CD163+ macrophages restrain vascular calcification, promoting the development of high-risk plaque.

Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.

Impact of lipoprotein(a) levels on primary patency after endovascular therapy for femoropopliteal lesions.

Lipoprotein(a) [Lp(a)] is a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and clinical events after endovascular therapy (EVT) for the femoropopliteal artery in PAD patients remains unclear. Thus, this study aimed to assess the impact of Lp(a) levels on primary patency after EVT for de novo femoropopliteal lesions in PAD patients. A retrospective analysis was conducted on 109 patients who underwent EVT for de novo femoropopliteal lesions, and Lp(a) levels were measured before EVT between June 2016 and December 2019. Patients were divided into low Lp(a) [Lp(a) < 30 mg/dL; 78 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. The main outcome was primary patency following EVT. Loss of primary patency was defined as a peak systolic velocity ratio > 2.4 on a duplex scan or > 50% stenosis on angiography. Cox proportional hazards analysis was performed to determine whether high Lp(a) levels were independently associated with loss of primary patency. The mean follow-up duration was 28 months. The rates of primary patency were 83 and 76% at 1 year and 75 and 58% at 2 years in the low and high Lp(a) groups, respectively (P = 0.02). After multivariate analysis, High Lp(a)[Lp(a) ≥ 30 mg/dL] (hazard ratio 2.44; 95% CI 1.10-5.44; P = 0.03) and female sex (hazard ratio 2.65; 95% CI 1.27-5.51; P < 0.01) were independent predictors of loss of primary patency. Lp(a) levels might be associated with primary patency after EVT for de novo femoropopliteal lesions.

Potential of optical frequency domain imaging for differentiation between early and advanced coronary atherosclerosis.

PURPOSE: This study evaluated whether optical frequency domain imaging (OFDI) accurately distinguish between fibroatheroma (FA) and pathological intimal thickening (PIT) compared with histopathology. METHODS: A total of 631 histological cross-sections from 14 autopsy hearts were analyzed for the comparison between OFDI and histological images. Of those, 190 (30%) sections were diagnosed with PIT and 120 (19%) with FA. The OFDI signal attenuation rate was calculated from an exponential. The lipid length was measured longitudinally by detection of sequential OFDI frames within a plaque segment containing lipids. The lipid arc was measured with a protractor centered in the center of the lumen. The fibrous cap thickness was defined as the minimum thickness of the signal rich band overlying PIT and FA. RESULTS: There was no significant difference in the OFDI signal attenuation rate between FA and PIT (3.09 ± 1.04 versus 2.79 ± 1.20, p = 0.13). However, the lipid length was significantly longer, the maximum lipid arc was significantly larger, and the fibrous cap thickness was significantly thinner in FA than in PIT (7.5 [4.3-10.3] mm versus 4.3 [2.7-5.8] mm, p < 0.0001, 125 [101-174]° versus 96 [74-131]°, p < 0.0001, and 220 [167-280] µm versus 260 [190-332] µm, p = 0.019). CONCLUSIONS: This study revealed OFDI may have the potential capability for discriminating FA from PIT based on the longitudinal and circumferential extent of lipid plaque, although the OFDI signal attenuation rate was similar between FA and PIT.

Impact of lipoprotein (a) on long-term outcome after percutaneous coronary intervention in the era of new generation drug-eluting stents.

BACKGROUND: High lipoprotein (a) [Lp (a)] levels are associated with worse long-term outcomes in patients undergoing percutaneous coronary intervention (PCI). However, there are limited studies investigating association between Lp (a) levels and long-term outcomes in the era of new generation drug-eluting stents (DES). METHODS: A total of 495 patients with available data on Lp (a) who underwent PCI for de novo lesions with new generation DES were enrolled between 2013 and 2017. The primary endpoint was the major adverse cardiovascular event (MACE), which was defined as a composite of cardiac death, myocardial infarction, stent thrombosis, clinically driven target lesion revascularization, and revascularization for new lesions during 3 years. Patients were divided into 2 groups according to the Lp (a) level: high Lp (a) group (≥30 mg/dL: n = 109) and low Lp (a) group (30 mg/dL>: n = 386). Multivariate Cox regression analysis was performed to identify the predictors for 3-year MACE. RESULTS: The incidence of 3-year MACE was significantly higher in high Lp (a) group than low Lp (a) group (33.0% vs. 15.9%, p < 0.001). Multivariable analysis showed that Lp (a) level of ≥30 mg/dL was an independent predictor for 3-year MACE (HR 2.01, 95%CI 1.30-3.11, p = 0.002). CONCLUSION: High Lp (a) level was associated with worse long-term outcome even in the era of new generation DES.

