Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

Aim: We used a dataset from a cross-sectional survey conducted in China to determine which of the anthropometric indices of obesity are important in terms of carotid atherosclerosis free of cardiovascular and cerebrovascular diseases.

Methods: A total of 5,245 participants who were volunteering for carotid ultrasound unit in this cross-sectional survey were included in the present analysis. All subjects were free of angina, myocardial infarction, heart failure and stroke, and cancer. A low-risk subgroup was defined as people free of hypertension, diabetes, and hyperlipidemia. All analyses based on logistic regression were gender-specific.

Results: The present study consisted of 2,501 males and 2,744 females, with 776 (31.03%) diagnosed as carotid artery plaque in males and 550 (20.04%) in females. Univariable analyses in unadjusted logistic model showed significant associations between disease presence and all central obesity indices. After adjusting for more variables, only a body shape index (ABSI) was associated with the presence of disease in both males and females. Moreover, stepwise regression approaches revealed that ABSI was always an independent determinant of the presence of subclinical carotid plaque. Multiple regression shows a linear and significant increase in the prevalence of atherosclerosis in males and females as ABSI decile levels increased. Similar results were obtained when the association between ABSI and carotid plaque was studied in this low-risk subgroup.

Conclusions: ABSI, as a novel anthropometric indicator compared with traditional indices, was found to have a closer relationship with subclinical carotid atherosclerosis, even in populations free of hypertension, diabetes, and hyperlipidemia.

Aim: Patients with chronic kidney disease (CKD) have elevated risk of death from cardiovascular disease (CVD). A low serum insulin-like growth factor 1 (IGF-1) level is known to predict higher risk for all-cause mortality in incident dialysis patients, although it is unknown whether IGF-1 predicts cardiovascular outcomes.

Methods: This was a prospective cohort study of maintenance hemodialysis patients followed up for 5 years. Serum IGF-1 levels were measured at baseline, and patients were divided into IGF-1 tertiles. The key outcomes were all-cause mortality, a composite of new CVD, and death after new CVD events. Additional outcomes were hospitalization for infection and subsequent death. Association was analyzed using Cox proportional hazards models.

Results: In the 516 patients that were analyzed, we identified 106 all-cause deaths, 190 new CVD events, and 61 subsequent deaths. In addition, there were 169 hospitalizations for infection and 47 subsequent deaths. The risk of all-cause death was the highest in the lowest IGF-1 tertile, and this association remained significant in multivariable-adjusted models. Regarding CVD outcomes, IGF-1 was not associated with new CVD events but significantly associated with subsequent death in adjusted models. Similarly, IGF-1 was not an independent predictor of hospitalization for infection, but it predicted subsequent death.

Conclusions: A low IGF-1 level was not a significant predictor of new CVD events but an independent predictor of subsequent death in hemodialysis patients. Since similar associations with infection outcomes were observed, IGF-1 may be a biomarker of fragility or frailty in this population.

Aims: Reports on the association between height and aortic disease have been modest, and there are only a few studies investigating the association between height and mortality from specific aortic disease types or by sex.

Methods: We conducted the Japan Collaborative Cohort Study, a prospective study of 99,067 Japanese (41,730 men and 57,337 women) aged 40–79 years old. Height was self-reported, and the participants were followed up from 1988–1989 to the end of 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease type according to sex-specific quartiles of height were analyzed using the Cox proportional hazards model.

Results: During the median follow-up period of 19.1 years, the numbers of deaths due to aortic aneurysm, thoracic aortic aneurysm, abdominal aortic aneurysm, and aortic dissection were 87, 29, 48, and 56 among men and 35, 17, 15, and 65 among women, respectively. The sex-specific multivariate hazard ratios (95% confidence intervals) and p for trend for the highest versus lowest quartiles of height were 1.10 (0.66–1.83), p=0.58 among men and 1.54 (0.85–2.79), p=0.06 among women for total aortic disease; 1.85 (0.80–4.28), p=0.16 among men and 5.67 (0.90–35.77), p=0.08 among women for abdominal aortic aneurysm; and 1.13 (0.48–2.64), p=0.65 among men and 1.70 (0.82–3.50), p=0.04 among women for aortic dissection. The positive association was observed for both sexes, albeit more prominent among women. No association was found between height and mortality from thoracic aortic aneurysms.

Conclusions: As per our findings, we were able to determine that height was positively associated with mortality from abdominal aortic aneurysm in the Japanese population.

Aims: Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH.

Methods: A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified.

Results: Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease.

Conclusions: Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

Aims: Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a low-density lipoprotein (LDL)–like particle with apolipoprotein (Apo)(a), attached via a disulfide bond to Apo B100. Previous studies have shown that high Lp(a) levels are associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia (FH). To date, limited data are available as to distribution of Lp(a) in FH and associations of Lp(a) with other lipid profiles and cardiovascular disease. Our study aimed to investigate serum Lp(a) levels in relation to other lipid profiles and clinical conditions in the national largest-ever cohort of Japanese FH patients.

Methods: This study is a secondary analysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study that includes a Japanese nationwide cohort of FH patients. In 399 patients under treatment for heterozygous FH who had a baseline measurement of serum Lp(a), the present study examined the distribution of Lp(a) levels and associations of Lp(a) with other lipid profiles and clinical conditions including coronary artery disease (CAD).

Results: The distribution of Lp(a) was skewed to the right with a median of 20.8 mg/dL, showing a log-normal distribution. Serum Apo B and Apo E levels were positively associated with Lp(a) levels. Age-adjusted mean of Apo B was 8.77 mg/dL higher and that of Apo E was 0.39 mg/dL higher in the highest category (40+ mg/dL) of Lp(a) than in the lowest category (＜20 mg/dL). LDL-C levels did not show such an association with Lp(a) levels. A tendency towards a positive relationship between Lp(a) and prevalent CAD was observed in men.

Conclusion: Our study demonstrated a distribution pattern of Lp(a) in Japanese FH patients and positive relationships of Lp(a) with Apo B and Apo E levels.

Aim: Genetic testing can provide a definitive diagnosis of familial hypercholesterolemia (FH). However, accessibility of genetic testing may be limited in certain countries where it is not considered “standard of care,” including Japan. In addition, mutations responsible for FH cannot be identified in approximately 30% of patients.

Methods: EXPLORE-J is a multicenter, prospective, observational study of patients presenting with acute coronary syndrome (ACS). The genetic data were analyzed and adjudicated as pathogenic, indeterminate, or nondetectable pathogenic variant.

Results: Of 1,944 patients, 431 underwent genetic screening. Overall, most patients had nonpathogenic variants of LDLR, LDLRAP1, or PCSK9 (n=396, 91.9%). Of the 25 (5.8%) patients with pathogenic variants, variants of the LDLR gene and the PCSK9 gene were seen in 10 and 15 patients, respectively. Indeterminate variants were observed in 10 (2.3%) patients. Of the 431 patients, eight (1.9%) met the criteria for a diagnosis of FH using the Japanese Atherosclerosis Society (JAS) 2017 guidelines. When genetic data were incorporated, 33 (7.7%) patients met the JAS guidelines. No patients with FH pathogenic variants satisfied the JAS clinical criteria for a diagnosis of FH.

Conclusions: The results revealed a higher prevalence of genetic mutations of FH among Japanese patients with ACS and a low sensitivity of the FH diagnostic criteria of the JAS 2017 guidelines. These findings highlight the difficulties of FH diagnosis in patients with ACS in the acute phase and suggest the importance of genetic testing and family history.

Aim: The safety concern of statins is still a major issue for Asians. The aim of this study is to compare the risk of statin-associated adverse events among potent statins.

Methods: We included patients from the Taiwan National Health Insurance Research Database who had been treated with atorvastatin, rosuvastatin, or pitavastatin and were without diabetes at baseline. They were classified into three groups: usual-dose statin (atorvastatin 10 mg/d or rosuvastatin 5–10 mg/d), high-dose statin (atorvastatin 20–40 mg/d and rosuvastatin 20 mg/d), and pitavastatin (2–4 mg/d). The primary endpoint is a composite of safety events, including hepatitis, myopathy, and new-onset diabetes mellitus (NODM). We matched age, sex, and year of recruitment among the three groups (n=50,935 in each group) and then used the multivariate Cox proportional hazards model to evaluate the relation between the safety endpoint and different statin groups.

Results: After a mean follow-up of 3.08±0.83 years, the safety events occurred in 9.84% in the pitavastatin group, 10.88% in the usual-dose statin group, and 10.49% in high-dose statin group. The multivariate Cox proportional hazards model indicated that usual-dose statin and high-dose statin were associated with a higher risk of the composite safety events compared with pitavastatin (adjusted hazard ratio [aHR]: 1.12, 95% confidence interval [CI]: 1.08–1.17 for usual-dose statin and aHR: 1.06, 95% CI: 1.02–1.10 for high-dose statin). The risks of hepatitis requiring hospitalization and NODM were especially lower in pitavastatin group.

Conclusions: Compared with atorvastatin and rosuvastatin, pitavastatin might be associated with a lower risk of safety events in Asians.

Aim: Recently, the atherogenic index of plasma (AIP) has been proposed as a novel, reliable plasma atherogenicity marker. This study aimed to investigate the association of AIP with the risk of in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS).

Methods: This study retrospectively enrolled patients with ACS followed by angiography within 6 to 18 months after successful percutaneous coronary intervention (PCI) with a drug-eluting stent (DES). And the participants were divided into ISR or non-ISR groups based on the angiographic follow-up results. AIP was defined as the base 10 logarithm of the ratio of serum triglyceride (mmol/L) to high-density lipoprotein cholesterol (mmol/L).

Results: This study recruited 1319 patients with ACS, 199 of which had ISR. Compared with the non-ISR group, patients in the ISR group had higher level of AIP (0.199±0.290 vs 0.131±0.282, p=0.002). In the multiple logistic regression analysis, AIP was an independent risk factor for DES-ISR (OR=2.100, 95% CI 1.134 to 3.891, p=0.018). When we modulated AIP as a categorical variable, the risk of DES-ISR increased in quartile 4 compared to quartile 1 (OR=1.713, 95% CI 1.040 to 2.822, p=0.034). Furthermore, this association remains stable in various subgroups. Unexpectedly, the subgroup analysis suggested AIP and DES-ISR had a stronger positive association in individuals with low-density lipoprotein cholesterol (LDL-C) ＜1.8 mmol/L.

Conclusions: AIP and the risk of DES-ISR were positively and independently correlated in patients with ACS, especially in those with an LDL-C ＜1.8 mmol/L.

Aims: We aimed to establish a practical method for the assessment of tradeoff between thrombotic and bleeding risks.

Methods: We aimed to investigate the balance between bleeding risk and coronary thrombotic risk according to the number of the Academic Research Consortium for high bleeding risk (ARC-HBR) criteria in the multicenter prospective ST/non-ST elevation myocardial infarction (STEMI/NSTEMI) registry (N=12,093). Patients were divided as follows by the number of ARC-HBR criteria fulfilled: group 0, 0 major with ≤ 1 minor (N=6,792); group 1, 1 major with 0 minor (N=1,705); group 2, 0 major with ≥ 2 minors (N=790); group 3, 1 major with ≥ 1 minor (N=1,709); group 4, 2 majors with ≥ 0 minors (N=861); and group 5, ≥ 3 majors with ≥ 0 minor (N=236). We assessed the acute-phase absolute risk differences between bleeding and coronary thrombotic events in each group.

Results: At 7-day follow-up, all patients (groups 0–5) had a higher risk of major bleeding than that of any myocardial infarction (MI). Patients at ARC-HBR (groups 1–5) had a balanced risk between fatal MI and fatal bleeding, whereas patients at non-ARC-HBR (group 0) had a higher risk of fatal MI than that of fatal bleeding.

Conclusions: All STEMI/NSTEMI patients have a relatively high risk of major bleeding as compared with the risk of any MI in the acute phase. The ARC-HBR criteria would be a practical tool for assessing the tradeoff between fatal bleeding and fatal MI risks. This practical assessment would be helpful for the optimal decision-making of appropriate treatment strategy considering the balance between bleeding and coronary thrombotic risks.

Aim: Individuals with chronic kidney disease (CKD) have a high prevalence of comorbidities, including cardiovascular disease (CVD) and its risk factors. However, epidemiological results to assess the association between multimorbidity and kidney function among the CKD population remains limited.

Methods: We performed a cross-sectional analysis of the association between 23 comorbid conditions and reduced kidney function in 4,476 patients with non-dialysis-dependent CKD enrolled in a multicenter cohort in Japan. Reduced kidney function was defined as an estimated glomerular filtration rate of ≤ 60 mL/min/1.73 m².

Results: The mean age of patients was 67 years (male, 56.0%). The prevalence of hypertension, diabetes mellitus, dyslipidemia, prior CVD, cancer, and bone fracture, which are the major comorbidities, was 83.3%, 28.7%, 45.9%, 23.3%, 12.7%, and 6.3%, respectively. Multivariable-adjusted analyses revealed that age, male sex, hypertension, dyslipidemia, prior CVD, body mass index, urinary protein excretion, and underlying kidney disease were independent factors associated with reduced kidney function. Importantly, the odds ratios (ORs) for reduced kidney function increased linearly as the number of major comorbid conditions increased (OR for 1–2 conditions: 2.22, 95% confidence interval [CI]: 1.65–2.97; OR for 3–4 conditions: 3.04, 95% CI: 2.12–4.37; OR for ≥ 5 conditions: 4.37, 95% CI: 1.75–10.9). The upward trend in OR was more pronounced with cardiovascular comorbidities but not significant with non-cardiovascular comorbidities.

Conclusions: In conclusion, we observed an independent association between cardiovascular comorbidity and its risk factors and reduced kidney function. The results of this study highlight the importance of managing multimorbidity among patients with CKD.