Extracellular Myocardial Volume in Patients With Aortic Stenosis

BACKGROUND: Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis. OBJECTIVES: This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes. METHODS: Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery-based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters. RESULTS: Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013). CONCLUSIONS: In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality

Use of Direct‐Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Significant Tricuspid Regurgitation

Background There are limited data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation with significant tricuspid regurgitation (TR), which can lead to hepatic dysfunction and intestinal malabsorption. We aimed to compare the efficacy and safety of DOACs and warfarin for patients with atrial fibrillation with significant (moderate to severe) TR. Methods and Results A total of 1215 patients with significant TR and atrial fibrillation who were treated with warfarin (N=491) or DOACs (N=724) were retrospectively analyzed. The primary outcomes were ischemic stroke, systemic embolic events, and hospitalization for major bleeding. The secondary outcomes were intracranial hemorrhage, hospitalization for gastrointestinal bleeding, all‐cause mortality, and a composite outcome. The median follow‐up duration was 2.4 years. In the inverse probability treatment weighting–adjusted cohort, DOACs and warfarin had a similar risk for ischemic stroke and systemic embolic events (adjusted hazard ratio [aHR], 0.95 [95% CI, 0.67–1.36]; P=0.79) and major bleeding (aHR, 0.78 [95% CI, 0.57–1.06]; P=0.11). For the secondary outcomes, relative to warfarin, DOACs had a lower risk of intracranial hemorrhage and the composite outcome, and a comparable risk for gastrointestinal bleeding and all‐cause mortality. In the subgroup analysis, the effects of DOACs on ischemic stroke and systemic embolic events were comparable to the effects of warfarin, even in patients with inferior vena cava plethora (increased right atrial pressure) or severe TR. Conclusions In this study, relative to warfarin, DOACs demonstrated comparable efficacy for ischemic stroke and systemic embolic events and major bleeding, with a lower intracranial hemorrhage risk in patients with significant TR and atrial fibrillation, indicating their effectiveness and safety

Agonist Antibody Converts Stem Cells into Migrating Brown Adipocyte-Like Cells in Heart

We present data showing that Iodotyrosine Deiodinase (IYD) is a dual-function enzyme acting as a catalyst in metabolism and a receptor for cooperative stem cell differentiation. IYD is present both in thyroid cells where it is critical for scavenging iodine from halogenated by-products of thyroid hormone production and on hematopoietic stem cells. To close the cooperative loop, the mono- and di-Iodotyrosine (MIT and DIT) substrates of IYD in the thyroid are also agonists for IYD now acting as a receptor on bone marrow stem cells. While studying intracellular combinatorial antibody libraries, we discovered an agonist antibody, H3 Ab, of which the target is the enzyme IYD. When agonized by H3 Ab, IYD expressed on stem cells induces differentiation of the cells into brown adipocyte-like cells, which selectively migrate to mouse heart tissue. H3 Ab also binds to IYD expressed on human myocardium. Thus, one has a single enzyme acting in different ways on different cells for the cooperative purpose of enhancing thermogenesis or of regenerating damaged heart tissue

Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p &lt; 0.05), while valsartan did not (471.2 ± 8.9 µL; p &gt; 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p &lt; 0.05). Transforming growth factor-β and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT

Adipokine Resistin Is a Key Player to Modulate Monocytes, Endothelial Cells, and Smooth Muscle Cells, Leading to Progression of Atherosclerosis in Rabbit Carotid Artery

Objectives We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms. Background Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified. Methods We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed. Results Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Periadventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 x vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo. Conclusions Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis. (J Am Coll Cardiol 2011;57:99-109) (C) 2011 by the American College of Cardiology FoundationDong B, 2008, ARTERIOSCL THROM VAS, V28, P1270, DOI 10.1161/ATVBAHA.108.164715Rader DJ, 2008, NATURE, V451, P904, DOI 10.1038/nature06796Maiellaro K, 2007, CARDIOVASC RES, V75, P640, DOI 10.1016/j.cardiores.2007.06.023Lubos E, 2007, ATHEROSCLEROSIS, V193, P121, DOI 10.1016/j.atherosclerosis.2006.05.039Xu WB, 2006, BIOCHEM BIOPH RES CO, V351, P376, DOI 10.1016/j.bbrc.2006.10.051Mu H, 2006, CARDIOVASC RES, V70, P146, DOI 10.1016/j.cardiores.2006.01.015Jung HS, 2006, CARDIOVASC RES, V69, P76, DOI 10.1016/j.cardiores.2005.09.015Yu YH, 2005, CIRC RES, V96, P1042, DOI 10.1161/01.RES.0000165803.47776.38Bokarewa M, 2005, J IMMUNOL, V174, P5789Hansson GK, 2005, NEW ENGL J MED, V352, P1685Reilly MP, 2005, CIRCULATION, V111, P932, DOI 10.1161/01.CIR.0000155620.10387.43Calabro P, 2004, CIRCULATION, V110, P3335, DOI 10.1161/01.CIR.0000147825.97879.E7Patel SD, 2004, SCIENCE, V304, P1154Degawa-Yamauchi M, 2003, J CLIN ENDOCR METAB, V88, P5452, DOI 10.1210/jc.2002-021808Lee JH, 2003, J CLIN ENDOCR METAB, V88, P4848, DOI 10.1210/jc.2003-030519Verma S, 2003, CIRCULATION, V108, P736, DOI 10.1161/01.CIR.0000084503.91330.49Fain JN, 2003, BIOCHEM BIOPH RES CO, V300, P674, DOI 10.1016/S0006-291X(02)02864-4Okamoto Y, 2002, CIRCULATION, V106, P2767, DOI 10.1161/01.CIR.0000042707.50032.19Sartore S, 2001, CIRC RES, V89, P1111, DOI 10.1161/hh2401.100844Steppan CM, 2001, NATURE, V409, P307, DOI 10.1038/35053000Steppan CM, 2001, P NATL ACAD SCI USA, V98, P5022001, JAMA, V285, P2486Festa A, 2000, CIRCULATION, V102, P42Doran AC, 2008, ARTERIOSCL THROM VAS, V28, P812, DOI 10.1161/ATVBAHA.107.159327Ross R, 1999, NEW ENGL J MED, V340, P115Friedman JM, 1998, NATURE, V395, P763Kolodgie FD, 1996, ARTERIOSCL THROM VAS, V16, P1454MOLOSSI S, 1995, J CLIN INVEST, V95, P2601MAY MJ, 1993, J CELL SCI, V106, P109HOTAMISLIGIL GS, 1993, SCIENCE, V259, P87