Flosequinan in chronic heart failure: how is exercise capacity improved?

OBJECTIVE: Diuretics, angiotensin converting enzyme inhibitors and digoxin have become "standard" triple therapy for many patients with chronic cardiac failure. Flosequinan increases exercise duration and improves symptoms when added to standard triple therapy. Despite intensive study, the clinical pharmacology of flosequinan remains uncertain. SETTING: The University Hospital of Wales, a Regional Cardiac Centre. PATIENTS: Twenty four patients with chronic heart failure who remained symptomatic despite standard therapy including ACE inhibitors. METHODS: A double-blind placebo-controlled parallel group study of 100 mg daily of flosequinan. We measured changes in exercise duration using cardiorespiratory exercise testing and changes in large artery distensibility using Doppler ultrasound. RESULTS: Exercise duration after 8 weeks flosequinan treatment was significantly greater than following placebo treatment. The flosequinan-related increase in exercise duration (+14%) was associated with a significant reduction in VE/VCO2 slope (-16%). Brachial-radial pulse wave velocities were unaltered by flosequinan treatment. CONCLUSIONS: Our results confirm that flosequinan improves exercise duration in patients with chronic heart failure. They suggest that this observed beneficial effect is independent of any change in large artery distensibility and that in the presence of ACE inhibitors, this improvement may be independent of any vasodilating action of flosequinan. Although this study confirms the beneficial symptomatic effects of flosequinan in chronic cardiac failure, clinical trials have subsequently demonstrated an overall increase in mortality in patients treated with 100 mg flosequinan daily. This has resulted in the withdrawal of flosequinan from routine clinical use.

Cholesterol rich apo B containing lipoproteins and smoking are independently associated with macrovascular disease in normotensive NIDDM patients.

A cross-sectional study of macrovascular disease (MVD) and associated metabolic and other risk factors was conducted in 87 normotensive NIDDM patients. MVD was assessed by Rose questionnaire, 12 lead resting ECG, duplex scanning of carotid and peripheral vessels, and ankle:brachial systolic blood pressure ratio. Fasting serum total cholesterol, total triglycerides, LDL cholesterol, HDL cholesterol, apolipoproteins AI and B, lipoprotein (a), HbA1, plasma glucose, insulin, and C-peptide responses to a carbohydrate rich meal, body mass index (BMI), waist-hip ratio, urinary albumin excretion rate, blood pressure, smoking and family history were assessed as possible 'risk factors'. Apolipoprotein:lipid ratios were calculated to estimate lipoprotein composition. Thirty-six patients had demonstrable MVD. The presence of MVD was associated with higher total triglycerides (p < 0.05), BMI (p < 0.05), systolic blood pressure (p < 0.01), a lower apo B:non HDL cholesterol ratio (p < 0.001), and smoking (p < 0.005) but no other measures. Multiple regression analysis revealed smoking and a low apo B:non HDL cholesterol to be independently associated with MVD. The low apo B:non HDL cholesterol suggests a high cholesterol content of apo B containing lipoproteins. This lipoprotein abnormality is not a feature of NIDDM, but when present in these patients may be particularly atherogenic.

An assessment of the long saphenous vein for potential use as a vascular conduit after varicose vein surgery.

PURPOSE: There is controversy in the surgical management of varicose veins between stripping of the long saphenous vein (LSV) and high ligation. Moreover, preservation of the LSV is desirable for future coronary or peripheral artery bypass. We have studied 75 limbs in 44 patients after high saphenous ligation with multiple stab phlebectomy. METHODS: Subjective assessment of the outcome of surgery was made with a linear analog scale, and objective cosmetic outcome was assessed by an independent observer (LF) who had not been involved in the surgical treatment of these patients with our modification from the criteria first described by Jakobsen. Patency, length, and diameter of the LSV was measured 6 to 14 months (mean 12 months) after operation with a duplex scanner and a color-flow scanner. Valvular incompetence in the LSV and perforators was also assessed. RESULTS: Results show a good subjective and objective outcome in 95% and 97% of limbs, respectively. The LSVs were patent from ankle to groin in 68% and from ankle to knee in 82%, with a mean diameter of 4.0 +/- 0.1 mm (mean +/- SEM). There was no statistically significant difference in symptomatic outcome and presence of reflux in the LSV (X2 = 0.465; p = 0.4954; NS) or objective cosmetic outcome and the presence of reflux in the LSV (chi 2 = 2.916; p = 0.0877; NS). CONCLUSIONS: It is concluded that high saphenofemoral ligation combined with multiple "stab avulsions" preserves an LSV with characteristics suggesting suitability for future use as a vascular prosthesis with good early symptomatic and cosmetic results.

Salivary gland tumours: is colour Doppler imaging of added value in their preoperative assessment?

Using a Toshiba SSA-270A Colour Duplex Scanner, 15 patients with suspected parotid and submandibular gland tumours had preoperative duplex scanning done. Peak systolic doppler shifts (fmax) were recorded and their vascularity was also subjectively scored. There were no arteries identified within the substance of contralateral normal glands. All recordings were analysed retrospectively and an independent histological assessment of tumours was made. Pleomorphic adenomas (n = 9) had a median peak systolic frequency (fmax) of 0.8 kHz, while adenolymphomas (n = 4) had a fmax of 1.65 and the two malignant tumours had fmax of 4.5 (P = 0.007 Kruskal-Wallis test). There appears to be a strong correlation between the fmax and the subjective vascular score (Corr 0.92). Colour duplex scanning is a non-invasive procedure which may be of help in the preoperative assessment of salivary gland tumours.

Postural changes in femoral artery blood flow in normal subjects, patients with peripheral vascular occlusive disease and patients undergoing lumbar sympathectomy, measured by duplex ultrasound flowmetry.

Regulatory peripheral vasoconstriction occurs in response to lower limb dependency. In mildly ischaemic limbs these responses are retained but are lost in patients with rest pain. Previously used methods have inherent difficulties when applied during postural change. We studied orthostatic responses in 12 normal subjects (aged 22-74 years, median 52 years) and 16 patients (aged 21-83 years, median 48 years) with mild and severe peripheral vascular disease using a duplex ultrasound flowmeter. In the normal subjects the 60-s mean common femoral artery volume flow values (ml min-1 +/- S.D.) were 77 +/- 83; -78 +/- 116; -190 +/- 136 for elevation, dependency and standing respectively. For claudicants (n = 7) the values were 18 +/- 37; -112 +/- 123; -216 +/- 103, respectively. In rest pain patients (n = 9) the responses were reversed, being -252 +/- 124; 131 +/- 89 and 184 +/- 85. Significant differences were apparent between elevation, dependency and standing flows, in each of the three groups (all p less than 0.0001). The rest pain group displayed characteristically different responses compared with both normal subjects and claudicants, for each postural change (p less than 0.0001 in all cases). Investigation of the dependency response was undertaken in eight further patients with rest pain before and after lumbar chemical sympathectomy and a characteristic pre-sympathectomy response predicted the clinical outcome.

Effect of postural change on common femoral artery volume flow, measured by duplex ultrasound, in normal subjects and patients with peripheral vascular disease.

Regulatory peripheral vasoconstriction occurs in response to adoption of the erect posture. Mildly ischaemic limbs are thought to exhibit near normal responses, but patients with rest pain show increases in blood flow on limb dependency. Previous methods of limb blood flow quantification (xenon clearance and venous occlusion plethysmography) have inherent difficulties when applied in these situations. We studied orthostatic responses in 12 normal subjects (aged 22-74 years (median 52) and 16 patients (aged 21-83 (median 48) with mild and severe peripheral vascular disease, using a duplex flowmeter system. In the normal subjects changes in the 60s mean, common femoral artery volume flow values were as follows (ml min-1 (1 SD]: 77 (83), -78 (116) and -190 (136), for elevation, dependency, and standing respectively. For claudicants (n = 7) the values were 18 (37), -112 (123) and -216 (103) respectively. In rest pain patients (n = 9) the responses were reversed, being -252 (124), 131 (89) and 184 (85) respectively. Significant differences were apparent between elevation, dependency and standing flows in each of the three groups (P less than 0.0001). Normal subject and claudicant responses on elevation and dependency differed significantly (P less than 0.0001 and 0.03 respectively). On standing, the responses were similarly significantly different. The rest pain group displayed characteristically different responses compared with both normal subjects and claudicants for each postural change (P less than 0.0001 in all cases). Duplex ultrasound volume flowmetry is non-invasive and offers an excellent method of quantifying physiological changes.

The perioperative changes in glomerular filtration and renal blood flow in patients with obstructive jaundice.

