Remote myocardial fibrosis predicts adverse outcome in patients with myocardial infarction on clinical cardiovascular magnetic resonance imaging.

BACKGROUND: Heart failure (HF) most commonly occurs in patients who have had a myocardial infarction (MI), but factors other than MI size may be deterministic. Fibrosis of myocardium remote from the MI is associated with adverse remodeling. We aimed to 1) investigate the association between remote myocardial fibrosis, measured using cardiovascular magnetic resonance (CMR) extracellular volume fraction (ECV), and HF and death following MI, 2) identify predictors of remote myocardial fibrosis in patients with evidence of MI and determine the relationship with infarct size. METHODS: Multicenter prospective cohort study of 1199 consecutive patients undergoing CMR with evidence of MI on late gadolinium enhancement. Median follow-up was 1133 (895-1442) days. Cox proportional hazards modeling was used to identify factors predictive of the primary outcome, a composite of first hospitalization for HF (HHF) or all-cause mortality, post-CMR. Linear regression modeling was used to identify determinants of remote ECV. RESULTS: Remote myocardial fibrosis was a strong predictor of primary outcome (χ2: 15.6, hazard ratio [HR]: 1.07 per 1% increase in ECV, 95% confidence interval [CI]: 1.04-1.11, p < 0.001) and was separately predictive of both HHF and death. The strongest predictors of remote ECV were diabetes, sex, natriuretic peptides, and body mass index, but, despite extensive phenotyping, the adjusted model R2 was only 0.283. The relationship between infarct size and remote fibrosis was very weak. CONCLUSION: Myocardial fibrosis, measured using CMR ECV, is a strong predictor of HHF and death in patients with evidence of MI. The mechanisms underlying remote myocardial fibrosis formation post-MI remain poorly understood, but factors other than infarct size appear to be important.

Phenogrouping heart failure with preserved or mildly reduced ejection fraction using electronic health record data.

BACKGROUND: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. METHODS: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. RESULTS: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. CONCLUSIONS: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.

PROTOCOL FOR HUMAN EXPOSURE TO OPIOIDS AND CONCENTRATED MEDETOMIDINE USED IN FIELD APPLICATIONS.

Wildlife professionals routinely use potent sedatives and anesthetics when chemically immobilizing wildlife and zoo species in remote environments. Accidental exposure to these prescription veterinary drugs is rare but could be rapidly fatal. Commonly used agents include opioids and α2 adrenoreceptor agonists. These drugs can be reversed with specific antagonists; however, they are often not approved for human use. The protocol created here can be used by wildlife health professionals in a field setting with basic human emergency medical response training in coordination with local Emergency Medical Services (EMS). Key components include, building local relationships between EMS and wildlife professionals, focused EMS training, administering opioid and α2 adrenergic antagonists off label, and local evacuation procedures. This framework could allow wildlife management agencies or zoos to mitigate the risk of human exposures to these commonly used drugs, significantly improving occupational safety in an otherwise high-risk environment.

rWCVP: a companion R package for the World Checklist of Vascular Plants.

The World Checklist of Vascular Plants (WCVP) is an extremely valuable resource that is being used to address many fundamental and applied questions in plant science, conservation, ecology and evolution. However, databases of this size require data manipulation skills that pose a barrier to many potential users. Here, we present rWCVP, an open-source R package that aims to facilitate the use of the WCVP by providing clear, intuitive functions to execute many common tasks. These functions include taxonomic name reconciliation, geospatial integration, mapping and generation of multiple different summaries of the WCVP in both data and report format. We have included extensive documentation and tutorials, providing step-by-step guides that are accessible even to users with minimal programming experience. rWCVP is available on cran and GitHub.

Endothelial function and atrial fibrillation: A missing piece of the puzzle?

Endothelial dysfunction, a term used to describe both the physical damage and dysregulated physiology of this endothelial lining, is an increasingly recognized pathophysiological state shared by many cardiovascular diseases. Historically, the role of endothelial dysfunction in atrial fibrillation (AF) was thought to be limited to mediating atrial thromboembolism. However, there is emerging evidence that endothelial dysfunction both promotes and maintains atrial arrhythmic substrate, predicts adverse outcomes, and identifies patients at high risk of recurrence following cardioversion and ablation therapy. Treatments targeted at improving endothelial function also represent a promising new therapeutic paradigm in AF. This review summarizes the current understanding of endothelial function in AF.

