Lipoprotein(a) and Long-Term Plaque Progression, Low-Density Plaque, and Pericoronary Inflammation.

Importance: Lipoprotein(a) (Lp[a]) is a causal risk factor for cardiovascular disease; however, long-term effects on coronary atherosclerotic plaque phenotype, high-risk plaque formation, and pericoronary adipose tissue inflammation remain unknown. Objective: To investigate the association of Lp(a) levels with long-term coronary artery plaque progression, high-risk plaque, and pericoronary adipose tissue inflammation. Design, Setting, and Participants: This single-center prospective cohort study included 299 patients with suspected coronary artery disease (CAD) who underwent per-protocol repeated coronary computed tomography angiography (CCTA) imaging with an interscan interval of 10 years. Thirty-two patients were excluded because of coronary artery bypass grafting, resulting in a study population of 267 patients. Data for this study were collected from October 2008 to October 2022 and analyzed from March 2023 to March 2024. Exposures: The median scan interval was 10.2 years. Lp(a) was measured at follow-up using an isoform-insensitive assay. CCTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography). Main Outcome and Measures: The association between Lp(a) and change in percent plaque volumes was investigated in linear mixed-effects models adjusted for clinical risk factors. Secondary outcomes were presence of low-density plaque and presence of increased pericoronary adipose tissue attenuation at baseline and follow-up CCTA imaging. Results: The 267 included patients had a mean age of 57.1 (SD, 7.3) years and 153 were male (57%). Patients with Lp(a) levels of 125 nmol/L or higher had twice as high percent atheroma volume (6.9% vs 3.0%; P = .01) compared with patients with Lp(a) levels less than 125 nmol/L. Adjusted for other risk factors, every doubling of Lp(a) resulted in an additional 0.32% (95% CI, 0.04-0.60) increment in percent atheroma volume during the 10 years of follow-up. Every doubling of Lp(a) resulted in an odds ratio of 1.23 (95% CI, 1.00-1.51) and 1.21 (95% CI, 1.01-1.45) for the presence of low-density plaque at baseline and follow-up, respectively. Patients with higher Lp(a) levels had increased pericoronary adipose tissue attenuation around both the right circumflex artery and left anterior descending at baseline and follow-up. Conclusions and Relevance: In this long-term prospective serial CCTA imaging study, higher Lp(a) levels were associated with increased progression of coronary plaque burden and increased presence of low-density noncalcified plaque and pericoronary adipose tissue inflammation. These data suggest an impact of elevated Lp(a) levels on coronary atherogenesis of high-risk, inflammatory, rupture-prone plaques over the long term.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Unexpected gaps in knowledge of familial hypercholesterolaemia among Dutch general practitioners.

BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.

Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Enhanced identification of familial hypercholesterolemia using central laboratory algorithms.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients. METHODS: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH. RESULTS: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients. CONCLUSIONS: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population.

Development and Validation of a Quantitative Coronary CT Angiography Model for Diagnosis of Vessel-Specific Coronary Ischemia.

BACKGROUND: Noninvasive stress testing is commonly used for detection of coronary ischemia but possesses variable accuracy and may result in excessive health care costs. OBJECTIVES: This study aimed to derive and validate an artificial intelligence-guided quantitative coronary computed tomography angiography (AI-QCT) model for the diagnosis of coronary ischemia that integrates atherosclerosis and vascular morphology measures (AI-QCTISCHEMIA) and to evaluate its prognostic utility for major adverse cardiovascular events (MACE). METHODS: A post hoc analysis of the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) and PACIFIC-1 (Comparison of Coronary Computed Tomography Angiography, Single Photon Emission Computed Tomography [SPECT], Positron Emission Tomography [PET], and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve) studies was performed. In both studies, symptomatic patients with suspected stable coronary artery disease had prospectively undergone coronary computed tomography angiography (CTA), myocardial perfusion imaging (MPI), SPECT, or PET, fractional flow reserve by CT (FFRCT), and invasive coronary angiography in conjunction with invasive FFR measurements. The AI-QCTISCHEMIA model was developed in the derivation cohort of the CREDENCE study, and its diagnostic performance for coronary ischemia (FFR ≤0.80) was evaluated in the CREDENCE validation cohort and PACIFIC-1. Its prognostic value was investigated in PACIFIC-1. RESULTS: In CREDENCE validation (n = 305, age 64.4 ± 9.8 years, 210 [69%] male), the diagnostic performance by area under the receiver-operating characteristics curve (AUC) on per-patient level was 0.80 (95% CI: 0.75-0.85) for AI-QCTISCHEMIA, 0.69 (95% CI: 0.63-0.74; P < 0.001) for FFRCT, and 0.65 (95% CI: 0.59-0.71; P < 0.001) for MPI. In PACIFIC-1 (n = 208, age 58.1 ± 8.7 years, 132 [63%] male), the AUCs were 0.85 (95% CI: 0.79-0.91) for AI-QCTISCHEMIA, 0.78 (95% CI: 0.72-0.84; P = 0.037) for FFRCT, 0.89 (95% CI: 0.84-0.93; P = 0.262) for PET, and 0.72 (95% CI: 0.67-0.78; P < 0.001) for SPECT. Adjusted for clinical risk factors and coronary CTA-determined obstructive stenosis, a positive AI-QCTISCHEMIA test was associated with an HR of 7.6 (95% CI: 1.2-47.0; P = 0.030) for MACE. CONCLUSIONS: This newly developed coronary CTA-based ischemia model using coronary atherosclerosis and vascular morphology characteristics accurately diagnoses coronary ischemia by invasive FFR and provides robust prognostic utility for MACE beyond presence of stenosis.

Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Accumulation of Iron Oxide-Based Contrast Agents in Rabbit Atherosclerotic Plaques in Relation to Plaque Age and Vulnerability Features.

Purpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats. Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.

Diacylglycerols and Lysophosphatidic Acid, Enriched on Lipoprotein(a), Contribute to Monocyte Inflammation.

BACKGROUND: Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). METHODS: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. RESULTS: Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1ß after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). CONCLUSIONS: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.

Beyond early LDL cholesterol lowering to prevent coronary atherosclerosis in familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) patients are subjected to a high lifetime exposure to low density lipoprotein cholesterol (LDL-C), despite use of lipid-lowering therapy (LLT). This study aimed to quantify the extent of subclinical atherosclerosis and to evaluate the association between lifetime cumulative LDL-C exposure and coronary atherosclerosis in young FH patients. METHODS AND RESULTS: Familial hypercholesterolaemia patients, divided into a subgroup of early treated (LLT initiated <25 years) and late treated (LLT initiated ≥25 years) patients, and an age- and sex-matched unaffected control group, underwent coronary CT angiography (CCTA) with artificial intelligence-guided analysis. Ninety genetically diagnosed FH patients and 45 unaffected volunteers (mean age 41 ± 3 years, 51 (38%) female) were included. Familial hypercholesterolaemia patients had higher cumulative LDL-C exposure (181 ± 54 vs. 105 ± 33 mmol/L ∗ years) and higher prevalence of coronary plaque compared with controls (46 [51%] vs. 10 [22%], OR 3.66 [95%CI 1.62-8.27]). Every 75 mmol/L ∗ years cumulative exposure to LDL-C was associated with a doubling in per cent atheroma volume (total plaque volume divided by total vessel volume). Early treated patients had a modestly lower cumulative LDL-C exposure compared with late treated FH patients (167 ± 41 vs. 194 ± 61 mmol/L ∗ years; P = 0.045), without significant difference in coronary atherosclerosis. Familial hypercholesterolaemia patients with above-median cumulative LDL-C exposure had significantly higher plaque prevalence (OR 3.62 [95%CI 1.62-8.27]; P = 0.001), compared with patients with below-median exposure. CONCLUSION: Lifetime exposure to LDL-C determines coronary plaque burden in FH, underlining the need of early as well as potent treatment initiation. Periodic CCTA may offer a unique opportunity to monitor coronary atherosclerosis and personalize treatment in FH.

This study reveals that young patients with familial hypercholesterolaemia (FH), as compared with individuals without FH, have a higher build-up of coronary artery plaque, linked directly to their increased lifetime exposure to LDL cholesterol. Genetically confirmed FH patients have a higher coronary plaque burden than those without FH, with every 75 mmol/L ∗ years increase in lifetime cumulative LDL cholesterol exposure resulting in a two-fold increase in total plaque volume. Early and potent LDL cholesterol lowering treatments are crucial for FH patients to prevent future cardiovascular diseases.

Long-Term Efficacy and Tolerability of PCSK9 Targeted Therapy: A Review of the Literature.

Increased plasma levels of low-density lipoprotein cholesterol (LDL-C) are causally associated with atherosclerotic cardiovascular disease (ASCVD), and statins that lower LDL-C have been the cornerstone of ASCVD prevention for decades. However, guideline-recommended LDL-C targets are not achieved in about 60% of statin users. Proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapy effectively lowers LDL-C levels and has been shown to reduce ASCVD risk. A growing body of scientific and clinical evidence shows that PCSK9-targeted therapy offers an excellent safety and tolerability profile with a low incidence of side effects in the short term. In this review, we present and discuss the current clinical and scientific evidence pertaining to the long-term efficacy and tolerability of PCSK9-targeted therapy.

AI-Guided Quantitative Plaque Staging Predicts Long-Term Cardiovascular Outcomes in Patients at Risk for Atherosclerotic CVD.

BACKGROUND: The recent development of artificial intelligence-guided quantitative coronary computed tomography angiography analysis (AI-QCT) has enabled rapid analysis of atherosclerotic plaque burden and characteristics. OBJECTIVES: This study set out to investigate the 10-year prognostic value of atherosclerotic burden derived from AI-QCT and to compare the spectrum of plaque to manually assessed coronary computed tomography angiography (CCTA), coronary artery calcium scoring (CACS), and clinical risk characteristics. METHODS: This was a long-term follow-up study of 536 patients referred for suspected coronary artery disease. CCTA scans were analyzed with AI-QCT and plaque burden was classified with a plaque staging system (stage 0: 0% percentage atheroma volume [PAV]; stage 1: >0%-5% PAV; stage 2: >5%-15% PAV; stage 3: >15% PAV). The primary major adverse cardiac event (MACE) outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and all-cause mortality. RESULTS: The mean age at baseline was 58.6 years and 297 patients (55%) were male. During a median follow-up of 10.3 years (IQR: 8.6-11.5 years), 114 patients (21%) experienced the primary outcome. Compared to stages 0 and 1, patients with stage 3 PAV and percentage of noncalcified plaque volume of >7.5% had a more than 3-fold (adjusted HR: 3.57; 95% CI 2.12-6.00; P < 0.001) and 4-fold (adjusted HR: 4.37; 95% CI: 2.51-7.62; P < 0.001) increased risk of MACE, respectively. Addition of AI-QCT improved a model with clinical risk factors and CACS at different time points during follow-up (10-year AUC: 0.82 [95% CI: 0.78-0.87] vs 0.73 [95% CI: 0.68-0.79]; P < 0.001; net reclassification improvement: 0.21 [95% CI: 0.09-0.38]). Furthermore, AI-QCT achieved an improved area under the curve compared to Coronary Artery Disease Reporting and Data System 2.0 (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.023) and manual QCT (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.040), although net reclassification improvement was modest (0.09 [95% CI: -0.02 to 0.29] and 0.04 [95% CI: -0.05 to 0.27], respectively). CONCLUSIONS: Through 10-year follow-up, AI-QCT plaque staging showed important prognostic value for MACE and showed additional discriminatory value over clinical risk factors, CACS, and manual guideline-recommended CCTA assessment.

Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.

BACKGROUND: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake. METHODS: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake. RESULTS: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis (P=0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels. CONCLUSIONS: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide.

Association Between Self-Rated Medication Adherence and Adverse Cardiovascular Outcomes in Patients With Hypertension.

Background Medication nonadherence contributes to poor health outcomes but remains challenging to identify. This study assessed the association between self-rated adherence and systolic blood pressure, low-density lipoprotein cholesterol levels, cardiovascular events, and all-cause mortality in SPRINT (Systolic Blood Pressure Intervention Trial). Methods and Results A total of 9361 patients randomized to 2 systolic blood pressure target groups, <120 mm Hg (intensive) and <140 mm Hg (standard), self-rated their medication adherence at each visit by marking a scale, ranging from 0% to 100%. Lower and high adherence were defined as scores ≤80% and >80%, respectively. Linear mixed effect regression models and Cox proportional hazard models were used to evaluate the association between self-rated adherence and systolic blood pressure and low-density lipoprotein cholesterol and cardiovascular events and all-cause mortality, respectively. A total of 9278 participants (mean age 68±9.4 years, 35.6% female) had repeated self-rated adherence measurements available, with a mean of 15±4 measurements per participant over 3.8 years follow-up. Of these, 2694 participants (29.0%) had ≥1 adherence measurements ≤80%. Compared with high-adherent patients, patients with lower adherence had significantly higher estimated on-treatment systolic blood pressure at 2-year follow-up: 128.7 (95% CI, 127.6-129.9) versus 120.0 (95% CI, 119.7-120.2) mm Hg in the intensive arm; and 139.8 (95% CI 138.4-141.1) versus 135.0 (95% CI 134.7-135.2) in the standard arm. Moreover, lower adherence was associated with an estimated 11 mg/dL higher low-density lipoprotein cholesterol level, more cardiovascular events (hazard ratio [HR], 1.69 [95% CI, 1.20-2.39]), and higher all-cause mortality (HR, 1.63 [95% CI, 1.16-2.31]). Conclusions Self-rated adherence allows identification of lower medication adherence and correlates with blood pressure control, low-density lipoprotein cholesterol levels, and adverse outcomes.

Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure.

BACKGROUND: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. OBJECTIVES: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. METHODS: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. RESULTS: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro-B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. CONCLUSIONS: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.