Contribution of circulating Mfge8 to human T2DM and cardiovascular disease.

MFGE8 is a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal studies. The pathophysiological role of this protein in obesity, T2DM, and cardiovascular disease is less investigated in humans. Earlier we reported a rare Asian Indian population-specific missense variant (rs371227978; Arg148His) in the MFGE8 gene associated with increased circulating Mfge8 and T2DM. We have further investigated the role of Mfge8 with T2DM risk in additional Asian Indians (n = 4897) and Europeans and other multiethnic cohorts from UK Biobank (UKBB) (n = 455,808) and the US (n = 1150). We also evaluated the exposure of Mfge8-enriched human EVs in zebrafish (ZF) for their impact on cardiometabolic organ system. Most individual carriers of Arg148His variant not only had high circulating Mfge8 but also revealed a positive significant correlation with glucose (r = 0.42; p = 4.9 × 10-04), while the non-carriers showed a negative correlation of Mfge8 with glucose (r = -0.38; p = 0.001) in Asian Indians. The same variant was monomorphic in non-South Asian ethnicities. Even without the variant, serum Mfge8 correlated significantly with blood glucose in other non-South Asian ethnicities (r = 0.47; p = 2.2 × 10-13). Since Mfge8 is an EV marker, we tested the exposure of Mfge8-enriched human EVs to ZF larvae as an exploratory study. The ZF larvae showed rapid effects on insulin-sensitive organs, developing fatty liver disease, heart hypertrophy and exhibiting redundant growth with poor muscular architecture with and without the high-fat diet (HFD). In contrast, the control group fishes developed fatty liver disease and heart hypertrophy only after the HFD feeding. Backed with strong support from animal studies on the role of Mfge8 in obesity, insulin resistance, and atherosclerosis, the current research suggests that circulating Mfge8 may become a potential marker for predicting the risk of T2DM and cardiovascular disease in humans.

Difference in acute and chronic stage ischemic stroke metabolic markers with controls.

BACKGROUND: Acute Ischemic Stroke (AIS), a major cause of disability, was previously associated with multiple metabolomic changes, but many findings were contradictory. Case-control and longitudinal study designs could have played a role in that. To clarify metabolomic changes, we performed a simultaneous comparison of ischemic stroke metabolome in acute, chronic stages of stroke and controls. METHODS: Through the nuclear magnetic resonance (NMR) platform, we evaluated 271 serum metabolites from a cohort of 297 AIS patients in acute and chronic stages and 159 controls. We used Sparse Partial Least Squares-Discriminant analysis (sPLS-DA) to evaluate group disparity; multivariate regression to compare metabolome in acute, chronic stages of stroke and controls; and mixed regression to compare metabolome acute and chronic stages of stroke. We applied false discovery rate (FDR) to our calculations. RESULTS: The sPLS-DA revealed separation of the metabolome in acute, chronic stages of stroke and controls. Regression analysis identified 38 altered metabolites. Ketones, branched-chain amino acids (BCAAs), energy, and inflammatory compounds were mostly elevated, while alanine and glutamine were decreased in the acute stage. These metabolites declined/increased in the chronic stage, often to the same levels as in controls. Levels of fatty acids, phosphatidylcholines, phosphoglycerides, and sphingomyelins did not change between acute and chronic stages, but were different comparing to controls. CONCLUSION: Our pilot study identified metabolites associated with acute stage of ischemic stroke and those that are altered in stroke patients comparing to controls regardless of stroke acuity. Future investigation in a larger independent cohort is needed to validate these findings.

Comparison of Acute and Chronic Stage Ischemic Stroke Metabolome with Controls.

Background: Acute Ischemic Stroke (AIS), a major cause of disability, was previously associated with multiple metabolomic changes, but many findings were contradictory. Case-control and longitudinal study designs could have played a role in that. To clarify metabolomic changes, we performed a simultaneous comparison of ischemic stroke metabolome in acute, chronic stages of stroke and controls. Methods: Through the nuclear magnetic resonance (NMR) platform, we evaluated 271 serum metabolites from a cohort of 297 AIS patients in acute and chronic stages and 159 controls. We used Sparse Partial Least Squares-Discriminant analysis (sPLS-DA) to evaluate group disparity; multivariate regression to compare metabolome in acute, chronic stages of stroke and controls; and mixed regression to compare metabolome acute and chronic stages of stroke. We applied false discovery rate (FDR) to our calculations. Results: The sPLS-DA revealed separation of the metabolome in acute, chronic stages of stroke and controls. Regression analysis identified 38 altered metabolites. Ketone bodies, branched-chain amino acids (BCAAs), energy, and inflammatory compounds were elevated in the acute stage, but declined in the chronic stage, often to the same levels as in controls. Levels of other amino acids, phosphatidylcholines, phosphoglycerides, and sphingomyelins mainly did not change between acute and chronic stages, but was different comparing to controls. Conclusion: Our pilot study identified metabolites associated with acute stage of ischemic stroke and those that are altered in stroke patients comparing to controls regardless of stroke acuity. Future investigation in a larger independent cohort is needed to validate these findings.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Flat-Detector CT to Quantify Response to Intra-Arterial Spasmolytic Therapy for Cerebral Vasospasm.

BACKGROUND AND PURPOSE: Cerebral vasospasm in the setting of subarachnoid hemorrhage causes morbidity and mortality due to delayed cerebral ischemia and permanent neurological deficits. Vasospasm treatment includes intra-arterial injection of a spasmolytic during cerebral angiography. To evaluate effectiveness, neurointerventionalists subjectively examine a posttreatment cerebral angiogram to determine change in vessel diameter or increase in microvascular perfusion. Flat-detector computed tomography (FDCT) scanner has the ability to quantitatively measure cerebral blood volume (CBV) within the parenchyma and detect a quantitative change following treatment. METHODS: This is a prospective study at a single institution between October 5, 2017 and June 3, 2019 that examines CBV studies from the Artis Q biplane (Siemens). Regions of interest were made in various territories to measure the CBV within the parenchyma before and after treatment with the spasmolytic verapamil. All instances of vasospasm involved vasculature within the left middle cerebral artery or internal carotid artery. The Wilcoxon signed-rank test was used to determine significance before and after treatment. RESULTS: Our cohort consists of 6 patients who underwent Digital Subtraction Angiography (DSA) and FDCT scans for cerebral vasospasm within the left hemisphere. After intra-arterial injection of 20 mg of verapamil, average increases in blood volume were 59%, 22%, and 24% for the temporal, frontal, and parietal lobes, respectively. P-values associated were .03. We also observed decrease in the mean arterial blood pressure and transcranial Doppler values after treatment. CONCLUSION: In conclusion, FDCT could measure the effectiveness of a change in CBV from infusion of verapamil in the setting of cerebral vasospasm. The authors believe quantifying the change allows for reassurance of improvement of cerebral vasospasm.