Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Preclinical Cardiotoxicity Screening in Cardio-Oncology.

• hiPSC-CM offer an alternative to in vivo models for predicting cardiotoxicity. • hiPSC-CM monolayers detect pro-arrhythmic effects; inotropic detection is less established. • Cardiac spheroids and engineered tissue may suit chronic cardiotoxicity studies (>2 weeks).

Adverse Outcomes Associated With Interleukin-6 in Patients Recently Hospitalized for Heart Failure With Preserved Ejection Fraction.

Background: Inflammation may play a role in the pathophysiology of heart failure with preserved ejection fraction. We examined whether circulating levels of interleukin-6 identify patients at greater risk of adverse outcomes following hospitalization with heart failure with preserved ejection fraction.

Methods: We assessed relationships between interleukin-6 (IL-6) tertiles (T1-3) and all-cause death, cardiovascular death, and subsequent heart failure hospitalization (sHFH) in 286 patients recently hospitalized with heart failure with preserved ejection fraction.

Adrenoceptor sub-type involvement in Ca current stimulation by noradrenaline in human and rabbit atrial myocytes.

Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca current (I) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such I-increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and β-AR antagonists on NA-stimulated atrial I.

Initiation of ventricular arrhythmia in the acquired long QT syndrome.

Aims: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear.

Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes.

Aims: Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.

Methods And Results: APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye.

In vivo grafting of large engineered heart tissue patches for cardiac repair.

Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.

Role of Reduced Sarco-Endoplasmic Reticulum Ca-ATPase Function on Sarcoplasmic Reticulum Ca Alternans in the Intact Rabbit Heart.

Sarcoplasmic reticulum (SR) Ca cycling is tightly regulated by ryanodine receptor (RyR) Ca release and sarco-endoplasmic reticulum Ca-ATPase (SERCA) Ca uptake during each excitation-contraction coupling cycle. We previously showed that RyR refractoriness plays a key role in the onset of SR Ca alternans in the intact rabbit heart, which contributes to arrhythmogenic action potential duration (APD) alternans. Recent studies have also implicated impaired SERCA function, a key feature of heart failure, in cardiac alternans and arrhythmias.

Cardiotoxic effects of angiogenesis inhibitors.

The development of new therapies for cancer has led to dramatic improvements in survivorship. Angiogenesis inhibitors represent one such advancement, revolutionising treatment for a wide range of malignancies. However, these drugs are associated with cardiovascular toxicities which can impact optimal cancer treatment in the short-term and may lead to increased morbidity and mortality in the longer term.

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts.

Key Points: Cardiac electrophysiology and Ca handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca transients in innervated mouse and rabbit hearts.

Dynamic clamping human and rabbit atrial calcium current: narrowing I window abolishes early afterdepolarizations.

Key Points: Early-afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca current (I ) in its 'window region' voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood.

β-Adrenergic Inhibition Prevents Action Potential and Calcium Handling Changes during Regional Myocardial Ischemia.

β-adrenergic receptor (β-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of β-AR blockers on ventricular electrophysiology and intracellular Ca handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts ( = 19).

Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart.

Key Points: Heart failure leads to dramatic electrophysiological remodelling as a result of numerous cellular and tissue-level changes. Important cellular changes include increased sensitivity of ryanodine receptors (RyRs) to Ca(2+) release and down-regulation of the inward rectifying K(+) current (IK1), both of which contribute to triggered action potentials in isolated cells. We studied the role of increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact non-failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and IK1.

Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart: ryanodine receptor refractoriness during alternans and fibrillation.

Rationale: Sarcoplasmic reticulum (SR) Ca(2+) cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia.

Objective: To measure intra-SR free [Ca(2+)] ([Ca(2+)]SR) changes in intact hearts during alternans and ventricular fibrillation (VF).

Methods And Results: Simultaneous optical mapping of Vm (with RH237) and [Ca(2+)]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts.

Subepicardial action potential characteristics are a function of depth and activation sequence in isolated rabbit hearts.

Background: Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface.

Spectral microvolt T-wave alternans testing has no prognostic value in patients recently hospitalized with decompensated heart failure.

Aims: Microvolt T-wave alternans (MTWA) testing identifies beat-to-beat fluctuations in T-wave morphology, which have been linked to ventricular arrhythmias. However, clinical studies have produced conflicting results and data in heart failure (HF) have been limited. The aim of this study was to determine the prevalence and incremental prognostic value of spectral MTWA testing in an unselected cohort of patients recently hospitalized with HF.

Optical and electrical recordings from isolated coronary-perfused ventricular wedge preparations.

The electrophysiological heterogeneity that exists across the ventricular wall in the mammalian heart has long been recognized, but remains an area that is incompletely understood. Experimental studies of the mechanisms of arrhythmogenesis in the whole heart often examine the epicardial surface in isolation and thereby disregard transmural electrophysiology. Significant heterogeneity exists in the electrophysiological properties of cardiomyocytes isolated from different layers of the ventricular wall, and given that regional heterogeneities of membrane repolarization properties can influence the electrophysiological substrate for re-entry, the diversity of cell types and characteristics spanning the ventricular wall is important in the study of arrhythmogenesis.

Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.

Rationale: β-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown.

Objective: To determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia.

Profile of microvolt T-wave alternans testing in 1003 patients hospitalized with heart failure.

Aims: Observational studies in selected populations have suggested that microvolt T-wave alternans (MTWA) testing may identify patients with heart failure (HF) at risk of sudden cardiac death. The aims of this study were to investigate the utility of MTWA testing in an unselected population of patients with HF and to evaluate the clinical characteristics associated with the MTWA results.

Methods And Results: A total of 1003 patients hospitalized with decompensated HF were enrolled.

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype.

Aims: The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes.

Methods And Results: Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence.

Alternans of action potential duration and amplitude in rabbits with left ventricular dysfunction following myocardial infarction.

T-wave alternans may predict the occurrence of ventricular arrhythmias in patients with left ventricular dysfunction and experimental work has linked discordant repolarization alternans to the induction of re-entry. The aim of this study was to examine the occurrence of transmural repolarization alternans and to investigate the link between alternans and ventricular arrhythmia in rabbits with left ventricular dysfunction following myocardial infarction. Optical mapping was used to record action potentials from the transmural surface of left ventricular wedge preparations from normal and post-infarction hearts during a progressive reduction in pacing cycle length at 30 and 37°C.

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium.

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits.