Drug Insight: angiotensin-converting-enzyme inhibitors and atrial fibrillation--indications and contraindications

Large clinical trials have demonstrated that angiotensin-converting-enzyme (ACE) inhibitors are associated with beneficial outcomes in patients with arterial hypertension, heart failure, coronary artery disease, or a combination of these conditions. Other reports have suggested that ACE inhibitors prevent the development or recurrence of atrial fibrillation (AF), a common arrhythmia. In the TRACE trial, in patients with reduced left ventricular function after myocardial infarction, trandolapril reduced the frequency of AF. In the SOLVD trial, a 78% reduction in the frequency of AF after infarction was noted with enalapril compared with placebo. Studies in patients with persistent AF undergoing cardioversion suggest that ACE inhibitors improve outcomes and prevent AF recurrences. The mechanism of AF prevention by ACE inhibitors is unclear, but experimental data show prevention or attenuation of pacing-induced atrial remodeling with ACE inhibitor use. ACE inhibitors decrease angiotensin II concentration; angiotension II stimulates mitogen-activated protein kinases, which in turn activate fibrosis formation and lead to conduction heterogeneity and induction of AF. On the other hand, AF induces atrial dilatation, atrial stretch and atrial secretion of ACE. Among other properties, ACE inhibitors have a sympatholytic effect and increase baroreceptor sensitivity. This review discusses the current data on the use of ACE inhibitors for AF prevention. Although these drugs represent a promising therapeutic option for AF patients, the data so far seem only supportive rather than definitive. Prospective trials are required to validate the benefit of ACE inhibitors and to investigate which patients are most likely to benefit from this pharmacological therapy.     

Post-perfusion syndrome and disturbed microcirculation after cardiac surgery: the role of angiotensin-converting-enzyme inhibitors

BACKGROUND: The sympathoadrenal and the renin-angiotensin system (RAS) are involved in blood pressure regulation. They are known to be activated during cardiac surgery. We investigated the influence of preoperative RAS-blockade using angiotensin-converting-enzyme inhibitors (ACEI) on hemodynamic variables and on the perioperative need for exogenous catecholamines. METHODS: 240 patients undergoing coronary artery bypass grafting (CABG) or valve surgery were divided into three matched groups (group A: pre- and postoperative ACEI; group B: ACEI only pre-, not postoperatively; group C: no ACEI). In these three groups we analyzed hemodynamic variables, the need for catecholamines and the incidence of a "post-perfusion syndrome" or systemic inflammatory response syndrome (SIRS) with impaired microcirculation. RESULTS: There were significant differences in the intra- and postoperative need for catecholamines in groups A and B compared to C (intraop. A: 35%, B: 35%, C: 15%; postop. A: 21.2%, B: 16.2%, C: 10%) (p < 0.05). In the ACEI groups (A and B) there were 9 patients with a postoperative SIRS, only 2 cases in group C. Furthermore 4 patients of group B suffered from disturbances of the intestinal microcirculation postoperatively. CONCLUSIONS: Long-term ACEI treatment before cardiac surgery raises the perioperative need for catecholamines. Patients with preoperative long-term use of ACEI who do not receive ACEI postoperatively face an increased risk of impaired microcirculation. The inhibition of angiotensin-II (AT II) generation causes the vasodilatatory effects of ACEI, and could be one reason for a post-perfusion syndrome or a SIRS.     

Variable response to oral angiotensin-converting-enzyme blockade in hypertensive scleroderma patients

Twelve scleroderma patients with hypertension, seven of whom had malignant hypertension and renal failure of scleroderma renal crisis, were treated with captopril. The first dose lowered mean pressure in all patients by 21.3 mmHg; in 6 patients it relieved encephalopathy. Blood pressure was controlled in all patients. Two of 7 patients with scleroderma renal crisis had improvement in renal function; the 5 patients who did not have malignant hypertension improved or stabilized. Despite good pressure control, however, renal failure developed in 5 patients with scleroderma renal crisis. The data indicated that captopril is effective antihypertensive therapy in scleroderma and, when given early, may prevent renal failure and death.     

Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis.

The level of serum angiotensin-converting enzyme (ACE) was elevated in 15 of 17 patients with active sarcoidosis. Serum ACE was studied to determine the effect of chronic lung disease upon the blood level of an enzyme believed to originate from the lungs. The assay was performed in approximately 200 control subjects and 200 patients with chronic lung disease using hippuryl-L-histidyl-L-leucine as substrate. Enzyme activity greater in male control subjects than in female subjects of comparable age and greater in children than in adults. Serum ACE was significantly reduced in patients with chronic obstructive lung disease, lung cancer, tuberculosis and cystic fibrosis, as compared to control subjects, and was even lower in those receiving corticosteroids. Of greatest interest, however, was that levels in patients with active sarcoidosis not receiving steroids were greater than 2 standard deviations above the mean for the adult control subjects (greater than 11.6 units) whereas levels in patients with sarcoidosis receiving steroids and in those with resolved disease were normal. A survey of subjects with other granulomatous diseases failed to reveal any other condition that was significantly associated with a similar elevation of serum ACE levels. Elevation of ACE levels in sarcoidosis appears to be associated with the active disease process and does not appear to be a familial inherited enzyme abnormality. An assay of serum ACE is a useful tool for regulating therapy in sarcoidosis and for confirming the diagnosis, since it readily distinguishes these patients from others with tuberculosis, lung cancer or lymphoma.     

