Background: Although heart failure with a preserved or normal ejection fraction (HFNEF or diastolic heart failure) is common, treatment outcomes on quality of life and cardiac function are lacking. The effect of reninangiotensin blockade by irbesartan or ramipril in combination with diuretics on quality of life (QoL), regional and global systolic and diastolic function was assessed in HFNEF patients. Methods: 150 patients with HFNEF (LVEF .45%) were randomised to (1) diuretics alone, (2) diuretics plus irbesartan, or (3) diuretics plus ramipril. QoL, 6-minute walk test (6MWT) and Doppler echocardiography were performed at baseline, 12, 24 and 52 weeks. Results: The QoL score improved similarly in all three groups by 52 weeks (246%, 51%, and 50% respectively, all p,0.01), although 6MWT increased only slightly (average +3-6%). Recurrent hospitalisation rates were equal in all groups (10-12% in 1 year). At 1 year, LV dimensions or LVEF had not changed in any group, though both systolic and diastolic blood pressures were lowered in all three groups from 4 weeks onwards. At baseline both mean peak systolic (Sm) and early diastolic (Em) mitral annulus velocities were reduced, and increased slightly in the diuretic plus irbesartan (Sm 4.5 (SEM 0.17) to 4.9 (SEM 0.16) cm/sec; Em 3.8 (SEM 0.25) to 4.2 (SEM 0.25) cm/sec) and ramipril (Sm 4.5 (SEM 0.24) to 4.9 (SEM 0.20) cm/sec; Em 3.3 (SEM 0.25) to 4.04 (SEM 0.32) cm/sec) groups (both p,0.05). NT-pro-BNP levels were raised at baseline (595 (SD 905) pg/ml; range 5-4748) and fell in the irbesartan (2124 (SD 302) pg/ml, p = 0.01) and ramipril (2173 (SD 415) pg/ml, p = 0.03) groups only. Conclusions: In this typically elderly group of HF patients with normal LVEF, diuretic therapy significantly improved symptoms and neither irbesartan nor ramipril had a significant additional effect. However, diuretics in combination with irbesartan or ramipril marginally improved LV systolic and diastolic longitudinal LV function, and lowered NT-proBNP over 1 year.

This study confirms that the restrictive filling pattern of transmitral flow velocity is a marker of more severe heart failure, as indicated by its association with higher atrial and brain natriuretic peptide levels, lower ejection fraction and higher pulmonary artery pressure. Thus, this easily obtained Doppler-derived marker of diastolic dysfunction is useful for identifying those patients with more severe heart failure.

Dysregulated apoptosis plays a critical role in the development of a number of aberrant cellular processes, including tumorigenesis and chemoresistance. However, the mechanisms that govern the normal apoptotic program are not completely understood. Soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) promote mammalian cell viability via an unknown mechanism and p53 status is a key determinant of cell fate in human ovarian cancer cells. Whether an interaction exists between these two determinants of cell fate is unknown. We hypothesized that basal sGC activity reduces p53 content and attenuates p53-dependent apoptosis in human ovarian cancer cells. Suppression of sGC activity with the specific inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) lowered cGMP content, and increased p53 protein content and induced apoptosis in three ovarian cancer cell lines, effects which were attenuated by the cGMP analog 8-Br-cGMP and by Atrial Natriuretic Factor, an activator of particulate guanylyl cyclase, which circumvent the inhibition of sGC. ODQ prolonged p53 half-life, induced phosphorylation of p53 on Ser15, and upregulated the p53-dependent gene products p21, murine double minute-2, and the proapoptotic, p53-responsive gene product Bax. ODQ activated caspase-3, and ODQ-induced apoptosis was inhibited by overexpression of X-linked inhibitor of apoptosis Protein. Pretreatment with the specific p53 inhibitor pifithrin or downregulation of p53 using a specific small inhibitory RNA significantly attenuated ODQ-induced apoptosis. Moreover, ODQ-induced upregulation of p21 and Bax and ODQ-induced apoptosis were significantly reduced in a p53 mutant cell line relative to the wild-type parental cell line. Thus, the current study establishes that basal sGC/cGMP activity regulates p53 protein stability, content, and function, possibly by altering p53 phosphorylation and stabilization, and promotes cell survival in part through regulation of caspase-3 and p53.Oncogene ( IntroductionDysregulated apoptosis contributes to the development of a number of pathologies, including cancer (Liebermann et al., 1995;Reap et al., 1995;Estevez et al., 1998;Fiscus, 2002;Fiscus et al., 2002). Tumor growth results, in part, from an imbalance between cell proliferation and apoptosis (Kerr et al., 1994;Levine et al., 1995;Sheets and Yeh, 1997;LaCasse et al., 1998) and our laboratory has been interested in the role of dysregulated apoptosis in the regulation of cell fate in human ovarian cancer cells (Sasaki et al., 2000;Asselin et al., 2001;Fraser et al., 2003).Soluble guanylyl cyclase (sGC) is one of the major producers of basal cyclic guanosine monophosphate (cGMP) content in mammalian cells (Waldman and Murad, 1987;Garthwaite et al., 1995;Fiscus, 2002), and is necessary for the survival of several cell types under normal growth conditions, as well as for protection against various apoptotic stimuli (Flamigni et al., 2001). Our previous studies have demonstrated that the basal activities of sGC and a downstream target pro...