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Background: Although cardiac troponin T (cTnT) and troponin I(cTnI) are expressed to similar amount in cardiac tissue, cTnI often reach ten-times higher peak levels compared to cTnT in patients with myocardial necrosis such as in acute myocardial infarction (MI). In contrast, similar levels of cTnT and cTnI are observed in other situations such as stable atrial fibrillation and after strenuous exercise.Objective: Examine cTnT and cTnI levels in relation to COVID-19 disease and MI. Methods: Clinical and laboratory data from the local hospital from an observational cohort study of 27 patients admitted with COVID-19 and 15 patients with myocardial infarction (MI) that were analyzed with paired cTnT and cTnI measurement during hospital care.Results: Levels of cTnI were lower than cTnT in COVID-19 patients (TnI/TnT ratio 0.3, IQR: 0.1-0.6). In contrast, levels of cTnI were 11 times higher compared to cTnT in 15 patients with MI (TnI/TnT ratio 11, IQR: 7-14). The peak cTnI/cTnT ratio among the patients with MI following successful percutaneous intervention were 14 (TnI/ TnT ratio 14, IQR: 12-23). The 5 COVID-19 patient samples collected under possible necrotic events had a cTnI/ cTnT ratio of 5,5 (IQR: 1,9-8,3).Conclusions: In patients with COVID-19, cTnT is often elevated to higher levels than cTnI in sharp contrast to patients with MI, indicating that the release of cardiac troponin has a different cause in COVID-19 patients.

Background: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49–75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. Methods: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. Results: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00–56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. Conclusions: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

Anti-tumour efficacy of doxorubicin is hindered by the cumulative dose-dependent cardiotoxicity induced by reactive oxygen species during its metabolism. As Cinnamomum zeylanicum has proven antioxidant potential, objective of this study was to investigate the cardioprotective activity of Cinnamomum bark extract against doxorubicin induced cardiotoxicity in Wistar rats. Physicochemical and phytochemical analysis was carried out and dose response effect and the cardioprotective activity of Cinnamomum were determined in vivo. 180 mg/kg dexrazoxane was used as the positive control. Plant extracts were free of heavy metals and toxic phytoconstituents. In vivo study carried out in Wistar rats revealed a significant increase (p

Background and Aims The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. Methods This large retrospective cohort study included 2073 patients with COVID-19 having definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted and determined their associated factors and death risk by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19 with and without hepatitis B were compared after 1:3 propensity score matching. Results Of the 2073 patients, 1282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of AST and D-Bil increased early after symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal admission AST (adjusted hazard ratio [HR]: 1.39, 95%CI: 1.04-1.86, P=0.027) and D-Bil (adjusted HR: 1.66, 95%CI: 1.22-2.26, P=0.001) levels were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes. Conclusions Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, in hospitalized patients with COVID-19, is necessary., Graphical abstract, Highlights 1. Levels of AST and D-Bil elevated early after the symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of COVID-19. 2. Abnormal admission AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. 3. A novel nomogram was built based on admission AST and D-Bil levels as well as other baseline characteristics to predict the in-hospital mortality of COVID-19. 4. Hepatitis B infection was not found to be associated with the risk of lethal outcome in patients with COVID-19., Lay Summary The AST and D-Bil levels increased early after symptom initiation in deceased patients of COVID-19 and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal AST and D-Bil levels at admission were independent predictors for COVID-19 mortality. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes.

Visual Abstract, Highlights • With aging, phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness compared with control mice. • Aged wild-type equivalent mice exhibited decreasing cMyBP-C phosphorylation (S273 and S282) along with worsening cardiac function and hypertrophy similarly to what was observed in hypophosphorylated cMyBP-C mice. • Intact papillary muscle experiments suggest that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism. • Phosphorylating cMyBP-C is therefore a novel mechanism that can prevent aging-related development of cardiac dysfunction., Summary Cardiac myosin binding protein-C (cMyBP-C) phosphorylation prevents aging-related cardiac dysfunction. We tested this hypothesis by aging genetic mouse models of hypophosphorylated cMyBP-C, wild-type equivalent, and phosphorylated-mimetic cMyBP-C for 18 to 20 months. Phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness. Wild-type equivalent mice showed decreasing cMyBP-C phosphorylation along with worsening cardiac function and hypertrophy approaching those found in hypophosphorylated cMyBP-C mice. Intact papillary muscle experiments suggested that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism. Thus, phosphorylating cMyBP-C is a novel mechanism with potential to treat aging-related cardiac dysfunction.

Purpose of review: Although the respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is evident from recent data that other systems, especially cardiovascular and hematological, are also significantly affected. In fact, in severe form, COVID-19 causes a systemic illness with widespread inflammation and cytokine flood, resulting in severe cardiovascular injury. Therefore, we reviewed cardiac injury biomarkers' role in various cardiovascular complications of COVID 19 in recent studies. Recent findings: Cardiac injury biomarkers were elevated in most of the complicated cases of COVID-19, and their elevation is directly proportional to the worst outcome. Evaluation of cardiac biomarkers with markers of other organ damage gives a more reliable tool for case fatalities and future outcome. Summary: Significant association of cardiac biomarkers in COVID-19 cases helps disease management and prognosis, especially in severely ill patients.

Cardiac muscle thin filaments are composed of actin, tropomyosin, and troponin that change conformation in response to Ca2+ binding, triggering muscle contraction. Human cardiac troponin C (cTnC) is the Ca2+-sensing component of the thin filament. It contains structural sites (III/IV) that bind both Ca2+ and Mg2+ and a regulatory site (II) that has been thought to bind only Ca2+. Binding of Ca2+ at this site initiates a series of conformational changes that culminate in force production. However, the mechanisms that underpin the regulation of binding at site II remain unclear. Here, we have quantified the interaction between site II and Ca2+/Mg2+ through isothermal titration calorimetry and thermodynamic integration simulations. Direct and competitive binding titrations with WT N-terminal cTnC and full-length cTnC indicate that physiologically relevant concentrations of both Ca2+/Mg2+ interacted with the same locus. Moreover, the D67A/D73A N-terminal cTnC construct in which two coordinating residues within site II were removed was found to have significantly reduced affinity for both cations. In addition, 1 mM Mg2+ caused a 1.4-fold lower affinity for Ca2+. These experiments strongly suggest that cytosolic-free Mg2+ occupies a significant population of the available site II. Interaction of Mg2+ with site II of cTnC likely has important functional consequences for the heart both at baseline as well as in diseased states that decrease or increase the availability of Mg2+, such as secondary hyperparathyroidism or ischemia, respectively.

Objective: To systematically investigate the relationship between cardiac biomarkers and COVID-19 severity and mortality. Methods: We performed a literature search using PubMed, Web of Science, and Google Scholar. The standardized mean difference (SMD) and 95% confidence interval (CI) were applied to estimate the combined results of 67 studies. A meta-analysis of cardiac biomarkers was used to evaluate disease mortality and severity in COVID-19 patients. Results: A meta-analysis of 7812 patients revealed that patients with high levels of cardiac troponin I (SMD = 0.81 U/L, 95% CI = 0.14–1.48, P = 0.017), cardiac troponin T (SMD = 0.78 U/L, 95% CI = 0.07–1.49, P = 0.032), high-sensitive cardiac troponin I (SMD = 0.66 pg/mL, 95% CI = 0.51–0.81, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.93 U/L, 95% CI = 0.21–1.65, P = 0.012), creatine kinase-MB (SMD = 0.54 U/L, 95% CI = 0.39−0.69, P < 0.001), and myoglobin (SMD = 0.80 U/L, 95% CI = 0.57–1.03, P < 0.001) were associated with prominent disease severity in COVID-19 infection. Moreover, 9532 patients with a higher serum level of cardiac troponin I (SMD = 0.51 U/L, 95% CI = 0.37–0.64, P < 0.001), high-sensitive cardiac troponin (SMD = 0.51 ng/L, 95% CI = 0.29–0.73, P < 0.001), high-sensitive cardiac troponin I (SMD = 0.51 pg/mL, 95% CI = 0.38–0.63, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.85 U/L, 95% CI = 0.63–1.07, P < 0.001), creatine kinase-MB (SMD = 0.48 U/L, 95% CI = 0.32–0.65, P < 0.001), and myoglobin (SMD = 0.55 U/L, 95% CI = 0.45−0.65, P < 0.001) exhibited a prominent level of mortality from COVID-19 infection. Conclusion: Cardiac biomarkers (cardiac troponin I, cardiac troponin T, high-sensitive cardiac troponin, high-sensitive cardiac troponin I, high-sensitive cardiac troponin T, creatine kinase-MB, and myoglobin) should be more frequently applied in identifying high-risk COVID-19 patients so that timely treatment can be implemented to reduce severity and mortality in COVID-19 patients.

Graphical abstract, Highlights • Qingfeng Paidu decoction + Western medicine are beneficial for COVID-19. • Combined therapy improves anti-inflammation in patients with COVID-19. • Combined therapy may mitigate the extent of multi-organ impairment in COVID-19. • Mortality rate and length of stay were unaffected by Qingfeng Paidu decoction., Background Coronavirus disease 2019 (COVID-19)2 has emerged as a global pandemic. However, as effective treatments for this disease are still unclear, safe and efficient therapies are urgently needed. Qingfei Paidu decoction (QPD)3 is strongly recommended in the Chinese Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6th Edition). However, clinical research data on the effects of QPD on COVID-19 are scarce. Our study aimed to explore the effects of combined treatment with QPD and Western medicine on COVID-19. Methods In this study, 63 patients with confirmed COVID-19 were analyzed. During the first 14 days of hospitalization, patients with deteriorating symptoms were administered QPD along with Western medicine therapy (the antiviral medicine selected from interferon, lopinavir, or arbidol). The clinical characteristics and blood laboratory indices (blood routine, inflammatory factors, and multi-organ biochemical indices) were examined, and the total lung severity scores were evaluated in each patient by reviewing chest computed tomography before treatment and at the end of treatment. Results Before QPD treatment, the combined treatment group showed higher blood C-reactive protein levels and more severe pulmonary inflammation and clinical symptoms than the Western medicine treatment group. Both groups met the discharge criteria after a similar length of hospitalization. At the end of treatment, circulating white blood cells, total lymphocyte count, and glutamic-oxaloacetic transaminase levels improved dramatically in both groups (P 0.05). Conclusion The combination of QPD with Western medicine demonstrated significant anti-inflammatory effects compared with those of only Western medicine in patients with mild and moderate COVID-19; however, neither mortality nor length of hospitalization was affected. Moreover, the combined treatment tended to mitigate the extent of multi-organ impairment. Long-term randomized controlled trials with follow-up evaluations are required to confirm the results presented here.

Highlights • COVID-19 patients with poorly-controlled HbA1c showed increased worsening rate. • A HbA1c level of 8.6% (70 mmol/mol) was the optimal cutoff value. • Antidiabetic/antihypertensive drug use was not related to worsening in COVID-19 patients., Aims This study evaluated the impact of previous glycemic control and in-hospital use of antidiabetic/antihypertensive drugs on the prognosis of COVID-19 patients with diabetes. Methods In this retrospective cohort study, consecutive inpatients with laboratory confirmed COVID-19 were enrolled from Tongji Hospital (Wuhan, China). Patients without diabetes were matched to those with diabetes based on age, sex, and comorbidities. All patients were followed up to a clinical endpoint (discharge, worsening including transferring to ICU or immediate death). Data and outcomes were extracted from medical records and analyzed. Results 64 patients with pre-existing diabetes were included in this study, with 128 matched patients without diabetes included as a control group. Patients with diabetes had a higher rate of worsening (18.8% versus 7.8%, p = 0.025). Multivariable regression showed increased odds of worsening associated with previous glycemic control reflected by HbA1c (odds ratio 3.29, 95% CI 1.19–9.13, p = 0.022) and receiver-operating characteristics (ROC) curve identified HbA1c of 8.6% (70 mmol/mol) as the optimal cut-off value. Univariate analysis demonstrated the in-hospital use of antidiabetic/antihypertensive drugs were not associated with a higher risk of worsening. Conclusions COVID-19 patients with diabetes had a higher risk of worsening, especially those with poorly-controlled HbA1c, with an optimal cut-off value of 8.6%. The in-hospital use of antidiabetic/antihypertensive drugs were not associated with increased odds of worsening in patients with diabetes.

Highlights • Clinical outcomes of 11 patients with 17 pleural drainages are reported. • The P/F ratio, PEEP and P(A-a)O2 improved after the procedure. • Dosage of norepinephrine, MAP and lactate kept deteriorating after the procedure. • 41.6% CVCS were obstructed while no chest tubes were obstructed., Background For patients with COVID-19, pneumothorax and hydrothorax are suggested to be negative prognostic indicators. However, the management of these two conditions has rarely been discussed. We aimed to describe the clinical outcomes of pleural drainage in critically ill patients with COVID-19. Methods A total of 17 pleural drainages were performed in 11 critically ill patients with pneumothorax or hydrothorax. Either chest tubes or central venous catheters (CVCs) were used. The clinical outcomes, including respiratory and circulation indicators at 24 h and 1 h before the procedure and 24 h and 48 h after the procedure, were retrospectively recorded. Results (1) Following pleural drainage, there was a 19.1% improvement in the PaO2/FiO2 ratio from 147.4 mmHg (-1 h) to 175.5 mmHg (24 h), while the mean positive end expiratory pressure (PEEP) decreased from 10.7 cmH2O (-1 h) to 8.9 cmH2O (24 h) and 8.1 cmH2O (48 h). The A-a gradients decreased from 313.3 mmHg (-1 h) to 261.3 mmHg (24 h). (2) The dosage of norepinephrine increased from 0.15 μg/kg/min (-1 h) to 0.40 μg/kg/min (24 h). (3) No haemorrhagic or infectious complications were observed. (4) A total of 41.6% of CVCs were partially or fully obstructed, while no chest tubes were obstructed. Conclusion For critically ill patients with COVID-19, pleural drainage leads to a significant improvement in oxygenation and gas exchange, but the deterioration of circulation is not reversed. It is safe to perform pleural drainage even though anticoagulation therapy and glucocorticoids are widely used. Chest tubes rather than CVCs are recommended.

Purpose To clarify the epidemiological, clinical, and therapeutic features of patients with severe COVID-19. Methods In this study, we enrolled 681 patients with confirmed cases of severe COVID-19. The epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected. Results The median age of the study participants was 65 years, 53.2% were male, and 104 (15.3%) died. Age, Neutrophil-To-Lymphocyte Ratio (NLR), acute myocardial injury, and levels of C-reactive protein (CRP), lactate dehydrogenase (LDH), and CD3 T cells counts were independently and negatively associated with death, while arbidol and ribavirin were protective from death. The combination of NLR and acute myocardial injury on admission (AUC = 0.914) predicted mortality better than NLR, CRP, LDH, and acute myocardial injury. There were 312 (45.8%) patients with cardiovascular disease, of whom 23.4% died. β-blockers, ACEI/ARB, arbidol, and ribavirin might have a beneficial effect for severe COVID-19 patients with cardiovascular disease. Conclusion The combination of NLR and acute myocardial injury on admission was highly predictive of mortality and survival. Clinicians should adopt more aggressive strategies for patients with a high NLR (>6.66) combined with myocardial injury. β-blockers and ACEI/ARB, as well as arbidol and ribavirin, were effective in COVID-19 patients with cardiovascular disease., Highlights • Combination of NLR and acute myocardial injury could predict mortality. • Patients combined with higher NLR and myocardial injury need aggressive strategies. • Arbidol and ribavirin may be benefit to severe COVID-19. • β-blockers and ACEI/ARB are effective for patients with cardiovascular disease.

Introduction This study describes presentation, cardiovascular abnormalities, etiology, and outcome of canine myocarditis in geographic areas not endemic for Trypanosoma or Leishmania. Animals Sixty-four (presumed antemortem diagnosis) and 137 (postmortem diagnosis only) client-owned dogs at two tertiary care facilities were included. Materials and methods Medical records of dogs with clinical or histopathological diagnosis of myocarditis were reviewed retrospectively. Results Common examination findings in dogs with a presumed antemortem diagnosis included fever (21%) and heart murmur (19%). Median cardiac troponin I was 12.2 ng/mL (range: 0.2–808.0 ng/mL), and troponin exceeded 1.0 ng/mL in 26 of 29 (90%) dogs. Ventricular ectopy was the most common arrhythmia (54%), whereas decreased left ventricular systolic function was the most common echocardiographic abnormality (56%). An infectious etiology was diagnosed in 35 of 64 (55%) dogs. Confirmed infectious etiologies included bacterial sepsis (n = 9) or extension of endocarditis (3), toxoplasmosis or neosporosis (3), parvovirus (2), and one case each of bartonellosis, trypanosomiasis, leptospirosis, and dirofilariasis. Median survival time was 4 days (range: 0–828 days) for all dogs vs. 82 days for dogs who survived at least 2 weeks after diagnosis. Presence of pericardial effusion or azotemia was a significant predictor of non-survival. The most common inflammatory infiltrate on histopathology was neutrophilic (47%), and 20 of 137 (14.5%) dogs had concurrent bacterial endocarditis on postmortem. Conclusions Bacterial infection was the most common confirmed etiology of myocarditis in this study. Prognosis for canine myocarditis is guarded and similar to that reported for infective endocarditis. Criteria for the antemortem diagnosis of canine myocarditis are suggested.

Background Type 2A protein phosphatase (PP2A) enzymes are serine/threonine phosphatases which comprise a scaffold A subunit, a regulatory B subunit and a catalytic C subunit, and have been implicated in the dephosphorylation of multiple cardiac phosphoproteins. B subunits determine subcellular targeting, substrate specificity and catalytic activity, and can themselves be regulated by post-translational modifications. We explored potential β-adrenergic regulation of PP2A in cardiomyocytes through phosphorylation of the regulatory B subunit isoform B56δ. Methods and results Phosphate affinity SDS-PAGE and immunoblot analysis revealed increased phosphorylation of B56δ in adult rat ventricular myocytes (ARVM) exposed to the β-adrenergic receptor (βAR) agonist isoprenaline (ISO). Phosphorylation of B56δ occurred at S573, primarily through stimulation of the β1AR subtype, and was dependent on PKA activity. The functional role of the phosphorylation was explored in ARVM transduced with adenoviruses expressing wild type (WT) or non-phosphorylatable (S573A) B56δ, fused to GFP at the N-terminus. C subunit expression was increased in ARVM expressing GFP-B56δ-WT or GFP-B56δ-S573A, both of which co-immunoprecipitated with endogenous C and A subunits. PP2A activity in cell lysates was increased in response to ISO in ARVM expressing GFP-B56δ-WT but not GFP-B56δ-S573A. Immunoblot analysis of the phosphoproteome in ARVM expressing GFP-B56δ-WT or GFP-B56δ-S573A with antibodies detecting (i) phospho-serine/threonine residues in distinct kinase substrate motifs or (ii) specific phosphorylated residues of functional importance in selected proteins revealed a comparable phosphorylation profile in the absence or presence of ISO stimulation. Conclusions In cardiomyocytes, βAR stimulation induces PKA-mediated phosphorylation of the PP2A regulatory subunit isoform B56δ at S573, which increases associated PP2A catalytic activity. This is likely to regulate the phosphorylation status of specific B56δ-PP2A substrates, which remain to be identified., Highlights • PP2A subunit B56δ is phosphorylated on β-adrenergic stimulation of cardiomyocytes. • Phosphorylation occurs at Ser573 and increases B56δ-PP2A catalytic activity. • Response is mediated by the β1-adrenoceptor subtype and protein kinase A. • Phosphorylated B56δ abundance is increased in pathological cardiac hypertrophy.

Visual Abstract, Highlights • SARP of coronary veins alone or in combination with focal MH-SARP provided cardioprotection following occlusion of the left anterior descending artery. • Significant reduction in infarct size was achieved with MH-SARP and SARP with preservation of myocardial function and cell integrity. • MH-SARP or SARP may provide a clinically relevant percutaneous short-term option of cardiac support to high-risk patients undergoing percutaneous coronary intervention., Summary Mild hypothermia (MH) and retroperfusion are 2 techniques proposed to reduce infarct size due to myocardial infarction. The authors evaluated the effects of focal MH combined with selective coronary venous autoretroperfusion (SARP) as an acute cardioprotective modality before percutaneous coronary intervention (PCI) in a swine model of left ventricular myocardial infarction. Significant reduction in infarct size with preservation of cardiac function and cardiomyocyte viability were achieved. The authors propose that SARP alone or in combination with MH may provide a clinically relevant percutaneous short-term option of cardiac support to high-risk patients undergoing PCI.

Visual Abstract, Highlights • A mitochondrial-derived peptide therapy, HNG, was safe and was delivered as adjunctive therapy with standard-of-care reperfusion in a translational large animal model of myocardial ischemia/reperfusion injury. • HNG reduced infarct size per area-at-risk by 41% with an ischemic time of 60 min followed by 48 h of reperfusion. • The infarct-sparing effects of HNG were abolished when the ischemic time was increased to 75 min followed by 48 h of reperfusion. • The use of rigorous translational large animal models that account for clinically relevant variables is a prerequisite to better predict the clinical efficacy and outcomes of novel therapeutic strategies., Summary With the complexities that surround myocardial ischemia/reperfusion (MI/R) injury, therapies adjunctive to reperfusion that elicit beneficial pleiotropic effects and do not overlap with standard of care are necessary. This study found that the mitochondrial-derived peptide S14G-humanin (HNG) (2 mg/kg), an analogue of humanin, reduced infarct size in a large animal model of MI/R. However, when ischemic time was increased, the infarct-sparing effects were abolished with the same dose of HNG. Thus, although the 60-min MI/R study showed that HNG cardioprotection translates beyond small animal models, further studies are needed to optimize HNG therapy for longer, more patient-relevant periods of cardiac ischemia.

