Review Form First Author, Year: ___________________ Ref ID #__________ Abstractor Initials: ___ ___ ___ Primary Inclusion/Exclusion Criteria 1. Relevant to SER topic Yes No Cannot Determine 2. Attempts internal or external validation Yes No Cannot Determine 3. Published in English Yes No Cannot Determine 4. Original research (exclude reviews, editorials, commentaries, letters to editor, etc.) Yes No Cannot Determine 5. Eligible Study types a. Randomized controlled trials b. Controlled clinical trials

Systematic Review of Cardiovascular Disease Risk Assessment Tools

The National Cholesterol Education Programme Adult Treatment Panel III accepted the predominance of small dense low-density lipoprotein (sdLDL) as an emerging cardiovascular disease (CVD) risk factor. Most studies suggest that measuring low-density lipoprotein (LDL) particle size, sdLDL cholesterol content and LDL particle number provides additional assessment of CVD risk. Therapeutic modulation of small LDL size, number and distribution may decrease CVD risk; however, no definitive causal relationship is established, probably due to the close association between sdLDL and triglycerides and other risk factors (e.g., high-density lipoprotein, insulin resistance and diabetes). This review addresses the formation and measurement of sdLDL, as well as the relationship between sdLDL particles and CVD. The effect of hypolipidaemic (statins, fibrates and ezetimibe) and hypoglycaemic (glitazones) agents on LDL size and distribution is also discussed.

Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles

Stroke is the fifth leading cause of death and the most frequent cause of disability worldwide. Currently, stroke diagnosis is based on neuroimaging; therefore, the lack of a rapid tool to diagnose stroke is still a major concern. In addition, therapeutic approaches to combat ischemic stroke are still scarce, since the only approved therapies are directed toward restoring blood flow to the affected brain area. However, due to the reduced time window during which these therapies are effective, few patients benefit from them; therefore, alternative treatments are urgently needed to reduce stroke brain damage in order to improve patients' outcome. The inflammatory response triggered after the ischemic event plays an important role in the progression of stroke; consequently, the study of inflammatory molecules in the acute phase of stroke has attracted increasing interest in recent decades. Here, we provide an overview of the inflammatory processes occurring during ischemic stroke, as well as the potential for these inflammatory molecules to become stroke biomarkers and the possibility that these candidates will become interesting neuroprotective therapeutic targets to be blocked or stimulated in order to modulate inflammation after stroke.

https://journals.sagepub.com/doi/pdf/10.1177/1756286418789340

Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management.

Objectives The aim of this study was to systematically collate and appraise the available evidence regarding the associations between small, dense low-density lipoprotein (sdLDL) and incident coronary heart disease (CHD), focusing on cholesterol concentration (sdLDL-C) and sdLDL particle characteristics (presence, density, and size). Background Coronary heart disease (CHD) is the leading cause of death worldwide. Small, dense low-density lipoprotein (sdLDL) has been hypothesized to induce atherosclerosis and subsequent coronary heart disease (CHD). However, the etiological relevance of lipoprotein particle size (sdLDL) versus cholesterol content (sdLDL-C) remains unclear. Methods PubMed, MEDLINE, Web of Science, and EMBASE were systematically searched for studies published before February 2020. CHD associations were based on quartile comparisons in eight studies of sdLDL-C and were based on binary categorization in fourteen studies of sdLDL particle size. Reported hazards ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) were standardized and pooled using a random-effects meta-analysis model. Results Data were collated from 21 studies with a total of 30,628 subjects and 5,693 incident CHD events. The average age was 67 years, and 53% were men. Higher sdLDL and sdLDL-C levels were both significantly associated with higher risk of CHD. The pooled estimate for the high vs. low categorization of sdLDL was 1.36 (95% CI: 1.21, 1.52) and 1.07 (95% CI: 1.01, 1.12) for comparing the top quartiles versus the bottom of sdLDL-C. Several studies suggested a dose response relationship. Conclusions The findings show a positive association between sdLDL or sdLDL-C levels and CHD, which is supported by an increasing body of genetic evidence in favor of its causality as an etiological risk factor. Thus, the results support sdLDL and sdLDL-C as a risk marker, but further research is required to establish sdLDL or sdLDL-C as a potential therapeutic marker for incident CHD risk reduction.

