Human-heart-model for hardware-in-the-loop testing of pacemakers.

To guarantee the safety of medical devices, including embedded systems, it is essential to consider both electronic components and the natural environment during validation and verification. In contrast to prior research, we present a hardware-in-the-loop environment that connects a real medical system to a biological model in real time for validation, including the modeling of the mechanical component of the heart valves in addition to the modeling of the electrical conduction and electrical stimulation of the heart chambers. Our model accounts for the dynamic adaptation of the temporal processes in the heart chambers to the pacing frequency of the individual chambers as a function of the action potential. This study investigates two additional risk factors affecting the heart under different conditions: pacemaker syndrome and electrical stimulation during the vulnerable phase. Both can be life-threatening to the patient if left untreated. In implementing our concept on a physical pacemaker connected to our software-based model of the heart, we discovered that the test pacemaker was unable to generate the required heart rate in three of the scenarios we tested. Additionally, our tests revealed occurrences of pacemaker syndrome and stimulation in the vulnerable phase.

Efficient electrocardiogram generation based on cardiac electric vector simulation model.

This study introduces a novel Cardiac Electric Vector Simulation Model (CEVSM) to address the computational inefficiencies and low fidelity of traditional electrophysiological models in generating electrocardiograms (ECGs). Our approach leverages CEVSM to efficiently produce reliable ECG samples, facilitating data augmentation essential for the computer-aided diagnosis of myocardial infarction (MI). Significantly, experimental results show that our model dramatically reduces computation time compared to conventional models, with the self-adapting regression transformation matrix method (SRTM) providing clear advantages. SRTM not only achieves high fidelity in ECG simulations but also ensures exceptional consistency with the gold standard method, greatly enhancing MI localization accuracy by data augmentation. These advancements highlight the potential of our model to generate dependable ECG training samples, making it highly suitable for data augmentation and significantly advancing the development and validation of intelligent MI diagnostic systems. Furthermore, this study demonstrates the feasibility of applying life system simulations in the training of medical big models.

Isolated Perfused Hearts for Cardiovascular Research: An Old Dog with New Tricks.

In modern cardiovascular research, isolated perfused hearts have become cost-effective and highly reproducible tools to investigate the mechanisms of cardiovascular diseases (CVDs). Since they were first introduced in the nineteenth century, isolated perfused hearts have been extensively used for testing novel therapies, elucidating cardiac metabolic and electrophysiological activities, and modeling CVDs, including ischemic heart disease, arrhythmias, and hyperacute rejection. In recent years, ex vivo heart perfusion (EVHP) has shown potential in cardiac transplantation by allowing prolonged preservation and reconditioning of donor hearts. In this review, we summarize the evolution of the isolated perfused heart technique and its applications in cardiovascular research to help researchers comprehensively understand the capabilities of isolated heart models and provide guidance to use them to investigate various CVDs.

Validation of the slaughterhouse porcine heart model for ex-situ heart perfusion studies.

INTRODUCTION: To validate slaughterhouse hearts for ex-situ heart perfusion studies, we compared cold oxygenated machine perfusion in less expensive porcine slaughterhouse hearts (N = 7) to porcine hearts that are harvested following the golden standard in laboratory animals (N = 6). METHODS: All hearts received modified St Thomas 2 crystalloid cardioplegia prior to 4 hours of cold oxygenated machine perfusion. Hearts were perfused with homemade modified Steen heart solution with a perfusion pressure of 20-25 mmHg to achieve a coronary flow between 100-200 mL/min. Reperfusion and testing was performed for 4 hours on a normothermic, oxygenated diluted whole blood loaded heart model. Survival was defined by a cardiac output above 3 L with a mean aortic pressure above 60 mmHg. RESULTS: Both groups showed 100% functional survival, with laboratory hearts displaying superior cardiac function. Both groups showed similar decline in function over time. CONCLUSION: We conclude that the slaughterhouse heart can be used as an alternative to laboratory hearts and provides a cost-effective method for future ex-situ heart perfusion studies.

