Simulating institutional heterogeneity in sustainability science.

Sustainability outcomes are influenced by the laws and configurations of natural and engineered systems as well as activities in socio-economic systems. An important subset of human activity is the creation and implementation of institutions, formal and informal rules shaping a wide range of human behavior. Understanding these rules and codifying them in computational models can provide important missing insights into why systems function the way they do (static) as well as the pace and structure of transitions required to improve sustainability (dynamic). Here, we conduct a comparative synthesis of three modeling approaches- integrated assessment modeling, engineering-economic optimization, and agent-based modeling-with underexplored potential to represent institutions. We first perform modeling experiments on climate mitigation systems that represent specific aspects of heterogeneous institutions, including formal policies and institutional coordination, and informal attitudes and norms. We find measurable but uneven aggregate impacts, while more politically meaningful distributional impacts are large across various actors. Our results show that omitting institutions can influence the costs of climate mitigation and miss opportunities to leverage institutional forces to speed up emissions reduction. These experiments allow us to explore the capacity of each modeling approach to represent insitutions and to lay out a vision for the next frontier of endogenizing institutional change in sustainability science models. To bridge the gap between modeling, theories, and empirical evidence on social institutions, this research agenda calls for joint efforts between sustainability modelers who wish to explore and incorporate institutional detail, and social scientists studying the socio-political and economic foundations for sustainability transitions.

Uncertainty in boundedly rational household adaptation to environmental shocks.

Despite the growing calls to integrate realistic human behavior in sustainability science models, the representative rational agent prevails. This is especially problematic for climate change adaptation that relies on actions at various scales: from governments to individuals. Empirical evidence on individual adaptation to climate-induced hazards reveals diverse behavioral and social factors affecting economic considerations. Yet, implications of replacing the rational optimizer by realistic human behavior in nature-society systems models are poorly understood. Using an innovative evolutionary economic agent-based model we explore different framings regarding household adaptation behavior to floods, leveraging on behavioral data from a household survey in Miami, USA. We find that a representative rational agent significantly overestimates household adaptation diffusion and underestimates damages compared to boundedly rational behavior revealed from our survey. This "adaptation deficit" exhibited by a population of empirically informed agents is explained primarily by diverse "soft" adaptation constraints-awareness, social influences-rather than heterogeneity in financial constraints. Besides initial inequality disproportionally impacting low/medium adaptive capacity households post-flood, our findings suggest that even under a nearly complete adaptation diffusion, adaptation benefits are uneven, with late or less-efficient actions locking households to a path of higher damages, further exacerbating inequalities. Our exploratory modeling reveals that behavioral assumptions shape the uncertainty of physical factors, like exposure and objective effectiveness of flood-proofing measures, traditionally considered crucial in risk assessments. This unique combination of methods facilitates the assessment of cumulative and distributional effects of boundedly rational behavior essential for designing tailored climate adaptation policies, and for equitable sustainability transitions in general.

The metamorphosis of amphibian myocardium: moving to the heart of the matter.

Amphibians are a classical object for physiological studies, and they are of great value for developmental studies owing to their transition from an aquatic larval form to an adult form with a terrestrial lifestyle. Axolotls (Ambystoma mexicanum) are of special interest for such studies because of their neoteny and facultative pedomorphosis, as in these animals, metamorphosis can be induced and fully controlled in laboratory conditions. It has been suggested that their metamorphosis, associated with gross anatomical changes in the heart, also involves physiological and electrical remodeling of the myocardium. We used whole-cell patch clamp to investigate possible changes caused by metamorphosis in electrical activity and major ionic currents in cardiomyocytes isolated from paedomorphic and metamorphic axolotls. T4-induced metamorphosis caused shortening of atrial and ventricular action potentials (APs), with no changes in resting membrane potential or maximum velocity of AP upstroke, favoring higher heart rate possible in metamorphic animals. Potential-dependent potassium currents in axolotl myocardium were represented by delayed rectifier currents IKr and IKs, and upregulation of IKs caused by metamorphosis probably underlies AP shortening. Metamorphosis was associated with downregulation of inward rectifier current IK1, probably serving to increase the excitability of myocardium in metamorphic animals. Metamorphosis also led to a slight increase in fast sodium current INa with no changes in its steady-state kinetics and to a significant upregulation of ICa in both atrial and ventricular cells, indicating stronger Ca2+ influx for higher cardiac contractility in metamorphic salamanders. Taken together, these changes serve to increase cardiac reserve in metamorphic animals.

