Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

Use of Intravascular Imaging During Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry

Background: Intravascular imaging can facilitate chronic total occlusion (CTO) percutaneous coronary intervention. Methods and Results: We examined the frequency of use and outcomes of intravascular imaging among 619 CTO percutaneous coronary interventions performed between 2012 and 2015 at 7 US centers. Mean age was 65.4±10 years and 85% of the patients were men. Intravascular imaging was used in 38%: intravascular ultrasound in 36%, optical coherence tomography in 3%, and both in 1.45%. Intravascular imaging was used for stent sizing (26.3%), stent optimization (38.0%), and CTO crossing (35.7%, antegrade in 27.9%, and retrograde in 7.8%). Intravascular imaging to facilitate crossing was used more frequently in lesions with proximal cap ambiguity (49% versus 26%, P<0.0001) and with retrograde as compared with antegrade‐only cases (67% versus 31%, P<0.0001). Despite higher complexity (Japanese CTO score: 2.86±1.19 versus 2.43±1.19, P=0.001), cases in which imaging was used for crossing had similar technical and procedural success (92.8% versus 89.6%, P=0.302 and 90.1% versus 88.3%, P=0.588, respectively) and similar incidence of major cardiac adverse events (2.7% versus 3.2%, P=0.772). Use of intravascular imaging was associated with longer procedure (192 minutes [interquartile range 130, 255] versus 131 minutes [90, 192], P<0.0001) and fluoroscopy (71 minutes [44, 93] versus 39 minutes [25, 69], P<0.0001) time. Conclusions: Intravascular imaging is frequently performed during CTO percutaneous coronary intervention both for crossing and for stent selection/optimization. Despite its use in more complex lesion subsets, intravascular imaging was associated with similar rates of technical and procedural success for CTO percutaneous coronary intervention. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02061436

Coronary artery spatial distribution of chronic total occlusions: Insights from a large US registry

ObjectiveTo assess the spatial distribution of chronic total occlusions (CTOs) within the coronary arteries and describe procedural strategies and outcomes during CTO percutaneous coronary intervention (PCI).BackgroundAcute occlusions due to plaque rupture tend to cluster within the proximal third of the coronary artery.MethodsWe examined the clinical and procedural characteristics of 1,348 patients according to lesion location within the coronary tree.ResultsA total of 1,369 lesions in 1,348 patients (mean age 66 ± 10 years, 85% male) were included. CTO PCI of proximal segments (n = 633, 46%) was more common than of mid (n = 557, 41%) and distal segments (n = 179, 13%). Patients undergoing CTO PCI of proximal segments were more likely to be smokers (P &lt; 0.01), have prior coronary artery bypass graft surgery (P = 0.03) and lower ejection fraction (P = 0.04). CTOs occurring in proximal segments had longer length (P &lt;0.01), proximal cap ambiguity (P &lt; 0.01), and moderate/severe calcification (P &lt; 0.01) compared to mid or distally located CTOs. Interventional collaterals were more often present in CTO PCI of proximal segments (64%, 53%, 56%, P &lt; 0.01) consistent with the higher use of retrograde approach (47%, 33%, 37%, P &lt; 0.01) relative to antegrade wire escalation (67%, 82%, 82%, P &lt; 0.01). Procedural complexity was higher in CTO PCI of proximal segments (vs. mid and distal): contrast volume= 275 ml (200-375), 260 ml (200-350), 250 ml (175-350), P = 0.01; fluoroscopy time 53 minutes (32-83), 39 minutes (24-65), 40 minutes (22-72), P &lt; 0.01. However, procedural success (87%, 90%, 85%, P = 0.1), technical success (89%, 91%, 88%, P = 0.24), and complications rates (2.8%, 2.5%, 2.2%, P = 0.88) were not different.ConclusionsThe most common target vessel location for CTO PCI is the proximal coronary segment. PCI of proximal occlusions is associated with adverse clinical and angiographic characteristics and often requires use of the retrograde approach, but can be accomplished with high procedural and technical success and low complication rates. © 2016 Wiley Periodicals, Inc

Use of Intravascular Imaging During Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry

Background-Intravascular imaging can facilitate chronic total occlusion (CTO) percutaneous coronary intervention. Methods and Results-We examined the frequency of use and outcomes of intravascular imaging among 619 CTO percutaneous coronary interventions performed between 2012 and 2015 at 7 US centers. Mean age was 65.4 +/- 10 years and 85% of the patients were men. Intravascular imaging was used in 38%: intravascular ultrasound in 36%, optical coherence tomography in 3%, and both in 1.45%. Intravascular imaging was used for stent sizing (26.3%), stent optimization (38.0%), and CTO crossing (35.7%, antegrade in 27.9%, and retrograde in 7.8%). Intravascular imaging to facilitate crossing was used more frequently in lesions with proximal cap ambiguity (49% versus 26%, P<0.0001) and with retrograde as compared with antegrade-only cases (67% versus 31%, P<0.0001). Despite higher complexity (Japanese CTO score: 2.86 +/- 1.19 versus 2.43 +/- 1.19, P=0.001), cases in which imaging was used for crossing had similar technical and procedural success (92.8% versus 89.6%, P=0.302 and 90.1% versus 88.3%, P=0.588, respectively) and similar incidence of major cardiac adverse events (2.7% versus 3.2%, P=0.772). Use of intravascular imaging was associated with longer procedure (192 minutes [interquartile range 130, 255] versus 131 minutes [90, 192], P<0.0001) and fluoroscopy (71 minutes [44, 93] versus 39 minutes [25, 69], P<0.0001) time. Conclusions-Intravascular imaging is frequently performed during CTO percutaneous coronary intervention both for crossing and for stent selection/optimization. Despite its use in more complex lesion subsets, intravascular imaging was associated with similar rates of technical and procedural success for CTO percutaneous coronary intervention

Prevalence, indications and management of balloon uncrossable chronic total occlusions: Insights from a contemporary multicenter US registry

BACKGROUND: Balloon uncrossable lesions can be challenging to treat, requiring specialized techniques and equipment. METHODS: We examined the prevalence, clinical and angiographic characteristics, management and procedural outcomes of balloon uncrossable lesions in a multicenter chronic total occlusion (CTO) percutaneous coronary intervention (PCI) registry. RESULTS: Between 2012 and 2016, 718 CTO PCIs (in which the occlusion was successfully crossed with a guidewire) were performed in 701 patients at 11 US centers. Mean age was 65.6 ± 10 years and 84% of the patients were men. Balloon uncrossable lesions represented 9% of all CTOs. Balloon uncrossable CTOs had more moderate/severe calcification (82% vs. 52%, P \u3c 0.0001), moderate/severe tortuosity (61% vs. 35% P \u3c 0.0001) and higher J-CTO score (2.95 ± 1.32 vs. 2.43 ± 1.23, P = 0.005) as compared with the remaining lesions. Technical and procedural success was significantly lower for balloon uncrossable lesions (90.5% vs. 98.3%, P \u3c 0.0001 and 88.9% vs. 96.6% P = 0.004), respectively, but the incidence of major adverse events was similar (1.6% vs. 2.2%, P = 0.751). Balloon uncrossable lesions required longer procedure (208 [interquartile range: 135, 258] vs. 135 [94, 194] min, P \u3c 0.0001) and fluoroscopy (77 [52, 100] vs. 45 min [27, 75], P \u3c 0.0001) time. Techniques used to treat balloon uncrossable lesions included balloon-assisted microdissection (23%), excimer laser atherectomy (18%), and rotational atherectomy (16%). Excimer laser atherectomy and balloon-assisted microdissection were associated with the highest technical and procedural success rates. CONCLUSIONS: Balloon uncrossable CTOs are common, are associated with high rates of technical failure, and require specialized techniques for successful treatment. © 2016 Wiley Periodicals, Inc

Prevalence, indications and management of balloon uncrossable chronic total occlusions: Insights from a contemporary multicenter US registry

BackgroundBalloon uncrossable lesions can be challenging to treat, requiring specialized techniques and equipment. MethodsWe examined the prevalence, clinical and angiographic characteristics, management and procedural outcomes of balloon uncrossable lesions in a multicenter chronic total occlusion (CTO) percutaneous coronary intervention (PCI) registry. ResultsBetween 2012 and 2016, 718 CTO PCIs (in which the occlusion was successfully crossed with a guidewire) were performed in 701 patients at 11 US centers. Mean age was 65.610 years and 84% of the patients were men. Balloon uncrossable lesions represented 9% of all CTOs. Balloon uncrossable CTOs had more moderate/severe calcification (82% vs. 52%, P<0.0001), moderate/severe tortuosity (61% vs. 35% P<0.0001) and higher J-CTO score (2.95 +/- 1.32 vs. 2.43 +/- 1.23, P=0.005) as compared with the remaining lesions. Technical and procedural success was significantly lower for balloon uncrossable lesions (90.5% vs. 98.3%, P<0.0001 and 88.9% vs. 96.6% P=0.004), respectively, but the incidence of major adverse events was similar (1.6% vs. 2.2%, P=0.751). Balloon uncrossable lesions required longer procedure (208 [interquartile range: 135, 258] vs. 135 [94, 194] min, P<0.0001) and fluoroscopy (77 [52, 100] vs. 45 min [27, 75], P<0.0001) time. Techniques used to treat balloon uncrossable lesions included balloon-assisted microdissection (23%), excimer laser atherectomy (18%), and rotational atherectomy (16%). Excimer laser atherectomy and balloon-assisted microdissection were associated with the highest technical and procedural success rates. ConclusionsBalloon uncrossable CTOs are common, are associated with high rates of technical failure, and require specialized techniques for successful treatment. (c) 2016 Wiley Periodicals, Inc

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia