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A 72-year-old man presented for routine dual chamber pacemaker interrogation 13 years following insertion for sick sinus syndrome. Increased noise, impedance and threshold of the right ventricular (RV) lead were identified. RV capture was maintained with an overall RV pacing burden of 47%. A routine generator replacement was scheduled alongside RV lead replacement. Fluoroscopy at the start of the procedure revealed an unexpected striking fracture of the RV pacing lead with complete separation of the proximal and distal portions within the RV. The patient was asymptomatic and described no predisposing factors. He underwent implantation of a new ventricular lead and generator and has remained well. This case demonstrates clear RV lead fracture as a late complication of pacemaker implantation despite maintained capture. This emphasises the need for a chest X-ray when a change in device parameters is noted at device interrogation even in the absence of symptoms.

Background: Kuan Xiong aerosol (KXA) is a Chinese herbal compound used to regulate qi-flowing to relieve pain and improve angina. However, only a few pharmacological studies on this traditional Chinese medicine preparation have been reported to confirm these activities. Objective: This article aims to observe the effect of resisting acute myocardial ischemia (AMI) in vivo and dilating vessel in vitro of KXA. Materials: The AMI model involves intravenously injecting pituitary (2 U.kg-1) into the ear of rabbits. Electrocardiograph (ECG) T waves were then recorded after administration and the falling range was calculated. Following this, the level of serum Cardiac troponin T (cTn-T) and the histopathology of the cardiac muscle tissue was evaluated. In vitro, the effect of KXA on vasodilation of isolated aortic rings that had been pre-contracted with KCl (30 mM) was observed. Results: The AMI model involves intravenously injecting the pituitary (2 U.kg-1) into the ear of rabbits. Electrocardiograph (ECG) T waves were then recorded after administration, and the falling range was calculated. Following this, the level of serum Cardiac troponin T (cTn-T) and the histopathology of the cardiac muscle tissue were evaluated. In vitro, the effect of KXA on vasodilation of isolated aortic rings that had been pre-contracted with KCl (30 mM) was observed. Conclusions: These results suggest that KXA protects against AMI, contributes to the dilation of blood vessels, and has long-acting effectiveness.

Background: Heart failure (HF) due to myocarditis might not respond in the same way to standard therapy as HF due to other aetiologies. The aim of this study was to investigate the value of endomyocardial biopsies (EMB) for clinical decision-making and its relation to the outcome of paediatric patients with myocarditis. Methods: Clinical and EMB data of children with myocarditis collected for the MYKKE-registry between 2013 and 2020 from 23 centres were analysed. EMB studies included histology, immunohistology, and molecular pathology. The occurrence of major adverse cardiac events (MACE) including mechanical circulatory support (MCS), heart transplantation, and/or death was defined as a combined endpoint. Results: Myocarditis was diagnosed in 209/260 patients: 64% healing/chronic lymphocytic myocarditis, 23% acute lymphocytic myocarditis (AM), 14% healed myocarditis, no giant cell myocarditis. The median age was 12.8 (1.4-15.9) years. Time from symptom-onset to EMB was 11.0 (4.0-29.0) days. Children with AM and high amounts of mononuclear cell infiltrates were significantly younger with signs of HF compared to those with healing/chronic or healed myocarditis. Myocardial viral DNA/RNA detection had no significant effect on outcome. The worst event-free survival was seen in patients with healing/chronic myocarditis (24%), followed by acute (31%) and healed myocarditis (58%, p=0.294). A weaning rate of 64% from MCS was found in AM. Conclusions: EMB provides important information on the type and stage of myocardial inflammation and supports further decision-making. Children with fulminant clinical presentation, high amounts of mononuclear cell infiltrates or healing/chronic inflammation and young age have the highest risk for MACE.

Background: In case of long-term and physiological loads (e.g. during pregnancy or regular athletics training), reversible morphological changes occur in the heart - cardiomyocytes undergo hypertrophy, however, this is not accompanied by impairment of left ventricular function or myocyte metabolism. However, in the course of various pathological processes, as time goes by, gradually permanent morphological changes occur. These changes are referred to as remodeling of the heart muscle, which, regardless of the primary cause, can lead to the development of chronic heart failure. Materials and methods: The study was performed on post-mortem material of 35 human hearts obtained from forensic sections and anatomopathological sections of people who died of non-cardiac causes (mainly traffic accidents, suicide attempts, strokes, acute infections); material was fixed in a 4% formalin solution. The hearts were subjected to macro- and microscopic assessment. During microscopic assessment the features of remodeling were evaluated. Results and conclusions: In vivo and echocardiographic tests, as well as macroscopic evaluation of post-mortem material, suggest the presence of some kind of right ventricular muscle remodeling, however classic microscopic observations, presented in this study do not provide such unambiguous evidence. Thus, the question arises: why and how the right ventricular function is disturbed, sometimes at early stages of arterial hypertension.

Drug deposition into the intrapericardial space is favourable for achieving localised effects and targeted cardiac delivery owing to its proximity to the myocardium as well as facilitating optimised pharmacokinetic profiles and a reduction in systemic side effects. Access to the pericardium requires invasive procedures but the risks associated with this have been reduced with technological advances, such as combining transatrial and subxiphoid access with different guidance methods. A variety of introducer devices, ranging from needles to loop-catheters, have also been developed and validated in pre-clinical studies investigating intrapericardial delivery of therapeutic agents. Access techniques are generally well-tolerated, self-limiting and safe, although some rare complications associated with certain approaches have been reported. This review covers these access techniques and how they have been applied to the delivery of drugs, cells, and biologicals, demonstrating the potential of intrapericardial delivery for treatments in cardiac arrhythmia, vascular damage, and myocardial infarction.

Acute myocarditis (AM) and hypertensive heart disease (HHD) have different pathophysiological backgrounds, thus potentially showing distinct patterns of altered myocardial deformation. Therefore, CMR left ventricular (LV) feature tracking (FT)- based strain parameters were indexed to myocardial mass index (LVMi) in order to evaluate potential additional value in the differentiation among AM, HHD, and healthy volunteers (HV) compared to non-indexed conventional strain.Patients with AM (n = 43) and HHD (n = 28) underwent CMR at 3T. 61 HV served as controls. Cine imaging-based FT-strain analysis was performed and natural strain (nStrain) values were evaluated for gender and age specific differences in HV. Strain parameters were indexed to LVMi yielding ratio Strain (rStrain). These were evaluated for their discriminatory accuracy compared to nStrain values.There were significant differences in nStrain between genders (p0.05), but not between age groups in HV. Circumferential strains differentiated best between HV and AM, reaching an area under the curve (AUC) of 0.86 (female) and 0.81 (male), yielding 93 (72) % sensitivity and 55 (75) % specificity. In discriminating between HV and HHD as well as AM and HHD, longitudinal strains outperformed all other parameters with AUCs of 1.00 (female)/ 0.92 (male) and 0.90 (female)/ 0.74 (male), respectively. Sensitivity and specificity levels of 100 %/ 100 % (female) and 91 %/ 72 % (male) for HV versus AM as well as 82 %/ 71 % (female) and 91%/ 57 % (male) for AM versus HHD could be demonstrated. The usage of rStrains significantly increased the AUC for circumferential and radial strains in male patients.rStrain provided additional value in the differentiation of diseases with increased LVM. As rStrain is derived from standard native cine imaging, such parameters can be time efficiently and reliably calculated, giving them the potential to be a powerful addition to the currently developing multiparametric native diagnostic approaches.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

Amyloid light-chain (AL) cardiac amyloidosis is known to result in restrictive cardiomyopathy, which has a poor prognosis. Although electrocardiography (ECG) is useful for its diagnosis and management, there are few reports on the long-term follow-up of electrocardiographic changes. The patient in the present case was a 62-year-old woman who visited our hospital due to palpitation and lower leg edema. A chest radiograph showed cardiac enlargement, and ECG revealed sinus rhythm, first-degree atrioventricular block, low QRS voltage in the limb leads and a pseudomyocardial infarction pattern in the precordial leads. Echocardiography revealed left ventricular hypertrophy with systolic and diastolic dysfunction. Immunoelectrophoresis demonstrated M-protein (IgGλ), and bone marrow biopsy implied IgGλ-type plasmacytoma. Myocardial biopsy findings were compatible with cardiac amyloidosis. Based on these findings, we diagnosed the patient with AL cardiac amyloidosis. Melphalan-prednisolone (MP) therapy was performed in conjunction with treatment for non-sustained ventricular tachycardia and congestive heart failure. Two years and four months later, the sinus rhythm converted to atrial tachycardia. At a follow-up examination at four years and eight months, right branch block appeared. Then degree of intraventricular conduction was worsened, and the low voltage of the limb leads was not observed. Seven years after the diagnosis, she was eventually hospitalized for the treatment of pneumonia and heart failure with tachycardia. On the seventh day of hospitalization, heart rhythm was changed to atrial stand-still with escaped ventricular rhythm and died of cardiac arrest. These ECG changes may provide valuable information regarding the pathophysiological changes that occur in AL cardiac amyloidosis.

BACKGROUND AND PURPOSE Small molecule BGP-15 has been reported to alleviate signs of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. EXPERIMENTAL APPROACH Rabbits were maintained on standard chow (Control) or atherogenic diet (HC) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed, and key molecules of the protein kinase G (PKG) axis were examined by ELISA and Western blot. Passive force generation was investigated in skinned cardiomyocytes. KEY RESULTS Both acute and chronic BGP-15 treatment improved the diastolic performance of the diseased heart, however, vasorelaxation and serum lipid markers were unaffected. Myocardial cGMP levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group, and the substance inhibited PDE1 enzyme. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased, and PKG-dependent N2B-titin phosphorylation elevated in the BGP-15-treated group. CONCLUSIONS AND IMPLICATIONS Here we report that BGP-15-treatment improves diastolic function, reduces cardiomyocyte stiffness, and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG axis. As BGP-15 is proven to be safe, it may have clinical value in the treatment of diastolic dysfunction.

Several recent publications have described myopericarditis cases after the coronavirus disease 2019 (COVID-19) vaccination. However, it is uncertain if these cases occurred secondary to the vaccination or more common etiologies of myopericarditis. To help determine whether a correlation exists between COVID-19 vaccination and myopericarditis, the present study compared the gender-specific cumulative incidence of myopericarditis and myocardial injury in a cohort of COVID-19 vaccinated patients at a tertiary care center in 2021 with the cumulative incidence of these conditions in the same subjects exactly 2 years earlier. We found that the age-adjusted incidence rate of myopericarditis in men was higher in the vaccinated than the control population, rate ratio 9.7 (p = 0.04). However, the age-adjusted incidence rate of myopericarditis in women was no different between the vaccinated and control populations, rate ratio 1.28 (p = 0.71). We further found that the rate of myocardial injury was higher in both men and women in 2021 than in 2019 both before and after vaccination, suggesting that some of the apparent increase in the diagnosis of myopericarditis after vaccination may be attributable to factors unrelated to the COVID-19 vaccinations. In conclusion, our study reaffirms the apparent increase in the diagnosis of myopericarditis after COVID-19 vaccination in men but not in women, although this finding may be confounded by increased rates of myocardial injury in 2021. The benefits of COVID-19 vaccination to individual and public health clearly outweigh the small potential increased risk of myopericarditis after vaccination.

The inherited connective tissue disorders (Marfan syndrome, Loeys-Dietz syndrome [LDS], and Ehlers-Danlos syndrome [EDS]) involve connective tissue of various organ systems. These pathologies share many common features, nonetheless compared to Marfan syndrome, LDS' cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis. The EDS are currently classified into thirteen subtypes. There is substantial symptoms overlap between the EDS subtypes, and they are associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection.

The study aimed to examine the effect of simultaneous application of florfenicol and lasalocid on the performance and vital organ function of chickens. For this, 300 chicks were divided into four groups. Group one to three received florfenicol, lasalocid and lasalocid plus florfenicol, respectively. Group four as the control group received a basic diet without lasalocid or florfenicol. Lasalocid was used from 7 to 35 days old, continuously. Florfenicol was used at 21 days old for 5 days. The growth indices were measured at the end of each week. The chickens were euthanized at the ages of 28 and 35 days old after collecting blood samples with and without anticoagulants. The liver, heart, muscle, kidney and sciatic nerve were collected in formalin 10% for histopathological examination. The blood and serum samples were used to determine clinical pathologic and hematologic indices. The ratio of internal organs to body weight and ratio of the right ventricle to the total ventricles (RV/TV) of the heart was measured. Results showed, the use of lasalocid decreased feed conversion rate and triglyceride, and increased total protein. Simultaneous administration of lasalocid and florfenicol affected histopathology of the liver and heart and significantly increased creatine phosphokinase, uric acid and the ratio of RV/TV of heart. The eosinophil percentage in the chickens who received florfenicol plus lasalocid was significantly higher than chickens who received florfenicol alone (p < 0.05). In conclusion, it seems that simultaneous administration of the florfenicol and lasalocid induces side‐effects especially on cardiac function and it is not recommended., In this research, we evaluated the co‐administration effect of florfenicol and lasalocid on vital organs in broiler chickens for the first time. the results revealed this combination can induce negative effects on the heart, skeletal muscle and kidney based on results of pathologic examinations and biochemical evaluation.

The present study aimed to characterize and compare β-adrenoceptors in the rat bladder with those in the heart and lungs of SD rats (8–10 weeks old) using subtype-selective agonists and antagonists in a radioligand binding assay with (-)-[125I]cyanopindolol ([125I]CYP), and also to clarify alterations in β-adrenoceptors in the bladder of spontaneously hypertensive rats (SHR) at 14 weeks old, from those of Wistar-Kyoto rats (WKY) and Wistar rats at the same age. A radioligand binding assay with [125I]CYP was used to measure β-adrenoceptor binding activity in rat tissues. Metoprolol exhibited the highest affinity to specific binding sites of [125I]CYP in the rat heart, indicating the dominance of β1-adrenoceptors. β3-selective agonists (BRL37344 and CL316243) and antagonist (SR59230A) exhibited higher affinity to specific binding sites of [125I]CYP in the bladder than in the heart and lungs. Furthermore, the binding affinity of the β2-selective antagonist, ICI118551 was the highest in the bladder. The Bmax of specific [125]CYP binding in the bladder was significantly lower in WKY and SHR than in Wistar rats. The present study provides further evidence for the coexistence of β2-and β3-adrenoceptors in the rat bladder, and indicates that β-adrenoceptor density is lower in the bladders of WKY and SHR.

Supplemental Digital Content is available in the text., Background: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. METHOD: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MVATP[rest]), at maximal workload (MVATP[max]), and by the myocardial ATP production reserve, representing the span between MVATP(rest) and MVATP(max). Results: Compared with controls, in both groups of patients, MVATP(rest) was increased and MVATP(max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MVATP(max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Conclusions: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03172338 and NCT04068740.

Barth syndrome (BTHS) is an X-linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early-onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age- and sex-matched patients with idiopathic dilated cardiomyopathy (DCM) and non-failing (NF) controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso-) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of Complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long-chain fatty acid oxidation enzymes and the tissue acyl-CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta-oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy. This article is protected by copyright. All rights reserved.

Background Strain analysis has become commonly used in clinical practice in various heart diseases. Purpose To explore whether late gadolinium enhancement (LGE)-negative areas with coronary artery chronic total occlusion (CTO) appear normal when analyzed for longitudinal strain using cardiac magnetic resonance (CMR) imaging. Material and Methods A total of 16 patients and 31 healthy controls who underwent 1.5-T MR at our hospital between January 2015 and July 2017 were included in the study. The LGE-CMR of patients with CTO was negative. Left ventricular functional parameters, segmental longitudinal strain/strain rate, and perfusion parameters were measured using CVI42 software. Results For myocardial segments supplied by CTO vessels, systolic longitudinal strain rate (SLSR)was significantly lower than that of healthy controls, and diastolic longitudinal strain rate (DLSR) was significantly higher (1.19 1/s vs. 1.02 1/s; P = 0.018). Moreover, longitudinal strain (LS), SLSR, and DLSR did not differ between good and poor collateral circulation. Perfusion index of CTO territory segments was lower than non-CTO territory segments (0.20 vs. 0.22; P = 0.027). No correlation was found between longitudinal strain parameters and perfusion parameters. Conclusion Although LGE-CMR was negative in patients with CTO, the myocardial SLSR of CTO territory segments was significantly lower than that of healthy controls.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen–progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen–progestin-treated female rats. From our data, estrogen–progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen–progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen–progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

Elevated intracellular Na (Nai) and metabolic impairment are interrelated pathophysiological features of the failing heart (HF). There have been a number of studies showing that myocardial sodium elevation subtly affects mitochondrial function. During contraction, mitochondrial calcium (Camito) stimulates a variety of TCA cycle enzymes, thereby providing reducing equivalents to maintain ATP supply. Nai elevation has been shown to impact Camito; however, whether metabolic remodelling in HF is caused by increased Nai has only been recently demonstrated. This novel insight may help to elucidate the contribution of metabolic remodelling in the pathophysiology of HF, the lack of efficacy of current HF therapies and a rationale for the development of future metabolism-targeting treatments. Here we review the relationship between Na pump inhibition, elevated Nai, and altered metabolic profile in the context of HF and their link to metabolic (in)flexibility and mitochondrial reprogramming.

Aims Cardiac involvement is crucial factor determining outcomes of light chain (AL) amyloidosis. This study evaluated whether capillary density (CD) quantified from endomyocardial biopsy is associated with structural and functional parameters of amyloid heart. Also, we investigated whether capillary density improves the prognostic value of the current staging system in AL amyloidosis patients with cardiac involvement. Methods and results A total of 67 patients with biopsy‐proven AL cardiac amyloidosis were prospectively enrolled in this study. All patients underwent transthoracic echocardiography and EBM at the time of diagnosis. Left ventricle global longitudinal strain was evaluated on two‐dimensional strain echocardiography. The primary endpoint was all‐cause mortality. Amyloid load and capillary density were calculated on endomyocardial biopsy stained immunohistochemically with antibody against amyloid P and CD31, respectively. Among the study population, 37 patients (55.2%) were classified as Stage IV, and the cumulative incidence of death at 1 year was 34% (23 patients). A total of 65 (97%) patients underwent chemotherapy. CD showed a significant correlation with left ventricle global longitudinal strain (r = 0.274, P = 0.025), log N‐terminal pro‐B type natriuretic peptide (r = −0.311, P = 0.005), and amyloid load (r = −0.438, P 220/mm2 (P = 0.026 by log‐rank test). A model based on the 2012 Mayo staging system and CD showed significantly better discrimination and reclassification ability than a model using the 2012 Mayo staging system alone (C‐index 0.582 vs.0.689, P for difference

Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (

Endotoxin shock is associated with severe impairments in cardiovascular and respiratory functions. We showed previously that choline or cytidine-5′-diphosphocholine (CDP-choline) provides beneficial effects in experimental endotoxin shock in dogs. The objective of the present study was to determine the effects of choline or CDP-choline on endotoxin-induced cardiovascular and respiratory dysfunctions. Dogs were treated intravenously (i.v.) with saline or endotoxin (LPS, 0.1 mg/kg) 5 min before i.v. infusion of saline, choline (20 mg/kg) or CDP-choline (70 mg/kg). Blood pressure, cardiac rate, myocardial and left ventricular functions, respiratory rate, blood gases, serum electrolytes and cardiac injury markers were determined before and at 0.5-48 h after endotoxin. Plasma tumor necrosis factor alpha (TNF-α), high mobility group box-1 (HMGB1), catecholamine and nitric oxide (NO) levels were measured 2 h and 24 h after the treatments. Endotoxin caused immediate and sustained reductions in blood pressure, cardiac output, pO2 and pH; changes in left ventricular functions, structure and volume parameters; and elevations in heart rate, respiratory rate, pCO2 and serum electrolytes (Na, K, Cl, Ca and P). Endotoxin also resulted in elevations in blood levels of cardiac injury markers, TNF-α, HMGB1, catecholamine and NO. In choline- or CDP-choline-treated dogs, all endotoxin effects were much smaller in magnitude and shorter in duration than observed values in controls. These data show that treatment with choline or CDP-choline improves functions of cardiovascular and respiratory systems in experimental endotoxemia and suggest that they may be useful in treatment of endotoxin shock in clinical setting.