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Association of small, dense LDL-cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: A systematic review and meta-analysis.

Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non-invasive CT scanning of the coronaries are increasingly used for the same purpose. Low-density lipoprotein (LDL) cholesterol and other lipid and lipoprotein variables are major risk factors for coronary artery disease. Small dense LDL particles may be of particular importance, but clinical studies evaluating their predictive value for coronary atherosclerosis are few. We performed a study of 194 consecutive patients with chest pain, a priori considered of low to intermediate risk for significant coronary stenosis (>50% lumen obstruction) who were referred for elective coronary angiography. Plasma lipids and lipoproteins were measured including the subtype pattern of LDL particles, and all patients were examined by coronary CT scanning before coronary angiography. The proportion of small dense LDL was a strong univariate predictor of significant coronary artery stenosis evaluated by both methods. After adjustment for age, gender, smoking, and waist circumference only results obtained by traditional coronary angiography remained statistically significant. Small dense LDL particles may add to risk stratification of patients with suspected angina pectoris.

https://link.springer.com/content/pdf/10.1186/1476-511X-10-21.pdf

Small dense LDL particles - a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study

Small dense LDL (sd-LDL) has recently emerged as an important coronary artery disease (CAD) risk factor. This study was performed to investigate how LDL particle size is related to CAD and acute coronary syndrome (ACS). Blood samples were collected from 504 patients that underwent coronary angiography to evaluate chest pain. The LDL particle size of these samples was measured. The mean LDL particle size was smaller in patients with angiographically proven CAD than in the controls (26.41 ± 0.95 vs 26.73 ± 0.64 nm, p < 0.001), and was negatively correlated with the Framingham risk score (r = -0.121, p = 0.007). Patients with more extensive CAD had smaller LDL particles. LDL particle size was also smaller in patients with acute coronary syndrome as compared to non-ACS patients (26.09 ± 1.42 vs 26.54 ± 0.63 nm, p = 0.011). These results suggest that sd-LDL is independently associated with the incidence and extent of CAD, and can be a risk factor for the development of ACS in the Korean population.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/122487/1/T008678.pdf

Significance of Small Dense Low-Density Lipoprotein as a Risk Factor for Coronary Artery Disease and Acute Coronary Syndrome

The objective of this study was to investigate the correlation between factor XIII (FXIII) activity and disseminated intravascular coagulation (DIC) parameters and also to evaluate the clinical usefulness of DIC diagnosis. Citrated plasma from eighty patients with potential DIC was analyzed for FXIII activity. The primary patient conditions (48 male and 32 female, mean age, 51 years) were malignancy (n = 29), infection (n = 25), inflammation (n = 6), heart disease (n = 3), thrombosis (n = 2), injury (n = 2), and other miscellaneous conditions (n = 13). FXIII testing was performed using the CoaLinkTM FXIII Incorporation Assay Kit (PeopleBio Inc.). Among 80 patients who were suspected to have DIC based on clinical analysis, 46 (57.5%) fulfilled the overt DIC criteria (DIC score > = 5) according to the International Society of Thrombosis and Haemostasis. FXIII levels in the plasma were significantly decreased in overt DIC compared to non-overt DIC patients (mean 75.1% and 199.7% respectively, p < 0.0001). Interestingly, we found a significant inverse correlation between DIC scores and FXIII activity. In addition, FXIII activity significantly correlated with other hemostatic markers that included platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer. FXIII levels were significantly lower in patients with liver or renal dysfunction. In conclusion, FXIII cross-linking activity measurements may have differential diagnostic value as well as predictive value in patients who are suspected to have DIC.

