Role of bradykinin in the vasodilator effects of losartan and enalapril in patients with heart failure.

BACKGROUND: ACE inhibitors have been shown to potentiate the effects of exogenous bradykinin by inhibition of its breakdown. Despite this, there is little evidence that inhibition of endogenous bradykinin breakdown actually contributes to the effects of ACE inhibitors, or indeed, other inhibitors of the renin-angiotensin system, such as angiotensin II type I receptor (AT(1)) antagonists, and no evidence at all that it does so in patients with heart failure. METHODS AND RESULTS: Twelve patients with heart failure (11 male, 1 female, ages 59 to 81 years) were randomized to double-blind crossover treatment with enalapril 10 mg BID followed by losartan 25 mg BID, or the reverse, each for 5 weeks. At the end of each treatment period, forearm blood flow was measured by venous occlusion plethysmography during an intrabrachial infusion of bradykinin before and after an intrabrachial infusion of Hoe-140 (a potent, selective, and long-acting bradykinin antagonist). Bradykinin caused profound vasodilatation after enalapril (peak, 357+/-67%) and less after losartan (peak, 230+/-46%). Despite this, Hoe-140 had no discernible effects after enalapril or losartan. Similarly, this was despite the finding that Hoe-140 significantly reduced vasodilatation to bradykinin after enalapril (peak, 192+/-35%) and losartan (peak, 66+/-13%). CONCLUSIONS: Inhibition of endogenous bradykinin breakdown does not appear to contribute to the effects of ACE inhibition or AT(1) antagonism in the forearm of patients with heart failure at rest, despite the very obvious effects of ACE inhibition compared with AT(1) antagonism on exogenous bradykinin.

Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure.

OBJECTIVES: We sought to determine the effect of aspirin on the venodilator effect of furosemide in patients with chronic heart failure (CHF) BACKGROUND: Furosemide has an acute venodilator effect preceding its diuretic action, which is blocked by nonsteroidal anti-inflammatory, drugs. The ability of therapeutic doses of aspirin to block this effect of furosemide in patients with CHF has not been studied. For comparison, the venodilator response to nitroglycerin (NTG) was also studied. METHODS: Eleven patients with CHF were randomized to receive placebo, aspirin at 75 mg/day or aspirin at 300 mg/day for 14 days in a double-blind, crossover study. The effect of these pretreatments on the change in forearm venous capacitance (FVC) after 20 mg of intravenous furosemide was measured over 20 min by using venous occlusion plethysmography. In a second study, the effect of 400 microg of sublingual NTG on FVC was documented in 11 similar patients (nine participated in the first study). RESULTS: Mean arterial pressure, heart rate and forearm blood flow did not change in response to furosemide. After placebo pretreatment, furosemide caused an increase in FVC of 2.2% (95% confidence interval [CI] -0.9% to 5.2%; mean response over 20 min). By comparison, FVC fell by -1.1% (95% CI -4.2% to 1.9%) after pretreatment with aspirin at 75 mg/day, and by -3.7% (95% CI -6.8% to -0.7%) after aspirin at 300 mg/day (p = 0.020). In the second study, NTG increased FVC by 2.1% (95% CI -1.6% to 5.8%) (p = 0.95 vs. furosemide). CONCLUSIONS: In patients with CHF, venodilation occurs within minutes of the administration of intravenous dose of furosemide. Our observation that aspirin inhibits this effect further questions the use of aspirin in patients with CHF.

Attenuation of endothelin-1 induced vasoconstriction by 17beta estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease.

