High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis, anti-inflammatory and pro-autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR signaling pathways in rats.

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.

Investigating the individual and combined effects of coenzyme Q10 and vitamin C on CLP-induced cardiac injury in rats.

Sepsis-induced cardiac injury represents a major clinical challenge, amplifying the urgency for effective therapeutic interventions. This study aimed to delve into the individual and combined prophylactic effects of Vitamin C (Vit C) and Coenzyme Q10 (CoQ10) against inflammatory heart injury in a cecal ligation and puncture (CLP) induced polymicrobial sepsis rat model. Thirty adult female Sprague-Dawley rats were randomly divided into five groups: Control, CLP, Vitamin C, CoQ10, and Vit C + CoQ10, each consisting of six rats. Treatments were administered orally via gavage for 10 days prior to the operation. Eighteen hours post-sepsis induction, the animals were euthanized, and specimens were collected for analysis. The study examined variations in oxidative (TOS, OSI, MDA, MPO) and antioxidative markers (TAS, SOD, CAT, GSH), histopathological changes, inflammatory cytokine concentrations (TNF-α, IL-1ß), nitric oxide (NO) dynamics, and cardiac indicators such as CK-MB. Impressively, the combined regimen markedly diminished oxidative stress, and antioxidative parameters reflected notable enhancements. Elevated NO levels, a central player in sepsis-driven inflammatory cascades, were effectively tempered by our intervention. Histological examinations corroborated the biochemical data, revealing diminished cardiac tissue damage in treated subjects. Furthermore, a marked suppression in pro-inflammatory cytokines was discerned, solidifying the therapeutic potential of our intervention. Interestingly, in certain evaluations, CoQ10 exhibited superior benefits over Vit C. Collectively, these findings underscore the potential therapeutic promise of Vit C and CoQ10 combination against septic cardiac injuries in rats.

Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice.

Doxorubicin (DOX) is a popular and potent anticancer drug, but its cardiotoxicity limits its clinical application. Shikonin has a wide range of biological functions, including antioxidant and anti-inflammatory effects. The aim of this study was to investigate the effects of shikonin on DOX-induced cardiac injury and to identify the underlying mechanisms. Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration. Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis. Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In conclusion, shikonin alleviates DOX-induced cardiotoxicity by inhibiting Mst1 and activating Nrf2. Shikonin may be used to treat DOX-induced cardiac injury.

Sulfide-modified nanoscale zero-valent iron as a novel therapeutic remedy for septic myocardial injury.

INTRODUCTION: Myocardial injury is a serious complication in sepsis with high mortality. Zero-valent iron nanoparticles (nanoFe) displayed novel roles in cecal ligation and puncture (CLP)-induced septic mouse model. Nonetheless, its high reactivity makes it difficult for long-term storage. OBJECTIVES: To overcome the obstacle and improve therapeutic efficiency, a surface passivation of nanoFe was designed using sodium sulfide. METHODS: We prepared iron sulfide nanoclusters and constructed CLP mouse models. Then the effect of sulfide-modified nanoscale zero-valent iron (S-nanoFe) on the survival rate, blood routine parameters, blood biochemical parameters, cardiac function, and pathological indicators of myocardium was observed. RNA-seq was used to further explore the comprehensive protective mechanisms of S-nanoFe. Finally, the stability of S-nanoFe-1d and S-nanoFe-30 d, together with the therapeutic efficacy of sepsis between S-nanoFe and nanoFe was compared. RESULTS: The results revealed that S-nanoFe significantly inhibited the growth of bacteria and exerted a protective role against septic myocardial injury. S-nanoFe treatment activated AMPK signaling and ameliorated several CLP-induced pathological processes including myocardial inflammation, oxidative stress, mitochondrial dysfunction. RNA-seq analysis further clarified the comprehensive myocardial protective mechanisms of S-nanoFe against septic injury. Importantly, S-nanoFe had a good stability and a comparable protective efficacy to nanoFe. CONCLUSIONS: The surface vulcanization strategy for nanoFe has a significant protective role against sepsis and septic myocardial injury. This study provides an alternative strategy for overcoming sepsis and septic myocardial injury and opens up possibilities for the development of nanoparticle in infectious diseases.