Efficacy of optical frequency domain imaging in detecting peripheral artery disease: the result of a multi-center, open-label, single-arm study.

Optical frequency domain imaging (OFDI) is a high-resolution intracoronary imaging modality with fast automated longitudinal pullback. We aimed to evaluate the ability of performing OFDI from the superficial femoral artery (SFA) to the below-knee (BK) artery. This clinical trial was a multi-center, single-arm, open-label study. The primary endpoint was to obtain a clear image of the intra-vascular lumen from the SFA to the BK artery, specifically > 270° visualization of the blood vessel lumen with > 16/21 cross sections. The proportion of the clear image (≥ 85%) was regarded as confirmatory of the ability of OFDI to visualize the vessel lumen. Overall, 20 patients were enrolled. The proportion of the primary endpoint was 90% (18/20), and the pre-specified criterion was successfully attained. The proportion of the clear image assessed by the operator was 100% (20/20), and an additional statistical analysis for the proportion of the visualization, > 270°, of the blood vessel lumen revealed a significantly higher cut-off value than that for the pre-specified criterion, 85% (p = 0.0315). There were three adverse events not related to OFDI. OFDI achieved acceptable visualization of the vessel lumen without any adverse event related to it. After regulatory approval based on the present study, OFDI will be available as a new option of endovascular imaging for peripheral artery diseases in daily practiceTrial registration: This study was registered in the Japanese Registry of Clinical Trials (jRCT 2052190025, https://jrct.niph.go.jp/latest-detail/jRCT2052190025 ).

Relationship Between Lipoprotein(a) and Angiographic Severity of Femoropopliteal Lesions.

AIM: High levels of lipoprotein(a) [Lp(a)] are a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and the severity of femoropopliteal lesions in patients with PAD has not been systematically studied. This study aimed to assess the impact of Lp(a) levels on angiographic severity of femoropopliteal lesions in patients with PAD. METHODS: We retrospectively analyzed a single-center database including 108 patients who underwent endovascular therapy for de novo femoropopliteal lesions and measured the Lp(a) levels before therapy between June 2016 and September 2019. Patients were divided into low Lp(a) [Lp(a) ＜30 mg/dL; 77 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. Trans-Atlantic Inter-Society Consensus (TASC) II classification, calcification [referring to the peripheral arterial calcium scoring system (PACSS) classification], and lesion length were compared between the groups. RESULTS: The prevalence of TASC II class D (13% vs 38%, P＜0.01) and severe calcification (PACSS 4) (6% vs 23%, P=0.02) was significantly higher and the lesion length longer (123±88 mm vs 175±102 mm, P＜0.01) in the high Lp(a) group than in the low Lp(a) group. In multivariate analysis, Lp(a) ≥ 30 was an independent predictor for the prevalence of TASC II class D (HR=3.67, 95% CI 1.27-10.6, P=0.02) and PACSS 4 (HR=4.97, 95% CI 1.27-19.4, P=0.02). CONCLUSION: The prevalence of TASC II class D and severe calcification of femoropopliteal lesions was higher in patients with high Lp(a) than those with low Lp(a).

Comparison of coronary atherosclerotic disease burden between ST-elevation myocardial infarction and non-ST-elevation myocardial infarction: Non-culprit Gensini score and non-culprit SYNTAX score.

BACKGROUND: Patients with non-ST-elevation myocardial infarction (NSTEMI) have worse long-term prognoses than those with ST-elevation myocardial infarction (STEMI). HYPOTHESIS: It may be attributable to more extended coronary atherosclerotic disease burden in patients with NSTEMI. METHODS: This study consisted of consecutive 231 patients who underwent coronary intervention for myocardial infarction (MI). To assess the extent and severity of atherosclerotic disease burden of non-culprit coronary arteries, two scoring systems (Gensini score and synergy between percutaneous coronary intervention with Taxus and cardiac surgery [SYNTAX] score) were modified by subtracting the score of the culprit lesion: the non-culprit Gensini score and the non-culprit SYNTAX score. RESULTS: Patients with NSTEMI had more multi-vessel disease, initial thrombolysis in myocardial infarction (TIMI) flow grade 2/3, and final TIMI flow grade 3 than those with STEMI. As compared to STEMI, patients with NSTEMI had significantly higher non-culprit Gensini score (16.3 ± 19.8 vs. 31.2 ± 25.4, p < 0.001) and non-culprit SYNTAX score (5.8 ± 7.0 vs. 11.1 ± 9.7, p < 0.001). CONCLUSIONS: Patients with NSTEMI had more advanced coronary atherosclerotic disease burden including non-obstruction lesions, which may at least in part explain higher incidence of cardiovascular events in these patients.

