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Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

Phlegmasia cerulea dolens is a rare presentation of deep venous thrombus treated with catheter directed thrombolysis and pharmacomechanical thrombectomy. This is the case of a 78-year-old woman who underwent catheter directed thrombolysis to treat phlegmasia cerulea dolens and subsequently developed left-sided hemiplegia and expressive aphasia in the setting of an international normalized ratio of 2.0. Further imaging revealed a lacunar infarct in the right thalamus with a middle cerebral artery distribution. Further workup revealed a patent foramen ovale. We highlight the unexpected enigmatic consequence from multimodal endovascular intervention, the consequence of long-term inferior vena cava filters.

Item does not contain fulltext Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

In der Notfallmedizin ist die Durchfuhrung der inhalativen Therapie auch durch Rettungsfachpersonal vorgesehen. Standard Operating Procedures (SOP) und Handlungsempfehlungen zum Einsatz sind nicht bundeseinheitlich und liegen im Falle der Vernebelung von Notfallmedikamenten nicht in allen Bundeslandern und Rettungsdienstbereichen vor. Es existieren auch keine Empfehlungen, welcher Verneblertyp genutzt werden soll. Die Medikamentendepositionsraten von Jet- und Mesh-Verneblern unterscheiden sich aber erheblich; klinisch ist die Verwendung von Mesh-Systemen mit einem besseren Patienten-Outcome assoziiert. Die vorliegende Umfrage sollte die Praxis des Vernebelns von Notfallmedikamenten im suddeutschen Rettungsdienst evaluieren. Ein besonderes Augenmerk wurde auf den eingesetzten Verneblertyp sowie den Einfluss von SOP und Handlungsempfehlungen auf die Anwendung gelegt. Insgesamt 4800 in Baden-Wurttemberg, Bayern und Rheinland-Pfalz tatige Notfallsanitater*innen und Rettungsassistent*innen erhielten insgesamt 17 Fragen zur Durchfuhrung der Medikamentenvernebelung in ihrer alltaglichen Praxis. Der Jet-Vernebler ist mit Abstand der am haufigsten eingesetzte Verneblertyp. Die Depositionsraten sowohl des Jet- als auch des Mesh-Verneblers werden deutlich uberschatzt. Nur 67,3 % aller Befragten vernebelten im Rahmen von SOP oder Handlungsempfehlungen. Das Vorhandensein dieser war allerdings masgeblich fur den Einsatz der Vernebelung ohne Beisein eines*er Notarzt*arztin und die gefuhlte Sicherheit beim Vernebeln. Der flachendeckende Einsatz von Mesh-Verneblern konnte die Therapie von Notfallpatient*innen homogenisieren und moglicherweise das Outcome verbessern. SOP und Handlungsempfehlungen zur Anwendung von Vernebelung in der Notfallsituation konnten die inhalative Therapie verbessern und homogenisieren.

Patients with atrial fibrillation (AF) have a higher risk of dementia and mild cognitive impairment, in addition to a fivefold higher risk of stroke, compared with patients in normal sinus rhythm. Potential mechanisms of cognitive impairment or dementia related to AF include recurrent micro emboli versus cerebral hypoperfusion in association with increased oxidative stress, inflammation and disruption of the blood-brain barrier. Using linked electronic health records from the Clinical Practice Research Datalink in the UK, Cadogan and colleagues1 compared the incidence of dementia or mild cognitive impairment in 39 200 patients (median age 76 years, 45% women) with AF treated with either a vitamin-K antagonist (VKA) or a direct oral anticoagulant (DOAC). Incident dementia was diagnosed in 3.2% with a 16% lower risk of dementia in patients treated with a DOAC versus VKA (adjusted HR 0.84, 95% CI: 0.73 to 0.98) . Mild cognitive impairment was diagnosed in 4.0% with a 26% lower risk in those treated with a DOAC versus VKA (adjusted HR 0.74, 95% CI: 0.65 to 0.84) (figure 1). For patients taking a VKA, greater time with anticoagulation in therapeutic range was associated with a lower risk of dementia. Figure 1 Association between oral anticoagulant use and incident dementia and mild cognitive impairment, defined using clinical codes. ∧Adjusted for age, calendar year, time-on-treatment and sex. *Adjusted for age, calendar year, time-on-treatment, sex, body mass index, smoking status, hazardous alcohol consumption, socioeconomic status (practice level Index of Multiple Deprivation), primary care consultation frequency, diabetes, hypertension, myocardial infarction, statins, heart failure, stroke, vascular disease, renal disease, liver disease, antiplatelet drugs, ACE/ARB inhibitors, beta-blockers, antiarrhythmics, digoxin, diuretics, antipsychotics, antidepressants and proton …

Atrial fibrillation (AF) is a major cause of morbidity and mortality with an increasing prevalence in our ageing population. Yet, we have few effective approaches to identifying patients at risk of AF so that many patients are diagnosed only when they present with a stroke or heart failure. In this issue of Heart , Sanz-Garcia and colleagues1 present a simple ECG-based score that predicts subsequent AF with a predictive value area under the curve (AUC) of 0.776 (95% CI: 0.738 to 0.814). This computer assisted ECG approach was developed and validated in a cohort of 16 316 patients with the risk score based on age (up to four points), P wave duration in lead aVF (>200 ms, 2 points) and lead V4 (>150 ms, 0.7 point), T wave duration in lead V3 >250 ms (0.4 point), mean QTc interval >450 ms (0.3 point), transverse P wave clockwise rotation (0.3 point) and frontal QRS complex clockwise rotation (0.4 point) (figure 1). Figure 1 Probability of AF based on risk score values. Bars show the number of patients in the training cohort for each score value (non-AF in grey and AF in black). The trend line shows the estimated probability of AF. The table below represents the percentage of patients in the training cohort for each score value. AF, atrial fibrillation. In the accompanying editorial, Kashou and Noseworthy2 point out that, compared with clinical AF …

Familial hypercholesterolaemia (FH) is the most common autosomal dominant genetic condition, affecting about 1 in 250 people, caused by a pathogenic variant in one of several genes involved in lipoprotein cholesterol catabolism. Treatment of elevated serum low-density lipoprotein cholesterol in people with FH substantially reduces the risk of ischaemic heart disease and cardiovascular mortality. Yet, the vast majority of FH cases are undiagnosed and, thus, untreated. Diagnosis is challenging because patients typically are asymptomatic, may not know their family history, are unaware of the seriousness of the diagnosis and may not even be seeing a physician regularly. In addition, the phenotypic diagnosis requires more than just serum cholesterol levels. In this issue of Heart , Carvalho and colleagues1 demonstrated the feasibility of the FH Case Ascertainment Tool (FAMCAT) for identifying patients likely to have FH in a cohort of 777 128 primary care patients in London. The FAMCAT score is based on systematic screening of routine primary care records for cholesterol measurements, age, triglycerides, family history, diabetes, kidney disease and current use of lipid-lowering drugs (figure 1). The use of FAMCAT to identify patients likely to have FH could ensure more accurate and rapid diagnosis (and subsequent treatment) for this group of patients at high risk of cardiovascular disease. Figure 1 Risk …

The purpose of this case study was to assess the degree to which a 12-month power-based resistance-training program improved bone mineral density (BMD) and fall risk for a 70-year-old postmenopausal woman with osteoporosis and increased risk of falling. After an eight-week strength-development phase, we had the patient perform 44 weeks of resistance training with maximal force mobilization by instructing her to complete as many repetitions as possible during each 60-s set. We used dual-energy X-ray absorptiometry (DEXA) to assess BMD and Dynamic Gait Index (DGI) to assess fall risk before and after the intervention. Post compared to pre-training testing indicated an increase in BMD in the lumbar spine (24%) and femoral neck (29%) resulting in changes in T-score of 0.7 and 0.4 SD, respectively. Testing also revealed a seven-point change in DGI which improved her status to "safe ambulator." After a 12-month period of power training, BMD was increased and fall risk was reduced for a postmenopausal woman with osteoporosis and increased risk of falling.

Purpose of Review Cardiopulmonary exercise testing (CPET) informs the preoperative evaluation process by providing individualised risk profiles; guiding shared decision-making, comorbidity optimisation and preoperative exercise training; and informing perioperative patient management. This review summarises evidence on the role of CPET in preoperative evaluation and explores the role of novel and emerging CPET variables and alternative testing protocols that may improve the precision of preoperative evaluation in the future. Recent Findings CPET provides a wealth of physiological data, and to date, much of this is underutilised clinically. For example, impaired chronotropic responses during and after CPET are simple to measure and in recent studies are predictive of both cardiac and noncardiac morbidity following surgery but are rarely reported. Exercise interventions are increasingly being used preoperatively, and endurance time derived from a high intensity constant work rate test should be considered as the most sensitive method of evaluating the response to training. Further research is required to identify the clinically meaningful difference in endurance time. Measuring efficiency may have utility, but this requires exploration in prospective studies. Summary Further work is needed to define contemporaneous risk thresholds, to explore the role of other CPET variables in risk prediction, to better characterise CPET’s role in combination with other tools in multifactorial risk stratification and increasingly to evaluate CPET’s utility for preoperative exercise prescription in prehabilitation.

Current guidelines for management of adults with aortic stenosis recommend aortic valve replacement for patients with clinical consequences due to hemodynamically severe valve obstruction. However, advances in surgical and transcatheter techniques, and improved valve design have led to decreased procedural risk and improved long-term outcomes. Transcatheter aortic valve replacement (TAVR) is recommended for patients with prohibitive surgical risk and is reasonable in intermediate and high-risk patients. Recent trials demonstrated favorable short-term outcomes in patients with low surgical risk undergoing TAVR compared with surgical AVR. We review the current Guidelines recommendations and highlight key controversies in management due to evidence gaps.

Atherosclerotic vascular calcification and bone mineral density (BMD) appear to mirror each other—less bone calcification goes hand-in-hand with excess vascular calcification—with plausible biological mechanisms to explain this apparent paradox. But whether the vascular-bone calcification relationship is an independent association or is simply related to the ageing process and shared risk factors has been unclear. In this issue of Heart , Park and colleagues1 investigated the association between BMD and atherosclerotic cardiovascular disease (ASCVD) events in a cohort of 12 681 women aged 50–80 years of age with a median of 9.2 years follow-up after BMD measurement. The primary endpoint of ASCVD death, non-fatal myocardial infarction or ischaemic stroke occurred in 3.7% of patients. As hypothesised, a lower BMD was associated with a higher risk for ASCVD events (adjusted HR 1.38, p

The proportion of cardiologists who are women remains low despite many decades of equal numbers of men and women entering medical school and continues to lag behind other medical specialties with respect to workforce representation. To further define the barriers and challenges facing women who choose to specialise in cardiology, Jaijee and colleagues1 used a validated questionnaire sent to 890 UK consultant cardiologists to measure experiences of sexism and sexual harassment. In contrast to sexual harassment, sexism is defined as acts, words or behaviours that imply a person is inferior because of their sex. Of the 174 respondents, 24% were female. Overall, 62% of female cardiologists experienced some type of discrimination, most often related to gender and parenting, compared to 20% of male cardiologists. Sexual harassment affected professional confidence in 43% of women compared to 3% of men. In addition, sexism limited opportunities for professional advancement in 33% of female cardiologists compared to 2% of male cardiologists. In the accompanying editorial, Babu-Narayan and Ray2 discuss the perceived and actual barriers to improved representation of women in cardiology. ‘There is no doubt that cardiology requires drive, dedication and commitment, but these should not be conflated with a requirement for excessively long working hours, ‘presenteeism’ and the exclusion of outside interests and family life either for men or for women.’ Underrepresentation of women does matter. ‘Lack …

Current clinical cardiovascular disease (CVD) research primarily is ‘about’ patients with CVD but performed by academic researchers with little or no input from the public or patients. As concisely summarised in the Cardiology in Focus article1 in this issue of Heart , public involvement in research both empowers patients and the public and can point researchers towards critical questions or outcomes important to patients. Public involvement in cardiovascular research also has the potential to reduce global inequity in health research. Even so, it can be daunting for a clinical investigator to actively involve patients, other than as enrolled participants, due to lack of knowledge about why or how to do so. The article by Ramakrishnan and Miller provides practical advice, with links to more detailed information online, that will help researchers effectively involve the public in clinical cardiovascular research; an approach that increasingly is considered an essential element of an ethical and rigorous research study (figure 1). Figure 1 Ways that people can be involved in the research cycle (adapted from UK Standards for Public Involvement; https://www.invo.org.uk/). Among adults with congenital heart disease (ACHD), heart failure (HF) is a primary cause of hospitalisation and mortality. In order to better define the healthcare burden of HF in ACHD patients, Burstein and colleagues2 used data from the US Nationwide Emergency Department Sample and the Nationwide …

Racial and ethnic healthcare disparities in cardiovascular care have been magnified during the COVID-19 pandemic. In this issue of Heart , Rashid and colleagues1 compared admission rates, treatment and mortality of black, Asian and minority ethnic (BAME) patients with acute myocardial infarction (AMI) in England in 2020 compared with the 3 previous years. Compared with white patients, a higher proportion of BAME patients were hospitalised with AMI during the pandemic (figure 1). However, in those with AMI, BAME patients less often underwent coronary angiography (86.1% vs 90.0%, p

Rheumatic mitral stenosis (MS) remains the most common type of valvular heart disease worldwide yet there are few studies on optimal timing of intervention in asymptomatic patients. Postulated benefits of intervention before symptom onset include prevention of left atrial dilation, atrial fibrillation (AF) and pulmonary hypertension leading to fewer thromboembolic events, less heart failure, preserved exercise capacity and in improved quality of life. In this issue of Heart , Kang and colleagues1 report a randomised clinical trial of in 374 patients with severe MS (valve area 1.0–1.5 cm2) comparing early percutaneous mitral commissurotomy (PMC) to conventional care. The primary composite endpoint of PMC-related complications, cardiovascular mortality, cerebral infarction and systemic thromboembolic events occurred in seven patients in the early PMC group (8.3%) compared with nine patients in the conventional care group (10.8%) (HR 0.77; 95% CI 0.29 to 2.07; p=0.61) at a median follow-up of 6 years (figure 1). Figure 1 Summary of the MITIGATE (mitral intervention vs conventional management in asymptomatic mitral stenosis) trial. MS, mitral stenosis; PMC, percutaneous mitral commissurotomy. Karthikeyan2 points out that there is only a sparse evidence base for management of mitral stenosis. Although this study by Kang and colleagues1 is commendable, replication in larger studies in countries with endemic rheumatic heart disease is needed. In the meanwhile, ‘even minimally symptomatic patients …

Sex differences in clinical management and outcomes of patients with cardiovascular disease sometimes are due to healthcare inequities (which should be eliminated) but also might be due to sex-related differences in aetiology and pathophysiology. For example, the optimal medical dose for management of heart failure with reduced ejection fraction (HFrEF) may be lower in women compared with men. In a study of 561 women and 615 men with a new diagnosis of either HRrEF or heart failure with preserved ejection fraction (HFpEF), Bots and colleagues1 found that although 79% of women and 86% of men with HFrEF were prescribed an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), the average dose was only about 50% of the recommended target dose for both sexes. A lower ACEI/ARB dose was associated with higher survival outcomes in women, but not men, with HFrEF. In patients of both sexes with HFpEF, there was no relationship between medication dose and survival (figure 1). Figure 1 Central figure summarising the design and main findings of this study. In the accompanying editorial, Hassan and Ahmed 2 comment that: ‘Sex differences in HF outcomes may be further exacerbated by differences in medication pharmacokinetics and pharmacodynamics, with female-specific physiological factors including lower body mass, as well as …

The potential association of recreational substance use and premature atherosclerotic cardiovascular disease (ASCVD) is controversial. In this issue of Heart, Mahtta and colleagues performed a cross-sectional analysis of 135 703 patients with premature ASCVD (first event at age

[ ]in this issue of Heart is a short summary of the key changes in the European Society of Cardiology 2020 Guidelines for management of acute coronary syndromes without ST-elevation 5 A few of the major points are use of 0 and 1 hours rapid rule-out protocols, a preference for prasugrel over ticagrelor in patients undergoing invasive intervention, delayed angiography after resuscitated out-of-hospital cardiac arrest in haemodynamically stable patients and consideration of complete revascularisation in patients with multivessel disease who are not in cardiogenic shock The unfolding story of the interaction between the COVID-19 pandemic and cardiovascular mortality is addressed in a systematic review and meta-analysis showing that despite reduced rates of admission for ST-elevation myocardial infarction (STEMI) during the COVID-19 pandemic, hospital mortality was unchanged 6 Danchin and Marijon7 express the concern that although this apparent decrease in STEMI might be due to an actual decrease in event rates, it also is possible that ‘if the decrease was primarily due to fear of getting admitted in patients actually having had an AMI, we should observe an unusually increased rate in late complications potentially related to larger myocardial infarctions caused by the lack of appropriate management at the acute stage (eg, congestive heart failure or ventricular arrhythmias) ’ The article then focuses on multimodality imaging for ischaemic heart disease;discussing the strengths and limitation of exercise treadmill testing, coronary CT angiography, exercise or pharmacological single-photon emission (SPECT), or positron emission tomographic (PET) myocardial perfusion imaging, stress cardiovascular magnetic resonance or stress echocardiography

Hypertension is a world-wide health burden that increases the risk of adverse cardiovascular outcomes with considerable geographical variation in awareness of the condition, appropriate treatment and blood pressure control. In this issue of Heart , O’Donnell and colleagues1 present the results of a standardised case–control study in 32 countries with over 13 000 cases of acute first stroke matched to controls by age, sex and site. The association of hypertension with stroke was highest in countries with a lower gross national income and higher in younger versus older patients (figure 1). Compared with those with treated hypertension, untreated hypertension was associated with a higher OR for stroke incidence, younger age at first stroke, risk of intracerebral haemorrhage versus ischaemic stroke. Figure 1 Figures report the association of hypertension with stroke by age (A) and GNI (B), demonstrating an increased slope in magnitude of association of hypertension with stroke by reducing age and reducing GNI, which is modified by treatment status. Within increasing intensity of antihypertensive therapy, there is a diminution in slope of curve. While a gradient remains for risk of stroke by age among treatment groups, there is an inversion of gradient by GNI. These figures illustrate that increased uptake of antihypertensive therapy are expected to have greatest impact in younger populations and in lower-income regions. Multivariable model including age, smoking, waist-to-hip ratio, diabetes, physical activity, alternate healthy eating index, alcohol intake, psychosocial factors, apolipoproteins and cardiac risk factors. GNI, gross national income; PAR, population attributable risk. In an editorial, Sarfo2 summarises the concept of population attributable risk (PAR) of hypertension for stroke in high income countries compared with low- and middle-income countries : ‘the PAR of aware and treated hypertension for stroke was 22.2% vs 17.3%, aware …

The potential impact of patient education on improving outcomes in patients with cardiovascular disease (CVD) has received little attention. In a randomised clinical trial, McIntyre and colleagues1 found that waiting room video-based education about CVD risk reduction resulted in more patients being motivated to implement heart healthy behaviours (29.6% vs 18.7%, relative risk 1.63, 95% CI 1.04 to 2.55) and higher levels of satisfaction with the clinic visit. Participants who were also randomised to receive education about cardio-pulmonary resuscitation (CPR) reported greater confidence in performing CPR. Overall, at baseline 16% of patients reported optimal CVD risk factors which increased to 25% at 30 days but there was no difference in improvement between the intervention group and usual care (figure 1). Figure 1 Informational graphic summary of the While You’re Waiting study. In an editorial, White2 comments that ‘Health literacy is an underused resource for improving cardiac outcomes with patients being better able to understand their disease, understand modifications in …

Overweight and obesity are major risk factors for cardiovascular disease (CVD) and meaningful weight loss is associated with a reduction in CVD risk. Yet patients’ efforts at weight reduction often are frustratingly futile. In this issue of Heart , Tijssen and colleagues1 evaluated weight change from baseline to 12-month follow-up in the subgroup of overweight patients (BMI ≥27 kg/m2) with coronary artery disease in the Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists-2 (RESPONSE-2) multicentre randomised trial. The 280 patients in the intervention arm were offered community-based programmes to achieve weight reduction, increase physical activity and stop smoking in addition usual care, which included cardiology visits, cardiac rehabilitation and counselling on secondary prevention. Although there was wide variation in weight loss for patients in both the intervention and usual care groups, participation in a weight loss programme was associated with weight loss of ≥5% (OR 3.33 compared with usual care) (figure 1). Other factors associated with meaningful weight loss were older age, lower educational level, not smoking and motivation to start weight loss at the baseline visit. Figure 1 Waterfall plots; weight change from baseline to …

Acute coronary syndrome due to spontaneous coronary artery dissection (SCAD) typically is managed conservatively because coronary anatomy returns to normal in most patients at follow-up and because there is a high rate of technical failure and complications with percutaneous coronary intervention (PCI). However, a subgroup of these patients is at risk of extensive myocardial infarction and might benefit from PCI, despite the risk of complications. In this issue of Heart , Kotecha and colleagues1 report outcomes in 215 SCAD patients (94% women, median age 48 years with a range of 42–54 years) who underwent PCI for ST-elevation myocardial infarction, cardiac arrest, TIMI grade 0/1 flow or proximal dissection (figure 1). As expected, PCI-related complications were frequent, occurring in 38.6% (83/215), with 13.0% (28/215) of patients suffering a serious complication. Even so, improved TIMI flow was achieved in 84.3% (118/140) with worsened TIMI flow in only 7% of patients. At a median follow-up of 900 days, 9.3% suffered recurrent acute myocardial infarction, 4.7% required further revascularisation, 1.5% had a stroke and 1.4% died. However, there was no difference in outcomes in SCAD-PCI patients compared with a matched cohort of SCAD patients who did not undergo PCI. Figure 1 Details of the PCI procedure in SCAD intervention patients (n=215): (A) interventional strategy, (B) number of stents deployed, (C) stent length compared with lesion length and (D) coronary heat map of stented AHA coronary segments. AHA, American Heart Association; PCI, percutaneous coronary intervention; SCAD, spontaneous coronary artery dissection. Adamson2 reminds us that SCAD …

The role of catheter ablation of atrial fibrillation (AF) in management of patients with paroxysmal AF is controversial. In this issue of Heart , Gupta and colleagues1 report data from a multicentre study of 329 consecutive patients with drug-refractory paroxysmal AF treated with AF ablation by pulmonary vein isolation guided by a standardised CLOSE (contiguous optimised lesions) protocol. Patient reported quality of life (QOL) measures showed significant improvement across all domains at 12 months. In addition, QOL improvement was associated with a lower AF burden, measured by ambulatory monitoring. Overall, cardiovascular hospitalisations decreased by 42% after AF ablation. Patients with the lowest QOL measures at baseline had the most improvement after AF ablation (figure 1). Figure 1 Atrial fibrillation effect on quality of life survey (AFEQT) change versus baseline score. In the accompanying editorial, Elvan2 comments: ‘Significant reduction of the impact of AF on healthcare utilisation and improvement of QOL metrics should be regarded as important and patient-relevant healthcare values gained by catheter ablation of paroxysmal AF. Moreover, Gupta and colleagues1 report an inverse association between the extent of QOL improvement and residual AF burden post-ablation. These results emphasise the importance of incorporating AF-specific QOL …

A key consideration in timing of aortic valve replacement (AVR) for patients with aortic stenosis (AS) is whether there is an increased risk of sudden cardiac death (SCD) that might be reduced by relief of outflow obstruction. Minners and colleagues1 addressed this issue in a retrospective analysis of outcomes in 1840 patients with mild to moderate AS (aortic maximum velocity 2.5–4.0 m/s) in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Overall the annualised rate of SCD was 0.39% per year with 27 events in asymptomatic patients. The most recent echocardiogram prior to SCD showed mild–moderate AS in most (80%) of these patients with no difference in SCD event rates in those who progressed to severe AS compared to those who did not develop severe valve obstruction. On Cox regression analysis, the only independent risk factors for SCD were age (HR 1.06, 95% CI 1.01 to 1.11 per year, p=0.02), increased left ventricular mass index (HR 1.20, 95% CI 1.10 to 1.32 per 10 g/m2, p

Outcomes of patients with an out-of-hospital cardiac arrest (OHCA) remain poor despite considerable efforts in many countries directed towards rapid access defibrillation, emergency medical services and advanced supportive care in those who survive to reach the hospital. Clearly, out long-term goal should be prevention of OHCA which requires an understanding of the environmental factors contributing to this condition, as well as prevention at the individual patient level. In a study from Korea of 38 928 OHCAs due to cardiac disease, Kim and colleagues1 found significant associated between OHCA and average temperature in the summer, temperature range in the winter and particulate matter (PM) ≤2.5 µm (PM2.5) air pollution levels. However, only PM2.5 was independently associated with the risk of OHCA regardless of seasonal changes (figure 1). Figure 1 Generalised additive model with cubic splines for the effects of selected meteorological factors on the number of out-of-hospital cardiac arrests (OHCA). The BOLD line estimates the relative effect sizes for OHCA, and the blue area estimates 95% CIs. The X-axis represents selected meteorological factors. The Y-axis shows the relative effect sizes for OHCA. PM2.5, particulate matter ≤2.5 µm. In an editorial, Chatterjee2 puts this data in the context that air pollution and meteorological factors have previously been shown to be associated with cardiovascular mortality and morbidity, including arrhythmias and heart failure. The current study provides robust data that OHCA also is affected by these environmental conditions, although data on the specific underlying arrhythmic mechanism was not available in most cases. Looking forward, ‘Studies such …

In patients at risk of ascending aortic dissection, timing of surgery typically is based on serial imaging measurements of aortic diameter. Clearly, the risk of dissection in an individual patient is higher at larger aortic diameters. Even so, from a population point-of-view, most acute dissections occur in patients with a diameter below the recommended threshold for prophylactic root replacement. In this issue of Heart , Heuts and colleagues1 evaluated the hypothesis that measures of aortic length and volume would be better predictors of the risk of dissection than diameter alone. (figure 1) In an observation cohort study of 477 consecutive patients with a Type A aortic dissection, 96% did not meet the surgical diameter threshold of 55 mm before dissection onset. Compared with a cohort 75 patients with an aortic aneurysm who did not suffer a dissection, the positive predictive values of aortic measurements for prediction of dissection were 20% for maximal aortic diameter, 55% for aortic volume and 70% for aortic length. Figure 1 Methodology of the three different aortic measurements in a patient with TAA and a patient with pre-ATAAD.(A–C) demonstrate aortic measurements in a patient with TAA. panel a depicts a stretched view of the curved planar CT reconstruction with diameter measurement perpendicular to the centreline. the two right …

