Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain.

Slowing and/or reversing brain ageing may alleviate cognitive impairments. Previous studies have found that exercise may mitigate cognitive decline, but the mechanisms underlying this remain largely unclear. Here we provide unbiased analyses of single-cell RNA sequencing data, showing the impacts of exercise and ageing on specific cell types in the mouse hippocampus. We demonstrate that exercise has a profound and selective effect on aged microglia, reverting their gene expression signature to that of young microglia. Pharmacologic depletion of microglia further demonstrated that these cells are required for the stimulatory effects of exercise on hippocampal neurogenesis but not cognition. Strikingly, allowing 18-month-old mice access to a running wheel did by and large also prevent and/or revert T cell presence in the ageing hippocampus. Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro-neurogenic effects and on peripheral immune cell presence in the ageing female mouse brain.

Phenotypic but not genetically predicted heart rate variability associated with all-cause mortality.

Low heart rate variability (HRV) has been widely reported as a predictor for increased mortality. However, the molecular mechanisms are poorly understood. Therefore, this study aimed to identify novel genetic loci associated with HRV and assess the association of phenotypic HRV and genetically predicted HRV with mortality. In a GWAS of 46,075 European ancestry individuals from UK biobank, we identified 17 independent genome-wide significant genetic variants in 16 loci associated with HRV traits. Notably, eight of these loci (RNF220, GNB4, LINCR-002, KLHL3/HNRNPA0, CHRM2, KCNJ5, MED13L, and C160rf72) have not been reported previously. In a prospective phenotypic relationship between HRV and mortality during a median follow-up of seven years, individuals with lower HRV had higher risk of dying from any cause. Genetically predicted HRV, as determined by the genetic risk scores, was not associated with mortality. To the best of our knowledge, the findings provide novel biological insights into the mechanisms underlying HRV. These results also underline the role of the cardiac autonomic nervous system, as indexed by HRV, in predicting mortality.

Sex differences in long-term outcomes following acute heart failure hospitalization: Findings from the Get With The Guidelines-Heart Failure registry.

AIMS: Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. METHODS AND RESULTS: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85-0.89; pinteraction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5-year follow-up (aHR 1.06, 95% CI 1.04-1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07-1.14; pinteraction [sex*HF subtype] = 0.001). CONCLUSIONS: While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age- and sex-matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization.

Brugada syndrome uncovered in patient with pseudohypoaldosteronism due to hyperkalaemia.

Brugada syndrome is a rare sodium channelopathy that predisposes to an increased risk of malignant arrythmias and sudden cardiac death. Previous studies have reported that metabolic disturbances can uncover a Brugada ECG pattern. Given the risk of malignant arrhythmias, it is important to correctly diagnose and treat Brugada syndrome. We report a case of Brugada syndrome uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.

Investigating the potential anti-depressive mechanisms of statins: a transcriptomic and Mendelian randomization analysis.

Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains unclear whether statins have any beneficial effects on depression, and if so, what the underlying molecular mechanisms are. Here, we aimed to use genomic approaches to investigate this further. Using Connectivity Map (CMap), we first investigated whether statins and antidepressants shared pharmacological effects by interrogating gene expression responses to drug exposure in human cell lines. Second, using Mendelian randomization analysis, we investigated both on-target (through HMGCR inhibition) and potential off-target (through ITGAL and HDAC2 inhibition) causal effects of statins on depression risk and depressive symptoms, and traits related to the shared biological pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins in HA1E cells (indicated by an average connectivity score with statins > 90) were found to be enriched for antidepressants (12 out of 38 antidepressants; p = 9E-08). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for diverse cellular and metabolic pathways, and various immune activation, development and response processes. MR analysis did not identify any significant associations between statin exposure and depression risk or symptoms after multiple testing correction. However, genetically proxied HMGCR inhibition was strongly associated with alterations in platelets (a prominent serotonin reservoir) and monocyte percentage, which have previously been implicated in depression. Genetically proxied ITGAL inhibition was strongly associated with basophil, monocyte and neutrophil counts. We identified biological pathways that are commonly perturbed by both statins and antidepressants, and haematological biomarkers genetically associated with statin targets. Our findings warrant pre-clinical investigation of the causal role of these shared pathways in depression and potential as therapeutic targets, and investigation of whether blood biomarkers may be important considerations in clinical trials investigating effects of statins on depression.

A Rare Case of Radiation-Associated Aortic and Mitral Valve Stenosis Treated With Transcatheter Valve Replacements.

Radiation therapy is the standard of care for achieving cure for many thoracic malignancies, but it can result in long-term cardiovascular sequelae such as valve disease. We describe a rare case of severe aortic and mitral stenosis due to prior radiation therapy for giant cell tumor treated successfully with percutaneous aortic and off-label mitral valve replacements. (Level of Difficulty: Intermediate.).

Mupirocin susceptibility of staphylococci 2022: Is it time for a change in MRSA decolonization protocols?

BACKGROUND: Nasal decolonization with mupirocin has been a common strategy for the prevention of surgical site infections (SSIs) and recurrent skin and soft tissue infections due to Staphylococcus aureus (SA). We recently noted an increase in SSIs due to SA, including a case of post-operative mupirocin-resistant methicillin-resistant SA (MRSA) infection despite attempted preoperative decolonization with mupirocin. We therefore evaluated the mupirocin susceptibility of SA at our hospital to determine the optimal regimen for decolonization. METHODS: SA isolates were recovered from clinical and screening samples received in the microbiology laboratory. Mupirocin susceptibility was determined using e-tests and isolates were categorized as susceptible or resistant using a breakpoint MIC value of 4mcg/ml. RESULTS: 223 unique SA isolates from 218 patients were tested. Twenty-four SA isolates (10.8%) were resistant to mupirocin (20 MRSA and 4 methicillin-sensitive SA [MSSA]). MRSA strains were more likely to be resistant to mupirocin than MSSA strains (22.5% vs 3.0%, P < .001). CONCLUSIONS: The emergence of drug resistance makes the policy of decolonization with nasal mupirocin a suboptimal strategy for the prevention of MRSA infections. In our study, less than 80% of MRSA strains were mupirocin susceptible. In patients colonized with MRSA at high risk for infection (eg, total joint replacement), other regimens such as intranasal povidone iodine may be preferable to mupirocin for patient decolonization.

Supranormal Left Ventricular Ejection Fraction, Stroke Volume, and Cardiovascular Risk: Findings From Population-Based Cohort Studies.

BACKGROUND: Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)-assessed by cardiac magnetic resonance (CMR)-in healthy, community-dwelling individuals is unknown. OBJECTIVES: The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD. METHODS: Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index. RESULTS: The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume. CONCLUSIONS: Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease.

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

K-29 linked ubiquitination of Arrdc4 regulates its function in extracellular vesicle biogenesis.

Extracellular vesicles (EVs) are important mediators of intercellular communication. However, EV biogenesis remains poorly understood. We previously defined a role for Arrdc4 (Arrestin domain containing protein 4), an adaptor for Nedd4 family ubiquitin ligases, in the biogenesis of EVs. Here we report that ubiquitination of Arrdc4 is critical for its role in EV secretion. We identified five potential ubiquitinated lysine residues in Arrdc4 using mass spectrometry. By analysing Arrdc4 lysine mutants we discovered that lysine 270 (K270) is critical for Arrdc4 function in EV biogenesis. Arrdc4K270R mutation caused a decrease in the number of EVs released by cells compared to Arrdc4WT , and a reduction in trafficking of divalent metal transporter (DMT1) into EVs. Furthermore, we also observed a decrease in DMT1 activity and an increase in its intracellular degradation in the presence of Arrdc4K270R . K270 was found to be ubiquitinated with K-29 polyubiquitin chains by the ubiquitin ligase Nedd4-2. Thus, our results uncover a novel role of K-29 polyubiquitin chains in Arrdc4-mediated EV biogenesis and protein trafficking.

Making Artificial Intelligence Lemonade Out of Data Lemons: Adaptation of a Public Apical Echo Database for Creation of a Subxiphoid Visual Estimation Automatic Ejection Fraction Machine Learning Algorithm.

