Vascular complications after percutaneous mitral valve repair and venous access closure using suture or closure device.

OBJECTIVE: The aim of this study was to assess the impact of different access-site closure strategies, suture or closure device (Proglide, Abbott Vascular), on vascular and bleeding complications after percutaneous mitral valve repair (MitraClip, Abbott Vascular). BACKGROUND: Considering the high-risk profile in patients receiving percutaneous mitral valve repair, complications related to the large 24 Fr access sheath and its relation to the closure technique have not been evaluated so far. METHODS AND RESULTS: Between 2009 and 2015, 277 consecutive high-risk patients with severe mitral valve regurgitation (MR) underwent percutaneous mitral valve repair at our institution using Z-suture (n = 150) or closure device (n = 127) to close the access-site. Duplex sonography was performed in all patients. The primary endpoint was access-site related complications according to the Valve Academic Research Consortium (VARC) criteria. Secondary outcomes were the incidence of bleeding complications and mortality. Access-site related VARC2 major and minor complications were comparable after closure with Z-suture or closure device (2,7% vs 3.1%, P = 0.81 and 15,3% vs 15.7%, P = 0.92). Three patients (2%) in the suture and four patients (3.1%) in the closure device group experienced unplanned endovascular intervention at the access site. Access-site related major bleeding was observed in 4 (2.7%) suture and 4 (3.1%) closure device treated patients (P = 0.81). No access site related mortality occurred. CONCLUSION: Both Z-suture and closure device use after percutaneous mitral valve repair are feasible and safe. However, there is no benefit of one strategy over the other according to VARC2 major and minor complications.

Molecular variants of soluble guanylyl cyclase affecting cardiovascular risk.

Soluble guanylyl cyclase (sGC) is the physiological receptor for nitric oxide (NO) and NO-releasing drugs, and is a key enzyme in several cardiovascular signaling pathways. Its activation induces the synthesis of the second messenger cGMP. cGMP regulates the activity of various downstream proteins, including cGMP-dependent protein kinase G, cGMP-dependent phosphodiesterases and cyclic nucleotide gated ion channels leading to vascular relaxation, inhibition of platelet aggregation, and modified neurotransmission. Diminished sGC function contributes to a number of disorders, including cardiovascular diseases. Knowledge of its regulation is a prerequisite for understanding the pathophysiology of deficient sGC signaling. In this review we consolidate the available information on sGC signaling, including the molecular biology and genetics of sGC transcription, translation and function, including the effect of rare variants, and present possible new targets for the development of personalized medicine in vascular diseases.

Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as ß1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.