Sodium current preserves electrical excitability in the heart of hibernating ground squirrel (Citellus undulatus).

Hibernating mammals are capable of maintaining normal cardiac function at low temperatures. Excitability of cardiac myocytes crucially depends on the fast sodium current (INa), which is decreased in hypothermia due to both depolarization of resting membrane potential and direct negative effect of low temperature. Therefore, INa in hibernating mammals should have specific features allowing to maintain excitability of myocardium at low temperatures. The current-voltage dependence of INa, its steady-state inactivation and activation and recovery from inactivation were studied in winter hibernating (WH) and summer active (SA) ground squirrels and in rats using whole-cell patch clamp at 10 °C and 20 °C. INa peak amplitude and the parameters of steady-state activation and inactivation curves did not differ between SA and WH ground squirrels at both temperatures. However, at both temperatures strong positive shift of activation and inactivation curves by 5-12 mV was observed in both WH and SA ground squirrels if compared to rats. This peculiarity of cardiac INa in ground squirrels helps to maintain excitability in conditions of depolarized resting membrane potential. The time course of INa recovery from inactivation at 10 °C was faster in WH than in SA ground squirrels, which could ensure normal activation of myocardium during hibernation.

Uncertainty in individual risk judgments associates with vulnerability and curtailed climate adaptation.

Risk assessments are key for the effective management of potential environmental threats. Across probabilistic phenomena, climate change is an exemplar of paramount uncertainties. These uncertainties have been embraced in supporting governments' decisions; yet receive scarce attention when studying individual behavior. Analyzing a survey conducted in the USA, China, Indonesia, and the Netherlands (N=6242), we explore socio-economic, psychological, and behavioral differences between individuals who can subjectively assess risks, and those who are risk-uncertain. We find that risk-uncertain individuals are more likely to belong to societal subgroups classically considered as vulnerable, and have reduced capacities and intentions to adapt to hazards-specifically floods. The distinctions between risk-aware and risk-uncertain individuals indicate that ignoring differences in individuals' capacity to assess risks could amount to persistent vulnerability and undermine climate-resilience efforts. While we use floods emblematically, these finding have consequences for the standard practice of dropping or bootstrapping uncertain responses, irrespective of the hazard, with implications for environmental management.

Ionic currents underlying different patterns of electrical activity in working cardiac myocytes of mammals and non-mammalian vertebrates.

The orderly contraction of the vertebrate heart is determined by generation and propagation of cardiac action potentials (APs). APs are generated by the integrated activity of time- and voltage-dependent ionic channels which carry inward Na+ and Ca2+ currents, and outward K+ currents. This review compares atrial and ventricular APs and underlying ion currents between different taxa of vertebrates. We have collected literature data and attempted to find common electrophysiological features for two or more vertebrate groups, show differences between taxa and cardiac chambers, and indicate gaps in the existing data. Although electrical excitability of the heart in all vertebrates is based on the same superfamily of channels, there is a vast variability of AP waveforms between atrial and ventricular myocytes, between different species of the same vertebrate class and between endothermic and ectothermic animals. The wide variability of AP shapes is related to species-specific differences in animal size, heart rate, stage of ontogenetic development, excitation-contraction coupling, temperature and oxygen availability. Some of the differences between taxa are related to evolutionary development of genomes, which appear e.g. in the expression of different Na+ and K+ channel orthologues in cardiomyocytes of vertebrates. There is a wonderful variability of AP shapes and underlying ion currents with which electrical excitability of vertebrate heart can be generated depending on the intrinsic and extrinsic conditions of animal body. This multitude of ionic mechanisms provides excellent material for studying how the function of the vertebrate heart can adapt or acclimate to prevailing physiological and environmental conditions.

One and done? Exploring linkages between households' intended adaptations to climate-induced floods.

