In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.

Endothelial glycolysis plays a critical role in the regulation of angiogenesis. We investigated the role of Sirtuin 3 (SIRT3) on endothelial cell (EC) glycolytic metabolism, angiogenesis, and diastolic function. Our aim was to test the hypothesis that loss of SIRT3 in ECs impairs endothelial glycolytic metabolism and angiogenesis and contributes to myocardial capillary rarefaction and the development of diastolic dysfunction. Using SIRT3 deficient ECs, SIRT3 was found to regulate a metabolic switch between mitochondrial respiration and glycolysis. SIRT3 knockout (KO)-ECs exhibited higher mitochondrial respiration and reactive oxygen species (ROS) formation. SIRT3 knockout (KO)-ECs exhibited a reduction in the expression of glycolytic enzyme, PFKFB3, and a fall in glycolysis and angiogenesis. Blockade of PFKFB3 reduced glycolysis and downregulated expression of VEGF and Angiopoietin-1 (Ang-1) in ECs. Deletion of SIRT3 in ECs also impaired hypoxia-induced expression of HIF-2α, VEGF, and Ang-1, as well as reduced angiogenesis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited a myocardial capillary rarefaction together with a reduced coronary flow reserve (CFR) and diastolic dysfunction. Histologic study further demonstrated that knockout of SIRT3 in ECs significantly increased perivascular fibrosis in the coronary artery. These results implicate a role of SIRT3 in modulating endothelial function and cardiac function. Ablation of SIRT3 leads to impairment of EC glycolytic metabolism and angiogenic signaling, which may contribute to coronary microvascular rarefaction and diastolic dysfunction in SIRT3 ECKO mice.

Sickle cell disease (SCD) nephropathy and lower estimated glomerular filtration rate (eGFR) are risk factors for early mortality. Furthermore, rate of eGFR decline predicts progression to end-stage renal disease in many clinical settings. However, factors predicting renal function decline in SCD are poorly documented. Using clinical, laboratory, genetic, and metabolomic data, we evaluated predictors of renal function decline in a longitudinal cohort of 288 adults (mean age 33.0 years). In 193 subjects with 5-year follow-up data, mean rate of eGFR decline was 2.35 mL/min/1.73 m /year, nearly twice that of African American adults overall. Hyperfiltration was prevalent at baseline (61.1%), and 36.8% of subjects experienced rapid eGFR decline (≥3 mL/min/1.73 m /year). Severe Hb genotype; proteinuria; higher platelet and reticulocyte counts, and systolic BP; and lower Hb level and BMI were associated with rapid decline. A risk scoring system was created using these 7 variables and was highly predictive of rapid eGFR decline, with odds of rapid decline increasing 1.635-fold for every point increment (P < 0.0001). Rapid eGFR decline was also associated with higher organ system severity score and peak creatinine. Additionally, two metabolites (asymmetric dimethylarginine and quinolinic acid) were associated with rapid decline. Further investigation into longitudinal SCD nephropathy (SCDN) trajectory, early markers of SCDN, and tools for risk stratification should inform interventional studies targeted to slowing GFR decline and improving SCD outcomes.

Accumulating evidence demonstrates that hypoxia‐inducible factor (HIF‐α) hydroxylase system has a critical role in vascular remodelling. Using an endothelial‐specific prolyl hydroxylase domain protein‐2 (PHD2) knockout (PHD2ECKO) mouse model, this study investigates the regulatory role of endothelial HIF‐α hydroxylase system in the development of renal fibrosis. Knockout of PHD2 in EC up‐regulated the expression of HIF‐1α and HIF‐2α, resulting in a significant decline of renal function as evidenced by elevated levels of serum creatinine. Deletion of PHD2 increased the expression of Notch3 and transforming growth factor (TGF‐β1) in EC, thus further causing glomerular arteriolar remodelling with an increased pericyte and pericyte coverage. This was accompanied by a significant elevation of renal resistive index (RI). Moreover, knockout of PHD2 in EC up‐regulated the expression of fibroblast‐specific protein‐1 (FSP‐1) and increased interstitial fibrosis in the kidney. These alterations were strongly associated with up‐regulation of Notch3 and TGF‐β1. We concluded that the expression of PHD2 in endothelial cells plays a critical role in renal fibrosis and vascular remodelling in adult mice. Furthermore, these changes were strongly associated with up‐regulation of Notch3/TGF‐β1 signalling and excessive pericyte coverage.

Rationale Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development. Objective This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI. Approach and results Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2+/Sca1+ and NG2+/c-kit+ progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2 weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b+ macrophage infiltration into ischemic areas compared to that of WT mice. Conclusion Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the preexisting coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation.

