Inhibition of sPLA2-IIA, C-reactive protein or complement: new therapy for patients with acute myocardial infarction?

Reperfusion of ischemic myocardium after acute myocardial infarction (AMI) induces a local activation of inflammatory reactions that results in ischemia/reperfusion (I/R)-injury. I/R-injury contributes considerably to the total cell damage in the heart after AMI. Secretory phospolipase A2-IIA (sPLA2-IIA), C-reactive protein (CRP) and complement are inflammatory mediators that have been demonstrated to play key roles in I/R injury. From studies by us and others a mechanism emerged in which sPLA2-IIA binds to reversibly damaged cardiomyocytes and subsequently induces cell death, partly by potentiating binding of CRP and subsequent complement activation. Next to this, sPLA2-IIA also has a direct toxic effect, independent of CRP or complement. Therefore, these studies indicate a crucial role of inflammatory mediators in ischemia/reperfusion injury. This review will focus on the pathogenic effects of sPLA2-IIA, CRP and complement and on the putative therapeutic effects of inhibitors of these inflammatory mediators in acute myocardial infarction

Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance

To determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants. The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry. We identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p &lt; 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke. Although community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.</p

C-Reactive Protein Activates Complement in Infarcted Human Myocardium

Circulating levels of C-reactive protein (CRP) constitute a cardiovascular risk marker. Immunohistochemical studies have revealed co-localization of CRP and activated complement in human infarcted myocardium suggesting CRP to enhance inflammation in ischemic myocardium by inducing local complement activation. The aim was to establish whether CRP activates complement in infarcted human myocardium and to assess the relationship between this activation and the duration of infarction. Myocardial tissue samples from 56 patients that had died from acute myocardial infarction were evaluated. Specimens were taken from infarcted as well as noninfarcted sites of the heart. CRP-mediated complement activation was assessed by immunohistochemistry and by measuring levels of complement, CRP, and CRP-complement complexes, specific markers for CRP-mediated activation, in homogenates of the heart. Infarctions of 12 hours to 5 days had significantly more extensive depositions of complement and CRP and contained significantly more CRP, activated complement, and CRP-complement complexes than infarctions that were less than 12 hours old. Levels of CRP complexes correlated significantly with CRP and complement concentrations in the infarctions, as well as with the extent of complement and CRP depositions as measured via immunohistochemistry. Specific activation products of CRP-mediated activation of complement are increased in infarcts of more than 12 hours in duration and correlate with the extent of complement depositions. Hence, CRP seems to enhance local inflammatory reactions ensuing in human myocardial infarcts of more than 12 hours duration

Effect of NOTCH3 EGFr Group, Sex, and Cardiovascular Risk Factors on CADASIL Clinical and Neuroimaging Outcomes

BACKGROUND A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers. METHODS Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count). RESULTS Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P=0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P=4.0×10-6), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P=1.1×10-12), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P=1.6×10-8). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers. CONCLUSIONS NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking

Secretory type II phospholipase A(2) binds to ischemic myocardium during myocardial infarction in humans

OBJECTIVE: An increase of circulating secretory Phospholipase A(2) (sPLA(2)) is a risk factor for coronary artery disease. We hypothesized that this reflects participation of sPLA(2) in local inflammatory reactions ensuing in ischemic myocardium. Therefore, we studied the course of circulating sPLA(2), in patients with acute myocardial infarction (AMI) or unstable angina pectoris (UAP), and investigated the presence of sPLA(2) in infarcted myocardial tissue. METHODS: Plasma samples of 107 patients with AMI or UAP, collected on admission and at varying intervals thereafter, were tested for the presence of sPLA(2) and C-reactive protein (CRP). Cumulative release values of these parameters were calculated, which allowed for comparison of the results rearranged in time according to the onset of symptoms. By immunohistochemistry we studied the presence of sPLA(2) and CRP in myocardial tissue of 30 patients who died subsequent to AMI. RESULTS: Levels of sPLA(2) became elevated during the disease course in 66 of the 87 patients with AMI, and were higher than those of the patients with UAP of whom 8 of the 20 had elevated levels. By immunohistochemistry sPLA(2) was found to be localized in the infarcted myocardium, particularly in its borderzone, from 12 h after the onset of AMI. Positive staining for sPLA(2) was more extensive than that for CRP. CONCLUSIONS: The localization pattern of sPLA(2) in infarcted myocardium as well as its plasma course, in relation to those of CRP, are in line with a supposed pro-inflammatory role during AMI for sPLA(2) as a generator of lysophospholipids serving as ligands for CR

Secretory type II phospholipase A(2) binds to ischemic myocardium during myocardial infarction in humans

OBJECTIVE: An increase of circulating secretory Phospholipase A(2) (sPLA(2)) is a risk factor for coronary artery disease. We hypothesized that this reflects participation of sPLA(2) in local inflammatory reactions ensuing in ischemic myocardium. Therefore, we studied the course of circulating sPLA(2), in patients with acute myocardial infarction (AMI) or unstable angina pectoris (UAP), and investigated the presence of sPLA(2) in infarcted myocardial tissue. METHODS: Plasma samples of 107 patients with AMI or UAP, collected on admission and at varying intervals thereafter, were tested for the presence of sPLA(2) and C-reactive protein (CRP). Cumulative release values of these parameters were calculated, which allowed for comparison of the results rearranged in time according to the onset of symptoms. By immunohistochemistry we studied the presence of sPLA(2) and CRP in myocardial tissue of 30 patients who died subsequent to AMI. RESULTS: Levels of sPLA(2) became elevated during the disease course in 66 of the 87 patients with AMI, and were higher than those of the patients with UAP of whom 8 of the 20 had elevated levels. By immunohistochemistry sPLA(2) was found to be localized in the infarcted myocardium, particularly in its borderzone, from 12 h after the onset of AMI. Positive staining for sPLA(2) was more extensive than that for CRP. CONCLUSIONS: The localization pattern of sPLA(2) in infarcted myocardium as well as its plasma course, in relation to those of CRP, are in line with a supposed pro-inflammatory role during AMI for sPLA(2) as a generator of lysophospholipids serving as ligands for CRP

Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance

To determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants. The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry. We identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p &lt; 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke. Although community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.Pattern Recognition and BioinformaticsIntelligent System

Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank

Objective To determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants. Methods The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry. Results We identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor–like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke. Conclusions Although community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance