Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly. For a patient with cutaneous or tendon xanthomas, the probability of FH is very high; however, an absence of xanthoma does not rule out FH.
Brown and Goldstein elucidated the pathogenesis of FH by their work on LDL-receptor (LDL-R), for which they were awarded the Nobel Prize in 1985. In the 1950s, FH patients were divided into heterozygous (hetero-) and homozygous (homo-) FH, and diagnosing homo- and hetero-FH based on the phenotypic features of ASCVD or xanthomas frequently became difficult without the DNA analysis of FH genes. It is estimated that heterozygous mutations in the LDL-R or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan.
Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it.
Muhammad Aziz, Shozab S. Ali, Sankalp Das, Adnan Younus, Rehan Malik, Muhammad A. Latif, Choudhry Humayun, Dixitha Anugula, Ghulam Abbas, Joseph Salami, Javier Valero Elizondo, Emir Veledar, Khurram Nasir
Aim: Abnormal daily sleep duration and quality have been linked to hypertension, diabetes, stroke, and overall cardiovascular disease (CVD) morbidity& mortality. However, the relationship between daily sleep duration and quality with subclinical measures of CVD remains less well studied. This systematic review evaluated how daily sleep duration and quality affect burden of subclinical CVD in subjects free of symptomatic CVD.
Methods: Literature search was done via MEDLINE, EMBASE, Web of Science until June 2016 and 32 studies met the inclusion criteria. Sleep duration and quality were measured either via subjective methods, as self-reported questionnaires or Pittsburg Sleep Quality Index (PSQI) or via objective methods, as actigraphy or polysomnography or by both. Among subclinical CVD measures, coronary artery calcium (CAC) was measured by electron beam computed tomography, Carotid intima-media thickness (CIMT) measured by high-resolution B-mode ultrasound on carotid arteries, endothelial/microvascular function measured by flow mediated dilation (FMD) or peripheral arterial tone (PAT) or iontophoresis or nailfold capillaroscopy, and arterial stiffness measured by pulse wave velocity (PWV) or ankle brachial index (ABI).
Results: Subjective short sleep duration was associated with CAC and CIMT, but variably associated with endothelial dysfunction (ED) and arterial stiffness; however, subjective long sleep duration was associated with CAC, CIMT and arterial stiffness, but variably associated with ED. Objective short sleep duration was positively associated with CIMT and variably with CAC but not associated with ED. Objective long sleep duration was variably associated with CAC and CIMT but not associated with ED. Poor subjective sleep quality was significantly associated with ED and arterial stiffness but variably associated with CAC and CIMT. Poor objective sleep quality was significantly associated with CIMT, and ED but variably associated with CAC.
Conclusions: Overall, our review provided mixed results, which is generally in line with published literature, with most of the studies showing a significant relationship with subclinical CVD, but only some studies failed to demonstrate such an association. Although such mechanistic relationship needs further evaluation in order to determine appropriate screening strategies in vulnerable populations, this review strongly suggested the existence of a relationship between abnormal sleep duration and quality with increased subclinical CVD burden.
Atherosclerosis begins in early life and has a long latent period prior to onset of clinical disease. Measures of subclinical atherosclerosis, therefore, may have important implications for research and clinical practice of atherosclerotic cardiovascular disease (ASCVD). In this review, we focus on coronary artery calcium (CAC) and carotid artery intima-media thickness (cIMT) and plaque as many population-based studies have investigated these measures due to their non-invasive features and ease of administration. To date, a vast majority of studies have been conducted in the US and European countries, in which both CAC and cIMT/plaque have been shown to be associated with future risk of ASCVD, independent of conventional risk factors. Furthermore, these measures improve risk prediction when added to a global risk prediction model, such as the Framingham risk score. However, no clinical trial has assessed whether screening with CAC or cIMT/plaque will lead to improved clinical outcomes and healthcare costs. Interestingly, similar levels of CAC or cIMT/plaque among various regions and ethnic groups may in fact be associated with significantly different levels of absolute risk of ASCVD. Therefore, it remains to be determined whether measures of subclinical atherosclerosis improve risk prediction in non-US/European populations. Although CAC and cIMT/plaque are promising surrogates of ASCVD in research, we conclude that their use in clinical practice, especially as screening tools for primary prevention in asymptomatic adults, is premature due to many vagaries that remain to be clarified.
This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still ＜5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.
Aim: Epicardial adipose tissue (EAT) has been suggested as a contributing factor for coronary atherosclerosis based on the previous cross-sectional studies and pathophysiologic background. However, a causal relationship between EAT and the development of non-calcified coronary plaque (NCP) has not been investigated.
