Transition mechanisms from atrial flutter to atrial fibrillation during anti-tachycardia pacing therapy.

BACKGROUND: Atrial anti-tachycardia pacing (aATP) has been shown to be effective for the termination of atrial tachyarrhythmias, but its success rate is still not high enough. OBJECTIVE: The main objective of this study was to investigate the mechanisms of atrial flutter (AFL) termination by aATP and the transition from AFL to atrial fibrillation (AF) during aATP. METHODS: We developed a multi-scale model of the human atrium based on magnetic resonance images and examined the atrial electrophysiology of AFL during aATP with a ramp protocol. RESULTS: In successful cases of aATP, paced excitation entered the excitable gap and collided with the leading edge of the reentrant wave front. Furthermore, the excitation propagating in the opposite direction collided with the trailing edge of the reentrant wave to terminate AFL. The second collision was made possible by the distribution of the wave propagation velocity in the atria. The detailed analysis revealed that the slowing of propagation velocity occurred at the exit of the sub-Eustachian isthmus, probably due to source-sink mismatch. During the transition from AFL to AF, the excitation collided with the refractory zone of the preceding wave and broke into multiple wave fronts to induce AF. A similar observation was made for the transition from AF to sinus rhythm. In both cases, the complex anatomy of the atria played an essential role. CONCLUSION: The complex anatomy of atria plays an essential role in the maintenance of stable AFL and its termination by aATP, which were revealed by the realistic three-dimensional simulation model.

Low-energy defibrillation using a base-apex epicardial electrode.

BACKGROUND: Current implantable cardioverter defibrillators (ICDs) require electric conduction with high voltage and high energy, which can impair cardiac function and induce another malignant arrhythmia. As a result, there has been a demand for an ICD that can effectively operate with lower energy to mitigate the risks of a strong electric shock. METHODS: A pair of sheet-shaped electrodes covering the heart were analyzed in three configurations (top-bottom, left-right, and front-back) using a heart simulator. We also varied the distance between the two electrodes (clearance) to identify the electrode shape with the lowest defibrillation threshold (DFT). We also investigated the ICD shock waveform, shock direction, and the effect of the backside insulator of the electrode. RESULTS: The DFT was high when the clearance was too small and the DFT was high even when the clearance was too large, suggesting that an optimal value clearance. The top-bottom electrodes with optimal clearance showed the lowest DFT when the biphasic shocks set the top electrode to a high potential first and then the bottom electrode was set to a high potential. An interval between a first shock waveform and a second shock waveform should be provided for low-energy defibrillation. Because the insulator prevents unnecessary current flow to the backside, the DFT of the electrodes with insulators is less than those without insulators. CONCLUSION: Painless defibrillation using sheet-shaped electrodes on the epicardium is predicated on the basis of results using a heart simulator.

Differences in muscle synergies between skilled and unskilled athletes in power clean exercise at various loads.

The purpose of this study was to determine the differences in muscle synergy between skilled and unskilled participants using various loading conditions for power clean. Nineteen participants (ten skilled and nine unskilled) performed power clean at 60-90% one repetition maximum (1RM), while measured 12 muscles across the entire body. The vertical impulse was calculated for the unweighting associated with the double-knee bend (DKB) manoeuvre in power clean. Muscle synergies were extracted using non-negative matrix factorization. The weighting of muscle synergies was subsequently compared between the two groups for all loads, and confidence intervals were calculated. The number of muscle synergies in both groups was three, and the functions of all muscle synergies were similar. Muscle synergy 1 involved the first pull, muscle synergy 2 involved the transition and the second pull, and muscle synergy 3 involved DKB. No significant difference in either muscle synergy was observed at 60-80% 1RM weight, while the 90% 1RM showed significantly active in the ankle plantar flexor and knee extensor muscles for muscle synergy 3, which involved DKB only in the skilled group. This indicates that increased joint stiffness during DKB may minimize unweighting. Unskilled individuals may acquire such muscle synergies to lift greater weights.

Ballistic Exercise Versus Heavy Resistance Exercise Protocols: Which Resistance Priming Is More Effective for Improving Neuromuscular Performance on the Following Day?