Volume and function changes of left atrium and left ventricle in patients with ejection fraction preserved heart failure measured by a three dimensional dynamic heart model.

The accurate diagnosis of HFpEF is still challenging and controversial. In this study, we used 3D-DHM technology to compare the differences of cardiac structure and function between HFpEF patients and healthy controls, as well as the differences of two-dimensional and three-dimensional cardiac function in HFpEF patients. Echocardiography with 3D-DHM and conventional two-dimensional (2D) methods were applied to measure the volume and function parameters of left atrium and ventricle of patients with HFpEF and healthy controls. Significant differences of 3D cardiac function indexes including LVESV, 3D-LVEF, ESL, SV, CI, EDmass, LAVmax, LAVmin, LAEF, and LAVI were observed between patients with HFpEF and controls (P < 0.05). However, no significant difference of LVEDV and EDL were observed (P > 0.05). In addition, we found no significant between-group difference in 2D cardiac function indexes such as LVDD and 2D-LVEF (P > 0.05), but the LAD, LVSD, LVPW, IVS, E, E/A, and E/e ' were significantly different between groups (P < 0.05). There was no significant difference between 3D-LVEF and 2D-LVEF in the control group (P > 0.05), while 3D-LVEF in the HFpEF group was lower than 2D-LVEF(P < 0.05). Among the two-dimensional and three-dimensional parameters of HFpEF patients, the parameters related to diastolic function changed more significantly than those of the normal group, and the three-dimensional LVEF of HFpEF patients decreased. The three-dimensional cardiac function parameters analyzed by DHM can provide more information regarding myocardial mechanics.

Corrigendum: A compact multi-functional model of the rabbit atrioventricular node with dual pathways.

[This corrects the article DOI: 10.3389/fphys.2023.1126648.].

Case report: Use of three-dimensional technology in criss-cross heart with double outlet right ventricle.

Background: In this case report, we utilized a three-dimensional printing model to replicate the complex anatomy of a criss-cross heart with double outlet right ventricle-an extremely rare congenital cardiac abnormality. This approach facilitated our understanding of the patient's unique condition and enabled us to plan the surgical procedure with greater precision. Case presentation: Our department received a 13-year-old female patient who presented with a pronounced heart murmur and a decrease in exercise capacity. Subsequent two-dimensional imaging revealed the presence of a criss-cross heart with double outlet right ventricle-an intricate and uncommon cardiac malformation that poses challenges for accurate visualization through conventional two-dimensional modalities. To address this challenge, we constructed and printed a three-dimensional model using computed tomography data, which enabled us to visualize and understand the complex intracardiac structures and plan surgical interventions with greater precision. Using this approach, we successfully performed a right ventricular double outlet repair, and the patient made a full recovery following the procedure. Conclusion: The criss-cross heart with double outlet right ventricle constitutes a complex and uncommon cardiac anomaly that poses considerable challenges in terms of diagnosis and surgical intervention. Employing three-dimensional modeling and printing represents a promising approach, given its potential to enhance the precision and comprehensiveness of the anatomical evaluation of the heart. As a result, this method holds significant promise in facilitating accurate diagnosis, meticulous surgical planning, and ultimately improving clinical outcomes for patients affected by this condition.

A compact multi-functional model of the rabbit atrioventricular node with dual pathways.

The atrioventricular node (AVN) is considered a "black box", and the functioning of its dual pathways remains controversial and not fully understood. In contrast to numerous clinical studies, there are only a few mathematical models of the node. In this paper, we present a compact, computationally lightweight multi-functional rabbit AVN model based on the Aliev-Panfilov two-variable cardiac cell model. The one-dimensional AVN model includes fast (FP) and slow (SP) pathways, primary pacemaking in the sinoatrial node, and subsidiary pacemaking in the SP. To obtain the direction-dependent conduction properties of the AVN, together with gradients of intercellular coupling and cell refractoriness, we implemented the asymmetry of coupling between model cells. We hypothesized that the asymmetry can reflect some effects related to the complexity of the real 3D structure of AVN. In addition, the model is accompanied by a visualization of electrical conduction in the AVN, revealing the interaction between SP and FP in the form of ladder diagrams. The AVN model demonstrates broad functionality, including normal sinus rhythm, AVN automaticity, filtering of high-rate atrial rhythms during atrial fibrillation and atrial flutter with Wenckebach periodicity, direction-dependent properties, and realistic anterograde and retrograde conduction curves in the control case and the cases of FP and SP ablation. To show the validity of the proposed model, we compare the simulation results with the available experimental data. Despite its simplicity, the proposed model can be used both as a stand-alone module and as a part of complex three-dimensional atrial or whole heart simulation systems, and can help to understand some puzzling functions of AVN.

Automated evaluation of cardiac contractile dynamics and aging prediction using machine learning in a Drosophila model.

The Drosophila model has proven tremendously powerful for understanding pathophysiological bases of several human disorders including aging and cardiovascular disease. Relevant high-speed imaging and high-throughput lab assays generate large volumes of high-resolution videos, necessitating next-generation methods for rapid analysis. We present a platform for deep learning-assisted segmentation applied to optical microscopy of Drosophila hearts and the first to quantify cardiac physiological parameters during aging. An experimental test dataset is used to validate a Drosophila aging model. We then use two novel methods to predict fly aging: deep-learning video classification and machine-learning classification via cardiac parameters. Both models suggest excellent performance, with an accuracy of 83.3% (AUC 0.90) and 77.1% (AUC 0.85), respectively. Furthermore, we report beat-level dynamics for predicting the prevalence of cardiac arrhythmia. The presented approaches can expedite future cardiac assays for modeling human diseases in Drosophila and can be extended to numerous animal/human cardiac assays under multiple conditions.

Three-dimensional printing and virtual reconstruction in surgical planning of double-outlet right ventricle repair.

Objectives: For more than a decade, 3-dimensional (3D) printing has been identified as an innovative tool for the surgical planning of double-outlet right ventricle (DORV). Nevertheless, lack of evidence concerning its benefits encourages us to identify valuable criteria for future prospective trials. Methods: We conducted a retrospective study involving 10 patients with DORV operated between 2015 and 2019 in our center. During a preoperative multidisciplinary heart team meeting, we harvested surgical decisions following a 3-increment step process: (1) multimodal imaging; (2) 3D virtual valvular reconstruction (3DVVR); and (3) 3D-printed heart model (3DPHM). The primary outcome was the proportion of predicted surgical strategy following each of the 3 steps, compared with the institutional retrospective surgical strategy. The secondary outcome was the change of surgical strategy through 3D modalities compared with multimodal imaging. The incremental benefit of the 3DVVR and 3DPHM over multimodal imaging was then assessed. Results: The operative strategy was predicted in 5 cases after multimodal imaging, in 9 cases after 3DVVR, and the 10 cases after 3DPHM. Compared with multimodal imaging, 3DVVR modified the strategy for 4 cases. One case was correctly predicted only after 3DPHM inspection. Conclusions: 3DVVR and 3DPHM improved multimodal imaging in the surgical planning of patients with DORV. 3DVVR allowed a better appreciation of the relationships between great vessels, valves, and ventricular septal defects. 3DPHM offers a realistic preoperative view at patient scale and enhances the evaluation of outflow tract obstruction. Our retrospective study demonstrates benefits of preoperative 3D modalities and supports future prospective trials to assess their impact on postoperative outcomes.

Use of a two-handed model to improve comprehension of ventricular outflow tract anatomy.

