Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Nucleotide-Binding Oligomerization Domain 2 Receptor Is Expressed in Platelets and Enhances Platelet Activation and Thrombosis
- Targeting Pathogenic Postischemic Self-Recognition by Natural IgM to Protect Against Posttransplantation Cardiac Reperfusion Injury
- Transcatheter Aortic Valve Implantation in the United Kingdom: Temporal Trends, Predictors of Outcome, and 6-Year Follow-Up: A Report From the UK Transcatheter Aortic Valve Implantation (TAVI) Registry, 2007 to 2012
- ADAMTS-7 Inhibits Re-endothelialization of Injured Arteries and Promotes Vascular Remodeling Through Cleavage of Thrombospondin-1
- Knockout of Adamts7, a Novel Coronary Artery Disease Locus in Humans, Reduces Atherosclerosis in Mice
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Nucleotide-Binding Oligomerization Domain 2 Receptor Is Expressed in Platelets and Enhances Platelet Activation and Thrombosis
Under infectious and inflammatory conditions, platelets usually become hyperactive to a variety of agonists including thrombin and collagen. This increased platelet activation contributes to the increased atherosclerosis and thrombosis risk, but its underlying mechanisms remain poorly deciphered. In this study, we show that nucleotide-binding oligomerization domain 2 (NOD2), an intracellular pattern recognition receptor critical to innate immunity, is also expressed in platelets. With the use of NOD2-specific agonist and NOD2-deficient mice, we find that NOD2 promotes platelet activation and thrombosis by activating mitogen activated-protein kinase and nitric oxide/soluble guanylyl cyclase/cGMP/protein kinase G signal pathway downstream of receptor-interacting protein 2. NOD2 also triggers platelet interleukin-1β maturation via caspase-1 activation. These data demonstrate a nonimmune activity of NOD2 that bridges immunity and hemostasis/thrombosis in platelets. This crosstalk sheds novel insights into the mechanism accounting for the increased platelet reactivity and thrombotic risk in infectious and inflammatory diseases. Blocking NOD2 and its downstream pathway could potentially reduce and prevent arterial thrombosis, especially in infectious and inflammatory conditions where hyperactive platelets are known to respond poorly to current antiplatelet drugs. See p 1160.
Targeting Pathogenic Postischemic Self-Recognition by Natural IgM to Protect Against Posttransplantation Cardiac Reperfusion Injury
There is an inflammatory reaction on reperfusion of a cardiac graft, the severity of which is linked to the development of primary graft failure, as well as acute and chronic rejection. Amelioration of these early injurious events will likely improve graft outcomes, but there is currently no approved therapeutic for treating ischemia/reperfusion injury. The mechanisms leading to ischemia/reperfusion injury are complex, but experimental and clinical studies indicate an important role for complement in driving graft injury. It has been shown previously that after warm murine focal myocardial ischemia, complement activation and injury are initiated by the binding of circulating natural IgM. Here, we demonstrate that the same is true in a transplantation setting that includes organ storage and cold ischemia, as well as a global ischemic insult. We identify neoepitopes (danger-associated molecular patterns) that become exposed within cardiac grafts, and we show that these neoepitopes bind natural self-reactive pathogenic IgM antibodies that activate complement. On the basis of neoepitope identification, we constructed a single-chain antibody (scFv) from variable chains derived from an anti–annexin IV IgM monoclonal antibody. We also prepared a fusion protein by linking this scFv to Crry, an inhibitor of complement C3 activation. In a cardiac allograft transplantation model in which recipients contain a full natural antibody repertoire, scFv-Crry inhibited graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Data indicate that a similar neoepitope recognition system occurs in humans; this strategy of targeted complement inhibition has several potential advantages over currently available approaches to complement inhibition. See p 1171.
Transcatheter Aortic Valve Implantation in the United Kingdom: Temporal Trends, Predictors of Outcome, and 6-Year Follow-Up: A Report From the UK Transcatheter Aortic Valve Implantation (TAVI) Registry, 2007 to 2012
We assessed trends in the performance of transcatheter aortic valve implantation in the United Kingdom by assessing every procedure from the first case in 2007 to the end of 2012. A total of 3980 transcatheter aortic valve implantation procedures were performed. In successive years, there was an increase in the frequency of impaired left ventricular function, but there was no change in other measured risk factors, including the composite of Logistic EuroSCORE. One-year survival was 81.7%, falling to 37.3% at 6 years. Overall 30-day mortality was 6.3%; it was highest in the first cohort (2007–2008), after which there were no further significant changes. However, longer-term survival was better in later cohorts despite no change in measured risk factors. There was a reduction in length of stay such that by 2012 discharge by the fifth day after transcatheter aortic valve implantation was possible in more than one quarter of these frail elderly patients. Early mortality was predicted only by a very high logistic EuroSCORE (≥40). During long-term follow-up, intrinsic patient factors dominated the predictors of mortality and included preprocedural atrial fibrillation, chronic obstructive pulmonary disease, creatinine >200 μmol/L, diabetes mellitus, and coronary artery disease. Periprocedural stroke was infrequent but had a devastating effect on long-term mortality (hazard ratio=3.00; P<0.0001). A focus on intrinsic patient factors may improve the selection of candidates for transcatheter aortic valve implantation. See p 1181.
ADAMTS-7 Inhibits Re-endothelialization of Injured Arteries and Promotes Vascular Remodeling Through Cleavage of Thrombospondin-1
Besides vascular smooth muscle cell proliferation and migration, the rate of luminal endothelial recovery is also a critical modulator of neointima formation after vascular injury. Here, we show that ADAMTS-7 may affect both processes. ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be genomewide significantly associated with human coronary artery disease. We have previously shown that ADAMTS-7 can promote vascular smooth muscle cell migration and neointima formation after artery injury via the degradation of cartilage oligomeric matrix protein. In this study, we show that Adamts7–/– mice exhibited greater re-endothelialization and were completely resistant to neointima formation on injury. ADAMTS-7 inhibition may serve as new strategy to promote endothelial recovery, and, simultaneously, to inhibit vascular smooth muscle cells activation for the effective prevention and treatment of atherosclerosis and postinjury restenosis. Furthermore, the identification of thrombospondin-1 as an ADAMTS-7 target on one hand, and as a modulator of vascular remodeling on the other, might lead to the elucidation of further druggable downstream targets. See p 1191.
Knockout of Adamts7, a Novel Coronary Artery Disease Locus in Humans, Reduces Atherosclerosis in Mice
Through genome-wide association studies, we recently identified the metalloproteinase ADAMTS7 as a locus for coronary artery disease. Other than low-density lipoprotein cholesterol–related genes, few of the >40 validated loci for coronary artery disease identified through genome-wide association studies have known mechanisms of action in atherosclerotic heart diseases. Indeed, for many loci, the gene(s) at the locus is (are) unknown or uncertain. ADAMTS7 is relatively unique as a genome-wide association study locus in having a single strong candidate gene at the locus, plausible biological mechanisms, and potential for therapeutic translation. Here, we present the first report of the Adamts7-deficient (Adamts7−/−) mouse, which, once crossed onto a hyperlipidemic background, displays reduced atherosclerotic lesion formation after prolonged feeding of a Western diet. We also show that Adamts7 expression is induced in response to both mechanical wire injury and hyperlipidemia and that primary smooth muscle cells from Adamts7−/− mice display reduced migration when stimulated by tumor necrosis factor-α. Our findings are the first in vivo data to provide directionality to the genetic association between ADAMTS7 and coronary artery disease in humans. These data clearly demonstrate that ADAMTS7 is proatherogenic, likely through modulation of vascular smooth muscle cell phenotype in response to injury and inflammation. Importantly, these data provide early promise that inhibition of ADAMTS7, which is tractable given its narrow substrate specificity, might represent a novel mechanism for prevention and treatment of clinical cardiovascular diseases. Thus, it is one of the very few novel nonlipid findings from genome-wide association studies of coronary artery disease that have the potential to be a bona fide novel therapeutic target. See p 1202.
- © 2015 American Heart Association, Inc.
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