Volume 5, Number 3, September 2004

PAPERStatin therapy increases vascular sensitivity to angiotensin II in hypercholesterolaemic patients
Justein SN Sim, John BC Dick, Allan D Struthers

Introduction: Cross-talk between various cardiovascular risk factors has been suggested by a number of studies. This study examines the interaction between hypercholesterolaemia and the renin-angiotensin system in vivo in man.
Methods: We performed a randomised, placebo-controlled, double-blind crossover study on 40 hypercholesterolaemic patients, comparing cholesterol-lowering therapy with a statin for six months versus placebo. Brachial artery function was assessed by bilateral venous occlusion plethysmography using intra-arterial infusions of the endothelial-dependent vasoconstrictors, angiotensin I (Ang I) and angiotensin II (Ang II), to measure vascular angiotensin-converting enzyme (ACE) and Ang II receptor response respectively. The endothelial-independent vasoconstrictor, noradrenaline, was used as a control vasoconstrictor. Results were analysed by multiple analysis of variance and statistical significance was taken as a p value <0.05.
Results: Cholesterol-lowering treatment with a statin significantly reduced the mean total cholesterol level to 5.71 mmol/L vs. 7.57 mmol/L on placebo (p<0.0001). Hypercholesterolaemia significantly increased the vasoconstriction response to noradrenaline (placebo versus statin treatment; p=0.046). In hypercholesterolaemia, there was a strong trend towards a reduction in the vasoconstriction response to Ang I (placebo versus statin treatment; p=0.089). In hypercholesterolaemia, the vasoconstriction response to Ang II was significantly reduced (placebo versus statin treatment; p=0.01).
Conclusions: Our in vivo results show that, unlike some other previous work, hypercholesterolaemia is associated with down-regulation of the vasoconstrictor response to Ang II and that statin therapy up-regulates the local vasoconstrictor response to Ang II. The possibility now arises that, in man, statins alter the balance between AT₁-receptors and AT₂-receptors.

JRAAS 2004;5:109-113.

POPULAR
TOPICPAPERPrevention of recurrences in patients with lone atrial fibrillation. The dose-dependent effect of angiotensin II receptor blockers
Antonio H Madrid, Irene Marín Marín, Carlos Escobar Cervantes, Enrique Bernal Morell, Jaime Escudero Estévez, Gerardo Moreno, Jorge Rondón Parajón, Jian Peng, Lilianna Limón, Sebastian Nannini, Concepción Moro

Background: Atrial fibrillation (AF) leads to the activation of the renin-angiotensin system (RAS), which seems to play an important role in atrial remodelling. It is not known yet whether RAS blockade may prevent recurrences in patients with lone AF.
Methods and results: Patients with an episode of persistent AF for >7 days, in the absence of cardiac or extracardiac causes and with normal blood pressure values (‘lone AF’), were recruited. Ninety patients were randomised and scheduled for electrical cardioversion. Three groups of patients were compared: Group I was treated with amiodarone 400 mg daily (30 patients), group II was treated with amiodarone 400 mg daily plus irbesartan 150 mg daily (30 patients) and group III with amiodarone 400 mg daily plus irbesartan 300 mg daily (30 patients). The primary endpoint was the time to a first recurrence of AF. The patients were cardioverted and followed. The Kaplan-Meier analysis of time to first recurrence during the follow-up period showed that patients treated with amiodarone 400 mg plus irbesartan 300 mg had a greater probability of remaining free of AF (77% vs. 52% for amiodarone and 65% for amiodarone+irbesartan 150 mg), hazard ratio for a recurrence in group III: 0.47 (95% CI 0.27–0.82; p=0.001).
Conclusions: The combination of irbesartan plus amiodarone decreased the rate of AF recurrences, with a dose-dependent effect, in lone AF patients.

JRAAS 2004;5:114-120.

POPULAR
TOPICPAPERBNP and ANP as diagnostic and predictive markers in heart failure with left ventricular systolic dysfunction
Luiz Menezes Falcão, Fausto Pinto, Luciano Ravara, Peter Adriaan van Zwieten