BACKGROUND: Mastering cardiac anatomy is a formidable obstacle in the learning process for cardiac electrophysiology trainees. The complex three-dimensional characteristics and contiguous relationship of the ventricular outflow tract are particularly difficult to visualize with the limited study methods available. The hands can recreate a morphology similar to the ventricular outflow tract; this study explored whether a two-handed model of the heart helps electrophysiology trainees improve their understanding of ventricular outflow tract anatomy. METHODS: After an initial assessment, trainees were randomly placed into variable and control groups. Subsequently, all trainees learned the outflow tract anatomy using routine methods, with the variable group receiving additional instruction using the two-handed model. One day and one week after the course conclusion, knowledge of the ventricular outflow tract anatomy was assessed for the participants in both groups. RESULTS: Thirty-eight trainees participated (19 in each group). The median scores obtained for the first, second, and third tests were 38 (24,55), 80 (70,86), and 75 (70,81) points, respectively. In the second test, trainees in the variable group had a mean score 6.8 points higher than those in the control group (p = 0.103); in the last test, the mean score was 9.7 points higher in the variable group than in the control group (p = 0.003). CONCLUSIONS: It is convenient to use hands to create a model representing the ventricular outflow tract. Trainees using this model had a better understanding and retention of the ventricular outflow tract anatomy compared to those of the control group.

Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome.

BACKGROUND: A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death remains unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients using gene panels including SLC4A3. METHODS: In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was validated in a zebrafish embryo heart model. RESULTS: Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in SLC4A3: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes. CONCLUSION: In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.

Calibration of Cohorts of Virtual Patient Heart Models Using Bayesian History Matching.

Previous patient-specific model calibration techniques have treated each patient independently, making the methods expensive for large-scale clinical adoption. In this work, we show how we can reuse simulations to accelerate the patient-specific model calibration pipeline. To represent anatomy, we used a Statistical Shape Model and to represent function, we ran electrophysiological simulations. We study the use of 14 biomarkers to calibrate the model, training one Gaussian Process Emulator (GPE) per biomarker. To fit the models, we followed a Bayesian History Matching (BHM) strategy, wherein each iteration a region of the parameter space is ruled out if the emulation with that set of parameter values produces is "implausible". We found that without running any extra simulations we can find 87.41% of the non-implausible parameter combinations. Moreover, we showed how reducing the uncertainty of the measurements from 10 to 5% can reduce the final parameter space by 6 orders of magnitude. This innovation allows for a model fitting technique, therefore reducing the computational load of future biomedical studies.

Advancing clinical translation of cardiac biomechanics models: a comprehensive review, applications and future pathways.

Cardiac mechanics models are developed to represent a high level of detail, including refined anatomies, accurate cell mechanics models, and platforms to link microscale physiology to whole-organ function. However, cardiac biomechanics models still have limited clinical translation. In this review, we provide a picture of cardiac mechanics models, focusing on their clinical translation. We review the main experimental and clinical data used in cardiac models, as well as the steps followed in the literature to generate anatomical meshes ready for simulations. We describe the main models in active and passive mechanics and the different lumped parameter models to represent the circulatory system. Lastly, we provide a summary of the state-of-the-art in terms of ventricular, atrial, and four-chamber cardiac biomechanics models. We discuss the steps that may facilitate clinical translation of the biomechanics models we describe. A well-established software to simulate cardiac biomechanics is lacking, with all available platforms involving different levels of documentation, learning curves, accessibility, and cost. Furthermore, there is no regulatory framework that clearly outlines the verification and validation requirements a model has to satisfy in order to be reliably used in applications. Finally, better integration with increasingly rich clinical and/or experimental datasets as well as machine learning techniques to reduce computational costs might increase model reliability at feasible resources. Cardiac biomechanics models provide excellent opportunities to be integrated into clinical workflows, but more refinement and careful validation against clinical data are needed to improve their credibility. In addition, in each context of use, model complexity must be balanced with the associated high computational cost of running these models.

A 3D-printed surgical guide for ischemic scar targeting and ablation.

