Despite its proven superiority over two-dimensional transthoracic echocardiography (2DTTE) for left ventricular (LV) volumes and ejection fraction, clinical use of 3DTTE remains very limited in the acute setting. 3DTTE may have significant clinical advantages in the assessment of acute heart failure. Further exploration of 3DTTE utilization may help in more precise assessment of the regional wall-motion abnormalities, early identification of acute ischemic from nonischemic LV dysfunction with a more precise approach to the AHF management. The use of other measures, especially the right ventricular and the left atrial assessment, and 3D strain methodology may further expand the potential future utility of 3DTTE in patients with new-onset HF.

We evaluated the impact of clopidogrel use on 3- and 12-months all-cause mortality in patients with acute heart failure (AHF) stratified by coronary artery disease (CAD) in patients admitted to 47 hospitals in 7 Middle Eastern countries with AHF from February to November 2012. Clopidogrel use was associated with significantly lower risk of all-cause mortality at 3 months (adjusted odds ratio [aOR], 0.61; 95% confidence interval [CI]: 0.42-0.87; P = .007) and 12 months (aOR, 0.61; 95% CI: 0.47-0.79; P < .001). When the analysis was stratified by CAD, the clopidogrel group in those with AHF and CAD was also associated with significantly lower risk of all-cause mortality at 3 months (aOR, 0.56; 95% CI: 0.38-0.83; P = .003) and 12 months (aOR, 0.58; 95% CI: 0.44-0.77; P < .001). However, in AHF patients without CAD, clopidogrel use was not associated with any survival advantages, neither at 3 months (aOR, 0.99; 95% CI: 0.32-3.11; P = .987) nor at 12 months (aOR, 0.80; 95% CI: 0.37-1.72; P = .566). Clopidogrel use was associated with short- and long-term all-cause mortality in patients with AHF and CAD. In AHF patients without CAD, clopidogrel use did not offer any survival advantage.

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

QSOX1, a sulfhydryl oxidase, was shown to be upregulated in the heart upon acute heart failure (AHF). The aim of the study was to unravel QSOX1 roles during AHF. We generated and characterized mice with QSOX1 gene deletion. The QSOX1-/- mice were viable but adult male exhibited a silent dilated cardiomyopathy. The QSOX1-/- hearts were characterized by low protein SERCA2a levels associated with a calcium homeostasis alteration, high levels of the endoplasmic reticulum (ER) chaperone proteins Grp78/Bip, and of the ER apoptosis sensor CHOP, indicating a chronic unfolded protein response (UPR). Importantly the QSOX1invalidation led to overexpression of two ER oxidases, ERO1-α and PRDX4. Acute stress was induced by isoproterenol injection (ISO, 300 mg/kg/12 h) for 2 days. In both groups, the PERK UPR pathway was transiently activated 6 h after the first ISO injection as indicated by eIF2 phosphorylation. By day-3 after the onset of stress, both WT and QSOX1-/- mice exhibited AHF profile but while high cardiac QSOX1 level was induced in WT hearts, ERO1-α and PRDX4 levels drop down in QSOX1-/-. At that time, QSOX1-/- hearts exhibited an enhanced inflammation (CD68+ cells and Galectin-3 expression) and oxidative stress (DHE staining and oxyblot) when compared to WT ones. In conclusion, the lack of QSOX1 promotes the upregulation of two ER oxidases ERO1α and PRDX4 that likely rescues oxidative protein folding in the hearts. However, signs of chronic ER stress remained present and were associated with a dilated cardiomyopathy. The superimposition of acute stress allowed us to propose that QSOX1 participate to the early response to cardiac stress but not to immediate UPR response. Taken altogether, the data indicated that QSOX1 is required 1) for a proper protein folding in the endo/sarcoplasmic reticulum (ER/SR) and 2) for resolution and protective response during acute stress.