Reflecting on the cardiac toxicity in non-small cell lung cancer in the era of immune checkpoint inhibitors therapy combined with thoracic radiotherapy.

In recent years, immune checkpoint inhibitors (ICIs) have become a widely used treatment for non-small cell lung cancer (NSCLC), and the combination with traditional radiotherapy (RT) has shown significant potential in prolonging patient survival. However, both thoracic RT and ICIs can lead to cardiac toxicity, including radiation-induced heart damage (RIHD) and immunotherapy-related heart damage (IRHD). It still remains uncertain whether the combination of thoracic RT and immunotherapy will exacerbate acute or late cardiovascular (CV) toxicity and incidence. In this review, we summarize safety data from relevant clinical studies regarding CV toxicity for the combination therapy in NSCLC patients, explore the underlying synergetic mechanisms and common risk factors, and proposed treatment and management strategies. We hope to increase emphasis on the long-term assessment of CV toxicity risks associated with the combination therapy, and reduce the incidence of CV deaths resulting from such regimens.

Capsaicin alleviates doxorubicin-induced acute myocardial injury by regulating iron homeostasis and PI3K-Akt signaling pathway.

BACKGROUND: Capsaicin (CAP), a frequently occurring alkaloid component found in spicy peppers, has demonstrated therapeutic potential against tumors, metabolic disease, and cardiovascular disorders. Doxorubicin (DOX), a widely used anthracycline drug in chemotherapy, is notorious for its cardiotoxicity. This study aimed to investigate the potential of CAP in mitigating DOX toxicity in mouse hearts and H9C2 cells, as well as to explore the underlying mechanisms. METHODS: In our study, we conducted experiments on both mice and H9C2 cells. The mice were divided into four groups and treated with different substances: normal saline, CAP, DOX and CAP+DOX. We evaluated the induction of ferroptosis by DOX and the remission of ferroptosis by CAP using various methods, including echocardiography, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining, and determination of ferroptosis metabolites, genes and proteins. Additionally, we employed RNA-seq to identify the inhibitory effect of CAP on DOX-induced myocardial apoptosis, which was further confirmed through western blotting. Similar approaches were applied to H9C2 cells, yielding reliable results. RESULTS: Our study demonstrated that treatment with CAP improved the survival rate of DOX-treated mice and reduced myocardial injury. Mechanistically, CAP downregulated transferrin (Trf) and upregulated solute carrier family 40 member 1 (SLC40A1), which helped maintain iron levels in the cells and prevent ferroptosis. Furthermore, CAP inhibited DOX-induced apoptosis by modulating the phosphoinositide 3-kinase (PI3K)- protein kinase B (Akt) signaling pathway. Specifically, CAP activated the PI3K-Akt pathway and regulated downstream BCL2 and BAX to mitigate DOX-induced apoptosis. Therefore, our results suggest that CAP effectively alleviates acute myocardial injury induced by DOX. CONCLUSION: Our findings demonstrate that CAP has the potential to alleviate DOX-induced ferroptosis by regulating iron homeostasis. Additionally, it can inhibit DOX-induced apoptosis by activating PI3K-Akt signaling pathway.

Epicardial placement of human placental membrane protects from heart injury in a swine model of myocardial infarction.

Cardiac ischemic reperfusion injury (IRI) is paradoxically instigated by reestablishing blood-flow to ischemic myocardium typically from a myocardial infarction (MI). Although revascularization following MI remains the standard of care, effective strategies remain limited to prevent or attenuate IRI. We hypothesized that epicardial placement of human placental amnion/chorion (HPAC) grafts will protect against IRI. Using a clinically relevant model of IRI, swine were subjected to 45 min percutaneous ischemia followed with (MI + HPAC, n = 3) or without (MI only, n = 3) HPAC. Cardiac function was assessed by echocardiography, and regional punch biopsies were collected 14 days post-operatively. A deep phenotyping approach was implemented by using histological interrogation and incorporating global proteomics and transcriptomics in nonischemic, ischemic, and border zone biopsies. Our results established HPAC limited the extent of cardiac injury by 50% (11.0 ± 2.0% vs. 22.0 ± 3.0%, p = 0.039) and preserved ejection fraction in HPAC-treated swine (46.8 ± 2.7% vs. 35.8 ± 4.5%, p = 0.014). We present comprehensive transcriptome and proteome profiles of infarct (IZ), border (BZ), and remote (RZ) zone punch biopsies from swine myocardium during the proliferative cardiac repair phase 14 days post-MI. Both HPAC-treated and untreated tissues showed regional dynamic responses, whereas only HPAC-treated IZ revealed active immune and extracellular matrix remodeling. Decreased endoplasmic reticulum (ER)-dependent protein secretion and increased antiapoptotic and anti-inflammatory responses were measured in HPAC-treated biopsies. We provide quantitative evidence HPAC reduced cardiac injury from MI in a preclinical swine model, establishing a potential new therapeutic strategy for IRI. Minimizing the impact of MI remains a central clinical challenge. We present a new strategy to attenuate post-MI cardiac injury using HPAC in a swine model of IRI. Placement of HPAC membrane on the heart following MI minimizes ischemic damage, preserves cardiac function, and promotes anti-inflammatory signaling pathways.

Protection against cancer therapy-induced cardiovascular injury by planed-derived polyphenols and nanomaterials.

Cancer therapy-induced heart injury is a significant concern for cancer patients undergoing chemotherapy, radiotherapy, immunotherapy, and also targeted molecular therapy. The use of these treatments can lead to oxidative stress and cardiomyocyte damage in the heart, which can result in heart failure and other cardiac complications. Experimental studies have revealed that chemotherapy drugs such as doxorubicin and cyclophosphamide can cause severe side effects such as cardiac fibrosis, electrophysiological remodeling, chronic oxidative stress and inflammation, etc., which may increase risk of cardiac disorders and attacks for patients that underwent chemotherapy. Similar consequences may also be observed for patients that undergo radiotherapy for left breast or lung malignancies. Polyphenols, a group of natural compounds with antioxidant and anti-inflammatory properties, have shown the potential in protecting against cancer therapy-induced heart injury. These compounds have been found to reduce oxidative stress, necrosis and apoptosis in the heart, thereby preserving cardiac function. In recent years, nanoparticles loaded with polyphenols have also provided for the delivery of these compounds and increasing their efficacy in different organs. These nanoparticles can improve the bioavailability and efficacy of polyphenols while minimizing their toxicity. This review article summarizes the current understanding of the protective effects of polyphenols and nanoparticles loaded with polyphenols against cancer therapy-induced heart injury. The article discusses the mechanisms by which polyphenols protect the heart, including antioxidant and anti-inflammation abilities. The article also highlights the potential benefits of using nanoparticles for the delivery of polyphenols.

Hydrogen inhalation enhances autophagy via the AMPK/mTOR pathway, thereby attenuating doxorubicin-induced cardiac injury.

AIMS: Doxorubicin is a drug widely used in clinical cancer treatment, but severe cardiotoxicity limits its clinical application. Autophagy disorder is an important factor in the mechanism of doxorubicin-induced cardiac injury. As the smallest molecule in nature, hydrogen has various biological effects such as anti-oxidation, anti-apoptosis and regulation of autophagy. Hydrogen therapy is currently considered to be an emerging therapeutic method, but the effect and mechanism of hydrogen on doxorubicin-induced myocardial injury have not been determined. The purpose of this study was to investigate the protective effect of hydrogen inhalation on doxorubicin-induced chronic myocardial injury and its effect and mechanism on autophagy. METHODS: In this study, we established a chronic heart injury model by intraperitoneal injection of doxorubicin in rats for 30 days, accumulating 20 mg/kg. The effect of hydrogen inhalation on the cardiac function in rats was explored by echocardiography, Elisa, and H&E staining. To clarify the influence of autophagy, we detected the expression of LC3 and related autophagy proteins in vivo and in vitro by immunofluorescence and western blot.In order to further explore the mechanism of autophagy, we added pathway inhibitors and used western blot to preliminarily investigate the protective effect of hydrogen inhalation on myocardial injury caused by doxorubicin. RESULTS: Hydrogen inhalation can improve doxorubicin-induced cardiac function decline and pathological structural abnormalities in rats. It was confirmed by immunofluorescence that hydrogen treatment could restore the expression of autophagy marker protein LC3 (microtubule-associated protein 1 light chain 3) in cardiomyocytes reduced by doxorubicin, while reducing cardiomyocyte apoptosis. Mechanistically, Western blot results consistently showed that hydrogen treatment up-regulated the ratio of p-AMPK (phosphorylated AMP-dependent protein kinase) to AMPK and down-regulated p-mTOR (phosphorylated mammalian target of rapamycin) and mTOR ratio. CONCLUSIONS: These results suggest that hydrogen inhalation can activate autophagy through the AMPK/mTOR pathway and protect against myocardial injury induced by doxorubicin. Hydrogen inhalation therapy may be a potential treatment for doxorubicin-induced myocardial injury.

Variations in Macrophage Activation Syndrome-associated Cardiac Diseases: A Report on Two Cases.

Macrophage activation syndrome (MAS), a secondary hemophagocytic lymphohistiocytosis characterized by an excessive systemic inflammatory response, is a life-threatening and rare disease. Cardiovascular damage is a common and severe complication of the disease, however, it is easily ignored and not well studied. Herein, we report two cases of patients with MAS-associated heart damage and review the clinical characteristics, mechanism, and treatment. Case 1 along with systemic lupus erythematosus and Kikuchi necrotizing lymphadenitis occurred in fatal acute heart failure, and case 2 complicated adult-onset Still's Disease began with atrial fibrillation and had some improvement with the treatment of high dose corticosteroids. MAS-associated heart damage is a critical issue in clinical settings, and the etiology and mechanisms of MAS-associated cardiovascular diseases are likely multifactorial. The manifestations were various and high levels of the cytokines and cardiac damage may contribute to poor prognosis. Therefore, early intensive immunosuppressive therapy probably improves the treatment outcome.

Identification of CCR2 as a hub in septic myocardial injury and cardioprotection of silibinin.

Myocardial injury is a serious complication of sepsis associated with high morbidity and mortality. Our previous work has confirmed that silibinin (SIL) alleviates septic myocardial injury, but the specific molecular mechanism has not been fully elucidated. This study aimed to identify its potential targets through network pharmacology combined with experimental verification. Firstly, a total of 29 overlapping genes between sepsis and SIL targets were obtained from RNA-seq analysis and the known databases. Subsequently, KEGG and GO analysis showed that these genes were enriched in immune response and cytokine-cytokine receptor interaction pathways. Notably, CCR2 was identified as an important candidate hub by protein-protein interaction analysis and molecular docking approach. In vivo experiments showed that SIL treatment significantly improved survival rate and cardiac function in septic mice, accompanied by decreased CCR2 expression. Moreover, in vitro experiments obtained the similar results. Especially, CCR2 siRNA attenuated inflammation response. In conclusion, this study systematically elucidated the key target of SIL in the treatment of septic myocardial injury. These findings provide valuable insights into the targets of sepsis and offer new avenues for exploring drug effect systematically.

The protective effect of rivaroxaban with or without aspirin on inflammation, oxidative stress, and platelet reactivity in isoproterenol-induced cardiac injury in rats.

Coronary artery diseases are principal sources of mortality and disability in global human population. Progressively, rivaroxaban is being evaluated for the prevention of atherosclerotic thrombi, particularly with anti-platelet agents. Hence, the current report aimed to investigate the cardioprotective effect of rivaroxaban on isoproterenol (ISO)-induced cardiac injury model in rats and the possible synergistic effect when combined with aspirin. Male Wistar rats were randomly assigned into five different groups. Cardiac injury was induced by subcutaneous injection of ISO (85 mg/kg) for 2 consecutive days. Rat tail bleeding time was performed prior to sacrifice. Cardiac enzymes, platelet activity, inflammatory, and oxidative stress biomarkers levels were measured using enzyme-linked immunoassay (ELISA). Pre-administration of rivaroxaban alone and on combination with aspirin prevented ISO-induced increase in cardiac thiobarbituric acid reactive substances (TBARS), interleukin 6 (IL-6), and thromboxane B2 (TXB2) levels. Moreover, a significant prolongation of bleeding time was demonstrated among aspirin, rivaroxaban, and aspirin plus rivaroxaban treated groups. On the other hand, the combination treatment of aspirin plus rivaroxaban showed no marked difference in these biomarkers and bleeding time relative to either drug administered separately. However, a prominent decrease of cardiac 6-keto prostaglandin F1α (6-Keto-PGF1α) level was displayed in the combination treatment when compared with ISO and rivaroxaban-treated groups, whereas no significant improvement was seen in cardiac glycoprotein V (GPV) levels except in aspirin-treated group. The study results demonstrated that rivaroxaban decreases cardiac oxidative stress, inflammation, and platelets reactivity. However, the addition of rivaroxaban to aspirin did not seem to show synergistic antioxidant, anti-inflammatory, or antiplatelet effect.