As climate change increases the probability and severity of natural hazards, the need for coordinated adaptation at all levels of society intensifies. Governmental-level adaptation measures are essential, but insufficient in the face of growing risks, necessitating complementary action from households. Apprehending the drivers of household adaptation is critical if governments are to stimulate protective behavior effectively. While past work has focused on the behavioral drivers of household adaptation, little attention has been paid to understanding the relationships between adaptation measures themselves-both previously undergone and additionally (planned) intended adaptation(s). Using survey data (N = 4,688) from four countries-the United States, China, Indonesia, and the Netherlands-we utilize protection motivation theory to account for the behavioral drivers of household adaptation to the most devastating climate-driven hazard: flooding. We analyze how past and additionally intended adaptations involving structural modification to one's home affect household behavior. We find that both prior adaptations and additionally intended adaptation have a positive effect on intending a specific adaptation. Further, we note that once links between adaptations are accounted for, the effect that worry has on motivating specific actions, substantially lessens. This suggests that while threat appraisal is important in initially determining if households intend to adapt, it is households' adaptive capacity that determines how. Our analysis reveals that household structural modifications may be nonmarginal. This could indicate that past action and intention to pursue one action trigger intentions for other adaptations, a finding with implications for estimating the speed and scope of household adaptation diffusion.

Repolarizing potassium currents in working myocardium of Japanese quail: a novel translational model for cardiac electrophysiology.

Birds developed endothermy and four-chambered high-performance heart independently from mammals. Though avian embryos are extensively studied and widely used as various models for heart research, little is known about cardiac physiology of adult birds. Meanwhile, cardiac electrophysiology is in search for easily accessible and relevant model objects which resemble human myocardium in the pattern of repolarizing currents (IKr, IKs, IKur and Ito). This study focuses on the configuration of electrical activity and electrophysiological phenotype of working myocardium in adult Japanese quails (Coturnix japonica). The resting membrane potential and action potential (AP) waveform in quail atrial myocardium were similar to that in working myocardium of rodents. Using whole-cell patch clamp and sharp glass microelectrodes, we demonstrated that the repolarization of quail atrial and ventricular myocardium is determined by voltage-dependent potassium currents IKr, IKs and Ito - the latter was previously considered as an exclusive evolutionary feature of mammals. The specific blockers of these currents, dofetilide (3 µmol l-1), HMR 1556 (30 µmol l-1) and 4-aminopyridine (3 mmol l-1), prolonged AP in both ventricular and atrial myocardial preparations. The expression of the corresponding channels responsible for these currents in quail myocardium was investigated with quantitative RT-PCR and western blotting. In conclusion, the described pattern of repolarizing ionic currents and channels in quail myocardium makes this species a novel and suitable experimental model for translational cardiac research and reveals new information related to the evolution of cardiac electrophysiology in vertebrates.

Integrated modeling of extended agro-food supply chains: A systems approach.

The current intense food production-consumption is one of the main sources of environmental pollution and contributes to anthropogenic greenhouse gas emissions. Organic farming is a potential way to reduce environmental impacts by excluding synthetic pesticides and fertilizers from the process. Despite ecological benefits, it is unlikely that conversion to organic can be financially viable for farmers, without additional support and incentives from consumers. This study models the interplay between consumer preferences and socio-environmental issues related to agriculture and food production. We operationalize the novel concept of extended agro-food supply chain and simulate adaptive behavior of farmers, food processors, retailers, and customers. Not only the operational factors (e.g., price, quantity, and lead time), but also the behavioral factors (e.g., attitude, perceived control, social norms, habits, and personal goals) of the food suppliers and consumers are considered in order to foster organic farming. We propose an integrated approach combining agent-based, discrete-event, and system dynamics modeling for a case of wine supply chain. Findings demonstrate the feasibility and superiority of the proposed model over the traditional sustainable supply chain models in incorporating the feedback between consumers and producers and analyzing management scenarios that can urge farmers to expand organic agriculture. Results further indicate that demand-side participation in transition pathways towards sustainable agriculture can become a time-consuming effort if not accompanied by the middle actors between consumers and farmers. In practice, our proposed model may serve as a decision-support tool to guide evidence-based policymaking in the food and agriculture sector.

A Stochastic Model of Gene Expression with Polymerase Recruitment and Pause Release.

Transcriptional bursting is a major source of noise in gene expression. The telegraph model of gene expression, whereby transcription switches between on and off states, is the dominant model for bursting. Recently, it was shown that the telegraph model cannot explain a number of experimental observations from perturbation data. Here, we study an alternative model that is consistent with the data and which explicitly describes RNA polymerase recruitment and polymerase pause release, two steps necessary for messenger RNA (mRNA) production. We derive the exact steady-state distribution of mRNA numbers and an approximate steady-state distribution of protein numbers, which are given by generalized hypergeometric functions. The theory is used to calculate the relative sensitivity of the coefficient of variation of mRNA fluctuations for thousands of genes in mouse fibroblasts. This indicates that the size of fluctuations is mostly sensitive to the rate of burst initiation and the mRNA degradation rate. Furthermore, we show that 1) the time-dependent distribution of mRNA numbers is accurately approximated by a modified telegraph model with a Michaelis-Menten like dependence of the effective transcription rate on RNA polymerase abundance, and 2) the model predicts that if the polymerase recruitment rate is comparable or less than the pause release rate, then upon gene replication, the mean number of RNA per cell remains approximately constant. This gene dosage compensation property has been experimentally observed and cannot be explained by the telegraph model with constant rates.

Warmer, faster, stronger: Ca2+ cycling in avian myocardium.

Birds occupy a unique position in the evolution of cardiac design. Their hearts are capable of cardiac performance on par with, or exceeding that of mammals, and yet the structure of their cardiomyocytes resembles those of reptiles. It has been suggested that birds use intracellular Ca2+ stored within the sarcoplasmic reticulum (SR) to power contractile function, but neither SR Ca2+ content nor the cross-talk between channels underlying Ca2+-induced Ca2+ release (CICR) have been studied in adult birds. Here we used voltage clamp to investigate the Ca2+ storage and refilling capacities of the SR and the degree of trans-sarcolemmal and intracellular Ca2+ channel interplay in freshly isolated atrial and ventricular myocytes from the heart of the Japanese quail (Coturnix japonica). A trans-sarcolemmal Ca2+ current (ICa) was detectable in both quail atrial and ventricular myocytes, and was mediated only by L-type Ca2+ channels. The peak density of ICa was larger in ventricular cells than in atrial cells, and exceeded that reported for mammalian myocardium recorded under similar conditions. Steady-state SR Ca2+ content of quail myocardium was also larger than that reported for mammals, and reached 750.6±128.2 µmol l-1 in atrial cells and 423.3±47.2 µmol l-1 in ventricular cells at 24°C. We observed SR Ca2+-dependent inactivation of ICa in ventricular myocytes, indicating cross-talk between sarcolemmal Ca2+ channels and ryanodine receptors in the SR. However, this phenomenon was not observed in atrial myocytes. Taken together, these findings help to explain the high-efficiency avian myocyte excitation-contraction coupling with regard to their reptilian-like cellular ultrastructure.

Statistics of Nascent and Mature RNA Fluctuations in a Stochastic Model of Transcriptional Initiation, Elongation, Pausing, and Termination.

Recent advances in fluorescence microscopy have made it possible to measure the fluctuations of nascent (actively transcribed) RNA. These closely reflect transcription kinetics, as opposed to conventional measurements of mature (cellular) RNA, whose kinetics is affected by additional processes downstream of transcription. Here, we formulate a stochastic model which describes promoter switching, initiation, elongation, premature detachment, pausing, and termination while being analytically tractable. We derive exact closed-form expressions for the mean and variance of nascent RNA fluctuations on gene segments, as well as of total nascent RNA on a gene. We also obtain exact expressions for the first two moments of mature RNA fluctuations and approximate distributions for total numbers of nascent and mature RNA. Our results, which are verified by stochastic simulation, uncover the explicit dependence of the statistics of both types of RNA on transcriptional parameters and potentially provide a means to estimate parameter values from experimental data.

Thermal acclimation and seasonal acclimatization: a comparative study of cardiac response to prolonged temperature change in shorthorn sculpin.

Seasonal thermal remodelling (acclimatization) and laboratory thermal remodelling (acclimation) can induce different physiological changes in ectothermic animals. As global temperatures are changing at an increasing rate, there is urgency to understand the compensatory abilities of key organs such as the heart to adjust under natural conditions. Thus, the aim of the present study was to directly compare the acclimatization and acclimatory response within a single eurythermal fish species, the European shorthorn sculpin (Myoxocephalus scorpio). We used current- and voltage-clamp to measure ionic current densities in both isolated atrial and ventricular myocytes from three groups of fish: (1) summer-caught fish kept at 12°C ('summer-acclimated'); (2) summer-caught fish kept at 3°C ('cold acclimated'); and (3) fish caught in March ('winter-acclimatized'). At a common test temperature of 7.5°C, action potential (AP) was shortened by both winter acclimatization and cold acclimation compared with summer acclimation; however, winter acclimatization caused a greater shortening than did cold acclimation. Shortening of AP was achieved mostly by a significant increase in repolarizing current density (IKr and IK1) following winter acclimatization, with cold acclimation having only minor effects. Compared with summer acclimation, the depolarizing L-type calcium current (ICa) was larger following winter acclimatization, but again, there was no effect of cold acclimation on ICa Interestingly, the other depolarizing current, INa, was downregulated at low temperatures. Our further analysis shows that ionic current remodelling is primarily due to changes in ion channel density rather than current kinetics. In summary, acclimatization profoundly modified the electrical activity of the sculpin heart while acclimation to the same temperature for >1.5 months produced very limited remodelling effects.

Intelligent judgements over health risks in a spatial agent-based model.

BACKGROUND: Millions of people worldwide are exposed to deadly infectious diseases on a regular basis. Breaking news of the Zika outbreak for instance, made it to the main media titles internationally. Perceiving disease risks motivate people to adapt their behavior toward a safer and more protective lifestyle. Computational science is instrumental in exploring patterns of disease spread emerging from many individual decisions and interactions among agents and their environment by means of agent-based models. Yet, current disease models rarely consider simulating dynamics in risk perception and its impact on the adaptive protective behavior. Social sciences offer insights into individual risk perception and corresponding protective actions, while machine learning provides algorithms and methods to capture these learning processes. This article presents an innovative approach to extend agent-based disease models by capturing behavioral aspects of decision-making in a risky context using machine learning techniques. We illustrate it with a case of cholera in Kumasi, Ghana, accounting for spatial and social risk factors that affect intelligent behavior and corresponding disease incidents. The results of computational experiments comparing intelligent with zero-intelligent representations of agents in a spatial disease agent-based model are discussed. METHODS: We present a spatial disease agent-based model (ABM) with agents' behavior grounded in Protection Motivation Theory. Spatial and temporal patterns of disease diffusion among zero-intelligent agents are compared to those produced by a population of intelligent agents. Two Bayesian Networks (BNs) designed and coded using R and are further integrated with the NetLogo-based Cholera ABM. The first is a one-tier BN1 (only risk perception), the second is a two-tier BN2 (risk and coping behavior). RESULTS: We run three experiments (zero-intelligent agents, BN1 intelligence and BN2 intelligence) and report the results per experiment in terms of several macro metrics of interest: an epidemic curve, a risk perception curve, and a distribution of different types of coping strategies over time. CONCLUSIONS: Our results emphasize the importance of integrating behavioral aspects of decision making under risk into spatial disease ABMs using machine learning algorithms. This is especially relevant when studying cumulative impacts of behavioral changes and possible intervention strategies.

Flood protection and endogenous sorting of households: the role of credit constraints.

Human migration is increasingly seen as a promising climate change adaptation and flood risk reduction strategy. The purpose of this paper is to investigate how spatial differences in flood risk, due to differences in flood protection, reduce the mobility of vulnerable households through a credit constraint mechanism. Using an equilibrium model with two households types and endogenous sorting, we show how spatial differences in flood protection lead to clustering of vulnerable households in a risky region, in a real-world setting of common United States (US) flood zones. We find clustering effects of some size for flood zones with return periods of less than 30 years.

Empirical analysis of farmers' drought risk perception: objective factors, personal circumstances, and social influence.

Drought-induced water shortage and salinization are a global threat to agricultural production. With climate change, drought risk is expected to increase as drought events are assumed to occur more frequently and to become more severe. The agricultural sector's adaptive capacity largely depends on farmers' drought risk perceptions. Understanding the formation of farmers' drought risk perceptions is a prerequisite to designing effective and efficient public drought risk management strategies. Various strands of literature point at different factors shaping individual risk perceptions. Economic theory points at objective risk variables, whereas psychology and sociology identify subjective risk variables. This study investigates and compares the contribution of objective and subjective factors in explaining farmers' drought risk perception by means of survey data analysis. Data on risk perceptions, farm characteristics, and various other personality traits were collected from farmers located in the southwest Netherlands. From comparing the explanatory power of objective and subjective risk factors in separate models and a full model of risk perception, it can be concluded that farmers' risk perceptions are shaped by both rational and emotional factors. In a full risk perception model, being located in an area with external water supply, owning fields with salinization issues, cultivating drought-/salt-sensitive crops, farm revenue, drought risk experience, and perceived control are significant explanatory variables of farmers' drought risk perceptions.

A methodology for eliciting, representing, and analysing stakeholder knowledge for decision making on complex socio-ecological systems: from cognitive maps to agent-based models.