Methods: A total of 122 asymptomatic individuals (age, 56.0±7.6 years; male, 80.3%) without prior history of coronary artery disease (CAD) or metabolic syndrome and without NCP or obstructive CAD at baseline cardiac computed tomography (CT) were enrolled. Repeat cardiac CT was performed with an interval of more than 5 years. Epicardial fat volume index (EFVi; cm3/m2) was assessed in relation to the development of NCP on the follow-up CT where the results were classified into “calcified plaque (CP),” “no plaque,” and “NCP” groups.
Results: On the follow-up CT performed with a median interval of 65.4 months, we observed newly developed NCP in 24 (19.7%) participants. Baseline EFVi was significantly higher in the NCP group (79.9±30.3 cm3/m2) than in the CP group (63.7±22.7 cm3/m2; P=0.019) and in the no plaque group (62.5±24.7 cm3/m2; P=0.021). Multivariable logistic regression analysis demonstrated that the presence of diabetes (OR, 9.081; 95% CI, 1.682–49.034; P=0.010) and the 3rd tertile of EFVi (OR, 4.297; 95% CI, 1.040–17.757; P=0.044 compared to the 1st tertile) were the significant predictors for the development of NCP on follow-up CT.
Conclusions: Greater amount of EAT at baseline CT independently predicts the development of NCP in asymptomatic individuals.
Aim: Information regarding the effects of omega-3 fatty acid on hypertriglyceridemic patients in Chinese is still limited. This study aimed to investigate the efficacy and safety of Omacor®, a prescription ethyl-ester omega-3 fatty acid for the treatment of hypertriglyceridemia, administered at doses of 2 g/day and 4 g/day to Taiwanese hypertriglyceridemic patients.
Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel study in adults with hypertriglyceridemia was conducted. After a five-week diet lead in period patients with triglycerides =200–1000 mg/dL were randomized to receive Omacor®, a concentrated preparation of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in a dose of 1 g twice daily (2 g Omacor®), 2 g twice daily (4 g Omacor®) or placebo, for eight weeks. The primary endpoint was the percentage change in triglyceride serum levels from baseline to the end of treatment.
Results: A total of 253 Taiwanese patients were randomized, of which 65.6% (166) were men. At the end of the treatment, the percentage change in triglyceride serum levels in both the Omacor® 4 g/day (－32.1%) and 2 g/day (－29.7%) groups was larger than in the placebo group (－5.4%) (p＜0.001). The incidence of drug-related adverse events was as follows: 0.0%, 1.2%, and 0.0% in Omacor® 4 g/day, Omacor® 2 g/day, and placebo groups, respectively. No drug-related serious adverse events were reported during the study.
Conclusions: Omacor® may be a feasible option to treat hypertriglyceridemia in Taiwanese patients.
Aim: Few studies have addressed stroke risk factors in older populations, particularly among the old-old. We examined differences in traditional risk factors for stroke among the old-old compared with the young-old in community-dwelling Japanese adults.
Methods: We followed 2,065 residents aged ≥ 60 years who had no history of stroke. Traditional risk factors for stroke were obtained from a self-administered questionnaire at baseline. We classified participants into two age categories, 60–74 years (n=1,502) and ≥ 75 years (n=563), and assessed whether traditional risk factors were differentially associated with stroke incidence according to age category. Hazard ratios were calculated by the Cox proportional hazards model, adjusting for confounding factors and competing risk of death.
Results: During a median follow-up of 12.8 and 7.9 years, 163 and 111 participants aged 60–74 and ≥ 75 years, respectively, developed a first stroke. Hypertension was consistently associated with increased risk of stroke, regardless of age category. Diabetes mellitus was associated with increased risk of stroke in those aged 60–74 years (hazard ratio, 1.50; 95% confidence interval, 1.00–2.25), but not in those aged ≥ 75 years (hazard ratio, 0.65; 95% confidence interval, 0.33–1.29), with significant interaction by age (P=0.035). No traditional risk factor other than hypertension was associated with stroke among those aged ≥ 75 years.
Conclusion: Those with hypertension had significantly higher stroke risk among old people, while diabetes mellitus was differentially associated with stroke according to age category. Our findings indicate the importance of different prevention strategies for stroke incidence according to age category.
Aim: Atherosclerosis is a kind of chronic inflammatory disease. A crucial pathology change of atherosclerosis is the migration of activated VSMCs to the intima where they interact with leukocytes by expressing adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Moreover, monocyte chemoattractant protein-1 (MCP-1) expressed by VSMCs plays an important role in recruiting monocytes and macrophages. Leech (Whitmania pigra Whitman) is a traditional Chinese medicine to treat cardiovascular diseases including atherosclerosis, however previous research has rarely reported the molecular mechanism for its curative effect. Thus, our study focuses on the effects of leech extracts on the expression of inflammatory factors, adhesion molecules and MCP-1 in rat VSMCs.