Local impedance-guided ablation and ultra-high density mapping versus conventional or contact force-guided ablation with mapping for treatment of cavotricuspid isthmus dependent atrial flutter.

INTRODUCTION: - Local impedance (LI) guided ablation as a method of judging lesion effectiveness for cavotricuspid isthmus dependent atrial flutter (CTI-AFL), and ultra-high density (UHD) mapping when breakthrough occurred across an ablation line has not previously been assessed. METHODS: This retrospective observational study evaluated patients undergoing CTI-AFL ablation using conventional, contact force (CF) and LI guided strategies. Ablation metrics were collected, and in the LI cohort, the use of UHD mapping for breakthrough evaluated. RESULTS: 30 patients were included, 10 per group. Mean total ablation time was significantly shorter with LI (3.2 ± 1.3min) vs conventional (5.6 ± 2.7min) and CF (5.7 ± 2.0min, p = 0.0042). Time from start of ablation to CTI block was numerically shorter with LI (14.2 ± 8.0min) vs conventional and CF (19.7 ± 14.1 and 22.5 ± 19.1min, p = 0.4408). Mean lesion duration was significantly shorter with LI, but there were no differences in the number of lesions required to achieve block, procedural success, complication rates or recurrence. 15/30 patients did not achieve block following first-pass ablation. UHD mapping rapidly identified breakthrough in the five LI patients, including epicardial-endocardial breakthrough (EEB). CONCLUSION: - The use of LI during ablation for real-time lesion assessment was as efficacious as the conventional and CF methods. UHD mapping rapidly identified breakthrough, including EEB.

Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid.

Proliferation and invasion of cancer cells require favorable pH, yet potentially toxic quantities of acid are produced metabolically. Membrane-bound transporters extrude acid from cancer cells, but little is known about the mechanisms that handle acid once it is released into the poorly perfused extracellular space. Here, we studied acid handling by myofibroblasts (colon cancer-derived Hs675.T, intestinal InMyoFib, embryonic colon-derived CCD-112-CoN), skin fibroblasts (NHDF-Ad), and colorectal cancer (CRC) cells (HCT116, HT29) grown in monoculture or coculture. Expression of the acid-loading transporter anion exchanger 2 (AE2) (SLC4A2 product) was detected in myofibroblasts and fibroblasts, but not in CRC cells. Compared with CRC cells, Hs675.T and InMyoFib myofibroblasts had very high capacity to absorb extracellular acid. Acid uptake into CCD-112-CoN and NHDF-Ad cells was slower and comparable to levels in CRC cells, but increased alongside SLC4A2 expression under stimulation with transforming growth factor ß1 (TGFß1), a cytokine involved in cancer-stroma interplay. Myofibroblasts and fibroblasts are connected by gap junctions formed by proteins such as connexin-43, which allows the absorbed acid load to be transmitted across the stromal syncytium. To match the stimulatory effect on acid uptake, cell-to-cell coupling in NHDF-Ad and CCD-112-CoN cells was strengthened with TGFß1. In contrast, acid transmission was absent between CRC cells, even after treatment with TGFß1. Thus, stromal cells have the necessary molecular apparatus for assembling an acid-venting route that can improve the flow of metabolic acid through tumors. Importantly, the activities of stromal AE2 and connexin-43 do not place an energetic burden on cancer cells, allowing resources to be diverted for other activities.

Giant negative magnetoresistance in Ni(quinoline-8-selenoate)2.

The magnetic, structural, conductivity and magnetoresistance properties of [Ni(quinoline-8-selenoate)2] ([Ni(qs)2]) have been studied. Despite the insolubility of the material necessitating its study as a powdered sample, a remarkably high conductivity has been measured. The conductivity is an order of magnitude greater than the thin-film processable thiol analogue previously reported and has been interpreted through the same space-charge limited conduction mechanism with charges injected from the electrodes. The introduction of selenium, results in a material with conductivity approaching metallic due to the enhanced interaction between adjacent molecules. Additionally, under an applied magnetic field, the material displays a negative magnetoresistance effect above 35% at 2 K. The effect can still be observed at 200 K and is interpreted in terms of a double-exchange mechanism.

