Prevention of endotoxin-induced cardiomyopathy using sodium tanshinone IIA sulfonate: Involvement of augmented autophagy and NLRP3 inflammasome suppression.

Increasing evidence indicates that patients or experimental animals exposure to endotoxin (lipopolysaccharides, LPS) exert deleterious cardiac functions that greatly contribute to morbidity and mortality. The pathophysiologic processes, including NLRP3 inflammasome overactivation and cardiac inflammatory injury, are complicated. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, is a naturally occurring compound extracted from Salvia miltiorrhiza and has anti-inflammatory and cardioprotective properties. In this study we examined the effect of STS on endotoxin-induced cardiomyopathy and investigated the underlying mechanisms. An endotoxemic mouse model was established by injecting LPS (10 mg/kg). Different doses of STS were administered intraperitoneally (5, 10, or 50 mg/kg) at different time points (2/12 h, 4/12 h, and 8/12 h) after LPS challenge to assess its effect on survival of mice with endotoxemia. In parallel, cardiac function, myocardial inflammatory cytokines, cardiomyocyte pyroptosis and autophagy were evaluated to determine the extent of myocardial damage due to sepsis in the presence and absence of STS at the optimal dose (10 mg/kg) and time-point (2/12 h). The results demonstrated that STS increased the survival rates, improved the compromised cardiac function and reduced myocardial inflammatory injury associated with enhanced autophagy and mitigated NLRP3 inflammasome activation. Moreover, inhibiting of autophagy or blocking the AMPK pathway reversed STS-elicited prevention of cardiomyopathy and activated the NLRP3 inflammasome in endotoxemic mice. Collectively, our study demonstrates that STS attenuates endotoxemia-induced mortality and cardiomyopathy, which may be associated with promotion of autophagy and inhibition of NLRP3 inflammasome overactivation.

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (R=0.35; P<0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02860156.

Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart.

Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and additional, less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound down-regulation of mitochondrial components. We also describe the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced inflammatory responses. In vitro, glycolysis inhibition reduces the production of tumor necrosis factor (TNF) by memory macrophages, whereas in vivo, it produces the reversion of the memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.

Syphilis-associated septic cardiomyopathy: case report and review of the literature.

BACKGROUND: Septic cardiomyopathy has been observed in association with influenza, indicating that not only bacteria but also other infective agents can cause this condition. There has been no systematic study as to whether Treponema pallidum infection induces septic cardiomyopathy, and we are the first to report this possibility. CASE PRESENTATION: We report two cases of a 48-year-old man and a 57-year-old man who were diagnosed with syphilis-related septic cardiomyopathy. The diagnosis of cardiomyopathy was made based on elevation of cardiogenic markers and decrease in ejection fraction evaluated by echocardiography. Screen for infective pathogens was negative except for syphilis, which supported our diagnosis. The two patients recovered following effective anti-syphilis treatment and advanced life support technology. Syphilis serology became negative after treatment. CONCLUSION: Syphilis has the potential to cause septic cardiomyopathy. Clinicians should consider Treponema pallidum in cases of septic cardiomyopathy with unknown pathogens. However, the specific pathophysiological mechanism of syphilis-associated septic cardiomyopathy has not been elucidated, and more specific studies are needed.

Risk factors for Keshan disease: a prospective cohort study protocol of gut flora.

