Lipoprotein(a) Lp(a), a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL ...drive disease progression and are therefore targets for therapeutic intervention.
This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.
This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.
Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year interquartile range: 142 to 483 AU/year vs. 93 AU/year interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.
In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of ...valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.
In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and
F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.
A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s 2.93-3.82 m/s; aortic valve calcium score, 1152 AU 655-2065 AU) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 0.18-0.33 µg/L to 0.11 µg/L 0.08-0.17 µg/L) and alendronic acid (0.20 0.14-0.28 µg/L to 0.09 µg/L 0.08-0.13 µg/L) but was unchanged with placebo (0.23 0.17-0.30 µg/L to 0.26 µg/L 0.16-0.31 µg/L). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 198-804 AU versus 354 AU 76-675 AU; P=0.41) or alendronic acid and placebo (326 138-813 AU versus 354 AU 76-675 AU;
=0.49). Similarly, there were no differences in change in peak aortic jet velocity or
F-sodium fluoride aortic valve uptake.
Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological ...characterization of the aortic valve and assessed whether they predicted disease progression.
Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/
=0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66).
18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.
First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis.
EF1 was ...measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death.
Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m
vs 20.6 (16.8-24.3) mL/m
, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR.
EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.
Abstract Background Soluble ST2 (sST2) is a marker of cardiac mechanical strain hypothesized to adversely impact short-term prognosis after myocardial infarction. We examined the association of sST2 ...with longer-term outcomes after myocardial infarction in a geographically defined community. Methods Olmsted County, Minnesota residents who experienced an incident (first-ever) myocardial infarction between 11/01/2002 and 12/31/2012 were prospectively enrolled; sST2 levels were measured. Patients were followed for heart failure and death. Results We studied 1401 patients with incident myocardial infarction (mean age 67 years; 61% men; 79% non ST-elevation myocardial infarction). Median sST2 (ng/ml) was 48.7 (25th -75th percentile 32.5-103.3). Soluble ST2 was elevated in 51% of patients. Higher values of sST2 were associated with increased age, female sex, and comorbidities. During 5 years of follow-up, 388 persons died and 360 developed heart failure. After adjustment for age, sex, comorbidities, Killip class and troponin T, the hazard ratios (HR) for death were 1.73 (95% CI 1.22-2.45) and 3.57 (95% CI 2.57-4.96) for sST2 tertiles 2 and 3, respectively (ptrend <0.001). For heart failure, the HRs were 1.67 (95% CI 1.18-2.37) and 2.88 (95% CI 2.05-4.05), respectively (ptrend <0.001). Results were similar among 30-day survivors. Conclusions In the community, sST2 elevation is present in half of myocardial infarctions. Higher values of sST2 are associated with a large excess risk of death and heart failure independently of other prognostic indicators. Measurement of sST2 should be considered for risk stratification after myocardial infarction.
Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular ...inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO)-enhanced MRI.
Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues.
Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p<0.0001). Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. Following repeated doses, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared with remote myocardium until days 10-16 (p<0.05). In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow-up period (p<0.01).
Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions.
Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02319278?term=DECIFER&rank=2).
Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we ...investigated whether this phenomenon occurs in humans.
Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 2.00 to 12.75 versus 2.00 0.50 to 4.00 mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 10 200 to >50 000 versus 3800 1000 to 9200 ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 95% CI 1.90 to 10.19, P=0.001), but not late, recurrent MI.
The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.
18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, ...analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging.
Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11).
Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.
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