Myocardial fibrosis, seen in ischemic and nonischemic cardiomyopathies, is associated with adverse cardiac outcomes. Noninvasive imaging plays a key role in early identification and quantification of myocardial fibrosis with the use of an expanding array of techniques including cardiac magnetic resonance, computed tomography, and nuclear imaging. This review discusses currently available noninvasive imaging techniques, provides insights into their strengths and limitations, and examines novel developments that will affect the future of noninvasive imaging of myocardial fibrosis.

Objectives The clinical manifestations of COVID-19 associated cardiac complications are heterogeneous, ranging from asymptomatic to severe symptoms, including arrhythmias and cardiogenic shock. For COVID-19 patients with cardiac sequela, only a small subset of patients have myocarditis; the pathogenesis of cardiac sequela caused by SARS-CoV-2 other than microthrombi associated sequela remains to be determined. Methods Retrospective analysis of 71 heart autopsy specimens from COVID-19 and putative COVID-19 in the NIH COVID Digital Pathology Repository. Results The most consistent observation was localized myocardial cell death not associated with either myocarditis or microthrombi. Red blood cells were typically absent from capillaries but, when observed, were predominately in linear clusters (stacks) of adjacent cells. Conclusions Based on our retrospective analysis, we propose that localized ischemia and subsequent cell death by anoxia contributes to the cardiac pathogenesis in some COVID-19 patients. We propose two new models predicting vasoconstriction of cardiac pericyte cells induced by elevated histamine from hyper-activated mast cells or direct infection. We propose that impeded blood flow and cell death by anoxia are initial steps in the development of SARS-CoV-2 induced cardiac injury in COVID-19 patients independent of microthrombi or myocarditis.

The lusitropic effect of quercetin was examined on isolated ventricular myocardial tissue preparations from normal and streptozotocin-induced diabetic mice. The time required for 90% relaxation of the myocardium, which was prolonged in the diabetic mice, was shortened by quercetin in both normal and diabetic myocardia. This effect of quercetin was completely inhibited by cyclopiazonic acid but not by SEA0400. These results indicated that quercetin accelerates myocardial relaxation through activation of the sarco-endoplasmic reticulum Ca2+-ATPase.

Cardiac muscle uses multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favors glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signaling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms, in the absence of any in vivo confounding regulators of cardiac metabolism, demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example, diabetes.NEW & NOTEWORTHY In hearts overexpressing vascular endothelial growth factor B (VEGFB), besides its known angiogenic response, multiple regulatory mechanisms lowered coronary LPL. This was accompanied by limited cardiac lipid metabolite accumulation with an augmentation of cardiac insulin action. Our data for the first time links VEGFB to coronary LPL in regulation of cardiac metabolism. VEGFB may be cardioprotective in metabolic disorders like diabetes.

Purpose This study aimed to evaluate whether quantification of myocardial susceptibility by cardiac magnetic resonance imaging (CMR) can be an imaging biomarker for cardiac amyloidosis (CA). Materials and methods Twenty-six patients with CA underwent CMR, including magnetic phase imaging with a 3.0-T magnetic resonance imaging scanner. Myocardial susceptibility was quantified as a phase shift slope value by magnetic phase analysis. Those values from patients with CA were compared with corresponding values from 18 controls and 15 healthy volunteers. A univariate logistic regression analysis was conducted to identify significant parameters related to CA. Results The phase shift slope, a quantitative parameter of myocardial susceptibility, was significantly lower in the CA group compared with the control group and compared with healthy volunteers (p p ≤ 0.05) during the univariate analysis. The phase shift slope yielded the best AUC of 0.89 (95% CI = 0.79–0.98) for the prediction of CA (p r = − 0.39, p r = − 0.35, p = 0.02). Conclusion Myocardial susceptibility analysis by CMR helps in the diagnosis of patients with CA and can be a new quantitative imaging biomarker for CA.

Objective. Myocardial ischemia-reperfusion (I/R) injury (MIRI) refers to the more serious myocardial injury after blood flow recovery, which seriously affects the prognosis of patients with ischemic cardiomyopathy. This study explored the new targets for MIRI treatment by investigating the effects of miR-190-5p and its downstream target on the structure and function of myocardial cells. Methods. We injected agomir miR-190-5p into the tail vein of rats to increase the expression of miR-190-5p in rat myocardial cells and made an I/R rat model by coronary artery occlusion. We used 2,3,5-triphenyl tetrazolium chloride staining, lactate dehydrogenase (LDH) detection, echocardiography, and hematoxylin-eosin (HE) staining to determine the degree of myocardial injury in I/R rats. In addition, we detected the expression of inflammatory factors and apoptosis-related molecules in rat serum and myocardial tissue to determine the level of inflammation and apoptosis in rat myocardium. Finally, we determined the downstream target of miR-190-5p by Targetscan system and dual luciferase reporter assay. Results. The expression of miR-190-5p in an I/R rat myocardium was significantly lower than that in normal rats. After treatment of I/R rats with agomir miR-190-5p, the ischemic area of rat myocardium and the concentration of LDH decreased. The results of echocardiography and HE staining also found that overexpression of miR-190-5p improved the structure and function of rat myocardium. miR-190-5p was also found to improve the viability of H9c2 cells in vitro and reduce the level of apoptosis of H9c2 cells. The results of Targetscan system and dual luciferase reporter assay found that miR-190-5p targeted to inhibit pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1). In addition, inhibition of PHLPP1 was found to improve the viability of H9c2 cells. Conclusion. Therefore, miR-190-5p can reduce the inflammation and apoptosis of myocardium by targeting PHLPP1, thereby alleviating MIRI.

Background: Lipid accumulation in the liver, skeletal and cardiac muscle, kidneys and pancreas causes cell dysfunction, death and inflammation, a biological phenomenon named lipotoxicity. Erythrocytes participate in the transport of lipids in the circulation, and their lipidome is determined by exchange with blood components. Objective: The objective of this study is to summarize the current knowledge regarding the effect of toxic lipid accumulation in erythrocytes. Results: Erythrocyte lipidome is altered in lipotoxic diseases, such as fatty liver disease, heart failure and diabetes. In addition, ceramide, lysophosphatidylcholine, lysophosphatidic acid, palmitic acid and free cholesterol induce erythrocyte malfunction. Conclusion: Erythrocytes are an additional cell target of lipotoxicity. Further exploration of the implicated molecular mechanisms could lead to novel therapeutic targets for cardiometabolic and hematological diseases.

