Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury.
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ABSTRACT:
SUBMITTER: Lewis GD
PROVIDER: S-EPMC2525696 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimThe aim of the study was to discover the metabolomic changes in plasma that occur during human Ischemia-Reperfusion (I/R) injury and to evaluate the diagnostic utility of plasma metabolomic biomarkers for determination of myocardial injury. Deciphering the details of plasma metabolome in ST-segment elevation myocardial infarction (STEMI) patients before and after primary percutaneous coronary interventions (PPCI) would allow for better understanding of the mechanisms involved during acute myocardial ischemia and reperfusion in humans. We performed a detailed non-targeted metabolomic analysis of plasma from 27 STEMI patients who had undergone PPCI in the first 48 hrs employing a LC-MS approach. Plasma metabolome at ischemic condition was compared to multiple time points after PPCI which allowed us to focus on changes in the reperfusion phase. Classification of the differential metabolites based on chemical taxonomy identified a major role for lipids and lipid-derived molecules. Biochemical pathway analysis identified valine, leucine and isoleucine biosynthesis, vitamin B6 metabolism and glutathione metabolism as the most significant metabolic pathways representing early response to I/R injury. We also identified phenyl alanine, tyrosine, linoleic acid and glycerophospholipid metabolism as the most significant pathways representing late response to I/R injury. A panel of three metabolites pentadecanoic acid, linoleoyl carnitine and 1-linoleoylglycerophosphocholine was discovered to have diagnostic value in determining the extent of I/R injury based on cardiac biomarkers. Using a non-targeted LC-MS approach, we have successfully generated the most comprehensive data to date on significant changes in the plasma metabolome in STEMI patients who had undergone PPCI in the first 48 hrs showing that lipid metabolites represent the largest cohort of molecules undergoing significant change.
| S-EPMC6692400 | biostudies-literature
Project description:ESRD is a state of small-molecule disarray. We applied liquid chromatography/tandem mass spectrometry-based metabolite profiling to survey>350 small molecules in 44 fasting subjects with ESRD, before and after hemodialysis, and in 10 age-matched, at-risk fasting control subjects. At baseline, increased levels of polar analytes and decreased levels of lipid analytes characterized uremic plasma. In addition to confirming the elevation of numerous previously identified uremic toxins, we identified several additional markers of ESRD, including dicarboxylic acids (adipate, malonate, methylmalonate, and maleate), biogenic amines, nucleotide derivatives, phenols, and sphingomyelins. The pattern of lipids was notable for a universal decrease in lower-molecular-weight triacylglycerols, and an increase in several intermediate-molecular-weight triacylglycerols in ESRD compared with controls; standard measurement of total triglycerides obscured this heterogeneity. These observations suggest disturbed triglyceride catabolism and/or beta-oxidation in ESRD. As expected, the hemodialysis procedure was associated with significant decreases in most polar analytes. Unexpected increases in several metabolites, however, indicated activation of a broad catabolic program, including glycolysis, lipolysis, ketosis, and nucleotide breakdown. In summary, this study demonstrates the application of metabolite profiling to identify markers of ESRD, provide perspective on uremic dyslipidemia, and broaden our understanding of the biochemical effects of hemodialysis.
| S-EPMC2900954 | biostudies-literature
Project description:IntroductionRecently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%).MethodsQuantitative targeted metabolomics in serum using an identical method as in the index study.ResultsWe failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples.DiscussionWe believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.
| S-EPMC4947451 | biostudies-literature
Project description:Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction
2024-10-17 | PXD055738 | Pride
Project description:BACKGROUND:Among older adults (age ?75 years) hospitalized for acute myocardial infarction, acute kidney injury after coronary angiography is common. Aging-related conditions may independently predict acute kidney injury, but have not yet been analyzed in large acute myocardial infarction cohorts. METHODS:We analyzed data from 2212 participants age ?75 years in the Comprehensive Evaluation of Risk Factors in Older Patients with Acute Myocardial Infarction (SILVER-AMI) study who underwent coronary angiography. Acute kidney injury was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria (serum Cr increase ?0.3 mg/dL from baseline or ?1.5 times baseline). We analyzed the associations of traditional acute kidney injury risk factors and aging-related conditions (activities of daily living impairment, prior falls, cachexia, low physical activity) with acute kidney injury, and then performed logistic regression to identify independent predictors. RESULTS:Participants' mean age was 81.3 years, 45.2% were female, and 9.5% were nonwhite; 421 (19.0%) experienced acute kidney injury. Comorbid diseases and aging-related conditions were both more common among individuals experiencing acute kidney injury. However, after multivariable adjustment, no aging-related conditions were retained. There were 11 risk factors in the final model; the strongest were heart failure on presentation (odds ratio [OR] 1.91; 95% confidence interval [CI], 1.41-2.59), body mass index [BMI] >30 (vs BMI 18-25: OR 1.75; 95% CI, 1.27-2.42), and nonwhite race (OR 1.65; 95% CI, 1.16-2.33). The final model achieved an area under the receiver operating characteristic curve of 0.72 and was well calibrated (Hosmer-Lemeshow P = .50). Acute kidney injury was independently associated with 6-month mortality (OR 1.98; 95% CI, 1.36-2.88) but not readmission (OR 1.26; 95% CI, 0.98-1.61). CONCLUSIONS:Acute kidney injury is common among older adults with acute myocardial infarction undergoing coronary angiography. Predictors largely mirrored those in previous studies of younger individuals, which suggests that geriatric conditions mediate their influence through other risk factors.
