Resting and exercise haemodynamic characteristics of patients with advanced heart failure and preserved ejection fraction.

AIMS: This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP-HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well-characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III-IV and heart failure (HF) hospitalization < 12 months and a 6 min walk test distance < 300 m. Twenty-four (22%) out of 108 patients met the AdHF criteria. On evaluation, clinical characteristics and resting haemodynamics were not different in the two groups. Patients with AdHF had lower work capacity compared with non-advanced patients (35 ± 16 vs. 45 ± 18 W, P = 0.021). Workload-corrected pulmonary capillary wedge pressure normalized to body weight (PCWL) was higher in AdHF patients compared with non-advanced (112 ± 55 vs. 86 ± 49 mmHg/W/kg, P = 0.04). Further, AdHF patients had a smaller increase in cardiac index during exercise (1.1 ± 0.7 vs. 1.6 ± 0.9 L/min/m2 , P = 0.028). CONCLUSIONS: A significantly higher PCWL and lower cardiac index reserve during exercise were observed in AdHF patients compared with non-advanced. These differences were not apparent at rest. Therapies targeting the haemodynamic compromise associated with advanced HFpEF are needed.

Pericardiocentesis practice in the United Kingdom.

BACKGROUND: Pericardial effusions frequently present challenging clinical dilemmas. Whether or not to drain an effusion, and if so by what method, are two common decisions facing cardiologists. We performed a survey to evaluate pericardiocentesis practice in the United Kingdom (UK). METHODS: A total of 640 questionnaires were sent to all cardiologists in the UK Directory of Cardiology in March 2003. RESULTS: A total of 274 (43%) completed questionnaires were returned, 88% from consultants, equally distributed between tertiary referral centres and district general hospitals. More than 1500 procedures were performed, largely using a paraxiphoid approach (89%). Clinical tamponade was the commonest indication for pericardiocentesis (83%). However, the majority of respondents (69%) considered echocardiographic features alone an indication for pericardiocentesis, even in the absence of clinical tamponade. The commonest perceived indications for drainage were right ventricular diastolic collapse and right atrial collapse (69% and 33% of respondents respectively). For guidance, 82% use echocardiography, either alone or with fluoroscopy or the electrocardiogram (ECG) injury trace. 11% employ fluoroscopy alone or with the ECG injury trace. The remaining 11% stated that they would use the ECG injury trace alone or use no guidance. Using the ECG injury trace alone is said by the European Society of Cardiology (ESC) guidelines to offer an inadequate safeguard. Reported complications included ventricular puncture (n = 12, 0.8%) and hepatic damage (n = 4, 0.3%). CONCLUSION: Pericardiocentesis practice varies substantially in the UK. Many cardiologists would perform pericardiocentesis based on echocardiographic features alone. 11% of cardiologists use guidance that is considered inadequate by the ESC guidelines.

Effects of intentional weight loss in patients with obesity and heart failure: a systematic review.

OBJECTIVE: Obesity is an independent risk factor for the development of heart failure, and the two commonly co-exist. The European Society of Cardiology does not provide guidance regarding weight loss strategies in heart failure. The aim of this study was to systematically review the evidence for outcomes following intentional weight loss in patients with heart failure and obesity. METHOD: A systematic review of English articles was undertaken using databases PubMed, Embase and CENTRAL. Randomized controlled trials and observational studies reporting outcomes following intentional weight loss by lifestyle, surgical or pharmacotherapy intervention in patients with obesity and heart failure were included. RESULTS: Four randomized controlled trials and seven observational studies were identified. Two randomized controlled trials used diet and exercise as an intervention, one used diet alone and one used a pharmacological intervention (orlistat). All but one reported significant weight loss. Two reported improvement in exercise capacity and quality of life. One reported improvement in New York Heart Association functional class in heart failure with preserved ejection fraction. The observational studies, five of which reported on outcomes following bariatric surgery, despite being small, heterogeneous and high risk of bias, suggested a trend in improvement of left ventricular function, quality of life and exercise capacity following weight loss. CONCLUSION: Weight loss is achievable with lifestyle intervention in those with heart failure and obesity and may result in improvements in New York Heart Association classification, quality of life and exercise capacity.