Visual Abstract, Highlights • A transient elevation in preload produces mechanical stretch-induced myocyte injury and measurable cardiac troponin I release that is associated with reversible contractile dysfunction and myocyte apoptosis. • Using a porcine model of intermittent pressure overload, this study demonstrates that repetitive exposure to cyclical elevations in preload elicits significant myocyte loss, yet left ventricular systolic function is preserved and chamber dilatation is absent. • Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis produces a reduction in left ventricular diastolic compliance that protects the heart from subsequent stretch-induced myocyte injury. • These results support a novel paradigm that links cardiac adaptations to repetitive stretch-induced injury with the pathogenesis of myocardial stiffening and may explain how reductions in left ventricular diastolic compliance can occur in the absence of sustained hypertension or anatomic hypertrophy., Summary Swine subjected to 2 weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but left ventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LV ejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiac adaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain how LV stiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

Objectives Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. Background Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. Methods In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. Results iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p, Graphical abstract

Summary Myocardial infarction (MI) remains a dreadful disease around the world, causing irreversible sequelae that shorten life expectancy and reduce quality of life despite current treatment. Here, the authors engineered a cell-enriched myocardial graft, composed of a decellularized myocardial matrix refilled with adipose tissue-derived progenitor cells (EMG-ATDPC). Once applied over the infarcted area in the swine MI model, the EMG-ATDPC improved cardiac function, reduced infarct size, attenuated fibrosis progression, and promoted neovascularization of the ischemic myocardium. The beneficial effects exerted by the EMG-ATDPC and the absence of identified adverse side effects should facilitate its clinical translation as a novel MI therapy in humans., Visual Abstract, Highlights • MI remains a major cause of morbidity and mortality despite major treatment advances achieved during the past decades. • Administration of an engineered myocardial graft, composed of decellularized myocardial matrix refilled with ATDPCs (EMG-ATDPC), in a porcine pre-clinical MI model, may support cardiac recovery following MI. • Thirty days post-EMG-ATDPC implantation, cardiac magnetic resonance imaging and comprehensive histological analysis were performed to evaluate its impact on myocardial restoration. • EMG-ATDPC resulted in better left ventricular ejection fraction, higher vessel density and neovascularization, and reduced infarct size by 68%, as well as limited fibrosis. • Accordingly, EMG-ATDPC is ready to start the translational avenue toward phase I first-in-man clinical trials.

Aim To describe the clinical characteristics and risk factors associated with the progression of COVID-19 in elderly diabetes patients. Methods This was a retrospective cohort study, including elderly COVID-19 patients admitted to Wuhan Huoshenshan Hospital between February 10 and 13, 2020. Demographic data, medical history, signs and symptoms, and laboratory parameters were collected and analysed. Results We included 131 elderly COVID-19 patients (50 patients with diabetes). COVID-19 diabetes patients experienced more severe pneumonia and abnormal organ functions than non-diabetes patients (P 8.0 mmol/L or maximum BG value > 12.0 mmol/L in all elderly patients, and BG value on admission > 5.1 mmol/L or maximum BG value > 5.4 mmol/L in non-diabetes patients. Conclusions Diabetes is an independent important risk factor, and glucose levels associate closely with COVID-19 progression in elderly patients.

Background: High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov. Methods: We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment. Keywords: High-sensitivity cardiac troponin, Immunoassay, Analytical characteristics, Clinical performance, 99th percentile, Sex-specific 99th percentile cutoffs

Ipilimumab and nivolumab for melanoma induced smoldering myocarditis remitting with steroids. Rechallenge with nivolumab produced steroid-refractory myocarditis confirmed by electron microscopy. Tacrolimus and mycophenolate transiently reduced inflammation, but antithymocyte globulin induced remission. Cardiomyopathy with fatty infiltration ensued, but the patient succumbed to rampant melanoma progression after lymphocyte depletion. (Level of Difficulty: Advanced.), Graphical abstract, Ipilimumab and nivolumab for melanoma induced smoldering myocarditis remitting with steroids. Rechallenge with nivolumab produced steroid-refractory…

