Value of BNP to estimate cardiac risk in patients on cardioactive treatment in primary care.

UNLABELLED: Cardiac dysfunction may be suspected in patients with cardiovascular disease but identifying those with the highest risk is problematic. B-type natriuretic peptide (BNP) is a strong marker of heart failure in un-treated patients. This study evaluates a combined BNP and clinical algorithm for detecting cardiac dysfunction and the risk of death, in patients receiving cardioactive medication. METHODS: 459 stable general practice patients, who were taking typical heart failure drugs for any indication, were included. Echocardiography, ECG, and assay of NT-proANP and BNP (two methods) were performed. Regression models were used to identify items in a Risk Score to detect cardiac dysfunction. RESULTS: A Risk Score based on history of myocardial infarction (1 point), abnormal ECG (2 points), atrial fibrillation (1 point) and raised BNP (1-2 points) detected cardiac dysfunction with an AUC of ROC of 0.85. A Risk Score > or = 2 had a sensitivity of 90%, specificity of 58%, and positive and negative predictive values of 37% and 96%. Risk Score and LVEF<0.36 also predicted mortality. Abnormal BNP defined as either >100 pg/ml (Shionogi), or as age and sex related values, had similar predictive value. CONCLUSION: In patients on cardioactive medication, a structured Risk Score based on raised BNP, history of MI, atrial fibrillation and abnormal ECG was useful for identifying patients for immediate further examination and those who could be evaluated later.

Induction of viral and tumour specific CTL responses using antibody targeted HLA class I peptide complexes.

The production of cytotoxic T cells with specificity for cancer cells is a rapidly evolving branch of cancer therapeutics. A variety of approaches aim to amplify anti-tumour cytotoxic T cell responses using purified peptides, tumour cell lysates or recombinant HLA/peptide complexes in differing antigen presenting systems. Using a two-step biotin-streptavidin antibody targeting system, recombinant HLA-class I/peptide complexes were attached to the surface of B cells via the anti-CD20 B9E9-scFvSA antibody-streptavidin fusion protein. Flow cytometry with a conformation dependant monoclonal antibody to HLA class I indicated that targeted HLA-class I/peptide complexes remain on the surface of B cells in culture for periods in excess of 72 h. PBMCs were stimulated in vitro for 8-14 days using the autologous B cells as antigen presenting cells. Following a single cycle of stimulation specific cytotoxic T cell responses to targeted HLA-A2 complexes containing the M1, BMLF1 and Melan A peptides could be demonstrated by tetramer staining and Cr release assays. With the HLA-A2/BMLF1 complex up to 2.99% of CD8+ve cells were tetramer positive producing 20% lysis (E : T 10 : 1) of CIR-A2 target cells in an in vitro cytotoxicity assay compared to baseline levels of 0.09% tetramer +ve and 2% lysis in the unstimulated population. PBMCs from a healthy donor treated with two cycles of stimulations with targeted HLA-A2/Melan A complexes, demonstrated expansion of the melanA tetramer +ve population from 0.03% to 1.4% producing 15% lysis of Melan A pulsed target cells. With further consideration to the key variables of HLA/peptide complex density, the ratio of stimulator to effector cells and optimum cytokine support, this system should offer an easy and effective method for the in vitro amplification of specific cytotoxic T cell responses and warrants development for the in vivo induction of cytotoxic T cell responses in cancer therapy.

Effect of photodynamic therapy in combination with ionizing radiation on human squamous cell carcinoma cell lines of the head and neck.

Photodynamic therapy (PDT) is a promising treatment modality for head and neck, and other tumours, using drugs activated by light. A second generation drug, 5-aminolaevulinic acid (5-ALA), is a precursor of the active photosensitizer protoporphyrin IX (PpIX) and has fewer side-effects and much more transient phototoxicity than previous photosensitizers. We have investigated the effect of 5-ALA mediated PDT in combination with gamma-irradiation on the colony forming ability of several human head and neck tumour cell lines. The effect of treatments on the DNA cell cycle kinetics was also investigated. Our results indicate that the combination of 5-ALA mediated PDT and gamma-irradiation results in a level of cytotoxicity which is additive and not synergistic. 5-ALA mediated PDT had no discernible effect on DNA cell cycle distributions. gamma-irradiation-induced cell cycle arrest in G2 did not enhance the phototoxicity of 5-ALA.

