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.

No abstract

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.

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.

Background: Acute ischemic stroke (AIS) is the fifth leading cause of death in the United States. Although early diagnosis is difficult, no reliable biomarker that categorizes ischemic stroke is currently available. Metabolome profiling is a useful method to identify such biomarkers. Correlation of these biomarkers to objective imaging data such as infarct volume can better delineate stroke pathophysiology and prognosis. Hypothesis: Disturbances of serum metabolites in AIS correlate with infarct volume. Methods: We conducted a prospective pilot study of 20 AIS patients with serum collection in the acute (72 hours) and chronic (2 to 9 months) phases. Global metabolite profiling of each serum sample was performed using Thermo Scientific Q Exactive Plus, and targeted analysis was performed using the in-house metabolomic database. We calculated the volume of ischemic lesions on diffusion-weighted imaging using the ABC/2 formula and correlated it to metabolite levels in the acute phase. The chronic phase served as a reference. We employed the LASSO (least absolute shrinkage and selection operator) regression with hypothesis testing to examine the association of the relative change of metabolite levels in acute and chronic phases with the volume of stroke in the acute phase. Results: The following four metabolites related to oxidative stress showed a significant correlation with infarct volume: 4-pyridoxic acid (B6 metabolism), asparagine (amino acid), serine (sphingolipid metabolism), and citraconic acid (fatty acid) [p-values for all <0.0001]. The infarct volume positively correlated with relative changes of 4-pyridoxic acid and serine (effect size 3.04 (95% CI [2.73, 3.35]) and 1.14 (95% CI [0.56, 1.73]), respectively), while asparagine and citraconic acid negatively correlated with infarct volume (effect size -2.20 (95% CI [-3.47, -0.93]) and -6.75 (95% CI [-10.34, -6.75]), respectively). Conclusion: Although all discovered metabolites were previously associated with ischemia, this is the first study that demonstrates that objective infarct volume correlates with these metabolite levels, which may have prognostic implications. Larger studies in the future are needed to validate our findings.