Impact of Age on Gender Difference in Long-term Outcome of Patients With Acute Myocardial Infarction (from J-MINUET).

Although gender difference in long-term outcomes after acute myocardial infarction have been shown previously, impact of age on gender difference is still controversial. This study focused on the association between age and gender difference in long-term outcome. We analyzed data from 3,283 consecutive patients who were included in a prospective, nationwide, multicenter registry (Japan Registry of Acute Myocardial Infarction Diagnosed by Universal Definition) from 2012 to 2014. The primary end point was the major adverse cardiovascular event (MACE), which was defined as a composite of death, myocardial infarction, stroke, heart failure, and revascularization for unstable angina during 3 years. Patients were divided into 4 strata according to age: those with age <65 years (group 1: n = 1161), 65 to 74 years (group 2: n = 954), 75 to 84 years (group 3: n = 866) and 84< years (group 4: n = 302). Although the crude incidence of 3-year MACE was significantly higher in women than men (36.4% vs. 28.5%, p <0.001), there was not significant gender difference in each group (group 1, 19.6% vs 19.0%, p = 0.74; group 2, 33.1% vs 28.3%, p = 0.25; group 3, 38.9% vs 39.6%, p = 0.54; and group 4, 54.0% vs 56.8%, p = 0.24). In conclusion, although women had higher crude incidence of 3-year MACE than men, there was no gender difference in each group.

Influence of Self-Expanding Paclitaxel-Eluting Stent Sizing on Neointimal Hyperplasia in Superficial Femoral Artery Lesions.

BACKGROUND: Although self-expanding drug-eluting stents (DES) have recently shown superior outcomes for superficial femoral artery (SFA) lesions, optimal sizing of DES diameter in SFA intervention is unclear.Methods and Results:A total of 40 de novo SFA lesions were randomized 1:1 to receive self-expanding DES with either a 1-mm or 2-mm larger diameter than the reference vessel diameter. Follow-up optical coherence tomography (OCT) was scheduled 6 months after DES implantation to evaluate the vascular response to the stents. Volume index (VI) was defined as volume divided by stent length. The primary endpoint was neointimal VI at 6 months. Baseline reference vessel diameter was similar between the 1-mm larger diameter group and the 2-mm larger diameter group (5.0±0.8 mm vs. 4.7±0.9 mm, P=0.35). Stent diameter was 6.3±0.6 mm in the 1-mm larger group and 7.1±0.6 mm in the 2-mm larger group (P<0.0001), and stent to reference vessel diameter ratio (SV ratio) was 1.3±0.2 and 1.5±0.2 (P<0.0001), respectively. At 6-month, neointimal VI was greater in the 2-mm larger diameter group (5.5±1.5 mm2vs. 9.6±3.4 mm2, P<0.001). The correlation analysis revealed that degree of neointimal VI was positively correlated with SV ratio (r=0.43, P<0.01). CONCLUSIONS: Implantation of self-expanding DES with a considerably high SV ratio resulted in neointimal hyperplasia in SFA lesions.

Impact of peripheral artery disease on prognosis after myocardial infarction: The J-MINUET study.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including myocardial infarction (MI), stroke, and cardiovascular death. However, the impact of PAD on prognosis in Japanese patients with acute MI remains unclear. METHODS: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry that registered 3283 patients with acute MI. Among them, 2970 patients with available data of PAD were divided into the following 4 groups: 2513 patients without prior MI or PAD (None group), 320 patients with only prior MI (Prior MI group), 100 patients with only PAD (PAD group), and 37 patients with both previous MI and PAD (Both group). The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina. RESULTS: The 3-year cumulative incidence of the primary endpoint was 26.9% in None group, 41.4% in Prior MI group, 48.0% in PAD group, and 60.3% in Both group (p < 0.001). In multivariate analysis, hazard ratio using None group as reference was 1.55 (95% confidence intervals 1.25-1.91; p < 0.001) for MI group, 2.26 (1.61-3.07; p < 0.001) for PAD group, and 2.52 (1.52-3.90; p < 0.001) for Both group. CONCLUSIONS: Concomitant PAD was associated with poor prognosis in Japanese patients with acute MI.

Impact of left ventricular diastolic dysfunction on long-term outcome in patients with lower extremity artery disease.

BACKGROUND: The relationship between long-term outcome in patients with lower extremity artery disease (LEAD) and left ventricular (LV) diastolic dysfunction has not been systematically studied. The aim of this study was to assess the impact of LV diastolic dysfunction on the long-term outcome in patients with LEAD. METHODS: Two hundred LEAD patients (male 66 %, mean age 76±9 years) with preserved LV systolic function assessed by echocardiography (ejection fraction ≥50 %) were enrolled from a single center database between January 2013 and May 2015. We divided the patients into two groups on the basis of LV diastolic dysfunction, which was diagnosed based on the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. The 3-year cumulative incidence of the primary endpoint was compared between LEAD patients with LV diastolic dysfunction and those without. The primary endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE: death, hospitalization for heart failure, myocardial infarction, and stroke). Multivariate analysis was performed to determine whether LV diastolic dysfunction was independently associated with the MACCE. RESULTS: LV diastolic dysfunction was identified in 31 % of LEAD patients. The mean observation period was 32±21 months. The 3-year cumulative incidence of MACCE occurred more frequently in patients with LV diastolic dysfunction than those without (35 % vs 23 %, p=0.01). In multivariate analysis, LV diastolic dysfunction (HR=1.96, 95 % CI 1.09-3.55, p=0.03) and critical limb ischemia (HR=2.52, 95 % CI 1.24-5.10, p=0.01) were an independent predictor for MACCE. CONCLUSION: LV diastolic dysfunction increased the risk for MACCE in patients with LEAD.

Impact of IVUS-Derived Vessel Size on Midterm Outcomes After Stent Implantation in Femoropopliteal Lesions.

Purpose: To identify intravascular ultrasound (IVUS) findings that predict midterm stent patency in femoropopliteal (FP) lesions. Materials and Methods: A retrospective analysis was undertaken of 335 de novo FP lesions in 274 consecutive patients (mean age 72.4±8.2 years; 210 men) who had IVUS assessment before and after successful stent implantation. The mean lesion length was 13.2±9.8 cm. The primary outcome was primary patency at 24 months, defined as freedom from major adverse limb event (MALE) and in-stent restenosis (ISR). MALE was defined as major amputation or any target lesion revascularization (TLR). ISR was defined by a peak systolic velocity ratio >2.4 by duplex ultrasonography. Logistic regression analyses were performed to identify independent predictors of stent patency at 24 months; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal threshold for prediction of stent patency at 24 months. Results: Over the 24-month follow-up, 18 (7%) patients died and 43 (15%) of 286 lesions were responsible for MALE (42 TLRs and 1 major amputation). Primary patency was estimated at 82.5% (95% CI 78.1% to 86.9%) at 12 months and 73.2% (95% CI 67.9% to 78.5%) at 24 months. Multivariable analysis revealed that longer lesion length (OR 0.89, 95% CI 0.82 to 0.97, p<0.01) was an independent predictor of declining patency, while cilostazol use (OR 3.45, 95% CI 1.10 to 10.78, p=0.03) and increasing distal reference external elastic membrane (EEM) area (OR 1.18, 95% CI 1.02 to 1.37, p=0.03) were associated with midterm stent patency. ROC curve analysis identified a distal reference EEM area of 29.0 mm2 as the optimal cut-point for prediction of 24-month stent patency (area under the ROC curve 0.764). Kaplan-Meier estimates of 24-month primary patency were 83.7% (95% CI 78.3% to 89.2%) in lesions with a distal EEM area >29.0 mm2 vs 53.1% (95% CI 42.9% to 63.3%) in those with a distal EEM area ≤29.0 mm2 (p<0.001). Conclusion: In FP lesions with a larger distal vessel area estimated with IVUS, stent implantation can be considered as a reasonable treatment option, with the likelihood of acceptable midterm results.

The impact of peripheral artery disease on left ventricular diastolic function.

BACKGROUND: Peripheral artery disease (PAD) is often accompanied by heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) diastolic dysfunction is related to HFpEF. The aim of this study was to compare LV diastolic function between patients with or without PAD. METHODS: One thousand one hundred twenty-one patients (male 56%, mean age 68±13 years) with available preserved LV systolic function assessed by echocardiography (ejection fraction ≥50%) were enrolled from a single-center database between January 2013 and May 2015. PAD was defined as ankle brachial index <0.9 or previous history of lower extremity bypass and/or endovascular therapy. Diagnosis of LV diastolic dysfunction was based on the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines. The prevalence of LV diastolic dysfunction was compared between patients with PAD and those without PAD. Multivariate analysis was performed by logistic regression analyses to assess predictors of LV diastolic dysfunction. RESULTS: Two hundred patients (18%) had PAD. Patients with PAD had higher E/e' (15.3±7.4 vs 11.8±5.5, p<0.01), tricuspid regurgitation velocity (2.37±0.33 vs 2.19±0.28m/s, p<0.01), left atrial volume index (40.6±20.2 vs 32.1±13.6mL/m2, p<0.01), and lower e' (5.68±1.70 vs 6.38±2.07cm/s, p<0.01) than patients without PAD. The prevalence of LV diastolic dysfunction was higher (31% vs 12%, p<0.01) in patients with PAD compared to patients without PAD. Multivariate analysis showed that PAD was an independent predictor of LV diastolic dysfunction (adjusted odds ratio: 1.77, 95% confidence interval: 1.13-2.65, p=0.01). CONCLUSION: The prevalence of LV diastolic dysfunction was higher in patients with PAD than patients without PAD.

Endovascular Therapy with a Covered Stent Graft for Pseudoaneurysm of the Peroneal Artery Complicating High Tibial Osteotomy-A Case Report.

Pseudoaneurysm of below-the-knee arteries after a high tibial osteotomy (HTO) is rare. A 69-year-old woman with history of right HTO a half year ago had performed a left HTO for osteoarthritis. Postoperatively, she had swelling and pain of the left lower leg. Computed tomography and echocardiography revealed the pseudoaneurysm of peroneal artery (PA). After the release of the covered stent graft, the pseudoaneurysm of the PA did not disappear, it was completely excluded in the completion angiogram.

Coronary restenosis of in-stent protruding bump with rapid progression: Optical frequency domain imaging and angioscopic observation.

In-stent restenosis (ISR) remains a tough problem after percutaneous coronary intervention (PCI) despite advances in technology of drug-eluting stents (DES). A 63-year-old man undergoing hemodialysis was diagnosed with non-ST elevation acute coronary syndrome (NSTE-ACS). An emergency coronary angiography (CAG) revealed severe stenosis in the middle left circumflex artery (LCx). After pre-dilatation with non-compliant balloon, primary PCI was successfully performed with DES implantation. Four months after, CAG was performed again and verified ISR of LCx under diagnosis of recurrent NSTE-ACS. Subsequently multimodality intravascular imaging assessment was performed for the ISR lesion. Optical frequency domain imaging showed the eccentric protruding mass with irregular surface with high-backscatter, whereas angioscopy revealed the in-stent bump with yellow color. The ISR lesion was successfully treated by drug-coated balloon angioplasty. However, he suffered recurrent NSTE-ACS five months later. CAG revealed de novo stenotic lesions not only in re-restenosis of LCx but also in proximal left anterior descending artery and ostium of right coronary artery. He was scheduled to undergo coronary artery bypass grafting for three-vessel disease. Multimodality assessment is useful to diagnose the recurrent restenosis lesion with calcified nodule. .

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Mechanisms of aortic stenosis.

The pathobiology of degenerative aortic valve stenosis (AS) is complex and involves multiple features such as fibrosis, inflammation, oxidative stress, angiogenesis, hemorrhage, and osteogenic differentiation. We summarize the mechanism of valve calcification and angiogenesis which is necessary for calcifying processes. A promising therapeutic target is nuclear factor (NF)-κB which activates bone morphogenetic protein (BMP)2 via interleukin-6. BMP2 activates Wnt signaling via msh homeobox 2 causing osteogenic differentiation. BMP2 also activates Runx2/Cbfa1 which is an osteoblast-specific transcription factor. Signals in the hypoxia-inducible factor-2 axis activated by the NF-κB signaling pathway also play important role in calcifying processes including angiogenesis. The reason why angiogenesis takes place in avascular valves is still unknown, but it is likely angiogenesis and angiogenesis-related hemorrhage play critical roles in the progression of AS.

CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury.

Macrophages are an essential component of the immune response to ischaemic injury and play an important role in promoting inflammation and its resolution, which is necessary for tissue repair. The type I transmembrane glycoprotein CD163 is exclusively expressed on macrophages, where it acts as a receptor for haemoglobin:haptoglobin complexes. An extracellular portion of CD163 circulates in the blood as a soluble protein, for which no physiological function has so far been described. Here we show that during ischaemia, soluble CD163 functions as a decoy receptor for TWEAK, a secreted pro-inflammatory cytokine of the tumour necrosis factor family, to regulate TWEAK-induced activation of canonical nuclear factor-κB (NF-κB) and Notch signalling necessary for myogenic progenitor cell proliferation. Mice with deletion of CD163 have transiently elevated levels of TWEAK, which stimulate muscle satellite cell proliferation and tissue regeneration in their ischaemic and non-ischaemic limbs. These results reveal a role for soluble CD163 in regulating muscle regeneration after ischaemic injury.