Rhodiola pre-conditioning reduces exhaustive exercise-induced myocardial injury of insulin resistant mice.

Myocardial injury reduction and recovery under acute cardiac stress are adversely impacted by insulin resistance (IR). We previously demonstrated that Rhodiola improved cardiac anti-stress capacity in mice. Thus, this study focuses on the preventive efficacy of Rhodiola on exhaustive exercise (EE)-induced myocardial injury of IR mice. An 8-week high-fat diet (HFD) model of IR mice was established. Rhodiola was administrated by garaging. After the 8-week intervention, half of the mice performed EE to simulate acute cardiac stress, and determine myocardial injury; The remaining mice were sacrificed following fasting to assess metabolic disorder. We found myocardial injury induced by EE in IR mice was worse and was alleviated by Rhodiola pre-conditioning. Further, the nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant system was impaired by HFD, while mitochondrial dynamic fusion and fission were activated by HFD as a physiological protective compensation. The Rhodiola administration rescued Nrf2 impairment and further facilitated mitochondrial fusion and fission. All these results indicate that Rhodiola is a potential treatment for the prevention of cardiac events in type 2 diabetes mellitus and metabolic syndrome patients, and the Nrf2-related antioxidant activity and mitochondrial dynamics are the proposed mechanisms.

Sodium houttuyfonate protects against cardiac injury by regulating cardiac energy metabolism in diabetic rats.

Diabetic cardiomyopathy is a diabetic complication with complicated pathophysiological changes and pathogenesis and difficult treatment. Sodium houttuyfonate is the adduct of sodium bisulfite and houttuynin, the main volatile component in Houttuynia cordata Thunb, possesses a variety of activities including multiple interventions on inhibiting ventricular remodeling. The study aims to explore effect of sodium houttuyfonate on diabetic myocardial injury and its underlying mechanisms. The diabetes model was established by intraperitoneal injection of streptozotocin at a dose of 85 mg/kg. By intragastric administration for 26 days, sodium houttuyfonate (50 and 100 mg/kg/d) reversed the abnormal serum levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, improved the abnormal levels of serum aspartate aminotransferase and brain natriuretic peptide, reduced electrocardiogram P-R and QRS interval extension, accelerated the heart rate, decreased serum malondialdehyde content, up-regulated the myocardial energy metabolism including elevated the contents of ATP, ADP, total adenine nucleotides and phosphocreatine in myocardium, decreased AMP/ATP ratio, elevated myocardial Ca2+-Mg2+-ATPase activity, and down-regulated the mRNA expressions of AMP protein activation kinase α2 (AMPK-α2) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). In a conclusion, these results suggest that sodium houttuyfonate can improve cardiac energy metabolism disorder caused by diabetes by increasing cardiac Ca2+-Mg2+-ATPase activity and regulating AMPK signaling pathway, and then attenuates cardiac injury caused by hyperglycemia. In addition, sodium houttuyfonate also has the effects of anti-oxidation and improving abnormal levels of blood lipid.

Astragalus polysaccharide alleviates transport stress-induced heart injury in newly hatched chicks via ERS-UPR-autophagy dependent pathway.

