New pharmacological strategies for the treatment of heart failure.

Heart failure still carries a high morbidity and mortality, necessitating new approaches for its management. Greater understanding of the pathophysiology of heart failure has opened the way for novel therapeutic approaches, including analogs of natriuretic peptides and drugs that modulate endothelin, cytokine release and endothelial vasoconstriction. Other drugs are undergoing laboratory and clinical trials that will eventually supersede or complement less optimal heart failure treatments. Clinical trials will ascertain if these new strategies in the treatment of heart failure will ultimately be successful in the management of these patients.

A case of resistant hypertension in a 69-year-old man.

A 69-year-old man presented with resistant hypertension, symptoms of calf claudication, faint femoral pulses and relative lower limb hypotension, suggestive of aortic coarctation. CT scanning revealed extensive arterial thrombosis from his lower abdominal aorta to both common iliac arteries as the aetiology of his apparent manifestation of aortic coarctation.

A study of platelet activation in paroxysmal, persistent and permanent atrial fibrillation.

We hypothesized that the 'residual' thromboembolic risk in therapeutically anticoagulated patients undergoing cardioversion could potentially be related to abnormal haemorheology and platelet activation. To test this hypothesis, we firstly investigated the role of haemorheology and platelet activation in patients with paroxysmal and persistent atrial fibrillation (AF), who were compared with healthy controls and patients with permanent AF. Second, we compared these indices in patients with persistent AF, before and after successful cardioversion. We measured indices of haemorheology (haematocrit, plasma viscosity, and fibrinogen), fibrin D-dimer (an index of thrombogenesis and fibrin turnover) and platelet activation (as assessed by platelet aggregation and plasma levels of beta-thromboglobulin, and soluble P-selectin) in 29 patients with paroxysmal AF, 87 patients with permanent AF and 29 healthy controls in sinus rhythm. The effects of cardioversion were studied in 20 patients with persistent AF, who maintained sinus rhythm at 2 months follow-up. Plasma levels of beta-thromboglobulin (P = 0.03) and fibrin D-dimer (P = 0.001) were higher in patients with AF, when compared with controls; the highest levels were seen in those with permanent AF (Tukey's test, < 0.05). Plasma viscosity was significantly higher in the patients with paroxysmal AF compared with healthy controls (P = 0.02). Plasma soluble P-selectin levels and platelet aggregation responses to all four platelet agonists (adenosine diphosphate, collagen, epinephrine and thrombin) in patients with paroxysmal AF and permanent AF were similar to controls. Plasma fibrinogen, viscosity and other markers of platelet activation (including platelet aggregation) were not significantly different in patients with paroxysmal AF, during episodes of AF and sinus rhythm (P = not significant), although mean haematocrit was significantly higher during the episodes of AF compared with episodes of sinus rhythm (P = 0.03). Among the patients with persistent AF who remained in sinus rhythm at 2 months following successful cardioversion, there was a significant decrease in the plasma levels of soluble P-selectin at 2 weeks and 2 months, when compared with baseline (pre-cardioversion) levels (P < 0.001). Haemorheology and platelet aggregation response to agonists did not change significantly, except for a transient increase in platelet aggregation response to collagen at 2 weeks (P = 0.045). In conclusion. abnormal haemostatic and platelet activation in patients with permanent AF are not consistently observed in patients with paroxysmal and persistent AF. Abnormal haemorheology appears to play an important role in patients with paroxysmal AF, especially during the paroxysms of AF. Cardioversion of persistent AF to sinus rhythm appears to decrease the platelet activation, but whether this translates into a beneficial reduction in thromboembolic risk requires further study.

Acquisition of extensive drug-resistant Pseudomonas aeruginosa among hospitalized patients: risk factors and resistance mechanisms to carbapenems.

Extensive drug-resistant Pseudomonas aeruginosa (XDRPA) strains, defined as resistant to all available antipseudomonal antibiotics, have been reported recently. This study aimed to investigate the risk factors for XDRPA acquisition by patients and the resistance mechanisms to carbapenems. From June to November 2007, XDRPA isolates were collected from patients in eight tertiary care hospitals. A case-control study was performed to determine factors associated with XDRPA acquisition. EDTA-imipenem disc synergy tests, and polymerase chain reaction amplification and sequencing were performed to detect the presence of metallo-ß-lactamases (MBLs). Risk factor analysis was performed for 33 patients. Mechanical ventilation [odds ratio (OR) 8.2, 95% confidence interval (CI) 1.3-52.2; P = 0.026] and APACHE II score (OR 1.2, 95% CI 1.0-1.3; P = 0.007) were identified as independent risk factors for XDRPA acquisition. Pulsed-field gel electrophoresis of XDRPA identified clonal epidemic isolates co-existing with sporadic isolates. Eight of 43 (19%) XDRPA isolates were shown to produce MBLs; four produced VIM-2 and four produced IMP-6. This study suggests a major role for mechanical ventilation in XDRPA acquisition. Moreover, pulsed-field gel electrophoresis identified a clonal epidemic within hospitals. Taken together, these results suggest that patient-to-patient transmission contributes to XDRPA acquisition in Korea.

Effects of congestive heart failure on plasma von Willebrand factor and soluble P-selectin concentrations in patients with non-valvar atrial fibrillation.

OBJECTIVE: To examine further the relations of plasma von Willebrand factor (vWf, an index of endothelial damage and dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation) concentrations to the presence and onset of clinical congestive heart failure (CHF) and the degree of left ventricular (LV) dysfunction in patients taking part in the SPAF (stroke prevention in atrial fibrillation) study. METHODS: Plasma concentrations of vWf and sP-sel were measured by enzyme linked immunosorbent assay (ELISA) in 1321 participants in the SPAF III study and related to the presence and onset of clinical CHF, as well as echocardiographic findings. Of the 1321 patients with atrial fibrillation (AF), 331 (25%) had a documented history of clinical heart failure, of which 168 cases were related to a new or recurrent episode of acute decompensated heart failure occurring within the preceding three months. RESULTS: Mean plasma vWf was higher among patients with AF and CHF (154 (29) v 144 (31) IU/dl, p < 0.001), particularly those with acute or recent decompensated symptoms. Patients with severe LV dysfunction on two dimensional echocardiography and low fractional shortening also had significantly higher vWf concentrations than those with no LV dysfunction. CHF patients with clinical features--with (156 (28) IU/dl) and without (152 (31) IU/dl) LV dysfunction--also had higher mean vWf concentrations than patients with asymptomatic LV dysfunction (146 (31) IU/dl, p < 0.001). The presence of mitral regurgitation in CHF was associated with lower vWf concentrations. Plasma sP-sel concentrations were not affected by presence, onset, or severity of heart failure. CONCLUSIONS: CHF may contribute to hypercoagulability and thrombotic risk in AF through increased endothelial damage and dysfunction. Patients with acute or recent decompensated features have the highest degree of endothelial damage and dysfunction. The presence of CHF clinical features was an important determinant of plasma vWf concentrations.

Inhibition of CD10/neutral endopeptidase 24.11 promotes B-cell reconstitution and maturation in vivo.

