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OBJECTIVES: Current antenatal care largely relies on widely spaced appointments, hence only a fraction of the pregnancy period is subject to monitoring. Continuous monitoring of physiological parameters could represent a paradigm shift in obstetric care. Here, we analyse the data from daily home monitoring in pregnancy and consider the implications of this approach for tracking pregnancy health. METHODS: Prospective feasibility study of continuous home monitoring of blood pressure, weight, heart rate, sleep and activity patterns from the first trimester to 6 weeks postpartum. RESULTS: Fourteen out of 24 women completed the study (58%). Compared to early pregnancy [week 13, median heart rate (HR) 72/min, interquartile range (IQR) 12.8], heart rate increased by week 35 (HR 78/min, IQR 16.6; P = 0.041) and fell postpartum (HR 66/min, IQR 11.5, P = 0.021). Both systolic and diastolic blood pressure were lower at mid-gestation (week 20: SBP 103 mmHg, IQR 6.6; DPB 63 mmHg, IQR 5.3 P = 0.005 and P = 0.045, respectively) compared to early pregnancy (week 13, SBP 107 mmHg, IQR 12.4; DPB 67 mmHg, IQR 7.1). Weight increased during pregnancy between each time period analyzed, starting from week 15. Smartwatch recordings indicated that activity increased in the prepartum period, while deep sleep declined as pregnancy progressed. CONCLUSION: Home monitoring tracks individual physiological responses to pregnancy in high resolution that routine clinic visits cannot. Changes in the study protocol suggested by the study participants may improve compliance for future studies, which was particularly low in the postpartum period. Future work will investigate whether distinct adaptative patterns predate obstetric complications, or can predict long-term maternal cardiovascular health.

Background: Rapid and accurate new biomarkers to predict risk of cardiovascular disease (CVD) are essential. The utility of extracellular vesicles in predicting the CVD risk is postulated, yet it remains unknown whether their expression is altered in response to statin therapy. Methods: We performed in-vitro studies with human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (hVSMC), and conducted a nested case-control study (nCCS) in hypertensive patients (n = 40) randomized to either atorvastatin or placebo in the ASCOT-LLA. Cases had a major adverse cardiovascular event or death (MACE) during 3.5 years of follow-up (median) from the time of extracellular vesicle characterization while controls, matched for age and duration of treatment, remained event-free. Conditional logistic regression models determined the risk of MACE. Additionally, the relationship of extracellular vesicle levels with statin therapy was assessed. Results: Added to HUVEC, extracellular vesicles increased neutrophil recruitment, and to hVSMC, aggravated calcification and proliferation. In the nCCS, compared with controls, cases (i.e. with MACE) had preceding higher levels of CD14+ and CD14+/CD41+ extracellular vesicles (P = 0.009 and P = 0.012, respectively) and a significant reduction in the median size of the vesicles (P = 0.037). On matched analysis, higher CD14+ extracellular vesicles were associated with a 3.7-fold increased risk of MACE (P = 0.032). Patients treated with atorvastatin (vs. placebo) had both reduced size of extracellular vesicles and the proportion of CD146+ extracellular vesicles (P = 0.034 and P = 0.020, respectively). Conclusion and relevance: These pilot analyses suggest a mechanistic role for extracellular vesicles in the development of CVD, with significant and differential changes in extracellular vesicles amongst those at risk of MACE, and those on atorvastatin therapy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

Background Ambulatory blood pressure (BP) monitoring has long been used to monitor BP in hypertension and lately emerged as a useful tool to detect hypotensive susceptibility in reflex syncope. However, hemodynamic characteristics in reflex syncope have not been sufficiently explored. The present study investigated the differences between ambulatory BP monitoring profiles associated with reflex syncope and normal population. Methods and Results This is an observational study comparing ambulatory BP monitoring data from 50 patients with reflex syncope and 100 controls without syncope, age‐ and sex‐matched 1:2. Mean 24‐hour systolic (SBP) and diastolic BP, pulse pressure (24‐hour PP), dipping status, and number of daytime SBP drops P =0.002), higher 24‐hour diastolic BP (85.2±9.6 versus 79.1±10.6 mm Hg, P P P Conclusions Patients with reflex syncope have lower 24‐hour SBP but higher 24‐hour diastolic BP and more frequent daytime SBP drops

Aims Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine the relationship between CPET parameters, myocardial ischaemia and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to percutaneous coronary intervention (PCI). Methods and results Patients with severe single-vessel coronary artery disease (CAD) were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE) and symptom assessment. These assessments were repeated at the end of a 6-week blinded follow-up period. A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (−0.07; 95% CI: −0.12 to −0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. Conclusion Although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD.

Cardiovascular disease remains the leading cause of death worldwide. Cardiovascular research has therefore never been more crucial. Cardiovascular researchers must be provided with a research environment that enables them to perform at their highest level, maximizing their opportunities to work effectively with key stakeholders to address this global issue. At present, cardiovascular researchers face a range of challenges and barriers, including a decline in funding, job insecurity and a lack of diversity at senior leadership levels. Indeed, many cardiovascular researchers, particularly women, have considered leaving the sector, highlighting a crucial need to develop strategies to support and retain researchers working in the cardiovascular field. In this Roadmap article, we present solutions to problems relevant to cardiovascular researchers worldwide that are broadly classified across three key areas: capacity building, research funding and fostering diversity and equity. This Roadmap provides opportunities for research institutions, as well as governments and funding bodies, to implement changes from policy to practice, to address the most important factors restricting the career progression of cardiovascular researchers.

Aims The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations. Methods and results Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options. Conclusion The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk. Key objective To improve upon prediction of 10-year residual atherosclerotic cardiovascular disease (ASCVD) event risk in individuals with established ASCVD, by taking into account competing risks and geographical differences in ASCVD incidence. Key findings Derivation in 8355 individuals with established ASCVD from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (SMART) cohort. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] to 0.772 (95% CI 0.659-0.886). Clinical utility was demonstrated across a range of treatment thresholds relevant to therapy intensification. Take-home messages The SMART2 risk score can be used to estimate 10-year residual risk of fatal and non-fatal ASCVD in individuals with established ASCVD. Adapted to the CVD incidence in several global regions. Facilitates shared decision-making on Step 2 prevention goals as recommended by the 2021 ESC Guidelines on cardiovascular prevention.

BACKGROUND We aimed to determine risk factors for incident CKD in a large population-based cohort. METHODS This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia enrolment database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely-collected databases. The primary outcome was the development of incident CKD, defined as eGFR

Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye domain containing (POPDC) proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that POPDC proteins exist in complexes with members of the PDE4 family in cardiac myocytes. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 modulates cycle length of spontaneous Ca2+ transients firing in intact mouse sinoatrial nodes.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

Post-transplant cardiovascular disease (CVD) is the single most common cause of death in solid organ transplant recipients. The prevailing school of thought is that post-transplant CVD is driven by the same underlying atherosclerotic processes as the CVD of aging seen in the general population. This is reflected in current management strategies, which focus on the minimisation of traditional cardiovascular risk factors. In this article, we argue that atherosclerosis is not the sole aetiology of post-transplant CVD. Instead, chronic rejection drives post-transplant CVD through an antibody-mediated systemic vasculopathy termed systemic accelerated arteriosclerosis (SAA). SAA is fundamentally distinct from atherosclerosis, associated with unique histology, pathophysiology and risk factors. In order to effectively manage post-transplant CVD, SAA needs to be addressed in current management strategies through revised risk factor minimisation and use of immunomodulatory pharmaceuticals.

Supplemental Digital Content is available in the text., Background: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. Methods: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases–based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Results: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). Conclusions: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45–2.49]; P =3.23×10 −6 ) and reduced birthweight (OR=0.83 [95% CI=0.79–0.86]; P =3.96×10 −18 ), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44–1.94]; P =7.45×10 −12 ; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04–1.19]; P =1.19×10 −3 ), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Background The efficacy of renal denervation has been controversial, but the procedure has now undergone several placebo-controlled trials. New placebo-controlled trial data has recently emerged, with longer follow-up of one trial and the full report of another trial (which constitutes 27% of the total placebo-controlled trial data). We therefore sought to evaluate the effect of renal denervation on ambulatory and office blood pressures in patients with hypertension. Methods We systematically identified all blinded placebo-controlled randomized trials of catheter-based renal denervation for hypertension. The primary efficacy outcome was ambulatory systolic blood pressure change relative to placebo. A random-effects meta-analysis was performed. Results 6 studies randomizing 1232 patients were eligible. 713 patients were randomized to renal denervation and 519 to placebo. Renal denervation significantly reduced ambulatory systolic blood pressure (−3.52 mmHg; 95% CI −4.94 to −2.09; p < 0.0001), ambulatory diastolic blood pressure (−1.93 mmHg; 95% CI −3.04 to −0.83, p = 0.0006), office systolic blood pressure size (−5.10 mmHg; 95% CI −7.31 to −2.90, p < 0.0001) and office diastolic pressure (effect size −3.11 mmHg; 95% CI −4.43 to −1.78, p < 0.0001). Adverse events were rare and not more common with denervation. Conclusions The totality of blinded, randomized placebo-controlled data shows that renal denervation is safe and provides genuine reduction in blood pressure for at least 6 months post-procedure. If this effect continues in the long term, renal denervation might provide a life-long 10% relative risk reduction in major adverse cardiac events and 7.5% relative risk reduction in all-cause mortality.

