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The prognosis and treatment outcomes of heart failure (HF) patients rely heavily on disease etiology, yet the majority of underlying signaling mechanisms are complex and not fully elucidated. Phosphorylation is a major point of protein regulation with rapid and profound effects on the function and activity of protein networks. Currently, there is a lack of comprehensive proteomic and phosphoproteomic studies examining cardiac tissue from HF patients with either dilated dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM). Here, we used a combined proteomic and phosphoproteomic approach to identify and quantify more than 5,000 total proteins with greater than 13,000 corresponding phosphorylation sites across explanted left ventricle (LV) tissue samples, including HF patients with DCM vs. nonfailing controls (NFC), and left ventricular infarct vs. noninfarct, and periinfarct vs. noninfarct regions of HF patients with ICM. Each pair-wise comparison revealed unique global proteomic and phosphoproteomic profiles with both shared and etiology-specific perturbations. With this approach, we identified a DCM-associated hyperphosphorylation cluster in the cardiomyocyte intercalated disc (ICD) protein, αT-catenin (CTNNA3). We demonstrate using both ex vivo isolated cardiomyocytes and in vivo using an AAV9-mediated overexpression mouse model, that CTNNA3 phosphorylation at these residues plays a key role in maintaining protein localization at the cardiomyocyte ICD to regulate conductance and cell–cell adhesion. Collectively, this integrative proteomic/phosphoproteomic approach identifies region- and etiology-associated signaling pathways in human HF and describes a role for CTNNA3 phosphorylation in the pathophysiology of DCM.

The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigated the role of Tmem65 in ICD organization in vivo . A mouse model was established by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA which resulted in a 90% reduction of Tmem65 expression in mouse ventricles compared to mice injected with scrambled shRNA. Tmem65 knockdown (KD) resulted in increased mortality which was accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection, progressing to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts displayed depressed hemodynamics, measured echocardiographically, accompanied by electrocardiogram changes (prolonged PR intervals and QRS duration) consistent with impaired conduction, which was confirmed with optical mapping of isolated hearts. Immunoprecipitation and super-resolution microscopy demonstrated a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appeared to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at the ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na + currents but did show reduced Ca 2+ and K + currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.

Heart rate (HR) and blood pressure as well as adverse cardiovascular events show clear circadian patterns, which are linked to interdependent daily variations in physical activity and cardiac autonomic nerve system (ANS) activity. We set out to assess the relative contributions of the ANS (alone) and physical activity to circadian HR fluctuations. To do so, we measured HR (beats per minute, bpm) in mice that were either immobilized using isoflurane anesthesia or free-moving. Nonlinear fits of HR data to sine functions revealed that anesthetized mice display brisk circadian HR fluctuations with amplitudes of 47.1±7.4bpm with the highest HRs in middle of the dark (active) period (ZT 18: 589±46bpm) and lowest HRs in the middle of the light (rest) period (ZT 6: 497±54bpm). The circadian HR fluctuations were reduced by ~70% following blockade of cardiac parasympathetic nervous activity (PNA) with atropine while declining by 2 consumption during running. We conclude that, independent of physical activity, the ANS is a major determinant of circadian HR variations with PNA playing a dominant role compared to SNA. The effects of physical activity to the daily HR variations are remarkably small unless mice get access to running wheels.

Background: The coronavirus disease-19 (COVID-19) and its variants have increased rapidly worldwide since December 2019, with respiratory disease being a prominent complication. As such, optimizing evaluation methods and identifying factors predictive of disease progress remain critical. The purpose of the study was to assess late phase (≥3 weeks) pulmonary changes using intensity-based computed tomography (CT) scoring in COVID-19 patients and determine the clinical characteristics predicting lung abnormalities and recovery.Methods: We conducted a retrospective study on 42 patients (14 males, 28 females; age 65±10 years) with COVID-19. Only patients with at least 3 CT scans taken at least 3 weeks after initial symptom onset were included in the study. Two scoring methods were assessed: (1) area-based scoring (ABS) and (2) intensity-weighted scoring (IWS). Temporal changes in the average lung lesion were evaluated by the calculating the averaged area under the curve (AUC) of the CT score-time curve. Correlations between averaged AUCs and clinical characteristics were determined. Results: Using the ABS system, temporal changes in lung abnormalities during recovery were highly variable (P=0.934). By contrast, the IWS system detected more subtle changes in lung abnormalities during in COVID-19 patients, with consistent week-to-week relative reductions in IWS (P=0.025). Strong relationships were observed with D-dimer and C-reactive protein (CRP) levels on admission, with hazard ratios (HR)(95%CI) of 5.32 (1.25-22.6)(P=0.026) and 1.05 (1.10-1.09)(P=0.017), respectively. Conclusion: Our results suggest COVID-19-mediated pulmonary abnormalities persist well-beyond 3-weeks of symptom onset, with intensity-weighted rather than area-based scoring being more sensitive. Moreover, D-dimer and CRP levels were predictive of the recovery from the disease.

Objectives: To assess the late phase CT changes of COVID-19 patients, and figure out factors predicting lung abnormality in late phase.Methods: We conducted a retrospective study on 42 patients (14 males, 28 females; age 65±10 years) with COVID-19 admitted between February 7, 2020 and March 27, 2020. Only patients with at least 3 CT scans taken at least 3 weeks after initial symptom onset were included in the study. CT images were analyzed by 2 independent radiologists using different scoring: (1) area-based scoring (ABS); and (2) intensity-weighted scoring (IWS). Temporal changes in the average lung lesion were evaluated by averaged area under the curve (AUC) of the CT score-time curve. Correlations between averaged AUCs and clinical characteristics were determined. Results: Temporal changes in lung abnormalities during recovery (weeks 3 through 8) of CT findings using the ABS system were variable (P=0.934). By contrast, the IWS system detected more subtle changes in lung abnormalities during the late phase of recovery in COVID-19 patients, with consistent week-to-week relative reductions in IWS (P=0.025). In assessing the correlation between averaged AUCs and clinical characteristics, strong relationships were observed with D-dimer and C-reactive protein (CRP) levels on admission, with hazard ratios (HR)(95%CI) of 5.32 (1.25-22.6)(P=0.026) and 1.05 (1.10-1.09)(P=0.017), respectively. Conclusion: Our results suggest an intensity-weighted rather than area-based scoring system is more sensitive to detect subtle temporal CT changes in COVID-19, with D-dimer and CRP levels on admission being predictive of the time course of late phase recovery from the disease.

Acute exhaustive endurance exercise can differentially impact the right ventricle (RV) versus the left ventricle (LV). However, the hemodynamic basis for these differences and its impact on postexercise recovery remain unclear. Therefore, we assessed cardiac structure and function along with hemodynamic properties of mice subjected to single bouts (216 ± 8 min) of exhaustive swimming (ES). One-hour after ES, LVs displayed mild diastolic impairment compared with that in sedentary (SED) mice. Following dobutamine administration to assess functional reserve, diastolic and systolic function were slightly impaired. Twenty-four hours after ES, LV function was largely indistinguishable from that in SED. By contrast, 1-h post swim, RVs showed pronounced impairment of diastolic and systolic function with and without dobutamine, which persisted 24 h later. The degree of RV impairment correlated with the time-to-exhaustion. To identify hemodynamic factors mediating chamber-specific responses to ES, LV pressure was recorded during swimming. Swimming initiated immediate increases in heart rates (HRs), systolic pressure, dP/d

Background Variability in the anatomy and orientation of the triangle of Koch (TK) complicates ablation procedures involving the atrioventricular (AV) node. We used CT angiography (CTA) to assess the anatomical TK orientation, the CS ostium direction, and the relationship between the two, and we validated an individualized CS-guided projection during ablation procedures. Methods In 104 patients without structural heart disease undergoing computed tomography (CT) angiography, TK orientations were determined in relation to the coronary sinus ostium (CSo) as well as two standard right anterior oblique (RAO) projection angles (30o and 45o) commonly used in ablation procedures. Results A CS-guided RAO projection (RAOCS) was shown to best track the orientation of the TK compared to RAO30° and 45°, with TK orientation strongly correlating with the CSo direction (r = 0.86, P Conclusion In hearts with a normal structure, the CSo direction offers a reliable predictor of the TK orientation which can be used to guide the projection of the TK during ablation procedures.

