Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK

Objective: To evaluate the cost of atrial fibrillation (AF) to health and social services in the UK in 1995 and, based on epidemiological trends, to project this estimate to 2000. Design, setting, and main outcome measures: Contemporary estimates of health care activity related to AF were applied to the whole population of the UK on an age and sex specific basis for the year 1995. The activities considered ( and costs calculated) were hospital admissions, outpatient consultations, general practice consultations, and drug treatment ( including the cost of monitoring anticoagulant treatment). By adjusting for the progressive aging of the British population and related increases in hospital admissions, the cost of AF was also projected to the year 2000. Results: There were 534 000 people with AF in the UK during 1995. The direct'' cost of health care for these patients was pound 244 million (similar toE350 million) or 0.62% of total National Health Service ( NHS) expenditure. Hospitalisations and drug prescriptions accounted for 50% and 20% of this expenditure, respectively. Long term nursing home care after hospital admission cost an additional pound46.4 million (similar toE66 million). The direct cost of AF rose to pound459 million (similar toE655 million) in 2000, equivalent to 0.97% of total NHS expenditure based on 1995 figures. Nursing home costs rose to pound111 million (similar toE160 million). Conclusions: AF is an extremely costly public health problem.

Use of real-time three-dimensional echocardiography to measure left atrial volume: Comparison with other echocardiographic techniques

Objectives: Left atrial (LA) volume (LAV) is a prognostically important biomarker for diastolic dysfunction, but its reproducibility on repeated testing is not well defined. LA assessment with 3-dimensional. (3D) echocardiography (3DE) has been validated against magnetic resonance imaging, and we sought to assess whether this was superior to existing measurements for sequential echocardiographic follow-up. Methods: Patients (n = 100; 81 men; age 56 +/- 14 years) presenting for LA evaluation were studied with M-mode (MM) echocardiography, 2-dimensional (2D) echocardiography, and 3DE. Test-retest variation was performed by a complete restudy by a separate sonographer within 1 hour without alteration of hemodynamics or therapy. In all, 20 patients were studied for interobserver and intraobserver variation. LAVs were calculated by using M-mode diameter and planimetered atrial area in the apical. 4-chamber view to calculate an assumed sphere, as were prolate ellipsoid, Simpson's biplane, and biplane area-length methods. All were compared with 3DE. Results: The average LAV was 72 +/- 27 mL by 3DE. There was significant underestimation of LAV by M-mode (35 +/- 20 mL, r = 0.66, P < .01). The 3DE and various 2D echocardiographic techniques were well correlated: LA planimetry (85 +/- 38 mL, r = 0.77, P < .01), prolate ellipsoid (73 +/- 36 mL, r = 0.73, P = .04), area-length (64 +/- 30 mL, r = 0.74, P < .01), and Simpson's biplane (69 +/- 31 mL, r = 0.78, P = .06). Test-retest variation for 3DE was most favorable (r = 0.98, P < .01), with the prolate ellipsoid method showing most variation. Interobserver agreement between measurements was best for 3DE (r = 0.99, P < .01), with M-mode the worst (r = 0.89, P < .01). Intraobserver results were similar to interobserver, the best correlation for 3DE (r = 0.99, P < .01), with LA planimetry the worst (r = 0.91, P < .01). Conclusions. The 2D measurements correlate closely with 3DE. Follow-up assessment in daily practice appears feasible and reliable with both 2D and 3D approaches.

Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: Effects in human, rat and guinea-pig tissues in vitro and in pigs in vivo

1. We have investigated the cardiovascular pharmacology of the crude venom extract (CVE) from the potentially lethal, very small carybdeid jellyfish Carukia barnesi, in rat, guinea-pig and human isolated tissues and anaesthetized piglets. 2. In rat and guinea-pig isolated right atria, CVE (0.1-10 mu g/mL) caused tachycardia in the presence of atropine (I mu mol/L), a response almost completely abolished by pretreatment with tetrodotoxin (TTX; 0.1 mu mol/L). In paced left atria from guinea-pig or rat, CVE (0.1-3 mu g/mL) caused a positive inotropic response in the presence of atropine (1 mu mol/L). 3. In rat mesenteric small arteries, CVE (0.1-30 mu g/mL) caused concentration-dependent contractions that were unaffected by 0.1 mu mol/L TTX, 0.3 mu mol/L prazosin or 0.1 mu mol/L co-conotoxin GVIA. 4. Neither the rat right atria tachycardic response nor the contraction of rat mesenteric arteries to CVE were affected by the presence of box jellyfish (Chironex fleckeri) antivenom (92.6 units/mL). 5. In human isolated driven right atrial trabeculae muscle strips, CVE (10 mu g/mL) tended to cause an initial fall, followed by a more sustained increase, in contractile force. In the presence of atropine (I mu mol/L), CVE only caused a positive inotropic response. In separate experiments in the, presence of propranolol (0.2 mu mol/L), the negative inotropic effect of CVE was enhanced, whereas the positive inotropic response was markedly decreased. 6. In anaesthetized piglets, CVE (67 mu g/kg, i.v.) caused sustained tachycardia and systemic and pulmonary hypertension. Venous blood samples demonstrated a marked elevation in circulating levels of noradrenaline and adrenaline. 7. We conclude that C. barnesi venom may contain a neural sodium channel activator (blocked by TTX) that, in isolated atrial tissue (and in vivo), causes the release of transmitter (and circulating) catecholamines. The venom may also contain a 'direct' vasoconstrictor component. These observations explain, at least in part, the clinical features of the potentially deadly Irukandji syndrome.

PKC-alpha-mediated remodeling of the actin cytoskeleton is involved in constitutive albumin uptake by proximal tubule cells

One key role of the renal proximal tubule is the reabsorption of proteins from the glomerular filtrate by constitutive receptor-mediated endocytosis. In the opossum kidney (OK) renal proximal tubule cell line, inhibition of protein kinase C (PKC) reduces albumin uptake, although the isoforms involved and mechanisms by which this occurs have not been identified. We used pharmacological and molecular approaches to investigate the role of PKC-α in albumin endocytosis. We found that albumin uptake in OK cells was inhibited by the pan-PKC blocker bisindolylmaleimide-1 and the isoform-specific PKC blockers Go-6976 and 2',3,3',4,4'-hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether, indicating a role for PKC-α. Overexpression of a kinase deficient PKC-α(K368R) but not wild-type PKC-α significantly reduced albumin endocytosis. Western blot analysis of fractionated cells showed an increased association of PKC-α-green fluorescent protein with the membrane fraction within 10-20 min of exposure to albumin. We used phalloidin to demonstrate that albumin induces the formation of clusters of actin at the apical surface of OK cells and that these clusters correspond to the location of albumin uptake. These clusters were not present in cells grown in the absence of albumin. In cells treated either with PKC inhibitors or overexpressing kinase-deficient PKC-α(K368R) this actin cluster formation was significantly reduced. This study identifies a role for PKC-α in constitutive albumin uptake in OK cells by mediating assembly of actin microfilaments at the apical membrane.

Attenuation of cardiovascular remodeling in DOCA-salt rats by the vasopeptidase inhibitor, omapatrilat

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 2 g, n=114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure.

