Cardiac Injury Biomarkers Research Articles

Estrogen downregulates CD73/adenosine axis hyperactivity via adaptive modulation PI3K/Akt signaling to prevent myocarditis and arrhythmias during chronic catecholamines stress

BackgroundDuring myocardial damage, the sex hormone estrogen and CD73, the main enzyme that converts AMP into adenosine, are cardioprotective molecules. However, it is unclear how these two molecules work together to provide cardioprotection. The current study aimed to elucidate the interaction between estrogen and CD73 under chronic stress.MethodsOvariectomy and SHAM operations were done on FVB wild-type (WT) female mice. Two weeks after the operation, the mice were treated with daily isoproterenol (10 mg/kg/day) injections for 14 days. The effect of E2 on relevant cardiac injury biomarkers (BNP, ANP), myocardial morphology (cardiomyocyte surface area), electrocardiography, CD73 protein expression and activity, and macrophage (CD86 + and CD206 +) infiltrations were assessed. In vitro, H9C2 cells were treated with 1 nM of estrogen and 10 mM APCP (CD73 inhibitor α, β-methylene adenosine-5'-diphosphate), 10 µM isoproterenol and 20 µm LY294002 (PI3K inhibitor) for 24 h and western blot was done to elucidate the mechanism behind the effect of estrogen on the CD73/adenosine axis.ResultsEstrogen deficiency during chronic catecholamine stress caused myocardial injury, thereby triggering the hyperactivity of the CD73/adenosine axis, which aggravated myocarditis, adverse remodeling, and arrhythmias. However, estrogen normalizes CD73/Adenosine axis via the upregulation of PI3K/Akt pathways to prevent adverse outcomes during stress. In vivo results showed that the inhibition of PI3K significantly decreased PI3K/Akt pathways while upregulating the CD73/adenosine axis and apoptosis.ConclusionEstrogen’s pleiotropy cardioprotection mechanism during stress includes its normalization of the CD73/Adenosine axis via the PI3K/Akt pathway.9z1eijmQFGaVTY6LcoepL6Video

Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition.

Reperfusion is essential for ischemic myocardium but paradoxically leads to myocardial damage that worsens cardiac functions. Ferroptosis often occurs in cardiomyocytes during ischemia/reperfusion (I/R). The SGLT2 inhibitor dapagliflozin (DAPA) exerts cardioprotective effects independent of hypoglycemia. Here, we investigated the effect and potential mechanism of DAPA against myocardial ischemia/reperfusion injury (MIRI)-related ferroptosis using the MIRI rat model and hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocytes. Our results show that DAPA significantly ameliorated myocardial injury, reperfusion arrhythmia, and cardiac function, as evidenced by alleviated ST-segment elevation, ameliorated cardiac injury biomarkers including cTnT and BNP and pathological features, prevented H/R-triggered cell viability loss in vitro. In vitro and in vivo experiments showed that DAPA inhibited ferroptosis by upregulating the SLC7A11/GPX4 axis and FTH and inhibiting ACSL4. DAPA notably mitigated oxidative stress, lipid peroxidation, ferrous iron overload, and reduced ferroptosis. Subsequently, network pharmacology and bioinformatics analysis suggested that the MAPK signaling pathway was a potential target of DAPA and a common mechanism of MIRI and ferroptosis. DAPA treatment significantly reduced MAPK phosphorylation in vitro and in vivo, suggesting that DAPA might protect against MIRI by reducing ferroptosis through the MAPK signaling pathway.

Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest

BackgroundGiven emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling. MethodsSwine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis. ResultsCompared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np. ConclusionsT3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Protective Role of Shenmai Injection on Radiation-Induced Heart Injury.

Radiation-induced heart injury (RIHI) limits the dose delivery of radiotherapy for thoracic cancer. Shenmai injection (SMI) is reported to have potential cytoprotective properties and is commonly used in cardiovascular diseases. So, we aimed to investigate the potential protective effects of SMI treatment on RIHI. In this study, we established the RIHI model using Sprague-Dawley rats and H9c2 cell line. In vivo, the biochemical assay was used to measure serum cardiac injury-related biomarkers and echocardiography to evaluate heart function. The pathological analysis was also applied to observe the myocardial structural changes. In vitro, we further measured the cell viability and reactive oxygen species (ROS) levels after irradiation with or without SMI treatment. Our data showed the administration of SMI reduced the level of serum cardiac injury biomarkers and ameliorated cardiac dysfunction after irradiation in rats. Pathological analysis revealed that SMI mitigated cardiac structural damage, fibrosis, and macrophage infiltration. Besides, treatment with SMI increased cell viability and decreased excess ROS production after irradiation in vitro. Taken together, our study demonstrated the protective role of SMI treatment on RIHI by inhibiting oxidative stress and decreasing structural remodeling.

Metformin and Dapagliflozin Attenuate Doxorubicin-Induced Acute Cardiotoxicity in Wistar Rats: An Electrocardiographic, Biochemical, and Histopathological Approach

Doxorubicin is a widely used anticancer drug whose efficacy is limited due to its cardiotoxicity. There is no ideal cardioprotection available against doxorubicin-induced cardiotoxicity. This study aimed to investigate the anticipated cardioprotective potential of metformin and dapagliflozin against doxorubicin-induced acute cardiotoxicity in Wistar rats. At the beginning of the experiment, cardiac screening of experimental animals was done by recording an electrocardiogram (ECG) before allocating them into the groups. Thereafter, a total of thirty healthy adult Wistar rats (150–200 g) were randomly divided into five groups (n = 6) and treated for eight days as follows: group I (normal control), group II (doxorubicin control), group III (metformin 250 mg/kg/day), group IV (metformin 180 mg/kg/day), and group V (dapagliflozin 0.9 mg/kg/day). On the 7th day of the treatment phase, doxorubicin 20 mg/kg was administered intraperitoneal to groups II, III, IV, and V. On the 9th day (immediately after 48 h of doxorubicin administration), blood was collected from anesthetized animals for glucose, lipid profile, CK-MB & AST estimation, and ECG was recorded. Later, animals were sacrificed, and the heart was dissected for histopathological examination. We found that compared to normal control rats, CK-MB, AST, and glucose were significantly increased in doxorubicin control rats. There was a significant reversal of doxorubicin-induced hyperglycemia in the rats treated with metformin 250 mg/kg compared to doxorubicin control rats. Both metformin (180 mg/kg and 250 mg/kg) and dapagliflozin (0.9 mg/kg) significantly altered doxorubicin-induced ECG changes and reduced the levels of cardiac injury biomarkers CK-MB and AST compared to doxorubicin control rats. Metformin and dapagliflozin protected the cellular architecture of the myocardium from doxorubicin-induced myocardial injury. Current study revealed that both metformin and dapagliflozin at the FDA-recommended antidiabetic doses mitigated doxorubicin-induced acute cardiotoxicity in Wistar rats. The obtained data have opened the perspective to perform chronic studies and then to clinical studies to precisely consider metformin and dapagliflozin as potential chemoprotection in the combination of chemotherapy with doxorubicin to limit its cardiotoxicity, especially in patients with comorbid conditions like type II diabetes mellitus.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy

BackgroundCirculating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. Methods and ResultsHigh-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. Conclusionshs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Beneficial effect of TLR4 blockade by a specific aptamer antagonist after acute myocardial infarction

Experimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction.

Cardiac Magnetic Resonance Imaging of COVID-19-Associated Cardiac Sequelae: A Systematic Review.

Many COVID-19 survivors experience persistent COVID-19 related cardiac abnormalities weeks to months after recovery from acute SARS-CoV-2 infection. Non-invasive cardiac magnetic resonance (CMR) imaging is an important tool of choice for clinical diagnosis of cardiac dysfunctions. In this systematic review, we analyzed the CMR findings and biomarkers of COVID-19 related cardiac sequela after SARS-CoV-2 infection. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we conducted a systematic review of studies that assessed COVID-19 related cardiac abnormalities using cardiovascular magnetic resonance imaging. A total of 21 cross-sectional, case-control, and cohort studies were included in the analyses. Ten studies reported CMR results 3 months after SARS-CoV-2 infection and 11 studies 3 months after SARS-CoV-2 infection. Abnormal T1, abnormal T2, elevated extracellular volume, late gadolinium enhancement and myocarditis was reported less frequently in the 3-month studies. Eight studies reported an association between biomarkers and CMR findings. Elevated troponin was associated with CMR pathology in 5/6 studies, C-reactive protein in 3/5 studies, N-terminal pro-brain natriuretic peptide in 1/2 studies, and lactate dehydrogenase and D-dimer in a single study. The rate of myocarditis via CMR was 18% (154/868) across all studies. Most SARS-CoV-2 associated CMR abnormalities resolved over time. There were CMR abnormalities associated with SARS-CoV-2 infection and most abnormalities resolved over time. A panel of cardiac injury and inflammatory biomarkers could be useful in identifying patients who are likely to present with abnormal CMR pathology after COVID-19. Multiple mechanisms are likely responsible for COVID-19 induced cardiac abnormalities.

Effect of combined lipid-lowering therapy on atherosclerotic plaque vulnerability in patients with acute coronary syndrome (Combi-LLT ACS): randomized trial protocol

Aim. To study the effect of high-dose combined lipid-lowering therapy (statins + ezetimibe vs statins + PCSK9 inhibitors) on plaque vulnerability assessed using multimodal imaging (coronary computed tomography angiography (CCTA) and optical coherence tomography, as well as biomarkers in patients with acute coronary syndrome (ACS).Material and methods. This open, prospective, randomized, single-center study will include 120 patients admitted urgently with an ACS. All patients will undergo percutaneous coronary intervention of the infarct-related artery, as well as intracoronary imaging using optical coherence tomography of one or two noninfarct-related arteries. During hospitalization, patients will receive standard therapy for ACS according to clinical guidelines, while statins will initially be prescribed at a maximum dosage of atorvastatin 80 mg/rosuvastatin 40 mg.Patients who showed high compliance and did not reach the target low-density lipoprotein cholesterol (LDL-C) values (≤1,4 mmol/l) 1 month after myocardial infarction/unstable angina at the second visit will be randomized into two groups. Patients of group 1 will receive PCSK9 inhibitors (alirocumab 150 mg by subcutaneous injection once every 2 weeks or evolocumab 140 mg by subcutaneous injection once every 2 weeks) in addition to maximum statin therapy (atorvastatin 80 mg/rosuvastatin 40 mg), while group 2 participants will take ezetimibe at a dose of 10 mg in combination with the maximum dose of statins. In addition, at the second visit, patients will undergo CCTA, assess the cardio-ankle vascular index (CAVI) index and laboratory tests (complete blood count (neutrophil-to-lymphocyte ratio NLR), lipid profile, alanine aminotransferase (ALT), aspartate aminotransferase (AST), Troponin I, Galectin-3, high-sensitivity C-reactive protein (hs-CRP), metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), neutrophil gelatinase-associated lipocalin (NGAL). Total follow-up will last 52 weeks. At the final visit, patients will undergo CCTA, assessment of the CAVI index and laboratory status (NLR, lipid profile, ALT, AST), Troponin I, Galectin-3, hs-CRP, MMP-9, TIMP-1, NGAL).Primary endpoint: reduction in plaque vulnerability according CCTA in non-infarct-related coronary arteries Secondary endpoints: death, stent thrombosis/restenosis, non-fatal myocardial infarction, readmissions with progressive angina, repeat revascularization; changes of the lipid profile (total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides) against the background of maximum combination therapy with statin + PCSK9 inhibitors or statin + ezetimibe; changes of the biomarkers of cardiac injury (Troponin I), inflammation (NLR, hs-CRP, NGAL, Galectin-3) and matrix remodeling (MMP-9, TIMP-1).Conclusion. Our study will allow for the first time to compare and evaluate the effect of both PCSK9 inhibitors and ezetimibe in combination with high-dose statin therapy on reducing the plaque vulnerability according to CCTA in non-infarction-related coronary arteries in patients with ACS undergoing percutaneous coronary intervention, as well as to evaluate the diagnostic value of inflammatory biomarkers (NLR, hs-CRP, NGAL, Galectin-3) and matrix remodeling (MMP-9, TIMP-1).

Blood metabolomes as non-invasive biomarkers and targets of metabolic interventions for doxorubicin and trastuzumab-induced cardiotoxicity.

This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.

Effects of Melatonin on Cardiac Injury and Inflammatory Biomarkers in Patients Undergoing Coronary Artery Bypass Graft Surgery: a Meta-analysis.

The antiinflammatory and antioxidative effects of melatonin have been established in recent years. Several studies indicate that oxidative stress and inflammation are key drivers of post-coronary artery bypass graft (CABG) surgery complications. In the present study, we aimed to investigate the effects of melatonin on cardiac injury and inflammatory biomarkers in CABG candidates. Embase, Medline/PubMed, Web of Science, Scopus, and the Cochrane library were searched up to 5 June 2022. All randomized controlled trials examining cardiac injury and inflammatory biomarkers of CABG patients who received melatonin were included. The random-effects model was utilized to perform the analysis. A total of 947 citations were retrieved through database searches. Finally, five articles (six trials with 342 patients) were included after the screening. Melatonin supplementation led to a significant reduction in cardiac troponin I (CTnI) [weighted mean difference(WMD): -2.28ng/ml; 95% CI -2.87, -1.69; P < 0.01; I2: 91.25%] and high sensitivity-C reactive protein (hs-CRP) levels (WMD: -0.62mg/L; 95% CI -0.73, -0.5; P < 0.01; I2: 99.98%) in patients undergoing CABG surgery. We found a nonsignificant decrease in creatine kinase isoenzyme muscle/brain (CK-MB) levels (WMD: -2.87ng/ml; 95% CI -5.97, 0.23; P = 0.07; I2: 99.98%) after melatonin supplementation. No publication bias was found according to Egger's test. Melatonin supplementation may be useful in reducing cardiac injury and inflammatory biomarkers in CABG candidates. Future studies should investigate the clinical significance of these findings.

Abstract 10334: Vital Exhaustion and Cardiac Biomarkers - The Atherosclerosis Risk in Communities Study

Introduction: Vital exhaustion (VE), defined as excessive fatigue and demoralization due to chronic stress, is a risk factor for cardiovascular disease (CVD), but the mechanism is unclear. We examined the association of VE with biomarkers of cardiac injury, neurohormonal stress and inflammation in the Atherosclerosis Risk in Communities (ARIC) study. Methods: Symptoms of VE were measured at ARIC visit 2 (1990-92, n= 11,588, mean age 57) using the Maastricht Vital Exhaustion Questionnaire (MVEQ). We analyzed the association of VE with cardiac biomarkers [High-sensitivity troponin T (Hs-TnT), N-terminal pro brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (Hs-CRP)] levels in adults without known CVD. Symptoms of VE (MVEQ scores) were categorized into quartiles. Elevated biomarker levels were defined as Hs-TnT ≥ 13 ng/L, NT-proBNP ≥ 125 pg/mL, and hs-CRP ≥ 2 mg/L. Logistic regression models adjusted for demographics and comorbidities were used to test for associations. The associations of VE (MVEQ score ≥16), elevated biomarkers, or both with incident CVD events after 6-year follow up was assessed by Cox proportional hazard regression. Results: Compared with the lowest quartile of VE (MVEQ ≤ 4), the highest quartile of VE (MVEQ 16-42), in adjusted models, was associated with elevated Hs-TnT, NT-proBNP, and hs-CRP [Odds Ratio (95% confidence interval) of 1.75 (1.34-2.29, p&lt;0.01), 1.40 (1.19-1.64, p&lt;0.01), and 1.14 (1.01-1.28, p&lt;0.01), respectively]. The highest quartile of VE was associated with increased risk of CVD events. The risk was increased further in the setting of both significant VE (MVEQ ≥16) and elevated biomarkers (Table). Conclusions: Symptoms of VE are associated with elevated Hs-TnT, NT-proBNP, and Hs-CRP independent of traditional CVD risk factors. The presence of VE and elevated cardiac biomarkers is associated with high risk of incident CVD events in adults without CVD.

Abstract 12121: Integrating Ketone Bodies in Multi-Marker Risk Prediction of Incident Heart Failure in the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: The Universal Definition of Heart Failure (HF) has incorporated N-terminal proB-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin (hs-cTnT) as markers to identify “stage B” HF (asymptomatic left ventricular dysfunction). Plasma ketone bodies (KB) have demonstrated an association with disease severity in HF patients. A multi-biomarker risk score may improve risk stratification of incident HF in the community. Methods: Participants free of CVD from the Multiethnic Study of Atherosclerosis (MESA) at the baseline visit were included. A multi-biomarker score was developed incorporating NT-proBNP ≥ 125 pg/mL, hs-cTnT ≥ 14 ng/L, and total KB ≥ 75 th percentile (316 μmol/L), with 1 point allocated for each abnormal marker. A multivariable Cox model was used to assess the association between multi-biomarker risk score categories and the risk of incident HF. The 5- year Kaplan Meier estimates for incident HF was determined for each biomarker score. Results: Among 6748 participants there were 383 incident HF events over a median follow-up of 15.7 yrs. Total KB displayed a poor correlation with other biomarkers (r&lt;0.06 for all). The addition of KB to the current standard of care to identify pre-HF (either elevation in NT-proBNP and/or hs-cTnT) improved risk prediction (C-statistic 0.70 vs. 0.73). The 3-biomarker score demonstrated good discrimination for predicting 5-year HF risk [C-statistic 0.74 (95%CI 0.70-0.78)]. A graded association was observed between biomarker score groups and the risk of HF independent of established clinical factors ( Figure ). 8% of participants with biomarker score ≥2 developed HF within 5 yrs, while those with biomarker scores≤1 faced very low risk (≤2% over 5 yrs). Conclusions: The addition of plasma KB to a clinical risk score using routinely collected biomarkers of cardiac injury and stress may further personalize risk estimation and reduce misclassification of those at risk of incident HF.

Puerarin-V Improve Mitochondrial Respiration and Cardiac Function in a Rat Model of Diabetic Cardiomyopathy via Inhibiting Pyroptosis Pathway through P2X7 Receptors

There is a new form of puerarin, puerarin-V, that has recently been developed, and it is unclear whether puerarin-V has a cardioprotective effect on diabetic cardiomyopathy (DCM). Here, we determined whether puerarin-V had any beneficial influence on the pathophysiology of DCM and explored its possible mechanisms. By injecting 30 mg/kg of STZ intraperitoneally, diabetes was induced in rats. After a week of stability, the rats were injected subcutaneously with ISO (5 mg/kg). We randomly assigned the rats to eight groups: (1) control; (2) model; (3) metformin; (4-6) puerarin-V at different doses; (7) puerarin (API); (8) puerarin injection. DCM rats were found to have severe cardiac insufficiency (arrythmia, decreased LVdP/dt, and increased E/A ratio). In addition, cardiac injury biomarkers (cTn-T, NT-proBNP, AST, LDH, and CK-MB), inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α), and oxidative damage markers (MDA, SOD and GSH) were markedly increased. Treatment with puerarin-V positively adjusts these parameters mentioned above by improving cardiac function and mitochondrial respiration, suppressing myocardial inflammation, and maintaining the structural integrity of the cardiac muscle. Moreover, treatment with puerarin-V inhibits the P2X7 receptor-mediated pyroptosis pathway that was upregulated in diabetic hearts. Given these results, the current study lends credence to the idea that puerarin-V can reduce myocardial damage in DCM rats. Furthermore, it was found that the effect of puerarin-V in diabetic cardiomyopathy is better than the API, the puerarin injection, and metformin. Collectively, our research provides a new therapeutic option for the treatment of DCM in clinic.

Spatial-temporal lipidomics profile of acute myocardial injury

Abstract Background Lipidome disturbance has long been recognized to occur after myocardial infarction (MI). Accumulation of excessive fatty acids induces production of reactive oxygen species and consequently deteriorates cardiac injury in MI. However, the spatial and temporal lipid profile in the heart following ischemic injury remains unknown. Purpose We aim to uncover the temporal-spatial lipidome profile of the heart following ischemia reperfusion (I/R) injury and identify circulating lipids released from injured myocardium that are potentially useful for diagnosis of ischemic heart disease. Methods C57/BL6 mice were subjected to 30 min myocardial ischemia followed by removal of the ligature to establish reperfusion injury. Porcine I/R injury was induced by 105 min myocardial ischemia followed by reperfusion. Human plasma was obtained from 143 post-MI patients. Myocardial lipid profiles were generated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MALDI-MSI) in different regions (infarct, remote and peri-infarct) at different time points. Moreover, the lipids in the heart and plasma were analysed by LC-MS/MS. Results We observed a drastic alteration in the lipidome with distinct spatial-temporal features in the injured heart by both MALDI-MSI and LC-MS/MS. In the infarct heart tissue, as revealed by LC-MS/MS, we observed an elevation of glycerolipids that peaked at 3 hours after I/R, and a sustained elevation of phospholipids and sphingolipids up to 3 days. Similar alternations in lipid profile was observed but much weaker in the remote and peri-infarct heart tissue compared to the infarct tissue. Among those lipids, PC 32:0 detected by MALDI-MSI highly overlapped CD68 staining at a single-cell level, showing a strong correlation of PC 32:0 with macrophage infiltration in mouse hearts (R2=0.93, p&amp;lt;0.0001). A similar increase of PC 32:0 in the infarct area was also observed in porcine hearts following I/R injury. Surprisingly, plasma levels of PC 32:0 in the mice decreased after I/R injury. In humans, plasma levels of PC 32:0 in post-MI patients were lower than that in healthy individuals (p=0.03). Further analysis demonstrated that plasma levels of PC 32:0 determined within 72 hours after percutaneous coronary intervention were negatively correlated with the 6-month post-MI cardiac ejection fraction in patients (R2=0.08, p&amp;lt;0.001). Conclusions A temporal-spatial lipidome profile was established in heart injury by synergizing LC-MS/MS and mass spectrometry imaging. PC 32:0 levels are positively correlated with myocardial macrophage infiltration but negatively correlated with cardiac function in cardiac I/R injury. Our findings indicate that PC 32:0 is a potential biomarker for cardiac injury and the inflammatory status in the injured heart. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore Ministry of Health's National Medical Research Council

Chronic Oxidative Stress as a Marker of Long-term Radiation-Induced Cardiovascular Outcomes in Breast Cancer.

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2'-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Women's Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD.

Deficiency in Beclin1 attenuates alcohol-induced cardiac dysfunction via inhibition of ferroptosis

BackgroundBinge drinking leads to compromised mitochondrial integrity and contractile function in the heart although little effective remedy is readily available. Given the possible derangement of autophagy in ethanol-induced cardiac anomalies, this study was designed to examine involvement of Beclin1 in acute ethanol-induced cardiac contractile dysfunction, in any, and the impact of Beclin1 haploinsufficiency on ethanol cardiotoxicity with a focus on autophagy-related ferroptosis. MethodsWT and Beclin1 haploinsufficiency (BECN+/−) mice were challenged with ethanol for one week (2 g/kg, i.p. on day 1, 3 and 7) prior to assessment of cardiac injury markers (LDH, CK-MB), cardiac geometry, contractile and mitochondrial integrity, oxidative stress, lipid peroxidation, apoptosis and ferroptosis. ResultsEthanol exposure compromised cardiac geometry and contractile function accompanied with upregulated Beclin1 and autophagy, mitochondrial injury, oxidative stress, lipid peroxidation and apoptosis, and ferroptosis (GPx4, SLC7A11, NCOA4). Although Beclin1 deficiency did not affect cardiac function in the absence of ethanol challenge, it alleviated ethanol-induced changes in cardiac injury biomarkers, cardiomyocyte area, interstitial fibrosis, echocardiographic and cardiomyocyte mechanical properties along with mitochondrial integrity, oxidative stress, lipid peroxidation, apoptosis and ferroptosis. Ethanol challenge evoked pronounced ferroptosis (downregulated GPx4, SLC7A11 and elevated NCOA4, lipid peroxidation), the effect was alleviated by Beclin1 haploinsufficiency. Inhibition of ferroptosis using LIP-1 rescued ethanol-induced cardiac mechanical anomalies. In vitro study noted that ferroptosis induction using erastin abrogated Beclin1 haploinsufficiency-induced response against ethanol. ConclusionsIn sum, our data suggest that Beclin1 haploinsufficiency benefits acute ethanol challenge-induced myocardial remodeling and contractile dysfunction through ferroptosis-mediated manner.

PACIENTES CARDIOVASCULARES COM COVID-19 EM TERAPIA INTENSIVA: UMA REVISÃO SISTEMÁTICA

Resumo: OBJETIVO: Analisar na literatura, a prevalência de doenças cardiovasculares (DCV) e o desenvolvimento de disfunções cardíacas ou vasculares, em indivíduos internados em unidades de terapia intensiva (UTI), devido Covid-19. MÉTODOS: Revisão integrativa da literatura, realizada nas bases de dados BVS: BDENF e LILACS; PuBMED: MEDLINE; Web of Science e CINAHL. Critérios de inclusão: artigos na íntegra, em português, inglês ou espanhol, publicados a partir de 2019. RESULTADOS: Foram selecionados seis artigos e elencados três temas centrais: pacientes com DCV prévia; pacientes que desenvolveram doenças cardíacas ou vasculares durante a internação; e, pacientes que cursaram com alterações de biomarcadores de lesão cardíaca e de degradação de fibrina. Observou-se prevalência de DCV entre 0 e 29% dos estudos, como doenças coronarianas, arritmias, disfunções valvares e ventriculares, e a incidência de DCV entre 2,6 e 59%, apresentando alterações elétricas, funcionais, estruturais e choque cardiogênico. CONCLUSÕES: Identificou-se percentagem importante de pacientes com Covid-19, internados em UTI, que apresentavam DCV prévias e que desenvolveram DCV. Entretanto, até a finalização do presente estudo, não havia pesquisas em que 100% da amostra possuísse DCV prévia, o que seria importante para a compreensão dos possíveis acometimentos sob ela. Assim como, pesquisas que especificassem os tipos de acometimentos desenvolvidos, nomeados apenas como “lesões cardíacas” ou aumento de biomarcadores. Como limitações do presente estudo, ressaltamos que novas pesquisas foram realizadas após a sua conclusão, que certamente agregarão melhor conhecimento. Desta forma, mantém-se a preocupação da gravidade em que a Covid-19 pode acometer pessoas com DCV prévia e suas manifestações cardiovasculares.

Repercussions of pathway inhibition response of Panaxginseng fractions ameliorate cardiac dysfunction in hypertensive model rats

This study examined the preventive and therapeutic benefits of various Panax ginseng fractions against NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension in rats. Rats injected with L-NAME plus vehicle exhibited persistently elevated SBP, serum concentrations of the cardiac injury biomarkers creatine kinase (CK), CK-MB, and troponin, total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), and interleukin (IL)-6, but lower high-density lipoprotein (HDL) compared to the vehicle control group. Furthermore, L-NAME disrupted the normal histological structure and function of rat cardiac tissue. All ginseng fractions and losartan restored SBP to a normal level, reversed the changes in CK, CK-MB, troponin, total cholesterol, TG, HDL, and LDH, and preserved normal myocardial histology, with the WGF demonstrating the greatest cardioprotective and antihypertensive effects. Compounds within multiple ginseng fractions, but especially the aqueous fraction, possess potent and effective antihypertensive, antilipidemic, anti-inflammatory, and cardioprotective properties.