Cardiac compromise in a patient with Down's Syndrome: a lesson learnt.

A 49 year old burn victim with Down's Syndrome (Trisomy 21) was admitted with 15% body surface area (BSA) superficial burns. This was complicated by a large atrioseptal defect. Her course was stormy with difficulties encountered in managing her fluid status. Adequate fluid resuscitation was difficult to maintain with a fragile compromise between pulmonary insufficiency and renal impairment. She expired 12 days post-injury. Cardiac anomalies are not uncommon in the subgroup of patients with major burns who respond poorly to fluid resuscitation.

In vitro and in vivo effects of a cyclic peptide with affinity for the alpha(nu)beta3 integrin in human melanoma cells.

Expression of the integrin alpha(nu)beta3 has been shown to be associated with increasing metastatic potential in malignant melanoma. It also has a functional role on vascular endothelial cells during angiogenesis. The cyclic oligopeptide cRGDfV is known to bind with high affinity to alpha(nu)beta3. We have investigated the cellular effects of cRGDfV on a panel of human melanoma cell lines in vitro and also on the A375 melanoma cell line growing as xenografts in nude mice. cRGDfV is a potent inhibitor of alpha(nu)beta3-mediated cell adhesion, however, we have found no convincing evidence that integrin ligation by cRGDfV induces apoptosis in melanoma cell lines. However, cRGDfV when administered subcutaneously into nude mice did inhibit the growth of A375 melanoma xenografts. Histological examination of the tumours indicated that this effect was primarily one of angiogenesis inhibition. The results suggest that agents which target the alpha(nu)beta3 integrin may have a useful role as anti-angiogenesis agents in clinical oncology, but that they may not exert a direct effect on alphavbeta3-expressing tumour cells.

Structural and functional assessment of small arteries in patients with chronic heart failure.

The physiological response to a chronically failing heart is the implementation of compensatory mechanisms intended to support blood pressure. These mechanisms, which are not fully understood, increase peripheral vascular tone, thus increasing the strain on the weakened myocardium. This study investigated the structure and function of small arteries from heart failure patients and controls without heart failure in an attempt to identify abnormalities associated with heart failure which may be related to these mechanisms. Small arteries were dissected from gluteal biopsies and studied using wire myography. Arterial morphological parameters were measured and concentration-response curves constructed for a number of vasoconstrictor and vasodilator agonists. Plasma concentrations of neuroendocrine hormones were also measured. There were no morphological differences between small arteries from control subjects and those from patients with chronic heart failure. In heart failure patients, vasoconstrictor responses to endothelin-1 were significantly reduced, although plasma endothelin-1 levels were increased. Arteries from heart failure patients also showed evidence of an impaired neuronal uptake mechanism, since blockade by cocaine had no effect on noradrenaline-induced vasoconstriction in these vessels. These results suggest that small-artery structure is not altered in chronic heart failure and so cannot account for the heightened vascular resistance in this syndrome. However, abnormal neuronal uptake and impaired vasoconstriction in response to endothelin-1 may be associated with the complex compensatory phenomenon involved in heart failure.

Impaired pulmonary diffusion during exercise in patients with chronic heart failure.

BACKGROUND: Pulmonary diffusion is impaired at rest in patients with chronic heart failure (CHF) and has been implicated in the generation of symptoms and exercise intolerance. The aim of this study was to determine whether pulmonary diffusion is impaired during exercise in CHF, to examine its relationship to pulmonary blood flow, and to consider its functional significance in relation to metabolic gas exchange. METHODS AND RESULTS: Carbon monoxide transfer factor (TLCO) and pulmonary blood flow (Q(C)) were measured by a rebreathe technique at rest and during steady-state cycling at 30 W in 24 CHF patients and 10 control subjects. Both patients and control subjects were able to raise TLCO and Q(C) during exercise. However, the patient group had a lower diffusion for a given blood flow (TLCO/Q(C)) both at rest (3.6+/-0.16 and 4.8+/-0.23 mL x L(-1) x mm Hg(-1); P<0.001) and during exercise (2.8+/-0.16 and 3.4+/-0.13 mL x L(-1) x mm Hg(-1) for CHF patients and control subjects, respectively; P<0.05). TLCO/Q(C) was related to the ventilatory equivalent for carbon dioxide (VEVCO(2)) production at 30 W (TLCO/Q(c) versus VEVCO(2), r = -0.58, P<0.01) and to peak exercise oxygen consumption measured during a progressive test (TLCO/Qc versus VO(2peak), r = 0.57, P<0.01) in these patients. CONCLUSIONS: Patients with CHF are able to recruit reserves of TLCO and Q(C) during exercise. However, the TLCO/Q(C) ratio is consistently impaired in these patients and relates to both exercise hyperpnea and peak exercise oxygen consumption. Whether this impairment in alveolar gas exchange is reversible in CHF and therefore is a potential target for therapy has yet to be determined.