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Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

BACKGROUND: As life expectancy in sickle cell disease (SCD) has continued to increase, chronic diseases are playing a bigger role in morbidity and mortality in this population. SCD nephropathy is a known risk factor for early mortality, and risk of death increases with worsening glomerular filtration rate (GFR) (Elmariah et al. 2014; Platt et al. 1994). Glomerular ischemia, hyperfiltration, and hyposthenuria characterize the renal dysfunction found in SCD, but the natural history of and risk factors contributing to progression of disease remain unclear. Potential markers of SCD nephropathy, such as anemia severity, hemolytic rate, blood pressure (BP), and albuminuria, have been studied with varied conclusions (Aoki and Saad 1995; Asnani et al. 2016; Elmariah et al. 2014; Falk et al. 1992; Guasch et al. 2006; Gurkan et al. 2010). Our recent work also identified two variant alleles (“G1” and “G2”) of the APOL1 gene as risk factors for SCD nephropathy (Ashley-Koch et al. 2011). We sought to evaluate clinical, laboratory, and genetic predictors of SCD nephropathy progression in a longitudinal SCD cohort. METHODS: We performed a chart review of 280 adults (age ≥18 at enrollment) with SCD followed regularly at the Duke University Medical Center and enrolled in a previously well-described study (Elmariah et al. 2014). All outpatient laboratory data were collected using the data extraction tool DEDUCE (Duke Enterprise Data Unified Content Explorer), and descriptive data were collected at time of enrollment and at most recent outpatient follow-up. APOL1 variants were genotyped as previously described (Ashley-Koch et al. 2011). Estimated GFR was calculated using both the extended MDRD and the CKD-EPI equations (Levey et al. 1999; Levey et al. 2009). CKD and hyperfiltration were defined as GFR <60 and >130 mL/min/1.73 m2, respectively. Statistical analysis was performed using SAS (SAS Systems, Cary, NC). RESULTS: Mean age at enrollment was 33.3 years, and mean baseline GFR was 148.6 mL/min/1.73 m2 by MDRD and 127 mL/min/1.73 m2 by CKD-EPI (see Table 1 for baseline characteristics). Results from the two equations correlated well for GFRs in the low to normal range but diverged for GFRs over ~150 mL/min/1.73 m2, with MDRD producing a wider range (Fig. 1). Given the high prevalence of hyperfiltration in our cohort, we chose to perform further analyses using CKD-EPI. Baseline GFR was associated with baseline proteinuria (p<0.0001), hemoglobinuria (p<0.0001), Hb level (p=0.03), platelet count (p<0.0001), reticulocyte count (p=0.03), bilirubin (p<0.0001), systolic BP (p=0.0003), diastolic BP (p<0.0001), and the APOL1 G1 allele (p=0.02). To characterize the pattern of progression of SCD nephropathy, we then identified 183 subjects with at least 5 years of follow-up and ≥3 outpatient GFR measurements in order to calculate a rate of GFR decline. There were no statistically significant differences in baseline characteristics for the two cohorts (Table 1). The mean rate of GFR decline was 2.5 ± 5.6 mL/min/1.73 m2 per year, higher than the 1.27 mL/min/1.73 m2 estimated annual GFR decline in African Americans in the general population (Young et al. 2016). We then defined a composite outcome of SCD nephropathy as either rapid rate of GFR decline (>3 mL/min/1.73 m2 per year, (Peralta et al. 2013; Young et al. 2016)), or incident CKD during the follow-up period. Seventy-three subjects (40%) developed nephropathy as thus defined. Using multivariable logistic regression modeling, with baseline GFR as a covariate, we found that lower baseline Hb (p=0.008), baseline proteinuria (p=0.01), higher reticulocyte count (p=0.03), and higher LDH (p=0.02) were all positive predictors of nephropathy. Baseline hemoglobinuria, white blood cell count, platelet count, bilirubin, BP, BMI, and APOL1 variants did not predict nephropathy. Subjects with hyperfiltration physiology at baseline also did not have a higher incidence of nephropathy over 5 years of follow up. DISCUSSION: Our results highlight the rapid rate of GFR decline and the high prevalence of hyperfiltration in adults with SCD, while not showing a correlation between the two. Proteinuria and markers of a higher hemolytic rate, among other measures, were most predictive of a rapid GFR decline. Additional investigation into the longitudinal trajectory of SCD nephropathy and potential interventions targeted to slowing the rate of GFR decline may improve outcomes in SCD. Disclosures No relevant conflicts of interest to declare.