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We present the case of a woman with a 2-month history of exertional dyspnoea and fatigue in which echocardiography revealed a cavity-obliterating right ventricular mass. Further imaging evaluation using cardiac magnetic resonance showed a thrombotic mass as well as diffuse myocardial oedema and endomyocardial fibrosis (EMF) that involved both ventricles. In the absence of any other cause (including peripheral eosinophilia), the diagnosis of idiopathic EMF was established. This case highlights this uncommon disease in non-tropical areas.

Evidence from human epidemiological studies suggests that exertional heat stroke (EHS) results in an elevated risk of long-term cardiovascular and systemic disease. Previous results using a preclinical mouse model of EHS demonstrated severe metabolic imbalances in ventricular myocardium developing at 9–14 days of recovery. Whether this resolves over time is unknown. We hypothesized that the long-term effects of EHS on the heart reflect retained maladaptive epigenetic responses. In this study, we evaluated genome-wide DNA methylation, RNA-Seq, and metabolomic profiles of the left ventricular myocardium in female C57BL/6 mice, 30 days after EHS (exercise in 37.5°C; n = 7–8), compared with exercise controls. EHS mice ran to loss of consciousness, reaching core temperatures of 42.4 ± 0.2°C. All mice recovered quickly. After 30 days, the left ventricles were rapidly frozen for DNA methyl sequencing, RNA-Seq, and untargeted metabolomics. Ventricular DNA from EHS mice revealed >13,000 differentially methylated cytosines (DMCs) and >900 differentially methylated regions (DMRs; ≥5 DMCs with ≤300 bp between each CpG). Pathway analysis using DMRs revealed alterations in genes regulating basic cell functions, DNA binding, transcription, and metabolism. Metabolomics and mRNA expression revealed modest changes that are consistent with a return to homeostasis. Methylation status did not predict RNA expression or metabolic state at 30 days. We conclude that EHS induces a sustained DNA methylation memory lasting over 30 days of recovery, but ventricular gene expression and metabolism return to a relative homeostasis at rest. Such long-lasting alterations to the DNA methylation landscape could alter responsiveness to environmental or clinical challenges later in life.

Stretch activation is defined as a delayed increase in force after rapid stretches. Although there is considerable evidence for stretch activation in isolated cardiac myofibrillar preparations, few studies have measured mechanisms of stretch activation in mammalian skeletal muscle fibers. We measured stretch activation following rapid step stretches [∼1%–4% sarcomere length (SL)] during submaximal Ca2+ activations of rat permeabilized slow-twitch skeletal muscle fibers before and after protein kinase A (PKA), which phosphorylates slow myosin binding protein-C. PKA significantly increased stretch activation during low (∼25%) Ca2+ activation and accelerated rates of delayed force development ( kef) during both low and half-maximal Ca2+ activation. Following the step stretches and subsequent force development, fibers were rapidly shortened to original sarcomere length, which often elicited a shortening-induced transient force overshoot. After PKA, step shortening-induced transient force overshoot increased ∼10-fold following an ∼4% SL shortening during low Ca2+ activation levels. kdf following step shortening also increased after PKA during low and half-maximal Ca2+ activations. We next investigated thin filament regulation of stretch activation. We tested the interplay between cardiac troponin I (cTnI) phosphorylation at the canonical PKA and novel tyrosine kinase sites on stretch activation. Native slow-skeletal Tn complexes were exchanged with recombinant human cTn complex with different human cTnI N-terminal pseudo-phosphorylation molecules: 1) nonphosphorylated wild type (WT), 2) the canonical S22/23D PKA sites, 3) the tyrosine kinase Y26E site, and 4) the combinatorial S22/23D + Y26E cTnI. All three pseudo-phosphorylated cTnIs elicited greater stretch activation than WT. Following stretch activation, a new, elevated stretch-induced steady-state force was reached with pseudo-phosphorylated cTnI. Combinatorial S22/23D + Y26E pseudo-phosphorylated cTnI increased kdf. These results suggest that slow-skeletal myosin binding protein-C (sMyBP-C) phosphorylation modulates stretch activation by a combination of cross-bridge recruitment and faster cycling kinetics, whereas cTnI phosphorylation regulates stretch activation by both redundant and synergistic mechanisms; and, taken together, these sarcomere phosphoproteins offer precision targets for enhanced contractility.

In a three-way blinded, randomized design, we determined whether allogeneic CDCs administered at reperfusion improved myocardial function and whether intravenous cyclosporine enhanced their efficacy. In contrast to prior studies using oral cyclosporine, CDCs with or without intravenous cyclosporine had no effect on function or infarct size. This indicates that CDCs may be most efficacious for treating chronic LV dysfunction where cyclosporine can be initiated at least 72 h before cell therapy.

Myocardial sleeves around pulmonary veins (PVs) are highly innervated structures with heterogeneous morphological and electrophysiological characteristics. Autonomic nerve dysfunction in the myocardium may be associated with an increased risk of cardiovascular morbidity and mortality. This article studied autonomic neural remodeling in myocardial sleeves around PVs and atrial-PV ostia with immunohistochemical and morphometric methods with clinicopathological correlations. PVs were collected from 37 and atrial-PV ostia from 17 human autopsy hearts. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth-associated protein 43 (GAP43). In the PV cohort, subjects with immediate cardiovascular cause of death had significantly decreased sympathetic nerve density in fibro-fatty tissue vs those with non-cardiovascular cause of death (1624.53 vs 2522.05 µm2/mm2, p=0.038). In the atrial-PV ostia cohort, parasympathetic nerve density in myocardial sleeves was significantly increased in subjects with underlying cardiovascular cause of death (19.48 µm2/mm2) than subjects with underlying non-cardiovascular cause of death with no parasympathetic nerves detected ( p=0.034). Neural growth regionally varied in sympathetic nerves and was present in most of the parasympathetic nerves. Heterogeneous autonomic nerve distribution and growth around PVs and atrial-PV ostia might play a role in cardiovascular morbidity and mortality. No association in nerve density was found with atrial fibrillation.

Positron Emission Tomography (PET) Myocardial Perfusion Imaging (MPI) is a robust diagnostic and prognostic test in patients with suspected or known coronary artery disease (CAD). We aimed to assess the incremental prognostic value of myocardial flow reserve (MFR) using the latest generation of digital PET scanners.Consecutive patients with clinically indicated PET MPI for suspected or known CAD were included. Myocardial blood flow (MBF) in ml/min/g was obtained from dynamic images at rest and peak hyperemia, and the myocardial flow reserve (MFR) was calculated as the ratio of stress to rest MBF. Patients were followed from the date of PET imaging for the occurrence of the primary outcome (composite of all-cause death, myocardial infarction, and Percutaneous Coronary Intervention or Coronary Artery Bypass Graft occurring90 days after imaging). Nested multivariable Cox regression models were used to assess the incremental prognostic role of MFR over traditional risk factors and PET relative perfusion parameters.The final cohort consisted of 3534 patients (mean age 67 ± 12 years, 48% female, 67% Caucasian, 53% obese, 55% hypertension, 32% diabetes, 42% dyslipidemia). During a median follow-up of 8.5 (3.0-15.4) months, 229 patients (6.5%, 6.4 per 1000 person-years) experienced the primary outcome. In nested multivariable Cox models, impaired MFR (MFR 2) was significantly associated with the primary outcome (HR 2.9, 95% CI 2.0-4.1, p 0.001) and significantly improved discrimination (Harrell's C 0.77, p = 0.002).MFR derived from digital PET scanners has an independent and incremental prognostic role in patients with suspected or known CAD.

Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts.Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified.The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues.Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

Cardiac involvement in Takayasu arteritis (TA) is the major cause of morbidity and mortality. Cardiovascular magnetic resonance (CMR) is an excellent modality for the assessment of myocardial involvement. Studies have shown myocardial involvement in 25%-27% of patients.To evaluate the prevalence and pattern of myocardial involvement in TA on CMR. We also evaluated any correlation between CMR changes and disease activity score (ITAS 2010 and ITAS-A) assessed at the time of CMR.Patients classified as Takayasu arteritis according to Sharma et al. criteria were enrolled in the study. Demographic, clinical, and laboratory data were documented in the predesigned proforma. CMR was performed on a dedicated cardiac 3Tesla MR machine. Disease activity was recorded by ITAS2010 and ITAS-A.A total of 37 TA patients were included. Mean (±SD) age was 29±11 years. Female to male ratio was 3:1. Five patients (14%) had myocardial involvement on CMR. Two (2/5) had myocarditis and three (3/5) patients had features of ischaemic myocardial fibrosis.The myocardium is affected in TA, however the prevalence of subclinical myocardial involvement in our study was less (8% vs. 25%-27%) compared to the previous studies. Myocardial involvement trends towards early age of onset, less disease duration, lack of classical risk factors, and more with disease activity.

Excessive cardiac fibrosis is central to adverse cardiac remodeling and dysfunction leading to heart failure in many cardiac diseases. Histone methylation plays a crucial role in various pathophysiological events. However, the role of histone methylation modification enzymes in pathological cardiac fibrosis needs to be fully elucidated. Here, we identified lysine demethylase 5B (KDM5B), a histone H3K4me2/me3 demethylase, as a key epigenetic mediator of pathological cardiac fibrosis. KDM5B expression was upregulated in cardiac fibroblasts and myocardial tissues in response to pathological stress. KDM5B deficiency markedly ameliorated cardiac fibrosis, improved cardiac function, and prevented adverse cardiac remodeling following myocardial infarction (MI) or pressure overload. KDM5B knockout or inhibitor treatment constrained the transition of cardiac fibroblasts to profibrogenic myofibroblasts and suppressed fibrotic responses. KDM5B deficiency also facilitated the transformation of cardiac fibroblasts to endothelial-like cells and promoted angiogenesis in response to myocardial injury. Mechanistically, KDM5B bound to the promoter of activating transcription factor 3 (Atf3), an antifibrotic regulator of cardiac fibrosis, and inhibited ATF3 expression by demethylating the activated H3K4me2/3 modification, leading to the enhanced activation of TGF-β signaling and excessive expression of profibrotic genes. Our study indicates that KDM5B drives pathological cardiac fibrosis and represents a candidate target for intervention in cardiac dysfunction and heart failure.

Background: RBPs (RNA-binding proteins) perform indispensable functions in the post-transcriptional regulation of gene expression. Numerous RBPs have been implicated in cardiac development or physiology based on gene knockout studies and the identification of pathogenic RBP gene mutations in monogenic heart disorders. The discovery and characterization of additional RBPs performing indispensable functions in the heart will advance basic and translational cardiovascular research. Methods: We performed a differential expression screen in zebrafish embryos to identify genes enriched in nkx2.5 -positive cardiomyocytes or cardiopharyngeal progenitors compared to nkx2.5 -negative cells from the same embryos. We investigated the myocardial-enriched gene RNA-binding protein with multiple splicing (variants) 2 [ RBPMS2 )] by generating and characterizing rbpms2 knockout zebrafish and human cardiomyocytes derived from RBPMS2 -deficient induced pluripotent stem cells. Results: We identified 1848 genes enriched in the nkx2.5 -positive population. Among the most highly enriched genes, most with well-established functions in the heart, we discovered the ohnologs rbpms2a and rbpms2b , which encode an evolutionarily conserved RBP. Rbpms2 localizes selectively to cardiomyocytes during zebrafish heart development and strong cardiomyocyte expression persists into adulthood. Rbpms2-deficient embryos suffer from early cardiac dysfunction characterized by reduced ejection fraction. The functional deficit is accompanied by myofibril disarray, altered calcium handling, and differential alternative splicing events in mutant cardiomyocytes. These phenotypes are also observed in RBPMS2-deficient human cardiomyocytes, indicative of conserved molecular and cellular function. RNA-sequencing and comparative analysis of genes mis-spliced in RBPMS2-deficient zebrafish and human cardiomyocytes uncovered a conserved network of 29 ortholog pairs that require RBPMS2 for alternative splicing regulation, including RBFOX2, SLC8A1 , and MYBPC3 . Conclusions: Our study identifies RBPMS2 as a conserved regulator of alternative splicing, myofibrillar organization, and calcium handling in zebrafish and human cardiomyocytes.

Evidence suggests that hearts that are perfused under ex-situ conditions lose normal coronary vasomotor tone and experience contractile failure over a few hours. We aimed to evaluate the effect of different coronary perfusion strategies during ex situ heart perfusion on cardiac function and coronary vascular tone.Porcine hearts (n = 6 each group) were perfused in working mode for 6 hours with either constant aortic diastolic pressure (40 mmHg) or constant coronary flow rate (500 mL/min). Functional and metabolic parameters, cytokine profiles, cardiac and vascular injury, coronary artery function and oxidative stress were compared between groups.Constant coronary flow perfusion demonstrated better functional preservation and less edema formation (Cardiac index: flow control = 8.33 vs pressure control = 6.46 mL·minA strategy of controlled coronary flow during ex situ heart perfusion provides superior functional preservation and less edema formation, together with less myocardial damage, leukocyte, platelet, endothelial activation, and oxidative stress. There was loss of coronary autoregulation and decrease of coronary vascular resistance during ESHP irrespective of coronary flow control strategy. Inflammation and oxidative stress state in the coronary vasculature may play a role.

Patients undergoing explantation of left ventricular assist devices (LVADs) after improvement of myocardial function remain a minority. Nevertheless, considering the growing population of LVAD patients, increasing demand for new explantation strategies is expected. Herein, we present a retrospective review of seven patients undergoing HeartMate3 explantation with the use of a custom-made apical ring plug in four medical centers. The primary outcome was status at intensive care unit discharge. Secondary outcomes included perioperative complications and transfusions. Six out of seven patients were males. The median age at explantation and time on LVAD support was 35 years (range:13-73) and 10 months (range:9-24), respectively. No technical difficulties were experienced during plug implantation via a conventional sternotomy or through a left lateral thoracotomy, either with or without cardiopulmonary bypass. Perioperative transfusions ranged from 0 to 3 units/patient. No re-operations for bleeding, hemorrhagic, embolic, or plug-related infective events were observed. Heparin was started 6 hours after surgery as a bridge to oral anticoagulation (international normalized ratio: 2-2.5). All patients were discharged alive from intensive care unit. This novel plug device for HeartMate3 explantation was successfully and safely implanted in this first patient series. Notwithstanding, its use should still be considered off-label and larger studies are required to investigate its long-term results.

Boiling histotripsy (BH) is a mechanical tissue liquefaction method that uses sequences of millisecond-long high intensity focused ultrasound (HIFU) pulses with shock fronts. The BH treatment generates bubbles that move within the sonicated volume due to acoustic radiation force. Since the velocity of the bubbles and tissue debris is expected to depend on the lesion size and liquefaction completeness, it could provide a quantitative metric of the treatment progression. In this study, the motion of bubble remnants and tissue debris immediately following BH pulses was investigated using high-pulse repetition frequency (PRF) plane-wave color Doppler ultrasound in ex vivo myocardium tissue. A 256-element 1.5 MHz spiral HIFU array with a coaxially integrated ultrasound imaging probe (ATL P4-2) produced 10 ms BH pulses to form volumetric lesions with electronic beam steering. Prior to performing volumetric BH treatments, the motion of intact myocardium tissue and anticoagulated bovine blood following isolated BH pulses was assessed as two limiting cases. In the liquid blood the velocity of BH-induced streaming at the focus reached over 200 cm/s, whereas the intact tissue was observed to move toward the HIFU array consistent with elastic rebound of tissue. Over the course of volumetric BH treatments tissue motion at the focus locations was dependent on the axial size of the forming lesion relative to the corresponding size of the HIFU focal area. For axially small lesions, the maximum velocity after the BH pulse was directed toward the HIFU transducer and monotonically increased over time from about 20-100 cm/s as liquefaction progressed, then saturated when tissue was fully liquefied. For larger lesions obtained by merging multiple smaller lesions in the axial direction, the high-speed streaming away from the HIFU transducer was observed at the point of full liquefaction. Based on these observations, the maximum directional velocity and its location along the HIFU propagation axis were proposed and evaluated as candidate metrics of BH treatment completeness.

Ischemic heart disease, a major risk factor for myocardial infarction (MI), occurs when the blood vessels supplying oxygen-rich blood to the heart become partially or fully occluded by lipid-rich plaques, resulting in myocardial cell death, remodeling, and scarring. In addition, MI occurs as result of lipid-rich plaque rupture, resulting in thrombosis and vessel occlusion. Cardiac fibroblasts (CFs) and CF-derived growth factors are crucial post-MI in myocardial remodeling. Information regarding the regenerative phenotypes of CFs is scarce; however, regenerative CFs are translationally relevant in myocardial regeneration following MI. The emerging technologies in regenerative cardiology offer cutting-edge translational opportunities, including synthetic cells. In this review, we critically reviewed the current knowledge and the ongoing research efforts on application of synthetic cells for improving cardiac regeneration post-MI. Impact statement Synthetic cells offer tremendous regenerative potential in otherwise deleterious cardiac remodeling postmyocardial infarction. Understanding the role of fibroblasts in cardiac healing and the therapeutic applications of synthetic cells would open a multitude of novel cardiac regenerative approaches. The novel concept of synthetic fibroblasts that emulate native cardiac fibroblasts can provide an effective solution in cardiac healing.

Myocardial ischemic injury and its resolution are the key determinants of morbidity or mortality in heart failure. The cause and duration of ischemia in patients vary. Numerous experimental models and methods have been developed to define genetic, metabolic, molecular, cellular, and pathophysiological mechanisms, in addition to defining structural and functional deterioration of cardiovascular performance. The rapid rise of big data, such as single-cell analysis techniques with bioinformatics, machine learning, and neural networking, brings a new level of sophistication to our understanding of myocardial ischemia. This mini-review explores the multifaceted nature of ischemic injury in the myocardium. We highlight recent state-of-the-art findings and strategies to show new directions of high-impact approach to understanding myocardial tissue remodeling. This next age of heart and circulatory physiology research will be more comprehensive and collaborative to uncover the origin, progression, and manifestation of heart failure while strengthening novel treatment strategies.

The study was aimed at understanding the nature and pattern of serum lactate, cardiac troponin I changes associated with acute Trypanosoma brucei infection of dogs. It also seeks to investigate the usefulness of these biomarkers in monitoring disease progression and predicting mortality. Twenty healthy adult dogs of both sexes were used for the study. All the dogs were intra-peritoneally inoculated with 1ml of phosphate buffered saline diluted blood containing 1x106 of Lafenwa strain of T. brucei. The serum lactate, cardiac troponin I, potassium, sodium, chloride and bicarbonate were monitored before and at 16 and 24 days after infection. There was a progressive increase in serum values of lactate, cardiac troponin I and potassium at various days after infection. A significant association was found between lactate and heart rate, chloride and heart rate, potassium and cardiac troponin I. This result has shown that there could be myocardial damage due to hypoxia of anemia and hypo-perfusion in canine African trypanosomiasis. The progressive increase in serum lactate and cardiac troponin I could help in predicting severity and outcome of Canine African Trypanosomiasis. The Lactic acidosis may increase ventilation drive and consequently the heart rates of infected dogs.

This study aims to determine the differences in myocardial enzymes in COVID-19 patients with and without hypertension. A total of 130 patients with COVID-19 in Yunmeng County People's Hospital were analyzed. The clinical manifestations and laboratory indicators were collected and analyzed. We found that COVID-19 patients with hypertension had higher mortality rate, greater age, and higher rates of basic disease such as diabetes than patients without hypertension. The γ-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), albumin/globulin (A/G), Ca, Mg, lactate dehydrogenase (LDH), and α-hydroxybutyric-dehydrogenase (α-HBD) levels in COVID-19 patients with hypertension were higher than in COVID-19 patients without hypertension. We found that the predictive effect of the creatine kinase isoenzyme (CK-MB), LDH-L, and α-HBD levels in the COVID-19 patients without hypertension were higher than in COVID-19 patients with hypertension. We used the ROC curve model to predict whether patients would have hypertension, and we found that CK-MB, LDH-L and HBD parameters could distinguish the COVID-19 patients with hypertension and non-hypertension, and could predict the mortality of COVID-19 patients.

Myocardial scar correlates with clinical outcomes. Traditionally, late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is used to detect and quantify scar. In this prospective study using LGE CMR as reference, the authors hypothesized that nonlinear ultrasound imaging, namely, power modulation, can detect and quantify myocardial scar in selected patients with previous myocardial infarction. In addition, given the different histopathology between ischemic and nonischemic scar, a further aim was to test the diagnostic performance of this echocardiographic technique in unselected consecutive individuals with ischemic and nonischemic LGE or no LGE on CMR.Seventy-one patients with previous myocardial infarction underwent power modulation echocardiography following CMR imaging (group A). Subsequently, 101 consecutive patients with or without LGE on CMR, including individuals with nonischemic LGE, were scanned using power modulation echocardiography (group B).In group A, echocardiography detected myocardial scar in all 71 patients, with good scar volume agreement with CMR (bias = -1.9 cmsup3/sup; limits of agreement [LOA], -8.0 to 4.2 cmsup3/sup). On a per-segment basis, sensitivity was 82%, specificity 97%, and accuracy 92%. Sensitivity was higher in the inferior and posterior segments and lower in the anterior and lateral walls. In group B, on a per-subject basis, the sensitivity of echocardiography was 62% (91% for ischemic and 30% for nonischemic LGE), with specificity and accuracy of 89% and 72%, respectively. The bias for scar volume between modalities was 5.9 cmsup3/sup, with LOA of 34.6 to 22.9 cmsup3/sup(bias = -1.9 cmsup3/sup[LOA, -11.4 to 7.6 cmsup3/sup] for ischemic LGE, and bias = 18.9 cmsup3/sup[LOA, -67.4 to 29.7.6 cmsup3/sup] for nonischemic LGE).Power modulation echocardiography can detect myocardial scar in both selected and unselected individuals with previous myocardial infarction and has good agreement for scar volume quantification with CMR. In an unselected cohort with nonischemic LGE, sensitivity is low.