Optimal management of adults with severe aortic stenosis (AS) remains controversial with several ongoing clinical trials evaluating the potential benefit of aortic valve replacement (AVR) earlier in the disease course when patients are still asymptomatic. To a large extent, these trials are based on evidence from the Contemporary Outcomes after Surgery and Medical Treatment in Patients with Severe Aortic Stenosis (CURRENT AS) registry.1 A comprehensive review article by the CURRENT-AS investigators in this issue of Heart summarises the data from this large Japanese multi-centre retrospective registry of consecutive adults with severe AS (figure 1). Both clinicians caring for patients with AS and researchers engaged in (or thinking about) clinical trials will want to read this data summary and review. Figure 1 Potential reasons for the poor prognosis of asymptomatic patients with severe AS without aortic valve intervention. AVR is indicated in asymptomatic patients with depressed LV function (LVEF

Lifestyle behaviours such as smoking, exercise and diet have received consideration attention as risk factors for cardiovascular disease (CVD) with lifestyle modification now serving as the foundation for primary prevention. Tub bathing is a potentially beneficial behaviour that has received less attention, possibly due to geographic and cultural variation in this behaviour. Japanese tub bathing, which typically involves sitting in hot water to shoulder depth, exposes the bather both to heat and to water pressure, which results in an increase in stroke volume and cardiac output with a reduction in systemic vascular resistance. Ukai and colleagues1 investigated the association between tub bathing and long-term CVD risk in a study of over 30 000 participants without CVD at baseline who were then followed for 20 years1 . On multivariable analysis, the risk of total CVD was lower in those who bathed almost daily or daily compared with those who bathed two or fewer times per week (HR 0.72, 95% CI 0.62 to 0.84, trend p

In patients with heart failure (HF), the increased risk of ischaemic stroke often is attributed to coexisting atrial fibrillation (AF). To test the hypothesis that there is a higher risk of ischaemic stroke in patients with HF, even in the absence of AF, Chou and colleagues1 used data from the Taiwan National Health Insurance programme. Over 12 000 patients with newly diagnosed HF were matched by propensity score to the same number of patients without HF, after excluding patients with AF or atrial flutter at baseline or during the follow-up period, as well as patients with previous stroke or acute myocardial infarction. The risk of stroke over a mean follow-up of about 6 years in those with HF was higher than in those without HF (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66). There also was a higher cumulative risk of stroke and acute myocardial infarction in those with HF (figure 1). In those with HF, multivariable risk factors for stroke were older age, male sex, diabetes and hypertension. These data support the author’s hypothesis that HF itself is associated with a higher risk of stroke in the absence of AF. Figure 1 Cumulative incidence of ischaemic stroke (A) and acute myocardial infarction (B) in individuals with HF or without HF by propensity score matching. HF, heart failure. In an editorial, Nelson and …

OBJECTIVE: Epidemiological estimates suggest that nearly half of individuals diagnosed with alcohol use disorder will be diagnosed with another mental health disorder, with strong associations involving other externalizing disorders. Molecular genetic studies investigating the relation between alcohol use disorder and externalizing behaviors (e.g., antisocial behavior) have focused on a cluster of chromosome 4 γ-aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) but have generated varying results. METHOD: The current study examined associations between common and rare variation in this region with alcohol use disorder and antisocial behavior using genetic sequencing data. Specifically, the University of California at San Francisco Family Alcoholism Sample (n = 1,610; 62% female) was used to conduct common and rare variant association tests in the GABRG1-A2-A4-B1 cluster with DSM-5 alcohol use disorder symptom counts, antisocial behavior, and a product term representing their interaction. RESULTS: Gene-based analyses of rare variation resulted in a significant association between rare GABRA2 variation and the interaction term. Single-variant analysis yielded only nominally significant associations. The strongest association for alcohol use disorder (rs3756007) was located in GABRA2, the strongest association for antisocial behavior (rs11941860) was located in GABRG1, and the interaction term yielded top associations in GABRA2 (rs2119183) and the intergenic region between GABRA2 and GABRG1 (rs536599). Common and rare variant associations for the interaction remained similar when covarying for the effects of the other type of variation, suggesting that the significant rare variant signal is independent of common variant contributions. CONCLUSIONS: The present study suggests that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly.

Ovarian cancer is known as a “silent killer” because of its nonspecific symptoms and generally late diagnosis due to the lack of reliable early detection tools. Medical detection canines have been shown to recognize the odor profile of malignant tumors of many types, including ovarian cancer, and may be utilized to help produce a much-needed early detection system for ovarian cancer. One significant drawback, however, is that to train detection canines on the odor signature of ovarian cancer, different samples or sets of samples must be used in every training session so that the canines do not begin to recognize an individual patient's odor signature or attune to patient-specific noncancerous olfactory cues. Therefore, numerous patient-derived samples must be obtained and stored for use in the training process. Ovarian cancer cell lines may be able to solve this obstacle, as they have low sample-to-sample variability and do not present patient-specific confounding olfactory cues. In this study, we attempted to train three medical detection dogs to alert to an ovarian cancer cell line (OVKATE) but not the culture media or nonmalignant cultured fallopian tube cells. Only one dog was able to discriminate between OVKATE and culture media and was able to be tested on other ovarian cancer cell lines (OVCAR-4, OVCAR-8, and SK-OV-3). The dog's responses suggest a common or related olfactory signature of malignant ovarian cancer cell lines. We then tested whether an OVKATE-trained dog recognized the blood plasma of patients with confirmed ovarian cancer. We did not find strong evidence that the dog recognized the blood plasma of a patient with confirmed ovarian cancer within three testing trials, with the dog only hesitating at the target odor, suggesting that while training on the cell lines may prepare medical dedication canines to recognize the blood plasma of patient with ovarian cancer, it is not a spontaneous switch to blood plasma. Despite this outcome, the behavior of the dog led us to believe that this method could help further the use of medical detection canines to inform the production of early detection tools for ovarian cancer, which would lead to earlier diagnoses and more favorable outcomes from therapy.

Patient-prosthesis mismatch (PPM) occurs when an implanted prosthetic valve is too small for the patient; severe PPM is defined as an indexed effective orifice area (iEOA) 2/m2following aortic valve replacement (AVR). This review examines articles from the past 10 years addressing the prevalence, outcomes and options for prevention and treatment of PPM after AVR. Prevalence of PPM ranges from 8% to almost 80% in individual studies. PPM is thought to have an impact on mortality, mainly in patients with severe PPM, although severe PPM accounts for only 10–15% of cases. Outcomes of patients with moderate PPM are not significantly different to those without PPM. PPM is associated with higher rates of perioperative stroke and renal failure and lack of left ventricular mass regression. Predictors include female sex, older age, hypertension, diabetes, renal failure and higher surgical risk score. PPM may be a marker of comorbidity rather than a risk factor for adverse outcomes. PPM should be suspected in patients with persistent cardiac symptoms after AVR when there is high prosthetic valve velocity or gradient and a small calculated effective orifice area. After exclusion of other causes of increased transvalvular gradient, re-intervention may be considered if symptoms persist and are unresponsive to medical therapy. However, this decision needs to consider the available options to relieve PPM and whether expected benefits justify the risk of intervention. The only effective intervention is redo surgery with implantation of a larger valve and/or annular enlargement. Therefore, focus needs to be on prevention.

Clinical management of patients with only moderate aortic stenosis (AS) but symptoms of heart failure with a reduced left ventricular ejection fraction (HFrEF) is challenging. Current guidelines recommend clinical surveillance with multimodality imaging; aortic valve replacement (AVR) is deferred until the stenosis becomes severe. Given the known benefits of afterload reduction in management of patients with HFrEF, it has been hypothesized that AVR may be beneficial in patients with only moderate AS who present with HFrEF. In this article, we first review the current approach for management of patients with moderate AS and HFrEF based on close clinical and imaging surveillance with AVR delayed until AS is severe. We then discuss the case for transcatheter AVR (TAVR) earlier in the disease course, when AS is moderate, based on stress echocardiographic data. We conclude with a detailed summary of the TAVR UNLOAD (Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure) trial, in which patients with moderate AS and HFrEF are randomized to guideline-directed heart failure therapy alone versus guideline-directed heart failure therapy plus TAVR.

Cardiovascular disease (CVD) is the leading cause of death in women in high-income countries. Most CVD events in women occur after menopause and there is a clear relationship between earlier age at menopause and increased CVD risk. Thus, it seems biologically plausible that the decrease in hormone levels after menopause might be related to CVD risk (figure 1). Yet, the potential role of post-menopausal hormone therapy (MHT) in reducing CVD risk in women remains controversial. In this issue of Heart , Gersh et al 1 summarise the pros and cons of MHT and provide a historical overview of MHT studies, highlighting limitations such as inclusion of women with pre-existing heart disease, and the type, dose and timing of MHT. They argue that ‘Human-identical hormones initiated early in menopause appear safe to be continued indefinitely, under close supervision, offering post-menopausal women greater potential for long-term CV health and improved quality of life.’ Of course, ‘Individualised decision-making is a key component of all MHT conversations; standard CVD risk reduction must be included in all therapeutic plans.’ Figure 1 Age-dependent shift in oestrogen levels. Levels of oestrogen decline with age and result in increased visceral fat, higher rates of insulin resistance and an increase in cardiovascular disease. In an editorial counterpoint, Thamman2 disagrees with this …

One of the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic is the utility of an early, flexible, and rapidly deployable disease screening and detection response. The largely uncontrolled spread of the pandemic in the United States exposed a range of planning and implementation shortcomings, which, if they had been in place before the pandemic emerged, may have changed the trajectory. Disease screening by detection dogs show great promise as a noninvasive, efficient, and cost-effective screening method for COVID-19 infection. We explore evidence of their use in infectious and chronic diseases; the training, oversight, and resources required for implementation; and potential uses in various settings. Disease detection dogs may contribute to the current and future public health pandemics; however, further research is needed to extend our knowledge and measurement of their effectiveness and feasibility as a public health intervention tool, and efforts are needed to ensure public and political support.

Canine sports medicine and rehabilitation recently have evolved to embody the optimization of performance, injury prevention, and mitigation of musculoskeletal degeneration. This article discusses the diverse factors and considerations of working dog wellness and injury prevention and the importance of recognizing normal and abnormal posture and anatomic structure for performance evaluation and early indication of musculoskeletal injury. The importance of a canine physical fitness program is highlighted and the need for a 4-phase recovery plan to determine if a working dog can safely return to work after injury discussed.

Cardiovascular disease (CVD) is a major risk factor for adverse outcomes with COVID-19 infection. Concerns raised early in the pandemic that renin-angiotensin system (RAS) blockade by treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers might increase that risk have not been supported by observational studies and meta-analyses.1 2 As Simon and Danchin3 point out, ‘jumping to therapeutic conclusions on the sole basis of pathophysiological or experimental considerations is hazardous. Nature can be tricky, and pathways that are blocked by a therapeutic intervention are often short-circuited by other, secondary, pathways that will result in the lack of clinical effect of the said therapeutic intervention. Here, in spite of the recognised interference between ACE2 and SARS-CoV-2, and of the possible link between RAS blockers and ACE2 in humans, these medications appeared clinically neutral.’ Age also is a major risk factor for COVID-19 infection, with previous analyses treating age as a potential confounder. While this approach often is appropriate, treating age as a confounder might obscure any differences in risk among younger and older patients with CVD. In order to examine the effect of age on the risk of fatal outcomes with COVID-19 infection in patients with CVD, Bae and colleagues4 performed a meta-analysis of 51 studies including …

