Gregory Y.H. Lip

Improving Stroke Risk Stratification Using the CHADS2 and CHA2DS2-VASc Risk Scores in Patients With Paroxysmal Atrial Fibrillation by Continuous Arrhythmia Burden Monitoring

Background and Purpose— In patients with atrial fibrillation (AF), stroke risk stratification schema do not consider AF parameters. The aim of the study is to assess the impact of combining risk factors with continuous AF burden monitoring. Methods— In this retrospective study 568 patients implanted with a DDDR-P pacemaker (AT-500; Medtronic) and a history of AF were continuously monitored for 1 year. Results— During follow-up, 14 patients (2.5%) had a thromboembolic event. Patients were divided into 3 groups: AF burden ⩽5 minutes per day (AF-free; n=223 [39%]), AF burden >5 minutes but <24 hours per day (AF-5 minutes; n=179 [32%]), and AF burden ≥24 hours (AF-24 hours; n=166 [29%]). Patients were also classified according to CHADS2 and CHA2DS2-VASc risk scores. The discrimination ability of each risk score was evaluated performing a logistic regression analysis and calculating the corresponding C-statistic. The addition of AF burden improved C-statistics: for CHADS2 from 0.653 (P=0.051) to 0.713 (P=0.007); for CHA2DS2-VASc, from 0.898 (P<0.0001) to 0.910 (P<0.0001). Conclusions— The CHA2DS2-VASc score had a high sensitivity to predict thromboembolism. Implementation of device data on AF presence/duration/burden has the potential to contribute to improved clinical risk stratification and should be tested prospectively.

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.

Device-detected subclinical atrial tachyarrhythmias: definition, implications and management—an European Heart Rhythm Association (EHRA) consensus document, endorsed by Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE)

Among atrial tachyarrhythmias (AT), atrial fibrillation (AF) is the most common sustained arrhythmia. Many patients with AT have no symptoms during brief or even extended periods of the arrhythmia, making detection in patients at risk for stroke challenging. Subclinical atrial tachyarrhythmia and asymptomatic or silent atrial tachyarrhythmia often precede the development of clinical AF. Clinical AF and subclinical atrial fibrillation (SCAF) are associated with an increased risk of thromboembolism. Indeed, in many cases, SCAF is discovered only after complications such as ischaemic stroke or congestive heart failure have occurred

Oxidised LDL-lipids alter redox ratio, lipid raft formation and increase amyloid beta production by SHSY-5Y cells

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 [1]. We have investigated the hypothesis that amyloid beta production and neurodegeneration can be driven by oxidised lipids derived from LDL following the loss of blood brain barrier integrity with ageing. Therefore, we have investigated amyloid beta formation in SHSY5Y cells treated with LDL, minimally modified (ox) LDL, and lipids extracted from both forms of LDL. LDL-treated SHSY-5Y cell viability was not significantly decreased with up to 8 μg LDL/2 × 104 cells compared to untreated cells. However, 8 μg oxLDL protein/2 × 104 cells decreased the cell viability significantly by 33.7% (P < 0.05). A more significant decrease in cell viability was observed when treating cells with extracted lipids from 8 μg of LDL (by 32.7%; P < 0.01) and oxLDL (by 41%; P < 0.01). In parallel, the ratio of reduced to oxidised GSH was decreased; GSH concentrations were significantly decreased following treatment with 0.8 μg/ml oxLD-L (7.35 ± 0.58;P < 0.01), 1.6 μg/ml (5.27 ± 0.23; P < 0.001) and 4 μg/ml (5.31 ± 0.31; P < 0.001). This decrease in redox potential was associated with an increase acid sphingomyelinase activity and lipid raft formation which could be inhibited by desipramine; SHSY5Y cells treated with oxLDL, and lipids from LDL and oxLDL for 16 h showed significantly increased acid sphingomyelinase activity (5.32 ± 0.35; P < 0.05, 5.21 ± 0.6; P < 0.05, and 5.58 ± 0.44; P < 0.01, respectively) compared to control cells (2.96 ± 0.34). As amyloid beta production is driven by the activity of beta secretase and its association with lipid rafts, we investigated whether lipids from ox-LDL can influence amyloid beta by SHSY-5Y cells in the presence of oxLDL. Using ELISA and Western blot, we confirmed that secretion of amyloid beta oligomers is increased by SHSY-5Y cells in the presence of oxLDL lipids. These data suggest a mechanism whereby LDL, and more significantly oxLDL lipids, can drive amyloid beta production and cytotoxicity in neuronal cells. [1] Li L, Willets RS, Polidori MC, Stahl W, Nelles G, Sies H, Griffiths HR. Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. Free Radic Res. 2010 Mar; 44(3): 241–8.