Growth differentiation factor-15 in patients with or at risk of heart failure but before first hospitalisation.

OBJECTIVE: Identification of patients at risk of adverse outcome from heart failure (HF) at an early stage is a priority. Growth differentiation factor (GDF)-15 has emerged as a potentially useful biomarker. This study sought to identify determinants of circulating GDF-15 and evaluate its prognostic value, in patients at risk of HF or with HF but before first hospitalisation. METHODS: Prospective, longitudinal cohort study of 2166 consecutive patients in stage A-C HF undergoing cardiovascular magnetic resonance and measurement of GDF-15. Multivariable linear regression investigated determinants of GDF-15. Cox proportional hazards modelling, Net Reclassification Improvement and decision curve analysis examined its incremental prognostic value. Primary outcome was a composite of first hospitalisation for HF or all-cause mortality. Median follow-up was 1093 (939-1231) days. RESULTS: Major determinants of GDF-15 were age, diabetes and N-terminal pro-B-type natriuretic peptide, although despite extensive phenotyping, only around half of the variability of GDF-15 could be explained (R2 0.51). Log-transformed GDF-15 was the strongest predictor of outcome (HR 2.12, 95% CI 1.71 to 2.63) and resulted in a risk prediction model with higher predictive accuracy (continuous Net Reclassification Improvement 0.26; 95% CI 0.13 to 0.39) and with greater clinical net benefit across the entire range of threshold probabilities. CONCLUSION: In patients at risk of HF, or with HF but before first hospitalisation, GDF-15 provides unique information and is highly predictive of hospitalisation for HF or all-cause mortality, leading to more accurate risk stratification that can improve clinical decision making. TRIAL REGISTRATION NUMBER: NCT02326324.

Sinoatrial node function and the role of sinoatrial conduction in the typical atrial flutter substrate.

BACKGROUND: Sinoatrial node (SAN) activation and sinoatrial conduction pathways (SACPs) have been assessed in animals, but not humans. OBJECTIVES: We used ultra-high density (UHD) mapping and simulated models to characterise the SAN and investigate whether slowed SAN conduction may contribute to the atrial flutter (AFL) substrate. METHODS: Twenty-seven patients undergoing electrophysiological procedures underwent right atrial (RA) mapping. SAN activation patterns and conduction block were analysed. The interaction between the SAN and the intercaval line of block (LOB) was analysed, and RA simulations with different degrees of block were created to investigate arrhythmia mechanisms. RESULTS: Fifteen AFL and 12 reference patients were enrolled. SACPs were identified in all patients with sinus rhythm maps. An SAN-adjacent LOB was observed in AFL patients. SAN conduction velocity (CV) was slower in AFL vs reference (0.60m/s [0.56-0.78m/s] vs 1.13m/s [1.00-1.21m/s], p=0.0021). Coronary sinus paced maps displayed an intercaval LOB in AFL patients but not reference, which was completed superiorly by the SAN-adjacent LOB. Corrected sinus node recovery time (cSNRT) was longer in AFL patients (552.3±182.9ms vs 325.4±138.3ms, p<0.0060) and correlated with degree of intercaval block (r=0.7236, p=0.0003). Computer modelling supported an important role of SAN-associated block in the flutter substrate. CONCLUSIONS: UHD mapping accurately identifies SAN activation and SACPs. The LOB important for typical AFL was longer in AFL patients, and when partial, always present inferiorly, and completed superiorly due to slowed conduction across the SAN. cSNRT correlated with intercaval block, suggesting a role for SAN disease in the genesis of the typical AFL substrate.

Identification of heart failure hospitalization from NHS Digital data: comparison with expert adjudication.