OBJECTIVES: A paucity of point-of-care ultrasound (POCUS) databases limits machine learning (ML). Assess feasibility of training ML algorithms to visually estimate left ventricular ejection fraction (EF) from a subxiphoid (SX) window using only apical 4-chamber (A4C) images. METHODS: Researchers used a long-short-term-memory algorithm for image analysis. Using the Stanford EchoNet-Dynamic database of 10,036 A4C videos with calculated exact EF, researchers tested 3 ML training permeations. First, training on unaltered Stanford A4C videos, then unaltered and 90° clockwise (CW) rotated videos and finally unaltered, 90° rotated and horizontally flipped videos. As a real-world test, we obtained 615 SX videos from Harbor-UCLA (HUCLA) with EF calculations in 5% ranges. Researchers performed 1000 randomizations of EF point estimation within HUCLA EF ranges to compensate for ML and HUCLA EF mismatch, obtaining a mean value for absolute error (MAE) comparison and performed Bland-Altman analyses. RESULTS: The ML algorithm EF mean MAE was estimated at 23.0, with a range of 22.8-23.3 using unaltered A4C video, mean MAE was 16.7, with a range of 16.5-16.9 using unaltered and 90° CW rotated video, mean MAE was 16.6, with a range of 16.3-16.8 using unaltered, 90° CW rotated and horizontally flipped video training. Bland-Altman showed weakest agreement at 40-45% EF. CONCLUSIONS: Researchers successfully adapted unrelated ultrasound window data to train a POCUS ML algorithm with fair MAE using data manipulation to simulate a different ultrasound examination. This may be important for future POCUS algorithm design to help overcome a paucity of POCUS databases.

The genomics of heart failure: design and rationale of the HERMES consortium.

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease.

Kidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/ß-catenin and TGF-ß signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial-mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/ß-catenin and TGF-ß signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/ß-catenin/TGF-ß signaling in progressive kidney disease.

Association of Antihypertensive Drug Target Genes With Psychiatric Disorders: A Mendelian Randomization Study.

Importance: Observational studies have reported associations between antihypertensive medication and psychiatric disorders, although the reported direction of association appears to be dependent on drug class. Objective: To estimate the potential effect of different antihypertensive drug classes on schizophrenia, bipolar disorder, and major depressive disorder. Design, Setting, and Participants: This 2-sample mendelian randomization study assessed the association between a single-nucleotide variant (SNV) and drug target gene expression derived from existing expression quantitative trait loci (eQTL) data in blood (sample 1) and the SNV-disease association from published case-control genome-wide association studies (sample 2). Significant associations were corroborated using published brain eQTL and protein QTL data. Participants included 40 675 patients with schizophrenia and 64 643 controls, 20 352 patients with bipolar disorder and 31 358 controls, and 135 458 patients with major depressive disorder and 344 901 controls. Blood eQTL levels were measured in 31 684 individuals from 37 cohorts (eQTLGen consortium); prefrontal cortex eQTLs were measured from the PsychENCODE resource in 1387 individuals; and protein QTLs were measured in cerebral spinal fluid from 544 individuals and plasma from 818 individuals. Data were collected from October 4, 2019, to June 1, 2020, and analyzed from October 14, 2019, to June 6, 2020. Exposures: Expression levels of antihypertensive drug target genes as proxies for drug exposure, and genetic variants robustly associated with the expression of these genes as mendelian randomization instruments. Main Outcomes and Measures: Risk for schizophrenia, bipolar disorder, and major depressive disorder. Results: A 1-SD lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with lower systolic blood pressure of 4.0 (95% CI, 2.7-5.3) mm Hg, but increased risk of schizophrenia (odds ratio [OR], 1.75; 95% CI, 1.28-2.38; P = 3.95 × 10-4). A concordant direction of association was also observed between ACE expression in prefrontal cortex (OR, 1.33; 95% CI, 1.13-1.56) and ACE protein levels in cerebral spinal fluid (OR per 1-SD decrease, 1.12; 95% CI, 1.05-1.19) and plasma (OR per 1-SD decrease, 1.04; 95% CI, 1.01-1.07). We found no evidence for an association between genetically estimated SBP and schizophrenia risk. Conclusions and Relevance: Findings suggest an adverse association of lower ACE messenger RNA and protein levels with schizophrenia risk. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on psychiatric symptoms in patients with schizophrenia, as well as the role of ACE inhibitor use in late-onset schizophrenia.

Adaptors as the regulators of HECT ubiquitin ligases.