This paper aims to contribute to developing better ways for incorporating essential human elements in decision making processes for modelling of complex socio-ecological systems. It presents a step-wise methodology for integrating perceptions of stakeholders (qualitative) into formal simulation models (quantitative) with the ultimate goal of improving understanding and communication about decision making in complex socio-ecological systems. The methodology integrates cognitive mapping and agent based modelling. It cascades through a sequence of qualitative/soft and numerical methods comprising: (1) Interviews to elicit mental models; (2) Cognitive maps to represent and analyse individual and group mental models; (3) Time-sequence diagrams to chronologically structure the decision making process; (4) All-encompassing conceptual model of decision making, and (5) computational (in this case agent-based) Model. We apply the proposed methodology (labelled ICTAM) in a case study of viticulture irrigation in South Australia. Finally, we use strengths-weakness-opportunities-threats (SWOT) analysis to reflect on the methodology. Results show that the methodology leverages the use of cognitive mapping to capture the richness of decision making and mental models, and provides a combination of divergent and convergent analysis methods leading to the construction of an Agent Based Model.

Distribution of economic damages due to climate-driven sea-level rise across European regions and sectors.

Economic costs of climate change are conventionally assessed at the aggregated global and national levels, while adaptation is local. When present, regionalised assessments are confined to direct damages, hindered by both data and models' limitations. This article goes beyond the aggregated analysis to explore direct and indirect economic consequences of sea level rise (SLR) at regional and sectoral levels in Europe. Using a dynamic computable general equilibrium model and novel datasets, we estimate the distribution of losses and gains across regions and sectors. A comparison of a high-end scenario against a no-climate-impact baseline suggests a GDP loss of 1.26% (€871.8 billion) for the whole EU&UK. Conversely our refined assessments show that some coastal regions lose 9.56-20.84% of GDP, revealing striking regional disparities. Inland regions grow due to the displaced demand from coastal areas, but the GDP gains are small (0-1.13%). While recovery benefits the construction sector, public services and industry face significant downturns. We show that prioritising recovery of critical sectors locally reduces massive regional GDP losses, at negligible costs to the overall European economy. Our analysis traces regional economic restructuring triggered by SLR, underscoring the necessity of region-specific adaptation policies that embrace uneven geographic impacts and unique sectoral profiles to inform resilient strategy design.

Characterization of hERG K+ channel inhibition by the new class III antiarrhythmic drug cavutilide.

Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(IKr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III IKr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of IhERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of IhERG by 100 nM cavutilide develops faster than at 0 mV and, especially, - 30 mV (τ of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces IhERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of IhERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of IKr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide.

3-Methyl-phenanthrene (3-MP) disrupts the electrical and contractile activity of the heart of the polar fish, navaga cod (Eleginus nawaga).

Alkylated polycyclic aromatic hydrocarbons are abundant in crude oil and are enriched during petroleum refinement but knowledge of their cardiotoxicity remains limited. Polycyclic aromatic hydrocarbons (PAHs) are considered the main hazardous components in crude oil and the tricyclic PAH phenanthrene has been singled out for its direct effects on cardiac tissue in mammals and fish. Here we test the impact of the monomethylated phenanthrene, 3-methylphenanthrene (3-MP), on the contractile and electrical function of the atrium and ventricle of a polar fish, the navaga cod (Eleginus nawaga). Using patch-clamp electrophysiology in atrial and ventricular cardiomyocytes we show that 3-MP is a potent inhibitor of the delayed rectifier current IKr (IC50 = 0.25 µM) and prolongs ventricular action potential duration. Unlike the parent compound phenanthrene, 3-MP did not reduce the amplitude of the L-type Ca2+ current (ICa) but it accelerated current inactivation thus reducing charge transfer across the myocyte membrane and compromising pressure development of the whole heart. 3-MP was a potent inhibitor (IC50 = 4.7 µM) of the sodium current (INa), slowing the upstroke of the action potential in isolated cells, slowing conduction velocity across the atrium measured with optical mapping, and increasing atrio-ventricular delay in a working whole heart preparation. Together, these findings reveal the strong cardiotoxic potential of this phenanthrene derivative on the fish heart. As 3-MP and other alkylated phenanthrenes comprise a large fraction of the PAHs in crude oil mixtures, these findings are worrisome for Arctic species facing increasing incidence of spills and leaks from the petroleum industry. 3-MP is also a major component of polluted air but is not routinely measured. This is also of concern if the hearts of humans and other terrestrial animals respond to this PAH in a similar manner to fish.