Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long-term cardiac monitoring. METHODS: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis. RESULTS: Eighty-five patients were monitored for a mean of 569 days (SD ±310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD ±48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). CONCLUSIONS: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF.

Brain angiotensin receptors and sympathoadrenal regulation during insulin-induced hypoglycemia.

Simultaneous blockade of systemic AT1 and AT2 receptors or converting enzyme inhibition (CEI) attenuates the hypoglycemia-induced reflex increase of epinephrine (Epi). To examine the role of brain AT1 and AT2 receptors in the reflex regulation of Epi release, we measured catecholamines, hemodynamics, and renin during insulin-induced hypoglycemia in conscious rats pretreated intracerebroventricularly with losartan, PD-123319, losartan and PD-123319, or vehicle. Epi and norepinephrine (NE) increased 60-and 3-fold, respectively. However, the gain of the reflex increase in plasma Epi (Deltaplasma Epi/Deltaplasma glucose) and the overall Epi and NE responses were similar in all groups. The ensuing blood pressure response was similar between groups, but the corresponding bradycardia was augmented after PD-123319 (P < 0.05 vs. vehicle) or combined losartan and PD-123319 (P < 0.01 vs. vehicle). The findings indicate 1) brain angiotensin receptors are not essential for the reflex regulation of Epi release during hypoglycemia and 2) the gain of baroreceptor-mediated bradycardia is increased by blockade of brain AT2 receptors in this model.

AT1 and AT2 receptor blockade and epinephrine release during insulin-induced hypoglycemia.

Angiotensin II facilitates epinephrine release during insulin-induced hypoglycemia, and this effect appears to be independent of type 1 angiotensin II (AT1) receptors in man. In the present study, we hypothesized that the action of angiotensin II on adrenomedullary epinephrine release is mediated by an AT2 receptor-dependent mechanism. In conscious chronically instrumented rats, we measured plasma concentrations of catecholamines during acute insulin-induced hypoglycemia in groups of rats pretreated with the AT1 receptor antagonist losartan (10 mg/kg i.v.), the AT2 receptor antagonist PD123319 (30 mg/kg i.v.), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg i.v.), or vehicle. In vehicle-treated rats, the area under the curve for changes in plasma epinephrine concentration [AUC(plasma epinephrine)] during insulin-induced hypoglycemia was 111+/-8 nmolXh/L (+/-SEM). Pretreatment with losartan alone did not affect AUC(plasma epinephrine) (113+/-17 nmol x h/L), while pretreatment with PD123319 tended to reduce the response (87+/-10 nmol x h/L; P=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68+/-5 nmol x h/L; P<.001 versus vehicle) or enalapril: 86+/-10 nmol x h/L (P<.05 versus vehicle). Thus, combined treatment with losartan + PD 123319 proved more effective in attenuating the reflex increase in plasma epinephrine concentration during hypoglycemia than either of the two AT receptor antagonists given alone. We speculate that angiotensin II through binding to both receptor subtypes facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia.

AT1 receptor blockade and the sympathoadrenal response to insulin-induced hypoglycemia in humans.

An important facilitating effect of angiotensin II on adrenal catecholamine release has been demonstrated in several species. To determine whether specific AT1 receptor blockade affects medullary epinephrine secretion and musculocutaneous norepinephrine release during insulin-induced hypoglycemia, 16 healthy volunteers received losartan vs. placebo followed by an intravenous insulin bolus and measurement of effect variables at short intervals for 150 min. AT1 receptor blockade was effective, as evidenced by substantially increased circulating renin and angiotensin II levels, a 60% inhibition of circulating aldosterone, and an 8.5% decrease of mean arterial pressure over time compared with placebo. Arterial glucose concentration fell to a nadir of 1.9 mM, arterial epinephrine concentration increased 23-fold, forearm musculocutaneous norepinephrine release increased 4-fold, heart rate increased 40%, and forearm blood flow increased 3-fold. All absolute values and the time course of these changes were independent of AT1 receptor blockade. It is concluded that a putative interaction between angiotensin II and the sympathoadrenal axis may not be mediated by AT1 receptors in humans.

Captopril does not blunt the sympathoadrenal response to cigarette smoking in normotensive humans.

The aim of this study was to assess whether an interaction exists between the renin-angiotensin system and the sympathetic nervous system at the level of the adrenal medulla during smoking in normal humans. Thirteen habitual smoking volunteers were studied in a randomized, single-dose, double-blind, cross-over fashion using 50 mg captopril vs placebo followed by smoking of two high nicotine content cigarettes within 15 min. Blood samples were obtained at frequent intervals before, during and after smoking. We found that the increase in plasma adrenaline concentration during cigarette smoking was modest. There was no difference between captopril treatment as compared to placebo. Thus, the adrenaline response to cigarette smoking was not blunted by acute blockade of angiotensin II generation. A significant increase in heart rate, and blood pressure was found as well. No increase in plasma noradrenaline concentration was found. Plasma renin concentration increased significantly during captopril treatment, whereas it decreased throughout the study period in the placebo phase. Plasma angiotensin II concentration decreased in both the captopril treatment and the placebo phase throughout the study period, but this was more pronounced during captopril treatment. In conclusion, cigarette smoking-induced activation of the sympathetic nervous system was not blunted by acute ACE-inhibition by captopril. This indicates that angiotensin II does not facilitate smoking-induced activation of sympathoadrenal activity in humans.

The etiology of hypertension in nonrenovascular unilateral renal disease--two cases of renin induced hypertension in congenital renal dysplasia.

We report two cases of severe hypertension and unilateral renal dysplasia. No renal artery stenosis and no other urogenital malformations were found. In both cases we found substantially enhanced secretion of renin from the dysplastic kidney. After nephrectomy both patients obtained a distinctive and permanent reduction or normalization of blood pressure. In the two cases reported, regional renin release induced by ischemia is a very likely etiological factor.