bete study.

Background and purpose Hypertension is known to be highly prevalent among patients with diabetes and associated with an increased risk of cardiovascular damage. In contrast, relatively few investigations have addressed the prevalence of diabetes among patients with hypertension. The purpose of the present study was to examine the prevalence of type 2 diabetes, the effectiveness of hypertension and diabetes control and the association with other cardiovascular risk factors and previous cardiovascular diseases in a cohort of patients with hypertension referred to 30 hospital outpatient clinics for the treatment of hypertension. Methods and patients Patients were considered as having diabetes if they were already on an antidiabetic treatment either with diet or medications. All other patients had fasting plasma glucose measured on two separate occasions and were classified as having diabetes if both values were at least 140 mg/dl (7.8 mmol/l) and as not having diabetes if both values were less than 110 mg/dl (6.1 mmol/l). In patients with a single determination of at least 110 mg/dl, the final diagnosis of diabetes was established according to the result of an oral glucose tolerance test. A secondary definition of diabetes was also used, that is two fasting plasma glucose values of at least 126 mg/dl (7.0 mmol/l). In all patients, serum total, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol, fasting serum triglycerides, serum creatinine and urinary albumin were also evaluated. Results and conclusion Among the 1397 recruited patients, 242 (17.3%) were diagnosed as having diabetes according to the primary definition and 244 (17.5%) according to the secondary definition. In 195 out of the 242 (14%), the diagnosis was already known whereas, in the remaining 47 (3.3%), it was made de novo. In 61.4% of those already having diabetes, plasma glucose was at least 140 mg/dl (7.8 mmol/l), whereas only in 8.4% of them was it less than 110 mg/dl (6.1 mmol/l). Patients with diabetes were older, heavier and with a greater familiar predisposition. Patients with diabetes had higher values of systolic blood pressure than individuals without diabetes (150 ± 17 vs. 144 ± 16 mmHg, respectively; P < 0.001), lower high-density lipoprotein cholesterol and higher triglycerides and microalbuminuria. Overall, among patients with hypertension and diabetes, only 3% had blood pressure and HbA1c within the recommended limits. The prevalence of previous cardiovascular disorders was two to three times higher than among individuals without diabetes.

Measurement of plasma renin concentration instead of plasma renin activity decreases the positive aldosterone-to-renin ratio tests in treated patients with essential hypertension

Background: The plasma aldosterone-to-renin ratio (ARR) for the diagnosis of primary aldosteronism is normally calculated with plasma renin activity (PRA) as denominator. However, new direct renin assays that measure plasma renin concentration (PRC) are progressively replacing PRA because these are faster, simpler, and more reproducible. Objective: To assess whether the calculation of ARR with a direct assay (ARRD, ng/dl/mU/l) instead of PRA (ARRP, ng/dl/ng/ml/h) affects the rate of positive tests in patients on liberal antihypertensive treatment. Design and participants: PRA, PRC, and plasma aldosterone concentration (PAC) were measured in 88 patients with essential hypertension, both in the supine position and after 60 min of active standing while on treatment with a variety of antihypertensive medications. The same measurements were carried out, for comparison, in 10 patients with proven aldosterone-producing adenoma. Setting: Single center, outpatient hypertension clinic in a tertiary care hospital. Results: In patients with essential hypertension, median ARRP was 12 (range 0–71) in the supine position and 13 (range 0–80) after standing. The corresponding values of ARRD were 0.4 (range 0.01–3) and 0.5 (range 0.02–7.8). Between ARRP and ARRD, there was a linear, highly significant relationship both in supine and standing position (r = 0.88 and r = 0.92, respectively). Using as threshold of normalcy for ARRP a value less than 30, as it is recommended by guidelines, there were 13 (15%) and 18 (20%) false positives, respectively in supine and standing position, whereas with the threshold of 3.7 for ARRD, there were no false positives in recumbent position and four (5%) after standing. Accordingly, the specificity of ARRP was 0.85 and 0.78 and that of ARRD 1 and 0.95. In 10 patients with primary aldosteronism, median supine ARRP was 298 (range 48–1222) and ARRD 34 (range 2.8–244). Among these patients, no false negatives were found with ARRP and just one with ARRD. Conclusion: The rate of positive tests calculating ARR with PRC is lower than with PRA, the lower rate being found in patients studied in the recumbent position and apparently it is not affected by ongoing antihypertensive treatment.

Clinical management of renovascular hypertension: practical recommendations from the Italian Society of Hypertension (SIIA).