BACKGROUND: Keshan disease is an endemic cardiomyopathy of undefined causes. Being involved in the unclear pathogenesis of Keshan disease, a clear diagnosis, and effective treatment cannot be initiated. However, the rapid development of gut flora in cardiovascular disease combined with omics and big data platforms may promote the discovery of new diagnostic markers and provide new therapeutic options. This study aims to identify biomarkers for the early diagnosis and further explore new therapeutic targets for Keshan disease. METHODS: This cohort study consists of two parts. Though the first part includes 300 participants, however, recruiting will be continued for the eligible participants. After rigorous screening, the blood samples, stools, electrocardiograms, and ultrasonic cardiogram data would be collected from participants to elucidate the relationship between gut flora and host. The second part includes a prospective follow-up study for every 6 months within 2 years. Finally, deep mining of big data and rapid machine learning will be employed to analyze the baseline data, experimental data, and clinical data to seek out the new biomarkers to predict the pathogenesis of Keshan disease. DISCUSSION: Our study will clarify the distribution of gut flora in patients with Keshan disease and the abundance and population changes of gut flora in different stages of the disease. Through the big data platform analyze the relationship between environmental factors, clinical factors, and gut flora, the main factors affecting the occurrence of Keshan disease were identified, and the changed molecular pathways of gut flora were predicted. Finally, the specific gut flora and molecular pathways affecting Keshan disease were identified by metagenomics combined with metabonomic analysis. TRIAL REGISTRATION: ChiCTR1900026639. Registered on 16 October 2019.

Life-threatening ventricular arrhythmia as first presentation of Tuberculosis-Early diagnosis and successful treatment: A case series.

BACKGROUND: Tuberculosis of the myocardium is an extremely rare entity with few published case reports. Diagnosis is often delayed, and outcomes are unfavorable: particularly when cardiac involvement has been the presenting entity. METHODS: Four patients, aged 24-51 years, presented with life-threatening ventricular arrhythmia (VA). None had a previous history of tuberculosis or any structural heart disease. Electrocardiogram during sinus rhythm and Echocardiography did not show any gross abnormality. All patients underwent contrast-enhanced computer tomography of thorax and cardiac magnetic resonance imaging. Attempts to obtain tissue (cardiac or associated mediastinal lymph nodes) were associated with increased risk to the patients thus indirect evidence of Mantoux skin test and interferon gamma release assay results were used to aid diagnosis. RESULTS: Based on clinicoradiological findings, patients were put on antitubercular therapy (ATT). Supportive therapy included antiarrhythmic drugs (all patients), catheter ablation (two patients), and implantable cardioverter defibrillator (one patient). Arrhythmia suppression was achieved in all patients predischarge. On a follow-up of 2-24 months, none of the patients has had any recurrence of arrhythmia. ATT and antiarrhythmic drug therapy have been stopped in two patients who have completed the 6 months of ATT. Their radiological lesions showed resolution. CONCLUSIONS: Myocardial tuberculosis presenting as life-threatening VA in a rare but definite clinical entity. A high index of suspicion and cardiac imaging can lead to early diagnosis and appropriate treatment that ensures survival in all patients.

Protective Effect of Lactobacillus rhamnosus GG and its Supernatant against Myocardial Dysfunction in Obese Mice Exposed to Intermittent Hypoxia is Associated with the Activation of Nrf2 Pathway.

Prolonged intermittent hypoxia (IH) has been shown to impair myocardial function (mainly via oxidative stress and inflammation) and modify gut microbiota in mice. Gut microbiota plays an important role in health and disease, including obesity and cardiovascular disease (CVD). Probiotics refer to live microorganisms that confer health benefits on the host after administration in adequate amounts. Research on novel probiotics related therapies has evoked much attention. In our previous study, both Lactobacillus rhamnosus GG (LGG) and LGG cell-free supernatant (LGGs) were found to protect against alcohol-induced liver injury and steatosis; however, the effects of LGG and LGGs on cardiac tissues of obese mice exposed to IH have not been determined. Here we exposed high-fat high-fructose diet (HFHFD)-induced obese mice to IH, to establish a model of obesity with obstructive sleep apnea (OSA). Mice were divided into four groups: (1) HFHFD for 15 weeks; (2) HFHFD for 15 weeks with IH in the last 12 weeks (HFHFD/IH); (3) and (4) HFHFD/IH plus oral administration of either LGG (109 CFU bacteria/day) or LGGs (dose equivalent to 109 CFU bacteria/day) over the 15 weeks, respectively. Compared to HFHFD mice, HFHFD/IH-mice showed heart dysfunction with significant cardiac remodeling and inflammation; all these pathological and functional alterations were prevented by treatment with both LGG and LGGs (no significant difference between LGG and LGGs in this respect). The cardioprotective effect of LGG and LGGs against IH/HFHFD was associated with up-regulation of nuclear factor erythroid 2-related factor 2(Nrf2)-mediated antioxidant pathways. Our findings suggest a cardioprotective effect of LGG and LGGs in obese mice with OSA.