Experimental alterations in renal haemodynamics have been observed in obstructive jaundice and these may be the pathophysiological mechanism of increased renal susceptibility to injury in obstructive jaundice. Dynamic 99mTc-DTPA renal scintigraphy was done before and eight weeks after elective hepatobiliary surgery in six patients with obstructive jaundice (bilirubin greater than 100 mumol/l) and in six non-jaundiced control patients to assess changes in glomerular filtration and renal blood flow. Glomerular filtration was lower preoperatively in the jaundiced patients than in the control patients. Glomerular filtration increased postoperatively in jaundiced patients, but decreased in control patients. Renal blood flow was reduced postoperatively in control patients, but not in jaundiced patients. The changes in renal blood flow were different for each group of patients. These results provide clinical evidence of altered renal haemodynamics and a reversible impairment of glomerular filtration in obstructive jaundice. The changes seen in renal blood flow may be the underlying mechanism of increased renal susceptibility to injury.

Effect of enprostil on gastric emptying, intestinal transit time and post-prandial release of gastro-intestinal peptides.

The effect of an oral dose of 70 micrograms enprostil (a prostaglandin E2 analogue) on the post-prandial hormone response to a test breakfast was examined in a double-blind, placebo-controlled, cross-over study in 10 healthy volunteers. Enprostil markedly reduced the post-prandial rises in insulin and glucose-dependent insulinotropic peptide (GIP) but plasma glucose remained unchanged. To study the effects on gut motility 8 healthy volunteers ingested a liquid meal containing 75 g glucose, 20 g lactulose and 99mTc colloid after taking placebo or 70 micrograms enprostil. Gastric emptying, measured using a gamma camera, was unchanged but mouth-to-caecum transit time was significantly longer on enprostil; time to half maximal breath hydrogen: placebo 119 min, enprostil 200 min (p less than 0.05). This delay was associated with a reduced and delayed post-prandial rise in GIP and insulin and with other changes in the gut hormone profile.

Digital and radial artery blood flow in patients with Raynaud's phenomenon in response to nifedipine.

The effect of nifedipine on haemodynamic changes in the hand after cooling in 10 patients with Raynaud's phenomenon is assessed. Nifedipine reduced the fall in digit blood flow induced by cooling and limited the increase in pulsatility index (a measure of peripheral resistance). There was good correlation between digital arterial inflow (measured by strain gauge plethysmography) and radial artery pulsatility index (measured by Doppler waveform analysis).

Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers.

The effect of an infusion of two doses of peptide YY (PYY), a novel putative gastrointestinal hormone, has been assessed on mouth to caecum intestinal transit time and on the rate of gastric emptying after ingestion of an inert 200 ml liquid meal thought unlikely to interrupt fasting gastrointestinal motility patterns. A low dose of PYY was chosen to give plasma concentrations within the range seen postprandially in healthy subjects, while the high dose mimicked the raised levels seen in several malabsorptive conditions. During infusion of PYY at 0.18 pmol/kg/min plasma concentrations rose from a basal of 8 +/- 2 pmol/l to 38 +/- 5 pmol/l and at 0.51 pmol/kg/min to 87 +/- 10 pmol/l. Mouth to caecum transit time was delayed from 67 +/- 4 mins on the saline infusion day to 94 +/- 7 mins (p less than 0.01) on the low dose and 192 +/- 9 mins (p less than 0.001) on the high dose infusion day. Time to 50% gastric emptying was prolonged from 37 +/- 8 mins during saline infusion to 63 +/- 10 mins (p less than 0.05) during low and 130 +/- 12 mins (p less than 0.001) during high dose infusion. Thus the infusion of PYY shows a dose related inhibition of mouth to caecum intestinal transit time and of the rate of gastric emptying and suggests this novel hormonal peptide to be of importance in gastrointestinal physiology.

Effect of a long-acting somatostatin analogue (SMS 201-995) on postprandial gastric emptying of 99mTc-tin colloid and mouth-to-caecum transit time in man.

The effect on gut motility of a single subcutaneous injection of 50 micrograms of the long-acting somatostatin analogue, SMS 201-995, was investigated in 8 normal volunteers who took a drink containing 99mTc and lactulose with a mixed meal. The rate of gastric emptying was assessed by disappearance of the isotope from the stomach area as measured by a gamma camera, and mouth-to-caecum transit time (MCTT) was measured by the appearance of hydrogen in the breath. Gastric emptying was accelerated, with a significant reduction of the time taken to 50% isotope disappearance (37.2 +/- 3.3 min during control study vs 23.3 +/- 3.4 min after SMS injection; p less than 0.01). In contrast, MCTT was prolonged from 57.3 +/- 9.4 min (control) to 203.6 +/- 14.7 min after SMS (p less than 0.001).