Dilation of forearm blood vessels after angiotensin-converting-enzyme inhibition by captopril in hypertensive patients

In eight hypertensive patients, forearm vascular tone was assessed by water plethysmography following inhibition of angiotensin II-converting-enzyme (ACE) activity with captopril. Acute captopril administration increased venous distensibility (VV30) and decreased forearm vascular resistance (FVR), while it lowered systemic blood pressure (BP). Alpha-one adrenergic receptor blockade by prazosin did not prevent captopril from decreasing vascular tone or lowering blood pressure (BP). Thus, captopril dilated both veins and arterioles. The primary mechanism of captopril's acute antihypertensive action did not involve inhibition of alpha1-adrenergic receptor activity. Moreover, captopril and prazosin together produced a greater reduction in BP and peripheral resistance than occurred with either agent alone.     

Effect of calmodulin inhibitors on thyroid hormone secretion

The effect of calmodulin inhibitors, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) and trifluoperazine, on TSH-induced thyroid hormone secretion from rat thyroid was examined in vivo and in vitro. The ip administration of 5 mg W-7 to the rat inhibited T4 and T3 secretion from rat thyroids at 2, 3, and 4 h after the ip injection of 2 IU TSH, and so did the ip injection of trifluoperazine at 3 and 4 h. However, the ip injection of N-(6-aminohexyl)-1-naphthalene sulfonamide as a control substance did not show any significant inhibition of T4 and T3 release. To identify the site of action of calmodulin, the effect of W-7 on (Bu)2cAMP-induced thyroid hormone secretion was tested in vitro. One hundred micromolar W-7 completely inhibited T4 release from the rat thyroid when it was enhanced by TSH or (Bu)2cAMP, suggesting that the inhibitory effect of W-7 is subsequent to cAMP formation. These results suggest that calmodulin may play a role in thyroid hormone secretion from the thyroid, acting beyond cAMP formation.     

血管紧张素转化酶活性变化在2型糖尿病早期肾损害诊断中的价值

目的探讨血管紧张素转化酶（ACE）在2型糖尿病早期肾损害中的诊断价值。方法采用全自动生化仪速率法检测65例2型糖尿病患者（观察组）及50例查体健康者（对照组）血、尿ACE活性,并对尿ACE与尿N-乙酰-β-D氨基葡萄糖苷酶（UNAG）、尿微量白蛋白（mAlb）及血ACE行Pearson相关分析。结果观察组尿ACE、mAlb、UNAG均明显高于对照组（P均〈0.05）,尿ACE活性随糖尿病病情加重而逐渐增高。相关性分析示尿ACE与UNAG、mAlb均呈正相关（r值分别为0.757、0.796,P均〈0.001）,与血ACE无明显相关性。结论尿ACE活性变化对2型糖尿病早期肾脏损害诊断有较好的临床价值,可作为筛选指标。     

雌激素替代疗法对绝经后妇女血清血管 紧张素转化酶及血脂代谢的影响

目的　探讨雌激素替代疗法 (ERT)对绝经后妇女血清血管紧张素转化酶 (ACE)含量及血脂代谢的影响。方法　测定 30例健康绝经后妇女应用ERT(治疗组 )前及应用ERT 14周后血清ACE、雌二醇 (E2 )及血清甘油三酯 (TG)、总胆固醇 (TC)、高密度脂蛋白胆固醇 (HDL C)、低密度脂蛋白胆固醇 (LDL C)、脂蛋白 (a) [Lp(a) ]含量 ,并与 30例健康绝经后妇女应用安慰剂 (对照组 )进行对照。结果　对照组应用安慰剂前后 ,ACE及血脂各项含量无变化 ;治疗组应用ERT后 ,ACE含量明显降低且与E2 呈负相关 ,血清TC、LDL C及Lp(a)含量降低 ,HDL C含量升高 ,TG无变化。结论　绝经后妇女补充雌激素 ,可通过降低血清ACE水平及改善血脂代谢共同发挥对心血管系统的保护作用。     

The angiotensin-converting-enzyme insertion/deletion polymorphism is not a risk factor for peripheral arterial disease

BACKGROUND: An insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for atherosclerotic vascular disease. The aim of the present study was to analyze the role of this polymorphism for peripheral arterial disease (PAD). METHODS: The study was designed as a case-control study including 522 patients with documented PAD and 522 sex- and age-matched controls. ACE genotype was determined by size-analysis of polymerase chain reaction products. RESULTS: ACE genotype frequencies were similar between patients (II: 23.4%; ID: 44.8%; DD: 31.8%) and controls (II: 23.8%; ID: 48.3%; DD: 27.9%, P=0.37). The adjusted odds ratio of carriers of the DD genotype for PAD was 1.29 (95% confidence interval 0.95-1.75). The polymorphism was furthermore not associated with age at onset of PAD (P=0.56), Fontaine stage of the disease (P=0.68) or ankle/brachial index of patients (P=0.86). CONCLUSION: The ACE I/D polymorphism is not a significant risk factor for PAD.