Chinese Society of Cardiology guidelines on the diagnosis and treatment of adult fulminant myocarditis

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium.It is characterized by acute onset,rapid progress and high risk of death.Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm.According to China’s practical experience,the adoption of the“life support-based comprehensive treatment regimen”(with mechanical circulation support and immunomodulation therapy as the core)can significantly improve the survival rate and long-term prognosis.Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics

Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).

A life support-based comprehensive treatment regimen dramatically lowers the in-hospital mortality of patients with fulminant myocarditis: a multiple center study

Fulminant myocarditis(FM) has unacceptable high mortality. This study aimed to evaluate the therapeutic efficacy of a life support-based comprehensive treatment regimen(LSBCTR), a completely novel treatment regimen, for FM. A total of 169 FM patients recruited from January 2008 to December 2018 were divided into two groups: patients receiving LSBCTR(81 cases),which includes(i) mechanical life support(positive pressure respiration, intra-aortic balloon pump with or without extracorporeal membrane oxygenation),(ii) immunomodulation therapy using sufficient doses of glucocorticoids and immunoglobulins, and(iii) application of neuraminidase inhibitors, and those receiving conventional treatment(88 cases). The endpoints were in-hospital death and heart-transplantation. Of all the population, 44 patients(26.0%) died in hospitals. Inhospital mortality was 3.7%(3/81) for LSBCTR group and 46.6%(41/88) for traditional treatment(P<0.001). Early application of LSBCTR, mechanical life support, neuraminidase inhibitors, and immunomodulation therapy significantly contributed to reduction in in-hospital mortality. This study describes a novel treatment regimen for FM patients that dramatically reduces inhospital mortality. Its generalization and clinical application will efficiently save lives although further optimization is needed.This study offers an insight that virus infection induced inflammatory waterfall results in cardiac injury and cardiogenic shock and is the therapeutic target.

Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases

Coronavirus disease 2019(COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients(≥18 years old) between January 29,2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups—non-critically ill,critically ill, and death groups—in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol(LDL-C), and high-density lipoproteins cholesterol(HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old(interquartile range(IQR), 52–71). Among the patients enrolled in the study, 2,008(76.6%) were diagnosed as non-critically ill and 615(23.4%) were critically ill patients, including 383(14.6%) critically ill survivors and 232(8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein(LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time(APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Coronavirus disease 2019(COVID-19)is a pandemic with no specific drugs and high fatality.The most urgent need is to find effective treatments.We sought to determine whether hydroxychloroquine(HCQ)application may reduce the death risk of critically ill COVID-19 patients.In this retrospective study,we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital,Wuhan,from February 1,2020 to April 4,2020.All 550 patients received comparable basic treatments including antiviral drugs and antibiotics,and 48 of them were treated with oral HCQ treatment(200 mg twice a day for 7–10 days)in addition to the basic treatments.Primary endpoint is fatality of patients,and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine(NHCQ)treatments.We found that fatalities are 18.8%(9/48)in HCQ group,which is significantly lower than 47.4%(238/502)in the NHCQ group(P<0.001).The time of hospital stay before patient death is 15(10–21)days and 8(4–14)days for the HCQ and NHCQ groups,respectively(P<0.05).The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2(8.3–118.9)pg mL–1 at the beginning of the treatment to 5.2(3.0–23.4)pg mL–1(P<0.05)at the end of the treatment in the HCQ group but there is no change in the NHCQ group.These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm.Therefore,HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients,with possible outcome of saving lives.

FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction:evidence from an Asian population

The association among plasma trimethylamine-N-oxide(TMAO),FMO3 polymorphisms,and chronic heart failure(CHF)remains to be elucidated.TMAO is a microbiota-dependent metabolite from dietary choline and carnitine.A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction,with the longest follow-up of 7 years.The concentrations of plasma TMAO and its precursors,namely,choline and carnitine,were determined by liquid chromatography-mass spectrometry,and the FMO3 E158K polymorphisms(rs2266782)were genotyped.The top tertile of plasma TMAO was associated with a significant increment in hazard ratio(HR)for the composite outcome of cardiovascular death or heart transplantation(HR=1.47,95%CI=1.13-1.91,P=0.004)compared with the lowest tertile.After adjustments of the potential confounders,higher TMAO could still be used to predict the risk of the primary endpoint(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).This result was also obtained after further adjustment for carnitine(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).The FM03 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort,and lower TMAO levels were found in the AA-genotype.Thus,higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders,and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Erratum to:Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

1.In the abstract,we missed a piece of information.The correct sentence should be“In this retrospective study,we included 550 critically ill COVID-19 patients who need mechanical ventilation(63.5%)and oxygen therapy(35.6%)in Tongji Hospital,Wuhan,from February 1,2020 to April 4,2020.”

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Aortic dissection （AD） is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases （MMPs）/tissue inhibitors of MMPs （TIMPs） system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens （45 genes）, MMPs/TIMPs （27 genes） in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% （64/72） genes in collagens-MMPs/TIMPs system and accounted for 31.05% （218/702） sporadic AD patients. In them, 84.86% patients （185/218） carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probablY pathogenic loss-of-function （LOF） variants （20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon） in 11.06% （50/452） AD patients, which were absent in 163 controls （P=2.5-10-5）. Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2-/- rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.

Beneficial effects exerted by hydroxychloroquine in treating COVID-19 patients via protecting multiple organs

Dear Editor.The coronavirus disease 2019(COVID-19)pandemic caused by widespread infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)(Chen et al.,2020;Guan et al.,2020)has led to a global health crisis.More than 3.5 million infections and 246,838 deaths have occurred as of May 4,2020(Saqrane and El Mhammedi,2020),with a rapid upward trend.Many CO VID-19 patients suffer from complicated systemic injuries such as cardiac(Chen et al.,2020)and hepatic(Huang et al.,2020)damages.

Poor adherence to P2Y12 antagonists increased cardiovascular risks in Chinese PCI-treated patients

Low adherence to secondary prevention medications （ATM） of patients after acute coronary syndrome （ACS） is associated with poor clinical outcomes. However, literature provides limited data on assessment of ATM and risks associated with poor in Chinese patients with ACS. In the current work, ATM was assessed in consecutively recruited patients with ACS in Tongji Hospital from November 5, 2013 to December 31, 2014. A total of 2126 patients were classified under low adherence （proportion of days covered （PDC）〈 50%） and high adherence （PDC〉50%） groups based on their performance after discharge. All patients were followed up at the 1st, 6th, and 12th month of discharge while recording ATM and major adverse cardiac events （MACE）. Bivariate logistic regression was used to identify the factors associated with ATM. Cox regression was used to analyze the association between ATM and MACE within one year after discharge. Results showed that coronary artery bypass grafting （CABG） alone had significantly lower proportion of high adherence to P2Y12 antagonists （83.0% vs. 90.7%, P 〈 0.01） than patients treated with percutaneous coronary intervention （PCI） only. Moreover, in patients undergoing PCI, high adherence to P2Y12 antagonists decreased the risk of MACE （hazard ratio = 0.172, 95% confidence interval： 0.039-0.763; P= 0.021）. In conclusion, PCI-treated patients are more prone to remaining adherent to medications than CABG-treated patients. High adherence to P2Y12 antagonists was associated with lower risk of MACE.

Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case-control study

Thoracic aortic dissection(TAD)without familial clustering or syndromic features is known as sporadic TAD(STAD).So far,the genetic basis of STAD remains unknown.Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population(N=637).After population structure and genetic relationship and ancestry analyses,we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD.We found that COL3A1 was significantly relevant to STAD(P=7.35×10^(−6))after 10000 times permutation test(P=2.49×10^(−3)).Moreover,another independent cohort,including 423 cases and 734 non-STAD subjects(N=1157),replicated our results(P=0.021).Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues,and its expression was related to the extracellular matrix(ECM)pathway.Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway.We wanted to expand the knowledge of the genetic basis and pathology of STAD,which may further help in providing better genetic counseling to the patients.