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ObjectivesTo investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC.MethodsWe included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC.ResultsThe prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (β 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase).ConclusionsLp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.

Background and aims Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. Methods In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation. Results A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks. Conclusion In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.

ObjectiveTo assess whether patients with aortic valve stenosis (AS) with elevated lipoprotein(a) (Lp(a)) are characterised by increased valvular calcification activity compared with those with low Lp(a).MethodsWe performed 18F-sodium fluoride (18F-NaF) positron emission tomography/CT in patients with mild to moderate AS (peak aortic jet velocity between 2 and 4 m/s) and high versus low Lp(a) (>50 mg/dL vs 18F-NaF uptake.Results52 individuals (26 matched pairs) were included in the analysis. The mean age was 66.4±5.5 years, 44 (84.6%) were men, and the mean aortic valve velocity was 2.80±0.49 m/s. The median Lp(a) was 79 (64–117) mg/dL and 7 (5–11) mg/dL in the high and low Lp(a) groups, respectively. Systolic blood pressure and low-density-lipoprotein cholesterol (corrected for Lp(a)) were significantly higher in the low Lp(a) group (141±12 mm Hg vs 128±12 mm Hg, 2.5±1.1 mmol/L vs 1.9±0.8 mmol/L). We found no difference in valvular 18F-NaF uptake between the high and low Lp(a) groups (3.02±1.26 vs 3.05±0.96, p=0.902). Linear regression analysis showed valvular calcium score to be the only significant determinant of valvular 18F-NaF uptake (β=0.63; 95% CI 0.38 to 0.88 per 1000 Agatston unit increase, p18F-NaF uptake (β=0.17; 95% CI −0.44 to 0.88, p=0.305 for the high Lp(a) group).ConclusionAmong patients with mild to moderate AS, calcification activity is predominantly determined by established calcium burden. The results do not support our hypothesis that Lp(a) is associated with valvular 18F-NaF uptake.

Background Lipoprotein(a) [Lp(a)] has been implicated in the etiology of aortic valve stenosis. Although Lp(a) is strongly associated with the presence of aortic valve calcium (AVC), there are no data evaluating the relationship of Lp(a) with AVC incidence and AVC progression. Purpose To assess whether high Lp(a) levels are associated with AVC incidence and progression. Methods In 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men) for whom Lp(a) measurements were available, non-enhanced cardiac CT imaging was performed at baseline and after a median follow-up of 14.0 [13.9–14.2] years. AVC incidence was defined as an AVC score >0 on the second scan, in absence of AVC on the first scan. We performed logistic regression analyses to evaluate the relationship of Lp(a) with AVC incidence and linear regression analyses to assess the relationship between Lp(a) and AVC progression. All analyses were corrected for age, sex, body mass index, smoking, non-high-density lipoprotein cholesterol, use of lipid-lowering medication, and hypertension. Additionally, we analyzed the progression conditional on the baseline AVC-score. Results Of the 702 (76.1%) individuals without AVC at baseline, 415 (59.1%) showed incident AVC at follow-up. The 220 (23.9%) individuals with AVC on baseline had a median AVC score of 52 [15–131], with a median yearly progression of 13 [5–38]. Lp(a) concentration was independently associated with AVC incidence (OR 1.32 for each 105 nmol/L Lp(a) increase; 95% CI: 1.03–1.68), but not with AVC progression (β −4.3 AU/year for each 105 nmol/L Lp(a) increase; 95% CI: −12.3–3.7). Conclusions Lp(a) is associated with AVC incidence but not AVC progression, suggesting that Lp(a)-lowering interventions may be futile after AVC has been established. Future studies should focus on whether Lp(a) lowering interventions can prevent the development of AVC in high-risk individuals. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam and the Netherlands Organization for Scientific Research

Background: Clinical assessments of peripheral artery disease (PAD) severity are insensitive to pathophysiological changes in muscle tissue oxygenation and energy metabolism distal to the affected artery. Purpose: To quantify the blood oxygenation level-dependent (BOLD) response and phosphocreatine (PCr) recovery kinetics on a clinical MR system during a single exercise-recovery session in PAD patients. Study Type: Case–control study. Subjects: Fifteen Fontaine stage II patients, and 18 healthy control subjects. Field Strength/Sequence: Interleaved dynamic multiecho gradient-echo 1H T 2* mapping and adiabatic pulse-acquire 31P-MR spectroscopy at 3T. Assessment: Blood pressure in the arms and ankles were measured to determine the ankle-brachial index (ABI). Subjects performed a plantar flexion exercise-recovery protocol. The gastrocnemius and soleus muscle BOLD responses were characterized using the T 2* maps. High-energy phosphate metabolite concentrations were quantified by fitting the series of 31P-MR spectra. The PCr recovery time constant (τ PCr) was derived as a measure of in vivo mitochondrial oxidative capacity. Statistical Tests: Comparisons between groups were performed using two-sided Mann–Whitney U-tests. Relations between variables were assessed by Pearson's r correlation coefficients. Results: The amplitude of the functional hyperemic BOLD response in the gastrocnemius muscle was higher in PAD patients compared with healthy subjects (–3.8 ± 1.4% vs. –1.4 ± 0.3%; P < 0.001), and correlated with the ABI (r = 0.79; P < 0.001). PCr recovery was slower in PAD patients (τ PCr = 52.0 ± 13.5 vs. 30.3 ± 9.7 sec; P < 0.0001), and correlated with the ABI (r = –0.64; P < 0.001). Moreover, τ PCr correlated with the hyperemic BOLD response in the gastrocnemius muscle (r = –0.66; P < 0.01). Data Conclusion: MR readouts of calf muscle tissue oxygenation and high-energy phosphate metabolism were acquired essentially simultaneously during a single exercise-recovery session. A pronounced hypoxia-triggered vasodilation in PAD is associated with a reduced mitochondrial oxidative capacity. Level of Evidence: 2. Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:98–107.