Methods: In our present study, wound-healing assay and Boyden chamber model were applied to evaluate the anti-migration effect of LEE (Leech Enzyme Extracts) on LPS induced VSMCs. The anti-adhesion effect was assessed using DiI-labeled THP-1 and RAW264.7.
Results: LEE suppressed LPS-induced VSMCs migration and decreased the chemotaxis and adhesive capacity of THP-1 and RAW264.7 to LPS-stimulated VSMCs. LEE also attenuated the upregulation of a variety of pro-atherosclerotic factors by inhibiting the phosphorylation of p38 MAPK. LEE was also observed to prevent NF-κB p65 nuclear localization using immune-fluorescent staining.
Conclusions: In conclusion, LEE suppresses LPS-induced upregulation of inflammatory factors, adhesion molecules and MCP-1 in rat VSMCs mainly via inhibiting the p38 MAPK/NF-κB pathways, thus partly uncovered LEE's molecular mechanisms for its therapeutic effect on atherosclerosis.
Aim: Accumulation level of fluorescent advanced glycation end products (AGEs) in the skin can be measured non-invasively as skin autofluorescence (skin AF) by autofluorescence reader. The aim of this study was to assess possible associations between skin AF and diabetic complications, especially early-stage atherosclerosis, in Japanese type 1 diabetic patients.
Methods: Skin AF was measured by AGE reader® in 105 Japanese type 1 diabetic patients (34 men and 71 women, aged 37.4±12.4 years (±SD)) and 23 age-matched healthy non-diabetic subjects. Ultrasonic carotid intima-media thickness (IMT), ankle-brachial index (ABI), and brachial ankle pulse wave velocity (baPWV) were evaluated as indices of early-stage diabetic macroangiopathy. Urinary albumin-to-creatinine ratio (UACR), the coefficient of variation of R-R intervals (CVR-R), and presence of retinopathy were also evaluated.
Results: Skin AF values were significantly higher in type 1 diabetic patients than in healthy controls (2.07±0.50 (mean±SD) and 1.90±0.26, respectively, p=0.024). Skin AF was associated with carotid IMT (r=0.446, p＜0.001) and baPWV (r=0.450, p＜0.001), but not with ABI (r=－0.019, p=0.8488). Notably, skin AF was an independent risk factor for IMT thickening. Similarly, skin AF was associated with log (UACR) (r=0.194, p=0.049) and was an independent risk factor for UACR. Furthermore, skin AF values were significantly higher in patients with diabetic retinopathy than in those without (2.21±0.08 and 1.97±0.06, respectively, p=0.020).
Conclusions: Skin AF was significantly associated with the presence and/or severity of diabetic complications and was an independent risk factor for carotid atherosclerosis.
Aim: After the Great East Japan Earthquake, over 160,000 residents near the Fukushima Daiichi Nuclear Power Plant were forced to evacuate due to a nuclear accident. Health problems in these evacuees have since become major issues. We examined the association between evacuation and incidence of metabolic syndrome (METS) among residents in Fukushima.
Methods: We conducted a cohort study among residents aged 40-74 years without METS at the time of the disaster in Fukushima. Among 20,269 residents who met the inclusion criteria before the disaster, 8,547 residents (3,697 men and 4,850 women; follow-up proportion: 42.2%) remained available for follow-up examinations after the disaster by the end of March 2013. The main outcome was incidence of METS, defined by guidelines from the Japanese committee, using data from the Comprehensive Health Check before and after the disaster. We divided participants by evacuation status and compared outcomes between groups. Using a logistic regression model, we estimated the odds ratio for incidence of METS, adjusting for potential confounders, age, gender, waist circumference, exercise habit, and alcohol consumption.
Results: Incidence of METS was higher in evacuees (men 19.2%, women 6.6%) than in non-evacuees (men 11.0%, women 4.6%). Evacuees had higher body mass index, waist circumference, triglycerides, and fasting plasma glucose after the disaster than non-evacuees. We found a significant association between evacuation and incidence of METS (adjusted odds ratio 1.72, 95% confidence interval; 1.46-2.02).
Conclusion: This is the first study to demonstrate that evacuation after a disaster is associated with increased incidence of METS.
Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.
Methods: A total of 85,716 subjects (male=29,282, 34.2%) aged 40–74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets.
Results: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends ＜0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value ＜0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value ＜0.001).
Conclusions: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention.