Aortic valve calcification in the era of non-coding RNAs: The revolution to come in aortic stenosis management?

Aortic valve stenosis remains the most frequent structural heart disease, especially in the elderly. During the last decade, we noticed an important consideration and a huge number of publications related to the medical and surgical treatment of this disease. However, the molecular aspect of this degenerative issue has also been more widely studied recently. As evidenced in oncologic but also cardiac research fields, the emergence of microRNAs in the molecular screening and follow-up makes them potential biomarkers in the future, for the diagnosis, follow-up and treatment of aortic stenosis. Herein, we present a review on the implication of microRNAs in the aortic valve disease management. After listing and describing the main miRNAs of interest in the field, we provide an outline to develop miRNAs as innovative biomarkers and innovative therapeutic strategies, and describe a groundbreaking pre-clinical study using inhibitors of miR-34a in a pre-clinical model of aortic valve stenosis.

Inhibition of miR-223 Expression Using a Sponge Strategy Decreases Restenosis in Rat Injured Carotids.

OBJECTIVE: Restenosis is a frequent complication of angioplasty. It consists of a neointimal hyperplasia resulting from progression and migration of vascular smooth muscle cells (VSMC) into the vessel lumen. microRNA miR-223 has recently been shown to be involved in cardiovascular diseases including atherosclerosis, vascular calcification and arterial thrombosis. In this study, our aim was to assess the impact of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. METHODS: The over and down-expression of miR-223 was induced by adenoviral vectors, containing either a pre-miR-223 sequence allowing artificial miR-223 expression or a sponge sequence, trapping the native microRNA, respectively. Restenosis was quantified on stained rat carotid sections. RESULTS: In vitro, three mRNA (Myocyte Enhancer Factor 2C (MEF2C), Ras homolog gene family, member B (RhoB) and Nuclear factor 1 A-type (NFIA)) reported as miR-223 direct targets and known to be implicated in VSMC differentiation and contractility were studied by RT-qPCR. Our findings showed that down-expression of miR-223 significantly reduced neointimal hyperplasia by 44% in carotids, and was associated with a 2-3-fold overexpression of MEF2C, RhoB and NFIA in a murine monocyte macrophage cell line, RAW 264.7 cells. CONCLUSION: Down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty.

miR-92a: A Novel Potential Biomarker of Rapid Aortic Valve Calcification.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the tissular expression of microRNAs (miRs) in bicuspid and tricuspid valves, and to evaluate their use as potential novel biomarkers of aortic valve calcification in bicuspid valves. METHODS: A prospective single-center observational study was conducted on stenotic bicuspid and tricuspid human aortic valves. According to their potential role in valve vascular and valvular calcification, a decision was taken to include miR- 92a, miR-141, and miR-223 in this analysis. A real-time quantitative polymerase chain reaction was used to measure the expression of each miR, using U6 and Cel-miR-39 as endogenous and exogenous gene controls, respectively. RESULTS: Among a total of 47 human calcified aortic valves collected, 30 (63.8%) were tricuspid valves. The mean preoperative transvalvular gradient was 50.8 mmHg (range: 37-89 mmHg), with no significant difference between bicuspid and tricuspid valves (50 mmHg versus 51.2 mmHg; p = 0.729). The mean aortic valve area was 0.79 cm2 (range: 0.33-1.3 cm2), again with no significant difference between the two groups (p = 0.34). The level of miR-92a expression was twofold higher in bicuspid valves compared to tricuspid valves (0.38 versus 0.17; p = 0.016), but no significant difference in miR-141 and miR-223 expression was observed between the two groups (p = 0.68 and p = 0.35, respectively). A positive correlation was observed between miR-92a expression and mean preoperative transvalvular gradient (r = 0.3257, p = 0.04). CONCLUSIONS: miR-92a is overexpressed in calcified bicuspid aortic valves, and may serve as a potential biomarker of rapid aortic valve calcification. Further studies based on these results may be designed to correlate the relative expression of miR-92a in the serum with its tissular expression in AS.

The Involvement of miRNA in Carotid-Related Stroke.

Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. Stroke is associated with a marked disability burden and has a major economic impact; this is especially true for carotid artery stroke. Major advances in primary and secondary prevention during the last few decades have helped to tackle this public health problem. However, better knowledge of the physiopathology of stroke and its underlying genetic mechanisms is needed to improve diagnosis and therapy. miRNAs are an important, recently identified class of post-transcriptional regulators of gene expression and are known to be involved in cerebrovascular disease. These endogenous, small, noncoding RNAs may have applications as noninvasive biomarkers and therapeutic tools in practice. Here, we review the involvement of several miRNAs in cell-based and whole-animal models of stroke, with a focus on human miRNA profiling studies of carotid artery stroke. Lastly, we describe the miRNAs' potential role as a biomarker of stroke.

Iliofemoral endarterectomy associated with systematic iliac stent grafting for the treatment of severe iliofemoral occlusive disease.

OBJECTIVE: Iliofemoral endarterectomy with external iliac artery (EIA) stent grafting can be an alternative to traditional open surgery in patients with severe iliac occlusive disease extending to the common femoral artery. We report the midterm outcomes of this approach. METHODS: Between 2009 and 2015, 108 patients (76% male; median age, 63 years) underwent a total of 127 iliofemoral endarterectomies combined with EIA stent grafting. Indications were claudication in 60%, rest pain in 20%, ulceration in 15%, and acute ischemia in 5%. Lesions exclusively involved only the EIA segment in 40% of cases, with occlusion in 28%. Lesions involved both the EIA and common iliac artery segments in 49% of cases, with 19% of common iliac artery occlusions and 24% of EIA occlusions. Iliac lesions extended into the aortic segment in 11% of cases. Iliofemoral endarterectomy was performed by eversion whenever possible. Deployment of the EIA stent graft systematically incorporated the EIA segment and the proximal end of the endarterectomy. Self-expanding covered stents were calibrated to the diameter of the endarterectomized EIA. RESULTS: The procedure was technically successful in 100% of patients. Median diameter of covered stents was 8 mm (range, 6-10 mm). No intraoperative arterial rupture or dissection was observed. Early reoperations (3%) were performed for bleeding, infection, or thrombosis. Median length of stay was 5 days. No 30-day mortality was observed. Median follow-up was 30 months (range, 0-6 years), and overall mortality was 13% (due to cancer in half of the cases). Repeated angioplasty was performed in three (2%) cases, and a subsequent open procedure on the iliofemoral segment was performed in seven (5%) cases. At 2 years, primary patency rate of the treated segment was 91%. The 2-year primary assisted patency and secondary patency rates were 94% and 98%, respectively. Five-year primary, primary assisted, and secondary patency rates were 87%, 92%, and 98%, respectively. CONCLUSIONS: Combined iliofemoral endarterectomy and covered stenting of the EIA for treatment of severe occlusive lesions provided acceptable midterm results, probably because of the gain of diameter provided by covered stents. This technique avoids complications due to an aortic or iliac surgical approach and clamping as well as complications related to the presence of a prosthetic implant in an intra-abdominal position.

microRNAs in the pathophysiology of CKD-MBD: Biomarkers and innovative drugs.

microRNAs comprise a novel class of endogenous small non-coding RNAs that have been shown to be implicated in both vascular damage and bone pathophysiology. Chronic kidney disease-mineral bone disorder (CKD-MBD) is characterized by vessel and bone damage secondary to progressive loss of kidney function. In this review, we will describe how several microRNAs have been implicated, in recent years, in cellular and animal models of CKD-MBD, and have been very recently shown to be deregulated in patients with CKD. Particular emphasis has been placed on the endothelial-specific miR-126, a potential biomarker of endothelial dysfunction, and miR-155 and miR-223, which play a role in both vascular smooth muscle cells and osteoclasts, with an impact on the vascular calcification and osteoporosis process. Finally, as these microRNAs may constitute useful targets to prevent or treat complications of CKD-MBD, we will discuss their potential as innovative drugs, describe how they could be delivered in a timely and specific way to vessels and bone by using the most recent techniques such as nanotechnology, viral vectors or CRISPR gene targeting.

Type II endoleak after endoluminal repair of thoracic aortic aneurysm associated with native coarctation.

Aneurysm formation and recurrent coarctation are common complications of coarctation repair, and various types of treatment have been described. Native aortic coarctation during adult life is rarer and can be responsible for severe complications. We report an original case of thoracic aortic aneurysm associated with native coarctation successfully treated by a hybrid approach, comprising retrograde implantation of a thoracic stent graft and carotid-axillary bypass graft. A large intercostal collateral was embolized with coils.

Primary Open Stenting to Simplify Distal Anastomosis on Heavily Calcified Artery: The POSE Technique.

Despite improvements in surgical techniques, performing distal anastomosis on a heavily calcified artery (HCA) remains technically challenging. Clamping lesions and arterial wall trauma while suturing can lead to immediate or delayed arterial dissection and thrombosis. These issues are generally overcome by performing an extensive search for supple arterial zones, using sutureless techniques with covered stent-grafts and/or stenting the anastomosis under fluoroscopic guidance after unclamping. We describe a technique intended to simplify open surgical procedures on HCA. It consists of primary open stenting followed by localized endarterectomy (namely, the primary open stenting followed by localized endarterectomy [POSE] technique) to secure a distal anastomosis on an HCA. So far, we have successfully used the POSE technique in 24 patients but the durability of the technique remains to be determined.