ABSTRACT: Nishioka, T and Okada, J. Ballistic exercise versus heavy resistance exercise protocols: which resistance priming is more effective for improving neuromuscular performance on the following day? J Strength Cond Res 37(10): 1939-1946, 2023-This study aimed to determine whether ballistic exercise priming (BEP) or heavy resistance priming (HRP) is more effective for improving ballistic performance after 24 hours. Ten resistance-trained men performed BEP and HRP conditions 72-144 hours apart in a randomized and counterbalanced order. Jumping performance was assessed before and 24 hours after the BEP and HRP sessions using 0 and 40% one-repetition maximum (1RM) squat jump (SJ), 0 and 40% 1RM countermovement jump (CMJ), and drop jump (DJ) reactive strength index (RSI). Statistical significance was accepted at p ≤ 0.05. In the BEP condition, 0% 1RM CMJ height (+3.62%) as well as theoretical maximum velocity (+5.14%) and theoretical maximum power (+2.55%) obtained from CMJ 24 hours after the priming session were significantly greater than those at the baseline ( p ≤ 0.05), but 0% 1RM SJ height and DJ RSI ( p > 0.05) were not greater than those at the baseline. In the HRP condition, the jump performances were not improved ( p > 0.05). The percentage change in 0% 1RM CMJ height in the BEP condition was significantly greater than that seen in the HRP condition ( p = 0.015) but did not differ for 0% 1RM SJ height and DJ RSI ( p > 0.05). These results suggest that the BEP is more effective than HRP in improving CMJ performance after 24 hours. Therefore, practitioners should consider prescribing resistance priming using low-load ballistic exercises rather than high-load traditional exercises when planning to enhance athlete performance on the following day.

Influence of Strength Level on Performance Enhancement Using Resistance Priming.

ABSTRACT: Nishioka, T and Okada, J. Influence of strength level on performance enhancement using resistance priming. J Strength Cond Res 36(1): 37-46, 2022-The current study aimed to investigate (a) whether resistance priming was effective in enhancing jump performance for both stronger and weaker individuals and (b) how resistance priming influences the lower-body force-velocity profile. A total of 20 resistance-trained men performed priming and control conditions 72-144 hours apart in a randomized and counterbalanced order. Jump performances (0 and 40% 1 repetition maximum [1RM] squat jump, 0 and 40% 1RM countermovement jump [CMJ] and drop jump) were assessed before and 24 hours after the priming session, and before and 24 hours after rest (control). Priming session-induced percentage change in 0% 1RM CMJ height was positively correlated with the individual's relative half squat 1RM (r = 0.612, p ≤ 0.05). Using the median split method, subjects were divided into stronger (relative half squat 1RM = 1.93-2.67 kg·kg-1) and weaker (relative half squat 1RM = 1.37-1.92 kg·kg-1) groups and subsequently analyzed. The stronger group showed specific improvement in 0% 1RM CMJ performance 24 hours after the priming session (p ≤ 0.05), whereas the weaker group showed no improvement in any of their jump performances. Moreover, the priming session enhanced the theoretical maximum velocity (p ≤ 0.05), but not the theoretical maximum force during CMJ in the stronger group; whereas none of the force-velocity profile variables were enhanced in the weaker group. These results suggest that stronger individuals are more likely to experience performance enhancement using resistance priming, which may be movement- and velocity-specific.

Free triiodothyronine /free thyroxine ratio as an index of deiodinase type 1 and 2 activities negatively correlates with casual serum insulin levels in patients with type 2 diabetes mellitus.