Background Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death. Methods We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005 to 2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socioeconomic status. Results 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N = 22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR = 1.30; 95% CI 1.21–1.40) but not COPD alone (HR = 0.89; 95% CI 0.83–0.94). Conclusions Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone.

Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

Effects of continuous positive airway pressure (CPAP) on right ventricular (RV) function in patients with untreated mild-to-moderate obstructive sleep apnea (OSA) are unclear. In this exploratory analysis of cardiac magnetic resonance (CMR)-derived indices of RV function in patients with minimally symptomatic OSA from the MOSAIC randomized control trial we found no effect of CPAP on RV CMR parameters. In those with lower RV ejection fraction and higher RV end-diastolic volume (EDV) at baseline, CPAP treatment appeared to improve RV function with a significant reduction in both RV EDV and RV end-systolic volume although between-group effects were not observed. These data suggest potential merit in a larger randomized study of CPAP in patients with mild-to-moderate OSA and a greater breadth of RV dysfunction.

Hypertension remains the leading cause of global mortality, with elevated systolic blood pressure (BP) leading to 10.8 million deaths each year. Despite this, only around 50% of individuals with hypertension are aware of their condition. Alongside low awareness rates, lack of patient adherence to medication and therapeutic inertia have been identified as factors contributing to the lack of hypertension control worldwide. This report summarizes presentations from the “one of a kind” Servier-sponsored symposium, Improving the Management of Hypertension: Acting on Key Factors, which was conducted as part of the European Society of Hypertension (ESH)-International Society of Hypertension (ISH) 2021 ON-AIR meeting. The symposium focused on how low awareness, therapeutic inertia, and nonadherence can be addressed by combining the experience of a patient with the expertise of physicians. May Measurement Month, the ongoing global BP measurement program, is raising awareness of hypertension in over 90 countries, and the 2018 European Society of Cardiology/ESH guidelines and the 2020 ISH guidelines now include recommendations that specifically address low adherence and therapeutic inertia, including involving patients in a shared decision-making process and the use of single-pill combination therapy. Understanding the role of emotion in decision making and addressing the different psychological states and attitudes in the patient’s “cycle of change” are key to effective shared decision making and improving adherence. Supplementary Information The online version contains supplementary material available at 10.1007/s40256-021-00505-6., Plain Language Summary Raised blood pressure (hypertension) is involved in the death of around 10.8 million people throughout the world each year. However, only about half of the people with hypertension are aware of their condition. In addition, many patients who are prescribed blood pressure-lowering medications do not take their pills regularly (intentional or nonintentional low adherence). Many doctors are not as strict as they should be in ensuring blood pressure control of their hypertensive patients (therapeutic inertia). This report presents ideas and data from a “first of its kind” symposium sponsored by Servier as part of the European Society of Hypertension (ESH)-International Society of Hypertension (ISH) 2021 ON-AIR meeting involving both patient and physicians. The report summarizes the ways in which low awareness, therapeutic inertia, and lack of adherence can be addressed and includes insights into patients’ perspectives. An ongoing global blood pressure screening program called May Measurement Month was discussed, which has detected almost a million people with untreated or inadequately treated hypertension worldwide since 2017. Recent ESH and ISH guidelines for managing hypertension now include recommendations on how to address low adherence and therapeutic inertia. Crucially, doctors should involve their patients with hypertension in decisions about their own treatment, which will help improve adherence to medication and ultimately reduce hypertension-related serious adverse events (e.g. heart attacks, strokes and deaths). Supplementary Information The online version contains supplementary material available at 10.1007/s40256-021-00505-6.

BackgroundAustralian Red Cross Lifeblood (Lifeblood) advises donors to visit their general practitioner (GP) for medical follow-up if they are deferred from donating due to having a lower than acceptable level of hemoglobin (Hb) and/or serum ferritin (iron-related deferrals).MethodsWe used the Sax Institute's 45 and Up Study data linked to Lifeblood's donor datasets and other health administrative datasets. We examined the rate of visits to a GP after iron-related deferral from donation, and investigated whether an early visit to a GP (within 30 days following the deferral) had an impact on return to make successful donation within 12, 18, and 24 months compared to a delayed or no GP visit.ResultsA total of 1928 donors underwent iron-related deferral. The rate of visits to a GP in the first month after deferral was double the rate observed a month prior. However, only 52.4% of those deferred visited a GP early with slightly more than half of those receiving an iron-monitoring test. Return to donate over the 24 months was lower in donors visiting their GP early (adjusted Hazard Ratio [aHR] 0.86, 95% CI 0.77-0.97). Early GP visitors were likely to have a relatively poorer health than the delayed or no GP visit group.ConclusionsOnly half of the donors with an iron-related deferral followed advice from Lifeblood and visited their GP within 30 days of deferral, and these donors have a significantly reduced likelihood of future successful blood donation which may be due to their relatively poorer health status.

