Central to the pathogenesis of ischaemic stroke are the normally protective processes of platelet adhesion and activation. Experimental evidence has shown that the ligand-receptor interactions in ischaemic stroke represent a thrombo-inflammatory cascade, which presents research opportunities into new treatment. However, as anti-platelet drugs have the potential to cause severe side effects in ischaemic stroke patients (as well as other vascular disease patients), it is important to carefully monitor the risk of bleeding and risk of thrombus in patients receiving treatment. Because thrombo-embolic ischaemic stroke is a major health issue, we suggest that the answer to adequate treatment is based on an individualized patient-centered approach, inline with the latest NIH precision medicine approach. A combination of viscoelastic methodologies may be used in a personalized patient-centered regime, including thromboelastography (TEG®) and the lesser used scanning electron microscopy approach (SEM). Thromboelastography provides a dynamic measure of clot formation, strength, and lysis, whereas SEM is a visual structural tool to study patient fibrin structure in great detail. Therefore, we consider the evidence for TEG® and SEM as unique means to confirm stroke diagnosis, screen at-risk patients, and monitor treatment efficacy. Here we argue that the current approach to stroke treatment needs to be restructured and new innovative thought patterns need to be applied, as even approved therapies require close patient monitoring to determine efficacy, match treatment regimens to each patient's individual needs, and assess the risk of dangerous adverse effects. TEG® and SEM have the potential to be a useful tool and could potentially alter the clinical approach to managing ischaemic stroke. As envisaged in the NIH precision medicine approach, this will involve a number of role players and innovative new research ideas, with benefits that will ultimately only be realized in a few years. Therefore, with this ultimate goal in mind, we suggest that an individualized patient-orientated approach is now available and therefore already within our ability to use.
Several international guidelines and consensus statements have recently been published on the care of familial hypercholesterolemia (FH)1-3). They agree on approaches to case detection and cascade testing, protocols in children, lifestyle and drug treatment strategies, and indications for lipoprotein apheresis. However, most countries in the world still do not have integrated, systematic FH screening programs to adequately detect and treat cases in the community. This study provides a comprehensive overview of recent and future international initiatives for closing the gaps in the care of FH.
Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic coronary heart disease (CHD). Patients with FH in Hong Kong were found by the identification of potential probands with primary hypercholesterolemia manifesting total cholesterol levels greater than 7.5 mmol/L or LDL-C levels greater than 4.9 mmol/L and undertaking cascade screening of available relatives in the Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong since the early 1990s. Our previous study in a group of 252 subjects from 87 pedigrees clinically diagnosed as having heterozygous FH reported the mean plasma LDL-C level as 7.2±1.5 mmol/L. Xanthomata were present in 40.6% of males and 54.8% of females. The prevalence of known CHD was relatively low at 9.9% in males and 8.5% in females. All FH patients were offered treatment with statins and many of them reached the LDL-C goal with a moderate or high dose of potent statin alone. Ezetimibe is usually added for patients who have not achieved target LDL-C levels on statin alone, particularly in patients with established CHD. Some FH patients who have not achieved the LDL-C targets with this combination have entered into clinical trials with new cholesterol-modifying agents such as the monoclonal antibodies to proprotein convertase subtilisin-kexin type 9. Increased awareness, early identification, and optimal treatment are essential to reduce the risk of CHD, increase life expectancy, and improve the quality of life of patients with FH.
Familial hypercholesterolemia (FH) is presently an important health issue worldwide. This condition shows phenotypic and genetic variations among affected people, and clinical and genetic data on FH are critical for effective diagnosis and management. Korean FH patients have relatively low levels of cholesterol and prevalence of xanthoma than patients from other countries, as determined by previous studies. The best predictive value of low-density lipoprotein cholesterol (LDL-C) for pathogenic mutations is suggested as 225 mg/dL. Many known and novel mutations on LDLR and some on APOB or PCSK9 have been identified in one-third of clinically diagnosed probands, and their locations on genes varied. Coronary artery disease was reported in 28% Korean FH patients, and traditional cardiovascular risk factors were associated with this complication. Aortic valve changes were also prevalent. However, the achievement rate of LDL-C target using lipid-lowering therapy is not satisfactory and is only 21%–44%. A further expanded registry and additional analysis may provide a more useful clinical tool for the diagnosis and treatment of Korean FH patients.
Familial hypercholesterolemia (FH) is the most common autosomal disorder characterized by an elevated low-density lipoprotein-cholesterol level and a high risk of premature cardiovascular disease. In this review, we summarize information on FH studies in Asian countries, focusing on mean cholesterol level, FH frequency, diagnostic criteria, genotypes, and clinical care of FH patients in Asian populations. Compared with Western countries, most Asian countries had lower mean cholesterol levels, with a significant variation between different countries. In the limited studies reported, a frequency of 1/900 was reported in Hokuriku district, Japan in 1977 and a frequency of 1/85 among Christian Lebanese in 1979. Recently, a population study in China reported frequencies of 0.47% and 0.28%. However, the different FH frequencies reported were based on different diagnostic criteria. Of 28 publications from 16 Asian countries or regions, 14 used self-defined FH criteria. Only one specific guideline for FH was available, which was developed by Japanese scientists. Six Asian countries joined the Make Early Diagnosis to Prevent Early Deaths program in the late 1990s, and the estimated diagnosis rates of FH ranged from 3% to 10% in these countries. A more recent study explored the awareness, knowledge, and perception of FH among practitioners in Japan, Korea, and Taiwan. The study found that the correct rates of these FH-related questions were low and concluded that lack of country-specific criteria and guidelines may contribute to the lack of FH knowledge in the present survey. More attention and resources should be focused on raising awareness, improving care, and increasing FH research in Asian populations.
Aim: Although plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in infarcted myocardium, the pathogenic role of myocardial PAI-1 remains unknown. This study examined whether PAI-1 in the infarcted lesion contributes to coronary endothelial dysfunction and left ventricular (LV) dysfunction in patients with acute myocardial infarction (AMI). Methods: Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) antigen were measured 2 weeks and 6 months after MI by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV) in 28 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD). Coronary blood flow responses in LAD to intracoronary infusion of acetylcholine (ACh) and left ventriculography were measured at the same time points: 2 weeks and 6 months after MI. Results: The trans-myocardial gradient of PAI-1 from AO to AIV, reflecting production/release of PAI-1 in the infarcted lesion, was inversely correlated with the coronary blood flow response to ACh 6 months after MI (r=-0.43, p=0.02) and with the percentage change in LV regional motion in the LAD territory from 2 weeks to 6 months after MI (r=-0.38, p=0.04). The trans-myocardial gradient of tPA level showed no significant correlations. Conclusions: PAI-1 produced in the infarcted myocardium and released into the coronary circulation is associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and with progressive dysfunction of the infarcted region of the left ventricle in AMI survivors.
Aim: Five multicentre, cross-sectional Centralized Pan-Regional Surveys on the Undertreatment of Hypercholesterolaemia (CEPHEUS) were conducted in 29 countries across Asia, Western Europe, Eastern Europe, the Middle East, and Africa. The surveys assessed the current use and efficacy of lipid-lowering drugs (LLDs) worldwide and identified possible patient and physician characteristics associated with failure to attain low-density lipoprotein cholesterol (LDL-C) goals. The aim of this analysis was to consolidate the global results from these surveys. Methods: The surveys involved patients aged ≥18 years who had been prescribed LLDs for at least 3 months without dose changes for at least 6 weeks. A single visit was scheduled for data collection, including fasting plasma lipid and glucose levels. Cardiovascular risk profile and LDL-C goal attainment were assessed according to the 2004 updated US National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: In total, 35 121 patients (mean age: 60.4 years) were included, and 90.3% had been prescribed statin monotherapy. Overall, only 49.4% of patients reached their recommended LDL-C level. LDL-C goals were attained in 54.8% (5084/9273) and 22.8% (3287/14 429) of patients were at high and very high cardiovascular risk, respectively. Factors associated with an increased likelihood of LDL-C goal attainment were lower baseline cardiovascular risk; presence of diabetes mellitus, hypertension, or history of cardiovascular disease; and treatment with simvastatin, atorvastatin, or rosuvastatin (vs. all other LLDs). Conclusion: LDL-C goal attainment in patients taking LLDs is suboptimal worldwide, particularly in patients at high and very high cardiovascular risk.
Aim: The aim of this study was to compare coronary calcium scores and aortic calcium scores between patients with severe hypercholesterolemia having a DNA-based diagnosis of FH (FH group) versus patients with severe hypercholesterolemia without the FH gene mutation (NFH group). Method: A total of 89 FH and 50 NFH patients underwent CT with coronary and thoracic aorta calcium scoring. Their CCS and TCS in ascending aorta (TCSasc) and descending aorta (TCSdesc) were determined and compared between the two patient groups. Results: TCSasc was significantly higher in the FH group when compared to the NFH group (30.6± 59 vs 4.7±13.4, p＜0.001. After adjusting for age, sex, smoking, blood pressure, history of diabetes mellitus and LDL cholesterol levels, FH gene mutation was an independent risk factor of having non-zero TCSasc 3.6 (95% CI, 1.4–9.5, p＜0.01), high TCSasc 9.6 (95% CI, 2.4–38.2, p＜0.01) and high CCS of 4.1 (95% CI, 1.2–13.2. p＜0.05). Conclusion: We found that when computed tomography calcium scores were used as an assessment, patients with familial hypercholesterolemia displayed an increased burden of ascending aorta atherosclerosis when compared to patients with nonfamilial severe hypercholesterolemia. This phenomenon appears to be more dependent on the presence of FH genotype than hypercholesterolemia itself.
Aim: We investigated whether cardio-ankle vascular index (CAVI), an arterial stiffness marker, independently predicts future cardiovascular events in subjects with metabolic disorders. Methods: 1562 outpatients underwent CAVI between April 2004 and March 2006 at Toho University, Sakura Medical Center in Chiba, Japan. Patients who already had cardiovascular events at baseline, patients with low ankle brachial index (＜0.9), and patients with atrial fibrillation were excluded. After exclusion, 1080 subjects with metabolic disorders including diabetes mellitus, hypertension and dyslipidemia were screened and followed prospectively. Results: Eventually, 1003 subjects (92.9% of 1,080 subjects) followed until March 2012 (follow-up duration 6.7±1.6 years) were analyzed. During the observation period, 90 subjects had new-onset myocardial infarction or angina pectoris confirmed by angiography. All subjects were stratified into quartiles by baseline CAVI (Q1: CAVI ≤8.27, Q2: CAVI 8.28-9.19, Q3: CAVI 9.20-10.08, Q4: CAVI ≥10.09). Age, male ratio and future cardiovascular events increased as CAVI quartile became higher. In Cox proportional hazards regression analysis, the factors independently associated with higher risk of future cardiovascular events were every 1.0 increment of CAVI [hazard ratio (HR) 1.126, p= 0.039], male gender (HR 2.276, p=0.001), smoking (HR 1.846, p=0.007), diabetes mellitus (HR 1.702,p=0.020), and hypertension (HR 1.682, p=0.023). Conclusion: In individuals with metabolic disorders, CAVI was a predictor of future cardiovascular events, independent of traditional coronary risk factors. CAVI is a potentially valuable tool to identify persons likely to benefit from more intensive therapeutic approaches.
Aims: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. Methods: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥110 mg/dL were administered an escalating lomitapide dose range of 10–60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. Results: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10–60 mg for both single- and multiple-dose administration. The correlation between AUC0–t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. Conclusions: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.
Aim: To evaluate the relationship between CYP genetic polymorphisms and CYP metabolite levels with carotid artery stenosis in acute ischemic stroke (IS) patients. Methods: Eleven single nucleotide polymorphisms (SNPs) of seven CYP genes were genotyped in 136 IS patients with carotid stenosis and 158 patients without carotid stenosis. CYP plasma metabolite levels [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] were assessed in a subsample of 90 patients with carotid stenosis and 96 patients without carotid stenosis. We evaluated the relationship between assessed variants and carotid stenosis risk, variants with CYP metabolite levels, and variants in mediating the differences of CYP metabolite levels between patients with carotid stenosis and those without. Additionally, gene–gene interactions were analyzed to assess the interactive role of the assessed variants in affecting CYP metabolite levels and risk of carotid stenosis. Results: The genotypes of rs17110453CC, rs751141GG, and rs9333025GG were significantly associated with carotid stenosis risk. Also these polymorphisms were associated with CYP plasma metabolite levels in patients with carotid stenosis. There was a significant gene–gene interaction between rs17110453 and rs9333025 in affecting the risk of carotid stenosis. Patients with rs17110453CC and rs9333025GG had a significantly higher risk of carotid stenosis than those with 17110453AA and rs9333025AA (OR=2.12, 95% CI: 1.13–7.26, P=0.013). Conclusions: Specific CYP450 gene SNPs and their interactions are associated with CYP450 plasma metabolite levels, which may partially explain their associations with carotid stenosis. Further studies are needed to validate our findings.
Aim: Immunologic dysfunction was recently found to be one of the most important mechanisms underlying the initiation and development of atherosclerosis. Thymus involution can contribute to immune disturbance and disequilibrium of T-cell subsets. This study aimed to explore whether recent thymic emigration (RTE) is impaired in patients with coronary artery disease (CAD). Methods: Content of signal-joint T cell receptor excision circles (sj-TREC) in T lymphocytes, a molecular marker of RTE, was assessed among CAD patients and age-matched controls. Monochrome multiplex quantitative PCR method was used to assess the samples' telomere length in order to exclude the potential influence of T cell proliferation on the dilution of sj-TREC. Patients were grouped according to Gensini score (GS) (low, GS ＜18; intermediate, GS 18–41; high, GS ＞41). Ordinary logistic regression models were used to determine potential risk factors for CAD and GS tertiles. Results: Average copy numbers of sj-TREC per 106 T lymphocytes among patients with unstable angina, stable angina, and controls were 726±429, 1213±465, and 1795±838, respectively (P＜0.001). However, there was no significant difference in telomere length among groups. Moreover, the content of sj-TREC in the high GS group was most significantly reduced than the low GS group (P＜0.001). Multivariate logistic regression analysis revealed that lower sj-TREC was independently associated with the progression of CAD (OR=0.44, P＜0.001) and higher GS (OR=0.4, P＜0.001). Conclusion: Impaired RTE could be partly responsible for CAD development. Mechanisms may be involved in the disturbance of T lymphocyte compartment and interruption of maintained immune tolerance resulting from thymus involution.