Association of hyponatremia and outcomes in pulmonary hypertension.

BACKGROUND: Hyponatremia is known to be an important marker and prognosticator in left-sided heart failure. However, less is known about the significance of hyponatremia in pulmonary hypertension, particularly in the absence of left ventricular dysfunction. METHODS AND RESULTS: We identified 635 patients with pulmonary hypertension and preserved ejection fraction who were normonatremic (n = 493) or hyponatremic (n = 142). End points were mortality and readmission at 1 year. Overall, 27% of all of the patients died within 1 year. Hyponatremia was significantly associated with an increased rate of 1-year mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.27-2.61; P = .001) and trended toward an association with the composite of mortality and readmission (HR 1.25, 95% CI 0.97-1.62; P = .08). Additionally, the severity of hyponatremia was directly related to the rate of 1-year mortality (P < .001). CONCLUSIONS: Hyponatremia is an indicator of poor prognosis in patients with echocardiographic evidence of pulmonary hypertension.

Association between off-label use of drug-eluting stents and subsequent stent thrombosis: a case-control analysis.

OBJECTIVES: We sought to examine the association between off-label drug-eluting stent (DES) use and stent thrombosis (ST) in unselected patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: DES are frequently used in clinical and angiographic scenarios not initially tested and approved by the FDA (off-label use) resulting in lingering concerns about the higher risk of ST in these situations. METHODS: Out of 5,383 patients undergoing PCI at a single center between 2004 and 2006, 380 had death or myocardial infarction within 1 year. After adjudication using Academic Research Consortium definitions, patients with possible, probable or definite ST were termed cases. Cases were matched with controls, free of ST at 1 year, using geographic and temporal similarities. Off-label usage was defined using manufacturer's instructions and other standard criteria. RESULTS: Overall, the proportion of off-label usage was higher among cases than controls (58% vs. 43%; p = 0.002) and both cases with definite/probable ST (77% vs. 59%; p = 0.08) and possible ST (54% vs. 37%; p = 0.002) had a higher off-label use than respective controls. Off-label use among cases with ST remained higher within the following subgroups: off-label by manufacturer's criteria (36% vs. 27%; p = 0.05), left main stent implantation (2% vs. 0%; p = 0.01), ostial (12% vs. 6%; p = 0.04) and bifurcated lesions (26% vs. 9%; p < 0.001). In multivariate analysis, being a case independently predicted off-label use (OR 1.68, 95% CI: 1.10-2.57; p = 0.02). CONCLUSIONS: In this case-control analysis, off-label use of DES was independently associated with ST within 1 year, although the increased risk was moderate.

Involvement of cathepsin D in chemotherapy-induced cytochrome c release, caspase activation, and cell death.

Treatment of cells with chemotherapy drugs activates the intrinsic mitochondrial pathway of apoptosis and the caspase protease cascade. Recently, the lysosomal protease cathepsin D has been implicated in apoptosis caused by oxidative stress, inhibition of protein kinase C, and stimulation of the TNFR1 and Fas death receptors. However, the role of cathepsin D in chemotherapy-induced cell death has remained largely unexplored. In this report, we show that treatment of U937 leukemia cells with the chemotherapy drug etoposide (VP-16) results in cathepsin D release into the cytosol within 4 hours after initiation of drug treatment. VP-16-induced cathepsin D release was not inhibited by z-VAD-FMK or pepstatin A, suggesting that it occurred independently of the activities of caspase proteases or cathepsin D. Down-regulation of cathepsin D expression in suspension U937 cells or adherent HeLa cells using cathepsin D small interfering RNA partially inhibited cell death resulting from treatment of cells with tumor necrosis factor-alpha, tumor necrosis factor-related apoptosis inducing ligand, or the chemotherapy drugs VP-16, cisplatin, and 5-fluorouracil. Moreover, cathepsin D down-regulation significantly delayed cytochrome c release and caspase-3 activation in response to chemotherapy treatment. Incubation of isolated mitochondria with cathepsin D-treated cytosolic extracts resulted in potent release of cytochrome c, indicating that a cytoplasmic substrate mediates the effects of cathepsin D on mitochondria. Together, these findings show that cathepsin D plays an important role in chemotherapy-induced cell death, and that cathepsin D lies upstream of cytochrome c release and caspase-3 activation in the chemotherapy-induced execution pathway.

Disruption of Mcl-1.Bim complex in granzyme B-mediated mitochondrial apoptosis.

Recently, we reported the identification of a novel mitochondrial apoptotic pathway for granzyme B (GrB). The newly identified GrB-mediated mitochondrial cascade was initiated by the cleavage and subsequent degradation of Mcl-1, resulting in the release of mitochondrial Bim from Mcl-1 sequestration. To investigate the biological significance of Mcl-1 cleavage by GrB, we mapped the major GrB cleavage sites and evaluated the apoptotic potential of the cleavage products. GrB cleaves Mcl-1 after aspartic acid residues 117, 127, and 157, generating C-terminal fragments that all contain BH-1, BH-2, BH-3, and transmembrane domains. These fragments accumulate at an early apoptotic phase but are eliminated by further degradation during the apoptotic process. The major Mcl-1 C-terminal fragment generated by GrB (residues 118-350) was unable to induce or enhance apoptosis when transfected into tumor cells. Instead, this Mcl-1 C-terminal fragment maintained a partial protective capability against GrB-mediated apoptosis via its lower affinity to Bim. In comparison with ectopically expressed full-length Mcl-1, the stably transfected C-terminal fragments of Mcl-1 were less efficiently localized to the mitochondria. Knockdown of Mcl-1, as achieved by transfection with Mcl-1-specific short interfering RNA, resulted in a significant level of apoptosis in the absence of external apoptotic stimulation and, in addition, enhanced the susceptibility of breast carcinoma cells to GrB cytotoxicity. The significance of Bim in this GrB apoptotic cascade was indicated by the marked protection against GrB-mediated apoptosis endowed on these cells through Bim knockdown. Our studies suggest that the disruption of the Mcl-1.Bim complex by GrB initiates a major Bim-mediated cellular cytotoxic mechanism that requires the elimination of Mcl-1 following its initial cleavage.