Summary Background Child mortality from sickle cell disease in sub-Saharan Africa is presumed to be high but is not well quantified. This uncertainty contributes to the neglect of sickle cell disease and delays the prioritisation of interventions. In this study, we estimated the mortality of children in Nigeria with sickle cell disease, and the proportion of national under-5 mortality attributable to sickle cell disease. Methods We did a model-estimated, population-level analysis of data from Nigeria's 2018 Demographic and Health Survey (DHS) to estimate the prevalence and geographical distribution of HbSS and HbSC genotypes assuming Hardy-Weinberg equilibrium near birth. Interviews for the survey were done between Aug 14 and Dec 29, 2018, and the embedded sickle cell disease survey was done in a randomly selected third of the overall survey's households. We developed an approach for estimating child mortality from sickle cell disease by combining information on tested children and their untested siblings. Tested children were aged 6–59 months at the time of the survey. Untested siblings born 0–14 years before the survey were also included in analyses. Testing as part of the DHS was done without regard to disease status. We analysed mortality differences using the inheritance-derived genotypic distribution of untested siblings older than the tested cohort, enabling us to estimate excess mortality from sickle cell disease for the older-sibling cohort (ie, those born between 2003 and 2013). Findings We analysed test results for 11 186 children aged 6–59 months from 7411 households in Nigeria. The estimated average birth prevalence of HbSS was 1·21% (95% CI 1·09–1·37) and was 0·24% (0·19–0·31) for HbSC. We obtained data for estimating child mortality from 10 195 tested children (who could be matched to the individual mother survey) and 17 205 of their untested siblings. 15 227 of the siblings were in the older-sibling cohort. The group of children with sickle cell disease born between 2003 and 2013 with at least one younger sibling in the survey had about 370 excess under-5 deaths per 1000 livebirths (95% CI 150–580; p=0·0008) than children with HbAA. The estimated national average under-5 mortality for children with sickle cell disease born between 2003 and 2013 was 490 per 1000 livebirths (95% CI 270–700), 4·0 times higher (95% CI 2·1–6·0) than children with HbAA. About 4·2% (95% CI 1·7–6·9) of national under-5 mortality was attributable to excess mortality from sickle cell disease. Interpretation The burden of child mortality from sickle cell disease in Nigeria continues to be disproportionately higher than the burden of mortality of children without sickle cell disease. Most of these deaths could be prevented if adequate resources were allocated and available focused interventions were implemented. The methods developed in this study could be used to estimate the burden of sickle cell disease elsewhere in Africa and south Asia. Funding Sickle Pan African Research Consortium, and the Bill & Melinda Gates Foundation.

Aims Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. Methods and results We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89–2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76–6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28–0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74–1.97]). Conclusion Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

Background Women are more likely to delay medical help-seeking for ACS symptoms. Understanding patients’ experience of the symptoms and their response is essential in improving help-seeking behaviors and timely diagnosis and treatment for ACS. This study aimed to explore women’s experience of ACS, their response to the symptoms, and treatment-seeking decisions. Methods This qualitative descriptive study was conducted in a tertiary referral specialized heart hospital affiliated with Tabriz University of Medical Sciences, Iran. Participants included 39 women who had experienced ACS for the first time. Results Four main themes emerged from the analysis of interview transcripts: (1) the onset of symptoms, (2) the types of symptoms, (3) response to symptoms and (4) arriving at the hospital. These themes and associated sub-themes explained women’s experience of ACS symptoms, their response to the symptoms, and decision to seek medical help. Conclusions This study identified and discussed factors contributing to the prehospital delay in women and their decision-making to seek medical care for ACS symptoms. The results are consistent with previous research indicating that ACS symptoms in women are somewhat different from men, and women tend to underestimate their symptoms and attribute them to non-cardiac causes. Women should be supported to develop awareness and understanding of ACS symptoms and appreciate the importance of early treatment-seeking in the disease outcomes.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background Patients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required. Abstract body Rate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change. Conclusions Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be used as an endpoint in clinical trials. Refresher training, automated alerts of problems and FVC changes, and patient support could help to overcome some practical issues. Despite the challenges, there is value in incorporating home handheld spirometry into clinical practice, and the COVID-19 pandemic has highlighted the potential for home monitoring technologies to help improve access to care for patients with ILD.

Background Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone. Methods Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing. Discussion Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence. Trial registration Clinicaltrials.gov NCT05161351. Registered on 16 December 2021.