Background Aortic valve calcium (AVC) is an important hallmark of aortic valve stenosis, which is the most common valvular heart disease in the Western world. Studies suggesting an important role for lipoprotein(a) [Lp(a)] in the etiology of AVC are accumulating, yet population-based evidence is scarce. Therefore, we investigated the association of Lp(a) with the presence of AVC in two large cohorts. Methods A total of 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3), and 859 asymptomatic persons from the Amsterdam Medical Center outpatient clinic for familial premature (non-valvular) atherosclerosis (57%women, mean age=45.9±11.6) underwent blood sampling to determine serum Lp(a) and non-enhanced cardiac CT-scan to assess AVC. We combined both cohorts and investigated the association of Lp(a) with the presence and amount of AVC using logistic and linear regression models, adjusting for age, sex, smoking, body mass index, non-high density lipoprotein cholesterol and use of antihypertensive medication. Results Out of a total of 3271 subjects with an average age of 63.4±7.98, AVC was present in 844 (25.8%) individuals. Higher levels of Lp(a) were associated with the presence of AVC, independent of age, sex and cardiovascular risk factors [Odds ratio (OR) per 1-SD increase in Lp(a): 1.39 (95% CI:1.27; 1.51). In persons with AVC, a higher level of Lp(a) was also related to larger volume of AVC [β per 1-SD increase in Lp(a): 0.76 (95% CI:1.27; 1.51)]. All findings were similar across both cohorts. Conclusion Lp(a) is a prominent and independent marker of the presence and amount of AVC in the general population. Future studies investigating the effect of Lp(a) lowering on the progression of AVC are warranted. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): NESTOR program for geriatric research, the Netherlands Heart Foundation, the Netherlands Organization for Scientific Research, the Health Research and Development Council (28-2975 and 97-1-364), and the Municipality of Rotterdam

Background and aims: Inflammation in atherosclerotic plaques is an important determinant of plaque vulnerability, and can be detected non-invasively using ultra-small superparamagnetic iron-oxide (USPIO) enhanced MRI. The aims of the current study were: 1) to determine whether ferumoxytol can be used for USPIO-MRI of atherosclerotic plaques, 2) to establish a protocol for quantitative USPIO-MRI of carotid artery plaques using ferumoxytol, and 3) to study the relation between USPIO uptake and plaque burden and F-18-fluorodeoxyglucose (FDG) uptake (measured by F-18-FDG PET/CT scan) in atherosclerotic plaques. Methods: In 9 patients with carotid artery stenosis >30% and 4 healthy controls, quantitative R2* MRI scans of the carotid arteries were performed before and 72 h after USPIO administration (4 mg/kg ferumoxytol). USPIO uptake was assessed by quantifying the difference in R2* (DR2*) between baseline and post-USPIO scans. In addition to MRI, F-18-FDG PET/CT was performed on both carotid arteries. MR and PET/CT images were co-registered, and F-18-FDG uptake was quantified in all slices containing atherosclerotic plaque. Results: Infusion of ferumoxytol resulted in higher R2* values after 72 h in atherosclerotic plaques (DR2* 24.6 +/- 19.8 s(-1); p = 0.0003), but not in the healthy control vessel wall (DR2* 2.6 +/- 5.6 s(-1), p = 0.23). USPIO uptake in patients was higher in atherosclerotic plaques compared to the patient non-plaque vessel wall (DR2* of 24.6 +/- 19.8 vs. 7.5 +/- 9.3 s(-1), p = 0.004). No correlation was found between USPIO uptake and F-18-FDG uptake in atherosclerotic plaques (R-2 = 0.03, p = 0.55). Conclusions: Ferumoxytol is selectively taken up by atherosclerotic plaques and can thus be used for carotid USPIO-MRI. As USPIO and F-18-FDG uptake in atherosclerotic plaque do not correlate in this cohort, these agents may visualize different pathophysiological aspects of plaque inflammation. (C) 2017 Elsevier B.V. All rights reserved

