Showing papers by "John G.F. Cleland published in 1995"

Losartan in Heart Failure Hemodynamic Effects and Tolerability

Abstract: Background The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure. Methods and Results A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction <40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure ≥13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne · s−1 · cm−5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no dis...

Reduced Alveolar–Capillary Membrane Diffusing Capacity in Chronic Heart Failure Its Pathophysiological Relevance and Relationship to Exercise Performance

Abstract: Background The pulmonary diffusing capacity for carbon monoxide (dlco) is reduced in chronic heart failure (CHF) and is an independent predictor of peak exercise oxygen uptake. The pathophysiological basis for this remains unknown. The aim of this study was to partition DLco into its membrane conductance (DM) and capillary blood volume components (Vc) and to assess if alveolar–capillary membrane function correlated with functional status, exercise capacity, and pulmonary vascular resistance. Methods and Results The classic Roughton and Forster method of measuring single-breath DLco at varying alveolar oxygen concentrations was used to determine DM and Vc in 15 normal subjects and 50 patients with CHF. All performed symptom-limited maximal bicycle exercise tests with respiratory gas analysis; 15 CHF patients underwent right heart catheterization. DLco was significantly reduced in CHF patients compared with normal subjects, predominantly because of a reduction in DM (7.0±2.6 versus 12.9±3.8 versus 20.0±6.1 ...

Is aspirin safe for patients with heart failure

Abstract: Accepted for publication 27 March 1995 Despite evidence that ACE inhibitors can improve the prognosis of patients with heart failure, mortality remains high even when symptoms are mild. The SOLVD studies have highlighted the contribution of coronary ischaemic events to subsequent outcome among patients with substantial ventricular dysfunction. In the presence of pre-existing left ventricular dysfunction a myocardial infarction carries a 50% mortality within three months of the event compared with a mortality of only 20% at four years among those who have had no such event.' Aspirin is widely used in patients with coronary disease, a common cause of heart failure, to try to reduce the frequency of myocardial infarction and death. However, enalapril did not improve prognosis among patients with heart failure taking aspirin in the SOLVD study, a finding that has not been well publicised. There are at least three possible explanations for the lack of apparent benefit with enalapril among those taking aspirin in the SOLVD trial. The interaction between aspirin and enalapril was statistically significant (P < 0 01) but was not pre-planned. The lack of benefit from ACE inhibition among those taking aspirin could have occurred by chance, an explanation favoured by the trialists. Alternatively, aspirin may negate the benefits of ACE inhibition. This would be a potentially serious and costly interaction. Finally, it is possible that some of the mortality benefit from ACE inhibition can be achieved by aspirin alone and that ACE inhibitors confer no additional advantage. If this were the case the less expensive option would be attractive. The benefits of ACE inhibitors are well established but the safety and efficacy of aspirin in heart failure have not been studied. This article is devoted to examining the arguments for and against aspirin in heart failure and the potential interaction with ACE inhibitors. The reader should be aware from the outset that the evidence of harm or benefit with aspirin in this group of patients is entirely inconclusive.

Sexual behaviour in developing countries: implications for HIV control.

Abstract: 18 sample surveys conducted in 1989-1993 of male and female respondents aged 15-49 years reporting sex with a nonregular partner in the preceding year were analyzed The proportion of men ranged from 4% to 47% and women from 1% to 19% In the five Asian sites 10-20 times more men than women reported nonregular sex Among the 18 surveys the proportion of men reporting five or more partners in the last 12 months varied from 0% in Sri Lanka and Hong Kong to 11% in Thailand; for women the level never exceeded 3% The proportion of male respondents with more than five nonmarital partners was consistently highest among those aged 25-34 years A significant relationship was found between the prevalence of premarital sex among 15-24 year old youths and the prevalence of nonregular sex among adults for both men and women (R2 = 043 for men; R2 = 057 for women) Prevalence of all men aged 15-49 years reporting commercial sex ranged from 1% to 25% with a median of 97% Among women the corresponding figures were <1% in nine countries but ranged up to 11% in Tanzania with a median of 13% In 1989-93 the proportion of men who never used a condom on these occasions in the last year varied from approximately 25% in Singapore to 80% in Togo Tanzania Manila and Rio In Lusaka and Burundi two areas where the HIV epidemic and the awareness of AIDS were already high more than 50% of men reported regular or occasional use of condoms Youthful age and unmarried status emerged as net predictors of risk behavior in eight of the 12 sex-specific study groups by multivariate analysis Among men significant positive associations between educational level and risk behavior were found in three of the six sites and among women in two of the four sites Regular alcohol drinking was also strongly correlated with risk behavior in most surveys but perceived vulnerability to HIV was not

The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy.

Abstract: Phenotypic heterogeneity in hypertrophic cardiomyopathy (HC) makes definitive diagnosis difficult, particularly during family screening. We studied the electrocardiogram (ECG) as a potential initial screening test in patients with HC. Using accepted diagnostic criteria, we examined the ECGs and echocardiograms of 159 patients with a confirmed clinical or genetic diagnosis of HC. An abnormal ECG was found in 154 patients (97%) while only 146 (92%) showed an abnormal echocardiogram. Of the former, 9 patients (6%) had normal echocardiograms and had been diagnosed on the basis of identification of a mutation in the beta myosin heavy chain gene (n = 8) or obligate carrier status (n = 1). Only 1 of these 9 patients was under age 20, the time at which hypertrophy is normally expressed on the echocardiogram. The remaining 5 patients (3%) without ECG abnormality consisted of 1 patient with an echocardiogram clearly diagnostic of HC and 4 clinically normal patients (aged 13, 24, 29, and 33 years) with normal echocardiograms who had been diagnosed by mutation identification (n = 3) or obligate carrier status (n = 1). Thus only these latter 4 patients (3%) would not have been diagnosed as having HC based on an abnormal ECG and/or abnormal echocardiogram. Screening relatives for HC by ECG criteria alone detects all those whom an echocardiogram will diagnose. While echocardiography aids in the specificity of HC diagnosis, the ECG, within the context of a family with a proven case of HC, is a more sensitive marker of the disease. It is therefore both a cost-effective and useful tool for screening those to proceed to echocardiography.

ACE inhibitors for the prevention and treatment of heart failure: why are they 'under-used'?

Abstract: Currently there is concern that ACE inhibitors are not being utilised to their maximum potential for the prevention or treatment of heart failure. Underutilisation of ACE inhibitors has been attributed to a lack of appropriate medical education of physicians. However, an alternative explanation is that the trials have failed to answer important questions about how ACE inhibitors should be used in heart failure and that physician prescribing is appropriate to the current state of knowledge. The lack of evidence of benefit in patients with heart failure over the age of 75 years and of any substantial controlled trial in patients with apparent heart failure and well-preserved left ventricular systolic function, a common finding in elderly patients, may be common reasons why ACE inhibitors appear to be prescribed infrequently for heart failure.

Plasma neuro-endocrine activity in very elderly subjects and patients with and without heart failure

Abstract: Marked neuro-endocrine activation in patients with heart failure indicates a worse prognosis and a greater prognostic benefit from the use of ACE inhibitors. However, although the incidence of heart failure rises rapidly with age, relatively little is known about activation of the renin-angiotensin and sympathetic nervous system in patients with heart failure over the age of 75 years. This study was undertaken to investigate plasma concentrations of neurohormonal variables in elderly patients referred to the cardiac clinic with a presumptive, but unconfirmed, diagnosis of heart failure, and to compare these values to plasma concentrations found in age-matched normal subjects. Fifty patients referred with a diagnosis of heart failure were studied. All were receiving a diuretic but not an ACE inhibitor. Patients with renal, haematological and valve disease were excluded Routine biochemistry and neuro-hormonal measurements were performed at their first visit, together with an electrocardiogram, chest X-ray and a full clinical examination by an experienced cardiologist. An echocardiogram and Doppler study was also performed and the diagnosis of heart failure either confirmed or refuted. Plasma concentrations of neuro-endocrine variables in healthy elderly subjects were similar to our normal laboratory range in younger subjects with the exception ofatrial natriuretic peptide (ANP) (40 ± 6 pg. ml−1, normal range <40) and noradrenaline (5.7±0.7 nmol. l−1), normal range <2.8). Impairment of left ventricular systolic function was confirmed in 38 of the 50 symptomatic patients (76%) and was associated with increases in plasma concentrations of active renin (58 ± 8 IU. mol−1 P<0.001 compared to healthy elderly subjects), angiotensin II (23 ± 5pg. ml−1, P<0.008), noradrenaline (7.7±1.2 nmol. l−1, P<0.01) and atrial natriuretic peptide (121 ± 18 pg. ml−1, P<0.002). Plasma concentrations were similar in normal subjects and those receiving treatment for heart failure but in whom the diagnosis was not confirmed A weak relationship between plasma atrial natriuretic peptide (ANP) and left ventricular fractional shortening was demonstrated (r= −0.5, P<0.001). Using an upper limit of ANP in the healthy elderly subjects of 62 pmol. ml−1 (mean+SD), plasma concentrations of ANP in the population with suspected heart failure had a sensitivity of 74% and specificity of 66% for the diagnosis of heart failure among elderly patients in the community or where access to echocardiography is limited. Left ventricular diastolic filling (assessed by Doppler) was abnormal in healthy elderly subjects and patients with heart failure, and appeared of limited value in the diagnosis of heart failure secondary to diastolic dysfunction. This study confirms that the renin-angiotensin system is activated in elderly patients with heart failure treated with diuretics. ANP may be helpful in diagnosing heart failure where it appears to have a complimentary role to echocardiography.