Current and emerging pharmacotherapy for ischemic stroke prevention in patients with atrial fibrillation

ABSTRACT Introduction: Atrial fibrillation (AF) is associated with high morbidity and mortality rates due to thromboembolic complications, and anticoagulation is central to the management of this common arrhythmia to prevent acute thromboembolic events. The traditional anticoagulants: heparin, fondaparinux, and vitamin K antagonists (VKA, e.g. warfarin, acenocoumarol or phenprocoumin) have long served as pharmacotherapy for ischemic stroke prophylaxis. Areas covered: In this review article, the authors provide an overview on current and emerging pharmacotherapy for ischemic stroke prevention. Furthermore, they review the data from novel therapeutic targets in the coagulation cascade, and investigational anticoagulant drugs currently assessed in preclinical and clinical studies. Expert opinion: The introduction of nonvitamin K antagonist oral anticoagulants (NOACs) was an important milestone, as these drugs show relative efficacy, safety, and convenience compared to the VKAs. Nevertheless, their clinical use still has some limitations with, for example, patients with severe renal impairment and those with mechanical heart valves, high bleeding risks, lack of standard laboratory monitoring and (some) reversal agents. To overcome some of these limitations, various attempts are now underway to discover new strategies and targets via the hemostatic pathway in order to develop new coagulation inhibiting drugs.

36 Monocyte Subpopulations Counts and Associations with Global Longitudinal Strain in St-Elevation Myocardial Infarction Patients with Normal Ejection Fraction

Introduction Monocytes, with 3 different subsets, are implicated in the initiation and progression of the atherosclerotic plaque contributing to plaque instability and rupture. Mon1 are the “classical” monocytes with inflammatory action, whilst Mon3 are considered reparative with fibroblast deposition ability. The function of the newly described Mon2 subset is yet to be fully described. In PCI era, fewer patients have globally reduced left ventricular ejection fraction post infarction, hence the importance of studying regional wall motion abnormalities and deformation at segmental levels using longitudinal strain. Little is known of the role for the 3 monocyte subpopulations in determining global strain in ST elevation myocardial infarction patients (STEMI). Methodology STEMI patients (n = 101, mean age 64 ± 13 years; 69% male) treated with percutaneous revascularisation were recruited within 24 h post-infarction. Peripheral blood monocyte subpopulations were enumerated and characterised using flow cytometry after staining for CD14, CD16 and CCR2. Phenotypically, monocyte subpopulations are defined as: CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2) and CD14+CD16++CCR2- (Mon3). Phagocytic activity of monocytes was measured using flow cytometry and Ecoli commercial kit. Transthoracic 2D echocardiography was performed within 7 days and at 6 months post infarct to assess global longitudinal strain (GLS) via speckle tracking. MACE was defined as recurrent acute coronary syndrome and death. Results STEMI patients with EF ≥50% by Simpson’s biplane (n = 52) had GLS assessed. Using multivariate regression analysis higher counts of Mon1 and Mon 2 and phagocytic activity of Mon2 were significantly associated with GLS (after adjusting for age, time to hospital presentation, and peak troponin levels) (Table 1). At 6 months, the convalescent GLS remained associated with higher counts of Mon1, Mon 2. At one year follow up, using multivariate Cox regression analysis, Mon1 and Mon2 counts were an independent predictor of MACE in patients with a reduced GLS (n = 21) (Table 2). Abstract 36 Table 1 Monocytes mean florescence intensity (cells/ µl) GLS (%) 7 dayspost infarct GLS (%) 6 monthspost infarct Mon 1Mon 2Phago Mon1Phago Mon 2 R value R2 value P-Value R Value R2 value P-Value 0.880.710.580.32 0.770.500.330.12 0.0010.030.240.03 0.850.740.520.50 0.730.540.270.25 0.0010.020.530.69 Abstract 36 Table 2 Monocytes Hazard ratio/ Mon Cell (CI) P-value Mon1Mon2 1.003 (1.001–1.005)1.006 (1.002–1.011) 0.0060.007 Conclusion In patients with normal or mildly impaired EF post infarction, higher counts of Mon1 and Mon2 are correlated with GLS within 7 days and at 6 months of remodelling post infarction. Adverse clinical outcomes in patients with reduced convalescent GLS were predicted with Mon1 and Mon2 suggestive of an inflammatory role for the newly identified Mon2 subpopulation. These results imply an important role for monocytes in myocardial healing when assessed by subclinical ventricular function indices.