Aortic stenosis was first described by the French surgeon and anatomist Lazare Riviere in 1663. While the last decade has seen impressive advances in our ability to treat aortic valve stenosis invasively and percutaneously, significant issues remain with regards to the optimal timing of valve replacement, periprocedural risks and long-term durability. There therefore remains major interest in developing medical treatments to halt or slow progression of aortic stenosis, which could obviate the need for surgical intervention altogether. A stitch in time saves nine; however, no pharmacotherapies are currently proven to be effective for the treatment of calcific aortic valve stenosis (CAVS). Atherogenic apolipoprotein B-containing lipoproteins, such as low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)), have clearly been implicated in the pathogenesis of aortic stenosis, particularly in the early initiation phase. However, LDL cholesterol lowering with statins or ezetimibe failed to modify progression of aortic valve stenosis in multiple randomised clinical trials (SEAS, SALTIRE and ASTRONOMER). Attention has instead switched to Lp(a), with a growing body of epidemiology, genetics and prospective imaging studies having built a convincing case for elevated Lp(a) levels being associated with an increased incidence of aortic stenosis, …

Calcific aortic valve stenosis is the commonest form of heart valve disease in high-income countries and set to become a major health care burden. Currently, there are no medical therapies that have proved to slow down or halt disease progression. The only available treatment is aortic valve replacement, of which the optimal timing is unknown and to which not all patients are suited. This review discusses the pathophysiology of aortic stenosis, how noninvasive imaging techniques have improved our understanding of the underlying biology, and how these emerging insights might translate into potential novel treatments targeting oxidized lipids, fibrosis, and calcification.

Purpose of review Because human genetic studies and large clinical trials have demonstrated that HDL-cholesterol levels are not causally related to cardiovascular disease risk, attention has shifted toward the functional properties of HDL. Infusion of HDL mimetics containing apolipoprotein A-I remains a potential strategy to exploit the atheroprotective effects of HDL. Recent findings Three HDL mimetic drugs are under development and currently being evaluated in clinical trials. Upon infusion, these drugs increase cholesterol efflux capacity. Although proof-of-concept studies are promising, large outcome studies are awaited. Alternatively, HDL particles may be used for targeted drug delivery in a nanomedicine approach. Finally, links between cholesterol efflux and myelopoeisis may prove to be a target for HDL infusion in the future. Summary Clinical studies are currently ongoing to evaluate the potential of several HDL mimetic drugs. Novel nanomedicinal approaches and emerging pathophysiological insights may further expand the relevance of HDL infusion.

A variety of novel therapeutic approaches presented by several trials (e.g., FOURIER [Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk]/ODYSSEY OUTCOMES [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With

Background Apolipoprotein B/apolipoprotein A‐I (apoB/apoA‐I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis ( AVS ) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA‐I ratio, Lp(a), and AVS incidence in a large population study. Methods and Results We analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the EPIC ‐Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA‐I and Lp(a) levels were measured. Participants were identified as having incident AVS if they were hospitalized or died with AVS as an underlying cause. After a median follow‐up of 19.8 years (17.9–21.0 years) there were 403 (2.2%) incident cases of AVS . The hazard ratio for AVS risk was 1.30 (95% CI , 1.19–1.41; P AVS incidence (hazard ratio, 1.06; 95% CI , 0.97–1.17 [ P =0.215]). Elevated Lp(a) (>50 mg/ dL ) remained an independent risk factor for AVS after adjustment for age, sex, low‐density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95% CI , 1.33–2.19 [ P Conclusions In this population study, apoB/apoA‐I ratio was associated with risk of AVS incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for AVS incidence. Interventional trials are needed to investigate whether modulating apoB/apoA‐I or lowering Lp(a) can prevent or slow down AVS .

Purpose An acute coronary syndrome (ACS) is characterized by a multi-level inflammatory response, comprising activation of bone marrow and spleen accompanied by augmented release of leukocytes into the circulation. The duration of this response after an ACS remains unclear. Here, we assessed the effect of an ACS on the multi-level inflammatory response in patients both acutely and after 3 months. Methods We performed 18F-DPA-714 PET/CT acutely and 3 months post-ACS in eight patients and eight matched healthy controls. DPA-714, a PET tracer binding the TSPO receptor and highly expressed in myeloid cells, was used to assess hematopoietic activity. We also characterized circulating monocytes and hematopoietic stem and progenitor cells (HSPCs) by flow cytometry in 20 patients acutely and 3 months post-ACS and in 19 healthy controls. Results In the acute phase, patients displayed a 1.4-fold and 1.3-fold higher 18F-DPA-714 uptake in, respectively, bone marrow (p = 0.012) and spleen (p = 0.039) compared with healthy controls. This coincided with a 2.4-fold higher number of circulating HSPCs (p = 0.001). Three months post-ACS, 18F-DPA-714 uptake in bone marrow decreased significantly (p = 0.002), but no decrease was observed for 18F-DPA-714 uptake in the spleen (p = 0.67) nor for the number of circulating HSPCs (p = 0.75). Conclusions 18F-DPA-714 PET/CT reveals an ACS- triggered hematopoietic organ activation as initiator of a prolonged cellular inflammatory response beyond 3 months, characterized by a higher number of circulating leukocytes and their precursors. This multi-level inflammatory response may provide an attractive target for novel treatment options aimed at reducing the high recurrence rate post-ACS. Electronic supplementary material The online version of this article (10.1007/s00259-018-4038-8) contains supplementary material, which is available to authorized users.