| S-EPMC6891160 | biostudies-literature
Project description:BACKGROUND:Data on radial access (RA) as an independent risk factor for acute kidney injury (AKI) in myocardial infarction (MI) patients are conflicting. Our aim was to assess how RA influences the incidence of AKI in MI patients undergoing percutaneous coronary intervention (PCI). METHODS:Data from 3842 MI patients undergoing PCI at our institution from January 2011 to December 2016, of which 35.8% were performed radially, were retrospectively analyzed. A propensity-matched analysis was performed to adjust for differences in the baseline characteristics between the RA and femoral access (FA) groups. The effect of RA on the incidence of AKI was observed. RESULTS:In the unmatched cohort, AKI occurred less often in the RA group [77 (5.6%) patients in the RA group compared to 250 (10.1%) patients in the FA group; p = 0.001]. After propensity-matched adjustment, the incidence of AKI was similar in the two groups. After adjustment for potential confounders, RA was not identified as an independent predictive factor for AKI in either the unmatched or the propensity-matched cohort. Bleeding, heart failure, age ≥ 70 years, renal dysfunction, and the contrast volume/GFR ratio predicted AKI in both cohorts. Additionally, diabetes, contrast volume, and hypertension were predictive of AKI in the unmatched cohort. CONCLUSION:The access site was not independently associated with the incidence of AKI in patients with MI in both a non-matched and a propensity-matched cohort. Our study result suggests that the lower incidence of AKI in patients treated with RA in an unmatched cohort might be substantially influenced by confounding factors, especially bleeding.
| S-EPMC6354416 | biostudies-literature
Project description:BACKGROUND:Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures 1129 proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury. METHODS:We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay 4783 human proteins (4137 distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls. RESULTS:We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P<1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P<1.33E-04, 1-way repeated measures analysis of variance); >90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P<6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F0 subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers. CONCLUSIONS:Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury.
| S-EPMC5860961 | biostudies-literature
Project description:BACKGROUND:Type 2 myocardial infarction (MI) is defined by a rise and fall of cardiac biomarkers and evidence of ischemia without unstable coronary artery disease (CAD) because of a mismatch in myocardial oxygen supply and demand. Myocardial injury is similar but does not fulfill the clinical criteria for MI. There is uncertainty in terms of the clinical characteristics, management, and outcomes of type 2 MI and myocardial injury in comparison with type 1 MI. PATIENTS AND METHODS:Patients admitted to a Veterans Affairs tertiary care hospital with a rise and fall in cardiac troponin were identified. MI and injury subtypes, presentation, management, and outcomes were determined. RESULTS:Type 1 MI, type 2 MI, and myocardial injury occurred in 137, 146, and 175 patients, respectively. Patients with type 2 MI were older (P=0.02), had lower peak cardiac troponin (P<0.001), and were less likely to receive aspirin and statin at discharge (P<0.001) than type 1 MI survivors. All-cause mortality (median follow-up: 1.8 years) was not different between patient groups (type 1 MI mortality: 29.9%, type 2 MI: 30.8%, myocardial injury: 29.7%; log rank P=0.94). A significant proportion of deaths were attributed to cardiovascular causes in all subgroups (type 1 MI: 34.1%, type 2 MI: 17.8%, myocardial injury: 30.8%). CONCLUSION:Patients with type 2 MI and myocardial injury were less likely to receive medical therapy for CAD than those with type 1 MI. No differences in all-cause mortality among MI subtypes were observed. Additional studies to determine optimal medical therapy and risk stratification strategies for these high-risk populations are warranted.
| S-EPMC5722665 | biostudies-literature
Project description:BackgroundInflammation is a key factor of myocardial damage in reperfused ST-segment-elevation myocardial infarction. We hypothesized that colchicine, a potent anti-inflammatory agent, may reduce infarct size (IS) and left ventricular (LV) remodeling at the acute phase of ST-segment-elevation myocardial infarction.MethodsIn this double-blind multicenter trial, we randomly assigned patients admitted for a first episode of ST-segment-elevation myocardial infarction referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day) or matching placebo from admission to day 5. The primary efficacy outcome was IS determined by cardiac magnetic resonance imaging at 5 days. The relative LV end-diastolic volume change at 3 months and IS at 3 months assessed by cardiac magnetic resonance imaging were among the secondary outcomes.ResultsWe enrolled 192 patients, 101 in the colchicine group and 91 in the control group. At 5 days, the gadolinium enhancement-defined IS did not differ between the colchicine and placebo groups with a mean of 26 interquartile range (IQR) [16-44] versus 28.4 IQR [14-40] g of LV mass, respectively (P=0.87). At 3 months follow-up, there was no significant difference in LV remodeling between the colchicine and placebo groups with a +2.4% (IQR, -8.3% to 11.1%) versus -1.1% (IQR, -8.0% to 9.9%) change in LV end-diastolic volume (P=0.49). Infarct size at 3 months was also not significantly different between the colchicine and placebo groups (17 IQR [10-28] versus 18 IQR [10-27] g of LV mass, respectively; P=0.92). The incidence of gastrointestinal adverse events during the treatment period was greater with colchicine than with placebo (34% versus 11%, respectively; P=0.0002).ConclusionsIn this randomized, placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days did not reduce IS assessed by cardiac magnetic resonance imaging. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03156816.
| S-EPMC8462445 | biostudies-literature
Project description:Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.
| S-EPMC7324567 | biostudies-literature