Animal models of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease(PH-LHD) is regarded as the most prevalent form of pulmonary hypertension(PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease(LHD). Clinically, there are no drugs or treatments that directly address PH-LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH-LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH-LHD are required. There are several available models for PH-LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH-LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH-LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH-LHD. Therefore, this review will summarize the characteristics of each PH-LHD animal model and discuss the advantages and limitations of the different models.

Survival after surgery for acute type A aortic dissection in octogenarians

Objective To evaluate the benefits of surgical repair acute type A aortic dissection(ATAAD)on survival of octogenarians.Methods Patients who underwent surgery for acute ATAAD from the multicenter European Registry of Type A Aortic Dissection(ERTAAD)were the subjects of the present analysis.Results 326(8.4%)patients were aged≥80 years.Among 280 propensity score matched pairs,in-hospital mortality was 30.0%in patients aged≥80 years and 20.0%in younger patients(P=0.006),while 10-year mortality were 93.2%and 48.0%,respectively(P<0.001).The hazard of mortality was higher among octogenarians up to two years after surgery,but it became comparable to that of younger patients up to 5 years.Among patients who survived 3 months after surgery,10-year relative survival was 0.77 in patients aged<80 years,and 0.46 in patients aged≥80 years.Relative survival of octogenarians decreased markedly 5 years after surgery.Age≥85 years,glomerular filtration rate,preoperative invasive ventilation,preoperative mesenteric mal-perfusion and aortic root replacement were independent predictors of in-hospital mortality among octogenarians(AUC=0.792;E:O ratio=0.991;CITL=0.016;slope=1.096).An additive score was developed.A risk score≤1 was observed in 68.4%of patients,and their in-hospital mortality was 20.9%.Conclusions Provided a thoughtful patient selection,surgery may provide a survival benefit in patients aged≥80 years with ATAAD that,when compared to younger patients and the general population,may last up to 5 years after the procedure.These findings have significant epidemiologic and clinical relevance because of the increasing longevity of the population of the Western countries.

Age-dependent impact of the SYNTAX-score on longer-term mortality after percutaneous coronary intervention in an all-comer population

Background The Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery （SYNTAX）-score is a validated tool for risk stratification and revascularization strategy selection in patients with complex coronary artery disease. The aim of this study was to analyse its age-related prognostic value. Methods SYNTAX-score was calculated in 1331 all-comer patients undergoing percutaneous coronary intervention （PCI）： 463 patients ≥ 75 years and 868 patients 〈 75 years. Outcomes of interest were all-cause mortality at one and two years. Results A significant interaction of age and SYNTAX-score for mortality was observed at two-year （Pinteraction= 0.019） but not at one-year follow-up （Pinteraction= 0.594）. In multivariable analysis, SYNTAX-score independently predicted 1-year mortality in both age groups （〈 75 years, hazard ratio （HR）： 1.43, 95% confidence intervals （CI）： 1.03-2.00, P = 0.034; and 〉 75 years, HR： 1.37, 95% CI： 1.01-1.85, P = 0.042）, but only two-year mortality among younger patients （〈 75 years, HR： 1.33, 95% CI： 1.01-1.76, P = 0.041; and ≥ 75 years, HR： 1.11, 95% CI： 0.87-1.41, P = 0.394）. SYNTAX-score tertiles were useful to stratify 1-year mortality in both, patients 〈 75 years （SYNTAX-score 〈 9, 3.8%; 9-20, 5.3%; 〉 20, 10.3%; P = 0.004） and 〉 75 years （SYNTAX-score 〈 11, 5.7%; 11-22.5, 16.1%; 〉 22.5, 18.7%; P = 0.003）, but two-year mortality only among patients 〈 75 years （SYNTAX-score 〈 9, 6.5%; 9-20, 7.6%; ≥ 20, 15%; P 〈 0.001） and not among ≥ 75 years old patients （SYNTAX-score 〈 11, 19.4%; 11-22.5, 26.3%; _〉 22.5, 27.9%; P = 0.138）. Conclusions Age modi- fies the impact of the SYNTAX-score on longer-term mortality after PCI. Among patients 〈 75 years, the SYNTAX-score independently predicts the risk of death at one and two years after PCI, while among patients 〉 75 years its predictive role is limited to the first year after PCI. Further studies are needed to evaluate the value of SYNTAX-score for selecting the most appropriate revascularization strategy among elderly patients.

Implication of proliferation gene biomarkers in pulmonary hypertension

Objective/Background:Proliferation is a widely recognized trigger for pulmonary hypertension(PH),a life-threatening,progressive disorder of pulmonary blood vessels.This study was aimed to identify some proliferation associated genes/targets for better comprehension of PH pathogenesis.Methods:Human pulmonary arterial smooth muscle cells(hPASMCs)were cultured in the presence or absence of human recombinant platelet derived growth factor(rhPDGF)-BB.Cells were collected for metabolomics or transcriptomics study.Gene profiling of lungs of PH rats after hypoxia exposure or of PH patients were retrieved from GEO database.Results:90 metabolites(VIP score>1,fold change>2 or<0.5 and p<.05)and 2701 unique metabolism associated genes(MAGs)were identified in rhPDGF-BB treated hPASMCs compared to control cells.In addition,1151 differentially expressed genes(313 upregulated and 838 downregulated)were identified in rhPDGF-BB treated hPASMCs compared to control cells(fold change>2 or<0.5 and p<.05).152 differentially expressed MAGs were then determined,out of which 9 hub genes(IL6,CXCL8,CCL2,CXCR4,CCND1,PLAUR,PLAU,HBEGF and F3)were defined as core proliferation associated hub genes in protein proten interaction analysis.In addition,the hub gene-based LASSO model can predict the occurrence of PH(AUC=0.88).The expression of CXCR4,as one of the hub genes,was positively correlated to immune cell infiltrates.Conclusion:Our findings revealed some key proliferation associated genes in PH,which provide the crucial information concerning complex metabolic reprogramming and inflammatory modulation in response to proliferation signals and might offer therapeutic gains for PH.

