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This article discusses the results of six randomized trials that examined the effects of fibrates and gemfibrozil on the prevention of atherosclerotic cardiovascular disease (ASCVD). The trials showed inconsistent results, and the authors sought to understand these discrepancies by examining the effects of mass changes in remnant cholesterol and LDL cholesterol. Using the Copenhagen General Population Study (CGPS) to mimic the study population of these trials, the authors compared estimated changes in ASCVD risk through mass changes in cholesterol with the observed changes in the original trials. The results suggest that mass changes in total atherogenic cholesterol can explain the results of these trials, regardless of whether statins were used or not. The authors conclude that to reduce ASCVD, cholesterol-lowering agents should aim to reduce the total mass of atherogenic cholesterol. [Extracted from the article]

Aims We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein. Methods and results In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n  = 5684; ASCVD = 852) and STRENGTH (n  = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93–0.99] mimicking REDUCE-IT and 0.94 (0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04–1.10) and 0.99 (0.98–0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84–0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68–0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93–0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90–1.09) in STRENGTH. Conclusion The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil. [ABSTRACT FROM AUTHOR]

The article presents the discussion on altered lipids and inflammation for the contrasting results of REDUCE-IT and STRENGTH including extensive human evidence for causing atherosclerotic cardiovascular disease (ASCVD), low-density lipoprotein (LDL) cholesterol, triglyceriderich lipoproteins.

Introduction: Low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been recognized as causative genes of heterozygous familial hypercholesterolemia (HeFH) which exhibited a marked elevation of LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). Recent study reported the presence of both mutations was infrequently observed in HeFH subjects. It remains to be fully elucidated whether this double-heterozygous mutation in LDLR and PCSK9 gene (LDLR/PCSK9) affects clinical demographics and cardiac outcome in HeFH patients. Methods: 377 clinically diagnosed HeFH probands were retrospectively analyzed. Clinical characteristics and the occurrence of MACE were compared among subjects stratified according to genotypes (LDLR/PCSK9 career, LDLR alone, and PCSK9 alone). Results: The frequency of probands with LDLR/PCSK9 , LDLR and PCSK9 gain-of-function mutation was 4, 48 and 9%, respectively. Probands with LDLR/PCSK9 were more likely to exhibit a higher LDL-C level at baseline (Table) and receive high-intensity statin (43, 16 and 6%, respectively, p=0.01 for trend). During follow-up period, probands with LDLR/PCSK9 demonstrated a lower on-treatment LDL-C level (p=0.02) and its greater percent reduction were observed under lipid-lowering therapy, although the latter comparison did not meet statistical significance (Table, p=0.08). However, probands with LDLR/PCSK9 were associated with 3.0 and 8.2-fold likelihood of experiencing cardiovascular events compared to LDLR and PCSK9 , respectively (Figure). Even after adjusting covariates, the presence of LDLR/PCSK9 was still an independent predictor for MACE (p=0.01 vs. LDLR ; p=0.007 vs. PCSK9). Conclusions: The presence of double-heterozygous mutation in the LDLR and PCSK9 gene predicted cardiac events in patients with HeFH. These findings underscore precise medicine to identify patients with double-heterozygous mutation who require more stringent management. [ABSTRACT FROM AUTHOR]

Background: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH., Methods and Results: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P =0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P =0.71; high-intensity statin, P =0.81; ezetimibe, P =0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P =0.39; low-density lipoprotein apheresis, P =0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P =0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P =0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P =0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P =0.002)., Conclusions: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.

Aim: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction., Methods: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated., Results: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ., Conclusion: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

One fifth of the world population live in East Asia comprising Japan, Korea, and China where ischemic heart disease, a major component of atherosclerotic cardiovascular disease (ASCVD), is the second most frequent cause of death. Each of low-density lipoproteins (LDL), remnant lipoproteins, and lipoprotein(a), summarized as non-high-density lipoproteins (non-HDL) or apolipoprotein B (apoB) containing lipoproteins, causes ASCVD. However, a significant proportion of the evidence on lipoproteins and lipoprotein cholesterol with risk of ASCVD came from White people mainly living in Europe and North America and not from people living in East Asia or of East Asian descent. With a unique biological, geohistorical, and social background in this world region, East Asians have distinctive characteristics that might have potential impact on the association of lipoproteins and lipoprotein cholesterol with risk of ASCVD. Considering the movement across national borders in the World, understanding of lipoprotein and lipoprotein cholesterol evidence on ASCVD in East Asia is important for both East Asian and non-East Asian populations wherever they live in the World.In this review, we introduce the biological features of lipoproteins and lipoprotein cholesterol and the evidence for their association with risk of ASCVD in East Asian and European populations. We also provide an overview of guideline recommendations for prevention of ASCVD in these two different world regions. Finally, specific preventive strategies and future perspectives are touched upon.

Background Heterozygous familial hypercholesterolemia (HeFH) more likely exhibits extensive atherosclerotic disease at multiple vascular beds. Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein that elevates HeFH-related atherosclerotic cardiovascular disease risks. Whether circulating Lp(a) level associates with polyvascular propagation of atherosclerosis in subjects with HeFH remains uncertain. Methods and Results The current study analyzed 370 subjects with clinically diagnosed HeFH who received evaluation of systemic arteries. Polyvascular disease (polyVD) was defined as more than 2 coexisting atherosclerosis conditions including coronary artery disease, carotid stenosis, or peripheral artery disease. Clinical characteristics and lipid features were analyzed in subjects with HeFH and polyVD; 5.7% of patients with HeFH (21/370) had polyVD. They were more likely to have a clustering of risk factors, tendon ( P <0.001) and skin xanthomas ( P =0.004), and corneal arcus ( P =0.026). Furthermore, an elevated Lp(a) level ( P =0.006) and a greater frequency of Lp(a) level ≥50 mg/dL ( P <0.001) were observed in subjects with HeFH and polyVD. On multivariable analysis adjusting risk factors and lipid-lowering agents, Lp(a) ≥50 mg/dL (odds ratio [OR], 5.66 [95% CI, 1.68-19.0], P =0.005), age, and family history of premature coronary artery disease independently predicted polyVD in subjects with HeFH. Of note, the prevalence of polyVD rose to 33.3% in patients with HeFH and age >58 years old, family history of premature coronary artery disease, and Lp(a) ≥50 mg/dL (OR, 10.3 [95% CI, 3.12-33.4], P <0.001). Conclusions An increased level of circulating Lp(a) levels predicted concomitance of polyVD in patients with HeFH. The current findings suggest subjects with HeFH and Lp(a) ≥50 mg/dL as a high-risk category who require meticulous screening of systemic vascular beds.

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis's potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.

Aims: We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein., Methods and Results: In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93-0.99] mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH., Conclusion: The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Vulnerable plaque features including lipidic plaque have been shown to affect fractional flow reserve (FFR). Given that formation and propagation of lipid plaque is accompanied by endothelial dysfunction which impairs vascular tone, the degree of lipidic burden may affect vasoreactivity during hyperemia, potentially leading to reduced FFR. Our aim is to elucidate the relationship of the extent of lipidic plaque burden with coronary physiological vasoreactivity measure., Methods: We analyzed 89 subjects requeuing PCI due to angiographically intermediate coronary stenosis with FFR ≤0.80. Near-infrared spectroscopy (NIRS) and intravascular ultrasound were used to evaluate lipid-core burden index (LCBI) and atheroma volume at both target lesion (maxLCBI 4mm ; maximum value of LCBI within any 4 mm segments) and entire target vessel (LCBI vessel : LCBI within entire vessel). In addition to FFR, delta-FFR was measured by difference of distal coronary artery pressure/aortic pressure (Pd/Pa) between baseline and hyperemic state., Results: The averaged FFR and delta-FFR was 0.74 (0.69-0.77), and 0.17±0.05, respectively. On target lesion-based analysis, maxLCBI 4mm was negatively correlated to FFR (ρ=-0.213, P=0.040), and it was positively correlated to delta-FFR (ρ=0.313, P=0.002). Furthermore, target vessel-based analysis demonstrated similar relationship of LCBI vessel with FFR (ρ=-0.302, P=0.003) and delta-FFR (ρ=0.369, P<0.001). Even after adjusting clinical characteristics and lesion/vessel features, delta-FFR (by 0.10 increase) was independently associated with maxLCBI 4mm (β=57.2, P=0.027) and LCBI vessel (β=24.8, P=0.007) by mixed linear model analyses., Conclusions: A greater amount of lipidic plaque burden at not only "target lesion" alone but "entire target vessel" was associated with a greater delta-FFR. The accumulation of lipidic plaque materials at both local site and entire vessel may impair hyperemia-induced vasoreactivity, which causes a reduced FFR., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/cdt-20-1024). Kota Murai has received honoraria from Abbot, ZEON MEDICAL. Yu Kataoka serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021, and has received research support from Nipro and Abbott, and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda and Daiichi-Sankyo. The other author has no conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background Patients with familial hypercholesterolemia who harbored both low-density lipoprotein receptor ( LDLR ) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low-density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. Methods and Results A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 ( LDLR/PCSK9 ) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low-density lipoprotein cholesterol ( P =0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66-11.0; P =0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P <0.001). Conclusions Patients with LDLR/PCSK9 gene variants were high-risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/PCSK9 gene variants, who require more stringent antiatherosclerotic management.

Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels using a statin is a cornerstone of preventive therapeutic management following acute myocardial infarction (AMI). In addition to its anti-atherosclerotic effects, recent studies reported a lower occurrence of heart failure (HF) under statin therapy. However, there is a wide variability in statin response. The association between the response to statin and the occurrence of HF in AMI subjects remains unclear. The purpose of present study is to examine whether the variability in statin response affects HF risk after AMI., Methods: We analyzed 505 statin-naïve AMI subjects undergoing primary percutaneous coronary intervention (PCI) who commenced atorvastatin, rosuvastatin, or pitavastatin. Statin hyporesponse was defined as a reduction in LDL-C levels <15% from baseline to 1 month after statin therapy. HF outcomes were compared between patients with and without statin hyporesponse., Results: Statin hyporesponse was identified in 15.2% (77/505) of study subjects. During a median 4.4-year observational period, statin hyporesponse was associated with a greater likelihood of HF [hazard ratio (HR) =3.01, 95% confidence interval (CI): 1.27-6.79, P=0.01]. This increased HF risk in statin hyporesponders was consistently observed in a multivariate Cox proportional hazards model (HR =2.74, 95% CI: 1.01-6.75, P=0.04), a propensity score-matched cohort (HR =12.30, 95% CI: 1.50-100.3, P=0.01) and in an inverse probability of treatment weights analysis with average treatment effects (coefficient =7.02, 95% CI: 2.29-21.58, P=0.0006)., Conclusions: Hyporesponse to statins increases HF risk after AMI. Our findings highlight statin hyporesponse as a high-risk feature associated with HF events., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-415). YK serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021. The other author has no conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Calcified lesions pose a technical challenge even in contemporary endovascular intervention. A 71-year-old man who had been receiving haemodialysis required infrapopliteal revascularisation for the treatment of ischaemic infectious gangrene of the right toes. Baseline angiography suggested that the multiple stenotic lesions in the anterior tibial artery were amenable to endovascular therapy for the purpose of establishing one straight-line flow to the foot. However, even a 1.25×15 mm semi-compliant balloon catheter failed to cross and dilate the focal lesion because of the underlying severe calcification in the mid segment of the anterior tibial artery. We adjunctively used high-speed rotational atherectomy with the ROTABLATOR device (1.5 mm burr) to ablate the focal calcified lesion while paying attention to minimise the ablation length and the ablation time. Subsequent balloon angioplasty with a 2.0×40 mm balloon catheter was successful. The skin perfusion pressure in the right foot increased from 32 to 48 mmHg, suggesting a high probability of wound healing. Pathological examination of the right toe amputated on schedule found non-clinically relevant microembolisation involving a couple of cholesterol crystals (20-30 µm) located in the arterioles and capillaries of the necrotic tissue. As an adjunctive device, the ROTABLATOR could provide a last resort for limb salvage, albeit that microembolisation can occur., Competing Interests: O. Kawarada reports receiving honoraria for lectures and advisory board fees from Boston Scientific Corporation, and honoraria for lectures and research grants from Terumo. The other authors have no conflicts of interest to declare.

Although high-quality cardiopulmonary resuscitation (CPR) is essential for survival from cardiac arrest, chest compressions can also sometimes lead to life-threatening chest injuries. In addition, post-cardiac arrest syndrome patients often have coagulopathy due to therapeutic hypothermia, mechanical hemodynamic support, or both. Therefore, when progressive anemia and prolonged shock are detected in patients who have received CPR, identifying the cause of hemorrhagic shock is crucial. We herein present an interesting case of hemorrhagic shock due to an internal mammary artery injury secondary to CPR that was detected by computed tomography and invasive angiography.