Background: The prevalence of chronic heart failure (CHF) with systolic dysfunction is increasing. Plasma natriuretic peptides have been envisaged as diagnostic and predictive markers.
Aims: To investigate the relationship between the levels of B-type natriuretic peptide (BNP) and A-type natriuretic peptide (ANP) and the clinical and functional parameters of CHF in outpatients with CHF at baseline, compared with normal healthy controls; to find out the differences in a randomised controlled trial between patients treated with an angiotensin-converting enzyme (ACE) inhibitor, captopril, or an angiotensin receptor blocker (ARB), irbesartan. These differences were assessed throughout the six-month treatment period and at the sixth month.
Methods: Plasma BNP (pmol/L) and ANP (pmol/L) were determined in 68 hypertensive patients with dilated cardiomyopathy, NYHA class III-IV and ejection fraction (EF) <40%, and in 26 normal controls. Statistical analysis for BNP and ANP was done by Student’s t-test. The patient group was randomly subdivided into two subgroups of 34 patients, each treated with either an ARB, irbesartan, or an ACE inhibitor (ACE-I), captopril. BNP and ANP were measured in both subsamples and correlated with clinical, functional and neurohormonal parameters throughout a follow-up period of six months and at the sixth month.
Results: The mean EF in the patient sample was 33.43±6.52% and in the controls was 61.96 ±3.53% (p=0.000). The mean BNP (pmol/L) in patients was 44.78±54.36 and in the controls was 7.12±8.28 (p=0.000) and the mean ANP (pmol/L) was 30.32±25.97 in patients and 11.18±7.92 in controls (p=0.000). A statistically significant difference was found between patients and healthy controls. Significant correlations were found between natriuretic peptides and EF. Between the baseline phase and the sixth month, BNP and ANP decreased significantly in the ARB group. At the sixth month, both BNP and ANP were lower in the ARB group. Evidence of clinical benefit was found with both ARB or ACE-I treatment throughout the six months, with patients moving from classes III and IV to class II NYHA. Improvement of EF was also found, with transition of patients with lower EF (even <30%) to higher values. EF was higher in the ARB group at the sixth month.
Conclusions: BNP and ANP can be useful diagnostic tools in hypertensive CHF patients with moderate-to-severe LV dysfunction. The decrease in BNP and ANP in the ARB group throughout six months, as well as the lower value at the sixth month, suggest a prognostic value of these parameters.

JRAAS 2004;5:121-129.

PAPERVascular effects of quinapril completely depend on ACE insertion/deletion polymorphism
Adriaan A Voors, Peter P van Geel, Margreeth Oosterga, Hendrik Buikema, Dirk J van Veldhuisen, Wiek H van Gilst

Introduction: The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described.
Materials and methods: In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries.
Results: In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2±5.11% [n=13] vs. 55.6±4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar between DD- and ID/II-genotype (59.6±9.19% [n=8] vs. 57.7±4.07% [n=35]; p=0.85).
Conclusions: DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.

JRAAS 2004;5:130-134.

PAPERAngiotensin II may mediate apoptosis via AT₁-receptors in the rat cardiac conduction system
Uraporn Vongvatcharanon, Surapong Vongvatcharanon, Nisaudah Radenahmad, Pornpimol Kirirat, Pranom Intasaro, Prasert Sobhon, Terry Parker

Introduction: Apoptosis and angiotensin II (Ang II) have been suggested as possible causes of arrhythmias. In addition, Ang II via Ang II type I (AT₁-) receptors, has been demonstrated to induce cardiomyocyte apoptosis. The transgenic m(Ren-2)27 (TG) rat carries the additional Ren-2 gene, the expression of which results in an increase in cardiac Ang II, thus potentially affecting the cell growth/death equilibrium. In this study we have investigated the effect of Ang II, via AT₁-receptors, on mediating apoptosis in a cardiac conduction system (SA node and AV nodes).
Materials and methods: Heart sections from male two-day, one-week and two-week TG and Sprague-Dawley (SD) rats were stained with Masson Trichrome to localise the SA and AV nodes. The sections containing SA or AV nodes were processed for quantitation of apoptotic nuclei and AT₁-receptors.
Results: The number of apoptotic nuclei/mm² in the SA and AV nodes were found to decrease from two days to two weeks in both the TG and the SD rats, and the number of apoptotic nuclei/mm² in the TG groups was significantly higher than that of the SD groups for all ages (p<0.05). The number of AT₁-receptors/mm² in the SA node were found to decrease with increasing age, whereas the number of AT₁-receptors/mm² in the AV node was increased in both TG and SD rats and the number of AT₁-receptors/mm² in the three TG groups was significantly more than that of the three SD groups (p<0.05).
Discussion and conclusion: As a consequence of the additional renin gene in the TG rats, which results in the alteration of the local renin-angiotensin system, the numbers of AT₁-receptors/mm² and apoptotic nuclei/mm² are increased. The number of apoptotic nuclei/mm² and AT₁-receptors/mm² in the SA node decrease with maturation, whereas, the number of AT₁-receptors in the AV node increase. Thus, there may be a correlation between Ang II and apoptosis in the SA node, which does not appear to be present in the AV node.

JRAAS 2004;5:135-140.