Background Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. Purpose We hypothesized that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM than control subjects and we aimed to define the SBP cut-off values that allow identification of patients with hypotensive susceptibility. Methods We compared ABPM data from reflex syncope patients and controls, matched by average 24-hour SBP, age, sex and hypertension. Patients with constitutional hypotension, orthostatic hypotension, predominant cardioinhibition or competing causes of syncope were excluded. Daytime and night-time SBP drops ( Results In the Derivation cohort, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drop Conclusion SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope. Funding Acknowledgement Type of funding sources: None.

A retrospective, observational cohort study was conducted to generate real-world evidence in adult patients diagnosed with sarcoidosis-associated pulmonary hypertension (SAPH) at a referral center in England between 2012 and 2019. Data from the referral center electronic medical record database were linked to the National Health Service Hospital Episode Statistics database to collect and analyze patient demographics, clinical characteristics, comorbidities, treatment patterns, health-related quality of life (HRQoL; assessed using the EmPHasis-10 questionnaire), healthcare resource utilization (HCRU), costs, and survival. Sixty-two patients with SAPH were identified. At diagnosis, 84% were in WHO functional class III and presented with significant pulmonary hemodynamic impairment. Cardiovascular and respiratory comorbidities were commonly reported prediagnosis. Median EmPHasis-10 score at diagnosis was 34, indicative of poor HRQoL. In the 1st year after diagnosis, median (Q1, Q3) per-patient HCRU was 1 (0, 2) all-cause inpatient hospitalizations; 3 (2, 4) same-day hospitalizations; and 9 (6, 11) outpatient consultations. In 24 patients who were hospitalized longer than 1 day in the 1st year after diagnosis, the median duration of hospitalization was 4 days. With a median follow-up of 1.8 years, the median overall survival was 2.9 years. In this cohort of patients with SAPH, poor HRQoL and high HCRU were observed following diagnosis. To our knowledge, this is the first study to report on HRQoL and HCRU in patients with SAPH. More research is needed on treatment options for this population with high unmet needs.

BACKGROUND: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). PURPOSE: To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. METHODS: COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. RESULTS: ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated β-galactosidase (SA-β-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. CONCLUSIONS: ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.

Background: Understanding public and patient attitudes to clinical research is paramount to successful recruitment. The COVID-19 pandemic has led to additional hurdles in achieving this. Our aim is to understand the current factors and attitudes towards clinical trial participation in order to assist recruitment to clinical trials. Methods: We conducted face-to-face interviews with patients in the outpatient department at a tertiary eye hospital facilitated by a 34-item questionnaire developed by the research team. Patient characteristics were correlated with their responses, in addition to qualitative thematic text analysis. Results: A total of 53 patients were interviewed. 40% indicated that they would be willing to participate in clinical research in the current climate. General motivating factors for involvement in research included personal gain, altruism and contribution to innovation. Factors limiting participation included concerns regarding own safety, inconvenience, accessibility and lack of benefit. 22.6% of participants felt that the COVID-19 pandemic has changed their outlook on research. These were categorised into positive (increased awareness of the importance and need for research, altruism) and negative influences (increased anxiety, need to minimise exposure to the hospital environment). Conclusions: Factors influencing patient’s decisions to participate in trials are similar to those observed prior to COVID-19 but with an increased focus on the environment the research is conducted in. The COVID-19 pandemic has had positive and negative impacts on patient attitudes towards research. Trial design, with a particular focus on setting and safety measures, in reassuring patients are increasingly important.

OBJECTIVE: Endogenous adenosine 5'-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum samples and explore their relationships with asthma control and exacerbations. METHODS: 20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood sampling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-β, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured. RESULTS: Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum samples. Compared to controlled asthma (n = 54), uncontrolled asthma (n = 58) showed higher AMP levels (P = 0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r = - 0.348) and asthma quality of life questionnaire scores (r = - 0.188) and positively correlated with blood monocytes percentage (r = 0.195), sputum MDC (r = 0.214), and IL-6 levels (r = 0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year. CONCLUSION: Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.

Objectives This study aims to examine uptake and dissemination of a National Institute for Health Research (NIHR) Health Technology Assessment (HTA)–funded trial – Graduated compression as an Adjunct to Pharmaco-thromboprophylaxis in Surgery (GAPS) (project number: 14/140/61) amongst health professionals in the UK. This study aims to evaluate the impact of the trial on venous thromboembolism (VTE) prevention policies 7 months after publication. Method A 12-question online survey emailed to 2750 individuals via several vascular societies, 34 VTE Exemplar Centre leads and 1 charity over a 3-month period. Results In total, 250 responses were received; a 9.1% response rate. Over half of all respondents (52.4%) had read the GAPS trial results prior to completing the survey. Precisely, 77.1% said their hospital had not yet made changes or did not intend to make changes to local hospital VTE policy based on the GAPS trial. Conclusions Findings must be interpreted in the context of the low response rate. Further in-depth interviews would aid understanding of barriers to implementing change.

