Hormone replacement therapy and adverse outcomes in women with atrial fibrillation: an analysis from the atrial fibrillation follow-up investigation of rhythm management trial.

BACKGROUND AND PURPOSE: Hormone replacement therapy (HRT) use has been related to thromboembolism, but whether HRT increases adverse outcomes in females with atrial fibrillation is uncertain. METHODS: We used the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data set that included 1594 women (39.3% of the population, mean age 71±8), of whom 376 (23.6%) were taking HRT at baseline. The primary end point, a composite of all-cause death, stroke, systemic/pulmonary embolism, and myocardial infarction, and secondary outcomes (ie, each individual end point) and major bleeding, were considered. RESULTS: HRT was not independently associated with the primary end point (hazard ratio=0.894; 95% confidence interval, 0.658-1.214; P=0.473) or any secondary outcome. Age (P<0.001), diabetes mellitus (P<0.001), previous stroke (P=0.011), and heart failure (P<0.001) predicted the primary end point. Lack of association between HRT and the primary end point was confirmed in a propensity score-matched control group (hazard ratio=0.966; 95% confidence interval, 0.663-1.409; P=0.858). CONCLUSIONS: HRT does not independently predict mortality, thromboembolism, or bleeding in a large cohort of women with atrial fibrillation.

Genetic diversity of the KCNE1 gene and susceptibility to postoperative atrial fibrillation.

BACKGROUND: The human KCNE1 protein forms the ß-subunit of the IKs potassium channel and is important in the regulation of the atrial action potential duration. The purpose of this study was to investigate the association between the nonsynonymous 112G>A mutation of the KCNE1 gene and postcardiac surgery atrial fibrillation (AF). METHODS AND RESULTS: A cohort of patients scheduled for cardiac surgery was prospectively recruited. The genotype of 112G>A polymorphism was determined using polymerase chain reaction/restriction fragment analysis and confirmed with direct sequencing of the polymerase chain reaction product. In total, 509 patients were recruited in the study, of whom 203 (39.9%) had at least 1 qualifying episode of postoperative AF. An increased frequency of the G allele was observed in the postoperative AF group compared with the group without postoperative AF (0.628 vs 0.552, respectively, P = .016). The individual's relative risk of postoperative AF increased as the number of G alleles increased from 1.36 (95% CI 0.89-2.08) for G allele heterozygotes to 1.62 (95% CI 1.08-2.43) for G allele homozygotes (P = .04 for trend). The multivariate analysis revealed the abnormal ejection fraction (odds ratio [OR] 1.585, 95% CI 1.076-2.331, P = .020), age (OR 1.043, 95% CI 1.022-1.064, P < .001), type of surgery (aortic valve replacement) (OR 1.869, 95% CI 1.094-3.194, P = .022), and the 112G>A genotype (OR 1.401 [in additive model], 95% CI 1.052-1.865, P = .021) to be independent predictors of postoperative AF. CONCLUSION: This study confirmed the association of the 112G>A polymorphism and postoperative AF in a cohort of patients undergoing cardiac surgery.

Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial.

AIMS: Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF). METHODS AND RESULTS: AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 ± 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl ≥60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort. CONCLUSION: Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

Chemokines and atherosclerosis: focus on the CX3CL1/CX3CR1 pathway.

Atherosclerosis is currently considered an inflammatory disease. Much attention has been focused on the potential role of inflammatory mediators as prognostic/diagnostic markers or therapeutic targets of atherosclerotic cardiovascular disease. CX3CL1 (or fractalkine) is a structurally and functionally unique chemokine with a well documented role in atherosclerosis. In its membrane bound form it promotes the firm adhesion of rolling leucocytes onto the vessel wall, while in its soluble form it serves as a potent chemoattractant for CX3CR1-expressing cells. Additionally, CX3CL1 exerts cytotoxic effects on the endothelium as well as anti-apoptotic and proliferative effects on vascular cells, affecting the context and stability of the atherosclerotic plaque. Studies on animal models have shown that the blockade of the CX3CL1/CX3CR1 pathway ameliorates the severity of atherosclerosis, while genetic epidemiology has confirmed that a genetically-defined less active CX3CL1/CX3CR1 pathway is associated with a reduced risk of atherosclerotic disease in humans. Although several studies support an important pathogenic role of CX3CL1/CX3CR1 in atherogenesis and plaque destabilization, this does not necessarily suggest that this pathway is a suitable therapeutic target or that CX3CL1 can serve as a prognostic/diagnostic biomarker. Further studies on the CX3CL1/CX3CR1 chemokine pathway are clearly warranted to justify the clinical relevance of its role in atherosclerosis.

Chemokines in respiratory viral infections: focus on their diagnostic and therapeutic potential.

Chemokines are small chemoattractant cytokines involved in cell trafficking and activation. Despite the general nonspecific nature of chemokine activity in certain instances, specific chemokine expression patterns have been associated with specific disease states. In the field of respiratory viral infection, evidence suggests that response to viral invasion is regulated by a distinct chemokine expression profile involving more CC chemokines than CXC chemokines. Moreover, among the CC chemokines, CCL3 and CCL5 appear to be most commonly implicated in viral respiratory disease. Most data available in this field have been derived from in vitro studies, as well as studies conducted in animal models with limited evidence obtained in settings of actual human disease. In the present review, we focus on the diagnostic, prognostic, and therapeutic potential of virus-induced chemokine activity as reflected by studies conducted in actual disease states, either in animal models or humans. We further discuss whether these data advocate chemokines as a realistic clinical tool for the management of viral infection.

The right ventricle in health and disease: insights into physiology, pathophysiology and diagnostic management.

Until recently, the right ventricle (RV) received little attention in adult patients with congenital heart disease and even less attention in the setting of acquired heart failure. However, in the last two decades, our perspective towards the right side of the heart has begun to change. Advances in imaging modalities have permitted the accurate study of RV physiology and made it apparent that RV function is an important determinant of prognosis in heart failure irrespective of the underlying etiology. This article summarizes the existing data on the unique anatomical and physiological features of the RV. The hemodynamic conditions and cellular and biochemical pathways that lead to right heart failure are presented. Moreover, the imaging modalities that aid in the assessment of RV structure and function are described and the importance of the diagnostic and prognostic information they provide is discussed.

Antiplatelet therapy in stroke prevention.

Ischemic stroke is a major cause of death and disability worldwide. Determination of the underlying stroke mechanism is critical for the optimization of treatment. The role of antiplatelet therapy in primary and secondary stroke prevention is of major significance. Antiplatelet agents predominantly in use are aspirin, clopidogrel, and combination regimens. Novel antiplatelet agents either in use or in advance clinical development seek an indication in the management of stroke patients; yet data are limited. The present review focuses on the optimization of antithrombotic therapy in the field of primary and secondary prevention of stroke, based on data obtained from randomized controlled trials and systemic reviews of the literature.

The unmet need of stroke prevention in atrial fibrillation in the far East and South East Asia.

The prevalence of atrial fibrillation (AF) is high in both community- and hospital-based studies in the Far East and South East Asia. Hypertension is the most common risk factor, but coronary heart disease and diabetes mellitus are other important co-morbidities in these countries. Anticoagulant therapy use was low, being 0.5%-28% in Malaysia, Singapore, and China. The reported rate of stroke related to AF was 13.0%-15.4% based on community studies in those countries, and was 3.1%-24.2% of stroke rate in hospital-based cohorts. Better assessment of thromboembolic and bleeding risks is important. International guidelines now recommend the use of the CHA2DS2-VASc score to identify the ''truly low-risk'' AF patients, who do not need antithrombotic therapy, whilst those with ≥ 1 stroke risk factors can be offered oral anticoagulation. Aspirin is ineffective and may not be any safer than oral anticoagulants, especially in the elderly. It is anticipated that the availability of the new oral anticoagulant drugs would improve our efforts for stroke prevention in the Far East and South East Asia, especially where anticoagulation monitoring for warfarin is suboptimal.

Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease.

Atherosclerosis is an inflammatory disease. The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development. Chemokines are crucial mediators in every step of this process. Additionally, cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions. However, until recently data were mostly focusing on leukocytes and platelets. Erythrocytes were considered unreceptive bystanders and limited data supported their importance in the progression and destabilization of the atherosclerotic plaque. Recently erythrocytes, through their Duffy antigen receptor for chemokines (DARC), have been proposed as appealing regulators of chemokine-induced pathways. Dissimilar to every other chemokine receptor DARC possesses high affinity for several ligands from both CC and CXC chemokine sub-families. Moreover, DARC is not coupled to a G-protein or any other intracellular signalling system; thus it is incapable of generating second messages. The exact biochemical role of erythrocyte DARC remains to be determined. It is however challenging the fact that DARC is a regulator of almost every CC and CXC chemokine ligand and therefore DARC antagonism could effectively block the complex pre-inflammatory chemokine network. In the present review we intent to provide recent evidence supporting the role of erythrocytes in atherosclerosis focusing on the erythrocyte-chemokine interaction through the Duffy antigen system.

Levosimendan reduces plasma cell-free DNA levels in patients with ischemic cardiomyopathy.