Sepsis-related myocardial injury is associated with Mst1 upregulation, mitochondrial dysfunction and the Drp1/F-actin signaling pathway.

LPS-induced septic cardiomyopathy has been found to be connected with mitochondrial stress through unknown mechanisms. Mitochondrial fission is an early event in mitochondrial dysfunction. The aim of our study was to determine the role and regulatory mechanism of mitochondrial fission in the progression of LPS-induced septic cardiomyopathy, with a particular focus on Mst1 and F-actin. Our data demonstrated that Mst1 expression was rapidly upregulated in LPS-treated hearts and that increased Mst1 promoted cardiomyocyte death by inducing mitochondrial stress. Mechanistically, elevated expression of Mst1 upregulated Drp1, and the latter initiated mitochondrial fission. Excessive mitochondrial fission caused mitochondrial oxidative injury, mitochondrial membrane potential reduction, mitochondrial proapoptotic element translocation into the cytoplasm/nucleus, mitochondrial energy dysfunction and mitochondrial apoptosis activation. Inhibition of mitochondrial fission sustained mitochondrial function and favored cardiomyocyte survival. Furthermore, we identified F-actin degradation as an apparent downstream event of mitochondrial fission activation in the context of LPS-induced septic cardiomyopathy. Stabilization of F-actin attenuated fission-mediated cardiomyocyte death. Altogether, our results define the Mst1/Drp1/mitochondrial fission/F-actin axis as a new signaling pathway that mediates LPS-related septic cardiomyopathy by inducing mitochondrial stress and cardiomyocyte death. Therefore, Mst1 expression, mitochondrial fission modification and F-actin stabilization may serve as potential therapeutic targets for sepsis-related myocardial injury.

Sepsis-induced Takotsubo syndrome in young premenopausal women: Two case reports.

RATIONALE: Takotsubo syndrome (TTS) most commonly occurs in postmenopausal women who have been exposed to a triggering event such as acute physical or emotional distress. Sepsis-induced TTS in young premenopausal women were rarely reported. In particular, the relationship between sepsis-induced TTS and sepsis-induced cardiomyopathy (SIC) remains to be illuminated. PATIENT CONCERNS: Two young premenopausal women were admitted to the hospital with sepsis and myocardial involvement. DIAGNOSIS: Both patients fully met the Mayo Clinic criteria for TTS. INTERVENTIONS: Both patients received anti-infection and fluid infusion treatment. OUTCOMES: Both patients were discharged without complications and the follow-up ultrasonic echocardiography showed normal results. LESSONS: In this report, we describe 2 young premenopausal women with sepsis-induced TTS. There is an overlap between sepsis-induced TTS and SIC, and SIC could be a special type of TTS, which occurs under the stress of sepsis.

Severity and properties of cardiac damage caused by Streptococcus pneumoniae are strain dependent.

Streptococcus pneumoniae is an opportunistic Gram-positive pathogen that can cause invasive disease. Recent studies have shown that S. pneumoniae is able to invade the myocardium and kill cardiomyocytes, with one-in-five adults hospitalized for pneumococcal pneumonia having a pneumonia-associated adverse cardiac event. Furthermore, clinical reports have shown up to a 10-year increased risk of adverse cardiac events in patients formerly hospitalized for pneumococcal bacteremia. In this study, we investigated the ability of nine S. pneumoniae clinical isolates, representing eight unique serotypes, to cause cardiac damage in a mouse model of invasive disease. Following intraperitoneal challenge of C57BL/6 mice, four of these strains (D39, WU2, TIGR4, and 6A-10) caused high-grade bacteremia, while CDC7F:2617-97 and AMQ16 caused mid- and low-grade bacteremia, respectively. Three strains did not cause any discernible disease. Of note, only the strains capable of high-grade bacteremia caused cardiac damage, as inferred by serum levels of cardiac troponin-I. This link between bacteremia and heart damage was further corroborated by Hematoxylin & Eosin and Trichrome staining which showed cardiac cytotoxicity only in D39, WU2, TIGR4, and 6A-10 infected mice. Finally, hearts infected with these strains showed varying histopathological characteristics, such as differential lesion formation and myocytolysis, suggesting that the mechanism of heart damage varied between strains.

