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Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean T max of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t ½ of 3.9–6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean −45% to −78%) 85 days after dose. Reductions in triglyceride (median −34% to −54%) and non-HDL-C (mean −18% to −29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224 First-in-human results from five cohorts of healthy volunteers and individuals with hepatic steatosis show that RNA interference treatment targeting ANGPTL3 was well tolerated and led to reduction in triglycerides and non-HDL cholesterol.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.

Background: Multi-omics delivers more biological insight than targeted investigations. We applied multi-omics to patients with heart failure with reduced ejection fraction (HFrEF). Methods: 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n = 73. Results: 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE > 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, p < 0.0001). Conclusion: Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.

Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current ( I K1 ). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current I K1 and increased inward sodium-calcium exchanger current ( I NCX ) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled I K1 . More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency.

Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca 2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca 2+ -ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca 2+ handling channels, we performed systematic analyses using the Maleckar et al . model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca 2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca 2+ ([Ca 2+ ] i ) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca 2+ in the uptake and release compartments in the SR ([Ca 2+ ] up and [Ca 2+ ] rel ). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of ‘lone’ AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

Personalised modelling has become dominant in personalised medicine and precision health. It creates a computational model for an individual based on large data repositories of existing personalised data, aiming to achieve the best possible personal diagnosis or prognosis and derive an informative explanation for it. Current methods are still working on a single data modality or treating all modalities with the same method. The proposed method, SAIN (Search-And-INfer), offers better results and an informative explanation for classification and prediction tasks on a new multimodal object (sample) using a database of similar multimodal objects. The method is based on different distance measures suitable for each data modality and introduces a new formula to aggregate all modalities into a single vector distance measure to find the closest objects to a new one, and then use them for a probabilistic inference. This paper describes SAIN and applies it to two types of multimodal data, cardiovascular diagnosis and EEG time series, modelled by integrating modalities, such as numbers, categories, images, and time series, and using a software implementation of SAIN.

ObjectiveThe Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) was established to investigate the drivers of secondary events after first-time acute coronary syndrome (ACS), including addressing inequitable outcomes by ethnicity. Herein, the first clinical outcomes and prognostic modelling approach are reported.MethodsFirst, in 28 176 New Zealanders with first-time ACS from a national registry, a clinical summary score for predicting 1-year death/cardiovascular readmission was created using Cox regression of 20 clinical variables. This score was then calculated in the 2015 participant MENZACS study to represent clinical risk. In MENZACS, Cox regression was used to assess N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a prognostic marker for death/cardiovascular readmission in four models, adjusting for (1) age and sex; (2) age, sex, ethnicity; (3) clinical summary score; (4) clinical summary score and ethnicity.ResultsOf the 2015 MENZACS participants (mean age 61 years, 79% male, 73% European, 14% Māori, 5% Pacific people), 2003 were alive at discharge. Of the 2003, 416 (20.8%) experienced all-cause death/cardiovascular readmission over a median of 3.5 years. In a simple model, age, male sex, Māori ethnicity and NT-proBNP levels were significant predictors of outcome. After adjustment for the clinical summary score, which includes age and sex, NT-proBNP and ethnicity were no longer statistically significant: log2(NT-proBNP) hazard ratio (HR) 1.03, 95% confidence interval (95% CI) 0.98 to 1.08, p=0.305; Māori ethnicity HR 1.26, 95% CI 0.97 to 1.62, p=0.084.ConclusionsIn 2015 patients with first-time ACS, recurrent events were common (20.8%). Increasing NT-proBNP levels and Māori ethnicity were predictors of death/cardiovascular readmission, but not after adjustment for the 20 clinical risk factors represented by the clinical summary score.Trial registration numberACTRN12615000676516.