Psoriatic disease is associated with vascular and myocardial dysfunction. We aimed to evaluate endothelial glycocalyx barrier properties and microvascular perfusion in psoriatic patients, as well as their correlation with carotid intima-media thickness (cIMT) and markers of left ventricular (LV) myocardial deformation. We examined 297 psoriatic patients and 150 controls, adjusted for age, sex, and atherosclerotic risk factors. The severity of psoriatic disease was estimated using the psoriasis area and severity index (PASI). Perfused boundary region (PBR), a marker of glycocalyx barrier function, was measured non-invasively in sublingual microvessels with a diameter 5-25 μm using Sidestream Dark Field camera (Microscan, GlycoCheck). Increased PBR indicates reduced glycocalyx thickness. Indexes of microvascular perfusion, including red blood cells filling (RBCF) and functional microvascular density, were also calculated. We measured cIMT, coronary flow reserve (CFR) and markers of myocardial deformation by speckle-tracking imaging, namely global longitudinal strain (GLS) and percentage changes between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO). Compared to controls, psoriatic patients had higher PBR5-25μm (2.13 ± 0.29μm versus 1.78 ± 0.25μm, p < 0.001) and lower RBCF and functional microvascular density (p < 0.001). Increased PASI was associated with elevated PBR and more impaired cIMT and GLS (p < 0.05). There was an inverse association of PBR with RBCF and functional microvascular density (p < 0.001). In psoriatic population, increased PBR was related to increased cIMT, reduced CFR, impaired GLS and decreased %dpTw-UtwMVO (p < 0.001). Glycocalyx thickness is reduced in psoriatic patients, which in turn impairs microvascular perfusion, and is associated with carotid IMT and impaired coronary and myocardial function.Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT02144857.

The objective of the study was to investigate the safety profile of high-risk micro-endomyocardial biopsy (micro-EMB) compared to conventional EMB in a large animal model. Twenty pigs were subjected to a maximum of 30 consecutive biopsies, including sampling from the free ventricular wall, with either micro-EMB (n = 10) or conventional EMB (n = 10). There were no major complications in the micro-EMB group (0/10), compared to six major complications in the EMB group (6/10; p = 0.003). Survival analysis further highlighted these differences (p = 0.004). There were significantly higher volumes of pericardial effusion in the EMB group (p = 0.01). The study shows a safety advantage of micro-EMB compared to standard EMB in the experimental high-risk circumstances investigated in this animal study. These results indicate enhanced possibilities to collect samples from sensitive areas by using the micro-EMB technique instead of standard EMB.

Myocardial injury after noncardiac surgery is a strong predictor of 30-day mortality and morbidity.The purpose of this study was to examine the incidence of myocardial injury in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol and its association with 90-day mortality and morbidity.This is a retrospective cohort study.This study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017.Adult patients undergoing colorectal cancer surgery were included if troponin was measured at least twice during the first 7 days after surgery. The patients were followed for 90 days.Myocardial injury was defined as an elevated troponin I measurement (45 ng/L) without evidence of a nonischemic origin causing the elevation. Ninety-day mortality and complications were assessed.A total of 586 patients were included of which 42 were diagnosed with myocardial injury. Thirteen patients (2%) died within 90 days of surgery. There was no significant difference in 90-day mortality between patients with and without myocardial injury (5% (2/42) versus 2% (11/544); p = 0.24). We found a higher incidence of postoperative complications within 90 days of surgery in the myocardial injury group than in the nonmyocardial injury group (43% (18/42) versus 20% (107/544); p0.01). We found a significant difference between the myocardial injury group and nonmyocardial injury group in terms of medical complications (33% (14/42) versus 9% (50/544); p0.01) but not surgical complications (19% (8/42) versus 16% (85/544); p = 0.56). Myocardial injury was an independent predictor of postoperative complications within 90 days of surgery (adjusted OR, 2.69; 95% CI, 1.31-5.55).This study was limited by its retrospective design.Myocardial injury occurs frequently in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol. Patients with myocardial injury did not have a significantly higher 90-day mortality but had higher risk of 90-day postoperative complications than patients without myocardial injury. Future research should examine the prevention and treatment of myocardial injury. See Video Abstract at http://links.lww.com/DCR/B692.ANTECEDENTES:La lesión del miocardio después de una cirugía no cardíaca es un fuerte predictor de mortalidad y morbilidad a los 30 días.OBJETIVO:El propósito fue examinar la incidencia de lesión miocárdica en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía y su asociación con la mortalidad y morbilidad a los 90 días.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Realizado en el Hospital Universitario de Zelanda, Dinamarca, entre junio de 2015 y julio de 2017.PACIENTES:Se incluyeron pacientes adultos sometidos a cirugía de cáncer colorrectal, si la troponina se midió al menos dos veces durante los primeros siete días después de la cirugía. Los pacientes fueron seguidos durante 90 días.PRINCIPALES MEDIDAS DE RESULTADO:La lesión miocárdica se definió como una medición de troponina I elevada (45 ng / l) sin evidencia de una etiología no isquémica que causara la elevación. Se evaluaron la mortalidad y las complicaciones a los noventa días.RESULTADOS:Se incluyeron un total de 586 pacientes, de los cuales 42 fueron diagnosticados de lesión miocárdica. Trece pacientes (2%) murieron dentro de los 90 días posteriores a la cirugía. No hubo diferencias significativas en la mortalidad a 90 días entre los pacientes con y sin lesión del miocardio, 5% [2/42] versus 2% [11/544], p = 0,24. Encontramos una mayor incidencia de complicaciones posoperatorias dentro de los 90 días de la cirugía en el grupo de lesión miocárdica en comparación con el grupo de lesión no miocárdica, 43% [18/42] versus 20% [107/544], p0,01. Encontramos una diferencia significativa entre el grupo de lesión miocárdica y el grupo de lesión no miocárdica en términos de complicaciones médicas (33% [14/42] versus 9% [50/544]; p0,01) pero no complicaciones quirúrgicas (19% [8/42] versus 16% [85/544]; p = 0,56). La lesión miocárdica fue un predictor independiente de complicaciones posoperatorias dentro de los 90 días posteriores a la cirugía (razón de probabilidades ajustada: 2,69; intervalo de confianza del 95%: 1,31 - 5,55).LIMITACIONES:Limitado por su diseño retrospectivo.CONCLUSIÓN:La lesión del miocardio ocurre con frecuencia en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía. Los pacientes con lesión miocárdica no tuvieron una mortalidad significativamente mayor a los 90 días, pero tuvieron un mayor riesgo de complicaciones posoperatorias a los 90 días en comparación con los pacientes sin lesión miocárdica. Las investigaciones futuras deben examinar la prevención y el tratamiento de la lesión miocárdica. Consulte Video Resumen en http://links.lww.com/DCR/B692.

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.

We aimed to explore the effects of emodin on the energy metabolism of myocardial cells in rats with post-myocardial infarction (MI) heart failure (HF) and the extracellular signal-regulated kinase (ERK) pathway. The model of MI was established by ligation of the left anterior descending branch. After 4 weeks, the rats with left ventricular ejection fraction (LVEF) of ≤45% were used aspost-MI HF model animals and randomly divided into model, low-dose, middle-dose, high-dose and control groups (n=10). Low-, middle- and high-dose groups were gavaged with 20 mg/kg, 40 mg/kg and 60 mg/kg emodin daily, respectively. After administration for 14 d, the changes in LVEF, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD) and interventricular septum thickness (IVS) were analyzed. The apoptosis rate of myocardial cells was detected by TUNEL staining. The levels of serum cardiac troponin I (cTnI) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) were determined using ELISA, and the expressions of mitochondrial respiratory chain complex I protein and phosphorylated-ERK (p-ERK) in myocardial tissues were determined by Western blotting. Compared with model group, LVEDD, LVESD, apoptosis rate of myocardial cells, levels of serum cTnI and PGC-1, and expressions of complex I and p-ERK in myocardial tissues significantly decreased, while LVEF and IVS increased in low-dose, middle-dose, high-dose and control groups (P

BACKGROUND: Non-invasive molecular imaging of recent ischemia can potentially be used to diagnose acute coronary syndrome (ACS) with high accuracy. OBJECTIVES: We hypothesized that bedside myocardial contrast echocardiography (MCE) ischemic memory imaging could be achieved with phosphatidylserine microbubbles (MB(PS)) that are retained in the microcirculation via ischemia-associated endothelial activation. METHODS: A dose-finding study was performed in healthy volunteers (n=17) to establish optimal MB(PS) dosing. Stable patients with ACS (n=30) and confirmed antecedent but resolved myocardial ischemia were studied within two hours of coronary angiography and PCI when indicated. MCE molecular imaging was performed 8 minutes after intravenous administration of MB(PS.) MCE perfusion imaging was used to assess status of the post-ischemic microcirculation. RESULTS. Based on dose-finding studies, 0.10 or 0.15 mL of MB(PS) based on body mass was selected. In patients with ACS, all but two underwent primary PCI. MCE molecular imaging signal intensity was greater in the post-ischemic risk area vs. remote territory (median [95% CI]: 56 [33–66] vs 8 [2–17] IU, p

Heme oxygenase-1 (HO-1), an inducible stress-response protein, exerts anti-oxidant and anti-apoptotic effects. However, its significance in forensic diagnosis of acute ischemic heart diseases (AIHD) such as myocardial infarction (MI) is still unknown. We examined the immunohistochemical expression of HO-1 in the heart samples to discuss their forensic significance to determine acute cardiac ischemia. The heart samples were obtained from 23 AIHD cases and 33 non-AIHD cases as controls. HO-1 positive signals in cardiomyocyte nuclear were detected in 78.2% of AIHD cases, however, that were detected in only 24.2% control cases with statistical difference between AIHD and non-AIHD groups. In contrast to HO-1 protein expression, there was no significant difference in the appearance of myoglobin pallor regions and leukocyte infiltration in the hearts between AIHD and non-AIHD groups. From the viewpoints of forensic pathology, intracardiac HO-1 expression would be considered a valuable marker to diagnose AIHD as the cause of death.

This study is aimed at investigating mechanisms and effects of Krüppel-like factor 16 (KLF16) affects myocardial ischemia-reperfusion. Patients with myocardial ischemia-reperfusion and normal volunteer were collected. C57BL6J male mice were located left anterior descending coronary artery (LAD). H9c2 cell was induced with hydrogen peroxide (H2O2) and Lipopolysaccharide (LPS). Serum KLF16 mRNA expression was increased in myocardial ischemia-reperfusion. Serum mRNA of KLF16 was positive correlation with serum creatine kinase MB (CK-MB) or creatine kinase (CK) levels in patients with myocardial ischemia-reperfusion. The expression of KLF16 mRNA and protein in mice with myocardial ischemia-reperfusion were also increased. The inhibition of KLF16 reduced oxidative stress and inflammation, and presented myocardial ischemia (MI) in vivo model of myocardial ischemia-reperfusion. Mitochondrial transcription factor A (TFAM)/peroxisome proliferator-activated receptor-beta (PPARβ) signal passage is target spot of KLF16 in Myocardial ischemia-reperfusion. TFAM interlink KLF16 in myocardial ischemia-reperfusion. TFAM participate in KLF16 affects myocardial ischemia-reperfusion. PPARβ promoter region KLF16 affects myocardial ischemia-reperfusion. These results firstly demonstrated that knock-out KLF16 reduced oxidative stress and inflammation, and presented MI in vivo model of myocardial ischemia-reperfusion through the induction of PPARβ by TFAM, may provide a novel therapeutic strategy for myocardial ischemia-reperfusion.

Premature ovarian failure (POF) is defined by amenorrhea, hypoestrogenism, elevated gonadotropin levels, and infertility. Chemotherapeutic agents are the most gonadotoxic agents that lead to POF. Although some previous studies have presented that mesenchymal stem cells (MSCs) transplantation could rescue the ovary function of POF animal models through the paracrine pathway, these mechanisms require further investigation. However, mechanisms of embryonic stem cell-derived MSCs (ES-MSCs) therapeutic effects on POF animal models have not been fully investigated yet. This study aimed to evaluate the migration and distribution of ES-MSCs in a model of chemotherapy-induced POF. Female mice received intraperitoneal injections of cyclophosphamide (Cy) to induce POF. Then, MSCs were labeled with green fluorescent protein (GFP) in vitro and injected intravenously into POF mice, and the distribution of MSCs was dynamically monitored at 1 week after transplantation. We harvested the lungs, liver, spleen, ovaries, heart, and kidneys 1 week after transplantation. The sections of these tissues were observed under the fluorescent microscope. More than 70% MSCs were successfully labeled with GFP at 72 h after labeling. MSCs were uniformly distributed in multiple organs and tissues including lungs, liver, spleen, ovaries, heart, and kidneys of POF mice. In mice, at 1week after intravenous transplantation, GFP labeled ES-MSCs were observed in the lungs, liver, spleen, ovaries, heart, and kidneys of POF mice, and the number of GFP labeled ES-MSCs in lungs, ovaries, and heart were higher than that in the spleen, kidneys, and liver. Our results revealed intravenously implanted ES-MSCs could migrate into the various tissues in chemotherapy-induced damaged POF mice.

