Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria.

Chronic intermittent hypoxia (CIH, a model for sleep apnoea) is a major risk factor for several cardiovascular diseases. Autonomic imbalance (sympathetic overactivity and parasympathetic withdrawal) has emerged as a causal contributor of CIH-induced cardiovascular disease. Previously, we showed that CIH remodels the parasympathetic pathway. However, whether CIH induces remodelling of the cardiac sympathetic innervation remains unknown. Mice (male, C57BL/6J, 2-3 months) were exposed to either room air (RA, 21% O2 ) or CIH (alternating 21% and 5.7% O2 , every 6 min, 10 h day-1 ) for 8-10 weeks. Flat-mounts of their left and right atria were immunohistochemically labelled for tyrosine hydroxylase (TH, a sympathetic marker). Using a confocal microscope (or fluorescence microscope) and Neurlocudia 360 digitization and tracing system, we scanned both the left and right atria and quantitatively analysed the sympathetic axon density in both groups. The segmentation data was mapped onto a 3D mouse heart scaffold. Our findings indicated that CIH significantly remodelled the TH immunoreactive (-IR) innervation of the atria by increasing its density at the sinoatrial node, the auricles and the major veins attached to the atria (P < 0.05, n = 7). Additionally, CIH increased the branching points of TH-IR axons and decreased the distance between varicosities. Abnormal patterns of TH-IR axons around intrinsic cardiac ganglia were also found following CIH. We postulate that the increased sympathetic innervation may further amplify the effects of enhanced CIH-induced central sympathetic drive to the heart. Our work provides an anatomical foundation for the understanding of CIH-induced autonomic imbalance. KEY POINTS: Chronic intermittent hypoxia (CIH, a model for sleep apnoea) causes sympathetic overactivity, cardiovascular remodelling and hypertension. We determined the effect of CIH on sympathetic innervation of the mouse atria. In vivo CIH for 8-10 weeks resulted in an aberrant axonal pattern around the principal neurons within intrinsic cardiac ganglia and an increase in the density, branching point, tortuosity of catecholaminergic axons and atrial wall thickness. Utilizing mapping tool available from NIH (SPARC) Program, the topographical distribution of the catecholaminergic innervation of the atria were integrated into a novel 3D heart scaffold for precise anatomical distribution and holistic quantitative comparison between normal and CIH mice. This work provides a unique neuroanatomical understanding of the pathophysiology of CIH-induced autonomic remodelling.

Organization and morphology of calcitonin gene-related peptide-immunoreactive axons in the whole mouse stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g., substance P [SP] and calcitonin gene-related peptide [CGRP]). We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: (1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. (2) CGRP-IR axons densely innervated the blood vessels. (3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. (4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. (5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. (6) CGRP-IR axons did not colocalize with tyrosine hydroxylase or vesicular acetylcholine transporter axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. (7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.

A Narrative Review of Personalized Musculoskeletal Modeling Using the Physiome and Musculoskeletal Atlas Projects.

In this narrative review, we explore developments in the field of computational musculoskeletal model personalization using the Physiome and Musculoskeletal Atlas Projects. Model geometry personalization; statistical shape modeling; and its impact on segmentation, classification, and model creation are explored. Examples include the trapeziometacarpal and tibiofemoral joints, Achilles tendon, gastrocnemius muscle, and pediatric lower limb bones. Finally, a more general approach to model personalization is discussed based on the idea of multiscale personalization called scaffolds.

Mapping the Organization and Morphology of Calcitonin Gene-Related Peptide (CGRP)-IR Axons in the Whole Mouse Stomach.

Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers [e.g., substance P (SP) and calcitonin gene-related peptide (CGRP)]. We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: 1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. 2) CGRP-IR axons densely innervated the blood vessels. 3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. 4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. 5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. 6) CGRP-IR axons did not colocalize with tyrosine hydroxylase (TH) or vesicular acetylcholine transporter (VAChT) axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. 7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.

Understanding the workflow of nurses in acute and subacute medical wards: A time and motion study.

AIMS AND OBJECTIVES: The aim of this study was to determine how much time nurses spend on direct and indirect patient care in acute and subacute hospital settings. BACKGROUND: Quantifying direct and indirect nursing care provided during inpatient stay is vital to optimise the quality of care and manage resources. DESIGN: Time and motion cross-sectional observational study and reported the study according to the STROBE guideline. METHODS: Nurses working in an acute or subacute medical wards of a single health service participated. Nurses were observed twice for 2 h on the same day with an observer break in between sessions. Real-time task-related data were digitally recorded using the Work Observation Method By Activity Timing (WOMBAT) tool by a single research assistant. Frequency and time spent on pre-determined tasks were recorded and included direct care, indirect care, documentation, medication-related tasks, communication (professional) and other tasks. Task interruptions and multitasking were also recorded. RESULTS: Twenty-one nurses (acute n = 12, subacute n = 9) were observed during shifts between 7 AM and 9 PM in May-July 2021. A total of 7240 tasks were recorded. Nurses spent a third of their time on direct patient care (27% direct care and 3% medication administration). A total of 556 task interruptions occurred, mostly during documentation, and medication-related tasks. A further 1385 tasks were performed in parallel with other tasks, that is multitasking. CONCLUSIONS: Time spent on tasks was similar regardless of the setting and was consistent with previous research. We found differences in the distribution of tasks throughout the day between settings, which could have implications for workforce planning and needs to be investigated further. Interruptions occurred during documentation, direct care and medication-related tasks. Local-level strategies should be in place and regularly revised to reduce interruptions and prevent errors. Relevance to clinical practice The association between interruption and increased risk of error is well-established and should be an ongoing area of attention including observations and education provided in local settings.

Exploring staff perspectives on caring for isolated hospitalised patients during the COVID-19 pandemic: a qualitative study.

BACKGROUND: Strict isolation of COVID-19 patients to prevent cross infection may inadvertently cause serious adverse outcomes including psychological harm, limitations to care, increased incidence of delirium, deconditioning and reduced quality of life. Previous research exploring the staff perspective of the effect of isolation on patients is limited. The aim of this study is to understand staff perceptions and interpretations of their experiences of the care and treatment of isolated patients and the impact of isolation on patients, families, and staff. METHOD: This qualitative, exploratory study is set in a major metropolitan, quaternary hospital in Melbourne, Australia. Data was collected in focus groups with clinical and non-clinical staff and analysed using content analysis. The hospital ethics committee granted approval. Each participant gave informed verbal consent. RESULTS: Participants included 58 nursing, medical, allied health, and non-clinical staff. Six main themes were identified: 1) Communication challenges during COVID-19; 2) Impact of isolation on family; 3) Challenges to patients' health and safety; 4) Impact on staff; 5) Challenging standards of care; 6) Contextual influences: policy, decision-makers and the environment. CONCLUSION: Isolating patients and restricting visitors resulted in good pandemic management, but staff perceived it came at considerable cost to staff and consumers. Innovative communication technology may facilitate improved connection between all parties. Mental health support is needed for patients, families, and staff. Further research using a co-design model with input from patients, families and staff is recommended to determine appropriate interventions to improve care. Preventing the spread of infection is essential for good pandemic management, but the cost to consumers and staff must be mitigated. Preparation for future pandemics must consider workforce preparedness, adapted models of care and workflow.

Optimising Multispectral Active Fluorescence to Distinguish the Photosynthetic Variability of Cyanobacteria and Algae.

This study assesses the ability of a new active fluorometer, the LabSTAF, to diagnostically assess the physiology of freshwater cyanobacteria in a reservoir exhibiting annual blooms. Specifically, we analyse the correlation of relative cyanobacteria abundance with photosynthetic parameters derived from fluorescence light curves (FLCs) obtained using several combinations of excitation wavebands, photosystem II (PSII) excitation spectra and the emission ratio of 730 over 685 nm (Fo(730/685)) using excitation protocols with varying degrees of sensitivity to cyanobacteria and algae. FLCs using blue excitation (B) and green−orange−red (GOR) excitation wavebands capture physiology parameters of algae and cyanobacteria, respectively. The green−orange (GO) protocol, expected to have the best diagnostic properties for cyanobacteria, did not guarantee PSII saturation. PSII excitation spectra showed distinct response from cyanobacteria and algae, depending on spectral optimisation of the light dose. Fo(730/685), obtained using a combination of GOR excitation wavebands, Fo(GOR, 730/685), showed a significant correlation with the relative abundance of cyanobacteria (linear regression, p-value < 0.01, adjusted R2 = 0.42). We recommend using, in parallel, Fo(GOR, 730/685), PSII excitation spectra (appropriately optimised for cyanobacteria versus algae), and physiological parameters derived from the FLCs obtained with GOR and B protocols to assess the physiology of cyanobacteria and to ultimately predict their growth. Higher intensity LEDs (G and O) should be considered to reach PSII saturation to further increase diagnostic sensitivity to the cyanobacteria component of the community.

Telehealth consultation before inter-hospital transfer after falls in a subacute hospital (the PREVENT-2 study).

OBJECTIVE: Inter-hospital transfers are increasingly common due to the regionalisation of healthcare, but are associated with patient discomfort, high costs and adverse events. The aim of the present study was to evaluate the effectiveness of a trauma outreach service for preventing inter-hospital transfers to a major trauma centre. METHODS: This was an observational pre- and post-intervention study over a 12-month period from 1 October 2020 to 30 September 2021. Eligible patients sustained a fall at Caulfield Hospital, a subacute care hospital specialising in community services, rehabilitation, geriatric medicine and aged mental health. The intervention was delivery of site-specific education at Caulfield Hospital and a trauma outreach service by specialist trauma clinicians at The Alfred Hospital who provided remote assessment, assisted with clinical management decisions and advised on appropriateness of transfer. RESULTS: The present study included 160 patients in the pre-intervention phase and 203 after the intervention. The primary outcome of transfer occurred in 19 (11.9%) patients in the pre-intervention phase and 4 (2.0%) in the post-intervention phase (P < 0.001). In the subgroup of patients without pelvis or long bone fractures, pre-intervention transfer occurred for 17 (10.9%) patients and post-intervention transfer occurred for 4 (2.0%) patients (P < 0.001). CT imaging was performed for 54 (33.8%) patients in the pre-intervention and 45 (22.2%) patients in the post-intervention group (P = 0.014). CONCLUSIONS: Telehealth consultation with a trauma specialist was associated with significant reduction of inter-hospital transfers, and significant reduction of CT imaging. This supports continuation of the service with scope for expansion and evaluation of patient-centred outcomes.

In silico modeling for the hepatic circulation and transport: From the liver organ to lobules.

The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro-hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies. These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state-of-the-art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project. This article is categorized under: Metabolic Diseases > Computational Models Metabolic Diseases > Biomedical Engineering Cardiovascular Diseases > Computational Models.

Mixed methods study to understand the experiences of adults with acquired brain injury and their family members who receive specialised rehabilitation.