Effects of urotensin II in human arteries and veins of varying caliber.

BACKGROUND: -Urotensin II (UII) is the ligand for the GPR14 receptor and the most potent vasoconstrictor in the cynomolgus monkey. UII also contracts rat thoracic aorta. We studied the effect of human UII (hUII) in human blood vessels Methods and Results-Small subcutaneous resistance arteries, internal mammary arteries, saphenous veins, and small subcutaneous veins were studied using standard techniques. Subcutaneous resistance arteries constricted in response to norepinephrine (maximum tension, 2.84+/-0.38 mN/mm; the concentration required to produce 50% of the maximum response [EC(50)], 0.52+/-0.07 micromol/L) and endothelin-1 (maximum tension, 4.19+/-0.93 mN/mm; EC(50), 1.6+/-0.1 nmol/L). hUII did not contract these arteries, internal mammary arteries, or either type of vein, but it was a potent vasoconstrictor in rat thoracic aorta (maximum tension, 2.36+/-0.2 mN/mm; EC(50), 1.13+/-0.36 nmol/L). CONCLUSIONS: -hUII has no vasoconstrictor action in human arteries and veins of different sizes and vascular beds. Marked species differences in the actions of UII question its importance in human cardiovascular regulation.

Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(11)(D)-Ala(12)] angiotensin I in human dorsal hand veins: in vivo demonstration of non-ace production of angiotensin II in humans.

BACKGROUND: [Pro(11)(D)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II-generating pathway exists in human dorsal hand veins. METHODS AND RESULTS: Using a modified Aellig technique, we studied the response to Ang I and [Pro(11)(D)-Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean+/-SEM venoconstrictor response of 45+/-11%, 40+/-10%, 55+/-8%, and 4+/-4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro(11)(D)-Ala(12)] Ang I induced a mean venoconstrictor response of 42+/-9%, 49+/-9%, 48+/-10%, and 54+/-11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro(11)(D)-Ala(12)] Ang I. CONCLUSIONS: We have demonstrated that [Pro(11)(D)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.

Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease.

OBJECTIVES: We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF). BACKGROUND: Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF. METHODS: Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat. RESULTS: In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01). CONCLUSIONS: Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Adrenomedullin selectively inhibits angiotensin II-induced aldosterone secretion in humans.

OBJECTIVE: Adrenomedullin inhibits angiotensin II stimulated aldosterone production in vitro and in vivo in experimental animals. The aim of this study was to investigate the effect of adrenomedullin on angiotensin II and adrenocorticotrophic hormone-stimulated aldosterone production in vivo in healthy humans. DESIGN AND METHODS: Seven volunteers were studied in a quiet, temperature-controlled laboratory. After 35 min of rest, an infusion of placebo or adrenomedullin (3 pmol/kg per min) was given over 60 min; 15 min after starting this first infusion, a second infusion of angiotensin II (0.96 fmol/kg per min) or adrenocorticotrophic hormone (0.1 mIU/kg per min) was co-infused and continued for 45 min. RESULTS: Adrenomedullin significantly inhibited angiotensin II stimulated aldosterone production: the increment in aldosterone on the placebo day was 691 pmol/l compared with 552 pmol/l on the adrenomedullin day (P< 0.004). Adrenomedullin did not inhibit adrenocorticotrophic hormone-stimulated aldosterone or cortisol release. CONCLUSION: Adrenomedullin selectively inhibits angiotensin II-stimulated aldosterone production.

Altered diaphragm position and function in patients with chronic heart failure.

