Low‐Density Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific

Background: Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex‐specific differential effect of genetically increased low‐density lipoprotein cholesterol (LDL‐C) on cardiovascular disease (CVD) and other lipid‐associated diseases. Methods and Results: This is a 2‐sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80‐variant LDL‐C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex‐specific LDL‐C effects on lipids, carotid‐intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL‐C effect on CVD events was sex specific: per SD genetically increased LDL‐C, female participants had a higher LDL‐C increase but an attenuated CVD risk increase compared with male participants (LDL‐C: female participants 0.71 mmol/L, 95% CI, 0.70–0.72 and male participants 0.57 mmol/L, 95% CI, 0.56–0.59. P for interaction: 5.03×10−60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24–1.40 and male participants: OR, 1.52; 95% CI, 1.46–1.58. P for interaction: 9.88×10−5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL‐C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL‐C was also associated with an attenuated carotid‐intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex‐specific weighted genetic scores showed similar results. Conclusions: We found that genetically increased LDL‐C has a sex‐specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL‐C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL‐C targeted therapies for CVD management than female patients and warranting investigations into the sex‐specific relative contribution of risk factors for CVD

An approach to the diagnosis and management of valvular heart disease

Valvular heart disease poses a common yet difficult problem in everyday clinical practice. A thorough clinical evaluation with basic commoninvestigations such as an electrocardiogram (ECG) and a chest radiograph (CXR) remains the cornerstone of diagnosis. Echocardiographyand more invasive testing, if needed, are usually performed at specialist level to confirm the diagnosis, assess severity and assist in definitivedecision-making.The causes and clinical, ECG and CXR features of the common valve lesions are described. Patients with symptomatic valve lesions shouldbe referred for specialist assessment. In most cases, medical therapy serves as a bridge to definitive mechanical or surgical therapy

An approach to the clinical assessment and management of syncope in adults

Syncope, defined as a brief loss of consciousness due to an abrupt fall in cerebral perfusion, remains a frequent reason for medicalpresentation. The goals of the clinical assessment of a patient with syncope are twofold: (i) to identify the precise cause in order to implementa mechanism-specific and effective therapeutic strategy; and (ii) to quantify the risk to the patient, which depends on the underlying disease,rather than the mechanism of the syncope. Hence, a structured approach to the patient with syncope is required. History-taking remains themost important aspect of the clinical assessment. The classification of syncope is based on the underlying pathophysiological mechanismcausing the event, and includes cardiac, orthostatic and reflex (neurally mediated) mechanisms. Reflex syncope can be categorised intovasovagal syncope (from emotional or orthostatic stress), situational syncope (due to specific situational stressors), carotid sinus syncope(from pressure on the carotid sinus, e.g. shaving or a tight collar), and atypical reflex syncope (episodes of syncope or reflex syncope thatcannot be attributed to a specific trigger or syncope with an atypical presentation). Cardiovascular causes of syncope may be structural(mechanical) or electrical. Orthostatic hypotension is caused by an abnormal drop in systolic blood pressure upon standing, and is defined asa decrease of >20 mmHg in systolic blood pressure or a reflex tachycardia of >20 beats/minute within 3 minutes of standing. The main causes oforthostatic hypotension are autonomic nervous system failure and hypovolaemia. Patients with life-threatening causes of syncope should bemanaged urgently and appropriately. In patients with reflex or orthostatic syncope it is important to address any exacerbating medicationand provide general measures to increase blood pressure, such as physical counter-pressure manoeuvres. Where heart disease is found to bethe cause of the syncope, a specialist opinion is warranted and where possible the problem should be corrected. It is important to rememberthat in any patient presenting with syncope the main objectives of management are to prolong survival, limit physical injuries and preventrecurrences. This can only be done if a patient is appropriately assessed at presentation, investigated as clinically indicated, and subsequentlyreferred to a cardiologist for appropriate management

Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Aims: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL-6 signalling perturbation through IL-6 or IL-6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL-6 or IL-6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL-6 and IL-6 receptor on cardiometabolic risk and potential side effects. // Methods: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL-6 or IL-6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. // Results: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL-filtered results were in concordance with the main results, but with wider confidence intervals. // Conclusions: IL-6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL-6 and IL-6R are potential therapeutic targets to lower CVD. Moreover, IL-6 rather than IL-6R inhibition might have a more favourable pneumonia risk

Spatial distribution of low-energy plasma around 2 comet 67P/CG from Rosetta measurements

International audienceWe use measurements from the Rosetta plasma consortium (RPC) Langmuir probe (LAP) and mutual impedance probe (MIP) to study the spatial distribution of low-energy plasma in the near-nucleus coma of comet 67P/Churyumov-Gerasimenko. The spatial distribution is highly structured with the highest density in the summer hemisphere and above the region connecting the two main lobes of the comet, i.e. the neck region. There is a clear correlation with the neutral density and the plasma to neutral density ratio is found to be ∼1-2·10 −6 , at a cometocentric distance of 10 km and at 3.1 AU from the sun. A clear 6.2 h modulation of the plasma is seen as the neck is exposed twice per rotation. The electron density of the collisonless plasma within 260 km from the nucleus falls of with radial distance as ∼1/r. The spatial structure indicates that local ionization of neutral gas is the dominant source of low-energy plasma around the comet

Observation of a New Type of Low Frequency Waves at Comet 67P/Churyumov-Gerasimenko

We report on magnetic field measurements made in the innermost coma of 67P/Churyumov-Gerasimenko in its low activity state. Quasi-coherent, large-amplitude ($\delta B/B \sim 1$), compressional magnetic field oscillations at $\sim$ 40 mHz dominate the immediate plasma environment of the nucleus. This differs from previously studied comet-interaction regions where waves at the cometary ion gyro-frequencies are the main feature. Thus classical pick-up ion driven instabilities are unable to explain the observations. We propose a cross-field current instability associated with newborn cometary ion currents as a possible source mechanism.Comment: 6 pages, 3 Figure