Successful use of combined blood purification techniques in splenectomised patient with septic shock in streptococcus pneumoniae infection - a case report.

BACKGROUND: Septic cardiomyopathy represents cardiac impairment in sepsis and is a part of systemic involvement in sepsis. Cytokine storm is responsible for septic shock and for myocardial dysfunction of potentially reversible septic cardiomyopathy. Several case reports and case series demonstrated successful removal of circulating cytokines by combined blood purification techniques. In this way, septic shock and survival of septic patients improved. However, the evidences for reversal of myocardial dysfunction are rare. CASE PRESENTATION: We present a patient with a history of chemotherapy for coat cell lymphoma, splenectomy and autologous bone marrow transplantation, who suffered severe pneumococcal sepsis, septic shock and septic cardiomyopathy, resistant to pharmacological therapy. Combined blood purification techniques 36 h after the start of treatment successfully decreased Interleukin-6 level, lactacidosis, the need for vasopressors to maintain normotension, improved systolic function of the left ventricle and clinical outcome. CONCLUSIONS: Our case suggests that combined blood purification techniques initiated even 36 h after the start of treatment successfully removed inflammatory cytokines, reversed circulatory failure and improved left ventricular systolic function in pneumococcal sepsis.

Septic cardiomyopathy: The value of lactoferrin and CD15 as specific markers to corroborate a definitive diagnosis.

Current scientific consensus about the physiopathology in the progression from severe sepsis to septic shock and death focuses on myocardial contractile dysfunction. Nevertheless, objective parameters to establish a pathological correlate of a fatal outcome are lacking; then a cause of death due to sepsis can remain an unsolved problem. We first reviewed all death cases recorded at our institutions during the period from 2007 until 2015. Then, we conducted a retrospective study of a selected autopsy series of people who had received "sepsis" as cause of death. Two pathologists re-examined the heart sections while the most suitable myocardial sample for each case was stained for immunohistochemistry with antibodies targeted for specific inflammatory-related molecules. We used specific antibodies for the following markers: alpha-smooth muscle actin (alpha-SMA); fibronectin; matrix metallopeptidase 9 (MMP-9); intercellular adhesion molecule 1 (ICAM-1); caspase-3; lactoferrin (LF); cluster differentiation 15 (CD15). The statistical significance of differences was assessed using student's t-test for unpaired data or non-parametric Mann-Whitney or Wilcoxon tests for skewed variables or one-way analysis of variance and post hoc Scheffe's test for continuous variables and Pearson's χ2-test for discrete variables. Linear regression analysis was used to determine the presence of a correlation between continuous variables. At our institutions, 2220 deaths have been recorded during the period study. Sepsis accounted as a cause of death for the 20% of total. We finally enrolled 56 cases; of these, only 20 were positive for microbiological analysis. At histological examination, clear inflammation was detectable in the 32% of cases; otherwise, immunohistochemical reaction showed a positive reaction for LF and CD15 in more than a half cases (56%). We still ignore all the underlying mechanisms of sepsis and all its pathophysiological connections with cardiac metabolism; in this sense, we aim to corroborate the diagnostic value of anti-LF and anti-CD15 staining for the post-mortem detection of myocardial inflammation.

[Recurrent postpartum pyoderma gangrenosum and fatal cardiomyopathy]. / Pyoderma gangrenosum récidivant du post-partum et cardiomyopathie fatale.

