Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations.

Aim: We aimed to investigate the relationship of trimethylamine N-oxide (TMAO) concentrations with ischemic stroke in a large-scale case–control study conducted among the hospital-based general population.

Methods: We recruited 953 case–control sex- and age-matched pairs, and cases were confined to first acute ischemic stroke in this study. Fasting plasma TMAO was measured using high-performance liquid chromatography–tandem mass spectroscopy. Conditional logistic regression analysis was conducted to calculate odds ratios (OR) for the association of plasma TMAO with ischemic stroke.

Results: We found that plasma TMAO concentrations in patients with ischemic stroke were significantly higher than that in the control group (median: 2.85 µmol/L vs. 2.33 µmol/L, P＜0.001). In multivariable conditional logistic regression models, higher plasma TMAO concentrations were associated with increased odds of ischemic stroke [fully adjusted OR for highest vs. lowest TMAO quartile: 1.81; 95% confidence interval (CI): 1.27, 2.59; P for trend ＜0.001]. The multivariable-adjusted OR for ischemic stroke per 1 µmol/L increment of plasma TMAO was 1.05 (95% CI: 1.02, 1.08). Additionally, the positive association also persisted in subgroups stratified by age, sex, body mass index, smoking status, alcohol habits, history of diabetes, and history of hypertension.

Conclusions: This study suggested a positive association between plasma TMAO and ischemic stroke. Further studies are required to explore the role of plasma TMAO concentrations in predicting stroke risk.

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)].

Methods: In Uku town, 674 residents (mean age; 69.2±8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose×insulin levels/405.

Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49-601) ng/mL and 60 (1-107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p=0.028), triglycerides (p＜0.001), and HOMA-IR (p＜0.001), but not with LDL-C (p=0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p＜0.001), Lp(a) (p=0.033) and HOMA-IR (p=0.041).

Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.

Aims: Reports on an association between body mass index and aortic disease, which remains controversial. This study investigated the association between body mass index and mortality from aortic disease.

Methods: We conducted the Japan Collaborative Cohort Study, a prospective study of 103,972 Japanese men and women aged 40–79 years. Body mass index was calculated on the basis of self-reported height and weight, and the participants were followed up from 1988–89 through 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease according to quintiles of body mass index were analyzed using the Cox proportional hazards model.

Results: During the median 18.8 years of follow-up, we documented 139 deaths due to aortic aneurysm (including 51 thoracic and 74 abdominal aortic aneurysms) and 134 deaths due to aortic dissection. We observed positive associations of body mass index with mortality from aortic aneurysm among men: the multivariable hazard ratios (95% confidence intervals) for highest versus lowest quintiles of body mass index were 4.48 (2.10–9.58), P for trend ＜0.0001 for aortic aneurysm; 6.52 (1.33–32.02), P=0.005 for thoracic aortic aneurysm; 3.81 (1.39–10.49), P=0.01 for abdominal aortic aneurysm; and 2.71 (1.59–4.62), P=0.001 for total aortic disease. No association was found for aortic dissection. Among ever-smokers (men ≥ 90%) but not never-smokers (women ≥ 84%), an association between body mass index and aortic disease mortality was observed regardless of sex, which may explain the sex difference (P for sex-interaction=0.046).

Conclusions: We found a positive association between body mass index and mortality from aortic aneurysm among Japanese men and smokers.

Aim: This study aims to describe the feasibility and safety of direct occluded vessel puncture as a new access site for complex peripheral artery occlusive disease.

Methods: Eleven consecutive patients with symptomatic peripheral artery disease underwent endovascular therapy using the direct occluded vessel puncture technique. The occluded vessel was punctured using a dedicated 20 G needle and the Hi-Torque Command 18 ST guidewire under duplex echo or fluoroscopic guidance, and a 6 Fr sheath was then inserted. Hemostasis was achieved with the Exoseal^® Vascular Closure Device.

Results: Direct occluded vessel puncture was achieved in 10 of 11 cases (90.9%), and procedural success was achieved in all cases. There were no in-hospital deaths or any complications, including bleeding, pseudoaneurysms, thrombosis, or surgical conversion.

Conclusion:The direct occluded vessel puncture technique using a 20 G needle and the Hi-Torque Command 18 ST is feasible and safe. This technique may also be used as an alternative option when there are no appropriate approach sites.