Background: 3D printing technology development in medical fields allows to create 3D models to assist preoperative planning and support surgical procedures. Cardiac ischemic scar is clinically associated with malignant arrhythmias. Catheter ablation is aimed at eliminating the arrhythmogenic tissue until the sinus rhythm is restored. The scope of this work is to describe the workflow for a 3D surgical guide able to define the ischemic scar and target catheter ablation. Materials and methods: For the patient-specific 3D surgical guide and 3D heart phantom model realization, both CT scan and cardiac MRI images were processed; this was necessary to extract anatomical structures and pathological information, respectively. Medical images were uploaded and processed in 3D Slicer. For the surgical guide modeling, images from CT scan and MRI were loaded in Meshmixer and merged. For the heart phantom realization, only the CT segmentation was loaded in Meshmixer. The surgical guide was printed in MED625FLX with Polyjet technology. The heart phantom was printed in polylactide with FDM technology. Results: 3D-printed surgical model was in agreement with prespecified imputed measurements. The phantom fitting test showed high accuracy of the 3D surgical tool compared with the patient-specific reproduced heart. Anatomical references in the surgical guide ensured good stability. Ablation catheter fitting test showed high suitability of the guide for different ablation tools. Conclusion: A 3D-printed guide for ventricular tachycardia ablation is feasible and accurate in terms of measurements, stability, and geometrical structure. Concerning clinical use, further clinical investigations are eagerly awaited.

An ECG generative model of myocardial infarction.

Background and Objective Computer-aided diagnosis (CAD) of Myocardial Infarction (MI) using machine learning depends on a large amount of clinical Electrocardiogram (ECG) data. Existing infarct ECG databases face the problem of class imbalance. Data augmentation using generative simulation models is a new approach to effectively address this problem. Methods A multiscale ECG generative model was established for ECG data augmentation. In the cellular layer, an ischemic Action Potential (AP) model was established to generate APs in cardiomyocytes with different transmural regions of infraction or different ischemic durations. In the tissue layer, a probability-driven cellular automata excitation propagation model was established to simulate the propagation speed and direction of excitation. An infarct tissue model and a coronary artery model were established to describe the spatiotemporal diversity of MI. A ventricle model, a human torso model, and a computational model of surface ECG based on field source theory were established in the heart-torso layer. Results The model generated pathological 12-lead ECGs of MI with different topography and different extent. When simulating different ventricular wall infarction, the lesions appear in the same leads as the clinical 12-lead ECG. The ST-segment decreases and the T-wave amplitude decreases, similar to the clinical ECG features when simulating subendocardial ischemia. The average fidelity of the 12-lead ECG the model generated is 95.6%, according to the designed DTW-GRA distance algorithm. Conclusions The generative model considers the electrophysiological properties of the natural heart, the pathology of myocardial infarction, and the diversity of clinical ECGs. The model can provide many reliable samples for machine learning of MI.

A Variable-Volume Heart Model for Galvanic Coupling-Based Conductive Intracardiac Communication.

Conductive intracardiac communication (CIC) has become one of the most promising technologies in multisite leadless pacemakers for cardiac resynchronization therapy. Existing studies have shown that cardiac pulsation has a significant impact on the attenuation of intracardiac communication channels. In this study, a novel variable-volume circuit-coupled electrical field heart model, which contains blood and myocardium, is proposed to verify the phenomenon. The influence of measurements was combined with the model as the equivalent circuit. Dynamic intracardiac channel characteristics were obtained by simulating models with varying volumes of the four chambers according to the actual cardiac cycle. Subsequently, in vitro experiments were carried out to verify the model's correctness. Among the dependences of intracardiac communication channels, the distance between pacemakers exerted the most substantial influence on attenuation. In the simulation and measurement, the relationship between channel attenuation and pulsation was found through the variable-volume heart model and a porcine heart. The CIC channel attenuation had a variation of less than 3 dB.

Left Heart Chamber Volumetric Assessment by Automated Three-Dimensional Echocardiography in Heart Transplant Recipients.