BACKGROUND Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis, and inflammation. We previously established adverse atrial changes and arrhythmogenesis required the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) in intense swim exercised mice. Thus, we hypothesize that stretch-mediated TNF-dependent signaling may provide a unifying mechanism linking AF in exercise and disease. METHODS AND RESULTS We developed a clinically-relevant mouse model of aortic regurgitation (AR), which is characterized by diastolic volume overload and elevated left ventricular end-diastolic (LVEDPs) and atrial pressures, to study atrial stretch-dependent TNF-mediated AF pathogenesis. AR was induced by retrograde puncture of the aortic valve in 8-week-old CD1 wild-type and whole-body TNF knockout (TNF-/-) mice. Four weeks after regurgitation, AR resulted in volume overload-mediated progressive LV dilatation, functional impairment, hypertrophy, and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both groups. In wild-type mice, AR resulted in adverse atrial remodeling, characterized by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial effective refractory period and action potential duration, and increased in vivo and ex vivo AF susceptibility. By contrast, TNF-/- prevented AR-induced adverse atrial remodeling and arrhythmia inducibility, independent of ventricular changes. CONCLUSION Our results establish that adverse atrial remodeling and AF vulnerability with AR requires TNF, providing a mechanistic link between elevated atrial pressures, adverse remodeling, and AF susceptibility with CV disease and exercise.

In health, the aortic valve facilitates unidirectional forward flow from the left ventricle (LV) to the systemic circulation. This article is protected by copyright. All rights reserved

Intense endurance exercise is linked to atrial fibrillation (AF). We established previously that interventions that simultaneously interfere with TNFα signaling, mediated via both the enzymatically liberated soluble and membrane-bound forms of TNFα, prevent atrial remodeling and AF vulnerability in exercised mice. To investigate which signaling modality underlies this protection, we treated exercised mice with XPRO®1595, a selective dominant-negative inhibitor of solTNFα. In male CD1 mice, 6 weeks of intense swim exercise induced reductions in heart rate, increased cardiac vagal tone, left ventricular (LV) dilation and enhanced LV function. By contrast, exercise induced hypertrophy, fibrosis, and increased inflammatory cell infiltrates in atria, and these changes were associated with increased AF susceptibility in isolated atria as well as mice, with and without parasympathetic nerve blockade. Although XPRO treatment had no effect on the beneficial physiological changes induced by exercise, it protected against adverse atrial changes as well as AF susceptibility. Our results establish that soluble TNFα is required for exercise-induced increases in AF vulnerability, which is linked to fibrosis, inflammation, and enlargement of the atria, but largely independent of changes in vagal tone.

Heart rate variability, a common and easily measured index of cardiovascular dynamics, is the output variable of complicated cardiovascular and respiratory control systems. Both neural and non-neural control mechanisms may contribute to changes in heart rate variability. We previously developed an innovative method using transfer function analysis to assess the effect of prolonged exercise training on integrated cardiovascular regulation. In the present study, we modified and applied this to investigate the effect of 2 years of high-intensity training on circulatory components to tease out the primary effects of training. Our method incorporated the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. The dynamic Starling mechanism gain and arterial-cardiac baroreflex gain were significantly increased in the exercise group. These parameters remained unchanged in the controls. Conversely, neither group experienced a change in dynamic arterial elastance. The integrated cardiovascular regulation gain in the exercise group was 1.34-fold larger than that in the control group after the intervention. In these previously sedentary, otherwise healthy, middle-aged adults, 2 years of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity.Assessing the effects of exercise training on cardiovascular variability is challenging because of the complexity of multiple mechanisms. In a prospective, parallel-group, randomized controlled study, we examined the effect of 2 years of high-intensity exercise training on integrated cardiovascular function, which incorporates the dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function. Sixty-one healthy participants (48% male, aged 53 years, range 52-54 years) were randomized to either 2 years of exercise training (exercise group: n = 34) or control/yoga group (controls: n = 27). Before and after 2 years, subjects underwent a 6 min recording of beat-by-beat pulmonary artery diastolic pressure (PAD), stroke volume index (SV index), systolic blood pressure (sBP) and RR interval measurements with controlled respiration at 0.2 Hz. The dynamic Starling mechanism, dynamic arterial elastance and arterial-cardiac baroreflex function were calculated by transfer function gain between PAD and SV index; SV index and sBP; and sBP and RR interval, respectively. Fifty-three participants (controls: n = 25; exercise group: n = 28) completed the intervention. After 2 years, the dynamic Starling mechanism gain (Group × Time interaction: P = 0.008) and the arterial-cardiac baroreflex gain (P = 0.005) were significantly increased in the exercise group but remained unchanged in the controls. There was no change in dynamic arterial elastance in either of the two groups. The integrated cardiovascular function gain in the exercise group increased 1.34-fold, whereas there was no change in the controls (P = 0.02). In these previously sedentary, otherwise healthy middle-aged adults, a 2 year programme of high-intensity exercise training improved integrated cardiovascular regulation by enhancing the dynamic Starling mechanism and arterial-cardiac baroreflex sensitivity, without changing dynamic arterial elastance.

Rationale: Anti-thrombosis therapy for atrial fibrillation (AF) management and stroke prevention is an important aspect of disease management. Novel oral anticoagulants (NOACs) are recommended by guidelines for AF management. However, if one can switch one NOAC to another when the former showed a poor effect has not been fully determined. Patient concerns: A 52-year-old man was admitted to our center for heart failure and AF with a thrombus in the left atrium. Diagnoses: Cardiomyopathy was diagnosed by cardiac magnetic resonance (CMR) and echocardiography. Interventions: He was prescribed rivaroxaban (20 mg daily) as treatment, and dabigatran (150 mg twice daily) was used when the thrombus was found to be non-response to rivaroxaban. Outcomes: The rivaroxaban did not diminish the atrial thrombus, and dabigatran was given instead which finally eliminated the thrombus. Lessons: Individualized responsiveness to NOACs should be considered and paid more attention to during clinical practice.

Rationale: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disorder related to thrombosis. Anticoagulant therapy is suggested for the treatment of this disease. The success of the novel oral anticoagulant rivaroxaban as a treatment option for this disorder is unclear. Patient concerns: A 43-year-old man who felt dizzy at rest was found to have an intraventricular thrombus. Diagnoses: The thrombus was confirmed by echocardiography. And LVNC was diagnosed by cardiac magnetic resonance (CMR) and echocardiography. Interventions: He was prescribed a low dose (10 mg daily) of rivaroxaban as treatment. Outcomes: After 3 months, the thrombus diminished, and the manifestation disappeared. Lessons: Low dose of rivaroxaban may serve as a viable option for anticoagulation therapy in LVNC patients, with large clinical trials needed to determine the best course of treatment.

We read with interest the paper by Katritsis et al. 1 published in Europace recently. In this study, the authors sought to assess the prevalence, electrophysiological characteristics, and mechanism underlying atypical atrioventricular nodal re-entrant tachycardia (AVNRT), which is not clinically well-defined. It was shown that the atrial-His (AH) interval in atypical ‘fast-slow’ (F-S) AVNRT is longer than His-atrial (HA) interval in typical ‘slow-fast’ (S-F) AVNRT, implying that different fast conduction pathways are utilized in these two types of tachycardia. However, we are holding the following interpretations: …

The systemic circulation consists of a pulsatile pump that delivers blood into a proximal vascular capacitor, subsequently distributing blood to the periphery with minimal variation in flow and pressure. In the face of chronic workload elevations, hypertrophic growth pathways activated in the left ventricle (LV) are thought to be an adaptive response to normalize wall stress and augment or maintain cardiac output via a proportionate increase in wall thickness and/or chamber size. Although initially compensatory, the long‐term pattern of cardiac hypertrophy is thought to be dependent on the nature of the overload stimulus, with chronic workload elevations elicited by exercise training or systemic hypertension having been linked to divergent adaptive and maladaptive patterns of cardiac hypertrophic growth, respectively. While these findings suggest the nature of the overload stimuli drive the pattern of cardiac remodelling, recently, long‐term, high‐intensity, high‐volume exercise has been associated with adverse structural and electrical cardiac remodelling (La Gerche et al. 2012). These observations suggest that excessive stimulation of physiological systems may result in adverse responses, and that the mode of cardiac stress may not be as important as the balance of frequency, duration and intensity of the cardiac overload in dictating whether an adaptive or maladaptive pattern of remodelling is observed.

Aerobic exercises such as running, walking and cycling are known to elicit a PEH (post-exercise hypotensive) response in both trained and UT (untrained) subjects. However, it is not known whether swim exercise produces a similar effect in normotensive individuals. The complex acute physiological responses to water immersion suggest swimming may affect BP (blood pressure) differently than other forms of aerobic exercises. We tested the hypothesis that an acute bout of swimming would fail to elicit a PEH BP response compared with an equivalent bout of stationary cycling, regardless of training state. We studied 11 UT and ten triathlon-trained young healthy normotensive [SBP/DBP (systolic BP/diastolic BP)

On a beat-to-beat basis, cardiac contractile function is driven by a multifaceted and dynamic process that is regulated by both intrinsic (e.g. mechanical loading) and extrinsic (e.g. neuro-hormonal) factors (de Tombe et al. 2010). Specifically, the level of contractile activation of adult mammalian cardiomyocytes is modulated by the magnitude of the Ca2+ transient, the dynamic activation–relaxation kinetic response of the sarcomere to activator Ca2+ and the responsiveness of the myofilament to Ca2+, the last of which is dependent on sarcomere length and is a primary mediator of the Frank–Starling response. While transgenic mouse models have provided important insight into the molecular mechanisms underlying cardiac contractile function in health and disease, they are associated with high cost and relatively long generation times. Recently, the zebrafish has emerged as a promising model for the study of cardiac structure–function relationships, due to short generation times, ease of genetic manipulation and low cost. While multiple studies have characterized zebrafish cardiac electrophysiology, Ca2+ dynamics and myofilament mechanical function, it remains unclear whether the cardiac contractile structure–function relationship of adult zebrafish is comparable to that of the mammalian system.

We read with great interest the article by Baldinger et al1 published in Circulation: Arrhythmia and Electrophysiology recently. The authors showed a correlation between electrogram characteristic with pace capture and S-QRS durations, and a complementary usage of the two was suggested. However, there are some issues that must be addressed before using this combined method in practice. First, 47% of sites without any characteristics for conduction delay on the electrogram showed a prolonged S-QRS duration with pacing. We owe this to the difference between recording ranges …

We read with interest the article by Liu et al. 1 published recently in EP-Europace . In this article, the authors showed that discrete potentials (DPs) appeared to be a prerequisite for idiopathic outflow tract premature ventricular contractions (PVCs) and ventricular tachyarrhythmias (VTs), with DPs-guided mapping predictive of ablation success. A comparison of DPs with more well-established predictors of substrate mapping and ablation success, including local activation time, pace mapping, and unipolar mapping, is needed. However, the additional information …

The pump function of the left ventricle (LV) is dependent on synchronous depolarization and contraction to expel blood efficiently. The propagation of the apical-to-basal ventricular contraction pattern is controlled by electrical signalling of the fibre system down the interventricular septum and woven through the free walls of the ventricular myocardium. Dyssynchronous contraction results in mechanical inefficiency, decreased external work, and reduced cardiac output. Myocardial infarction (MI) may cause wall motion abnormalities not only through disturbed electrical conduction, but also through myocardial damage and non-viable tissue. Therapy targeted at preventing adverse remodelling and improving the viability of non-contracting tissue may have the potential for great improvement in ventricular synchronization by addressing mechanical disturbances in the myocardium. Recent advances in stem cell therapy hold promise for regenerative cardiac interventions, as the use of undifferentiated stem cells delivered to the myocardium may be effective in forming functional cardiac tissue and restoring global heart function. While the potential use of such therapies has gained recent attention, the administration of stem cell therapy to ameliorate regional dyssynchrony related to MI has not been examined.

The cardiac cycle is tightly regulated by a number of proteins that function to transfer the electrical stimulus to the contracting chambers of the heart. Movement of calcium ions (Ca2+) within the cell is central to the excitation–contraction coupling, and a key component in the modulation of the strength of each cycle. Increasing demand for greater cardiac output – through changes in myocardial loading or from exogenous stressors (e.g. exercise) – activates the sympathetic nervous system to initiate compensatory mechanisms to augment inotropic function. This occurs through cardiomyocyte β-adrenoreceptor activation. While this response ensures adequate cardiac output, there is evidence that chronic activation of β-adrenoreceptors can initiate maladaptive responses within contractile cells.

MANY agents, including drugs and alcohol, can cause rhabdomyopathy. 1 Alcoholic myopathy may have a varied presentation and is classified as acute, subacute, or chronic. 2-6 Acute or subacute alcoholic myopathy is related to the ingestion of excessive amounts of alcohol and generally characterized by diffuse or focal tenderness and muscle cramps. 2-6 The serum creatinine phosphokinase (CPK) activity is elevated, and muscle biopsy specimens frequently show a nonspecific pattern with degeneration and regeneration of muscle fibers. 2-7 Chronic alcoholic myopathy is characterized by proximal muscle weakness with minimal, nonspecific changes on muscle biopsy specimens. 2,3,5 Even in healthy volunteers receiving a nutritious diet supplemented with vitamins, 225 g of alcohol ingested daily for three weeks caused slight elevations in serum CPK activity and minimal but definite abnormalities on muscle biopsy specimens. 8 We present a case of a young man with a puzzling myopathy. After alengthy examination with nonspecific findings, a diagnostic alcohol challenge disclosed