Endothelin B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction.

OBJECTIVES: This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist. BACKGROUND: Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1. METHODS: We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. RESULTS: Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. CONCLUSIONS: Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction.

OBJECTIVES: Plasma levels of immunoreactive endothelin-1 (ET-1) are raised in chronic heart failure. Whether plasma ET-1 contributes to the haemodynamic derangement found in chronic heart failure is not known. We investigated the effects of exogenous ET-1 on the pulmonary and systemic vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. METHODS: ET-1 was infused at 1, 5 and 15 pmol/min into a distal pulmonary artery of ten patients with LVD to achieve plasma concentrations of ET-1 similar to those found in patients with heart failure and pulmonary hypertension. Haemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. RESULTS: Systemic haemodynamic changes occurred with ET-1 infusion: mean arterial pressure (100 +/- 3 [standard error of the mean]) to 107 +/- 3 mmHg; p < 0.01) and systemic vascular resistance (1699 +/- 118 to 2033 +/- 135 dynes s/cm5; p < 0.001) rose, while the cardiac index fell from 2.43 +/- 0.17 to 2.20 +/- 0.16 l/min/m2 (p < 0.002). Mean pulmonary artery pressure (21 +/- 2 mmHg) and pulmonary vascular resistance (151 +/- 14 to 147 +/- 14 dynes s/cm5) did not change however. CONCLUSIONS: Exogenous ET-1, when infused to achieve plasma concentrations similar to those in severe heart failure and pulmonary hypertension, causes systemic but not pulmonary vasoconstriction.

Beta-blockers for chronic heart failure: from prejudice to enlightenment.

Experience accumulated from several large trials strongly suggest that beta-blockers should be used for the management of congestive heart failure (CHF). Beta-blockade should be added to conventional therapy such as diuretics, ACE inhibitors, and digoxin, as this was the approach used in the major trials. It is appropriate to treat patients with mild, moderate and, when stable, severe CHF. The benefits obtained include improvements in left ventricular function, reductions in symptoms and morbidity, improvement of quality of life, and delay of clinical progression, reflected by a reduced need for hospitalization and a reduction in mortality. Beta-blockers are much better tolerated, when used appropriately in selected patients, than was previously supposed.

Pulmonary and systemic responses to exogenous endothelin-1 in patients with left ventricular dysfunction.

Plasma levels of immunoreactive endothelin-1 (ET-1) are elevated in chronic heart failure (CHF) and have been reported to correlate closely with pulmonary hemodynamic measurements. We investigated the effects of exogenous ET-1 on the pulmonary vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. ET-1 was infused at 1, 5, and 15 pmol/min into a distal pulmonary artery of 10 patients with LVD. Hemodynamics were measured by a thermodilution catheter and arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. Systemic hemodynamic changes occurred with ET-1 infusion in a dose-dependent fashion. Mean arterial pressure (100 +/- 8-107 +/- 11 mm Hg; p < 0.01) and systemic vascular resistance (1,699 +/- 375-2,033 +/- 427 dynes/s/cm-5; p < 0.001) rose, whereas the cardiac index fell from 2.43 +/- 0.53 to 2.20 +/- 0.491/min/m2 (p < 0.002). However, mean pulmonary artery pressure (21 +/- 7 mm Hg) and pulmonary vascular resistance (151 +/- 43-147 +/- 43 dynes/s/cm-5) did not change. Exogenous ET-1, when infused into patients with LVD, causes systemic but not pulmonary vasoconstriction.

Should all patients with atrial fibrillation receive warfarin? Evidence from randomized clinical trials.