The common acute lymphoblastic leukemia antigen [(CALLA) CD10, neutral endopeptidase 24.11 (NEP)] is a cell-surface zinc metalloprotease expressed by a subpopulation of early murine B-lymphoid progenitors and by bone marrow stromal cells that support the earliest stages of B lymphopoiesis. In previous in vitro studies in which uncommitted murine hematopoietic progenitors plated on a stromal cell layer differentiate into immature B cells, the inhibition of CD10/NEP increased early lymphoid colony numbers. To further characterize CD10/NEP function during lymphoid ontogeny in vivo, we utilized a Ly5 congenic mouse model in which the lymphoid differentiation of uncommitted hematopoietic progenitors from Ly5.1 donors was followed in sublethally irradiated Ly5.2 recipients treated with a specific long-acting CD10/NEP inhibitor (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta- alanine (SCH32615)). The expression of Ly5.1, B220, and surface IgM (sIgM) was utilized to characterize donor-derived hematopoietic cells (Ly5.1+), B lymphocytes (B220+), and mature B cells (B220+ sIgM+) from the lymphoid organs of recipient animals treated with SCH32615 or vehicle alone. SCH32615-treated animals had higher percentages of Ly5.1+ donor splenocytes than animals treated with vehicle alone (16.9% vs. 10.4%, 63% increase, P = 0.013). Animals treated with the CD10/NEP inhibitor also had relatively more Ly5.1+ splenic B (B220+) cells than vehicle-treated animals (14.4% vs. 8.2%, 75% increase, P = 0.018). To more specifically characterize the effects of CD10/NEP inhibition on B-cell differentiation, Ly5.1+ splenocytes from animals treated with SCH32615 or vehicle alone were analyzed for coexpression of B220 and sIgM. Animals treated with the CD10/NEP inhibitor had a significantly higher percentage of mature donor B cells (Ly5.1+ B220+ sIgM+, 10.2% vs. 5.2%, 90% increase, P = 0.006) and a more modest relative increase in immature donor B cells (Ly5.1+ B220+ sIgM-, 4.7% vs. 3.4%, 38% increase, P = not significant). Taken together, these results suggest that CD10/NEP inhibition promotes the reconstitution and maturation of splenic B cells. Therefore, CD10/NEP may function to regulate B-cell ontogeny in vivo by hydrolyzing a peptide substrate that stimulates B-cell proliferation and/or differentiation.

The impact of coronary heart disease in determining use of hormone replacement therapy in a general practice population.

The use of hormone replacement therapy (HRT) for cardiovascular risk reduction remains uncertain. Although previous epidemiological surveys have suggested a clear benefit and nearly 50% mortality risk reduction with HRT in postmenopausal women, recent randomised trials have largely failed to support this. The epidemiological surveys may have been biased in a number of ways including the possibility that HRT users in these studies may have been healthier and taken a greater interest in modifying cardiovascular risks. The aim of the present study was to determine to what extent the revelations from all these trials have influenced HRT prescribing in general practice, in relation to cardiovascular disease. We reviewed 140 women on HRT and 140 age-matched controls from one city centre general practice in the west of Birmingham who were randomly selected by computer. The main indication for HRT use was presence of symptoms associated with oestrogen deficiency. The prevention of osteoporosis accounted for 7.1% of HRT indications, while the primary prevention of CHD was not an issue discussed by either the patient or the GP. Among non-users, 86.4% did not have a known contraindication and many did not have serum lipid measurements or estimations of cardiovascular risk. There was no difference between HRT users and non-users for smoking habits and presence of cardiovascular risk factors including diabetes, hypertension and coronary heart disease. HRT users were also less likely to undergo investigations, such as cervical smear tests and mammograms. In conclusion, this survey reflects the current uncertainty surrounding the use of HRT for cardiovascular risk prevention. Importantly, women on HRT may not be any healthier than non-users, nor do they seek more preventive care than non-users. This is contrary to previous presumptions that selection and prevention bias were the explanation for the apparent cardioprotective effects of HRT.

Transient disappearance of left bundle branch block pattern: an unusual ECG presentation of acute pulmonary embolism.

A 61 year old man developed acute pulmonary embolism while in hospital. His previous and admission electrocardiograms (ECGs) showed a typical left bundle branch block (LBBB) pattern. Immediately after the onset of acute pulmonary embolism, LBBB disappeared from his body surface ECG with sinus bradycardia, normalisation of QRS duration, prolonged QT interval, and marked T abnormalities to the right precordial leads. Recovery from pulmonary embolism resulted in reappearance of his left bundle branch pattern. Delayed conduction of the previously unaffected right bundle branch resulting in roughly equivalent onset of ventricular activation is the most likely reason. Rate dependent LBBB is also discussed.

Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) carries a poor prognosis with a high mortality rate, frequent hospitalizations and increased risk of thrombotic complications such as stroke. Cytokines may contribute to the progression and prothrombotic state of CHF, including the pro-inflammatory interleukin-6 (IL-6) and the pro-angiogenic vascular endothelial growth factor (VEGF), both of which are raised in CHF. The procoagulant properties of both cytokines may be mediated via tissue factor (TF), a potent clotting activator. We hypothesized that plasma levels of these markers, as well as levels of plasma viscosity, fibrinogen, soluble P-selectin and von Willebrand factor (markers of abnormal rheology, clotting, platelet activation, and endothelial damage, respectively) will be useful in predicting morbidity and mortality in chronic stable CHF. METHODS AND RESULTS: One hundred and twenty consecutive out-patients with chronic stable CHF (92 males; mean [SD] age 64 [11] years, mean [SD] left ventricular ejection fraction of 29 [6]%) were recruited and followed for 2 years during which 42 patients reached a clinical end-point of all-cause mortality and cardiovascular hospitalizations, including stroke and myocardial infarction. Plasma IL-6 (P=0.003) and TF (P=0.013) levels, but not other research indices, were higher in those who suffered events compared with those without events. Predictors of end-points were high (> or =median) TF (P=0.011), and IL-6 (P=0.023) levels, as well as the lowest quartile of a left ventricular ejection fraction (P=0.007). A strong correlation was present between TF and IL-6 levels (r=0.59; P<0.0001) and with VEGF levels (r=0.43; P<0.0001). CONCLUSION: IL-6 and TF are predictors of poor prognosis in chronic CHF, raising the hypothesis that IL-6 may contribute to the progression and thrombotic complications of CHF via its actions on TF expression. Although VEGF did not independently predict outcome in chronic CHF, the possibility arises that it may act with IL-6 to induce TF expression.

A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy.

BACKGROUND: Platelet function may be abnormal in patients with atrial fibrillation (AF) and could be related to abnormal thrombogenesis. The aim of this cross-sectional study was to investigate new aspects of platelet biology in AF, predominantly focusing on platelet activation and the effects of concomitant antiplatelet and anticoagulant therapy. PATIENTS AND METHODS: The study group of 238 patients were (i). 93 patients on no antithrombotic therapy, (ii). 60 patients taking 75-325 mg aspirin/day, and (iii). 85 patients on dose-adjusted warfarin (International Normalised Ratio [INR] range 2.0-3.0). Results were compared with those from 50 age- and sex-matched normal subjects. Platelet markers (plasma beta-thromboglobulin, soluble glycoprotein V [both ELISA]), coagulation markers (fibrin D-dimer [ELISA] and fibrinogen [Clauss]), and platelet aggregation in response to standard platelet agonists were studied. RESULTS: beta-thromboglobulin (P=0.01), soluble glycoprotein V (P<0.001) and fibrin D-dimer (P=0.002) were higher in untreated AF patients compared to healthy controls. AF patients on warfarin had lower fibrin D-dimer (P<0.001) when compared to AF patients on no therapy. Plasma fibrinogen and platelet aggregation was no different between patients with AF and healthy controls. Aspirin use was associated with reduced platelet aggregation response to epinephrine (P=0.01), whilst patients established on warfarin had significantly lower plasma fibrin D-dimer levels. CONCLUSION: AF patients exhibit changes in plasma markers of platelet function but no significant abnormalities of platelet aggregation. However, treatment with warfarin or aspirin failed to demonstrate any significant benefit on platelet activation, although warfarin use was associated with reduced thrombogenesis (fibrin D-dimer). We suggest that platelet activation may not play an important role in the pathogenesis of thromboembolism in AF.