Background-The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis. Methods and Results-We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and
Background-Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction.Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure. Methods and Results-We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [meanϮSEM]: 181Ϯ19% versus 120Ϯ22% allopurinol versus placebo; Pϭ0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346Ϯ128 nmol/L versus 461Ϯ101 nmol/L, allopurinol versus placebo; Pϭ0.03), consistent with reduced oxidative stress with allopurinol therapy. Conclusions-We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.
Experimental studies have suggested a role for aldosterone and glucocorticoids in the pathogenesis of endothelial dysfunction. We therefore set out to characterize the acute effects of these hormones on vascular function in vivo in normal humans. A randomized, placebo-controlled, double-blind crossover study was performed on 16 healthy male volunteers (aged 19-29 years), examining the vascular effects of acute intravenous aldosterone infusion (12 pmol.min(-1).kg(-1) for 4 h) and of oral prednisolone (single 50 mg dose). Peripheral arterial vascular function was assessed by bilateral forearm venous occlusion plethysmography using two parallel study protocols. In the first protocol, eight subjects received, successively, acetylcholine, sodium nitroprusside, noradrenaline, angiotensin I and angiotensin II. The remaining eight subjects received, successively, acetylcholine, sodium nitroprusside, verapamil and noradrenaline. Aldosterone attenuated endothelium-dependent vasodilatation to acetylcholine as compared with either prednisolone or placebo (maximum vasodilatation: placebo, 357+/-38%; aldosterone, 257+/-21%; P <0.05). However, background endothelium-independent vasodilatation was not affected by either aldosterone or prednisolone. There were also no significant changes in vasoconstriction induced by angiotensin or noradrenaline following aldosterone or prednisolone treatment compared with placebo. Blood pressure and baseline blood flow did not differ between any of the study phases. Thus acute short-term systemic administration of aldosterone results in endothelial vasodilator dysfunction in normal men, providing evidence for an aldosterone-induced vasculopathy, which may be particularly relevant not only in heart failure but also in hypertensive patients with high aldosterone/renin ratios.
Vascular AI/AII conversion reactivates over time during chronic ACE inhibitor therapy even if the CHF disease process is clinically stable. It also occurs as the CHF disease process progresses. Even if vascular AI/AII conversion has reactivated, it can be suppressed by increasing the dose of the ACE inhibitor.
Abstract-The effect of salt on blood pressure (BP) is controversial. A more important question is whether salt can produce cardiac target-organ damage, irrespective of its effect on BP. We assessed the effect of salt with fludrocortisone on QT dispersion and echocardiographic left ventricular diastolic function in a prospective interventional study involving 29 hypertensive subjects with a raised aldosterone/renin ratio who were hospitalized for investigation of possible primary aldosteronism. Each subject over 4 days was given a total of 28.8 g (480 mmol) of sodium chloride and 1.5 mg of fludrocortisone with potassium supplementation. Baseline and posttreatment 12-lead ECGs and echocardiograms were obtained. There were no significant changes in body weight, pulse rate, or BP after treatment with salt and fludrocortisone. Plasma sodium was significantly increased from 141.4 (SD 2.1) to 142.6 (SD 2.4) mmol/L (Pϭ0.001).QT and QTc dispersion both significantly increased: ϩ19.6 (SD 16.5) ms (95% CI, 13.4 to 25.9) (PϽ0.001) and ϩ19.8 (SD 20.9) ms (95% CI, 11.8 to 27.7) (PϽ0.001), respectively. There were no significant changes in (nϭ15) Key Words: sodium Ⅲ fludrocortisone Ⅲ hypertension Ⅲ QT dispersion Ⅲ diastole T he etiologic importance of sodium chloride (salt) in the genesis or maintenance of hypertension remains controversial. Salt is, however, an independent predictor of left ventricular hypertrophy (LVH), 1 which raises the intriguing possibility that salt can damage target organs independently of its effects on blood pressure (BP). In general, confusion about the role of salt may well have arisen for 2 reasons. First, only certain subpopulations of hypertensive patients may be harmed by excess salt. Second, to this point most studies have examined whether salt alters BP per se rather than whether salt adversely affects the target organs independently of any effect on BP. In the present study we examined the effect of salt on QT dispersion and on left ventricular (LV) diastolic function in patients with relative aldosterone excess. QT dispersion is thought to be an index that represents the degree of inhomogeneity of cardiac electric repolarization. QT dispersion Ͼ80 ms has been reported to be a potent prognostic marker of sudden cardiac death in hypertension. 2 The diagnostic test of salt loading with the addition of low-dose fludrocortisone is used in hypertensive subjects who have a raised aldosterone/renin ratio (ARR) to look for evidence of autonomous aldosterone production, as occurs in primary aldosteronism. Patients undergoing this routine procedure provided us with a susceptible group in whom to test our hypothesis that salt could worsen QT dispersion and LV diastolic relaxation. Patients with raised ARR have inappropriate aldosterone activity, 3 and animal studies 4 suggest an important interaction between excess salt and excess aldosterone in producing target-organ damage in the heart. Methods Subject SelectionAll hypertensive patients referred to our center had blood samples taken for plasma renin...
Objectives: To test whether simply increasing plasma potassium with amiloride would exert any of the same beneficial effects on "surrogate outcome measures" that are seen with spironolactone. The latter has been shown to improve mortality in chronic heart failure, possibly as a result of improvements in endothelial dysfunction, vascular angiotensin converting enzyme (ACE), autonomic function, myocardial fibrosis, ventricular arrhythmias, and QT interval indices. Design: Randomised, placebo controlled trial. Setting: Teaching hospital. Patients and interventions: Double blind crossover study involving 10 patients with New York Heart Association functional class II-III chronic heart failure comparing 5 mg/day amiloride (one month) with placebo. Main outcome measures: Endothelial function, vascular ACE, collagen markers, 24 hour ECG, and QT interval results. Results: The amiloride induced increase in serum potassium (0.4 mmol/l) did not significantly change endothelial dysfunction, vascular ACE, collagen markers, or heart rate variability. However, amiloride significantly improved QT interval indices, reducing both QT dispersion (from 65.7 ms to 50.9 ms, p = 0.001) and mean maximal corrected QT (from 445 ms to 435 ms, p = 0.008). Amiloride also reduced ventricular extrasystoles (p < 0.05). Conclusions: Amiloride shortens QT interval length and reduces ventricular extrasystoles in chronic heart failure, implying that this effect is caused by potassium retention per se. However, unlike spironolactone, amiloride did not improve endothelial dysfunction, vascular ACE, heart rate variability, or myocardial fibrosis, implying that spironolactone improves these latter effects by aldosterone blockade rather than by simply increasing serum potassium. Therefore, amiloride has fewer beneficial mechanistic effects than spironolactone, but it does share with spironolactone the ability to shorten the QT interval and reduce ventricular extrasystoles. R ecently RALES (randomized aldactone evaluation study) showed a significant 30% survival advantage in patients with chronic heart failure (CHF) receiving spironolactone compared with placebo.1 Mechanisms that may contribute to this mortality benefit in CHF include spironolactone's ability to improve endothelial dysfunction, to suppress vascular angiotensin converting enzyme (ACE), to reduce myocardial fibrosis, to improve heart rate variability (HRV), to reduce QT interval length and dispersion, and to reduce ventricular extrasystoles. 2-5Interestingly, a recently published retrospective analysis of SOLVD (studies of left ventricular dysfunction) focusing specifically on diuretic use showed that potassium losing diuretics were associated with increased risk of arrhythmic death but potassium sparing diuretics were not. 6 We recently also found a beneficial effect of potassium sparing diuretic use on mortality in patients with CHF.7 Amiloride, triamterene, and spironolactone are all potassium sparers but spironolactone has the added effect of blocking aldosterone. In both of the above ...
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 mm Hg and 155/95 mm Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments
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