Anticoagulants should be used more widely in patients with atrial fibrillation. Legitimate concerns exist about the risk/benefit ratio in younger patients with no risk factors and in patients over the age of 75 years. Use of lower doses of anticoagulation (potential target range INR of 1.5-2.5) than used heretofore is probably the solution to most of the problems associated with anticoagulation, but conclusive proof of the efficacy of this strategy is needed. Although aspirin may reduce the risk of stroke the effect may be no more than among patients with a similar level of cardiovascular risk factors and in sinus rhythm. As such, aspirin is a valid alternative for patients with atrial fibrillation at a low risk of stroke but should not be used as an excuse to withhold anticoagulants in patients at greater risk. Several larger studies investigating the effects of different intensities of anticoagulation and the use of aspirin-warfarin combinations are underway. Indeed SPAF-III, comparing a combination of low dose warfarin and aspirin with formal anticoagulation has been stopped and reported in March 1996. A summary of the results will appear in the July issue. Identification of the minimum effective dose of warfarin and effective monitoring systems remain a priority.

Detection of microemboli by transcranial Doppler ultrasound.

Doppler ultrasound detection of abnormally high-pitched signals within the arterial waveform offers a new method for diagnosis, and potentially for prediction, of embolic complications in at-risk patients. The nature of Doppler "microembolic" signals is of particular interest in patients with prosthetic heart valves, where a high prevalence of these signals is observed. Monitoring the middle cerebral artery with 2-MHz transcranial Doppler ultrasound (TC-2000, Nicolet Biomedical; Warwick, UK), we looked for microemboli signals in 150 patients (95 women and 55 men), and found 1 or more signals during a 30-min recording in 89% of 70 patients with Bjork-Shiley valves (principally monostrut), 54% of 50 patients with Medtronic-Hall valves, and 50% of 30 patients with Carpentier-Edwards valves (p < 0.001, chi 2). In the patients with Bjork-Shiley valves, the mean number of signals per hour was 59 (range, 42-86; 95% confidence interval), which was significantly higher than the mean in patients with Medtronic-Hall and Carpentier-Edwards valves (1.5[range, 0.5-2.5] and 1 [range, 0-5.3], respectively; both p < 0.04, multiple comparisons. Bonferroni correction). In the patients undergoing serial pre- and postoperative studies, the causative role of the valve implant was emphasized. There was no correlation between the number of emboli signals and a prior history of neurologic deficit, cardiac rhythm, previous cardiac surgery, or the intensity of oral anticoagulation, in patients with prosthetic heart valves. In Bjork-Shiley patients, dual (mitral and aortic) valves were associated with more signals than were single valves. In Medtronic-Hall patients, the signal count was greater for valves in the aortic position than it was for valves in the mitral position. Comparative studies of Doppler emboli signals in other clinical settings suggest a difference in composition or size of the underlying maternal between prosthetic valve patients and patients with carotid stenosis. These studies also suggest that the signals are of gaseous origin in valve patients. The clinical significance of continuing microembolism remains to be determined.

Ultrasound detection of cerebral emboli in patients with prosthetic heart valves.

This study was undertaken in 64 patients, 50 with mechanical and 14 with porcine prosthetic valves, to evaluate the incidence of intracranial emboli and their distribution in the basal cerebral arteries. The patients were studied using transcranial Doppler (EME TC2-64B, Uberlingen, Germany), with a monitoring time of two minutes over each of the internal carotid arteries, middle and anterior cerebral arteries, vertebral arteries and the basilar artery. Sixty-three of the 64 patients were stabilized on warfarin at the time of the study. The incidence of emboli signals was significantly higher in patients with mechanical compared to porcine cardiac valves (88% versus 14%, p < 0.01). The number of emboli signals was significantly higher in the anterior compared with the posterior circulation, with a median of eight signals in the internal carotid arteries (95% confidence interval 5-15), 2.5 in the vertebral arteries (95% confidence interval 1-5.5)(p < 0.03). It was also significantly higher in those patients who had undergone double (aortic and mitral) as opposed to those who had undergone single aortic valve replacement: 18 versus two signals per minute (confidence intervals 5-30.5 versus 0.5-3.5) (p < 0.01). It is concluded that subclinical emboli signals are readily detectable using transcranial Doppler and are common in patients with prosthetic heart valves. Their number depends on both the type and the number of the prosthesis, while their distribution in the basal cerebral arteries is consistent with their cardiac source.