Aim: This executive summary of the valvular heart disease guideline provides recommendations for clinicians to diagnose and manage valvular heart disease as well as supporting documentation to encourage their use. Methods: A comprehensive literature search was conducted from January 1, 2010, to March 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected database relevant to this guideline. Structure: Many recommendations from the earlier valvular heart disease guidelines have been updated with new evidence and provides newer options for diagnosis and treatment of valvular heart disease. This summary includes only the recommendations from the full guideline which focus on diagnostic work-up, the timing and choice of surgical and catheter interventions, and recommendations for medical therapy. The reader is referred to the full guideline for graphical flow charts, text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in developing these guidelines.

The COVID-19 pandemic created challenges which exposed inefficiencies, inequities, lack of resiliency and outdated models for the delivery of cardiovascular care around the globe. At the same time, the response to this crisis has allowed rapid transformation of our systems of care, including widespread use of digital interfaces, streamlining of care pathways and improved integration of patient-centric clinical services. In the hope of ensuring that this positive transformation is carried forward the British Cardiovascular Society (BCS) has outlined these changes and identified additional areas that require improvement as summarised in a short article in this issue of Heart 1 with the full report available on the BCS website.2 As they conclude: ‘cardiology, like other specialties, needs to assimilate and act on the lessons learnt during the pandemic. This will require a restructuring of the way that we all work and deliver clinical services.’ The insights summarised in the BCS report and the changes implemented by the NHS in the UK can provide a useful frame of reference that other healthcare systems around the world might consider in their long-term approach to improving care of patients with cardiovascular disease (figure 1). Figure 1 Potential interactions between primary and secondary care. AECG, ambulatory ECG; CP, chest pain; CTCA, CT coronary angiography; EHR, electronic health records; EOL, end of life; EP, electrophysiology; GP, general …

Aim Neurofilament light chain (NfL) is recognized as a blood biomarker in several neurodegenerative disorders, but its possible relevance in Ataxia Telangiectasia (A-T) has not been examined. The aim of this study was to investigate the biomarker potential of blood NfL concentrations in patients with A-T. Method Blood (serum/plasma) NfL concentrations were measured in a Dutch and an American cohort of patients with A-T and compared to control values. Additionally, correlations between NfL concentrations and disease phenotype (classic versus variant A-T) were studied. Results In total 40 (23 Dutch and 17 American) patients with A-T (32 patients with classic A-T and 7 patients with variant A-T) and 17 age- and gender-matched (to the American cohort) healthy controls were included in this study. Blood (serum/plasma) NfL concentrations in patients with classic A-T and age ≤ 12 years were elevated compared to age matched controls. Patients with classic A-T > 12 years also had higher blood (serum/plasma) NfL concentrations (here: compared to age-dependent reference values found in the literature). Patients with classic A-T had higher blood (serum/plasma) NfL concentrations than patients with the variant phenotype. Conclusion Blood (serum/plasma) NfL concentrations are elevated in patients with classic A-T and appear to correlate with the disease phenotype (classic versus variant). Therefore, blood (serum/plasma) NfL may be a promising biomarker in A-T.

A major goal in management of adults with atrial fibrillation (AF) is prevention of stroke. In an editorial, our stroke neurology colleagues1 point out that about 1/3 of patients with an AF-related stroke had a diagnosis of AF before the stroke but were not on anticoagulation therapy. When vitamin K-antagonists were the only option for anticoagulation, ‘many patients did not receive anticoagulant therapy despite a clear-cut indication due to a highly inconvenient treatment (repeated international normalised Ratio measurements, many food and drug-interactions, frequent dose adjustments) and a significant risk of intracerebral (and other major) bleeding.’ Now, with the availability of non-vitamin K oral anticoagulants (NOACs) the risk–benefit balance has shifted towards therapy to prevent AF-related stroke. Still, hesitation remains due to the higher cost of these newer medications. In order to better understand temporal changes in AF-related stroke incidence, anticoagulant medication prescribing and overall and per-patient costs in the UK, Orlowski and colleagues2 compared the time periods of 2011–2014 versus 2014–2017, using National Health Service data. A dramatic increase (over 85%) in oral anticoagulation prescribing was seen, mostly due to increased use of NOACs (figure 1). As expected, greater use of NOACs was associated with an increase in total medication costs by over 780%, mainly due to the increased number of AF patients being treated, corresponding to an increase in medication cost of about 51% per patient. …

Aims Valvular heart disease can be identified by calcification on coronary computed tomography angiography (CCTA) and has been associated with adverse clinical outcomes. We assessed aortic and mitral valve calcification in patients presenting with stable chest pain and their association with cardiovascular risk factors, coronary artery disease, and cardiovascular outcomes. Methods and results In 1769 patients (58 ± 9 years, 56% male) undergoing CCTA for stable chest pain, aortic and mitral valve calcification were quantified using Agatston score. Aortic valve calcification was present in 241 (14%) and mitral calcification in 64 (4%). Independent predictors of aortic valve calcification were age, male sex, hypertension, diabetes mellitus, and cerebrovascular disease, whereas the only predictor of mitral valve calcification was age. Patients with aortic and mitral valve calcification had higher coronary artery calcium scores and more obstructive coronary artery disease. The composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke was higher in those with aortic [hazard ratio (HR) 2.87; 95% confidence interval (CI) 1.60–5.17; P