Treatment of sac expansion after endovascular aneurysm repair with obliterating endoaneurysmorrhaphy and stent graft preservation.

BACKGROUND: Persistent type II endoleaks (T2Ls) with sac enlargement after endovascular abdominal aortic aneurysm repair are still of concern in view of the potential for rupture. Current treatments (embolization and stent graft [SG] explantation) are associated with lack of efficacy or high perioperative morbidity and mortality. This study evaluated an alternative technique that combines sacotomy, ligation of patent back-bleeding vessels, and SG preservation for T2L or unspecified endoleak repair. METHODS: This multicenter study in France included 28 patients (27 men; median age, 78 years). Twenty-one patients (75%) had a bifurcated SG (including 3 fenestrated SGs) and seven (25%) had an aortouni-iliac SG (2 for ruptured aneurysm). Unsuccessful embolization had been performed in 10 patients (36%). Four patients (14%) presented sac enlargement with no endoleak visible on computed tomography. The origin of the endoleak remained unspecified in three patients 3 (11%). The median diameter of the aneurysmal sac was 78 mm (vs 55 mm at the time of endovascular abdominal aortic aneurysm repair) after a median follow-up of 24 months. RESULTS: A transperitoneal approach was used in 21 patients (75%) and a retroperitoneal approach was used in seven (25%). A guidewire was placed in the supraceliac aorta in 14 patients, and an occlusion balloon was temporarily inflated in six. Aortic cross-clamping was performed in five patients. T2Ls were identified in 26 patients, and associated with a distal type I endoleak in 1 patient, a type III endoleak in 3, and a type IV endoleak in 1. Two patients presented with endotension. All the endoleaks were treated successfully, with a mean operating time of 120 minutes and a mean blood loss of 450 mL. One SG was explanted 12 days after the procedure because of early infection. One patient died during SG explantation for an aortoduodenal fistula 26 months after the endoaneurysmorrhaphy. During a median follow-up of 24 months, the control computed tomography scan showed shrinkage of the aneurysmal sac with stable diameters in all patients. No missed T2Ls, no recurrence of T2L, and no SG migration or disjunction was observed. CONCLUSIONS: Obliterating endoaneurysmorrhaphy with SG preservation can be considered as an alternative to SG removal in cases of persistent T2L responsible for aneurysmal sac enlargement after embolization failure. By avoiding extensive dissection for surgical aortic cross-clamping, minimizing hemodynamic changes, and reducing blood loss and operating time, this procedure can be performed even in patients initially considered unfit for surgery.

MicroRNA deregulation in symptomatic carotid plaque.

OBJECTIVE: Embolization of carotid stenotic plaques is the direct cause of stroke in nearly 20% of cases. Genetic mechanisms and especially the roles played by microRNAs in the regulation of plaque destabilization and rupture are mostly unknown. The aim of this pilot study was to compare the expression of seven microRNAs allegedly involved in plaque growth and instability (miR-100, 125a, 127, 133a, 145, 155, and 221), between symptomatic and asymptomatic human carotid plaques. METHODS: Thirty patients undergoing carotid endarterectomy in our department were prospectively included. Carotid plaques were subdivided into symptomatic (n = 15) and asymptomatic (n = 15) according to the presence or absence of stroke. After isolation of total RNA from atherosclerotic plaques, microRNAs were quantified by real-time polymerase chain reaction. RESULTS: The two groups of patients were comparable in terms of age, gender, risk factors for cerebral ischemia, medication, and stenosis severity. All seven microRNAs were quantified in extracted carotid plaques. miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 were significantly overexpressed in symptomatic vs asymptomatic plaques. miR-125a expression was significantly inversely correlated with the circulating level of low-density lipoprotein cholesterol in the symptomatic group. CONCLUSIONS: This pilot study evaluated the expression of seven selected miRNAs in human carotid plaques from a small group of patients and suggested a potential regulatory role for these miRNAs in evolution of the plaque towards growth, instability and rupture. Studies based on larger sample sizes are required to determine the potential use of miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 as biomarkers or therapeutic targets for stroke.

Superficial femoral artery transposition repair for traumatic popliteal rupture.

Closed dislocation of the knee with complete popliteal rupture is an uncommon injury. It requires prompt recognition and treatment to prevent limb loss. We describe a case of acute ischemia caused by complete knee dislocation with rupture of the popliteal artery that was successfully repaired with superficial femoral artery transposition. To the best of our knowledge, this is the first reported clinical experience of the use of an arterial autograft for revascularization of traumatic popliteal artery rupture.