The effect of blocking the persistent component of the sodium channel current (late I

Acute myocarditis is a rare complication of mRNA-based COVID-19 vaccination. Little is known about the natural history of this complication.Baseline and convalescent (≥ 90 days) cardiac magnetic resonance (CMR) imaging assessments were performed in 20 consecutive patients meeting Updated Lake Louise Criteria for acute myocarditis within 10 days of mRNA-based vaccination. CMR-based changes in left ventricular volumes, mass, ejection fraction (LVEF), markers of tissue inflammation (native T1 and T2 mapping), and fibrosis (late gadolinium enhancement [LGE] and extracellular volume [ECV]) were assessed between baseline and convalescence. Cardiac symptoms and clinical outcomes were captured.Median age was 23.1 years (range 18-39 years), and 17 (85%) were male. Convalescent evaluations were performed at a median (IQR) 3.7 (3.3-6.2) months. The LVEF showed a mean 3% absolute improvement, accompanied by a 7% reduction in LV end-diastolic volume and 5% reduction in LV mass (all P0.015). Global LGE burden was reduced by 66% (P0.001). Absolute reductions in global T2, native T1, and ECV of 2.1 ms, 58 ms, and 2.9%, repectively, were documented (all P ≤ 0.001). Of 5 patients demonstrating LVEF ≤ 50% at baseline, all recovered to above this threshold in convalescence. A total of 18 (90%) patients showed persistence of abnormal LGE although mean fibrosis burden was5% of LV mass in 85% of cases. No patient experienced major clinical outcomes.COVID-19 mRNA vaccine-associated myocarditis showed rapid improvements in CMR-based markers of edema, contractile function, and global LGE burden beyond 3 months of recovery in this young patient cohort. However, regional fibrosis following edema resolution was commonly observed, justifying need for ongoing surveillance.

Alteration in myocardial tissue, such as myocardial fibrosis, edema, inflammation, or accumulation with amyloid, lipids, or iron, has an important role in the cardiac remodeling that leads to diastolic and/or systolic dysfunction and the development of chronic heart failure, increasing the risk of adverse cardiovascular events. Thus, the early detection of changes at myocardial tissue level has great diagnostic and prognostic potential. The gold standard technique to assess these myocardial alterations is endomyocardial biopsy. However, this has been limited to a few patients due to the invasive nature, sampling errors, and its inability to assess the entire myocardium. Cardiovascular magnetic resonance (CMR) has emerged as the gold standard imaging not only for assessing cardiac volume, function quantification, and viability but also for noninvasive myocardial tissue characterization over the past decade. Its ability to characterize myocardial tissue composition is unique among noninvasive imaging modalities in cardiovascular disease. Currently, multi-parametric myocardial characterization with T1, T2, and extracellular volume has the potential to identify and track diffuse pathology in various diseases. In this review article, we present the role of established and emerging CMR techniques in myocardial tissue characterization, with an emphasis on T1 and T2 mapping, in clinical practice.

Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high and have trended upwards over the last few years. Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus. G protein-coupled receptors (GPCRs) are critical myocardial signal transducers which regulate cardiac contractility, growth, adaptation and metabolism. Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target these receptors. Currently-approved treatments have improved patient outcomes, but therapies to stop or reverse HF are lacking. A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target for combating HF. Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD. Additionally, the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted with a high level of specificity unique to various cardiac pathologies. These data support the premise that GRK2 should be at the forefront of a novel investigative drug search. This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase across cellular, animal and human models of cardiac dysfunction and HF.

Cardiac involvement in recovered COVID-19 patients assessed by cardiac magnetic resonance imaging (MRI).Subjects recently recovered from COVID-19 and with an abnormal left ventricular global longitudinal strain were enrolled. Cardiac MRI in all the enrolled subjects was done at baseline (within 30-90 days following recovery from COVID-19) with a follow-up scan at 6 months in individuals with an abnormal baseline scan. Additionally, 20 age-and sex-matched individuals were enrolled as healthy controls (HCs).All the 30 enrolled subjects were symptomatic during active COVID-19 disease and were categorized as mild: 11 (36.7%), moderate: 6 (20%), and severe: 13 (43.3%). Of the 30 patients, 16 (53.3%) had abnormal CMR findings. Myocardial edema was reported in 12 (40%) patients while 10 (33.3%) had late gadolinium enhancement (LGE). No difference was observed in terms of conventional left ventricular (LV) parameters; however, COVID-19-recovered patients had significantly lower right ventricular (RV) ejection fraction, RV stroke volume, and RV cardiac index compared to HCs. Follow-up scan was abnormal in 4/16 (25%) with LGE persisting in three patients (who had severe COVID-19 [3/4;75%]). Subjects with severe COVID-19 had a greater frequency of LGE (53.8%) and myocardial edema (61.5%) as compared to mild and moderate cases. Myocardial T1 (1284 ± 43.8 ms vs. 1147.6 ± 68.4 ms; p lt; .0001) and T2 values (50.8 ± 16.7 ms vs. 42.6 ± 3.6 ms; p = .04) were significantly higher in post COVID-19 subjects compared to HCs. Similarly, T1 and T2 values of severe COVID-19 patients were significantly higher compared to mild and moderate cases.An abnormal CMR was seen in half of the recovered patients with persistent abnormality in one-fourth at 6 months. Our study suggests a need for closer follow-up among recovered subjects in order to evaluate for long-term cardiovascular sequelae. COVID-19 causes structural changes in the myocardium in a small segment of patients with partial spontaneous resolution.

Sepsis remains a complicated and incompletely understood syndrome, and myocardial dysfunction is one of the main complications contributing to poor clinical outcomes. Accumulating evidence has revealed the critical involvement of the deregulated expression of specific microRNAs (miRNAs) in cardiac pathologies caused by sepsis. Intriguingly, miR-377 has been correlated with cardiomyocyte apoptosis, whereas its effect on myocardial hypertrophy remains to be illustrated. Thus, the current study sets out to explore the impact and underlying mechanism of miR-377 on myocardial hypertrophy induced by sepsis. The expression pattern of miR-377 was detected in myocardial tissues of septic mice induced by cecal ligation-perforation (CLP). We found that miR-377 was highly expressed in myocardial tissues of CLP-induced septic mice with cardiomyocyte hypertrophy. Besides, miR-377 inhibition could relieve cardiomyocyte hypertrophy and reduce inflammation in septic mice. Further, mechanistic studies found that miR-377 could target Rcan2 and then regulate calcineurin (CaN) activity via Ca2+/CaN signaling pathway. Collectively, our findings illuminate that miR-377 enhances myocardial hypertrophy caused by sepsis, by targeting Rcan2 and further regulating the Ca2+/CaN signaling pathway. This work highlights downregulation of miR-377 as a novel target for the management of sepsis-induced myocardial hypertrophy.