The HECT (homologous to E6AP C-terminus) ubiquitin ligases (E3s) are a small family of highly conserved enzymes involved in diverse cellular functions and pathological conditions. Characterised by a C-terminal HECT domain that accepts ubiquitin from E2 ubiquitin conjugating enzymes, these E3s regulate key signalling pathways. The activity and functional regulation of HECT E3s are controlled by several factors including post-translational modifications, inter- and intramolecular interactions and binding of co-activators and adaptor proteins. In this review, we focus on the regulation of HECT E3s by accessory proteins or adaptors and discuss various ways by which adaptors mediate their regulatory roles to affect physiological outcomes. We discuss common features that are conserved from yeast to mammals, regardless of the type of E3s as well as shed light on recent discoveries explaining some existing enigmas in the field.

Impact of cognitive behavioral therapy on depression symptoms after transcatheter aortic valve replacement: A randomized controlled trial.

BACKGROUND: Depression is a significant concern after cardiac surgery and has not been studied in patients undergoing transcatheter aortic valve replacement (TAVR). We sought to examine the prevalence of pre-procedure depression and anxiety symptoms and explore whether brief bedside cognitive behavioral therapy (CBT) could prevent post-TAVR psychological distress. METHODS: We prospectively recruited consecutive TAVR patients and randomized them to receive brief CBT or treatment as usual (TAU) during their hospitalization. Multi-level regression techniques were used to evaluate changes by treatment arm in depression, anxiety, and quality of life from baseline to 1 month post-TAVR adjusted for sex, race, DM, CHF, MMSE, and STS score. RESULTS: One hundred and forty six participants were randomized. The mean age was 82 years, and 43% were female. Self-reported depression and anxiety scores meeting cutoffs for clinical level distress were 24.6% and 23.2% respectively. Both TAU and CBT groups had comparable improvements in depressive symptoms at 1-month (31% reduction for TAU and 35% reduction for CBT, p = .83). Similarly, both TAU and CBT groups had comparable improvements in anxiety symptoms at 1-month (8% reduction for TAU and 11% reduction for CBT, p = .1). Quality of life scores also improved and were not significantly different between the two groups. CONCLUSIONS: Pre-procedure depression and anxiety may be common among patients undergoing TAVR. However, TAVR patients show spontaneous improvement in depression and anxiety scores at 1-month follow up, regardless of brief CBT. Further research is needed to determine whether more tailored CBT interventions may improve psychological and medical outcomes.

Novel Use of Home Pulse Oximetry Monitoring in COVID-19 Patients Discharged From the Emergency Department Identifies Need for Hospitalization.

OBJECTIVES: Our objective was to evaluate patient-reported oxygen saturation (SpO2 ) using pulse oximetry as a home monitoring tool for patients with initially nonsevere COVID-19 to identify need for hospitalization. METHODS: Patients were enrolled at the emergency department (ED) and outpatient testing centers. Each patient was given a home pulse oximeter and instructed to record their SpO2 every 8 hours. Patients were instructed to return to the ED for sustained home SpO2  < 92% or if they felt they needed emergent medical attention. Relative risk was used to assess the relation between hospitalization and home SpO2  < 92% in COVID-19-positive patients. RESULTS: We enrolled 209 patients with suspected COVID-19, of whom 77 patients tested positive for COVID-19 and were included. Subsequent hospitalization occurred in 22 of 77 (29%) patients. Resting home SpO2  < 92% was associated with an increased likelihood of hospitalization compared to SpO2  ≥ 92% (relative risk = 7.0, 95% confidence interval = 3.4 to 14.5, p < 0.0001). Home SpO2  < 92% was also associated with increased risk of intensive care unit admission, acute respiratory distress syndrome, and septic shock. In our cohort, 50% of patients who ended up hospitalized only returned to the ED for incidental finding of low home SpO2 without worsening of symptoms. One-third (33%) of nonhospitalized patients stated that they would have returned to the ED if they did not have a pulse oximeter to reassure them at home. CONCLUSIONS: This study found that home pulse oximetry monitoring identifies need for hospitalization in initially nonsevere COVID-19 patients when a cutoff of SpO2 92% is used. Half of patients who ended up hospitalized had SpO2  < 92% without worsening symptoms. Home SpO2 monitoring also reduces unnecessary ED revisits.

A genetic model of ivabradine recapitulates results from randomized clinical trials.

BACKGROUND: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints. METHODS: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. RESULTS: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61). CONCLUSION: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.