PAPERHow different urinary albumin excretion rates can predict progression to nephropathy and the effect of treatment in hypertensive diabetics
DE Huw Llewelyn, Juan Garcia-Puig

Hypothesis: The efficacy of a treatment in a clinical trial depends in part on where the cut-off point is placed for the test result used to select patients for the trial, and this applies to irbesartan in the Irbesartan Microalbuminuria II (IRMA II) trial for preventing nephropathy.
Patients and methods: Patients in the IRMA II trial were stratified into different pre-treatment albumin excretion rate (AER) ranges to compare the proportion of patients starting in these different ranges (i) that progressed to develop nephropathy within 24 months and (ii) whose AER was over 40 µg/minute at three months.
Results: The proportion of patients with pre-treatment AER values between 20 and 40 µg/minute progressing to develop nephropathy was 1.25% in the placebo group and 0.78% in the irbesartan group, while for pre-treatment AER values between 41 and 200 µg/minute, 24.4% and 11.2% develop nephropathy respectively in the placebo and irbesartan groups. In patients with a pre-treatment AER of 20 to 30 µg/minute, 32.5% and 13.6% respectively in the placebo and irbesartan groups had a value exceeding 40 µg/minute at three months.
Conclusions: The data demonstrate that irbesartan is effective in reducing the onset of nephropathy within two years when the pre-treatment AER is above 40 µg/minute, but if the AER is below this level it progresses unusually to nephropathy within two years. Irbesartan also slows progression of AER to over 40 µg/minute for patients with pre-treatment AER values at or above 20 µg/minute and these patients should be treated.

JRAAS 2004;5:141-145.

POPULAR
TOPICPAPERRenin-angiotensin system blockade prevents the increase in plasma transforming growth factor ?1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat
Arie Erman, Semyon Veksler, Uzi Gafter, Geoffrey Boner, Clara Wittenberg, David Jonathan van Dijk

Introduction: Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor ?1 (TGF-?1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-?1 in diabetic rats.
Materials and methods: Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.
Results: Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-?1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-?1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).
Conclusions: Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-?1.

JRAAS 2004;5:146-151.

EDITORIAL REVIEWThe VALUE trial: a commentary
Peter Sever

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial compared coronary heart disease outcome in two anti-hypertensive treatment strategies based on either an angiotensin receptor blocker, valsartan, or a calcium channel blocker (CCB), amlodipine. In both patient groups a diuretic was added, if necessary, in an attempt to achieve blood pressure (BP) goals. Follow-up of over 15,000 patients was maintained for 4.2 years. There were no differences in the primary composite endpoint of cardiac morbidity and mortality (which included interventional procedures, hospitalised heart failure, non-fatal myocardial infarction and fatal coronary heart disease, however myocardial infarction and stroke events occurred less commonly on amlodipine than on valsartan – the former achieving statistical significance [p=0.02 and p=0.08 respectively]). There was a non-significant excess of hospitalised heart failure on amlodipine (p=0.012). However, lower BPs early in the trial probably accounted for most of the observed benefits in favour of the CCB. The angiotensin receptor blocker arm was associated with less new onset diabetes.
The results of VALUE add further support to the evidence that blood pressure control is the major determinant in outcome in trials of antihypertensive therapy.

JRAAS 2004;5:99-101.

POPULAR
TOPICEDITORIAL REVIEWArterial stiffness and the renin-angiotensin-aldosterone system
Azra Mahmud, John Feely

Arterial stiffness has recently been recognised as an independent risk factor for cardiovascular morbidity and mortality in hypertension. Many of the complications seen with angiotensin II (Ang II) excess or hyperaldosteronism – an increased event rate, left ventricular hypertrophy, endothelial dysfunction and target organ damage – are also associated with arterial stiffness. It is possible that reduced arterial compliance may be one mechanism whereby increased activity of the renin-angiotensin-aldosterone system (RAAS) produces adverse vascular effects. Common pathophysiological processes, altered collagen turnover and increased fibrosis may underlie both arterial stiffness and RAAS-associated vascular damage.
While it is recognised that patients with hyperaldosteronism have increased arterial stiffness, the role of the RAAS in modulating arterial compliance in essential hypertension and in normotensive subjects is less clear cut. There is, however, more consistent data which show that drugs that interfere with Ang II or aldosterone, namely angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists, all reduce arterial stiffness. In many cases, this is to a greater extent than predicted from the extent of reduction in blood pressure (BP), suggesting a role for RAAS in vascular stiffness in hypertensive subjects. There is also evidence that combined ACE inhibitors (ACE-Is) and ARBs may have an additive effect in reducing stiffness. The reduction in cardiovascular mortality in end-stage renal disease patients treated with ACE-Is was preferentially seen in those who had reduced arterial stiffness. These data suggest that, in addition to regulation of vascular biology and BP, the RAAS is an important determinant of arterial stiffness in health and, more particularly, in disease.

JRAAS 2004;5:102-108.