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Atrial fibrillation (AF) is the most common sustained arrhythmia, that substantially increases morbidity and mortality. AF is gaining in clinical and economic importance, with stroke and thromboembolism being major complications. In this article, the evidence for AF treatment trial of antithrombotic therapy is reviewed. Stroke risk stratification of patients with AF is discussed, and practical recommendations for thromboprophylaxis are presented. [ABSTRACT FROM AUTHOR]

We report a double-blind, multicenter, multinational, placebo-controlled, and well-controlled trial to prove that the sustained-release (SR) formulation of propafenone is superior to placebo in preventing symptoms of paroxysmal atrial fibrillation (AF). A total of 594 patients were enrolled in the qualifying period of the study and 293 patients were randomized at 53 centers. There were significant increases in the arrhythmia-free periods from day 5 of randomization to the first recurrence of symptomatic atrial arrhythmia in the propafenone SR 325 mg twice daily (p = 0.004) and propafenone SR 425 mg twice daily (p = 0.003) treatment groups compared with placebo. The median arrhythmia-free time was 9 days in the placebo group, 35 days in the propafenone SR 325 mg twice daily group, and 44 days in the propafenone SR 425 mg twice daily group. There was a significant reduction in average heart rate during the first recurrence of symptomatic arrhythmia after day 5 in the low-dose propafenone group compared with placebo. The median treatment failure time from day 5 (arrhythmia recurrence, adverse events, and withdrawals) was prolonged from 8 days in the placebo group to 19 days in the propafenone SR 325 mg twice daily group (p = 0.002) and to 24 days in the propafenone SR 425 mg twice daily group (p = 0.006). The percentage of patients with >/=1 serious adverse event was similar in the propafenone SR treatment groups (propafenone SR 325 mg twice daily, 10.0%; propafenone SR 425 mg twice daily, 11.2%) but lower in the placebo group (1.1%). In conclusion, the SR formulation of propafenone is superior to placebo, well-tolerated, and prevents symptoms of paroxysmal AF. [ABSTRACT FROM AUTHOR]

Journal of Human Hypertension (2002) 16, 663–666. doi: 10.1038/sj.jhh.1001457 [ABSTRACT FROM AUTHOR]

Thrombosis is a frequent complication of cancer, so it follows that the presence of a tumour confers a prothrombotic state. Indeed, in patients with cancer, each of the three components of Virchow's triad that predispose for thrombus formation have abnormalities, thus fulfilling the requirement for a prothrombotic or hypercoagulable state. The many signs and symptoms of the prothrombotic state in cancer range from asymptomatic basic abnormal coagulation tests to massive clinical thromboembolism, when the patient may be gravely ill. Many procoagulant factors, such as tissue factor and cancer procoagulant, are secreted by or are expressed at the cell surface of many tumours. Platelet turnover and activity are also increased. Damaged endothelium and abnormalities of blood flow in cancer also seem to play a part, as does abnormal tumour angiogenesis. Some studies have even suggested that these abnormalities may be related to long-term prognosis and treatment. We briefly describe the various clinical manifestations of thrombosis in cancer and discuss the evidence for the existence of a prothrombotic or hypercoagulable state associated with this disease. Further work is needed to examine the mechanisms leading to the prothrombotic state in cancer, the potential prognostic and treatment implications, and the possible value of quantifying indices of hypercoagulability in clinical practice. [ABSTRACT FROM AUTHOR]

Investigates the role of renin-angiotensin-aldosterone system (RAAS) in atrial fibrillation and its potential as a therapeutic target. Overview of atrial fibrillation; Usefulness of the blockade of the RAAS in several cardiovascular disorders; Beneficial effect of losartan in the Losartan Intervention for Endpoint reduction in hypertension trial; Left ventricular hypertrophy; Role of RAAS on thrombogenesis.

Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged. Increased systemic oxidative modification (oxLDL) and nitration is also observed during hypercholesterolemia. We have investigated the hypothesis that disruption of blood brain barrier (BBB) function by oxLDL and their lipids may increase risk of neurodegeneration in later life and that statin intervention can mitigate the effects of hyperlipidaemia in mid-life. LDL isolated from statin-naïve hypercholesterolaemic subjects had higher mobility by agarose gel electrophoresis (Rf;0.53±0.06) and 8-isoprostane F2α concentration (43.5±8.42 pg/ml) compared to control subjects (Rf; 0.46±0.05 and 24.2±5.37 pg/ml respectively; p<0.05). Compared to HMVEC treatment with the LDL-lipids (5 μM) from normolipidaemic subjects, LDL-lipids from hypercholesterolaemic subjects increased barrier permeability (103.4±12.5 Ωcm2 v 66.7±7.3 Ωcm2,P<0.01) and decreased cellular glutathione levels (18.5 nmol/mg v 12.3 nmol/mg) compared to untreated cells (26.2±3.6 nmol/mg). LDL-lipids isolated from normolipidaemic subjects shows reduced risk to damage a BBB model compared with LDL-lipids from hypercholesterolaemic subjects. Moreover, a three month statin-intervention reduced the propensity for LDL-lipids from subjects with hyperlipidaemia to damage HMVEC. Post-statin treatment the cytotoxic and pro-inflammatory effects of LDL lipids disappeared. These data support the hypothesis that in vivo intervention with statins modifies LDL lipid oxidation, exerting a protective effect against in microvascular damage independent of cholesterol concentration. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that an incremental shuttle walk test (ISWT) affects plasma indices of endothelial damage and dysfunction (von Willebrand factor (vWf)), platelet activation (soluble P-selectin), thrombogenesis (D-dimer), fibrinogen, and plasma viscosity more adversely in coronary artery disease (CAD) than in health. ISWT is a standardised walking test that provokes maximal performance and correlates strongly with maximum oxygen uptake.Methods: Research indices were measured before a practice ISWT and immediately after the second ISWT in 53 patients with CAD (48 men, mean (SD) age 59 (10) years) and in 19 matched healthy controls (16 men, 61 (10) years). Data were analysed before and after ISWT.Results: Despite no significant difference in total distance walked between patients and controls, vWf (162 (45) before v 170 (48) UI/dl after) and fibrinogen (2.9 (0.7) v 3.1 (0.7) g/l) concentrations, plasma viscosity (1.63 (0.12) v 1.71 (0.14) mPa.s), and D-dimer (0.20 (interquartile range 0.10-0.30) v 0.21 (0.12-0.31 mg/l; all p < 0.05), but not soluble P-selectin, were significantly increased after ISWT in patients with CAD, even after correction for plasma volume change. Only fibrinogen (2.5 (0.7) v 2.7 (0.7 g/l) and plasma viscosity (1.60 (0.08) v 1.64 (0.08) mPa.s; both p < 0.01) increased among controls. The increment of fibrinogen was significantly higher in patients than in controls (p = 0.035) and correlated with total walking distance (r = 0.46, p < 0.001) and peak heart rate (r = 0.28, p = 0.02). The increment of plasma viscosity rise also significantly correlated with total distance walked (r = 0.66, p < 0.001).Conclusions: ISWT in patients with CAD appears to increase fibrinogen, vWf, and D-dimer compared with healthy controls. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of intensified cardiovascular risk management on soluble markers of platelet, endothelial and rheological function in a population of middle-aged hypertensive patients at high risk of cardiovascular complications.Design: Prospective follow-up study.Subjects and Methods: A total of 159 hypertensive patients [138 male, mean age 64 (+/-8) years] and 80 healthy controls were studied. Plasma levels of soluble P-selectin (sP-sel, a marker of platelet function), von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and rheological indices [fibrinogen (Fib), plasma viscosity (PV), haematocrit (HCT), white blood count (WBC) and platelet count] were measured at baseline and again (in the patients) after 6 months' treatment.Results: As expected, 6 months of intensified cardiovascular risk management resulted in a significant fall in mean blood pressure (BP) and total cholesterol. It also resulted in reduced haematocrit, vWF, sP-sel, WBC and PV levels (all P < 0.001), but not plasma fibrinogen. There were no correlations between the fall in BP and the improvement in any of the research indices.Conclusions: Intensified cardiovascular risk management results in significant improvements in indices of endothelial, platelet and rheological function in a population of hypertensives at high risk of cardiovascular events. These improvements appear to be independent of the degree of change in BP. Given the fundamental role of interactions between the endothelium and circulating blood components in the pathogenesis of hypertensive complications this may be of importance in preventing adverse cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Increasing evidence points toward a prothrombotic state in hypertension and atherosclerosis, conditions associated with thrombosis-related complications, such as myocardial infarction and stroke. We hypothesized that this increased risk of thrombogenesis may be related to endothelial damage/dysfunction and abnormal angiogenesis, and thus, an increased risk of future cardiovascular disease. Thrombogenesis, endothelial damage/dysfunction, and angiogenesis can be assessed by measurement of tissue factor (TF), von Willebrand Factor (vWF), flow-mediated dilatation (FMD), and vascular endothelial growth factor (VEGF), respectively. To test this hypothesis, we measured TF, vWF, FMD, and VEGF in 76 patients with systemic hypertension (71 men; mean age 64; mean blood pressure 167/72 mm Hg), considered additional risk factors such as diabetes, and related them to the patient's 10-year cardiovascular and cerebrovascular risk score using the Framingham equation. Patients were compared with 48 healthy normotensive controls. In these patients, the effects of 6 months of intensified blood pressure and (where appropriate) lipid-lowering treatment were investigated. In our patients, TF, VEGF, and vWF levels were higher, but FMD was lower (all p <0.001) compared with the controls. All markers correlated with each other and with both cardiovascular and cerebrovascular risk scores (all p <0.001). After intensified blood pressure and hypercholesterolemia treatment, total cholesterol, blood pressure, TF, VEGF, and vWF levels all decreased, whereas FMD increased (all p <0.001). Thus, in subjects with hypertension and other risk factors, endothelial damage/dysfunction (and thus, atherogenesis), thrombogenesis, and angiogenesis are abnormal, correlate with overall cardiovascular risk, and importantly, can be related to each other in a "Birmingham Vascular Triangle." Furthermore, these processes are beneficially affected by intensive blood pressure and lipid treatment. [ABSTRACT FROM AUTHOR]