Is pulse palpation helpful in detecting atrial fibrillation? A systematic review

Background Atrial fibrillation in the elderly is common and potentially life threatening. The classical sign of atrial fibrillation is an irregularly irregular pulse. Objective The objective of this research was to determine the accuracy of pulse palpation to detect atrial fibrillation. Methods We searched Medline, EMBASE, and the reference lists of review articles for studies that compared pulse palpation with the electrocardiogram (ECG) diagnosis of atrial fibrillation. Two reviewers independently assessed the search results to determine the eligibility of studies, extracted data, and assessed the quality of the studies. Results We identified 3 studies (2385 patients) that compared pulse palpation with ECG. The estimated sensitivity of pulse palpation ranged from 91% to 100%, while specificity ranged from 70% to 77%. Pooled sensitivity was 94% (95% confidence interval [CI], 84%-97%) and pooled specificity was 72% (95% CI 69%-75%). The pooled positive likelihood ratio was 3.39, while the pooled negative likelihood ratio was 0.10. Conclusions Pulse palpation has a high sensitivity but relatively low specificity for atrial fibrillation. It is therefore useful for ruling out atrial fibrillation. It may also be a useful screen to apply opportunistically for previously undetected atrial fibrillation. Assuming a prevalence of 3% for undetected atrial fibrillation in patients older than 65 years, and given the test's sensitivity and specificity, opportunistic pulse palpation in this age group would detect an irregular pulse in 30% of screened patients, requiring further testing with ECG. Among screened patients, 0.2% would have atrial fibrillation undetected with pulse palpation.

Remodeling of extracellular matrix at ovulation of the bovine ovarian follicle

Using immunohistochemistry and RNA analyses we examined the fate of components of a newly identified matrix that develops between granulosa cells (focimatrix, abbreviated from focal intraepithelial matrix) and of the follicular basal lamina in ovulating bovine ovarian follicles. Pre- and postovulatory follicles were generated by treatment with estradiol (Day 1), progesterone (Days 1-10), and prostaglandin analogue (Day 9) with either no further treatment (Group 1, n = 6) and or with 25 mg porcine LH (Day 11, Group 2, n = 8 or Day 10, Group 3, n = 8) and ovariectomy on Day 12 (12-14 hr post LH in Group 2, 38-40.5 hr in Group 3). In the time frame examined no loss of follicular basal lamina laminin chains beta 2 and gamma 1 or nidogen 1 was observed. In the follicular basal lamina collagen type IV alpha 1 and perlecan were present prior to ovulation; after ovulation collagen type IV alpha 1 was discontinuously distributed and perlecan was absent. Versican in the theca interna adjacent to the follicular basal lamina in preovulatory follicles was not observed post ovulation, however, the granulosa cells then showed strong cytoplasmic staining for versican. Expression of versican isoforms V0, V1, and V3 was detected at all stages. Focimatrix was observed in preovulatory follicles. It contained collagen type IV alpha 1, laminins beta 2 and gamma 1, nidogen 1 and perlecan and underwent changes in composition similar to that of the follicular basal lamina. In conclusion focimatrix and the follicular basal lamina are degraded at ovulation. Individual components are lost at different times.

Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats

The pleiotropic effects of statins represent potential mechanisms for the treatment of end-organ damage in hypertension. This study has investigated the effects of rosuvastatin in a model of cardiovascular remodeling, the DOCA-salt hypertensive rat. Male Wistar rats weighing 300 to 330 g were uninephrectomized (UNX) or UNX and treated with DOCA (25 mg subcutaneously every fourth day) and 1% NaCl in the drinking water. Compared with UNX controls, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, inflammation with perivascular and interstitial cardiac fibrosis, endothelial dysfunction, and prolongation of ventricular action potential duration at 28 days. Rosuvastatin-treated rats received 20mg/kg/d of the drug in 10% Tween 20 by oral gavage for 32 days commencing 4 days before uninephrectomy. UNX and DOCA-salt controls received vehicle only. Rosuvastatin therapy attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation, but did not modify hypertension or vascular dysfunction. We conclude that the pleiotropic effects of rosuvastatin include attenuation of aspects of cardiovascular remodeling in the DOCA-salt model of hypertension in rats without altering systolic blood pressure.

Vitamin D action and regulation of bone remodeling: Suppression of osteoclastogenesis by the mature osteoblast

Vitamin D acts through the immature osteoblast to stimulate osteoclastogenesis. Transgenic elevation of VDR in mature osteoblasts was found to inhibit osteoclastogenesis associated with an altered OPG response. This inhibition was confined to cancellous bone. This study indicates that vitamin D-mediated osteoclastogenesis is regulated locally by OPG production in the mature osteoblast.