ACE inhibitors in heart failure. What dose

Abstract: The role of ACE (angiotensin converting enzyme) inhibitors in the treatment of heart failure is now well established. A large body of published work has demonstrated relief ofsymptoms, increased exercise performance, a reduction in hospital admissions and superiority to conventional vasodilators. Three large survival studies (CONSENSUS-1,' V-HEFT II,2 and SOLVD3 have also shown that enalapril can alter the natural history of heart failure with a significant improvement in long-term prognosis. Similarly, the SAVE,4 AIRE,5 ISIS 4,6 and GISSI 37 studies demonstrated an improvement in prognosis following myocardial infarction with captopril, ramipril, and lisinopril. Many more ACE inhibitors have recently become available. The British National Formulary now lists five for the treatment of cardiac failure. The clinical benefit of these drugs to patients is beyond doubt and they now represent a cornerstone in the treatment of heart failure.8 However, there are a number of important unresolved issues with regard to their clinical use. The most important of these is the optimal dose required to achieve the full benefit of ACE inhibitor action. The target doses of theACE inhibitor used in each study are summarised in the box. For the most part, these target doses were achieved. For example, in CONSENSUS-I the mean dose of enalapril was 18.4 mg daily. Despite these high-dose protocols market research has shown that, in general practice, much lower doses of ACE inhibitors are being used for the treatment of chronic heart failure. When enalapril is used, 42% of the doses are 5 mg or less, 75% of the doses of captopril are 75 mg or less and 65% of lisinopril prescriptions are for 10 mg or less. The information from the large outcome studies is mostly based on higher doses but it is possible that significant clinical benefit in terms of symptoms is being achieved at these lower doses. Alternatively, general practitioners may be cautious in increasing the dose ofanACE inhibitor because they are concerned with the possibility of precipitating hypotension, reducing renal function, or causing cough. Certainly many doctors remain wary ofACE inhibitors in heart failure and refer patients to a local physician to initiate therapy in hospital. Some patients may be started on an ACE inhibitor in hospital at the lowest dose, but never have this dose increased when they return to the community. The actual reasons are, at present, unknown. However, since low-dose ACE inhibitor therapy has become common practice in the treatment of heart failure, there is a need to ascertain whether the benefits observed in terms of the nature history at high doses, will similarly be achieved with the lower dose regimens.

Genetic testing for familial hypertrophic cardiomyopathy in newborn infants.

Abstract: Identification of genes for hypertrophic cardiomyopathy has made preclinical diagnosis possible in families with a mutation. As yet, however, no treatment prevents the development of myocardial hypertrophy, and medical intervention has not been shown to improve prognosis. A team from Hammersmith Hospital carrying out research into genetic causes of the disease report that they were asked by a couple to screen their daughter at birth. The couple also give their view of screening. We asked two medical geneticists, a cardiologist, and a paediatrician with an interest in ethics to comment on the implications. Hypertrophic cardiomyopathy is inherited as an autosomal dominant but has considerable genetic and phenotypic heterogeneity.1 2 Clinical screening is inaccurate. Several patients from affected families in whom the diagnosis had previously been excluded by electrocardiography and echocardiography have since been shown to have a mutation of the cardiac β myosin heavy chain gene MYH7.3 Once a mutation of MYH7 has been identified in a family genetic testing is relatively …

Clinical Trials Report: Cardiovascular & Renal: Ongoing and planned clinical trials in chronic heart failure and left ventricular dysfunction

Abstract: Chronic heart failure (CHF) remains an extremely disabling disease with high mortality. Current therapy for CHF encompasses unloading drugs (e.g., the loop diuretics), inotropic agents (e.g., digoxin) and inhibitors of the sympathetic nervous system (e.g., β-blockers) and renin-angiotensin-aldosterone system (e.g., angiotensin converting enzyme inhibitors). This report reviews current therapies for CHF, the rationale behind the development of new agents for this indication, and the ongoing and planned clinical trials for the treatment of CHF and left ventricular dysfunction.

Angiography and the aetiology of heart failure.

Abstract: The diagnosis of idiopathic dilated cardiomyopathy should not be made without first performing a coronary angiogram. If the cause of heart failure is unknown this should be stated rather than attributing the cause to dilated cardiomyopathy. Severe ventricular dysfunction may improve dramatically after revascularisation in some cases of coronary disease. Preservation of R waves on the surface electrocardiogram suggests the presence of hibernating myocardium but thallium scintigraphy or positron emission tomography scanning should be employed to investigate this further.