Aim: Hemorrhagic transformation is the major complication of intravenous thrombolysis. Calcification is used widely as an imaging indicator of atherosclerotic burden and cerebrovascular function. The relationship between intracranial calcification and hemorrhagic transformation has not been explored fully. We aimed to identify and quantify calcification in the main cerebral vessels to investigate the correlations between quantitative calcification parameters, hemorrhagic transformation, and prognosis.

Methods: Acute, non-cardiogenic, ischemic stroke patients with anterior circulation who received intravenous thrombolysis therapy in the First Hospital of Jilin University were retrospectively and consecutively included. All included patients underwent a baseline CT before intravenous thrombolysis and a follow-up CT at 24 hours. A third-party software, ITK-SNAP, was used to segment and measure the calcification volume. A vascular non-bone component with a CT value ＞130 HU was considered calcified. Hemorrhagic transformation was determined based on the ECASS II classification criteria.

Results: The study included 242 patients, 214 of whom were identified as having calcification. Thirty-one patients developed hemorrhagic transformation. The calcification volume on the lesion side (0.1ml) was associated with hemorrhagic transformation (p=0.004, OR=1.504, 95% CI: 1.140–1.985). Ninety-six patients had poor prognoses. The poor prognosis group had more calcified vessels than the good prognosis group (p=0.014, OR=1.477, 95% CI: 1.083–2.015).

Conclusions: The arterial calcification volume on the lesion side is associated with hemorrhagic transformation after thrombolysis. The higher the number of calcified vessels, the greater the risk of poor prognosis.

Aims: This study aimed to assess the clinical efficacy of intravascular ultrasound (IVUS)-guided intraplaque wiring for femoropopliteal (FP) chronic total occlusion (CTO).

Methods: This single-center, retrospective, observational study was performed at the Japanese Red Cross Kyoto Daini Hospital. From March 2013 to June 2017, a total of 75 consecutive patients (mean age: 75.4±8.5 years; 59 males), who underwent endovascular treatment (EVT), having 82 de novo FP-CTO lesions, were enrolled in this study. Eleven of the lesions that met the exclusion criteria were excluded, and the remaining 71 lesions were divided into the IVUS-guided wiring group (n=34) and non-IVUS-guided wiring group (n=37). Primary patency, defined as a peak systolic velocity ratio of ＜2.4 on duplex ultrasonography, and freedom from clinically driven target lesion revascularization (CD-TLR) at 12 months were the primary outcomes.

Results: The mean lesion length was 21.6±8.9 cm. The frequencies of primary patency and freedom from CD-TLR were significantly higher in the IVUS-guided wiring group than in the non-IVUS-guided wiring group (70.0% vs. 52.2%, p=0.045; 83.9% vs. 62.8%, p=0.036, respectively). The complete clinically true lumen angioplasty rate was also higher in the IVUS-guided wiring group than in the non-IVUS-guided wiring group (91.1% vs. 51.3%, p＜0.001, respectively). The clinically true and false wire passage rates were respectively 97.3% and 2.7% in the IVUS-guided wiring group.

Conclusion: IVUS-guided wiring improves the clinical outcomes of EVT for FP-CTO by achieving a high clinically true lumen wire passage rate.

Aim: Activin receptor-like kinase 7 (ALK7) acts as a key receptor for TGF-β family members, which play important roles in regulating cardiovascular activity. However, ALK7’s potential role, and underlying mechanism, in the macrophage activation involved in atherogenesis remain unexplored.

Methods: ALK7 expression in macrophages was tested by RT-PCR, western blot, and immunofluorescence co-staining. The loss-of-function strategy using AdshALK7 was performed for functional study. Oil Red O staining was used to observe the foam cell formation, while inflammatory mediators and genes related to cholesterol efflux and influx were determined by RT-PCR and western blot. A PPARγ inhibitor (G3335) was used to reveal whether PPARγ was required for ALK7 to affect macrophage activation.

Results: The results exhibited upregulated ALK7 expression in oxidized low-density lipoprotein (Ox-LDL) induced bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs), isolated from ApoE-deficient mice, while ALK7’s strong immunoreactivity in BMDMs was observed. ALK7 knockdown significantly attenuated pro-inflammatory, but promoted anti-inflammatory, macrophage markers expression. Additionally, ALK7 silencing decreased foam cell formation, accompanied by the up-regulation of ABCA1 and ABCG1 involved in cholesterol efflux but the down-regulation of CD36 and SR-A implicated in cholesterol influx. Mechanistically, ALK7 knockdown upregulated PPARγ expression, which was required for the ameliorated effect of ALK7 silencing macrophage activation.