BACKGROUND AND AIM: Rehabilitation therapy is a key part of the recovery pathway for people with severe acquired brain injury (ABI). The aim of this study was to explore inpatients' and their family members' experiences of a specialist ABI rehabilitation service. METHODS: A cross sectional, prospective mixed method study was undertaken at a metropolitan specialist ABI rehabilitation unit in Victoria, Australia. All inpatients and their family members of the service were invited to complete a satisfaction survey. Employing purposive sampling, semi-structured interviews were conducted with inpatients and/or their family members. RESULTS: In total, 111 people completed the satisfaction survey and 13 were interviewed. High levels of satisfaction with the specialist service were reported; the majority of inpatients (74%) and family members (81%) rated the overall quality of care received in the service as 'high' or 'very high'. Interviews revealed four main themes: (i) satisfaction with rehabilitation services, (ii) inconsistent communication, (iii) variable nursing care, and (iv) strengths and weakness of the rehabilitation environment. Overall, important components of a positive experience were being involved in decision making and discharge planning, effective communication and information processes, and being able to form therapeutic relationships with staff. Key sources of dissatisfaction for inpatients and family members related to inconsistency in care, accessing information about treatments in a format easily understood, and communication. CONCLUSION: Specialised rehabilitation is valued by inpatients and their family members alike. The findings highlight the importance of exploring inpatient experiences to optimise service delivery in a tailored, specialised rehabilitation programme.

A novel modular modeling approach for understanding different electromechanics between left and right heart in rat.

While ion channels and transporters involved in excitation-contraction coupling have been linked and constructed as comprehensive computational models, validation of whether each individual component of a model can be reused has not been previously attempted. Here we address this issue while using a novel modular modeling approach to investigate the underlying mechanism for the differences between left ventricle (LV) and right ventricle (RV). Our model was developed from modules constructed using the module assembly principles of the CellML model markup language. The components of three existing separate models of cardiac function were disassembled as to create smaller modules, validated individually, and then the component parts were combined into a new integrative model of a rat ventricular myocyte. The model was implemented in OpenCOR using the CellML standard in order to ensure reproducibility. Simulated action potential (AP), Ca2+ transient, and tension were in close agreement with our experimental measurements: LV AP showed a prolonged duration and a more prominent plateau compared with RV AP; Ca2+ transient showed prolonged duration and slow decay in LV compared to RV; the peak value and relaxation of tension were larger and slower, respectively, in LV compared to RV. Our novel approach of module-based mathematical modeling has established that the ionic mechanisms underlying the APs and Ca2+ handling play a role in the variation in force production between ventricles. This simulation process also provides a useful way to reuse and elaborate upon existing models in order to develop a new model.

A method for investigating spatiotemporal growth patterns at cell and tissue levels during C-looping in the embryonic chick heart.

We developed a workflow using multi-scale and multi-disciplinary experimental and computational approaches to analyze C-looping (the first phase of cardiac looping) of the chick across four developing hearts. We provide the first 3D datasets for the C-looping heart with cell to organism level information, including datasets of heart images and segmented myocardial cells within the heart. We used these datasets to investigate, as a proof-of-concept, the differential spatiotemporal patterns of growth at both the cellular and tissue levels, and demonstrate how geometrical changes of C-looping at the tissue level are linked to growth features at the cellular level. Our methodological pipeline provides preliminary results for qualitative and quantitative evidence of various cellular and tissue features as potential candidates regarding the mechanism of C-looping. This pipeline can be used and extended in future studies to include larger specimen samples for detailed analyses of, and potentially new insights into, cardiac C-looping.

Determination of optical markers of cyanobacterial physiology from fluorescence kinetics.

Compared to other methods to monitor and detect cyanobacteria in phytoplankton populations, fluorometry gives rapid, robust and reproducible results and can be used in situ. Fluorometers capable of providing biomass estimates and physiological information are not commonly optimized to target cyanobacteria. This study provides a detailed overview of the fluorescence kinetics of algal and cyanobacterial cultures to determine optimal optical configurations to target fluorescence mechanisms that are either common to all phytoplankton or diagnostic to cyanobacteria. We confirm that fluorescence excitation channels targeting both phycocyanin and chlorophyll a associated to the Photosystem II are required to induce the fluorescence responses of cyanobacteria. In addition, emission channels centered at 660, 685 and 730 nm allow better differentiation of the fluorescence response between algal and cyanobacterial cultures. Blue-green actinic light does not yield a robust fluorescence response in the cyanobacterial cultures and broadband actinic light should be preferred to assess the relation between ambient light and photosynthesis. Significant variability was observed in the fluorescence response from cyanobacteria to the intensity and duration of actinic light exposure, which needs to be taken into consideration in field measurements.

Mental Health Outcomes in Australian Healthcare and Aged-Care Workers during the Second Year of the COVID-19 Pandemic.

OBJECTIVE: the COVID-19 pandemic has incurred psychological risks for healthcare workers (HCWs). We established a Victorian HCW cohort (the Coronavirus in Victorian Healthcare and Aged-Care Workers (COVIC-HA) cohort study) to examine COVID-19 impacts on HCWs and assess organisational responses over time. METHODS: mixed-methods cohort study, with baseline data collected via an online survey (7 May-18 July 2021) across four healthcare settings: ambulance, hospitals, primary care, and residential aged-care. Outcomes included self-reported symptoms of depression, anxiety, post-traumatic stress (PTS), wellbeing, burnout, and resilience, measured using validated tools. Work and home-related COVID-19 impacts and perceptions of workplace responses were also captured. RESULTS: among 984 HCWs, symptoms of clinically significant depression, anxiety, and PTS were reported by 22.5%, 14.0%, and 20.4%, respectively, highest among paramedics and nurses. Emotional exhaustion reflecting moderate-severe burnout was reported by 65.1%. Concerns about contracting COVID-19 at work and transmitting COVID-19 were common, but 91.2% felt well-informed on workplace changes and 78.3% reported that support services were available. CONCLUSIONS: Australian HCWs employed during 2021 experienced adverse mental health outcomes, with prevalence differences observed according to occupation. Longitudinal evidence is needed to inform workplace strategies that support the physical and mental wellbeing of HCWs at organisational and state policy levels.

Genomic dissection of Klebsiella pneumoniae infections in hospital patients reveals insights into an opportunistic pathogen.

Klebsiella pneumoniae is a major cause of opportunistic healthcare-associated infections, which are increasingly complicated by the presence of extended-spectrum beta-lactamases (ESBLs) and carbapenem resistance. We conducted a year-long prospective surveillance study of K. pneumoniae clinical isolates in hospital patients. Whole-genome sequence (WGS) data reveals a diverse pathogen population, including other species within the K. pneumoniae species complex (18%). Several infections were caused by K. variicola/K. pneumoniae hybrids, one of which shows evidence of nosocomial transmission. A wide range of antimicrobial resistance (AMR) phenotypes are observed, and diverse genetic mechanisms identified (mainly plasmid-borne genes). ESBLs are correlated with presence of other acquired AMR genes (median n = 10). Bacterial genomic features associated with nosocomial onset are ESBLs (OR 2.34, p = 0.015) and rhamnose-positive capsules (OR 3.12, p < 0.001). Virulence plasmid-encoded features (aerobactin, hypermucoidy) are observed at low-prevalence (<3%), mostly in community-onset cases. WGS-confirmed nosocomial transmission is implicated in just 10% of cases, but strongly associated with ESBLs (OR 21, p < 1 × 10-11). We estimate 28% risk of onward nosocomial transmission for ESBL-positive strains vs 1.7% for ESBL-negative strains. These data indicate that K. pneumoniae infections in hospitalised patients are due largely to opportunistic infections with diverse strains, with an additional burden from nosocomially-transmitted AMR strains and community-acquired hypervirulent strains.

The Cell Physiome: What Do We Need in a Computational Physiology Framework for Predicting Single-Cell Biology?

Modern biology and biomedicine are undergoing a big data explosion, needing advanced computational algorithms to extract mechanistic insights on the physiological state of living cells. We present the motivation for the Cell Physiome Project: a framework and approach for creating, sharing, and using biophysics-based computational models of single-cell physiology. Using examples in calcium signaling, bioenergetics, and endosomal trafficking, we highlight the need for spatially detailed, biophysics-based computational models to uncover new mechanisms underlying cell biology. We review progress and challenges to date toward creating cell physiome models. We then introduce bond graphs as an efficient way to create cell physiome models that integrate chemical, mechanical, electromagnetic, and thermal processes while maintaining mass and energy balance. Bond graphs enhance modularization and reusability of computational models of cells at scale. We conclude with a look forward at steps that will help fully realize this exciting new field of mechanistic biomedical data science.