Heart failure (HF) is a condition associated with the apoptosis and cell death of both cardiac myocytes and cardiac non-myocytes. DNA fragments released from programmed cell death or acute cellular injury are the main sources of disease-associated elevation of cell-free (cf) DNA. We hypothesized that cfDNA could be a relevant marker of cardiac apoptosis in HF patients that could be affected by the improvement of myocardial performance. To test our hypothesis, we measured plasma cfDNA in 19 patients with ischemic HF and severe left ventricular (LV) systolic dysfunction before and 12 h after completion of levosimendan infusion. Echocardiographic and biochemical markers of LV diastolic pressure and LV systolic function were also assessed. In accordance with previous observations levosimendan improved echocardiographic and biochemical indices of LV function. Plasma cfDNA was significantly reduced in HF patients post-levosimendan treatment (median: 89.4, interquartile range: 87.1 to median: 25.9, interquartile range: 12.3, P = 0.028). Notably, in 15/19 patients there was a reduction in cfDNA levels post-levosimendan infusion; while in 12/19 patients, a more than 50% reduction in plasma cfDNA was observed. Since cfDNA is a marker of tissue injury and apoptosis these results indicate that improvement of LV function has a potential impact on cell preservation and survival. Further studies are needed to substantiate our promising results regarding the role of plasma cfDNA as a marker of HF.

ECG changes in hospitalised patients with COVID-19 infection.

The coronavirus disease 2019 (COVID-19) commonly involves the respiratory system but increasingly cardiovascular involvement is recognised. We assessed electrocardiogram (ECG) abnormalities in patients with COVID-19. We performed retrospective analysis of the hospital's COVID-19 database from April to May 2020. Any ECG abnormality was defined as: 1) new sinus bradycardia; 2) new/worsening bundle-branch block; 3) new/worsening heart block; 4) new ventricular or atrial bigeminy/trigeminy; 5) new-onset atrial fibrillation (AF)/atrial flutter or ventricular tachycardia (VT); and 6) new-onset ischaemic changes. Patients with and without any ECG change were compared. There were 455 patients included of whom 59 patients (12.8%) met criteria for any ECG abnormality. Patients were older (any ECG abnormality 77.8 ± 12 years vs. no ECG abnormality 67.4 ± 18.2 years, p<0.001) and more likely to die in-hospital (any ECG abnormality 44.1% vs. no ECG abnormality 27.8%, p=0.011). Coxproportional hazard analysis demonstrated any ECG abnormality (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.12 to 3.47, p=0.019), age (HR 1.03, 95%CI 1.01 to 1.05, p=0.0009), raised high sensitivity troponin I (HR 2.22, 95%CI 1.27 to 3.90, p=0.006) and low estimated glomerular filtration rate (eGFR) (HR 1.73, 95%CI 1.04 to 2.88, p=0.036) were independent predictors of in-hospital mortality. In conclusion, any new ECG abnormality is a significant predictor of in-hospital mortality.

Therapeutic implications of chemokine-mediated pathways in atherosclerosis: realistic perspectives and utopias.

Current perspectives on the pathogenesis of atherosclerosis strongly support the involvement of inflammatory mediators in the establishment and progression of atherosclerostic lesions. Chemokine-mediated mechanisms are potent regulators of such processes by orchestrating the interactions of inflammatory cellular components of the peripheral blood with cellular components of the arterial wall. The increasing evidence supporting the role of chemokine pathways in atherosclerosis renders chemokine ligands and their receptors potential therapeutic targets. In the following review, we aim to highlight the special structural and functional features of chemokines and their receptors in respect to their roles in atherosclerosis, and examine to what extent available data can be applied in disease management practices.

Apical hypertrophic cardiomyopathy associated with multiple coronary artery-left ventricular fistulae: a report of a case and review of the literature.

We present a rare case of multiple coronary artery-left ventricular (LV) fistulae, associated with apical hypertrophic cardiomyopathy in an 83-year-old woman with electrocardiographic abnormalities and a history of arterial hypertension and paroxysmal atrial fibrillation. In order to evaluate the clinical significance and obtain further insights into this unusual disease, the patient has undergone coronary angiography, left ventriculography, and magnetic resonance imaging which better substantiated the structural abnormalities of the LV and the coronary network.

Angiotensin II up-regulates CX3CR1 expression in THP-1 monocytes: impact on vascular inflammation and atherogenesis.

The potential regulatory effect of angiotensins on circulating mononuclear cell activation and migration has not yet been thoroughly evaluated. Using flow cytometry we assessed the possible effect of angiotensin I and II on the expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) in THP-1 monocytes, Jurcat T lymphocytes and primary monocytes-isolated from healthy donors. Fluorescence intensity and the rate of chemokine-positive cells was measured in naïve cells and cells treated with angiotensin I and II. Neither angiotensin I nor angiotensin II exhibited any effect on fluorescence intensity and the rate of CX3CR1-, CCR5- and CXCR4-positive cells in primary peripheral blood mononuclear cells and Jurkat T cells. However, angiotensin II significantly increased the rate of CX3CR1-positive THP-1 cells. This effect was not attenuated by the pre-incubation of THP-1 cells with the AT-1 receptor blocker losartan, suggesting that this was not an AT-1-mediated effect. Angiotensin I and II had no effect on fluorescence intensity and the rate of CCR5- and CXCR4-positive THP-1 cells. In conclusion, angiotensin II increases the rate of CX3CR1-positive THP-1 cells. By extrapolating this in vitro observation to disease mechanisms, we speculate that angiotensin II induces up-regulation of CX3CR1 and promotes firm adhesion of circulation CX3CR1-positive monocytes on CX3CL1 expressing endothelial cells inducing vascular inflammation and atherogenesis.