BACKGROUND: Breathlessness is a common symptom experienced by patients with chronic heart failure (CHF) but its etiology remains controversial. Various molecular and histological adaptations have been reported for the diaphragm in CHF but their functional consequences are poorly described. AIMS: This study aims to determine the position and function of the diaphragm in CHF patients. METHODS: The diaphragm position was measured, relative to the renal pelvis, by ultrasound in 20 CHF patients and ninety controls matched for age and body mass. The extent and velocity of diaphragm movement was also measured during quiet breathing and sniffing. RESULTS: At the end of expiration, the diaphragm was significantly nearer to the renal pelvis in CHF patients (89.3+/-16.8 vs. 96.3+/-19.2 mm, P<0.05) and also moved further during quiet breathing (18.2+/-4.4 vs. 12.7+/-4.6 mm, P<0.001) and sniffing (23.9+/-7.4 vs. 18.2+/-5.7 mm, P<0.005). Velocity of diaphragm movement was also increased in CHF patients during quiet breathing (26.5+/-8.2 vs. 15.9+/-6.1 mm s(-1), P<0.001). CONCLUSIONS: These data demonstrate that the position and function of the diaphragm is altered in CHF.

Novel neuropeptides in the pathophysiology of heart failure: adrenomedullin and endothelin-1.

The clinical success of neurohumoral manipulation by ACE inhibitors and beta blockers in heart failure has led to new therapeutic approaches. New neurohumoral factors are now viewed as offering the potential for treatment interventions. Not only do we consider blocking the production of deleterious hormones, but also, more recently, consideration has been given to augmenting the actions of factors with potentially beneficial actions. Hopefully such manipulation of ADM and ET-1 can result in further improvement in the well-being of heart failure patients.

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

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.

Transthoracic echocardiography: a survey of current practice in the UK.

BACKGROUND: Echocardiography is one of the cornerstones of cardiovascular investigation. The escalating demands on echocardiography services necessitate close examination of how we organize our departments on a day-to-day basis, in order to provide a consistent, high-quality service. AIM: To evaluate current transthoracic echocardiography practice in the UK. DESIGN: National postal survey. METHODS: A questionnaire was sent to the chief cardiac physiologist (CP) of every hospital in the UK with echocardiographic facilities. RESULTS: Three hundred and thirty six echocardiographic departments were identified. One hundred and twenty six (37.5%) completed questionnaires were returned. In 87% of hospitals, CPs both performed and reported over 80% of echocardiograms. Fifty-seven percent of CPs and 22% of doctors performing echocardiography held an accreditation in echocardiography. Only 60% of hospitals had formal criteria that had to be met prior to an operator being allowed to report echocardiograms unsupervised. Fewer than half of hospitals regularly audited their echocardiography service. Both outpatient and inpatient waiting times for echocardiography were highly variable and frequently excessive. Fewer than half of hospitals used modern techniques for assessing diastolic function, mechanical dyssynchrony or severity of mitral regurgitation. CONCLUSION: In the UK, many transthoracic echocardiograms are performed and reported by operators without formally assessed competence. Fewer than half of hospitals regularly audited their service or used modern echocardiographic techniques. Services are likely to be improved by developing and instituting mandatory national guidelines.

"Diastolic heart failure" or heart failure caused by subtle left ventricular systolic dysfunction?

OBJECTIVES: To determine whether patients with suspected heart failure but preserved systolic function, as determined by conventional echocardiographic measures (often said to have "diastolic heart failure), might have subtle left ventricular systolic dysfunction detectable by a new measure of left ventricular systolic function-left ventricular systolic atrioventricular plane displacement. DESIGN: Observational study. SETTING: Direct access echocardiography. PATIENTS: 147 patients with suspected heart failure referred by general practitioners. MEASUREMENTS: Echocardiographic assessment of conventional measures of left ventricular systolic function (fractional shortening, ejection fraction (by Simpson's biplane method) and "eyeball" assessment) and measurement of left ventricular systolic atrioventricular plane displacement. RESULTS: Between 21% and 33% of patients with "normal" left ventricular systolic function by conventional methods were found to have abnormal left ventricular systolic atrioventricular plane displacement. CONCLUSIONS: Approximately one quarter of patients with suspected heart failure but preserved systolic function by conventional methods have abnormal atrioventricular plane displacement. These patients with suspected heart failure but preserved systolic function by conventional echocardiographic measures may have heart failure caused by subtle systolic dysfunction rather than isolated "diastolic heart failure".

Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure.

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.