Free triiodothyronine/free thyroxine (FT3/FT4) ratio is considered as an index of the activities of iodothyronine deiodinase types 1 and 2 (DIO1 and DIO2, respectively) and is reportedly associated with insulin resistance in euthyroid adults. Euthyroid women with polycystic ovary syndrome accompanied with insulin resistance have lesser deiodinase activities. Correspondingly, the serum insulin level in a fasted condition positively correlates with the FT3/FT4 ratio, and insulin depletion decreases the DIO2 activity in mice. Selected genetic variants in DIO1 are also associated with insulin resistance measures. Therefore, if insulin positively regulates DIO1 and DIO2, the FT3/FT4 ratio should decrease under impaired insulin action, and the casual insulin level and FT3/FT4 ratio should be negatively correlated. To evaluate this hypothesis, we conducted a single-center retrospective study between 2018 and 2021. All participants visited the selected hospitals monthly for type 2 diabetes mellitus treatment and casual plasma glucose and HbA1c level measurements. Furthermore, their casual serum insulin levels were measured annually. Meanwhile, we excluded patients treated with insulin injection. Ultimately, we evaluated 71 patients, which all exhibited euthyroid conditions. The FT3/FT4 ratio was independently associated with thyroid-stimulating hormone, casual plasma glucose, and casual insulin levels. In terms of the regression coefficients of the univariate linear regression analysis, the FT3/FT4 ratio negatively correlated with the casual serum insulin levels. Therefore, the risk of FT3/FT4 ratio underestimation should be considered when diagnosing Graves' disease, which is often accompanied with insulin resistance.

Angiotensin receptor blockers significantly reduce hemoglobin level in patients with type 2 diabetes mellitus not suffered chronic cardiac failure and chronic kidney disease.

Anemia due to angiotensin receptor blocker (ARB) therapy has been previously reported in patients with diabetes mellitus with glomerular filtration rates of <60 mL min-1/1.73 m2. However, whether Japanese patients with type 2 diabetes mellitus (T2DM) receiving ARB therapy for chronic cardiac failure and chronic kidney disease develop reduced hemoglobin (Hb) levels has not been elucidated. Thus, this cross-sectional study was conducted, and Hb levels were compared between patients with T2DM with and without ARB administration. No significant difference in the prescribed proportion of antidiabetic medicines such as biguanide, sodium glucose co-transporter 2 inhibitors, and α-glucosidase inhibitors was found between the group treated with ARBs and the group without ARBs. Thus, we considered that the effects of antidiabetic medicines on the results were minimum. In this study, the Hb levels of patients who received ARBs (13.8 ± 1.7 g/dL) were significantly lower than those of patients without ARBs (14.9 ± 1.35 g/dL) (p = 0.034). The difference between this study and a previous study relies on eGFR levels. Thus, the eGFR levels of the patients in this study and the previous study were above 60 and below 60 mL min-1/1.73 m2, respectively. Despite those differences, both studies showed that the use of ARBs was associated with a decrease in Hb levels in patients with T2DM. Thus, the evaluation of glycated Hb levels should be focused on whether ARBs are prescribed for patients with T2DM.

In patients with type 2 diabetes the presence of Hashimoto's thyroiditis reduces the beneficial effect of dipeptidyl peptidase-4 inhibitor on plasma glucose control.

In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT.

An application of a patient-specific cardiac simulator for the prediction of outcomes after mitral valve replacement: a pilot study.

Despite advancements in preoperative prediction of patient outcomes, determination of the most appropriate surgical treatments for patients with severely impaired cardiac function remains a challenge. "UT-Heart" is a multi-scale, multi-physics heart simulator, which can be used to assess the effects of treatment without imposing any burden on the patients. This retrospective study aimed to assess whether UT-Heart can function as a tool that aids decision making for performing mitral valve replacements (MVR) in patients with severe mitral regurgitation (MR) and impaired left ventricular (LV) function. We used preoperative clinical data to create a patient-specific heart model using UT-Heart for a patient who had dilated cardiomyopathy with severe MR. After confirming that this heart model reproduced the preoperative state of the patient, we performed an in silico MVR operation without changing any parameters, such as the end-diastolic volume of the left ventricle, systemic vascular resistance, and the number of myocardiocytes. Among the functional changes introduced by in silico surgery, we found two indices, forward flow and the mechanical efficiency of the work done to the systemic circulation, which may relate positively to the favorable outcome observed in the real world. Thus, multi-scale, multi-physics heart simulators can reproduce the pathophysiology of MR with impaired LV function. By performing in silico MVR and examining the resultant functional changes, we identified two indices, whose usefulness should be tested in future studies.

Comparison of the Power Output Between the Hang Power Clean and Hang High Pull Across a Wide Range of Loads in Weightlifters.

ABSTRACT: Takei, S, Hirayama, K, and Okada, J. Comparison of the power output between the hang power clean and hang high pull across a wide range of loads in weightlifters. J Strength Cond Res 35(2S): S84-S88, 2021-The current study compared the peak power output during the hang power clean (HPC) and hang high pull (HHP) across a wide range of external loads in weightlifters. Eight weightlifters completed 1 repetition maximum (1RM) assessment for the HPC (1.59 ± 0.17 kg/body mass) and a power test for the HPC and HHP at relative loads of 40, 60, 70, 80, 90, 95, and 100% 1RM of the HPC. The ground reaction force and 2-dimensional bar position data were recorded to determine the system (barbell + body mass) kinetics and bar height, respectively. System power was calculated as force multiplied by system velocity. The HHP produced significantly greater peak power than the HPC at 40, 60, and 70% 1RM. Conversely, there was no statistical or practical difference in peak power between the exercises at 80, 90, 95, and 100% 1RM. No significant interaction was found in force at peak power, whereas velocity at peak power was significantly greater during the HHP than during the HPC at 40, 60, and 70% 1RM. In addition, significantly greater peak bar height was observed for the HHP than the HPC at 40, 60, and 70% 1RM. From the power output comparisons across loads, the HHP should be used over the HPC at loads of 40-70% 1RM, whereas the HPC and HHP can be interchangeably used at loads of 80-100% 1RM.

EID1 suppresses lipid accumulation by inhibiting the expression of GPDH in 3T3-L1 preadipocytes.

The imbalance between food intake and energy expenditure causes high accumulation of triglycerides in adipocytes. Obesity is related with the increased lipid accumulation in white adipose tissue, which is a major risk factor for the development of metabolic disorders, such as type 2 diabetes and cardiovascular disease. This study highlights the role of E1A-like inhibitor of differentiation 1 (EID1) in the modulation of adipogenesis through the downregulation of glycerol-3-phosphate dehydrogenase (GPDH), which is a key enzyme in the synthesis of triglycerides and is considered to be a marker of adipogenesis. By analyzing DNA microarray data, we found that when EID1 is overexpressed in preadipocytes (3T3-L1 cells) during adipocyte differentiation, EID1 inhibits lipid accumulation through the downregulation of GPDH. In contrast, EID1 is not involved in the regulation of intracellular glucose via the translocation of glucose transporter. A confocal image analysis showed that EID1 is located in the nucleus of preadipocytes in the form of speckles, which could be involved as a regulator of the transcriptional process. We further confirmed that EID1 is able to bind to the promoter sequence of GPDH in the nucleus. These findings provide a molecular explanation for the inhibitory effect of EID1 on lipid accumulation in adipocytes.

Patient-specific heart simulation can identify non-responders to cardiac resynchronization therapy.

To identify non-responders to cardiac resynchronization therapy (CRT), various biomarkers have been proposed, but these attempts have not been successful to date. We tested the clinical applicability of computer simulation of CRT for the identification of non-responders. We used the multi-scale heart simulator "UT-Heart," which can reproduce the electrophysiology and mechanics of the heart based on a molecular model of the excitation-contraction mechanism. Patient-specific heart models were created for eight heart failure patients who were treated with CRT, based on the clinical data recorded before treatment. Using these heart models, bi-ventricular pacing simulations were performed at multiple pacing sites adopted in clinical practice. Improvement in pumping function measured by the relative change of maximum positive derivative of left ventricular pressure (%ΔdP/dtmax) was compared with the clinical outcome. The operators of the simulation were blinded to the clinical outcome. In six patients, the relative reduction in end-systolic volume exceeded 15% in the follow-up echocardiogram at 3 months (responders) and the remaining two patients were judged as non-responders. The simulated %ΔdP/dtmax at the best lead position could identify responders and non-responders successfully. With further refinement of the model, patient-specific simulation could be a useful tool for identifying non-responders to CRT.

FAM83G Is a Novel Inducer of Apoptosis.

The family with sequence similarity 83 (FAM83) protein family G (FAM83G) possesses a predicted consensus phosphorylation motif for serine/threonine-protein kinase D1/protein kinase C mu (PKD1/PKCµ) at serine residue 356 (S356). In this study, overexpressed wild-type FAM83G coimmunoprecipitated with PKD1/PKCµ in Chinese hamster ovary (CHO) cells inhibited heat shock protein 27 (HSP27) phosphorylation at S82 and reduced the living cell number. The expression of a FAM83G phosphorylation-resistant mutant (S356A-FAM83G) had no effect on the living cell number or the induction of spontaneous apoptosis. By contrast, the introduction of a synthetic peptide encompassing FAM83G S356 into HCT116 and HepG2 cells decreased HSP27 S15 and S82 phosphorylation and induced spontaneous apoptosis. On the other hand, the introduction of FAM83G phosphorylation-resistant mutant synthesized peptides (S356A-AF-956 and S356A-AG-066) did not reduce the living cell number or induce spontaneous apoptosis. The endogenous expression of HSP27 and FAM83G was apparently greater in HCT116 and HepG2 cells compared with in CHO cells. In various types of lung cancer cell lines, the FAM83G messenger RNA (mRNA) level in non-small lung cancer cells was at a similar level to that in non-cancerous cells. However, the FAM83G mRNA level in the small cell lung cancer cell lines was variable, and the HSP27 mRNA level in FAM83G mRNA-rich types was greater than that in FAM83G mRNA-normal range types. Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.

Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity.

Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose by the kidneys. Dapagliflozin is metabolized and inactivated by UGT1A9. Empagliflozin is metabolized and inactivated by UGT1A9 and by other related isoforms UGT2B7, UGT1A3, and UGT1A8. Tofogliflozin is metabolized and inactivated by five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, and CYP4F3. Dapagliflozin treatment of HCT116 cells, which express SGLT2 but not UGT1A9, results in the loss of cell adhesion, whereas HepG2 cells, which express both SGLT2 and UGT1A9, are resistant to the adhesion-related effects of dapagliflozin. PANC-1 and H1792 cells, which do not express either SGLT2 or UGT1A9, are also resistant to adhesion related effects of dapagliflozin. On the other hand, either empagliflozin or tofogliflozin treatment of HCT116, HepG2, PANC-1, and H1792 cells are resistant to the adhesion-related effects as observed in dapagliflozin treated HCT116 cells. Knockdown of UGT1A9 by shRNA in HepG2 cells increased dapagliflozin sensitivity, whereas the overexpression of UGT1A9 in HCT116 cells protected against dapagliflozin-dependent loos of cell adhesion. Dapagliflozin treatment had no effect on cellular interactions with fibronectin, vitronectin, or laminin, but it induced a loss of interaction with collagen I and IV. In parallel, dapagliflozin treatment reduced protein levels of the full-length discoidin domain receptor I (DDR1), concomitant with appearance of DDR1 cleavage products and ectodomain shedding of DDR1. In line with these observations, unmetabolized dapagliflozin increased ADAM10 activity. Dapagliflozin treatment also significantly reduced Y792 tyrosine phosphorylation of DDR1 leading to decrement of DDR1 function and detachment of cancer cells. Concomitant with these lines of results, we experienced that CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus treated by dapagliflozin in addition to chemotherapy was decreased (case 1). CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus was treated by dapagliflozin alone after radiation therapy was decreased but started to rise after cessation of dapagliflozin (case 2). CA19-9 in two of patients with pancreatic cancer and type 2 diabetes mellitus was resistant to the combination therapy of dapagliflozin and chemotherapy (case 3 and 4 respectively). PIVKAII in patients with liver cancer and type 2 diabetes mellitus, and CYFRA in patients with squamous lung cancer and type 2 diabetes mellitus was also resistant the combination therapy of dapagliflozin and chemotherapy (case 5 and 6 respectively). Taken together, these data suggest a potential role for dapagliflozin anticancer therapy against colon cancer cells that express SGLT2, but not UGT1A9.

Comparing the efficacy of apple peels and a sodium-glucose cotransporter 2 inhibitor (ipragliflozin) on interstitial glucose levels: A pilot case study.

BACKGROUND: Apple peels contain phlorizin, which can reduce plasma glucose levels in a manner similar to that of inhibitors for sodium-glucose cotransporters. OBJECTIVES: In this study, we examined the influence of a peeled apple, a sodium-glucose cotransporter-2 inhibitor (ipragliflozin) in combination with a peeled apple, and an unpeeled apple on interstitial glucose in a healthy individual across 3 experiments. METHODS: For Experiments 1, 2, and 3, the healthy volunteer consumed 327 g peeled Sun Fuji apple, took 50 mg ipragliflozin, and then consumed 327 g peeled Sun Fuji apple, or consumed 370 g unpeeled Sun Fuji apple (peel weight was 43 g), respectively. In each condition, the apple was eaten within a 15-minute period and interstitial glucose levels were measured every 15 minutes for 11.5 hours using FreeStyle Libre (Abbott Laboratories, Abbott Park, Illinois). RESULTS: Results showed that neither consumption of the unpeeled apple nor ipragliflozin were able to suppress the rapid or transient increases in postprandial glucose; however, the 2 were found to comparably suppress interstitial glucose during the late phase. CONCLUSIONS: On the whole, these findings demonstrate that eating unpeeled apples may be beneficial for plasma glucose management, but ipragliflozin is a superior option because the apple peel's function did not last as long as ipragliflozin. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Differences in the effects of Kenyan, Tanzanian, and Ethiopian coffee intake on interstitial glucose levels measured by FreeStyle Libre: A pilot case study.

BACKGROUND: Although generally considered part of a healthy diet, coffee consumption has been suspected to be associated with elevated epinephrine levels and increasing insulin resistance. OBJECTIVES: We studied the effects of the intake of 3 different types of coffee (Tanzanian, Ethiopian, and Kenyan) on postprandial interstitial glucose levels. METHOD: Interstitial glucose levels were measured every 15 minutes using the FreeStyle Libre glucose monitoring system (Abbott Diabetes Care Ltd, Witney, United Kingdom) in each individual after drinking coffee compared with when not consuming coffee. RESULTS: Unlike Tanzanian and Ethiopian coffees, Kenyan coffee suppressed the increase of postprandial interstitial glucose levels. Kenyan coffee beans contain less anhydrous caffeine and more chlorogenic acid than Tanzanian and Ethiopian coffee beans. These findings may explain the different effects of these coffee types on postprandial interstitial glucose levels. Furthermore, Kenyan coffee beans inhibited α-glucosidase activity, which may partially explain why Kenyan coffee reduces postprandial interstitial glucose levels. CONCLUSIONS: Coffee is widely consumed as a beverage worldwide, and our findings suggest that patients with diabetes mellitus may benefit from drinking Kenyan coffee because of its ability to reduce postprandial interstitial glucose levels. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Changes in Urinary Titin N-terminal Fragment Concentration after Concentric and Eccentric Exercise.

We aimed to compare the urinary titin N-terminal fragment (UTF) concentration after concentric and eccentric exercise and to clarify the specific response of UTF to exercise-induced muscle damage (EIMD). Nine healthy young men performed 30 concentric elbow flexion exercises with maximum effort, rested for at least eight weeks, and performed eccentric exercises at the same workload using the same arm. Changes in the maximal voluntary isometric contraction (MVIC), muscle soreness (SOR), range of motion (ROM), serum creatine kinase (CK) activity, and UTF concentrations were recorded before and after for six consecutive days after exercise. There was no significant difference in workload during exercise between the two exercise types. However, serum CK activity increased after eccentric exercise (p < 0.05). Additionally, MVIC, SOR, ROM, and UTF concentration were significantly higher after eccentric exercise than after concentric exercise (p < 0.05). Although workload was the same, the UTF concentration greatly increased after eccentric exercise. Based on these results, we suggest that UTF can be a non-invasive and highly specific biomarker of EIMD.

Longitudinal dissociation and transition in thickness of the His-Purkinje system cause various QRS waveforms of surface ECG under His bundle pacing: A simulation study based on clinical observations.

AIMS: His bundle pacing (HBP) is a feasible and reliable alternative to conventional right ventricular pacing (RVP), but associated ECG (electrocardiogram) changes have not been well-studied. This study aimed to determine the mechanisms underlying ECG changes associated with HBP using patient-specific multiscale heart simulations. METHODS: ECGs were recorded in two patients who were treated by HBP under a native rhythm and HBP at high and low voltages. We created patient-specific multiscale simulation heart models of these patients and performed ECG simulation under these conditions. Using these results and detailed information on the electrical field around the pacing lead, we investigated mechanisms underlying the observed ECG changes. RESULTS: Heart simulations successfully reproduced ECGs under a native rhythm for both cases. In case 1, nonselective HBP produced a left bundle branch (LBB) block pattern, which was reproduced as a selective right bundle branch (RBB) pacing. However, in case 2, ECG under nonselective HBP showed an RBB block pattern, which could not be reproduced by the commonly used framework. Findings on the electrical field and anatomy of the His bundle and its branches suggested that longitudinal dissociation of the His bundle and transition of thickness in the stem of the LBB caused a conduction delay in the RBB to produce these ECG changes in this patient. CONCLUSION: Variations in the anatomy of the His bundle and its branches may underlie the diverse ECG responses to HBP. These variations should be taken into account when performing this therapy.

Clinical and pharmacological application of multiscale multiphysics heart simulator, UT-Heart.

A heart simulator, UT-Heart, is a finite element model of the human heart that can reproduce all the fundamental activities of the working heart, including propagation of excitation, contraction, and relaxation and generation of blood pressure and blood flow, based on the molecular aspects of the cardiac electrophysiology and excitation-contraction coupling. In this paper, we present a brief review of the practical use of UT-Heart. As an example, we focus on its application for predicting the effect of cardiac resynchronization therapy (CRT) and evaluating the proarrhythmic risk of drugs. Patient-specific, multiscale heart simulation successfully predicted the response to CRT by reproducing the complex pathophysiology of the heart. A proarrhythmic risk assessment system combining in vitro channel assays and in silico simulation of cardiac electrophysiology using UT-Heart successfully predicted druginduced arrhythmogenic risk. The assessment system was found to be reliable and efficient. We also developed a comprehensive hazard map on the various combinations of ion channel inhibitors. This in silico electrocardiogram database (now freely available at http://ut-heart.com/) can facilitate proarrhythmic risk assessment without the need to perform computationally expensive heart simulation. Based on these results, we conclude that the heart simulator, UT-Heart, could be a useful tool in clinical medicine and drug discovery.

Multi-scale, tailor-made heart simulation can predict the effect of cardiac resynchronization therapy.

BACKGROUND: The currently proposed criteria for identifying patients who would benefit from cardiac resynchronization therapy (CRT) still need to be optimized. A multi-scale heart simulation capable of reproducing the electrophysiology and mechanics of a beating heart may help resolve this problem. The objective of this retrospective study was to test the capability of patient-specific simulation models to reproduce the response to CRT by applying the latest multi-scale heart simulation technology. METHODS AND RESULTS: We created patient-specific heart models with realistic three-dimensional morphology based on the clinical data recorded before treatment in nine patients with heart failure and conduction block treated by biventricular pacing. Each model was tailored to reproduce the surface electrocardiogram and hemodynamics of each patient in formats similar to those used in clinical practice, including electrocardiography (ECG), echocardiography, and hemodynamic measurements. We then performed CRT simulation on each heart model according to the actual pacing protocol and compared the results with the clinical data. CRT simulation improved the ECG index and diminished wall motion dyssynchrony in each patient. These results, however, did not correlate with the actual response. The best correlation was obtained between the maximum value of the time derivative of ventricular pressure (dP/dtmax) and the clinically observed improvement in the ejection fraction (EF) (r=0.94, p<0.01). CONCLUSIONS: By integrating the complex pathophysiology of the heart, patient-specific, multi-scale heart simulation could successfully reproduce the response to CRT. With further verification, this technique could be a useful tool in clinical decision making.