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Plasma Factor XIII Activity in Patients with Disseminated Intravascular Coagulation

Procoagulant or impaired fibrinolytic states as well as inflammatory reactions mediated by cytokines are likely involved in the pathogenesis of acute ischemic stroke. We examined the potential relationship between interleukin 6 (IL-6) and hemostatic markers. The procoagulant and fibrinolytic states were assessed in 46 patients with acute stroke by measuring plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), and plasminogen-antiplasmin complex (PAP). Circulating IL-6 levels were measured using ELISA (Quantikine, RD lacunar 3.2 ng/mL; cardiogenic 9.9 ng/mL, p = 0.021). Neither procoagulant levels nor fibrinolytic markers significantly correlated with circulating IL-6 levels. Our findings suggest that elevated proinflammatory cytokines during the initial hours of ischemic stroke may be an independent pathogenic factor or a consequence of the thrombotic event with no relationship to the procoagulant or fibrinolytic states.

/pdf/plasma-level-of-il-6-and-its-relationship-to-procoagulant-45fmos6jwm.pdf

Plasma level of IL-6 and its relationship to procoagulant and fibrinolytic markers in acute ischemic stroke.

Purpose Plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂) binds to low-density lipoprotein. The levels of Lp-PLA₂ reflect the plaque burden, and are upregulated in acute coronary syndrome (ACS). We investigated the diagnostic value of Lp-PLA2 levels and found that it might be a potential biomarker for ACS. Materials and methods We classified 226 study participants into three groups: patients without significant stenosis (control group), patients with significant stenosis with stable angina (SA group), and patients with ACS (ACS group). Results Lp-PLA₂ and high-sensitivity C-reactive protein (hs-CRP) levels were significantly greater in the ACS group than in the SA group (p=0.044 and p=0.029, respectively). Multivariate logistic regression analysis revealed that Lp-PLA₂ levels are significantly associated with ACS (odds ratio=1.047, p=0.013). The addition of Lp-PLA₂ to the ACS model significantly increased the global χ² value over traditional risk factors (28.14 to 35.602, p=0.006). The area under the receiver operating characteristic curve for Lp-PLA₂ was 0.624 (p=0.004). The addition of Lp-PLA₂ level to serum hs-CRP concentration yielded an integrated discrimination improvement of 0.0368 (p=0.0093, standard error: 0.0142) and improved the ability to diagnose ACS. Conclusion Lp-PLA₂ levels are related to plaque stability and might be a diagnostic biomarker for ACS.

/pdf/lipoprotein-associated-phospholipase-a2-is-related-to-plaque-3g0xq2sqi7.pdf

Lipoprotein-Associated Phospholipase A2 Is Related to Plaque Stability and Is a Potential Biomarker for Acute Coronary Syndrome

The hepatopulmonary syndrome (HPS) is defined as the triad of liver disease, pulmonary gas exchange abnormalities leading to arterial deoxygenation, and widespread pulmonary vascular dilatation. Although both acute and chronic liver diseases have been associated with HPS, most commonly it is associated with cirrhosis. Portal hypertension seems to be the predominant factor related to this syndrome. The hallmark of pulmonary vascular changes in HPS is dilated vessels at the precapillary and capillary level and direct arteriovenous communications. This causes right-to-left shunting of blood flow, mismatch between ventilation and perfusion, and diffusion limitation. Contrast transthoracic echocardiography may be the only diagnostic test to demonstrate right-to-left shunt in these patients. It is performed by intravenous injection of agitated saline as an echocardiographic contrast, while visualizing the atria. In the case of HPS, contrast appears in the left atrium 2 to 5 s after it is seen in the right atrium. Case Report

Jihyuk Rhee

Papers

Significance of Small Dense Low-Density Lipoprotein as a Risk Factor for Coronary Artery Disease and Acute Coronary Syndrome

Plasma Factor XIII Activity in Patients with Disseminated Intravascular Coagulation

Plasma level of IL-6 and its relationship to procoagulant and fibrinolytic markers in acute ischemic stroke.

Lipoprotein-Associated Phospholipase A2 Is Related to Plaque Stability and Is a Potential Biomarker for Acute Coronary Syndrome

The Hepatopulmonary Syndrome