Tracing the failing heart: dual genetic fate mapping for target identification

In a recent study published in Nature Genetics,1 Han and colleagues employed a dual genetic lineage tracing approach in combination with a model of heart failure(HF)to identify a key sub-population of endocardium-derived fibroblasts,which gives rise to excessive myofibroblast formation in a Wnt pathway-mediated manner and contributes to cardiac fibrosis.1 The identified fibroblast sub-population and Wnt signaling pathway could be novel targets for the therapy of HF.Improvements in risk management and cardiovascular inter-vention have significantly reduced age-specific cardiovascular disease-related mortality.In contrast,the rate of HF-related hospitalisations has increased over the past decades and HF is a disease with highest social and economic cost in industrialized countries.HF is defined as impairment of the heart’s blood pumping function and its severity is assessed based on ejection fraction.HF often occurs after myocardial infarction(MI),with infarct size and quality of ventricular remodeling after MI influencing ventricular dysfunctions.Causes of HF also include hypertension,atrial fibrillation,and cardiomyopathies(Fig.1).Especially elderly patients with recurrent MI and comorbidities are increasingly presenting with signs of HF.

Breaking barriers:noncanonical inflammasome executes blood–brain barrier disruption

In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

Excessive release of neutrophil extracellular traps(NETs)is associated with disease severity and contributes to tissue injury,followed by severe organ damage.Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models,indicating that NETs are potential therapeutic targets.Here,we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody(tACPA)has broad therapeutic potential.Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology,including inflammatory arthritis(IA),pulmonary fibrosis,inflammatory bowel disease and sepsis.We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention,whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects.Because citrullinated histones are generated during NET release,we investigated the ability of tACPA to inhibit NET formation.tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli.Moreover,tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo,which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA.To our knowledge,we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases,as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

Opening a window to skin biomarkers for diabetes stage with optoacoustic mesoscopy

Being the largest and most accessible organ of the human body,the skin could offer a window to diabetes-related complications on the microvasculature.However,skin microvasculature is typically assessed by histological analysis,which is not suited for applications to large populations or longitudinal studies.We introduce ultra-wideband rasterscan optoacoustic mesoscopy(RSOM)for precise,non-invasive assessment of diabetes-related changes in the dermal microvasculature and skin micro-anatomy,resolved with unprecedented sensitivity and detail without the need for contrast agents.Providing unique imaging contrast,we explored a possible role for RSOM as an investigational tool in diabetes healthcare and offer the first comprehensive study investigating the relationship between different diabetes complications and microvascular features in vivo.We applied RSOM to scan the pretibial area of 95 participants with diabetes mellitus and 48 age-matched volunteers without diabetes,grouped according to disease complications,and extracted six label-free optoacoustic biomarkers of human skin,including dermal microvasculature density and epidermal parameters,based on a novel image-processing pipeline.We then correlated these biomarkers to disease severity and found statistically significant effects on microvasculature parameters as a function of diabetes complications.We discuss how label-free RSOM biomarkers can lead to a quantitative assessment of the systemic effects of diabetes and its complications,complementing the qualitative assessment allowed by current clinical metrics,possibly leading to a precise scoring system that captures the gradual evolution of the disease.

Fire up the pyre:inosine thermogenic signaling for obesity therapy

In a recent study published in Nature,Niemann et al.may have discovered a metabolite signaling pathway that could pave the way to new weight loss drugs1(Fig.1).Obesity and its comorbidities are a major threat to public health,but efficient therapeutics are still scarce.

Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C

Hepatitis C virus(HCV)infection is a major problem worldwide.HCV is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis.A fatal complication of HCV-associated vascular disease is thrombosis.Polyriboinosinic:polyribocytidylic acid(poly(I:C)),a synthetic analog of viral RNA,induces a Toll-like receptor 3(TLR3)-dependent arteriolar thrombosis without significant thrombus formation in venules in vivo.These procoagulant effects are caused by increased endothelial synthesis of tissue factor and PAI-1 without platelet activation.In addition to human umbilical endothelial cells(HUVEC),human mesangial cells(HMC)produce procoagulatory factors,cytokines and adhesion molecules after stimulation with poly(I:C)or HCV-containing cryoprecipitates from a patient with a HCV infection as well.Activated protein C(APC)is able to prevent the induction of procoagulatory factors in HUVEC and HMC in vitro and blocks the effects of poly(I:C)and HCV-RNA on the expression of cytokines and adhesion molecules in HMC but not in HUVEC.In vivo,protein C inhibits poly(I:C)-induced arteriolar thrombosis.Thus,endothelial cells are de facto able to actively participate in immune-mediated vascular thrombosis caused by viral infections.Finally,we provide evidence for the ability of protein C to inhibit TLR3-mediated arteriolar thrombosis caused by HCV infection.