Heart Failure With Reduced Ejection Fraction Is Characterized by Systemic NEP Downregulation.

Based on the investigation of neprilysin (NEP) regulation in a translational porcine model of chronic heart failure (HF), this study concluded: 1) that kidneys might play a crucial part in systemic NEP regulation based on 20 to 100 higher NEP content and/or activity compared with any other organ; 2) NEP seems to be downregulated under HF conditions; and 3) that the value of plasma NEP concentrations and activity as biomarkers is questionable. For the first time, these data provide basic knowledge on HF-related pathophysiological alterations of the NEP system and contribute to understanding the mechanism of action of angiotensin-receptor neprilysin-inhibitors, which remains elusive despite broad clinical applications.

Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling.

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.

Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion.

We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium.

YKL-40 is elevated in patients with peripheral arterial disease and diabetes or pre-diabetes.

OBJECTIVE: YKL-40 is secreted by macrophages in atherosclerotic lesions and involved in plaque rupture. YKL-40 is elevated in coronary artery disease, and predicts cardiovascular mortality. Experimental in vivo and in vitro data suggest a role of YKL-40 in tissue remodeling. A disease modulating potency of YKL-40 was not investigated in peripheral arterial disease (PAD). METHODS: We measured YKL-40 in 460 subjects: 316 PAD: 71 normal glucose metabolism (PAD-NGM), 90 pre-diabetes (PAD-PREDM) and 155 diabetes (PAD-DM); 20 diabetes with atherosclerosis but without PAD (AS-DM); 85 diabetes without macro-vascular complications (DM) and 39 healthy controls (CO). RESULTS: YKL-40 is higher in PAD vs. CO (median [25-75 percentile]: 103 [69-159] vs. 43 [30-80]ng/ml; p<0.001). In addition, YKL-40 is elevated in DM (p<0.001), PAD-NGM (p=0.001), PAD-PREDM (p<0.001), PAD-DM (p<0.001) and AS-DM (p=0.002) compared to CO. Among PAD, YKL-40 is increased in PAD-PREDM (p=0.001) and PAD-DM (p=0.01) vs. PAD-NGM. By multivariate regression YKL-40 is significantly associated with age (beta=0.272), triglycerides (beta=0.216), aspartate-amino-transferase (beta=0.177) and c-reactive-protein (beta=0.178). Underpinning its role YKL-40 was found to be associated with micro-/macroalbuminuria (p=0.014/p=008)--a strong remodeling inducer. In addition, YKL-40 was elevated in existence of mediasclerosis (p=0.008), a remodeling process. CONCLUSION: We are first to show that YKL-40 is higher in subjects with peripheral arterial disease. YKL-40 was higher in PAD patients with pre-/diabetes. In addition, YKL-40 was associated with the "severity" of generalized atherosclerosis estimated by affected vascular beds. All our findings point towards a role of YKL-40 in the progression/prognosis of patients with PAD and concomitant diabetes.

Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease.

OBJECTIVE: Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS: We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes-PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes-non-PAD) were examined. RESULTS: Type 2 diabetes-PAD subjects (399 ± 155 µg/ml) had significantly higher fetuin-A levels than type 2 diabetes-non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes-non-PAD subjects (P < 0.001). Type 2 diabetes-PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes-PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1-3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0-1.7, P = 0.039) for the prevalence of myocardial infarction. CONCLUSIONS: In contrast to previous findings, fetuin-A was higher in type 2 diabetes-PAD patients than in type 2 diabetes-non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes-non-PAD patients. In type 2 diabetes-PAD patients, fetuin-A was inversely associated with mediasclerosis-the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.