AIMS: Population-wide, person-level, linked electronic health record data are increasingly used to estimate epidemiology, guide resource allocation, and identify events in clinical trials. The accuracy of data from NHS Digital (now part of NHS England) for identifying hospitalization for heart failure (HHF), a key HF standard, is not clear. This study aimed to evaluate the accuracy of NHS Digital data for identifying HHF. METHODS AND RESULTS: Patients experiencing at least one HHF, as determined by NHS Digital data, and age- and sex-matched patients not experiencing HHF, were identified from a prospective cohort study and underwent expert adjudication. Three code sets commonly used to identify HHF were applied to the data and compared with expert adjudication (I50: International Classification of Diseases-10 codes beginning I50; OIS: Clinical Commissioning Groups Outcomes Indicator Set; and NICOR: National Institute for Cardiovascular Outcomes Research, used as the basis for the National Heart Failure Audit in England and Wales). Five hundred four patients underwent expert adjudication, of which 10 (2%) were adjudicated to have experienced HHF. Specificity was high across all three code sets in the first diagnosis position {I50: 96.2% [95% confidence interval (CI) 94.1-97.7%]; NICOR: 93.3% [CI 90.8-95.4%]; OIS: 95.6% [CI 93.3-97.2%]} but decreased substantially as the number of diagnosis positions expanded. Sensitivity [40.0% (CI 12.2-73.8%)] and positive predictive value (PPV) [highest with I50: 17.4% (CI 8.1-33.6%)] were low in the first diagnosis position for all coding sets. PPV was higher for the National Heart Failure Audit criteria, albeit modestly [36.4% (CI 16.6-62.2%)]. CONCLUSIONS: NHS Digital data were not able to accurately identify HHF and should not be used in isolation for this purpose.

Disease-specific therapy for the treatment of the cardiovascular manifestations of Fabry disease: a systematic review.

OBJECTIVE: The cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Disease-specific therapy, including enzyme replacement therapy (ERT) and chaperone therapy (migalastat), is recommended for patients exhibiting cardiovascular involvement, but its efficacy for modulating cardiovascular disease expression and optimal timing of initiation remains to be fully established. We therefore aimed to systematically review and evaluate the effectiveness of disease-specific therapy compared with placebo, and to no intervention, for the cardiovascular manifestations of Fabry disease. METHODS: Eight databases were searched from inception using a combination of relevant medical subject headings and keywords. Randomised, non-randomised studies with a comparator group and non-randomised studies without a comparator group were included. Studies were screened for eligibility and assessed for bias by two independent authors. The primary outcome comprised clinical cardiovascular events. Secondary outcomes included myocardial histology and measurements of cardiovascular structure, function and tissue characteristics. RESULTS: 72 studies were included, comprising 7 randomised studies of intervention, 16 non-randomised studies of intervention with a comparator group and 49 non-randomised studies of intervention without a comparator group. Randomised studies were not at serious risk of bias, but the others were at serious risk. Studies were highly heterogeneous in their design, outcome measurements and findings, which made assessment of disease-specific therapy effectiveness difficult. CONCLUSION: It remains unclear whether disease-specific therapy sufficiently impacts the cardiovascular manifestations of Fabry disease. Further work, ideally in larger cohorts, with more standardised clinical and phenotypic outcomes, the latter measured using contemporary techniques, are required to fully elucidate the cardiovascular impact of disease-specific therapy. PROSPERO REGISTRATION NUMBER: CRD42022295989.

Characterizing the connection between swine production sites by personnel movements using a mobile application-based geofencing platform.

Biosecurity is critical to productivity and profitability in swine production systems and can be achieved by incorporating external (bioexclusion) and internal (biocontainment) practices. Although increasing threats of foreign animal diseases have justified the need of rigorous external biosecurity plans, their effectiveness highly depend on the compliance of on-farm employees, farm-related personnel, and visitors. In this study, we evaluated the uses of a mobile application-based geofencing platform in two swine production systems for accurately identifying personnel movements between swine production sites and detecting potential biosecurity breaches by violating required downtime between site visits. The geofencing platform accurately recognized 95.2% (379/398) of personnel entries comparing to physical entry logs. Further, among 1861 entries over a period of one month, 19 strongly connected components and 12 potential biosecurity breaches were identified. Personnel with duty in communications and information systems committed 75% of biosecurity breaches. The results reported herein demonstrated the possible uses of geofencing platforms for investigating connections among swine production sites by personnel movements and identifying biosecurity breaches.