Conclusions: Our study demonstrated that ALK7 was a positive regulator for macrophage activation, partially through down-regulation of PPARγ expression, which suggested that neutralizing ALK7 might be promising therapeutic strategy for treating atherosclerosis.

Aim: Multivascular disease, indicating concurrent arteriosclerotic lesions in a number of different vascular beds, is an independent risk factor for recurrent ischemic events in the general population. However, the impact of multivascular disease on the risk of developing cardiovascular disease has not been fully evaluated in patients receiving hemodialysis.

Methods: A total of 3,504 hemodialysis patients were prospectively followed for 10 years. In this study, multivascular disease was defined as the coexistence of coronary artery disease and stroke. We examined the relationship between multivascular disease and the occurrence of composite cardiovascular endpoint, consisting of cardiovascular death, nonfatal coronary artery disease, nonfatal stroke, and peripheral artery disease.

Results: The proportion of participants with multivascular disease was 5.7% (n=200) at baseline. During follow-up (median, 106.6 months; interquartile range, 50.1–121.8 months), 1,311 patients experienced the composite endpoint, which was defined as at least one of the following: cardiovascular death (n=620), nonfatal coronary artery disease (n=318), nonfatal stroke (n=340), and peripheral artery disease (n=257). Compared with the group with no history of cardiovascular disease, the risk of experiencing the composite endpoint increased significantly with higher numbers of injured vascular beds in patients with single vascular disease (hazard ratio, 1.68; 95% confidence interval, 1.49–1.89) and in those with multivascular disease (hazard ratio, 2.11; 95% confidence interval, 1.71–2.60). In a multivariable analysis, multivascular disease was an independent predictor of cardiovascular events, in addition to diabetes, aging, and hypertension.

Conclusions: This study clearly demonstrated that multivascular disease was a powerful predictor for cardiovascular mortality and morbidity in patients receiving hemodialysis.

Patients with severe COVID-19 often experience complications including coagulopathy and fatal thrombosis. COVID-19 pneumonia sometimes leads to acute respiratory distress syndrome, requiring extracorporeal membrane oxygenation (ECMO), during which thrombosis and bleeding are major causes of death. Anticoagulation such as heparin is essential for COVID-19 patients on ECMO; however, bleeding might be caused by not only heparin, but also acquired von Willebrand syndrome (AVWS). To date, no study has examined ECMO-related bleeding and AVWS in COVID-19 patients.

We report a COVID-19 patient who experienced bleeding from AVWS in addition to disseminated intravascular coagulation (DIC) during ECMO. The level of high–molecular weight VWF multimers decreased during ECMO therapy, and these findings promptly improved after discontinuation of ECMO. Plasma levels of VWF antigen were extremely high, probably due to endothelial cell damage caused by COVID-19. On the other hand, plasma levels of ADAMTS13 activity were moderately reduced, to 20–30% of normal. The patient was successfully treated with cryoprecipitate in bleeding during ECMO without a reduction in heparin, which might have induced thromboembolism. Bleeding found in this patient might be caused by AVWS and DIC.

Severe COVID-19 patients are in a thrombotic state and need to receive anticoagulant therapy. However, once they receive ECMO therapy, bleeding symptoms could be observed. In such cases, physicians should think of AVWS in addition to the side effect of heparin and DIC.

A questionnaire on COVID-19-related thrombosis in patients hospitalized before Aug 31, 2020, was sent to 399 hospitals throughout Japan. Responses were received from 111 (27.8%) with information on 6,202 COVID-19 patients. Of these, 333 and 56 required ventilation or extracorporeal membrane oxygenation (ECMO), respectively, and 212 died (3.4%). D-dimer levels were measured in 75.0% of the patients, revealing that 9.2% and 7.6% exhibited D-dimer increases of 3-8-fold and ≥8-fold the reference value, respectively. Thrombotic events occurred in 108 patients (1.86% of the 5,807 patients with available data) including symptomatic cerebral infarction in 24, myocardial infarction in 7, deep vein thrombosis in 41, pulmonary thromboembolism in 30, and other thrombotic events in 22. Some patients developed multiple thrombotic events. Thrombosis occurred in 32 patients with mild or moderate COVID-19 severity (0.59% of those with data available) and in 52 patients on ventilation or ECMO (13.5% of severe patients for whom data were available). Thrombosis occurred in 67 patients during worsening clinical condition and in 26 during recovery. Anticoagulant therapy was provided to 893 patients (14.6% of the 6,119 patients with available data), the main reasons being provided as elevated D-dimer levels and worsening clinical condition.