OBJECTIVES: The goal of this study was to determine the long-term effects of estrogen replacement therapy on the response to endothelin-1 (ET-1) in postmenopausal women with coronary heart disease. BACKGROUND: It is thought that the vasoconstrictor ET-1 is involved in the development and progression of atherosclerosis. Estrogen replacement may slow the development of atherosclerosis in postmenopausal women. METHODS: Nineteen of 20 postmenopausal women randomized to either three months of 2 mg oral estradiol or placebo completed the double-blind placebo-controlled protocol. Change in forearm blood flow (FBF) in response to a 60 min brachial arterial infusion of ET-1 (5 pmol/min) was measured before randomization, after one month of randomized therapy and after three months of therapy using venous occlusion plethysmography. RESULTS: Estrogen treatment had no effect on baseline FBF. Systolic and diastolic blood pressure and heart rate did not change in response to estrogen therapy or ET-1. Before randomization, in response to ET-1, FBF was reduced by -21.9% (mean response over 60 min) in the placebo group and -19.0% in the estradiol group (p = 0.67). After one month of therapy, the response was attenuated in the estrogen group, -10.0%, compared with the placebo group, -23.6 (difference in means 13.6%, 95% confidence interval [0.7%, 26.6%], p = 0.041). After three months of therapy, there was no difference in response between the placebo group, -27.0%, and estrogen group, -30.2% (p = 0.65). CONCLUSIONS: In postmenopausal women with coronary heart disease, estrogen therapy inhibits the vasoconstrictor response to ET-1 after one month of therapy. This effect is lost after three months of therapy, suggesting that tachyphylaxis to one potentially beneficial action of estradiol develops during chronic treatment.

Effect of angiotensin-(1-7) and bradykinin in patients with heart failure treated with an ACE inhibitor.

Angiotensin-(1-7) is a product of angiotensin processing that has been proposed to have vasodepressor effects, both on its own and in combination with bradykinin, which may be pathophysiologically and therapeutically important. Despite this, there has been very little examination of its effects in humans and none in heart failure patients or in other patients treated with ACE inhibitors. We therefore sought to determine the effects of angiotensin-(1-7) in patients with heart failure treated with an ACE inhibitor, as well as any interaction with the effects of bradykinin. A locally active dose of angiotensin-(1-7), alone and in combination with bradykinin, was infused into the nondominant brachial artery while forearm blood flow was measured by venous occlusion plethysmography in 8 patients with heart failure treated with ACE inhibitors. Although bradykinin on its own caused profound vasodilation, there was no effect of angiotensin-(1 to 7) on its own or any effect of angiotensin-(1-7) on the response to bradykinin. We conclude that angiotensin-(1-7) is biologically inactive in the forearm circulation of patients with heart failure treated with an ACE inhibitor. The contrast between these findings and previously reported preclinical findings calls into question the relevance of angiotensin-(1-7) to the hemodynamic effects of ACE inhibitors.

Even low-dose aspirin inhibits arachidonic acid-induced vasodilation in heart failure.

BACKGROUND: There is some evidence that aspirin may be harmful to patients with congestive heart failure treated with angiotensin-converting enzyme (ACE) inhibitors, but there has never been any direct examination of the vascular effects of aspirin in these patients. We sought to determine whether there is an arachidonic acid-dependent vasodilator pathway in resistance arteries in humans, whether it is affected by congestive heart failure, and whether it is inhibited by low-dose aspirin. METHODS: A locally active dose of arachidonic acid was infused into the nondominant brachial artery while forearm blood flow was measured by venous occlusion plethysmography in 10 healthy subjects in a control group and 15 patients with congestive heart failure treated with ACE inhibitor. Patients with congestive heart failure were studied after administration of 0 mg, 75 mg, and 300 mg aspirin for 14 days. RESULTS: Arachidonic acid produced progressive and incremental vasodilation (up to 64%). There was no significant difference between patients and healthy control subjects studied after administration of 0 mg aspirin. In patients, however, administration of 75 mg and 300 mg aspirin inhibited mean vasodilation by 55% and 59%, respectively. CONCLUSIONS: There is an arachidonic acid-dependent vasodilator pathway in humans. This pathway is not significantly affected by congestive heart failure. It is significantly inhibited by even low-dose aspirin therapy. These results imply that even the very lowest dose of aspirin in common use for cardioprotection has potentially detrimental vasoconstrictor effects.

Assessing diagnosis in heart failure: which features are any use?

We assessed the value of symptoms, past history, medications and signs in the evaluation of patients who might have heart failure secondary to left ventricular systolic dysfunction. An open-access echocardiography service was set up to help identify patients with left ventricular systolic dysfunction who might benefit from treatment with an angiotensin-converting-enzyme inhibitor. History and examination were recorded for each of these patients. The patients were divided into groups according to whether left ventricular systolic function was preserved or not and whether various clinical features were present or not. Of 259 consecutive patients studied, 41 had impairment of left ventricular systolic function as assessed by echocardiography. Past history of myocardial infarction and displaced apex beat were the best single predictors of left ventricular systolic dysfunction as assessed by echocardiography. The combination of past history of myocardial infarction and displaced apex had the best positive predictive value of all. Patients with such clinical features or combinations of clinical features may not need echocardiography, and where access to this resource is limited, it could be reserved for patients without such diagnostic features.

Outcome from a rapid-assessment chest pain clinic.

Chest pain accounts for much of the rising numbers of emergency admissions, but in-patient assessment is not necessarily the best way of dealing with these patients. We ran a 'rapid-assessment chest pain clinic' to provide an alternative route of assessment, and audited its outcome. General practitioners referred patients with recent-onset chest pain, increasing chest pain, chest pain at rest, or other chest pain of concern, on the understanding that they would be seen within 24 h. During 8 1/2 months, 334 patients were referred and 317 patients were seen, most of whom had exercise electrocardiography. A median of 6 months later, 278 patients were personally contacted to determine outcome. Of these, 18% had been admitted immediately with acute coronary syndromes, and 49% had been diagnosed as non-coronary chest pain (none of whom subsequently infarcted or died). Continuing symptoms were infrequent, and satisfaction was high, although 13% of patients had been revascularized. A significant number of patients required immediate admission and/or ultimate revascularization, but many more did not. The majority of these patients had non-coronary chest pain, and this diagnosis was substantiated by their excellent outcome and (in some cases) by further investigation.

QT dispersion in patients with chronic heart failure: beta blockers are associated with a reduction in QT dispersion.

OBJECTIVE: To compare QT dispersion in patients with impaired left ventricular systolic function and in matched control patients with normal left ventricular systolic function. DESIGN: A retrospective, case-control study with controls matched 4:1 for age, sex, previous myocardial infarction, and diuretic and beta blocker treatment. SETTING: A regional cardiology centre and a university teaching hospital. PATIENTS: 25 patients with impaired left ventricular systolic function and 100 patients with normal left ventricular systolic function. MAIN OUTCOME MEASURES: QT and QTc dispersion measured by three methods: the difference between maximum and minimum QT and QTc intervals, the standard deviation of QT and QTc intervals, and the "lead adjusted" QT and QTc dispersion. RESULTS: All measures of QT/QTc dispersion were closely interrelated (r values 0.86 to 0.99; all p < 0.001). All measures of QT and QTc dispersion were significantly increased in the patients with impaired left ventricular systolic function v controls (p < 0.001): 71.9 (6.5) (mean (SEM)) v 46.9 (1.7) ms for QT dispersion, and 83.6 (7.6) v 54.3 (2.1) ms(-1-2) for QTc dispersion. All six dispersion parameters were reduced in patients taking beta blockers (p < 0.05), regardless of whether left ventricular function was normal or impaired-by 9.4 (4.6) ms for QT dispersion (p < 0.05) and by 13.8 (6. 5) ms(-1-2) for QTc dispersion (p = 0.01). CONCLUSIONS: QT and QTc dispersion are increased in patients with systolic heart failure in comparison with matched controls, regardless of the method of measurement and independently of possible confounding factors. beta Blockers are associated with a reduction in both QT and QTc dispersion, raising the possibility that a reduction in dispersion of ventricular repolarisation may be an important antiarrhythmic mechanism of beta blockade.

ACE inhibitors and health-care economics.

These economic analyses differ widely in their methods and results because not only do they make different assumptions, they also consider different costs and apply different sensitivity analyses (to factors including costs). All of the economic analyses considered hospitalization costs and drug costs, not surprisingly, because these are the two main variables in the equation. Only the Dutch and UK studies, however, gave consideration to general practice costs, only the Dutch study included nursing home and district nursing costs, and only the UK study included initiation costs, monitoring costs and out-patient costs. Only the Dutch study attempted to make some allowance for indirect costs, although it was somewhat dismissive of their effects. The SOLVD study was the only one to attempt to estimate the direct costs of deaths and none of the studies made any attempt to estimate the indirect costs. With respect to sensitivity analysis, only the Dutch, UK, and USA studies examined the effect of varying the proposed efficacy of treatment, and all found the economic analysis to be sensitive to this variable; indeed, the Dutch study found it to be highly sensitive. The UK, USA, as well as SOLVD studies, examined the sensitivity of the analysis to varying hospital costs and all found it to be sensitive. The UK and USA studies found their analyses to be relatively insensitive to the effects of a discount rate. The USA study found greater sensitivity to varying mortality than the Dutch study. Other factors considered included initiation and follow-up strategies in the UK study and dose regime in the SOLVD study.

ACE inhibitors after myocardial infarction. Clinical and economic considerations.

Economic analysis has been extensively used to guide the use of ACE inhibitors in chronic heart failure. More recently, it has been used to guide the use of ACE inhibitors after myocardial infarction. The results of major clinical trials leave us in no doubt that ACE inhibitors are useful in the treatment of patients after myocardial infarction. The results of economic analysis unanimously indicate that ACE inhibitors are cost effective when used to treat patients after myocardial infarction. Any comparison of the different treatment strategies available suggests that all are comparably cost effective and argues for the widest possible use of ACE inhibitors in this setting. The evidence suggests that, in this context as in so many others, ACE inhibitors remain under-utilized.

Do patients with suspected heart failure and preserved left ventricular systolic function suffer from "diastolic heart failure" or from misdiagnosis? A prospective descriptive study.

OBJECTIVES: To characterise the clinical features of patients with suspected heart failure but preserved left ventricular systolic function to determine if they have other potential causes for their symptoms rather than being diagnosed with "diastolic heart failure." DESIGN: Prospective descriptive study. SETTING: Outpatient based direct access echocardiography service. PARTICIPANTS: 159 consecutive patients with suspected heart failure referred by general practitioners. MAIN OUTCOME MEASURES: Symptoms (including shortness of breath, ankle oedema, and paroxysmal nocturnal dyspnoea) and history of coronary heart disease and chronic pulmonary disease. Transthoracic echocardiography, body mass index, pulmonary function tests, and electrocardiography. RESULTS: 109 of 159 participants had suspected heart failure in the absence of left ventricular systolic dysfunction, valvular heart disease, or atrial fibrillation. Of these 109, 40 were either obese or very obese, 54 had a reduction in forced expiratory volume in 1 second to

Cohort study of plasma natriuretic peptides for identifying left ventricular systolic dysfunction in primary care.

OBJECTIVES: To determine whether blood natriuretic peptide concentrations are helpful in identifying or excluding left ventricular systolic dysfunction in stable survivors of acute myocardial infarction. DESIGN: Comparison of blood natriuretic peptide concentrations with echocardiographic assessment of left ventricular systolic function in a general practice population. SETTING: Practices in Western District of Glasgow audit group. SUBJECTS: 134 long term survivors of myocardial infarction recalled for echocardiography as part of a primary care secondary prevention audit. MAIN OUTCOME MEASURES: Area under the receiver operating curve for brain natriuretic peptide and N-terminal atrial natriuretic peptide. RESULTS: Brain natriuretic peptide was of some diagnostic utility in identifying the minority of subjects with severe left ventricular dysfunction (area under curve=0.73) but was unable to discriminate between patients with moderately severe dysfunction and those with preserved left ventricular function (area under curve for moderate or severe dysfunction=0.54). The corresponding values for N-terminal atrial natriuretic peptide for severe and moderate or severe dysfunction were 0.55 and 0.56 respectively. CONCLUSIONS: Blood natriuretic peptide concentrations are not useful in identifying important left ventricular systolic dysfunction in stable survivors of myocardial infarction.

Randomised controlled trial of specialist nurse intervention in heart failure.

OBJECTIVES: To determine whether specialist nurse intervention improves outcome in patients with chronic heart failure. DESIGN: Randomised controlled trial. SETTING: Acute medical admissions unit in a teaching hospital. PARTICIPANTS: 165 patients admitted with heart failure due to left ventricular systolic dysfunction. The intervention started before discharge and continued thereafter with home visits for up to 1 year. MAIN OUTCOME MEASURES: Time to first event analysis of death from all causes or readmission to hospital with worsening heart failure. RESULTS: 31 patients (37%) in the intervention group died or were readmitted with heart failure compared with 45 (53%) in the usual care group (hazard ratio=0.61, 95% confidence interval 0.33 to 0.96). Compared with usual care, patients in the intervention group had fewer readmissions for any reason (86 v 114, P=0.018), fewer admissions for heart failure (19 v 45, P<0.001) and spent fewer days in hospital for heart failure (mean 3.43 v 7.46 days, P=0.0051). CONCLUSIONS: Specially trained nurses can improve the outcome of patients admitted to hospital with heart failure.

ACE inhibitors and heart failure in hospital: any difference between cardiologists and general physicians?

Cardiologists and generalists have been reported to diverge in terms of their self-reported use of angiotensin-converting enzyme (ACE) inhibitors, but information on their actual use of ACE inhibitors has been lacking. In order to assess ACE inhibitor use in patients with heart failure in a teaching hospital and any differences between specialties we studied all patients in the Western Infirmary of Glasgow between 1 April and 1 October 1996 with an echocardiogram showing moderate or severe left ventricular systolic dysfunction (n = 236). We found that most patients were on an ACE inhibitor (66%), 12% had been tried but found to be intolerant, 10% had not been tried because of a contraindication, but 12% had not been tried despite no contraindication. Of those on treatment, 58% were on a dose used in a major survival study (38% of all patients). Most patients were treated by a cardiologist (64%). Of these, more were on an ACE inhibitor (77% vs 53%, p < 0.01), fewer had been tried but found intolerant (11% vs 18%), and fewer had never been tried (11% vs 29%, p < 0.01), irrespective of whether they had a contraindication (5% vs 18%, p < 0.01) or not (6% vs 12%). More were on a dose used in a major survival study (48% vs 31%, p < 0.05). We conclude that, despite improvements over time, ACE inhibitors are still under-used, sometimes without good reason. There are also differences in the use of ACE inhibitors between cardiologists and generalists which may affect outcome, and could affect resource utilisation.

The prevalence of left ventricular diastolic filling abnormalities in patients with suspected heart failure.

AIMS: It is reported that one third of patients with heart failure have normal left ventricular systolic function, and may or may not have left ventricular diastolic dysfunction. We sought to define the prevalence of left ventricular diastolic filling abnormalities in a large unselected group of patients, unlike the diagnosis by exclusion in the small highly selected groups of patients studied previously. METHODS AND RESULTS: Patients were referred by general practitioners to an open-access echocardiography service for assessment of possible heart failure. Echocardiography included a Doppler study of transmitral flow at the tips of the mitral leaflets and calculation of an E/A ratio. Of 534 patients referred and assessed, 371 patients had normal systolic function and a measurable E/A ratio. These were compared with age-adjusted reference ranges to give 9 above the reference range and 19 below. This is only 10 more than would be expected if our patients were normal. In the same group of patients we found 96 cases of left ventricular systolic dysfunction, or 52 amongst the 423 with a measurable E/A ratio. CONCLUSION: Either left ventricular diastolic filling abnormalities are very much less common than previously supposed or the E/A ratio is almost useless for their detection.