Objectives The purpose of this study was to detect cardiovascular changes after mild severe acute respiratory syndrome coronavirus 2 infection. Background Concern exists that mild coronavirus disease 2019 may cause myocardial and vascular disease. Methods Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post-infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative control subjects were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated cardiovascular magnetic resonance and blood biomarkers). Analysis was blinded, using objective artificial intelligence analytics where available. Results A total of 149 subjects (mean age 37 years, range 18 to 63 years, 58% women) were recruited. Seropositive infections had been mild with case definition, noncase definition, and asymptomatic disease in 45 (61%), 18 (24%), and 11 (15%), respectively, with 1 person hospitalized (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T1, T2, extracellular volume fraction mapping, late gadolinium enhancement) or biomarkers (troponin, N-terminal pro–B-type natriuretic peptide). With abnormal defined by the 75 seronegatives (2 SDs from mean, e.g., ejection fraction 1,072 ms, septal T2 >52.4 ms), individuals had abnormalities including reduced ejection fraction (n = 2, minimum 50%), T1 elevation (n = 6), T2 elevation (n = 9), late gadolinium enhancement (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all N-terminal pro–B-type natriuretic peptide normal). These were distributed equally between seropositive and seronegative individuals. Conclusions Cardiovascular abnormalities are no more common in seropositive versus seronegative otherwise healthy, workforce representative individuals 6 months post–mild severe acute respiratory syndrome coronavirus 2 infection., Central Illustration

Aim To study the clinical value of markers for myocardial electrical instability in combination with echocardiographic parameters for predicting the risk of cardiovascular complications (CVC) in the postinfarction period.Material and methods This study included 118 patients with ST segment elevation myocardial infarction (STEMI) and hemodynamically significant stenosis of one coronary artery. A percutaneous coronary intervention (PCI) with stenting of the infarct-related artery was performed for all patients. On day 7-9 and at 24 and 48 weeks after the treatment, ECG Holter monitoring was performed, which included analyses of ventricular late potentials, dispersion of QT interval duration, heart rate turbulence (HRT) and variability (HRV), and heart chronotropic load (HCL). At baseline and during postinfarction week 12, all patients underwent echocardiography with calculation of indexes of end-diastolic volume (iEDV) and end-systolic volume (iESV) to verify the signs of left ventricular (LV) myocardial remodeling. The criteria for LV pathological remodeling included increases in iEDV >20 % and/or iESV >15 % at 12 weeks after STEMI. The group without remodeling, R(-), consisted of 79 (67 %) patients and the group with signs of LV pathological remodeling, R(+), consisted of 39 (33 %) patients. Quality of life and achieved endpoints were evaluated during 144 weeks.Results By week 48 in group R(-), the stabilization of electrical processes in the myocardium was more pronounced as indicated by a decrease in HFLA by 12 % (р=0.004) and by a fourfold increase in RMS (р=0.047). Only in this group, the baroreflex sensitivity restored; pathological ТРС decreased from 20 to 5% (p=0.002) by the end of the active treatment. Stabilization of the repolarization phase duration in various parts of the myocardium was more active in patients without pathological remodeling as shown by decreases in disp QTa (р=0.009), disp QTe (р=0.03), sd QTa (р=0.006), and sd QTe (р=0.009). This was not observed in the group R(+). The recovery of vagosympathetic balance due to leveling the sympathetic component also was more effective in the group R(-), which was reflected in increased spectral and temporal HRV indexes (рvs. 27.8 % (odds ratio, 11.8; 95 % confidence interval, 4.6–30.8; р=0.00001).Conclusion Pathological myocardial remodeling in early postinfarction period is associated with electrophysiological instability of the myocardium, which results in the development of CVC and low quality of life in patients with STEMI.

Cardiovascular disease is the second highest cause of death across the globe. Myocardial infarction is one of the heart diseases that cause permanent impairment of the heart wall leads to heart failure. Cellular therapy might give hope to regenerate the damaged myocardium. Single cells isolated from an excess heart tissue obtained from the correction of the right ventricular hypertrophy in patients with Tetralogy of Fallot for future heart study were investigated. Methods: Once resected, the heart tissues were transported at 37 °C, in Dulbecco's Modified Eagle's medium/ DMEM (4.5 g.L−1, antibiotic–antimycotic 3x, PRP10% (v/v)), to reach the lab within 30 min, weighted and grouped into less than 500 mg and more than 1000 mg (n = 4). Each sample was digested with 250 U.mL−1 Collagenase type V and 4U.mL−1 Proteinase XXIV in the MACS™ C-tube (Milltenyi, Germany), then dissociated using the MACS™ Octo Dissociator with Heater (Milltenyi, Germany) for 60 min at 37 °C. Results: All cells isolated were rod-shaped cells; viability was up to 90%. The cell density obtained from the 500 mg group were 4,867 ± 899 cells.mg−1 tissue weight, significantly higher compared to the 1,000 mg group; had 557 ± 490 cells.mg−1 tissue weight (mean of (n = 3) ± 95% C.l). The isolated cells were analyzed using FACs BD Flowcytometer, expressed cTnT + 13.38%, PECAM-1 + /VCAM-1- 32.25%, cKit + 7.85%, ICAM + 85.53%, indicating the cardiomyocyte progenitor cells. Conclusion: Cardiomyocytes taken from the wasted heart tissue might be a candidate of cardiomyocytes source to study interventions to the heart as it contained up to 13.38% cardiomyocytes, and 32.25% of cardiac progenitor cells. Moreover, perhaps when cardiac cell therapy needs autologous cardiomyocytes, less than 500 mg tissue weight can be considered as sufficient.

金沢大学疾患モデル総合研究センター, Background: This study chronologically evaluated the expression of the intensity and distribution of the sigma-1 receptor (σ1R) demonstrated by radiolabeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) in a rat model of myocardial ischemia and reperfusion. Methods and Results: The left coronary artery was occluded for 30 min, followed by reperfusion. Dual-tracer autoradiography with 125I-OI5V and 99 mTc-MIBI was performed to assess the spatiotemporal changes in 125I-OI5V uptake (n=5-6). Significant and peaked 125I-OI5V uptake in the ischemic area was observed at 3 days after reperfusion, and the 125I-OI5V uptake ratio of ischemic area to normally perfused left ventricular area decreased gradually from 3 to 28 days (mean value ± SD; 0.90±0.12 at 1 day, 1.89±0.19 at 3 days, 1.52±0.17 at 7 days, 1.34±0.13 at 14 days, and 1.16±0.14 at 28 days, respectively). Triple-tracer autoradiography with 125I-OI5V, 99 mTc-MIBI, and 201TlCl was performed to evaluate 125I-OI5V uptake in the ischemic area in relation to the residual perfusion at 7 days (n=4). The 125I-OI5V uptake ratio of the non-salvaged area was higher compared to that of the salvaged area in the ischemic area. 123I-OI5V and 99 mTc-MIBI SPECT/CT was performed 3 days after reperfusion (n=3), and the in vivo images showed clear uptake of 123I-OI5V in the perfusion defect area. Conclusions: The present study confirmed the spatiotemporal expression pattern of σ1R expression. Non-invasive σ1R imaging with 123I or 125I-OI5V was feasible to monitor the expression of σ1R after myocardial ischemia and reperfusion. © 2021 Japanese Circulation Society. All rights reserved.

Diabetic cardiomyopathy (DCM) is a cardiovascular complication that tends to occur in patients with diabetes, obesity, or insulin resistance, with a higher late mortality rate. Sustained hyperglycemia, increased free fatty acids, or insulin resistance induces metabolic disorders in cardiac tissues and cells, leading to myocardial fibrosis, left ventricular hypertrophy, diastolic and/or systolic dysfunction, and finally develop into congestive heart failure. The close connection between all signaling pathways and the complex pathogenesis of DCM cause difficulties in finding effective targets for the treatment of DCM. It reported that hydrogen sulfide (H2S) could regulate cell energy substrate metabolism, reduce insulin resistance, protect cardiomyocytes, and improve myocardial function by acting on related key proteins such as differentiation cluster 36 (CD36) and glucose transporter 4 (GLUT4). In this article, the relative mechanisms of H2S in alleviating metabolic disorders of DCM were reviewed, and how H2S can better prevent and treat DCM in clinical practice will be discussed.

The beneficial effect of curcumin (CU) on dietary AGEs (dAGEs) involves blocking the overexpression of proinflammatory cytokine genes in the heart and kidney tissues of experimental mice. The animals were divided into six groups (n = 6/group) and were fed a heat-exposed diet (dAGEs) with or without CU for 6 months. Their blood pressure (BP) was monitored by a computerized tail-cuff BP-monitoring system. The mRNA and protein expression levels of proinflammatory genes were analyzed by RT-PCR and western blot, respectively. A marked increase in BP (108 ± 12 mmHg vs 149 ± 15 mmHg) accompanied by a marked increase in the heart and kidney weight ratio was noted in the dAGE-fed mice. Furthermore, the plasma levels of proinflammatory molecules (C5a, ICAM-1, IL-6, MCP-1, IL-1β and TNF-α) were found to be elevated (3-fold) in dAGE-fed mice. mRNA expression analysis revealed a significant increase in the expression levels of inflammatory markers (Cox-2, iNOS, and NF-κB) (3-fold) in cardiac and renal tissues of dAGE-fed mice. Moreover, increased expression of RAGE and downregulation of AGER-1 (p

BACKGROUND The present study evaluates the development of edema, the change in the AQP3, AQP4, p53 and Bax gene expressions, and the protective effects of melatonin in rat hearts administered with cisplatin. METHODS AND RESULTS A total of 28 Wistar albino rats were divided into four groups. The vehicle was administered intraperitoneally (i.p.) to the rats in the control group. The melatonin group (Mel) received melatonin at a dose of 10 mg/kg for 13 days. The cisplatin group (Cis) received cisplatin on days 1, 5, 9 and 13 at a dose of 4 mg/kg. The rats in the cisplatin + melatonin (Cis+Mel) group underwent the procedures both in the Mel and Cis groups. Blood and left ventricular samples were taken and analyzed on day 14 of the study. AQP3, p53 and Bax gene expressions were found to be significantly increased following cisplatin administration compared to the control, while melatonin administration significantly decreased the expression of these genes (p

Introduction: ICl,stretch have been reported to be involved in the development of atrial fibrillation, so we observed the changes of transcription and translation levels of ICl,stretch in isolated atrial myocardium of heart failure canine models. Material and methods: In the control group (N = 10), five dogs were untreated and the other five received sham operation, while dogs in the heart failure group (N = 10) were implanted with cardiac pacemakers and underwent right ventricular pacing to induce heart failure. Cardiac structure and function were evaluated. The gene expression and protein level of ICl,stretch in the left atrial appendage were detected. Results: The left atrial diameter, right atrial dimension, left ventricular diastolic dimension, and right ventricular diastolic dimension were significantly larger in the heart failure group (P < 0.05). In contrast, the ejection fraction and the left ventricular shorten fraction were higher in the control group (P < 0.05). Both the mRNA and protein expression levels of ICl,stretch in atrial myocardium of the heart failure group were significantly higher compared with the control group. Conclusion: ICl,stretch might play an important role in the vulnerability to atrial fibrillation in dilated atria with heart failure and could be a potential therapeutic target for atrial fibrillation.

Background: Circulating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown. Objectives: This study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI). Methods: KBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses. Results: Circulating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = −1.78; 95% CI: (−3.17 to −0.39; P = 0.012). Conclusions: Circulating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307)

Background HSCR, a colonic neurocristopathy affecting 1/5000 births, is suggested to associate with cardiac septal defects and conotruncal malformations. However, we question subtle cardiac changes maybe more commonly present due to multi-regulations by HSCR candidate genes, in this instance, ETB. To investigate, we compared the cardiac morphology and quantitative measurements of sl/sl rat to those of the control group. Methods Eleven neonatal rats were generated from heterozygote (ETB+/−) crossbreeding. Age and bodyweight were recorded at time of sacrifice. Diffusion-staining protocols with 1.5% iodine solution was completed prior to micro-CT scanning. All rats were scanned using an in vivo micro-CT scanner, Caliper Quantum FX, followed by two quality-control scans using a custom-built ex vivo micro-CT system. All scans were reviewed for gross cardiac dysmorphology. Micro-CT data were segmented semi-automatically post-NLM filtering for: whole-heart, LV, RV, LA, RA, and aortic arch. Measurements were taken with Drishti. Following image analysis, PCR genotyping of rats was performed: five sl/sl rats, three wildtype, and three heterozygotes. Statistical comparisons on organ volume, growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control group. Results Cardiac morphology and constituents were preserved. However, significant volumetric reductions were recorded in sl/sl rats with respect to the control: whole heart (38.70%, p value = 0.02); LV (41.22%, p value = 0.01), RV (46.15%, p value = 0.02), LA (44.93%, p value = 0.06), and RA (39.49%, p value = 0.02). Consistent trend was observed in growth rate (~ 20%) and organ-volume/bodyweight ratios (~ 25%). On the contrary, measurements on aortic arch demonstrated no significant difference among the two groups. Conclusion Despite the presence of normal morphology, significant cardiac growth retardation was detected in sl/sl rat, supporting the likely association of cardiac anomalies with HSCR, at least in ETB−/− subtype. Structural reduction was likely due to a combination of failure to thrive from enteric dysfunction, alterations to CaNCC colonization, and importantly coronary hypoperfusion from elevated ET-1/ETA-mediated hypervasoconstriction. Little correlation was detected between aortic arch development and sl/sl rat, supporting minor ETB role in large vessels. Although further clinical study is warranted, HSCR patients may likely require cardiac assessment in view of potential congenital cardiac defects. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-021-02281-2., Highlights ETB−/− HSCR model was associated with body-growth impairment; neonatal sl/sl rat has 16% less bodyweight than the control group.sl/sl rat has a normal cardiac morphology.Significant reductions were detected in cardiac structures of sl/sl rats: 40% in whole-heart volume, 20% in growth rate, and 25% in whole heart/bodyweight ratios. Similar trend was observed in the measurements of LA, LV, RA, and RVNo consistent correlation was observed between ETB genotype and aortic arch sizes.These findings supported HSCR patients may have various degrees of neonatal cardiac anomalies; wholistic post-operative care should be considered, including screening for cardiac risk factors.In consideration of the result from this paper, genotyping study of patients with and without heart failure would be an interesting step study to evaluate possible correlation between ETB genotype and risks of hypertension, ischemic heart disease, exercise capacity, and heart failure. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-021-02281-2.