Simplifying the Process of Going From Cells to Tissues Using Statistical Mechanics.

The value of digital twins for prototyping controllers or interventions in a sandbox environment are well-established in engineering and physics. However, this is challenging for biophysics trying to seamlessly compose models of multiple spatial and temporal scale behavior into the digital twin. Two challenges stand out as constraining progress: (i) ensuring physical consistency of conservation laws across composite models and (ii) drawing useful and timely clinical and scientific information from conceptually and computationally complex models. Challenge (i) can be robustly addressed with bondgraphs. However, challenge (ii) is exacerbated using this approach. The complexity question can be looked at from multiple angles. First from the perspective of discretizations that reflect underlying biophysics (functional tissue units) and secondly by exploring maximum entropy as the principle guiding multicellular biophysics. Statistical mechanics, long applied to understanding emergent phenomena from atomic physics, coupled with the observation that cellular architecture in tissue is orchestrated by biophysical constraints on metabolism and communication, shows conceptual promise. This architecture along with cell specific properties can be used to define tissue specific network motifs associated with energetic contributions. Complexity can be addressed based on energy considerations and finding mean measures of dependent variables. A probability distribution of the tissue's network motif can be approximated with exponential random graph models. A prototype problem shows how these approaches could be implemented in practice and the type of information that could be extracted.

Improved hyperspectral inversion of aquatic reflectance under non-uniform vertical mixing.

Estimating the concentration of water constituents by optical remote sensing assumes absorption and scattering processes to be uniform over the observation depth. Using hyperspectral reflectance, we present a method to direct the retrieval of the backscattering coefficient (bb(λ)) from reflectance (> 600 nm) towards wavebands where absorption by water dominates the reflectance curve. Two experiments demonstrate the impact of hyperspectral inversion in the selected band set. First, optical simulations show that the resulting distribution of bb(λ) is sensitive to particle mixing conditions, although a robust indicator of non-uniformity was not found for all scenarios of stratification. Second, in the absence of spectral backscattering profiles from in situ data sets, it is shown how substituting the median of bb(λ) into a near infra-red / red band ratio algorithm improved chlorophyll-a estimates (root mean square error 75.45 mg m-3 became 44.13 mg m-3). This approach also allows propagation of the uncertainty in bb estimates to water constituent concentrations.

An integrative multiscale view of early cardiac looping.

The heart is the first organ to form and function during the development of an embryo. Heart development consists of a series of events believed to be highly conserved in vertebrates. Development of heart begins with the formation of the cardiac fields followed by a linear heart tube formation. The straight heart tube then undergoes a ventral bending prior to further bending and helical torsion to form a looped heart. The looping phase is then followed by ballooning, septation, and valve formation giving rise to a four-chambered heart in avians and mammals. The looping phase plays a central role in heart development. Successful looping is essential for proper alignment of the future cardiac chambers and tracts. As aberrant looping results in various congenital heart diseases, the mechanisms of cardiac looping have been studied for several decades by various disciplines. Many groups have studied anatomy, biology, genetics, and mechanical processes during heart looping, and have proposed multiple mechanisms. Computational modeling approaches have been utilized to examine the proposed mechanisms of the looping process. Still, the exact underlying mechanism(s) controlling the looping phase remain poorly understood. Although further experimental measurements are obviously still required, the need for more integrative computational modeling approaches is also apparent in order to make sense of the vast amount of experimental data and the complexity of multiscale developmental systems. Indeed, there needs to be an iterative interaction between experimentation and modeling in order to properly find the gap in the existing data and to validate proposed hypotheses. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Molecular and Cellular Physiology.