Objective Myocardial infarction remains the number one killer disease worldwide. Cellular therapy using cardiac c-kit cells (CCs) are capable of regenerating injured heart. Previous studies showed mesenchymal stem cell-derived (MSC) extracellular matrices can provide structural support and are capable of regulating stem cell functions and differentiation. This study aimed to evaluate the effects of human MSC-derived matrices for CC growth and differentiation. Methods Human Wharton's Jelly-derived MSCs were cultured in ascorbic acid supplemented medium for 14 days prior to decellularisation using two methods. 1% SDS/Triton X-100 (ST) or 20 mM ammonia/Triton X-100 (AT). CCs isolated from 4-week-old C57/BL6N mice were cultured on the decellularised MSC matrices, and induced to differentiate into cardiomyocytes in cardiogenic medium for 21 days. Cardiac differentiation was assessed by immunocytochemistry and qPCR. All data were analysed using ANOVA. Results In vitro decellularisation using ST method caused matrix delamination from the wells. In contrast, decellularisation using AT improved the matrix retention up to 30% (p, Highlights • Ammonia is better than SDS for decellularization of cells in 2D culture. • ECM confers cardiac c-kit cell resistance towards oxidative stress. • ECM minimally promotes cardiac c-kit cell cardiomyocyte differentiation.

We previously reported that a restrictive N-terminal truncation of cardiac troponin I (cTnI-ND) is up-regulated in the heart in adaptation to hemodynamic stresses. Over-expression of cTnI-ND in the hearts of transgenic mice revealed functional benefits such as increased relaxation and myocardial compliance. In the present study, we investigated the subsequent effect on myocardial remodeling. The alpha-smooth muscle actin (α-SMA) isoform is normally expressed in differentiating cardiomyocytes and is a marker for myocardial hypertrophy in adult hearts. Our results show that in cTnI-ND transgenic mice of between 2 and 3 months of age (young adults), a significant level of α-SMA is expressed in the heart as compared with wild-type animals. Although blood vessel density was increased in the cTnI-ND heart, the mass of smooth muscle tissue did not correlate with the increased level of α-SMA. Instead, immunocytochemical staining and Western blotting of protein extracts from isolated cardiomyocytes identified cardiomyocytes as the source of increased α-SMA in cTnI-ND hearts. We further found that while a portion of the up-regulated α-SMA protein was incorporated into the sarcomeric thin filaments, the majority of SMA protein was found outside of myofibrils. This distribution pattern suggests dual functions for the up-regulated α-SMA as both a contractile component to affect contractility and as possible effector of early remodeling in non-hypertrophic, non-failing cTnI-ND hearts., Highlights • N-terminal truncated cardiac troponin I (cTnI-ND) upregulates α-smooth muscle actin. • This myocardial hypertrophy marker is expressed early in cardiomyocytes. • Increased relaxation by cTnI-ND has a potent effect on myocardial remodeling. • The majority of α-smooth muscle actin was found outside of myofibrils.

Brugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the individual genetic background of a patient. Patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPS-CM) may uncover cellular phenotypical characteristics not observed in heterologous models. Our objective was to determine the properties of the sodium current in iPS-CM with a mutation in SCN5A associated with Brugada syndrome. Dermal fibroblasts from a Brugada syndrome patient with a mutation in SCN5A (c.1100G > A, leading to Nav1.5_p.R367H) were reprogrammed to iPS cells. Clones were characterized and differentiated to form beating clusters and sheets. Patient and control iPS-CM were structurally indistinguishable. Sodium current properties of patient and control iPS-CM were compared. These results were contrasted with those obtained in tsA201 cells heterologously expressing sodium channels with the same mutation. Patient-derived iPS-CM showed a 33.1–45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation. Co-expression of wild-type and mutant channels in tsA201 cells did not compromise channel trafficking to the membrane, but resulted in a reduction of 49.8% in sodium current density without affecting any other parameters. Cardiomyocytes derived from iPS cells from a Brugada syndrome patient with a mutation in SCN5A recapitulate the loss of function of sodium channel current associated with this syndrome; including pro-arrhythmic changes in channel function not detected using conventional heterologous expression systems., Highlights • iPS-CM were generated from a Brugada Syndrome patient who carries an SNV in SCN5A. • Patient-specific iPS-CM show a loss of function of the sodium current. • Use of iPS-CM uncovers changes in INa properties not apparent in tsA201 cells.

The field of point-of-care (POC) testing technology is developing quickly and producing instruments that are increasingly reliable, while their size is being gradually reduced. Proteins are a common target for POC analyses and the detection of protein markers typically involves immunoassays aimed at detecting different groups of proteins such as tumor markers, inflammation proteins, and cardiac markers; but other techniques can also be used to analyze plasma proteins. In the case of nucleic acids, hybridization and amplification strategies can be used to record electromagnetic or electric signals. These techniques allow for the identification of specific viral or bacterial infections as well as specific cancers. In this review, we consider some of the latest advances in the analysis of specific nucleic acid and protein biomarkers, taking into account their trend toward miniaturization and paying special attention to the technology that can be implemented in future applications, such as lab-on-a-chip instruments.