Background: Recently, a new automated software (Heart Model) was developed to obtain three-dimensional (3D) left heart chamber volumes. The aim of this study was to verify the feasibility and accuracy of the automated 3D echocardiographic algorithm in heart transplant (HTx) patients. Conventional manual 3D transthoracic echocardiographic (TTE) tracings and cardiac magnetic resonance (CMR) images were used as a reference for comparison. Methods: This study enrolled 103 healthy HTx patients prospectively. In protocol 1, left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), left atrial max volume (LAVmax), LA minimum volume (LAVmin) and LV ejection fraction (LVEF) were obtained using the automated 3D echocardiography (3DE) and compared with corresponding values obtained through the manual 3DE. In protocol 2, 28 patients' automated 3DE measurements were compared with CMR reference values. The impacts of contour edit and surgical technique were also tested. Results: Heart Model was feasible in 97.1% of the data sets. In protocol 1, there was strong correlation between 3DE and manual 3DE for all the parameters (r = 0.77 to 0.96, p<0.01). Compared to values obtained through manual measurements, LV volumes and LVEF were overestimated by the automated algorithm and LA volumes were underestimated. All the biases were small except for that of LAVmin. After contour adjustment, the biases reduced and all the limits of agreement were clinically acceptable. In protocol 2, the correlations for LV and LA volumes were strong between automated 3DE with contour edit and CMR (r = 0.74 to 0.93, p<0.01) but correlation for LVEF remained moderate (r = 0.65, p < 0.01). Automated 3DE overestimated LV volumes but underestimated LVEF and LA volumes compared with CMR. The limits of agreement were clinically acceptable only for LVEDV and LAVmax. Conclusion: Simultaneous quantification of left heart volumes and LVEF with the automated Heart Model program is rapid, feasible and to a great degree it is accurate in HTx recipients. Nevertheless, only LVEDV and LAVmax measured by automated 3DE with contour edit seem applicable for clinical practice when compared with CMR. Automated 3DE for HTx recipients is a worthy attempt, though further verification and optimization are needed.

A Multi-Domain Simulation Study of a Pulsatile-Flow Pump Device for Heart Failure With Preserved Ejection Fraction.

Mechanical circulatory support (MCS) devices are currently under development to improve the physiology and hemodynamics of patients with heart failure with preserved ejection fraction (HFpEF). Most of these devices, however, are designed to provide continuous-flow support. While it has been shown that pulsatile support may overcome some of the complications hindering the clinical translation of these devices for other heart failure phenotypes, the effects that it may have on the HFpEF physiology are still unknown. Here, we present a multi-domain simulation study of a pulsatile pump device with left atrial cannulation for HFpEF that aims to alleviate left atrial pressure, commonly elevated in HFpEF. We leverage lumped-parameter modeling to optimize the design of the pulsatile pump, computational fluid dynamic simulations to characterize hydraulic and hemolytic performance, and finite element modeling on the Living Heart Model to evaluate effects on arterial, left atrial, and left ventricular hemodynamics and biomechanics. The findings reported in this study suggest that pulsatile-flow support can successfully reduce pressures and associated wall stresses in the left heart, while yielding more physiologic arterial hemodynamics compared to continuous-flow support. This work therefore supports further development and evaluation of pulsatile support MCS devices for HFpEF.

Chronic magnesium deficiency causes reversible mitochondrial permeability transition pore opening and impairs hypoxia tolerance in the rat heart.

Chronic magnesium (Mg) deficiency induces and exacerbates various cardiovascular diseases. We previously investigated the mechanisms underlying decline in cardiac function caused by chronic Mg deficiency and the effectiveness of Mg supplementation on this decline using the Langendorff-perfused isolated mouse heart model. Herein, we used the Langendorff-perfused isolated rat heart model to demonstrate the chronic Mg-deficient rats (Mg-deficient group) had lower the heart rate (HR) and left ventricular pressure (LVDP) than rats with normal Mg levels (normal group). Furthermore, decline in cardiac function due to hypoxia/reoxygenation injury was significantly greater in the Mg-deficient group than in the normal group. Experiments on mitochondrial permeability transition pore (mPTP) using isolated mitochondria revealed that mitochondrial membrane was fragile in the Mg-deficient group, implying that cardiac function decline through hypoxia/reoxygenation injury is associated with mitochondrial function. Mg supplementation for chronic Mg-deficient rats not only improved hypomagnesemia but also almost completely restored cardiac and mitochondrial functions. Therefore, proactive Mg supplementation in pathological conditions induced by Mg deficiency or for those at risk of developing hypomagnesemia may suppress the development and exacerbation of certain disease states.