Monocyte subpopulation counts and functional characteristics predict adverse clinical events post ST elevation myocardial infarction

Background Monocytes are implicated in the initiation of the atherosclerotic plaque through to plaque instability and rupture during presentation with an acute coronary syndrome (ACS). Little is known about the predictive role of monocytes on clinical outcome. We studied the role of the three phenotypically and functionally discrete monocyte subpopulations in predicting major adverse cardiac events (MACE)—defined as recurrent ACS, heart failure and death- following ST elevation myocardial infarction (STEMI). Method STEMI patients treated with percutaneous revascularisation, were recruited in the first 24 h post-infarction. Peripheral blood monocyte subpopulations were enumerated and characterised using flow cytometry after staining for CD14, CD16 and CCR2. Phenotypically, monocyte subpopulations are defined as: CD14++CD16−CCR2+ (Mon1), CD14++CD16+CCR+ (Mon2) and CD14+CD16++CCR2− (Mon3) cells. Functionally, monocyte subpopulation activation of nuclear factor κ B (NFκB) was analysed. Activation of NFκB was determined by flow cytometry as the mean fluorescent intensity (MFI) of intracellular κ-B kinase β (IKKβ), as a downstream activation product of the NFkB pathway. MACE events were recorded at follow-up. Results We recruited 96 patients (average age 61.5 years±13.3; 64.6% male). Patients were followed-up for a median of 187 days (112–222 days). MACE events occurred in 14 patients (14.6%). Using logistic regression analysis, increased total monocyte count (p<0.032), Mon2 counts (p<0.047) and Mon3 IKKβ (p<0.013) were significantly predictive of MACE at follow-up (Abstract 125 table 1). Mon2 counts were an independent predictor of MACE after adjusting for age and sex.Abstract 125 Table 1 Monocyte subpopulations and IKKβ predict MACE Monocytes OR (95% CIs) p Value Phenotypic characterisation and enumeration Total Mon 1.002 (1 to 1.004) 0.032 Mon1 1.001 (0.998 to 1.003) 0.111 Mon2 1.008 (1.003 to 1.013) 0.047 Mon3 1.01 (0.999 to 1.022) 0.388 Functional assessment IKKβ Mon1 0.982 (0.944 to 1.022) 0.388 IKKβ Mon2 0.983 (0.948 to 1.019) 0.373 IKKβ Mon3 1.038 (0.993 to 1.086) 0.013 Conclusion Increased total monocyte and Mon2 counts in the first 24 h post infarction is predictive of MACE in STEMI patients. Mon3, despite an assumed role in reparation and fibroblast deposition, are also predictive of MACE. Monocytes remained functionally active throughout the acute and healing phases, and thus may have prognostic implications.

Chapter 4 Hypertension

Non-drug therapy of hypertension is needed more than ever but its application remains much below optimum. The greater need reflects the much larger population of asymptomatic people being identified as mildly hypertensive in whom, if non-drug therapy were even moderately effective, the pressures could be lowered to a level deemed safe without the need for pills. The need is heightened by the increasing recognition that antihypertensive drug therapy, as it has been applied in six large clinical trials, has not clearly provided protection against coronary heart disease (Kaplan, 1986). Although this failure may reflect a misguided attempt to reverse a process that is little related to high blood pressure alone, it may also reflect biochemical abnormalities induced by the drugs (Kuller et al. 1986). Diuretics and P-blockers, the two most widely used drugs today, are particularly suspect for their induction of unfavourable changes in blood lipids (Weidmann et al. 1985). The less than optimum use of non-drug therapy in large part reflects two interrelated factors: first, many practitioners doubt their effectiveness, partly because so few properly controlled trials have been done; second, many patients are unwilling to use them, without ongoing encouragement from many of their physicians on the one hand, but with too many stringent demands by some practitioners who prescribe them on the other. For both practitioners and patients to adopt these non-drug therapies, the demonstration that they will lower the blood pressure without risk or undue interference with the quality of life should be all that is required. To expect proof that they will not only lower blood pressure but also prevent cardiovascular morbidity and mortality is unrealistic and unnecessary. Despite carefully controlled 5to 10-year trials involving over 30000 patients with the use of drugs that are much more potent than any non-drug therapy, we still lack proof that drugs will protect against coronary heart disease. To demand that non-drug therapy, less potent and much more difficult to monitor, must do more than lower the blood pressure before accepting it as worth while, then, immediately negates its use for the treatment of hypertension. I will present a small sample of the recent evidence that various non-drug therapies that can be implemented without risk or undue interference with the quality of life will lower blood pressure. More evidence is available elsewhere (Kaplan, 1985). Many non-drug therapies will also improve overall cardiovascular risk in other waysj e.g. lowering blood lipids, reducing body-weight , improving glucose tolerance. These extra advantages need to be gained by patients with hypertension because they tend to carry more of these other risk burdens than do non-hypertensive people. Untreated hypertensives have been found to have higher prevalences of hypercholesterolaemia (MacMahon & Macdonald, 1986), obesity (Velasquez & Hoffmann, 1985) and glucose intolerance (Modan et al. 1985). In addition, their hypertension may be related to high levels of alcohol consumption (Jackson et al. 1985) and associated with the Type A behaviour pattern (Matthews & Haynes, 1986), all potential targets for broad-based non-drug therapy. Thus, even if such therapy does little for the blood pressure, it may do more for the overall cardiovascular risk status of the patient, which after all is the major goal of medical management.

Chapter 3 Cardiac arrhythmias

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