Effects of Sacubitril-Valsartan in Patients With Various Types of Heart Failure: A Meta-analysis.

ABSTRACT: We performed a meta-analysis investigating the efficacy and adverse effects of sacubitril-valsartan in various types of heart failure including more recent studies and a larger sample size. We conducted an electronic search through Cochrane, Web of Science, PubMed, and Embase. Included studies were randomized controlled trials analyzing the efficacy of sacubitril-valsartan compared with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) in patients with heart failure. Fourteen trials were included. Pooled estimates were analyzed using RevMan 5.4.1. The odds ratio (OR) of hospitalization from worsening heart failure that compared sacubitril-valsartan with control was 0.70 (95% CI, 0.51-0.97; P = 0.03) in patients with heart failure with reduced ejection fraction (HFrEF) with a relative risk reduction (RRR) of 24.3% and absolute risk reduction (ARR) of 3.4%. In patients with heart failure with midrange (HFmEF) and preserved (HFpEF) ejection fraction, the OR was 0.80 (95% CI, 0.71-0.90; P = 0.0001) with RRR of 14.5% and ARR of 3.3%. There was a significant reduction in cardiovascular deaths (OR = 0.79; 95% CI, 0.70-0.89; P = <0.0001) and all-cause mortality (OR = 0.84; 95% CI, 0.75-0.94; P = 0.002) in patients with HFrEF, with no significant differences in patients with HFmEF and HFpEF. Hospitalization rate was significantly reduced in patients taking sacubitril-valsartan across all analyzed cohorts. Sacubitril-valsartan significantly reduced the risk of all-cause mortality and cardiovascular death in patients with HFrEF but not in patients with HFmEF/HFpEF. These findings support sacubitril-valsartan use in reducing hospitalization of patients with HFmEF and HFpEF. More studies should be performed to further analyze the efficacy of sacubitril-valsartan in patients with HFmEF/HFpEF.

Yeast Kinesin-5 Motor Protein CIN8 Promotes Accurate Chromosome Segregation.

Accurate chromosome segregation depends on bipolar chromosome-microtubule attachment and tension generation on chromosomes. Incorrect chromosome attachment results in chromosome missegregation, which contributes to genome instability. The kinetochore is a protein complex that localizes at the centromere region of a chromosome and mediates chromosome-microtubule interaction. Incorrect chromosome attachment leads to checkpoint activation to prevent anaphase onset. Kinetochore detachment activates the spindle assembly checkpoint (SAC), while tensionless kinetochore attachment relies on both the SAC and tension checkpoint. In budding yeast Saccharomyces cerevisiae, kinesin-5 motor proteins Cin8 and Kip1 are needed to separate spindle pole bodies for spindle assembly, and deletion of CIN8 causes lethality in the absence of SAC. To study the function of Cin8 and Kip1 in chromosome segregation, we constructed an auxin-inducible degron (AID) mutant, cin8-AID. With this conditional mutant, we first confirmed that cin8-AID kip1∆ double mutants were lethal when Cin8 is depleted in the presence of auxin. These cells arrested in metaphase with unseparated spindle pole bodies and kinetochores. We further showed that the absence of either the SAC or tension checkpoint was sufficient to abolish the cell-cycle delay in cin8-AID mutants, causing chromosome missegregation and viability loss. The tension checkpoint-dependent phenotype in cells with depleted Cin8 suggests the presence of tensionless chromosome attachment. We speculate that the failed spindle pole body separation in cin8 mutants could increase the chance of tensionless syntelic chromosome attachments, which depends on functional tension checkpoint for survival.