Transport stress (TS) not only affects animal welfare but also eventually leads to higher morbidity and mortality. Moreover, TS could induce heart injury in animals, but the possible mechanism has yet to be fully explored. Astragalus polysaccharide (APS) is a main active component of Radix Astragali, which has an extensive anti-stress effect. However, the effect of APS on TS-induced heart injury has not yet been elucidated. In this study, a chick model of simulated TS was used. 240 newly hatched chicks were arranged into 4 groups: Control (Con), Transport group (T), Transport + water group (TW), and Transport + APS group (TA). Before transport, the chicks of the TW and TA groups were treated with deionized water and APS (0.25 mg/mL, 100 µL) by oral drops respectively. The histopathological analysis of myocardial tissue was assessed by hematoxylin and eosin staining. qRT-PCR and Western Blotting assays were employed to measure the expression of genes and proteins. Semiquantitative PCR was performed for the X box-binding protein-1 (XBP-1) mRNA splicing assay. The results indicated that APS significantly reduced TS-induced myocardial histopathological changes. Meanwhile, TS induced endoplasmic reticulum stress (ERS), evidenced by an activation of the unfolded protein response (UPR) signaling pathway and up-regulation of ERS-markers (P < 0.05). Moreover, TS markedly triggered autophagy induction by activating AMP-activated protein kinase (AMPK), reflected by augmented LC3-II/LC3-I, AMPK phosphorylation and autophagy-related genes (ATGs) expression (P < 0.05). Importantly, our study manifested that treatment of APS could reduce TS-induced ERS and AMPK-activated autophagy, accordingly alleviating heart injury of transported chicks. In summary, these findings indicate that TS induces heart injury in chicks via an ERS-UPR-autophagy-dependent pathway, and APS as an effective therapeutic method to alleviate it.

Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study.

BACKGROUND: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage. RESULTS: Our findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype. CONCLUSIONS: In conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.

Differential Impact of Biologic Therapy on Heart Function Biomarkers in Rheumatoid Arthritis Patients: Observational Study on Etanercept, Adalimumab, and Tocilizumab.

BACKGROUND: Rheumatoid arthritis (RA) represents the most frequent form of inflammatory arthritis, affecting approximately 1% of the population worldwide. The introduction of novel therapeutic strategies targeting proinflammatory cytokines (TNF-α and interleukin-6) revolutionized the treatment of RA. This kind of treatment, although effective in a substantial portion of patients, may potentially cause many side effects. Among them, cardiovascular safety is one of the main concerns. OBJECTIVES: In the present study, we investigated the impact of treatment with anti-TNF-α and anti-IL-6 agents on heart function and levels of heart function biomarkers. METHODS: To measure this, we used cardiac function biomarkers, such as NT-pro Brain Natriuretic Peptide, mid regional pro-Atrial Natriuretic Peptide, Galectin-3, and Heart-Type Fatty Acid-Binding Protein and compared them to patients treated with methotrexate as well as healthy controls. RESULTS: Patients treated with biologics were characterized by low disease activity or were in remission. The disease activity in these groups was significantly lower than in the methotrexate group. All patients recruited for the study were characterized by normal heart function measured using echocardiography (EF>50%). With the exception of MR-proANP between tocilizumab and adalimumab (median: 1.01 vs. 0.49 nmol/L, p<0.05), we failed to observe any significant differences in biomarkers levels between groups treated with biologics. Contrary to this, patients on MTX showed higher NT-proBNP levels compared to adalimumab and healthy controls (p<0.05 for both). Striking differences have been shown in regard to H-FABP. The levels of these biomarkers were elevated in all biologics and the methotrexate group compared to healthy controls. CONCLUSION: As this biomarker reflects potential heart injury, we suggest that heart damage proceeds in a continuous manner in RA patients despite effective treatment and attainment of remission/low disease activity. This finding, however, should be verified in a larger cohort of RA patients to ascertain if the routine assessment of H-FABP may be useful for the detection of patients with RA who are at risk of development of heart damage.

MiR-24-3p Attenuates Doxorubicin-induced Cardiotoxicity via the Nrf2 Pathway in Mice.

OBJECTIVE: The nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is associated with doxorubicin (DOX)-induced cardiac injury. It has been reported that microRNA-24-3p (miR-24-3p) may regulate the Keapl by mRNA degradation, whereas Keapl can suppress the activation of Nrf2. However, the role of miR-24-3p in DOX-related cardiotoxicity remains unclear. METHODS: The mice receiving DOX were used as cardiac injury model. In this study, an adenoassociated virus 9 system was used to deliver miR-24-3p or miR-scramble to mice hearts. The echocardiographic and hemodynamic analyses were used to evaluate the effects of miR-24-3p on cardiac function under DOX stimulation. ELISA and RT-PCR were used to detect protein or mRNA expressions associated with cardiac injury, inflammation response, apoptosis and oxidative stress. Western Blot were used for quantitative analysis of the roles of miR-24-3p in regulating Nrf2 expression. H9C2 cells used to verify the role of miR-24-3p in vitro. RESULTS: We found that miR-24-3p mRNA was significantly decreased in DOX-treated mice and cardiomyocytes. Overexpression of miR-24-3p blocked cardiac injury caused by DOX injection, as reflected by the reduction in the levels of cardiac troponin I, creatinine kinase isoenzyme MB and the N-terminal pro brain natriuretic peptide. Furthermore, miR-24-3p reduced oxidative stress and cell loss without affecting the inflammation response. As expected, we found that Nrf2 was upregulated by miR-24-3p supplementation, and that the protective efforts of miR-24-3p supplementation were abolished when Nrf2 was silenced. CONCLUSION: The results from this study suggest that miR-24-3p protects cardiomyocytes against DOX-induced heart injury via activation of the Nrf2 pathway. miR-24-3p supplementation may be a novel strategy to counteract the cardiac side effects of DOX treatment.

The Cost Implications of Dabigatran in Patients with Myocardial Injury After Non-Cardiac Surgery.

BACKGROUND: The Management of Myocardial Injury after Non-Cardiac Surgery (MANAGE) trial demonstrated that dabigatran 110 mg twice daily was more effective than placebo in preventing the primary composite outcome of vascular mortality, non-fatal myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, amputation and symptomatic venous thromboembolism in patients with myocardial injury after non-cardiac surgery (MINS). The cost implications of dabigatran for this population are unknown but are important given the significant clinical implications. METHODS: Hospitalized events, procedures, and study and non-study medications were documented. We applied Canadian unit costs to healthcare resources consumed for all patients in the trial, and calculated the average cost per patient in Canadian dollars for the duration of the study (median follow-up of 16 months). A sensitivity analysis was performed using only Canadian patients, and subgroup analyses were also conducted. RESULTS: The total study cost for the dabigatran group was $9985 per patient, compared with $10,082 for placebo, a difference of - $97 (95% confidence interval [CI] - $2128 to $3672). Savings arising from fewer clinical events and procedures in the dabigatran 110 mg twice-daily group were enough to offset the cost of the study drug. In Canadian patients, the difference was $250 (95% CI -$2848 to $4840). Both differences were considered cost neutral. Dabigatran 110 mg twice daily was cost saving or cost neutral in many subgroups that were considered. CONCLUSION: Dabigatran 110 mg twice daily was cost neutral for patients in the MANAGE trial. Our cost findings support the use of dabigatran 110 mg twice daily in patients with MINS. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT01661101.

Post-cardiac injury syndrome triggered by radiofrequency ablation for AVNRT.

BACKGROUND: Post-cardiac injury syndrome (PCIS) is an inflammatory condition following myocardial or pericardial damage. In response to catheter ablation, PCIS most frequently occurs after extensive radiofrequency (RF) ablation of large areas of atrial myocardium. Minor myocardial injury from right septal slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT) is not an established cause of the syndrome. CASE PRESENTATION: A 62-year-old women with a 6-year history of symptomatic narrow-complex tachycardia was referred to perform an electrophysiological study. During the procedure AVNRT was recorded and a total of two RF burns were applied to the region between the coronary sinus and the tricuspid annulus. Pericardial effusion was routinely ruled out by focused cardiac ultrasound. In the following days, the patient developed fever, elevated inflammatory and cardiac markers, new-onset pericardial effusion, characteristic ECG changes, and complained of pleuritic chest pain. An extensive workup for infectious, metabolic, rheumatologic, neoplastic, and toxic causes of pericarditis and myocarditis was unremarkable. Cardiac magnetic resonance imaging showed no signs of ischemia, infiltrative disease or structural abnormalities. The patient was diagnosed with PCIS and initiated on aspirin and low-dose colchicine. At a 1-month follow-up visit the patient was free of symptoms but still had a small pericardial effusion. After three  months of treatment the pericardial effusion had resolved completely. CONCLUSIONS: Inflammatory pericardial reactions can occur after minor myocardial damage from RF ablation without involvement of structures in close proximity to the pericardium.