Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk.

BACKGROUND: Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype. METHODS: A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed. RESULTS: Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted. CONCLUSIONS: High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.

Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates With Vascular Risks and Is Involved in Atherosclerosis.

RATIONALE: Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated. OBJECTIVE: To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS. METHODS AND RESULTS: Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migration and proliferation of human aortic SMC and increased expression of proinflammatory molecules and activation of ERK (extracellular signal-regulated kinase) 5/p38 pathways. Neutralization of Rap1 by specific antibody or pharmacological inhibition of Rap1 completely prevented the effects of lEVs from MetS patients. High-fat diet-fed ApoE-/- mice displayed an increased expression of Rap1 both in aortas and circulating lEVs. lEVs accumulated in plaque atherosclerotic lesions depending on the progression of atherosclerosis. lEVs from high-fat diet-fed ApoE-/- mice, but not those from mice fed with a standard diet, enhanced SMC proliferation. Human atherosclerotic lesions were enriched in lEVs expressing Rap1. CONCLUSIONS: These data demonstrate that Rap1 carried by MetS-lEVs participates in the enhanced SMC proliferation, migration, proinflammatory profile, and activation of ERK5/p38 pathways leading to vascular inflammation and remodeling, and atherosclerosis. These results highlight that Rap1 carried by MetS-lEVs may be a novel determinant of diagnostic value for cardiometabolic risk factors and suggest Rap1 as a promising therapeutic target against the development of atherosclerosis. Graphical Abstract: A graphical abstract is available for this article.

A rare location of the glomus tumor in the abdominal aorta.

Glomus tumors are rare, mostly benign, and often superficial tumors that commonly occur on the upper and lower extremities. Whereas other locations have been described in the literature, we report the first case of glomus tumor in the abdominal aorta in a 21-year-old patient.

Synthesis and Automated Labeling of [18F]Darapladib, a Lp-PLA2 Ligand, as Potential PET Imaging Tool of Atherosclerosis.

Atherosclerosis and its associated clinical complications are major health issues in industrialized countries. Lipoprotein-associated phospholipase A2 (Lp-PLA2) was demonstrated to play an important role in atherogenesis and to be a potential risk prediction factor of plaque rupture. Darapladib is one of the most potent Lp-PLA2 inhibitors with an IC50 of 0.25 nM. Using its affinity for Lp-PLA2, we describe herein the total synthesis of darapladib radiolabeling precursor and the automated radiolabeling process for positron emission tomography (PET) imaging via an arylboronate moiety. The tracer thus obtained was tested in a mouse model of atherosclerosis (ApoE KO) and compared with the widely used [18F]fluorodeoxyglucose ([18F]FDG) PET tracer, known to label metabolically active cells. [18F]Darapladib showed a significant accumulation within mice aortic atheromatous plaques dissected out ex vivo compared to [18F]FDG. Incubation of the radiotracer with human carotid samples showed a strong accumulation within the atherosclerotic plaques and supports its potential for use in PET imaging.

Development, synthesis, and 68Ga-Labeling of a Lipophilic complexing agent for atherosclerosis PET imaging.

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Atherosclerosis accounts for 50% of deaths in western countries. This multifactorial pathology is characterized by the accumulation of lipids and inflammatory cells within the vascular wall, leading to plaque formation. We describe herein the synthesis of a PCTA-based 68Ga3+ chelator coupled to a phospholipid biovector 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which is the main constituent of the phospholipid moiety of High-Density Lipoprotein (HDL) phospholipid moiety. The resulting 68Ga-PCTA-DSPE inserted into HDL particles was compared to 18F-FDG as a PET agent to visualize atherosclerotic plaques. Our agent markedly accumulated within mouse atheromatous aortas and more interestingly in human endarterectomy carotid samples. These results support the potential use of 68Ga-PCTA-DSPE-HDL for atherosclerosis PET imaging.

Recurrent coronary syndromes in a patient with isolated very-high lipoprotein (a) and the prothrombin genetic variant rs1799963 (G20210A): a case report.

BACKGROUND: Elevated lipoprotein (a) [Lp(a)] is an under-diagnosed genetically inherited risk factor for coronary heart disease (CHD) and calcific aortic valve stenosis. Premature myocardial infarction (MI) could stem from the association between elevated Lp(a) and other non-traditional cardiovascular risk factors. CASE SUMMARY: Here, we report a male patient with extremely high Lp(a) plasma levels [610 nmol/L (244 mg/dL); normal <75 nmol/L (<30 mg/dL)] associated with the prothrombin genetic variant rs1799963 (G20210A) and no other CHD risk factor. At the age of 32, he suffered recurrent episodes of MI treated by coronary angioplasty and drug eluting stents. The patient who was initially prescribed antiplatelet therapy, beta-blockers, and statins, has subsequently been treated by lipoprotein apheresis every fortnight for 43 months. He has never experienced any recurrent episode of angina or chest pain since. DISCUSSION: The rare association between extremely elevated circulating Lp(a) levels and prothrombotic genetic variants of coagulation factors appears to be a deadly combination that can only be adequately treated by antiplatelet therapy and lipoprotein apheresis.

PCSK9: from biology to clinical applications.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial protein governing the circulating levels of low density lipoprotein-cholesterol (LDL-C), by virtue of its pivotal role in the degradation of the LDL receptor (LDLR). In the last 15 years, in vitro and in vivo studies have allowed our understanding of the physiological role of PCSK9. In the current report, we review the key studies that have established the mode of action of PCSK9, leading to the development of PCSK9 inhibitors for clinical use. Data from clinical trials investigating these therapies clearly and unambiguously demonstrate the safety and efficacy of these new drugs that have the power to dramatically reduce LDL-C and associated cardiovascular diseases.

PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate.

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivoSix nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (-28%), LDL-C (-67%), Lp(a) (-56%), apolipoprotein B100 (apoB100) (-53%), and apo(a) (-53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (-42%), but not significantly that of apoB100, compared with IgG1, respectively.In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.

Homemade proximal scalloped stent graft for thoracic endovascular aortic repair of zone 2 acute aortic syndrome.

OBJECTIVE: The aim of this study was to evaluate the outcomes of homemade proximal scalloped stent grafts for thoracic endovascular aortic repair of zone 2 acute aortic syndrome. METHODS: Between May 2015 and December 2015, 10 patients with unremitting symptoms or rupture secondary to an acute aortic syndrome involving zone 2 underwent urgent or emergency thoracic endovascular aortic repair. Among them, 8 were treated using homemade proximal scalloped stent grafts to preserve the patency of the left subclavian artery. Indications included traumatic transection (n = 3) and acute (n = 4) and subacute (n = 1) complicated type B aortic dissection. Follow-up computed tomography scans were performed at 1 week and 3 and 6 months. RESULTS: The median duration for stent graft modification was 15 minutes (range, 14-17 minutes). The technical success rate was 100%; sealing was achieved in all cases with no type I endoleaks. All left subclavian arteries were patent, although 1 case was associated with a 50% stenosis. No deaths occurred as a consequence of the aortic repair, but 1 patient died of a traumatic renal hematoma on postoperative day 5. During a mean follow-up of 7.2 ± 2 months, there were no conversions to open surgical repair, aortic ruptures, paraplegia, retrograde dissection, or other aortic complications. CONCLUSIONS: The use of the homemade proximal scalloped stent graft is both feasible and effective for left subclavian artery revascularization during thoracic endovascular aortic repair involving a spectrum of acute thoracic aortic pathology. This approach provides a rapid, reproducible method of scalloping the endograft. Durability concerns will need to be assessed in additional studies with long-term follow-up.

The significance of endoleaks in thoracic endovascular aneurysm repair.

BACKGROUND: Endoleak is one of the rare complications that occur after thoracic endovascular aneurysm repair (TEVAR). The aim of this study was to assess the incidence of endoleaks and the predictive factors for their occurrence, as well as their effect on secondary interventions after TEVAR. METHODS: Medical and radiological data of all TEVAR procedures performed between 2004 and 2008 were entered prospectively into our database and reviewed retrospectively. Primary endpoints included were the incidence and the type of endoleak, aneurysmal sac expansion, and secondary interventions. RESULTS: In all, 67 patients (18 women and 49 men; mean age, 67 ± 14 years) were treated consecutively for descending thoracic aortic aneurysms (mean diameter: 69 ± 18 mm) by TEVAR during the observed period, using 83 stent-grafts (11 Cook TX2, 31 Gore TAG, and 41 Medtronic Valiant), with a median follow-up of 27 months (range: 2-64). In 13 of 67 patients, 14 (19.4%) endoleaks were diagnosed, of which 71% (10 of 14) were type I, 29% (4 of 14) were type II, and none were type III. Ten endoleaks (71%) were diagnosed on the first postoperative computed tomographic angiography at 1 month, and the other four (29%) developed later on. Predictive factors for endoleaks on univariate analysis included age (p = 0.04), length of the proximal neck immediately after the left subclavian artery (p = 0.04), the fusiform morphology of the descending thoracic aortic aneurysms (p = 0.04), and the type of stent-graft used (p = 0.02). Eight of the 10 type I endoleaks (80%) were successfully treated by endovascular means, using proximal cuffs (n = 5) or distal extensions (n = 3). None of type II endoleaks were treated by secondary intervention. The six endoleaks treated conservatively were all associated with a significant mean increase of their aneurysmal sac (+3.2 ± 2.6 mm) during follow-up. No secondary conversion to open surgery was performed to treat an endoleak. CONCLUSIONS: On the basis of the study, it seems as if endoleaks are detected in one of the five patients treated with TEVAR during follow-up period, particularly if they are old with a proximal and fusiform aneurysm. Short- and mid-term follow-up suggest that most type I endoleaks can successfully be treated by endovascular techniques and that type II endoleaks treated conservatively require a close radiological monitoring.

[Surgical treatment of critical limb ischemia]. / Place de la chirurgie dans l'ischémie critique des membres inférieurs (ICMI).

Effective management of critical limb ischemia (CLI) requires a multidisciplinary approach. Vascular surgeons have a wide range of methods that can avoid major amputation. From January 2004 to December 2005, we treated 95 lower limbs with CLI in 81 patients. Various techniques were used to revascularize the ischemic limbs, including endovascular and conventional surgery. With aggressive treatment, 93.7% of CLI limbs were revascularized, with a peri-operative mortality rate of 2.5%. The limb salvage rate was 68% in 59 patients after a mean follow-up of 6.9 months. Failed revascularization was often due to late patient referral.