Renovascular hypertension (RVH) is one of the most frequent forms of secondary hypertension but this diagnosis is often missed because of insufficient care taken in collecting patient’s history and clinical signs. Herein we summarize the clinical, instrumental and laboratory clues which should raise the suspicion of RVH. In addition we briefly discuss the available evidence in favour and against the revascularization therapy and, at the light of the uncertain benefit of this procedure, the alternative approach with pharmacological treatment.

Hypertension and Erectile Dysfunction

Erectile dysfunction (ED) is frequently reported by hypertensive patients. The prevalence increases from 30% at the age of 50 years to 50% or more in patients aged over 70 years, i.e. 2-fold higher than that observed in normotensive subjects of the same age. The conventional view holds that ED is an adverse effect of the antihypertensive treatment, but the results of several controlled trials addressing this issue indicate that the incidence of ED is essentially similar in treated and untreated hypertensive patients, suggesting that ED is due to the elevation in blood pressure rather than to its pharmacological reduction. A number of psychological, hormonal and vascular alterations associated with hypertension justify the findings of these observational studies and explain why ED should, at present, be considered as an early marker of cardiovascular risk. However, it is still possible that in specific cases some antihypertensive agents (namely the diuretics and the sympatholytic agents) may contribute to ED, but the more modern drugs such as the calcium antagonists and the antagonists of the renin-angiotensin system are neutral with respect to ED; actually, some recent studies carried out with the sartans suggest that these compounds may ameliorate ED. Finally, there is no evidence that antihypertensive treatment increases the adverse effects of the phosphodiesterase inhibitors recently introduced for the treatment of ED; thus, the use of these drugs is not contraindicated in hypertensive patients.

[OP.1A.03] CORRELATIONS BETWEEN WHITE-COAT EFFECT AND MORNING BLOOD PRESSURE SURGE ON AMBULATORY BLOOD PRESSURE MONITORING.

Objective: White-coat effect (WCE) and morning blood pressure surge (MBPS) are two particular phenomena assessable with ambulatory blood pressure monitoring (ABPM), that could have common pathophysiological mechanisms represented by an hyper-activation of the sympathetic nervous system. Design and method: We examined the relationship between WCE and MPBS in 252 ABPM (M/F 94/158) characterized by WCE, i.e. when the first recorded value was at least 10 mmHg greater than the mean diurnal systolic blood pressure (SBP). In these ABPM we also evaluated WCE duration and WCE magnitude (WCEd and WCEm, respectively represented as number of values at least 10 mmHg greater than mean diurnal SBP multiplied by the interval between recordings and the mean of SBP values both calculated during the first two hours of recording). MBPS was examined as mean of SBP values between 6:00 and 10:00 AM and their increase with respect to mean nocturnal SBP (mNSBP). Results: As expected, we found a progressive decrease of systolic values during the first three hours of recording, expression of WCE (WCEm 148 mmHg, WCEd 65 minutes) and an increase of hourly SBP from 6:00 AM to 10:00 AM (respectively 125, 132, 137 and 140 mmHg) while mNSBP was 124 mmHg. We found a significant but week correlation between mean SBP values of the whole four hours period and in particular with 8:00 – 9:00 AM mean, and WCEm (r = 0.56, r = 0.53; p < 0.01 for both); correlations were even weaker when considering WCEm and hourly increment from mNSBP; whereas the correlation between WCEd and MBPS (hourly increment and mean) were not statistically significant. Figure. No caption available. Conclusions: Our data suggest that WCE and MSBP share only in part the same pathophysiological mechanisms.

Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men

T he first percutaneous transluminal renal angioplasty (PTRA) was performed by Andreas Gruntzig and coworkers in 1978 in a 61 years old woman and yielded a rapid and marked fall in blood pressure associated with some increase in renal blood flow [1]. However, quite soon after that report, it became clear that the expectations of patients undergoing PTRA were not fulfilled always and particularly so for those with atherosclerotic renal artery stenosis (AS RAS). Indeed in one of the first meta-analyses published on this topic [2] reporting the experience of 10 centres, only 88 of 464 (19%) hypertensive patients with AS RAS were cured by renal angioplasty whereas this occurred in 50% of 193 patients with renal artery stenosis due to fibromuscular dysplasia (FMD RAS). In spite of the uncertainties on the benefit of PTRA in controlling blood pressure, the propagation of this procedure continued unrelentingly [3] without undergoing the rigorous scientific scrutiny that is usually applied to assess the benefit of pharmacological treatment. At present PTRA, because of its lower rate of morbidity and mortality, the lower cost and shorter hospitalization has, almost entirely, replaced surgery for treatment of renovascular hypertension (RVH) [4]. Actually, nowadays, the surgical approach is confined to the few cases in which PTRA technically fails or to patients with major atheromatous lesions that require extensive vascular intervention [5]. Until recently only few controlled, relatively underpowered studies have addressed the antihypertensive effects of PTRA in patients with AS RAS [6–8]. In 2009, the results of the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study, the first large randomized controlled trial that compared the blood pressure and renal outcome of hypertensive patients with atherosclerotic

[PP.27.23] IN PATIENTS WITH WHITE-COAT EFFECT DURING AMBULATORY BLOOD PRESSURE MONITORING THE THIRD HOUR VALUES PARTIALLY REFLECT MEAN DIURNAL BLOOD PRESSURE VALUES

Objective: In previous studies we found that the increase in blood pressure (BP) induced by clinical measurement, the so called white coat effect (WCE), is frequently observed also during ambulatory blood pressure monitoring (ABPM). As in these hyperreactive patients performing a full 24-hours examination can be cumbersome, we examined to what extent the mean values of systolic BP collected at the third hour (3hSBP), when WCE tends to wear off, are representative of the mean diurnal systolic BP values (mDSBP). Design and method: In 429 ABPM (M/F 144/285) in which WCE was detected when the first systolic recorded value was at least 10 mmHg higher than mDSBP, we compared 3hSBP and mDSBP assuming a mean value of 135 mmHg as the upper limit of normotension. Results: As expected considering all ABPM there was a progressive decrease of mean values from the first to the third hour of recording (respectively 153, 139 and 134 mmHg) whereas mDSBP was 135 mmHg. Out of the 429 ABPM, 190 (44%) were above this limit with 3hSBP and 206 (48%) for mDSBP. However only 147 (34%) and 180 (42%) were diagnosed respectively as hypertensive or normotensive with both measurements, whereas 43 (10%) of those found hypertensive with 3hSBP were not so with mDSBP and 59 (14%) normotensive with 3hSBP were diagnosed as hypertensive with mDSBP. Thus inspite of the fact that overall there was a significant correlation between 3hSBP and mDSBP (r = 0.72; p < 0.01), 102 (24%) patients had a discordant diagnosis. Figure. No caption available. Conclusions: Although 3hSBP provides some insight on DSBP in patients with WCE, the percent of incorrect diagnoses with 3hSBP is too high to justify the use of 3hSBP as a surrogate of conventional DSBP.

Are the Antagonists of the Renin–Angiotensin System Also Anticancer Agents?

The antagonists of the renin–angiotensin system (RAS) have gained increasing popularity in the last two decades due to their indisputable efficacy in a number of cardiovascular disorders, coupled with an unsurpassed tolerability. However some years ago a partial and non-predefined meta-analysis raised the possibility that angiotensin receptor antagonists in particular may increase the incidence of cancer. This observation, although not confirmed by subsequent, larger analyses, caused a remarkable and understandable concern even outside the medical community. Herein we will summarize the available evidence pro and con the hypothesis of a carcinogenetic activity of RAS antagonists coming to the conclusion that these drugs may actually exert an anticancer action.

ARR screening using IDS-iSYS aldosterone and direct renin: effects of medication in essential and renovascular hypertension, Cushing's syndrome and primary aldosteronism

Background Primary aldosteronism (PA), a more frequent form of secondary hypertension than previously thought, is commonly produced by either an aldosterone-producing adenoma or by adrenal hyperplasia. PA is characterized by elevated plasma levels of aldosterone and suppressed renin secretion. Calculation of the aldosterone-to-renin ratio (ARR) was introduced 30 years ago as a convenient screening test for the diagnosis of PA due to the unique and characteristic profile of aldosterone and renin levels observed in this disorder. The relationship between the ARR and aldosterone values can be used to easily depict subgroup differentiation of primary and secondary hyperand hypoaldosteronism as well as normal subjects (Fig. 1; McKenna et al., 1991). By assessing the levels of plasma aldosterone in relation to ARR, a variety of disorders of the renin-angiotensin-aldosterone axis can be described. Identifying hypertensive patients with PA is crucial for optimizing their treatment. Various medications used to treat hypertension are known to alter levels of aldosterone and renin, thus affecting the ARR. As withdrawing all medication before screening is often unrealistic, we aimed to determine the degree of interference of some commonly used agents on the ARR using assays on the automated IDS-iSYS platform (Boldon, UK).