Interleukin 8 gene polymorphisms and susceptibility to restenosis after percutaneous coronary intervention.

Interleukin-8 is a strong mediator of inflammation and has been implicated in the biochemical pathways involved in a wide range of inflammatory diseases including atherosclerosis. We investigated the potential influence of two common functional polymorphisms of the interleukin (IL)-8 gene: -251A/T and 781C/T on susceptibility to in stent restenosis (ISR) following percutaneous coronary intervention (PCI). The hypothesis was tested by screening for the prevalence of the above polymorphisms in 201 coronary artery disease (CAD) patients subjected to PCI and presenting with symptoms or signs of recurrent ischemia. Patients were angiographically re-evaluated and formed the ISR group (n = 73) and the non-ISR group (n = 128) based on the presence or absence of ISR. One hundred and forty-seven subjects without angiographic evidence of CAD formed a reference control group (non-CAD group). A borderline statistically significant higher frequency of the TT(251)TT(781) combined genotype was observed in patients with ISR on re-evaluation compared with patients with normal follow-up angiography. The predominance of TT(251)TT(781) was independent of conventional risk factors for cardiovascular disease. Consequently, T(251)T(781) haplotype was significantly more common in the ISR group. The above observations indicate that the genetic diversity of the IL-8 gene influences patient susceptibility to ISR and suggests the implication of IL-8-mediated pathways in the process of ISR. However, the rarity of T(251)T(781) haplotype makes any clinical application of the above observations unfeasible.

Genetic variability of the distal promoter of the ST2 gene is associated with angiographic severity of coronary artery disease.

Genetic polymorphy of the distal promoter region of the ST2 gene influences transcriptional activity and susceptibility to atopic dermatitis and asthma. Based on the inflammatory background of atherosclerosis we hypothesized that ST2 distal promoter genetic polymorphy could also affect susceptibility to coronary artery disease (CAD). To test our hypothesis we performed direct sequencing of a 825 bp locus of the distal promoter -with previously reported significant polymorphy in 63 angiographically diagnosed CAD patients and 63 age and sex matched controls with negative coronary angiography. We identified 13 polymorphisms spanning this region two of which (-27307 T/A and -27614 C/A) had allele frequencies greater than 0.05. We further genotyped 111 subjects by applying allele-specific real-time PCR for the -27307 T/A and 27614 C/A polymorphisms, thereby increasing our sample to 129 CAD patients and 108 age- and sex-matched controls. We identified no phenotype-genotype interactions between cases and controls. However, among case subjects the severity of CAD expressed as a mean number of diseased vessels was greater in -27307 A allele carriers and either allele carriers (-27614 A or -27307 A) than in non-carriers (2.56 ± 0.73 vs. 1.83 ± 0.84, adjusted P = 0.027; 2.47 ± 0.74 vs. 1.8 ± 0.83, adjusted P = 0.023). Additionally, either allele carriers (-27614 A or -27307 A) were significantly more common in the multi-vessel disease group (n = 54) than in the single-vessel disease group (n = 75). In conclusion, we reported two new polymorphisms in the distal promoter region of the ST2 gene that possibly influence susceptibility to severe CAD. The functional impact of these polymorphisms remains to be determined.

British Society of Echocardiography Departmental Accreditation Standards 2019 with input from the Intensive Care Society.

This article sets out a summary of standards for departmental accreditation set by the British Society of Echocardiography (BSE) Departmental Accreditation Committee. Full accreditation standards are available at www.bsecho.org. The BSE were the first national organisation to establish a quality standards framework for departments that support the practice of individual echocardiographers. This is an updated version which recognises that, not only should all echocardiographers be individually accredited as competent to practice, but that departments also need to be well organised and have the facilities, equipment and processes to ensure the services they deliver are of an appropriate clinical standard. In combination with individual accreditation, departmental accreditation lays down standards to help ensure safe and effective patient care. These standards supersede the 2012 BSE Departmental Accreditation Standards. Standards are set to cover all potential areas of practice, including transthoracic (level 2) echocardiography, transoesophageal echocardiography, stress echocardiography, training, and emergency (level 1) echocardiography. The emergency echocardiography standard is a new addition to departmental accreditation and has been developed with input from the Intensive Care Society.