Aims Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin–angiotensin–aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. Methods and results The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and Conclusion Among patients treated with renin–angiotensin–aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.

OBJECTIVES: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use. BACKGROUND: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks. METHODS: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized. RESULTS: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p

Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P, The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

Learning objectives Machine learning (ML) is a revolution in computer science and is set to change the face of cardiology practice. In ML, humans no longer need to convert an understanding of a problem into a stepwise algorithmic solution; instead, the computer learns to solve a task for itself. While ML can seem intimidating, the underlying principles build on familiar and established techniques. The recent revolution that made ML so effective, however, was the recognition that numerous sequential layers of simple arithmetic, termed neural networks, become surprisingly effective at solving difficult problems. This ‘deep learning’ has been startlingly effective across a variety of problems, and a particular type, the convolutional neural network (CNN) has revolutionised image analysis. CNNs are inspired by the human visual cortex and have been used successfully in cardiology to process data that are one-dimensional (1D) (ECGs, pressure waveforms), two-dimensional (2D) (X-rays, MRIs) and three-dimensional (3D) (echocardiography videos, cardiac magnetic resonance cine videos and CT volumes). We are now entering the stage where these CNNs’ performances are starting to equal that of cardiologists in some domains.1 2 In this review, we will cover the basics of ML, before explaining the workings of neural networks, and particularly CNNs. ML will play an increasing role in medical practice and, as with any diagnostic test or piece of medical equipment, an understanding of these systems will better equip medical staff to interpret these systems’ results. The first chapter in an ML textbook is often made up of topics that a decade ago would have been called ‘statistics’. A simple example that we commonly encounter in cardiology is the formula for predicting …

Background Although Alzheimer’s disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer’s disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer’s disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer’s disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer’s disease. Methods The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer’s disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. Discussion This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer’s disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer’s disease. Trial registration ClinicalTrials.govNCT03489044. Registered on April 5, 2018.

Objective: To encompass the needs of all stakeholders and allow effective data synthesis from trials, registries, and other studies; a core outcome set for infrarenal abdominal aortic aneurysm (AAA) repair is needed. In this first stage, the aim was to report the range, frequency, and time of pre-specified outcomes reported following AAA repair. Data Sources: Medline, Embase, and CENTRAL databases 2010 – 2019 were searched using ProQuest Dialog™. Review Methods: The systematic review was reported to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA), PROSPERO registration CRD42019130119. Outcomes were coded using Core Outcome Measures in Effectiveness Trials (COMET) taxonomy and presented separately for intact and rupture repairs, endovascular aneurysm repair (EVAR) and open repair, and time from repair (acute < 90 days vs. ≥ 1 year) (COMET Initiative 1582). Results: For intact AAA and rupture repair, a total of 231 and 70 reports with 589 255 and 177 465 patients respectively were included: only 98 and 19 respectively provided ≥ 1 year outcomes. Most studies were retrospective, with 13 randomised trials of intact AAA repair and five randomised trials of ruptured AAA repair. For intact AAA, the most common pre-specified COMET taxonomy outcomes were mortality (181), vascular complications (137), and re-intervention (52). EVAR studies dominated the vascular outcomes in acute and later time periods: excluding 47 reports from device registries, reduced vascular outcomes to 83. For ruptured AAA, the three most common outcomes were mortality (64), vascular (11), and hospital stay (10). The range of outcomes reported was wide with functioning outcomes reported from most randomised trials but few retrospective studies. Conclusion: This review identifies the paucity of long term data and the disproportionate attention paid to vascular complications vs. patient functioning outcomes, this skew being accentuated by reporting from EVAR device registries. These data will inform focus groups, prior to a pan-European Delphi consensus, involving clinicians, patients, carers and providers, for developing core outcomes for repair of intact and ruptured AAA.

Atrial fibrillation (AF) and flutter (AFL) are the most common clinically significant arrhythmias in older adults with an increasing disease burden due to an aging population. However, up-to-date trends in disease burden and regional variation remain unknown. In an observational study utilizing the Global Burden of Disease (GBD) database, age-standardized mortality and incidence rates for AF overall and for each state in the United States (US) from 1990 to 2017 were determined. All analyses were stratified by gender. The relative change in age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) over the observation period were determined. Trends were analyzed using Joinpoint regression analysis. The mean ASIR per 100,000 population for men was 92 (+/-8) and for women was 62 (+/-5) in the US in 2017. The mean ASDR per 100,000 population for men was 5.8 (+/-0.3) and for women was 4.4 (+/-0.4). There were progressive increases in ASIR and ASDR in all but 1 state. The states with the greatest percentage change in incidence were New Hampshire (+13.5%) and Idaho (+16.0%) for men and women, respectively. The greatest change regarding mortality was seen in Mississippi (+26.3%) for men and Oregon (+53.8%) for women. In conclusion these findings provide updated evidence of increasing AF and/or AFL incidence and mortality on a national and regional level in the US, with women experiencing greater increases in incidence and mortality rates. This study demonstrates that the public health burden related to AF in the United States is progressively worsening but disproportionately across states and among women.