Purpose: To characterise morphological and phenotypical differences between small-size platelet MPs (sPMP) released from resting platelets, thrombin activation and platelet disruption (termed as platelet debris [PD]) using our novel technological approach. Besides, we aimed to assess their prothrombotic properties by evaluating the ability to induce thrombus formation, platelet and monocyte activation ex vivo.Methods: sPMP produced in resting conditions and thrombin stimulation were analysed by high-resolution flow cytometry and transmission electron microscopy. Platelet debris (PD) were produced by platelet disruption. Plasmatic counts of sPMP were analysed in coronary artery disease (CAD) patients (n=40) and healthy controls (HC) (n=40). The effect of sPMP in pathophysiologically relevant doses on platelet and monocyte activation parameters and thrombogenesis was investigated via flow cytometry and thromboelastometry.Results: New generation flow cytometry identifies differences in size, levels and surface molecules of sPMP derived in the absence of stimulus, thrombin activation and platelet disruption. Higher sAMP counts were released under thrombin stimulation compared to resting conditions (p=0.002). CD42b+, CD61+ and CD63+ counts were not altered after thrombin stimulation. Platelets and sPMP after thrombin stimulation did express CD62P (p=0.03). PD and residual platelets after disruption and resting did not express CD62P. Patients with CAD had 2-fold higher sAMP counts compared to sex- and age-matched HC (p=0.003). Addition of sPMP in these pathophysiological doses resulted in platelet degranulation and P-selectin redistribution to the membrane (p=0.019) in a dose and time-dependent manner. Addition of sPMP had no effect in PAC-1 binding. Blood clotting time (CT) decreased after addition of sPMP (p=0.005), but was not affected by PD. Blocking CD62P+ sPMP before blood incubation markedly reverted the effect on thrombus kinetics (p=0.035). In addition, exposure to sPMP stimulated monocytes (different monocyte subsets) expression of intercellular adhesion molecule-1 (all p<0.03) and decreased monocyte interleukin-6 receptor density (all p<0.01). No effect of sPMP was observed on monocyte CXCR4 and CD163 expression.Conclusions: There are significant phenotypic differences between sPMP depending on the stimulus which should be taken into account for future sPMP quantification. The findings of this study demonstrate that, far from platelet debris, sPMP have complex implications as a direct source of downstream platelet, monocyte activation and thrombogenesis, in part through P-selectin expression. [ABSTRACT FROM AUTHOR]

This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0-3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75-325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age < or =75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75-325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S-629S. For patients with AF of > or =48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of > or = 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0-3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non-TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C). [ABSTRACT FROM AUTHOR]