Aims In response to pro-fibrotic signals, scleraxis regulates cardiac fibroblast activation in vitro via transcriptional control of key fibrosis genes such as collagen and fibronectin; however, its role in vivo is unknown. The present study assessed the impact of scleraxis loss on fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced heart failure. Methods and results Scleraxis expression was upregulated in the hearts of non-ischemic dilated cardiomyopathy patients, and in mice subjected to pressure overload by transverse aortic constriction (TAC). Tamoxifen-inducible fibroblast-specific scleraxis knockout (Scx-fKO) completely attenuated cardiac fibrosis, and significantly improved cardiac systolic function and ventricular remodelling, following TAC compared to Scx+/+ TAC mice, concomitant with attenuation of fibroblast activation. Scleraxis deletion, after the establishment of cardiac fibrosis, attenuated the further functional decline observed in Scx+/+ mice, with a reduction in cardiac myofibroblasts. Notably, scleraxis knockout reduced pressure overload-induced mortality from 33% to zero, without affecting the degree of cardiac hypertrophy. Scleraxis directly regulated transcription of the myofibroblast marker periostin, and cardiac fibroblasts lacking scleraxis failed to upregulate periostin synthesis and secretion in response to pro-fibrotic transforming growth factor β. Conclusion Scleraxis governs fibroblast activation in pressure overload-induced heart failure, and scleraxis knockout attenuated fibrosis and improved cardiac function and survival. These findings identify scleraxis as a viable target for the development of novel anti-fibrotic treatments.

Although hydrogel-based patches have shown promising therapeutic efficacy in myocardial infarction (MI), synergistic mechanical, electrical, and biological cues are required to restore cardiac electrical conduction and diastolic-systolic function. Here, an injectable mechanical-electrical coupling hydrogel patch (MEHP) is developed via dynamic covalent/noncovalent cross-linking, appropriate for cell encapsulation and minimally invasive implantation into the pericardial cavity. Pericardial fixation and hydrogel self-adhesiveness properties enable the MEHP to highly compliant interfacial coupling with cyclically deformed myocardium. The self-adaptive MEHP inhibits ventricular dilation while assisting cardiac pulsatile function. The MEHP with the electrical conductivity and sensitivity to match myocardial tissue improves electrical connectivity between healthy and infarcted areas and increases electrical conduction velocity and synchronization. Overall, the MEHP combined with cell therapy effectively prevents ventricular fibrosis and remodeling, promotes neovascularization, and restores electrical propagation and synchronized pulsation, facilitating the clinical translation of cardiac tissue engineering.

Convolutional neural networks (CNN) have demonstrated their ability to segment 2D cardiac ultrasound images. However, despite recent successes according to which the intra-observer variability on end-diastole and end-systole images has been reached, CNNs still struggle to leverage temporal information to provide accurate and temporally consistent segmentation maps across the whole cycle. Such consistency is required to accurately describe the cardiac function, a necessary step in diagnosing many cardiovascular diseases. In this paper, we propose a framework to learn the 2D+time apical long-axis cardiac shape such that the segmented sequences can benefit from temporal and anatomical consistency constraints. Our method is a post-processing that takes as input segmented echocardiographic sequences produced by any state-of-the-art method and processes it in two steps to (i) identify spatio-temporal inconsistencies according to the overall dynamics of the cardiac sequence and (ii) correct the inconsistencies. The identification and correction of cardiac inconsistencies relies on a constrained autoencoder trained to learn a physiologically interpretable embedding of cardiac shapes, where we can both detect and fix anomalies. We tested our framework on 98 full-cycle sequences from the CAMUS dataset, which are available alongside this paper. Our temporal regularization method not only improves the accuracy of the segmentation across the whole sequences, but also enforces temporal and anatomical consistency., 12 pages, accepted for publication in IEEE TMI

TGF-βs regulate macrophage responses, by activating Smad2/3. We have previously demonstrated that macrophage-specific Smad3 stimulates phagocytosis and mediates anti-inflammatory macrophage transition in the infarcted heart. However, the role of macrophage Smad2 signaling in myocardial infarction remains unknown. We studied the role of macrophage-specific Smad2 signaling in healing mouse infarcts, and we explored the basis for the distinct effects of Smad2 and Smad3. In infarct macrophages, Smad3 activation preceded Smad2 activation. In contrast to the effects of Smad3 loss, myeloid cell-specific Smad2 disruption had no effects on mortality, ventricular dysfunction and adverse remodeling, after myocardial infarction. Macrophage Smad2 loss modestly, but transiently increased myofibroblast density in the infarct, but did not affect phagocytic removal of dead cells, macrophage infiltration, collagen deposition, and scar remodeling. In isolated macrophages, TGF-β1, -β2 and -β3, activated both Smad2 and Smad3, whereas BMP6 triggered only Smad3 activation. Smad2 and Smad3 had similar patterns of nuclear translocation in response to TGF-β1. RNA-sequencing showed that Smad3, and not Smad2, was the main mediator of transcriptional effects of TGF-β on macrophages. Smad3 loss resulted in differential expression of genes associated with RAR/RXR signaling, cholesterol biosynthesis and lipid metabolism. In both isolated bone marrow-derived macrophages and in infarct macrophages, Smad3 mediated synthesis of Nr1d2 and Rara, two genes encoding nuclear receptors, that may be involved in regulation of their phagocytic and anti-inflammatory properties. In conclusion, the in vivo and in vitro effects of TGF-β on macrophage function involve Smad3, and not Smad2.

BACKGROUND: Postoperative myocardial injury (PMI) after major vascular surgery, detected by elevated cardiac troponin (cTn), has been associated with morbidity and mortality. It is unclear whether the pathophysiology of PMI is determined by increased platelet activity.OBJECTIVE: To examine the relationship between platelet activation (P-selectin expression) and PMI in patients undergoing elective open abdominal aortic surgery.METHODS: This prospective, single-centre, observational, cohort study included 33 patients undergoing elective open abdominal aortic surgery between March 2018 and April 2021. Patients were routinely treated with aspirin. Unstimulated platelet activation was measured by platelet bound P-selectin expression (range 0-100 %). Explorative coagulation measurements were: stimulated platelet aggregation measured with the VerifyNow® assay (aspirin cartridge), with the Multiplate® analyzer (ASPI, ADP and TRAP) and stimulated coagulation status evaluated by the TEG® Hemostasis Analyzer System (global hemostasis cartridge). The primary outcome was cTn release assessed by the fifth generation high-sensitive cTn assay. Multivariable generalized linear mixed models were used to evaluate the association between platelet function and cTn concentrations over time.RESULTS: Ten patients (30.3 %) developed PMI. Increased P-selectin expression directly after surgery was associated with the cTn concentrations over 48 h (β = 1.39 (1.1-1.75), P = 0.0064). No association was found between P-selectin measured later after surgery (at 24 h or 48 h) and cTn concentrations. Furthermore, there was no association between the explorative coagulation parameters and cTn release.CONCLUSION: Platelet reactivity, assessed by P-selectin expression measured directly after surgery is associated with PMI, assessed by elevated cTn concentrations in the early postoperative period in patients undergoing elective open abdominal aortic surgery.

Cardiovascular involvement is a common complication of COVID-19 infection and is associated to increased risk of unfavorable outcome. Advanced imaging modalities (coronary CT angiography and Cardiac Magnetic Resonance) play a crucial role in the diagnosis, follow-up and risk stratification of patients affected by COVID-19 pneumonia with suspected cardiovascular involvement. In the present manuscript we firstly review current knowledge on the mechanisms by which SARS-CoV-2 can trigger endothelial and myocardial damage. Secondly, the implications of the cardiovascular damage on patient's prognosis are presented. Finally, we provide an overview of the main findings at advanced cardiac imaging characterizing COVID-19 in the acute setting, in the post-acute syndrome, and after vaccination, emphasizing the potentiality of CT and CMR, the indication and their clinical implications.

Clinical and prognostic role of cardiac magnetic resonance (CMR) in adult population with hypertrophic cardiomyopathy (HCM) have been largely assessed. We sought to investigate the role of CMR for predicting cardiovascular events in children with HCM.CMR was performed in 116 patients with HCM (37 sarcomeric mutations, 31 other mutations, mean age 10.4 ± 4.3 yrs). CMR protocol included cine imaging for evaluation of morphology and function and late gadolinium enhancement (LGE). Hard cardiac events (sustained VT, resuscitated cardiac arrest, sudden cardiac death, end-stage heart failure, heart transplant and appropriate ICD intervention) were recorded through a median follow-up of 4 (1-7) years.During follow-up 21 heart cardiac events occurred. At maximal-rank statistic the optimal cut-point for LGE extent for predicting events was ≥2%. Syncope, non-sustained ventricular tachycardia (NSVT) and LGE extent ≥2% were independent predictors of events. At Harrel's C statistic combination of LGE extent ≥2% and syncope was the strongest model for predicting events. HR of patients with LGE extent ≥2% and no history of syncope was 3.6 (1.1-12.2) that increased to 37.6 (5.4-161) in those with LGE extent ≥2% and syncope. The median time dependent AUC of LGE extent (0.88, 95% CI 0.86-0.89) was significantly higher than that of syncope (0.63, 95% CI 0.61-0.66, p 0.0001) and NSVT (0.52, 95% CI 0.50-0.53, p 0.0001).In children with HCM, LGE and syncope were independent predictors of hard cardiac events at follow-up.

Late gadolinium enhanced cardiac magnetic resonance (LGE-CMR) imaging may help identify radiofrequency ablation lesions, which have been poorly described in patients with nonischemic cardiomyopathy (NICM).The purpose of this study was to describe LGE-CMR characteristics of ablation lesions in patients with NICM and correlate them with histopathology.Twenty-six patients (24 men; ejection fraction 38% ± 14%; age 61 ± 9 years) who had undergone CMR imaging after ventricular tachycardia (VT) ablation were included. Areas of both dark and bright core lesions correlating with previous radiofrequency ablation lesions were identified. Histology was performed on an explanted heart.Mean time between the ablation procedure and the LGE-CMR study was 8 [2-20] months. Twenty-three of 26 patients demonstrated dark core lesions (volume 2.16 ± 1.8 cmAblation lesions can be detected by LGE-CMR after VT ablation in NICM patients and have a different appearance than scar tissue. These lesions can be observed in the acute and chronic settings after ablations.

Congenital heart defects are the leading cause of right heart failure in pediatric patients. Implantation of c-kitsup+/supcardiac-derived progenitor cells (CPCs) is being clinically evaluated to treat the failing right ventricle (RV), but faces limitations due to reduced transplant cell survival, low engraftment rates, and low retention. These limitations have been exacerbated due to the nature of cell delivery (narrow needles) and the non-optimal recipient microenvironment (reactive oxygen species (ROS)). Extracellular matrix (ECM) hydrogels derived from porcine left ventricular (LV) myocardium have emerged as a potential therapy to treat the ischemic LV and have shown promise as a vehicle to deliver cells to injured myocardium. However, no studies have evaluated the combination of an injectable biomaterial, such as an ECM hydrogel, in combination with cell therapy for treating RV failure. In this study we characterized LV and RV myocardial matrix (MM) hydrogels and performed in vitro evaluations of their potential to enhance CPC delivery, including resistance to forces experienced during injection and exposure to ROS, as well as their potential to enhance angiogenic paracrine signaling. While physical properties of the two hydrogels are similar, the decellularized LV and RV have distinct protein signatures. Both materials were equally effective in protecting CPCs against needle forces and ROS. CPCs encapsulated in either the LV MM or RV MM exhibited similar enhanced potential for angiogenic paracrine signaling when compared to CPCs in collagen. The RV MM without cells, however, likewise improved tube formation, suggesting it should also be evaluated as a potential standalone treatment.

Background To improve myocardial delayed enhancement (MDE) CT, a deep learning (DL)-based post hoc denoising method supervised with averaged MDE CT data was developed. Purpose To assess the image quality of denoised MDE CT images and evaluate their diagnostic performance by using late gadolinium enhancement (LGE) MRI as a reference. Materials and methods MDE CT data obtained by averaging three acquisitions with a single breath hold 5 minutes after the contrast material injection in patients from July 2020 to October 2021 were retrospectively reviewed. Preaveraged images obtained in 100 patients as inputs and averaged images as ground truths were used to supervise a residual dense network (RDN). The original single-shot image, standard averaged image, RDN-denoised original (DL

Aims Left ventricular non-compaction cardiomyopathy (LVNC) is a poorly understood entity resulting in heart failure. Whether it is a distinct form of cardiomyopathy or an anatomical phenotype is a subject of discussion. The current diagnosis is based on morphologic findings by comparing the compacted to non-compacted myocardium. The study aimed to compare demographic and prognostic variables of patients with dilated cardiomyopathy (DCM) and LVNC. Emphasis was given to cardiac magnetic resonance (CMR) imaging analysis. Data on survival were also assessed. Methods and results We retrospectively evaluated the characteristics and outcomes of 262 non-ischaemic cardiomyopathy patients with LVNC and DCM phenotypes. Petersen's CMR criteria of non-compacted to the compacted myocardial ratio 2.3 were used to diagnose LVNC. The primary endpoint was a composite endpoint of major adverse cardiovascular events comprising cardiovascular-related death, left ventricular assisted device implantation, or heart transplantation. A total of 262 patients with CMR data were included in the study. One hundred fifty-five patients who fulfilled CMR criteria were diagnosed as LVNC. CMR findings revealed that LVNC patients had higher left ventricular end-diastolic (137.2 +/- 51.6, 116.8 +/- 44.6, P = 0.002) and systolic volume index (98.4 +/- 49.5, 85.9 +/- 42.7, P = 0.049). Cardiac haemodynamics, cardiac output (5.61 +/- 2.03, 4.96 +/- 1.83; P = 0.010), stroke volume (73.9 +/- 28.8, 65.1 +/- 25.1; P = 0.013), and cardiac index (2.85 +/- 1.0, 2.37 +/- 0.72; P < 0.0001), were higher in LVNC patients. Of all the 249 patients, 102 (40.9%) patients demonstrated late gadolinium enhancement (LGE). According to Petersen's criteria, the Kaplan-Meier survival outcome did not reveal significant differences (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: [0.89-2.63], P = 0.11). The presence or pattern of LGE did not show significant importance for endpoint-free survival. Most of the sub-epicardial LGE pattern was found in LVNC patients (94.4%). When receiver operator characteristics analysis was applied to NC/C ratio to discriminate the primary endpoint, a higher NC/C ratio of 2.57 was associated with adverse events (HR: 1.90, 95% CI: [1.12-3.24], P = 0.016). Conclusions Our study questions the criteria being used for the diagnosis of LVNC. Further evaluation of CMR variables and association of these findings with demographic variables and survival is mandatory.

