Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.

Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.

Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Atherosclerosis comprises two components, atherosis and sclerosis, characterized by morphological wall thickening and functional stiffening, respectively, of the arterial wall. In recent years, much interest has been directed to the role of functional changes in large arteries, i.e., increased stiffness or decreased elasticity, on the development of cardiovascular diseases. In fact, the clinical evaluation of arterial stiffness is increasingly performed in patients with cardiovascular risk factors. Local arterial stiffness is measured using an ultrasound technique implemented with an echo-tracking system at the common carotid and femoral arteries. Several indices of local arterial stiffness are obtained by ultrasound, among which stiffness parameter β is unique because it is the least affected by blood pressure at the time of measurement. Evidence from cross-sectional studies indicates that increased stiffness parameter β is associated with a number of cardiovascular risk factors, such as older age, smoking, insufficient physical activity, hypertension, obesity, metabolic syndrome, insulin resistance, type 2 diabetes, chronic kidney disease, and comorbid cardiovascular disease. Results from several prospective observational studies also suggest that carotid stiffness parameter β is a useful surrogate marker of cardiovascular events and/or mortality, although the results differ depending on the characteristics of the study subjects. Furthermore, several interventional studies have shown that carotid stiffness parameter β improved after lifestyle modification or drug treatment. In this review, we summarize the current evidence of stiffness parameter β of the carotid artery and discuss its clinical implications as a marker of vascular health or as a predictor of cardiovascular outcomes.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory degenerative aortic disease, which particularly affects older people. Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome is a multi-protein complex and mediates inflammatory responses by activating caspase 1 for processing premature interleukin (IL)-1β and IL-18. In this review, we first summarize the principle of NLRP3 inflammasome activation and the functionally distinct classes of small molecule NLRP3 inflammasome inhibitors. Next, we provide a comprehensive literature review on the expression of NLRP3 inflammasome effector mediators (IL-1β and IL-18) and components (caspase 1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and NLRP3) in clinical and experimental AAAs. Finally, we discuss the influence of genetic deficiency or pharmacological inhibition of individual effector mediators and components of NLRP3 inflammasome on experimental AAAs. Accumulating clinical and experimental evidence suggests that NLRP3 inflammasome may be a promise therapeutic target for developing pharmacological strategies for clinical AAA management.

Aim: The latest Global Vascular Guidelines (GVG) recommend assessing the 2-year mortality risk in patients with chronic limb-threatening ischemia (CLTI) before revascularization. This study aimed to reveal whether the Wound, Ischemia and foot Infection (WIfI) classification, developed originally as a risk assessment tool for limb prognosis, would be useful in predicting the 2-year mortality risk in patients with CLTI in the era of GVG and WIfI.

Methods: We retrospectively analyzed 849 patients with CLTI who were primarily treated with endovascular therapy (EVT) between April 2010 and December 2016. The impact of baseline characteristics, including the WIfI classification on mortality risk, was investigated using the Cox proportional hazards regression model.

Results: During a mean follow-up of 19.3 months, 243 deaths were observed. The 2-year mortality rate was 32.3%. Multivariate analysis demonstrated that WIfI classification stages (p=0.037), in addition to male sex (p=0.010), age (p＜0.001), non-ambulatory status (p＜0.001), body mass index (p=0.002), and hemodialysis (p＜0.001), were independent predictors for an increased risk of mortality, while the Rutherford classification was not.

Conclusions: WIfI classification stages were independently associated with mortality risk in patients with CLTI undergoing EVT, while the Rutherford classification was not. The WIfI classification would be a practical tool for planning the revascularization strategy in CLTI treatment.

Aim: The fact that low concentrations of high-density lipoprotein cholesterol are associated with the risk of cardiovascular disease is well known, but high-density lipoprotein metabolism has not been fully understood. Apolipoprotein A2 (ApoA2) is the second-most dominant apolipoprotein of high-density lipoprotein. We tested the hypothesis that ApoA2 isoforms are inversely associated with myocardial infarction.

Methods: We measured the plasma levels of three ApoA2 isoforms (ApoA2-ATQ/ATQ, ApoA2-ATQ/AT, ApoA2-AT/AT) in nested case-control study samples of 1:2 from the Japan Public Health-Center-based Study (JPHC Study): 106 myocardial infarction incidence cases and 212 controls.