Increased spatial QRS-T angle has been shown to predict appropriate implantable cardioverter defibrilIator (ICD) therapy in patients with left ventricular systolic dysfunction (LVSD). We performed a retrospective cohort study in patients with left ventricular ejection fraction (LVEF) 31-40% to assess the relationship between the spatial QRS-T angle and other advanced ECG (A-ECG) as well as echocardiographic metadata, with all-cause mortality or ICD implantation for secondary prevention. 534 patients ≤75 years of age with LVEF 31-40% were identified through an echocardiography reporting database. Digital 12-lead ECGs were retrospectively matched to 295 of these patients, for whom echocardiographic and A-ECG metadata were then generated. Data mining was applied to discover novel ECG and echocardiographic markers of risk. Machine learning was used to develop a model to predict possible outcomes. 49 patients (17%) had events, defined as either mortality (n = 16) or ICD implantation for secondary prevention (n = 33). 72 parameters (58 A-ECG, 14 echocardiographic) were univariately different (p<0.05) in those with vs. without events. After adjustment for multiplicity, 24 A-ECG parameters and 3 echocardiographic parameters remained different (p<2x10-3). These included the posterior-to-leftward QRS loop ratio from the derived vectorcardiographic horizontal plane (previously associated with pulmonary artery pressure, p = 2x10-6); spatial mean QRS-T angle (134 vs. 112°, p = 1.6x10-4); various repolarisation vectors; and a previously described 5-parameter A-ECG score for LVSD (p = 4x10-6) that also correlated with echocardiographic global longitudinal strain (R2 = - 0.51, P < 0.0001). A spatial QRS-T angle >110° had an adjusted HR of 3.4 (95% CI 1.6 to 7.4) for secondary ICD implantation or all-cause death and adjusted HR of 4.1 (95% CI 1.2 to 13.9) for future heart failure admission. There was a loss of complexity between A-ECG and echocardiographic variables with an increasing degree of disease. Spatial QRS-T angle >110° was strongly associated with arrhythmic events and all-cause death. Deep analysis of global ECG and echocardiographic metadata revealed underlying relationships, which otherwise would not have been appreciated. Delivered at scale such techniques may prove useful in clinical decision making in the future.

The response to most medication, including antiplatelet drugs, is highly variable between individuals. Observational studies have shown that nonresponders to antiplatelet agents appear to have an increased incidence of vascular events. This review article reviews the background, mechanisms, and evidence in support of the clinial significance of this phenomenon.

Background. Each year, approximately 5000 New Zealanders are admitted to hospital with first-time acute coronary syndrome (ACS). The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a prospective longitudinal cohort study embedded within the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry in six hospitals. The objective of MENZACS is to examine the relationship between clinical, genomic, and cardiometabolic markers in relation to presentation and outcomes post-ACS. Methods. Patients with first-time ACS are enrolled and study-specific research data is collected alongside the ANZACS-QI registry. The research blood samples are stored for future genetic/biomarker assays. Dietary information is collected with a food frequency questionnaire and information about physical activity, smoking, and stress is also collected via questionnaire. Detailed family history, ancestry, and ethnicity data are recorded on all participants. Results. During the period between 2015 and 2019, there were 2015 patients enrolled. The mean age was 61 years, with 60% of patients aged <65 years and 21% were female. Ethnicity and cardiovascular (CV) risk factor distribution was similar to ANZACS-QI: 13% Māori, 5% Pacific, 5% Indian, and 74% NZ European. In terms of CV risk factors, 56% were ex-/current smokers, 42% had hypertension, and 19% had diabetes. ACS subtype was ST elevation myocardial infarction (STEMI) in 41%, non-ST elevation myocardial infarction (NSTEM) in 54%, and unstable angina in 5%. Ninety-nine percent of MENZACS participants underwent coronary angiography and 90% had revascularization; there were high rates of prescription of secondary prevention medications upon discharge from hospital. Conclusion. MENZACS represents a cohort with optimal contemporary management and will be a significant epidemiological bioresource for the study of environmental and genetic factors contributing to ACS in New Zealand’s multi-ethnic environment. The study will utilise clinical, nutritional, lifestyle, genomic, and biomarker analyses to explore factors influencing the progression of coronary disease and develop risk prediction models for health outcomes.