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Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data., Using a network propagation approach with integrated multi-omic data, Selevsek et al. develop a reproducible workflow for identifying drug toxicity effects in cellular systems. This is demonstrated with the analysis of anthracycline cardiotoxicity in cardiac microtissues under the effect of multiple drugs.

Hydrogen sulfide (H2S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H2S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia. Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit

Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a "safe dose" of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration.

AIMS: B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) predict cardiovascular endpoints in patients and all-cause death in the general population. This was assigned to their association with clinical cardiac remodelling defined as changes in size, shape and function of the heart. The aim of this study was to evaluate whether NT-proBNP and BNP were associated with cardiovascular and overall death independent of clinical cardiac remodelling measured by echocardiography as left ventricular hypertrophy (LVH), diastolic dysfunction and left ventricular ejection fraction (EF). METHODS AND RESULTS: In a general population-based cohort study from Germany (KORA-S3) with subjects' baseline age ranging from 25 to 74 years, cardiac morphology and function were assessed as left ventricular mass (LVM), diastolic dysfunction and EF by echocardiography and circulating NT-proBNP and BNP were measured at baseline. In 1,223 subjects with mortality follow-up information, we examined the association of baseline NT-proBNP and BNP with cardiovascular mortality (number of deaths = 52, median follow-up time = 12.9years) using Cox regression without and with adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF. The risk of cardiovascular mortality increased with higher NT-proBNP levels measured at baseline (hazard ratio HR = 1.67 per unit increment in logNT-proBNP, p = 2.78*10-4, adjusted for age and sex). This increased risk persisted after adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF (HR = 1.73; p = 0.047). When excluding subjects with relevant LVH (LVM to body surface area > 149g/m2 in men / 122g/m2 in women), the NT-proBNP association with mortality was still significant (n = 1,138; number of deaths = 35; HR = 1.48; p = 0.04). We found similar results for BNP. CONCLUSION: Our data confirms NT-proBNP and BNP as predictor of cardiovascular mortality in a large general population-based study with long-term follow-up. Our study extends previously published population-based studies to younger and potentially healthier individuals without relevant LVH, diastolic dysfunction or LVD.

It is well known that atrial tachycardia causes atrial electrical remodeling, characterized by shortening of atrial effective refractory periods (AERPs) and loss of physiological adaptation of AERP to rate. However, the nature and time course of changes in ventricular effective refractory periods (VERP) caused by rapid rates are to be established. After being instrumented with epicardial electrodes on both atria and both ventricles nine goats were subjected to 1 week of rapid AV pacing with a rate of 240 beats/min and an AV delay of 100 ms. Pacing was only interrupted for measurement of left and right AERPs and VERPs at three basic cycle lengths (BCL) of 400 ms, 300 ms, and 200 ms during sinus rhythm in the conscious animal. Left and right AERPs decreased at all BCLs, reaching minimum values after 3 days (right AERP at BCL of 400 ms, 96+/-16 ms after 3 days vs 144+/-16 ms at baseline, P

It is well known that atrial tachycardia causes atrial electrical remodeling, characterized by shortening of atrial effective refractory periods (AERPs) and loss of physiological adaptation of AERP to rate. However, the nature and time course of changes in ventricular effective refractory periods (VERP) caused by rapid rates are to be established. After being instrumented with epicardial electrodes on both atria and both ventricles nine goats were subjected to 1 week of rapid AV pacing with a rate of 240 beats/min and an AV delay of 100 ms. Pacing was only interrupted for measurement of left and right AERPs and VERPs at three basic cycle lengths (BCL) of 400 ms, 300 ms, and 200 ms during sinus rhythm in the conscious animal. Left and right AERPs decreased at all BCLs, reaching minimum values after 3 days (right AERP at BCL of 400 ms, 96+/-16 ms after 3 days vs 144+/-16 ms at baseline, P

Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current ( Ito1), the slow component of the delayed rectifier K+ current ( IKs), the L-type Ca2+ channel current ( ICa,L), and the Na+-K+ pump current ( INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca2+ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca2+ entry via ICa,L at fast rate drives increased Na+-Ca2+ exchanger Ca2+ extrusion and Na+ entry, which in turn increases Na+ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.

It is well known that atrial tachycardia causes atrial electrical remodeling, characterized by shortening of atrial effective refractory periods (AERPs) and loss of physiological adaptation of AERP to rate. However, the nature and time course of changes in ventricular effective refractory periods (VERP) caused by rapid rates are to be established. After being instrumented with epicardial electrodes on both atria and both ventricles nine goats were subjected to 1 week of rapid AV pacing with a rate of 240 beats/min and an AV delay of 100 ms. Pacing was only interrupted for measurement of left and right AERPs and VERPs at three basic cycle lengths (BCL) of 400 ms, 300 ms, and 200 ms during sinus rhythm in the conscious animal. Left and right AERPs decreased at all BCLs, reaching minimum values after 3 days (right AERP at BCL of 400 ms, 96 +/- 16 ms after 3 days vs 144 +/- 16 ms at baseline, P0.05). In contrast, both left and right VERPs did not change at any BCL. This study demonstrates a difference between the atria and ventricles with respect to tachycardia induced changes in refractoriness.