Refractory vasodilatory shock secondary to metformin overdose supported with VA ECMO.

Metformin overdose may result in vasodilatory shock, lactic acidosis and death. Hemodialysis is an effective means of extracorporeal elimination, but may be insufficient in the shock setting. We present a case of a 39 yo male who presented with hypotension, coma, hypoglycemia, and lactate of 6.5 mmol/L after ingesting an unknown medication. Metformin overdose was suspected, and he was started on hemodialysis. He developed profound vasoplegia refractory to high doses of norepinephrine, vasopressin, epinephrine and phenylephrine. Venoarterial extracorporeal membrane oxygenation (VA ECMO) was initiated and he had full recovery. Serum analysis with high resolution liquid chromatography mass spectrometry revealed a metformin level of 678 µg/mL and trazodone level of 2.1 µg/mL. This case is one of only a handful of reported cases of metformin overdose requiring ECMO support, and we report the highest serum metformin levels in the literature to date. We recommend early aggressive hemodialysis and vasopressor support in all suspected cases of metformin toxicity as well as VA ECMO if refractory to these therapies. OBJECTIVE: We present a case of vasodilatory shock secondary to metformin overdose requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) support. This case is one of only a handful of reported cases of metformin overdose requiring ECMO support, and we report the highest serum metformin levels in the literature to date. DATA SOURCES: University of San Francisco, Fresno. STUDY DESIGN: Case report. DATA EXTRACTION: Clinical records and high resolution liquid chromatography mass spectroscopy analysis. DATA SYNTHESIS: None. CONCLUSIONS: Venoarterial ECMO provided an effective means of hemodynamic support for a patient with severe metformin toxicity.

Turnover events of animal caretakers and its impact on productivity in swine farms.

Attracting and retaining quality animal caretaking personnel is one of most pressing issues the US swine industry currently faces. On-farm employee turnover can be costly and have an impact on productivity. The primary objectives of this study were to describe the amount of animal caretaker turnover events that occurred in a single year in eleven swine farms, and to investigate associations between employee turnover events and two subsequent production parameters of interest: number of pigs weaned per sow (PWS) and pre-weaning mortality (PWM). A retrospective cohort study was conducted with eleven commercial farrow-to-wean swine farms belonging to two vertically integrated multi-site production systems within two swine production companies. Human resources and production data for the year of 2019 were obtained monthly from each farm. The primary predictor of interest was the occurrence of an employee turnover event, defined as 'voluntary' (employee decided to leave or quit) or 'involuntary' (employee was terminated by company decision). The primary outcomes of interest included the monthly average PWS and PWM. These associations were assessed with 1-, 2-, 3-, and 6-months between the turnover events and the outcome. Linear mixed effects models were fit in STATA 15, with system and farm included as random effects. To account for temporal and seasonal trends of production, season and the monthly production were included in the models. There were a total of 152 turnover events, with 4 and 148 turnover events in systems 1 and 2, respectively. The average turnover, calculated as a percent of total turnover among full time employee positions, was 92 % (SD = 62 %; Range = 8-217 %). Improved production efficiency in both monthly PWS (p = 0.01) and PWM (p = 0.02) was observed with the occurrence of an involuntary turnover event two months prior, after controlling for season, previous month production, farm, and system. For the PWS outcome, there was a significant interaction between an involuntary turnover event two months prior and monthly county-level unemployment rate (p = 0.02), indicative of the improved performance being most profound at the lowest levels of unemployment rate and diminishing at the highest levels. Turnover of animal caretaking personnel in farrow-to-wean farms was confirmed to be highly variable and high for the majority of farms in this study. Furthermore, animal caretaker turnover was associated with subsequent trends of production efficiency, warranting closer consideration of prioritizing managerial efforts in worker recruitment, training and retention.

The World Checklist of Vascular Plants, a continuously updated resource for exploring global plant diversity.

The World Checklist of Vascular Plants (WCVP) is a comprehensive list of scientifically described plant species, compiled over four decades, from peer-reviewed literature, authoritative scientific databases, herbaria and observations, then reviewed by experts. It is a vital tool to facilitate plant diversity research, conservation and effective management, including sustainable use and equitable sharing of benefits. To maximise utility, such lists should be accessible, explicitly evidence-based, transparent, expert-reviewed, and regularly updated, incorporating new evidence and emerging scientific consensus. WCVP largely meets these criteria, being continuously updated and freely available online. Users can browse, search, or download a user-defined subset of accepted species with corresponding synonyms and bibliographic details, or a date-stamped full dataset. To facilitate appropriate data reuse by individual researchers and global initiatives including Global Biodiversity Information Facility, Catalogue of Life and World Flora Online, we document data collation and review processes, the underlying data structure, and the international data standards and technical validation that ensure data quality and integrity. We also address the questions most frequently received from users.

Association between different types of within-farm worker movements and number of pigs weaned per sow in U.S. Swine farms.

The integration and intensification of modern swine production has amplified the importance of biosecurity, as diseases are more easily able to spread and persist in large swine farms, resulting in economic losses. Advancements in accessible technology and computational methods offer new applications for precision livestock farming, such as monitoring internal movements to better understand biosecurity compliance on farm. In this study, a beacon-sensor based internal movement system (PigChamp Pro Europa®) was utilized to investigate the association between weekly within-farm movements of workers and an important production parameter: average weekly number of pigs weaned per sow (PWS), on three US swine farms. Sensors were installed in each room of each farm and Bluetooth-based beacons were distributed individually to farm employees. Movement data was collected for approximately one year and production data was extracted from each farm retrospectively. A linear mixed effects model was fit in STATA 15 with the primary outcome as the average weekly number of pigs weaned per sow and farm included as a random effect. The main predictors included the weekly frequency of three movement types thought to be risky with respect to disease transmission and maintenance in the herd. The frequency values of the three movements were categorized based on the tertile values for each farm. The movement with the highest average frequency was between farrowing rooms for all three farms. The medium frequency of movements category between farrowing rooms the two-weeks preceding the outcome was significantly associated with a decrease in PWS by nearly 1-pig for every 5-sows after controlling for farm, pre-weaning mortality, PWS the week prior, and season (p = 0.03). The random effect variance estimate for the model was 0.21 with a standard error of 0.18. The intraclass correlation coefficient was 0.67 with a standard error of 0.19, indicating that 67% of the unexplained variability in PWS could be attributed to the farm level. This study demonstrates the application of beacon-sensor technology to monitor internal personnel movements in swine production. Technological applications to monitoring trends of within farm movements of farm personnel, such as the system used here, may have the potential to identify specific movements related to farm-specific biosecurity protocol allowing corrective measures and facilitating focused efforts on disease control and mitigation; in turn maintaining productivity and improving overall animal health.

A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.

BACKGROUND: Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night. OBJECTIVE: The lower heart rate during sleep is assumed to be neural in origin, but here we tested whether a day-night difference in intrinsic pacemaking is involved. METHODS: In vivo and in vitro electrocardiographic recordings, vagotomy, transgenics, quantitative polymerase chain reaction, Western blotting, immunohistochemistry, patch clamp, reporter bioluminescence recordings, and chromatin immunoprecipitation were used. RESULTS: The day-night difference in the average heart rate of mice was independent of fluctuations in average locomotor activity and persisted under pharmacological, surgical, and transgenic interruption of autonomic input to the heart. Spontaneous beating rate of isolated (ie, denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic messenger RNA expression of ion channels including hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4). In vitro studies demonstrated 24-hour rhythms in the human HCN4 promoter and the corresponding funny current. The day-night heart rate difference in mice was abolished by HCN block, both in vivo and in the isolated SN. Rhythmic expression of canonical circadian clock transcription factors, for example, Brain and muscle ARNT-Like 1 (BMAL1) and Cryptochrome (CRY) was identified in the SN and disruption of the local clock (by cardiomyocyte-specific knockout of Bmal1) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local clock with intrinsic rate control. CONCLUSION: The circadian variation in heart rate involves SN local clock-dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.