Introduction Conferences are an important avenue for dissemination of knowledge, research and provide networking opportunities for career development. The COVID-19 pandemic has prompted adoption of virtual platforms for delivery of these conferences. The aim of the study was to determine the utility and educational impact of a student-led virtual webinar to deliver an undergraduate cardiovascular conference compared to a traditional in-person conference. Methods We conducted a two-day virtual conference using the Zoom platform in June 2021. The conference consisted of cardiology subspecialty lectures and workshops conducted by a junior doctor, senior cardiology trainees and consultants. The conference also outlaid a virtual poster hall and oral presentation session while networking opportunities were encouraged using breakout rooms and poster hall chat function. A 38-item self-administered online questionnaire was designed and disseminated at the end of the conference to all attending delegates. All data analysis and data visualisation strategies were conducted on R statistical programming. Results Eight-hundred and forty students from 55 countries attended the event. 490 participants (58.5% response rate, 55.9% female) completed the questionnaire. Factors such as weekend conference (84.9%), student-led or organised (84.1%), environmental/sustainable (82.3%), appropriate level for me (81.5%) and comfort to present (80.8%) were deemed to be at least equal to traditional in-person conference. The conference also increased participants’ interest, their core cardiology knowledge and improved their critical analysis and basic echocardiography skills [median 4 (IQR 3-5) for all parameters]. Overall, participants also found it easy to use the virtual platform [median 5 (IQR 5-5)] and easier to ask questions compared to in-person conferences [median 5 (IQR 4-5) vs median 4 (IQR 3-5), p< 0.001]. Conclusion Our virtual conference provided opportunities to students that the COVID-19 pandemic would have otherwise affected, however its utility and educational impact will need to be assessed within its individual context of delivery.

Genetic testing has advanced significantly since the publication of the 2011 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies.1 In addition to single-gene testing, there is now the ability to perform whole-exome sequencing (WES) and whole-genome sequencing (WGS). There is growing appreciation of oligogenic disorders,2,3 the role of modifier genes,2 and the use of genetic testing for risk stratification, even in common cardiac diseases such as coronary artery disease or atrial fibrillation (AFib), including a proposal for a score awaiting validation.4 This document reviews the state of genetic testing at the present time, and addresses the questions of what tests to perform and when to perform them. It should be noted that, as articulated in a 1999 Task Force Document by the European Society of Cardiology (ESC) on the legal value of medical guidelines,5 ‘The guidelines from an international organization, such as the ESC, have no specific legal territory and have no legally enforcing character. Nonetheless, in so far as they represent the state-of-the-art, they may be used as indicating deviation from evidence-based medicine in cases of questioned liability’. In the case of potentially lethal and treatable conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS), it is the responsibility of the physician, preferably in conjunction with an expert genetics team, to communicate to the patient/family the critical importance of family screening, whether this be facilitated by cascade genetic testing or by broader clinical family screening

Background This study explored the educational and self‐management needs of adults living with atrial fibrillation (AF). Methods and Results This is a qualitative study of adults living with AF, clinicians, and expert key stakeholders. Interviews were conducted via a one‐to‐one semistructured videoconference or phone and transcribed verbatim for thematic analysis. A total of 34 participants were recruited and included in analyses (clinicians n=13; experts n=13, patients n=8). Interviews were on average 40 (range 20–70) minutes in duration. Three key themes were identified: (1) “Patient‐centered AF education”; (2) “Prioritizing AF education”; and (3) “Timing AF education.” The availability of credible information was perceived as highly variable. Information primarily focused on anticoagulation, or procedural information, as opposed to other aspects of management, such as risk factor reduction. Factors to optimize learning, such as multimedia, apps, case studies, or the use of visuals were perceived as important. Continuity of care, including engagement of caregivers, was important to help develop relationships, and facilitate understanding, while concurrently creating opportunities for timely targeted education. Clinicians described acute care as a suboptimal setting to deliver education. Competing interests aligned with the time‐pressured context of acute care were prioritized over patient education. In contrast, patients valued continuity of care. AF education strategies need to pivot from a “one size fits all” approach and modernize to implement a range of approaches. Conclusions There remain many unmet needs in the provision of quality AF education to support self‐management. Multimodal offerings and the ability to tailor to individual patient needs are important design considerations for new education programs.

BACKGROUND: Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis.OBJECTIVES: The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants.METHODS: The authors created hybridomas from an unimmunized low-density lipoprotein (LDL) receptor-deficient (Ldlr -/-) mouse and selected an IgG2b isotype autoantibody, LO9, for further characterization. RESULTS: LO9 reacted well with native LDL bound to immobilized matrix components and less well to oxidized LDL. LO9 binding to immobilized native LDL was not neutralized by fluid-phase native LDL, indicating an adhesion-dependent epitope. The authors localized the epitope to a 20 amino-acid peptide sequence (P5) in the globular amino-terminus of apolipoprotein B. LO9 reacted with antigen in mouse atherosclerosis and in both human stable and ruptured coronary atherosclerosis. Furthermore, in vivo near-infrared fluorescence molecular tomographic imaging, and ex vivo confocal microscopy showed that intravenously injected LO9 localized beneath endothelium of the aortic arch in Ldlr -/- mice, in the vicinity of macrophages. CONCLUSIONS: The authors believe LO9 is the first example of an IgG autoantibody that reacts with a native LDL epitope revealed by adherence to tissue matrix. Antibodies against adherent native LDL have potential as molecular targeting agents for imaging of and therapeutic delivery to atherosclerosis.

Background Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. Objective To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. Methods In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, − 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, − 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation “in vitro”. Results The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm2 correlated positively with scored total IgA in lamina propria of all patients. “In vitro” stimulation of 16HBE cells with LPS (10 μg/ml) and IL-8 (10 ng/ml) induced a significant increase while H2O2 (100 μM) significantly decreased pIgR epithelial expression. Conclusion These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD.

Introduction Chronic Obstructive Pulmonary Disease (COPD) is associated with significant mortality and well-defined aetiological factors. Previous reports indicate that mortality from COPD is falling worldwide. This study aims to assess the burden of COPD using prevalence, mortality, and disability-adjusted life years (DALYs) between 2001 and 2019 in 28 European countries (the European Union and the United Kingdom). Methods We extracted COPD data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 (J41, 42, 43, 44 and 47). Age-standardised prevalence rates (ASPRs), age-standardised mortality rates (ASMRs), and DALYs were analysed for European countries by sex for each year (2001–2019) and reported per 100,000 population. We used Joinpoint regression analysis to quantify changing trends in the burden of COPD. Results In 2019, the median ASPR across Europe was 3230/100,000 for males and 2202/100,000 for females. Between 2001 and 2019, the median percentage change in ASPR was − 9.7% for males and 4.3% for females. 23/28 countries demonstrated a decrease in ASPRs in males, and 11/28 demonstrated a decrease in females. The median percentage change in ASMR between 2001 and 2019 was − 27.5% for males and − 10.4% for females. 25/28 and 19/28 countries demonstrated a decrease in ASMR in males and females, respectively. Conclusion In the EU between 2001 and 2019 COPD prevalence has overall increased in females but continues to decrease in males and in some countries, female prevalence now exceeds that of males. COPD mortality in the EU has decreased overall between 2001 and 2019; however, this decrease is not universal, particularly in females, and therefore remains a substantial source of amenable mortality.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is associated with significant mortality and well-defined etiological factors. Previous reports indicate that mortality from COPD is falling worldwide. This study aims to assess the burden of COPD using prevalence, mortality, and disability-adjusted life years (DALYs) between 2001-2019 in 28 European countries (the European Union and the United Kingdom). Methods: We extracted COPD data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 (J41,42,43,44, and 47). Age-standardised prevalence rates (ASPRs), age-standardised mortality rates (ASMRs), and DALYs were analysed for European countries by sex for each year (2001-2019) and reported per 100,000 population. We used Joinpoint regression analysis to quantify changing trends in the burden of COPD. Results: In 2019, the median ASPR across Europe was 3230/100,000 for males and 2202/100,000 for females. Between 2001 and 2019, the median percentage change in ASPR was -9.7% for males and 4.3% for females. 23/28 countries demonstrated a decrease in ASPRs in males, and 11/28 demonstrated a decrease in females. The median percentage change in ASMR between 2001-2019 was -27.5% for males and -10.4% for females. 25/28 and 19/28 countries demonstrated a decrease in ASMR in males and females, respectively. Conclusion: In the EU between 2001 and 2019 COPD prevalence has overall increased in females but continues to decrease in males and in some countries, female prevalence now exceeds that of males. COPD mortality in the EU has decreased overall between 2001 and 2019; however, this decrease is not universal, particularly in females, and therefore remains a substantial source of amenable mortality. Funding: DCM is supported by an NIHR Academic Clinical Fellowship acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. KFC is a Senior Investigator of the National Institute for Health Research (NIHR), UK.