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from gene mutations to the HCM phenotype remain incompletely understood, partially because current mouse models of HCM do not faithfully reflect the human situation and early hypertrophy confounds the interpretation of functional alterations. The goal of this study was to evaluate whether myofilament Ca2+ sensitization and diastolic dysfunction are associated or precede the development of left ventricular hypertrophy (LVH) in HCM. We evaluated the function of skinned and intact cardiac myocytes, as well as the intact heart in a recently developed Mybpc3-targeted knock-in mouse model carrying a point mutation frequently associated with HCM. Compared to wild-type, 10-week old homozygous knock-in mice exhibited i) higher myofilament Ca2+ sensitivity in skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster Ca2+ transient decay in intact myocytes, and iii) LVH, reduced fractional shortening, lower E/A and E′/A′, and higher E/E′ ratios by echocardiography and Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit LVH or systolic dysfunction, but exhibited higher myofilament Ca2+ sensitivity, faster Ca2+ transient decay, and diastolic dysfunction. These data demonstrate that myofilament Ca2+ sensitization and diastolic dysfunction are early phenotypic consequences of Mybpc3 mutations independent of LVH. The accelerated Ca2+ transients point to compensatory mechanisms directed towards normalization of relaxation. We propose that HCM is a model for diastolic heart failure and this mouse model could be valuable in studying mechanisms and treatment modalities., Highlights ► Absence of left ventricular hypertrophy in heterozygous Mybpc3-targeted knock-in mice. ► Myofilament Ca2+ sensitization in heterozygous Mybpc3-targeted knock-in mice. ► Diastolic dysfunction independent of left ventricular hypertrophy. ► Hypertrophic cardiomyopathy as a model of diastolic heart failure.

Familial hypertrophic cardiomyopathy (FHC) is characterized by severe abnormal cardiac muscle growth. The traditional view of disease progression in FHC is that an increase in the Ca2 +-sensitivity of cardiac muscle contraction ultimately leads to pathogenic myocardial remodeling, though recent studies suggest this may be an oversimplification. For example, FHC may be developed through altered signaling that prevents downstream regulation of contraction. The mutation L29Q, found in the Ca2 +-binding regulatory protein in heart muscle, cardiac troponin C (cTnC), has been linked to cardiac hypertrophy. However, reports on the functional effects of this mutation are conflicting, and our goal was to combine in vitro and in situ structural and functional data to elucidate its mechanism of action. We used nuclear magnetic resonance and circular dichroism to solve the structure and characterize the backbone dynamics and stability of the regulatory domain of cTnC with the L29Q mutation. The overall structure and dynamics of cTnC were unperturbed, although a slight rearrangement of site 1, an increase in backbone flexibility, and a small decrease in protein stability were observed. The structure and function of cTnC was also assessed in demembranated ventricular trabeculae using fluorescence for in situ structure. L29Q reduced the cooperativity of the Ca2 +-dependent structural change in cTnC in trabeculae under basal conditions and abolished the effect of force-generating myosin cross-bridges on this structural change. These effects could contribute to the pathogenesis of this mutation., Graphical abstract, Highlights • The cTnC L29Q mutation causes a small change in the NMR structure of site 1 in cTnC. • L29Q reduces the cooperativity of Ca2 +-dependent structural changes in cTnC in situ. • L29Q removes the impact of force-generating myosin heads on cTnC structural changes.

Background: Patients with manifest atrioventricular accessory pathways (mAPs) have a greater tendency to develop atrial fibrillation (AF) compared with patients with concealed atrioventricular accessory pathways (cAPs). However, the risk factors of developing AF in patients with various atrioventricular accessory pathways (APs) are not clear. Methods: This retrospective study included 460 symptomatic patients with either cAPs (n = 246) or mAPs (n = 214) who underwent electrophysiological study and successful radiofrequency catheter ablation of APs. Clinical and electrophysiological characteristics were compared between cAPs and mAPs and between AF and non-AF groups with cAPs or mAPs. Independent risk factors of AF were analyzed using multivariate logistic regression. Results: AF was more frequent in mAPs group than in cAPs group (23.4% vs 9.8%, p