Recent reports confirmed the notion that there exists a rudimentary cardiac conduction system (CCS) in the crocodylian heart, and development of its ventricular part is linked to septation. We thus analyzed myocardial development with the emphasis on the CCS components and vascularization in two different crocodylian species.Using optical mapping and HNK-1 immunostaining, pacemaker activity was localized to the right-sided sinus venosus. The atrioventricular conduction was restricted to dorsal part of the atrioventricular canal. Within the ventricle, the impulse was propagated from base-to-apex initially by the trabeculae, later by the ventricular septum, in which strands of HNK-1 positivity were temporarily observed. Completion of ventricular septation correlated with transition of ventricular epicardial activation pattern to mature apex-to-base direction from two periapical foci. Despite a gradual thickening of the ventricular wall, no morphological differentiation of the Purkinje network was observed. Thin-walled coronary vessels with endothelium positive for QH1 obtained a smooth muscle coat after septation. Intramyocardial vessels were abundant especially in the rapidly thickening left ventricular wall.Most of the CCS components present in the homeiotherm hearts can be identified in the developing crocodylian heart, with a notable exception of the Purkinje network distinct from the trabeculae carneae.

Angiopoietin-like protein 2 (ANGPTL2) plays versatile roles in various cardiovascular diseases. Its connection to doxorubicin (DOX)-related cardiomyopathy, however, remains elusive. To determine the role of ANGPTL2, an adeno-associated viral vector was used to overexpress ANGPTL2 in the murine heart 4 weeks before DOX treatment (15 mg/kg). Moreover, mice were injected with adenoviral vectors to knock down ANGPTL2 in the myocardium. Echocardiography and hemodynamics were used to determine the cardiac function. The effect of ANGPTL2 and its downstream target were elucidated by applying molecular and biochemical strategies. We found that ANGPTL2 expression was significantly increased in response to DOX stimulation. Moreover, cardiac-specific ANGPTL2 overexpression exacerbated DOX-related cardiac dysfunction, myocardial apoptosis, and oxidative stress. Mechanistically, ANGPTL2 aggravated DOX-induced cardiac injury via inhibiting the dual specificity phosphatase 1 (DUSP1) pathway and DUSP1 overexpression significantly impeded DOX-induced cardiomyopathy in ANGPTL2-overexpressed mice. Altogether, ANGPTL2 aggravated DOX-related cardiac injury by suppressing the DUSP1 pathway.

Nitric oxide (NO) has essential roles in heart physiology, including the regulation of myocardial contractility and coronary blood flow, and in heart pathophysiology, particularly in the ischemic heart. NO is produced by both NO synthase (NOS)-dependent and NOS-independent pathways in the heart. This review summarizes quantitative aspects of NO production in the heart; the contribution of cardiomyocytes, endothelial cells (ECs), red blood cells (RBCs), and neurons are also discussed. Based on the available data, under normal conditions, the human heart produces about 50-70 µmol NO per day, primarily attributed to eNOS activity; ECs produce the highest amount of NO compared to other cell types in the heart. On the other hand, during ischemic conditions, NOS-independent NO production participates a significant role in the heart NO production that can exceed NOS-dependent NO generation. These data are relevant as most cardiovascular disorders are associated with NO dysfunction, and increasing NO bioavailability and signaling is a potential therapeutic approach for cardiovascular diseases.

Prolonged and intense stress can exceed the body's normal self-regulation and limited compensatory and repair capacity, resulting in pathological damage to the body. In this study, we established a rat stress myocardial injury (SMI) model to explore the protective effect of melatonin (MLT) on SMI and its possible mechanisms of action. Adult female Sprague Dawley (SD) rats were randomly divided into 5 groups: blank control group (NC), SMI group, MLT low-dose group, MLT medium-dose group, and MLT high-dose group, and 10 rats in each group were used to establish a SMI model by the water immersion restraint method. We observed the changes in body weight and tail vein glucose of each group. Serum levels of corticosterone (Cort), creatine kinase isoenzyme (CK-MB), and Troponin Ⅰ (Tn-Ⅰ) and activity of lactic acid dehydrogenase were measured by ELISA. Transcriptome sequencing was used to find differentially expressed genes in the control and model groups, and the results were verified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). HE staining was used to visualize the pathological changes in the heart tissue of each group, and Western blot was used to study the differences in protein expression in the cardiomyocytes of each group to further corroborate the results. The body weight growth rate of rats in the SMI group was significantly lower than that of the NC group ( P0.01), and the body weight growth rate of rats in the MLT high-dose group was significantly higher than that of the SMI group ( P0.05) with no significant difference compared with the NC group rats. The mean blood glucose of rats in the SMI group was significantly higher compared with the NC group ( P0.001), while the mean blood glucose of rats in the MLT administration groups was dose-dependently reduced compared with the SMI group. By RNA-seq and bioinformatics tools such as KEGG and Gene ontology, we found that the circadian clock-related genes Ciart , Arnt1 , Per1 , and Dbp were significantly downregulated in the SMI group during water immersion stress, and differentially expressed genes were enriched in the p38MAPK signaling pathway and p53 signaling pathway. Moreover, genes related to inflammation and apoptosis were differentially expressed. ELISA results showed that Cort, CK-MB, and Tn-Ⅰ levels were significantly higher in the SMI group compared with the NC group ( P0.01) and melatonin reduced the levels of Cort, CK-MB, and Tn-Ⅰ and decreased lactic acid dehydrogenase activity in rat serum. HE staining results showed that melatonin could attenuate stress-generated myocardial injury. Western blot showed that melatonin reduced the expression of p38MAPK, p53, Bax, and caspase-3 and increased the expression of Bcl-2 protein in rat heart. Melatonin can inhibit myocardial injury caused by water immersion, and its mechanism of action may be related to the regulation of the expression of circadian clock genes such as Ciart , Arnt1 , Per1 , and Dbp ; the inhibition of the expression of proapoptotic proteins such as p38MAPK, p53, Bax, and caspase-3; and the increase of the expression of Bcl-2 antiapoptotic protein.

In patients undergoing interventional or surgical coronary revascularization, subclinical hypothyroidism is common and associated with worse outcome, including the need for postoperative inotropic support. In isolated rat hearts with global ischemia/reperfusion, exogenous triiodothyronine (T3) reduces infarct size. Aim of this study was, to investigate whether or not exogenous T3 protects human myocardium from ischemia/reperfusion injury.Right atrial trabeculae from patients undergoing routine coronary artery bypass grafting were isolated and transferred to Tyrode's buffer. Electrically initiated (1 Hz) contractile stress (mN/mmAt baseline, contractile stress was comparable. T3 improved the cumulative recovery of contractile stress during reoxygenation from 41 ± 16 with NaOH to 55 ± 11% of baseline with T3, when given continuously in A or from 52 ± 13 with NaOH to 63 ± 11% of baseline with T3 when given just before and during reoxygenation in B. The ratio of mitochondrial complex I matrix arm to membrane NADH:ubiquinone oxidoreductase subunits (NDUF)V2 to NDUFA9 was reduced, reflecting increased complex I activity.T3 increases contractile recovery of human right atrial trabeculae from hypoxia/reoxygenation.

To determine the sensitivity of a noncontrast T1 dispersion cardiovascular magnetic resonance technique for detecting diffuse fibrosis in hypertrophic cardiomyopathy (HCM).Thirty-two adult HCM patients and ten age- and gender-matched healthy volunteers were prospectively included in this study. Patients and controls underwent cine, T1ρ-mapping, and pre- and post-contrast T1-mapping imaging using a 3-T magnetic resonance system. Myocardial extracellular volume fraction (ECV) maps were obtained using pre- and post-contrast T1 maps to determine reference values for diffuse fibrosis. Myocardial T1ρ and T1ρ dispersion maps called myocardial fibrosis index (mFI) maps provided 570 myocardial segments for Pearson or Spearman correlation analysis. The left ventricle myocardia of the HCM patients were divided into 16 segments that were further classified as either normal-thickness myocardium (15 mm) (HCM-N) or hypertrophic myocardium (≥15 mm) (HCM-H).ECV and mFI values increased progressively on a per-segment basis from healthy controls to the HCM-N group and then to the HCM-H group (ECV: 27.4 ± 2.8% vs. 31.1 ± 4.2% vs. 37.6 ± 6.9%, respectively [P 0.0001]; mFI: 6.1 ± 0.9 ms vs. 8 ± 1.9 ms vs. 11 ± 3.3 ms, respectively [P 0.0001]). There was a strong positive correlation between the segmented ECV and the mFI (r = 0.878). The mFI was equally or significantly better than the ECV for differentiating fibrosis content in HCM-N and HCM-H according to their receiver operating characteristic curves.A T1ρ dispersion imaging mFI can sensitively detect diffuse myocardial fibrosis in HCM, even in HCM-N.

To identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis.In this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses.Patients with T2DM (n = 49, median [interquartile range] age 61 [56-63] years, 61% male, diabetes duration 11 [7-20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9-8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8-30.0] vs 23.4 [22.4-25.5) %, p 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VOPatients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.

Understanding tissue macrophage biology has become challenging in recent years due the ever-increasing complexity in macrophage-subset identification and functional characterization. This is particularly important within the myocardium, as we have come to understand that macrophages play multifaceted roles in cardiac health and disease, and heart disease remains the leading cause of death worldwide. Here, we review recent progress in the field, focusing on resident cardiac macrophage heterogeneity, origins, and functions at steady state and after injury. We stratify resident cardiac macrophage functions by the ability of macrophages to either directly influence cardiac physiology or indirectly influence cardiac physiology through orchestrating multi-cellular communication with cardiomyocytes and stromal and immune populations.

Cardiac fibrosis is a common irreversible pathological feature of diverse heart disorders. Uncontrolled cardiac fibrosis contributes to maladaptive cardiac remodeling and eventually heart failure. However, the molecular determinants of ischemic and non-ischemic pathological cardiac fibrosis remain largely unknown. Here, we investigated the role of Bruton's tyrosine kinase (BTK) in cardiac fibrosis and remodeling of mice under various pathological conditions. BTK expression was increased in myocardium of mice after pressure overload or myocardial infarction (MI). BTK was mainly located in cardiac fibroblasts of myocardium, and its expression in isolated cardiac fibroblasts was also upregulated following TGF-β treatment. The deficiency or pharmacological inhibition of BTK with the second-generation inhibitor Acalabrutinib attenuated cardiac fibrosis, preserved cardiac function and prevented adverse cardiac remodeling, which protected against heart failure in mice following pressure overload or MI. BTK deficiency or inhibitor treatment significantly decreased the expression of pro-fibrotic molecules in isolated cardiac fibroblasts and inhibited the transition of fibroblasts to myofibroblasts in response to diverse pathological stresses. BTK directly bound and phosphorylated TGF-β receptor Ⅰ (TβRⅠ) at tyrosine 182, and then promoted the activation of downstream SMAD-dependent or -independent TGF-β signaling, leading to the enhanced transition of fibroblasts to pro-fibrotic myofibroblasts and the excessive extracellular matrix gene expression. Our finding uncovers a driving role of BTK in cardiac fibrosis and dysfunction following pressure overload and MI stress, and highlights novel pathogenic mechanisms in ischemic and non-ischemic maladaptive cardiac remodeling, which presents as a promising target for the development of anti-fibrotic therapy.

Recent advances the cardiac biomedical sciences have been propelled forward by the development and implementation of human iPSC-derived cardiac muscle. These notable successes notwithstanding, it is well recognized in the field that a major roadblock persists in the lack of full "adult cardiac muscle-like" maturation of hiPSC-CMs. This Perspective centers focus on maturation roadblocks in the essential physiological unit of muscle, the sarcomere. Stalled sarcomere maturation must be addressed and overcome before this elegant experimental platform can reach the mountaintop of making impactful contributions in disease pathogenesis, drug discovery, and in clinical regenerative medicine.

Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) have conventionally been used for surveillance of cardiac function after cancer therapy, but indices of myocardial work (MW) are potentially superior for this purpose because they take into account both myocardial deformation and loading conditions.We aimed to investigate the usefulness of MW in the follow-up of children and young adults following anthracycline chemotherapy.Conventional markers of LV function (LV fractional shortening [LVFS], LVEF, GLS) and MW indices (global work index [GWI], global constructive work [GCW], global wasted work [GWW], and global work efficiency [GWE]) were obtained from 2342 echocardiographic examinations in 598 patients (354 male, 12.2 [4.7-17.3] years at initiation of chemotherapy).GWI, GCW, GLS, LVFS, and LVEF all deteriorated significantly during and after anthracycline chemotherapy, while GWW decreased and GWE was preserved. On multivariable analysis, MW indices were correlated with conventional markers of LV function and with clinical information relating to underlying malignancy and chemotherapy. Cox regression analysis revealed that similar levels of deterioration in GWW, GWI, and GCW preceded those in GLS, LFS, and LVEF.Non-invasive MW indices correlate well with conventional markers of LV function. Indices of MW appear to provide an earlier and more sensitive marker of progression towards chemotherapy-related cardiac dysfunction. Future studies are warranted to validate whether the incorporation of non-invasive MW into the routine clinical surveillance in patients after chemotherapy would improve outcomes.

Adrenergic receptors (ARs) are G protein-coupled receptors that are stimulated by catecholamines to induce a wide array of physiological effects across tissue types. Both α1- and β-ARs are found on cardiomyocytes and regulate cardiac contractility and hypertrophy through diverse molecular pathways. Acute activation of cardiomyocyte β-ARs increases heart rate and contractility as an adaptive stress response. However, chronic β-AR stimulation contributes to the pathobiology of heart failure. By contrast, mounting evidence suggests that α1-ARs serve protective functions that may mitigate the deleterious effects of chronic β-AR activation. Here, we will review recent studies demonstrating that α1- and β-ARs differentially regulate mitochondrial biogenesis and dynamics, mitochondrial calcium handling, and oxidative phosphorylation in cardiomyocytes. We will identify potential mechanisms of these actions and focus on the implications of these findings for the modulation of contractile function in the uninjured and failing heart. Collectively, we hope to elucidate important physiological processes through which these well-studied and clinically relevant receptors stimulate and fuel cardiac contraction to contribute to myocardial health and disease.

Even though rodents are accessible model animals, their electrophysiological properties are deeply different from those of humans, making the translation of rat studies to humans rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of humans by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the IK1 current (10 µmol/L barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dogs, and did not affect it in humans. On the contrary, IKr inhibition (50 nmol/L dofetilide) significantly prolonged repolarization in humans, rabbits, and dogs, but not in rats. Inhibition of the IKur current (1 µmol/L XEN-D0101) only prolonged rat ventricular repolarization and had no effect in humans or dogs. Inhibition of the IKs (500 nmol/L HMR-1556) and Ito currents (100 µmol/L chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest translational value and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments.