IMPORTANCEGlobal longitudinal strain (GLS) is an emerging echocardiographic biomarker of cardiac function in heart failure (HF). Evidence from large-scale studies comprehensively investigating GLS for its association with clinical phenotypes and mortality in asymptomatic and symptomatic chronic HF is limited.OBJECTIVE To assess the factors associated with GLS and its prognostic value in patients with chronic HF.

Background:Reperfusion or reopening of occluded vessels is the gold standard to terminate ischemia. However, early functional recovery after reperfusion is often low requiring inotropic intervention. Although catecholamines increase inotropy and chronotropy, they are not the best choice because they increase myocardial oxygen and substrate demand. As nitric oxide (NO) contributes to cardiac function, we tested the hypothesis that addition of citrulline during the onset of reperfusion improves post-ischemic recovery because citrulline can reenter arginine consumption of NO synthases (NOS) but not of arginases.Methods:Hearts from adult rats were used in this study, exposed to 45-minute global ischemia and subsequently reperfused for 180 minutes. Citrulline (100 µM) or arginine (100 µM) was added with reperfusion and remained in the perfusion buffer for 180 minutes. Nω-nitro-l-arginine methyl ester (l-NAME) was used to antagonize NOS activity.Results:Citrulline increased load-free cell shortening of isolated adult rat cardiomyocytes and improved left ventricular developed pressure (LVDP) under normoxic conditions, indicating that citrulline can affect heart function. Ischemia/reperfusion caused a constitutive loss of function during 3 hours of reperfusion, whereas citrulline, but not arginine, improved the functional recovery during reperfusion. This effect was attenuated by co-administration of l-NAME. Although citrulline increased the formation of nitrite, l-NAME attenuated this effect indicating again a positive effect of citrulline on NO formation. Citrulline, but not arginine, increased the expression of arginase-1 (protein and mRNA) but l-NAME attenuated this effect again. Collectively, citrulline improved the post-ischemic recovery in an NO-dependent way.Conclusions:Citrulline, known to block arginase and to support NO formation, improves the early functional recovery of post-ischemic hearts and may be an alternative to catecholamines to improve early post-ischemic recovery.

Aims To establish reference values and clinically relevant determinants for measures of heart rate variability (HRV) and to assess their relevance for clinical outcome prediction in individuals with heart failure. Methods Data from the MyoVasc study (NCT04064450; N = 3289), a prospective cohort on chronic heart failure with a highly standardized, 5 h examination, and Holter ECG recording were investigated. HRV markers were selected using a systematic literature screen and a data-driven approach. Reference values were determined from a healthy subsample. Clinical determinants of HRV were investigated via multivariable linear regression analyses, while their relationship with mortality was investigated by multivariable Cox regression analyses. Results Holter ECG recordings were available for analysis in 1001 study participants (mean age 64.5 ± 10.5 years; female sex 35.4%). While the most frequently reported HRV markers in literature were from time and frequency domains, the data-driven approach revealed predominantly non-linear HRV measures. Age, sex, dyslipidemia, family history of myocardial infarction or stroke, peripheral artery disease, and heart failure were strongly related to HRV in multivariable models. In a follow-up period of 6.5 years, acceleration capacity [HRperSD 1.53 (95% CI 1.21/1.93), p = 0.0004], deceleration capacity [HRperSD: 0.70 (95% CI 0.55/0.88), p = 0.002], and time lag [HRperSD 1.22 (95% CI 1.03/1.44), p = 0.018] were the strongest predictors of all-cause mortality in individuals with heart failure independently of cardiovascular risk factors, comorbidities, and medication. Conclusion HRV markers are associated with the cardiovascular clinical profile and are strong and independent predictors of survival in heart failure. This underscores clinical relevance and interventional potential for individuals with heart failure. ClinicalTrials.gov identifier NCT04064450.

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