Results: ApoA2-AT/AT was inversely associated with risk of myocardial infarction, in a matched model (OR, 2.78; 95% CI, 1.26–6.09 for lowest compared with the highest quartile), but its association was attenuated after adjustment for smoking only (OR=2.13; 95% CI, 0.91–4.97) or drinking only (OR=2.11; 0.91–4.89), and the multivariable OR was 1.20 (95% CI, 0.41–3.57). Neither ApoA2-ATQ/ATQ nor ApoA2-ATQ/AT was associated with the risk of myocardial infarction.

Conclusions: Our nested case-control study did not show a significant association of ApoA2 isoforms with a risk of myocardial infarction.

Aim: We aimed to examine the association between the maximum intima-media thickness of the carotid artery (Max IMT) and renal prognosis, considering their potential interaction with age.

Methods: Survival analyses were performed in 112 patients with chronic kidney disease (CKD), to assess renal prognosis, with the endpoint defined as a ≥ 30% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease.

Results: During a median follow-up of 12.5 years, 44 participants reached the study endpoint. The major determinant of Max IMT was the maximum IMT of the internal carotid artery (Max ICA-IMT), which was the distribution ratio of 50.0% of Max IMT. Kaplan–Meier analyses showed that Max IMT ≥ 1.5 mm was significantly associated with renal prognosis when age and eGFR were matched. On multivariate Cox regression analysis, Max IMT was significantly associated with the renal outcomes and had a significant interaction with the age categories (≥ 65 years or ＜65 years) (P=0.0153 for interaction). A 1-mm increase in Max IMT was significantly associated with disease progression in the sub-cohort ＜65 years age-category, but not in the ≥ 65 years age-category; similarly the hazard ratio (HR) in the ＜65 years age-category was higher than in the ≥ 65 years age-category (HR: 2.52 vs. 0.95). Comparable results were obtained for Max ICA-IMT, Max bulb-IMT, but not for Max common carotid artery-IMT.

Conclusions: A higher Max IMT was a significant renal prognosis factor in patients with CKD aged ＜65 years. Our results may provide new insights into treating CKD.

Aim: During surgery for an aortic arch aneurysm, aortic plaque in the descending aorta should be evaluated, but there are currently no suitable biomarkers for it. Surgeons should be especially aware of cerebral embolism from femoral perfusion and of peripheral embolism from stent graft deployment. Cystatin C is a known useful marker of renal dysfunction with a role as a biomarker for severity of coronary artery disease. In the absence of a suitable biomarker for aortic plaque in the descending aorta, we examine cystatin C as a candidate.

Methods: In all, 75 patients who underwent surgery for an aortic arch aneurysm were enrolled. They were divided into two groups, depending on whether they had chronic kidney disease or not. The serum cystatin C value and creatinine value were evaluated preoperatively. The aortic plaque volume ratio and components in the descending aorta were calculated from preoperative enhanced computed tomography.

Results: The soft plaque volume ratio was higher in patients with chronic kidney disease than in patients without it. Cystatin C positively correlated with the total aortic plaque volume ratio in all cases, and it positively correlated with the soft plaque volume ratio in both groups. Creatinine had no correlation with any type of plaque volume ratio in either group. In patients without chronic kidney disease, the soft plaque volume ratio was higher in patients with higher cystatin C levels than in patients with normal levels.

Conclusion: The preoperative serum cystatin C level could be a biomarker of aortic plaque in the descending aorta in patients with an aortic arch aneurysm.

Aims: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke.

Methods: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients’ clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed.

Results: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959–6.500, p= 0.061).

Conclusions: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA’s clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

Aim: Fatty liver and the liver fibrosis are known risk factors for cardiovascular disease (CVD). The severity of fatty liver can be assessed by determining the fatty liver index (FLI), and the severity of liver fibrosis can be assessed by determining the fibrosis-4 (FIB-4) score. We examined the differences in the associations of these two liver scoring systems with the pathophysiological abnormalities associated with the risk of development of CVD.

Methods: The FLI and FIB-4 score were calculated in 2,437 Japanese men without any history of CVD. The serum NT-pro-BNP levels and brachial-ankle pulse wave velocity (baPWV) were also measured at the start of the study and the end of three years’ follow-up.

Results: The FLI was significantly correlated with the baPWV (p＜0.01) and the FIB-4 score was significantly correlated with the serum NT-pro-BNP level (p＜0.01). Furthermore, the delta change of the FLI was significantly correlated with the delta change of the baPWV during the study period (p=0.01), and the delta change of the FIB-4 score was significantly correlated with the delta change of the serum NT-pro-BNP level during the study period (p＜0.01).

Conclusions: While the FIB-4 score may serve as a marker of the risk of development of heart failure, the FLI may be a marker of arterial stiffness in Japanese men without any history of CVD.

Aim: Clinical evidence on cardiovascular health metrics of couples, as defined by the American Heart Association (AHA), remains to be scarce. This study aims to explore the correlation of the AHA-defined cardiovascular health metrics within couples using a nationwide epidemiological database.

Methods: We examined the modified cardiovascular health metrics among 87,160 heterosexual couples using the health claims database from the Japan Medical Data Center. The ideal cardiovascular health metrics is comprised of (1) nonsmoking, (2) body mass index ＜25 kg/m², (3) physical activity at goal, (4) untreated blood pressure ＜120/80 mm Hg, (5) untreated fasting glucose ＜100 mg/dL, and (6) untreated total cholesterol ＜200 mg/dL.

Results: A correlation was noted on the ideal modified cardiovascular health metrics between couples. The prevalence of meeting ≥ 5 ideal components in the female partners increased from 32 % in the male partners meeting 0–1 ideal component to 56 % in those meeting 6 ideal components. The same trend has been observed in all generations (20–39 years, 40–49 years, 50–59 years, ≥ 60 years). The association between couples is found to be better in terms of smoking status, blood pressure, and fasting glucose level.

Conclusion: There was an intracouple correlation of the ideal modified cardiovascular health metrics, suggesting the importance of couple-based intervention to improve cardiovascular health status.

Aim: This study aimed to investigate the diagnostic yield of 7-day Holter monitoring for detecting covert atrial fibrillation (AF) in patients with recent embolic stroke of undetermined source (ESUS) and to identify the pre-entry screening biomarkers that had significant associations with later detection of AF (clinicaltrials.gov. NCT02801708).

Methods: A total of 206 patients who have recent ESUS without previously documented AF underwent Holter electrocardiography using a chest strap-style monitor. External validation of biomarkers predictive of AF was performed using 83 patients with ESUS who were implanted with insertable cardiac monitors.

Results: The 7-day Holter monitoring started at a median of 13 days after the onset of stroke. AF was detected in 14 patients, and three of these showed a single AF episode lasting ＜2 min. The median time delay to the first documented AF was 50 h. Each of serum brain natriuretic peptide ≥ 66.0 pg/mL (adjusted odds ratio 5.23), atrial premature contractions (APCs) ≥ 345 beats (3.80), and APC short runs ≥ 13 (5.74) on 24-h Holter prior to the 7-day Holter showed a significant association with detection of AF, independent of age and physiological findings in this derivation cohort, and all of these showed a significant association in the validation cohort (adjusted odds ratio 6.59, 7.87, and 6.16, respectively).

Conclusions: In recent ESUS patients, the detection rate of AF using the 7-day Holter monitoring was 6.8% (95% CI 4.1%–11.1%). Brain natriuretic peptide, APC count, and APC short runs in the standard clinical workup seemed to be predictors of covert AF.

Aim: High levels of lipoprotein(a) [Lp(a)] are a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and the severity of femoropopliteal lesions in patients with PAD has not been systematically studied. This study aimed to assess the impact of Lp(a) levels on angiographic severity of femoropopliteal lesions in patients with PAD.

Methods: We retrospectively analyzed a single-center database including 108 patients who underwent endovascular therapy for de novo femoropopliteal lesions and measured the Lp(a) levels before therapy between June 2016 and September 2019. Patients were divided into low Lp(a) [Lp(a) ＜30 mg/dL; 77 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. Trans-Atlantic Inter-Society Consensus (TASC) II classification, calcification [referring to the peripheral arterial calcium scoring system (PACSS) classification], and lesion length were compared between the groups.

Results: The prevalence of TASC II class D (13% vs 38%, P＜0.01) and severe calcification (PACSS 4) (6% vs 23%, P=0.02) was significantly higher and the lesion length longer (123±88 mm vs 175±102 mm, P＜0.01) in the high Lp(a) group than in the low Lp(a) group. In multivariate analysis, Lp(a) ≥ 30 was an independent predictor for the prevalence of TASC II class D (HR=3.67, 95% CI 1.27–10.6, P=0.02) and PACSS 4 (HR=4.97, 95% CI 1.27–19.4, P=0.02).

Conclusion: The prevalence of TASC II class D and severe calcification of femoropopliteal lesions was higher in patients with high Lp(a) than those with low Lp(a).