BACKGROUND: We report a case of recurrent post-partum pyoderma gangrenosum (PG) complicated by post-partum cardiomyopathy (PPCM). PATIENTS AND METHODS: A 23-year-old woman presented with a previous medical history of aseptic abscess of the left breast in her fourth pregnancy, which developed after surgical drainage of an inflammatory ulceration treated by atraumatic topical care. During her fifth pregnancy, the patient presented a large and painful ulceration in relation to the scar of the Caesarean section, despite the introduction of broad-spectrum antibiotic therapy. Bacteriological samples were negative. Histological examination militated in favor of PG. One week after initiation of corticosteroid therapy, the patient suddenly showed signs of heart failure. Based on trans-thoracic echocardiography PPCM was diagnosed, and the outcome was fatal. DISCUSSION: This observation raises the question of the relationship between PG and pregnancy and describes the association of PG and PPCM. PG occurs rarely during pregnancy and it may be induced by the rise in G-CSF levels found in pregnant women. The association with PPCM seen in our patient could have been due to the development of an anti-angiogenic climate at the end of pregnancy, together with inflammatory myocardial aggression linked to the PG.

Sepsis and Septic Shock Strategies.

Three therapeutic principles most substantially improve organ dysfunction and survival in sepsis: early, appropriate antimicrobial therapy; restoration of adequate cellular perfusion; timely source control. The new definitions of sepsis and septic shock reflect the inadequate sensitivity, specify, and lack of prognostication of systemic inflammatory response syndrome criteria. Sequential (sepsis-related) organ failure assessment more effectively prognosticates in sepsis and critical illness. Inadequate cellular perfusion accelerates injury and reestablishing perfusion limits injury. Multiple organ systems are affected by sepsis and septic shock and an evidence-based multipronged approach to systems-based therapy in critical illness results in improve outcomes.

Dual Behavior of Exosomes in Septic Cardiomyopathy.

Sepsis is one of the main causes of ICU hospitalization worldwide, with a high mortality rate, and is associated with a large number of comorbidities. One of the main comorbidities associated with sepsis is septic cardiomyopathy. This process occurs mainly due to mechanisms of damage in the cardiovascular system that will lead to changes in cardiovascular physiology, such as decreased Ca2+ response, mitochondrial dysfunction and decreased ß-adrenergic receptor response. Within this process the exosomes play an important role in the pathophysiology of this disease, in which the exosomal content is related to mechanisms that will trigger its development. After platelet activation through ROS exposition, exosomes containing high concentrations of NADPH are released in heart blood vessels, those exosomes will be internalized in endothelial cells leading to cell death and cardiac dysfunction. On the opposite, exosomes derived from mesenchymal stem cells contain miR-223, that have anti-inflammatory properties, are released in less quantities in septic patients causing an imbalance that leads to cardiac dysfunction.

A reminder of Escherichia coli sepsis-induced reversible cardiomyopathy.

Cardiomyopathy is a progressive disease of myocardium causing either mechanical or electrical disturbances. Sepsis-induced cardiomyopathy (SICM) is an entity of cardiomyopathy which is reversible in 1â€"2 weeks after recovery from sepsis or septic shock. SICM is thought to have unpredictable cumulative mortality towards sepsis but its exact mechanism remains elusive. We report a case of Escherichia coli SICM in a 63-year-old woman presented with sudden onset of dyspnoea on exertion and orthopnoea following nausea, vomiting and diarrhoea after consuming Chinese foods. Transthoracic echocardiogram revealed severely reduced global left ventricular ejection fraction (LVEF) of <20% which returned back to normal LVEF of 57% after 10 days. Subsequent cardiac catheterisation showed non-obstructive coronaries. No specific therapy intended for reversal of SICM presents to date despite current sepsis survival guideline available for haemodynamic support. Initiation of beta blockers after recovery from septic shock has been beneficial.

Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients.

BACKGROUND: Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. METHODS AND RESULTS: We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. CONCLUSIONS: Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.