Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

Catestatin (CST) is an important peptide in the pathophysiology of chronic inflammatory disorders. However, clinical studies on inflammatory bowel disease (IBD) patients are lacking. Our goal was to investigate CST concentrations in IBD patients compared to healthy subjects. Additionally, we aimed to determine arterial stiffness parameters in relation to CST. This cross-sectional study compared 80 IBD patients (45 Crohn's disease (CD) and 35 ulcerative colitis (UC) patients) with 75 control subjects. Serum CST levels were significantly higher in the IBD group compared to control subjects (11.29 ± 9.14 vs. 7.13 ± 6.08 ng/mL, p = 0.001) and in the UC group compared to CD patients (13.50 ± 9.58 vs. 9.03 ± 6.92 ng/mL, p = 0.021), irrespective of age and BMI. IBD patients exhibited significantly higher values of heart rate adjusted central augmentation index (cAIx-75) (14.88 ± 10.59 vs. 6.87 ± 9.50 %, p < 0.001) and pulse wave velocity (PWV) (8.06 ± 3.23 vs. 6.42 ± 1.47 m/s, p < 0.001) compared to control group. Furthermore, PWV was the only significant independent correlate of CST (B = 1.20, t = 4.15, p < 0.001), while CST, PWV, cAIx-75, high-sensitivity C-reactive protein and BMI were significant predictors of positive IBD status (1.089 (1.022-1.161), 1.515 (1.166-1.968), 1.060 (1.024-1.097), 1.458 (1.116-1.906), 0.793 (0.683-0.920), respectively). Serum CST levels were significantly higher in IBD patients compared to controls and an independent positive correlation of CST with PWV existed. Therefore, it is possible that CST could have a role in the complex pathophysiology of IBD and its cardiovascular complications.

https://www.mdpi.com/2077-0383/9/3/628/pdf

Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease

AIMS Soluble suppression of tumourigenicity 2 (sST2) and catestatin (CST) reflect myocardial fibrosis and sympathetic overactivity during the acute worsening of heart failure (AWHF). We aimed to determine serum levels and associations of sST2 and CST with in-hospital death as well as the association between sST2 and CST among AWHF patients. METHODS AND RESULTS A total of 96 AWHF patients were consecutively enrolled, while levels of sST2 and CST were determined and compared between non-survivors and survivors. Predictive values of sST2 and CST for in-hospital death were determined by the penalized multivariable Firth logistic regression. The diagnostic ability of sST2 and CST for in-hospital death was assessed by the receiver operating characteristic analysis and examined with respect to the N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and C-reactive protein. The in-hospital death rate was 6.25%. Serum sST2 and CST levels were significantly higher among non-survivors than survivors [146.6 (inter-quartile range, IQR 65.9-156.2) vs. 35.3 (IQR 20.6-64.4) ng/mL, P < 0.001, and 19.8 (IQR 9.9-28.0) vs. 5.6 (IQR 3.4-9.8) ng/mL, P < 0.001, respectively]. Both sST2 and CST were independent predictors of in-hospital death [Firth coefficient (FC) 6.00, 95% confidence interval (CI), 1.48-15.20, P = 0.005, and FC 6.58, 95% CI 1.66-21.78, P = 0.003, respectively], while NT-proBNP was not a significant predictor (FC 1.57, 95% CI 0.51-3.99, P = 0.142). In classifying non-survivors from survivors, sST2 provided area under the curve (AUC) of 0.917 (95% CI 0.819-1.000, P < 0.001) followed by CST (AUC 0.905, 95% CI 0.792-1.000, P < 0.001), while NT-proBNP yielded AUC of 0.735 (95% CI 0.516-0.954, P = 0.036). High-sensitivity cardiac troponin I and C-reactive protein were not found as significant classifiers of in-hospital death (AUC 0.719, 95% CI 0.509-0.930, P = 0.075, and AUC 0.682, 95% CI 0.541-0.822, P = 0.164, respectively). Among survivors, those with sST2 serum levels ≥35 ng/mL had significantly higher CST levels, compared with those with sST2 < 35 ng/mL (9.05 ± 5.17 vs. 5.06 ± 2.76 ng/mL, P < 0.001). Serum sST2 levels positively and independently correlated with CST levels in the whole patient cohort (β = 0.437, P < 0.001). CONCLUSIONS Elevated sST2 and CST levels, reflecting two distinct pathophysiological pathways in heart failure, might indicate impending clinical deterioration among AWHF patients during hospitalization and facilitate prognosis beyond traditional biomarkers regarding the risk of in-hospital death (CATSTAT-HF ClinicalTrials.gov Number NCT03389386).

Circulating sST2 and catestatin levels in patients with acute worsening of heart failure: a report from the CATSTAT-HF study.

Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.

Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective

Catestatin is a multifunctional peptide that is involved in the regulation of the cardiovascular and immune systems as well as metabolic homeostatis. It mitigates detrimental, excessive activity of the sympathetic nervous system by inhibiting catecholamine secretion. Based on in vitro and in vivo studies, catestatin was shown to reduce adipose tissue, inhibit inflammatory response, prevent macrophage-driven atherosclerosis, and regulate cytokine production and release. Clinical studies indicate that catestatin may influence the processes leading to hypertension, affect the course of coronary artery diseases and heart failure. This review presents up-to-date research on catestatin with a particular emphasis on cardiovascular diseases based on a literature search.

/pdf/role-of-catestatin-in-the-cardiovascular-system-and-s9puojnu.pdf

Role of Catestatin in the Cardiovascular System and Metabolic Disorders

Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypothesized that CST moderates the adrenergic overdrive and studied its effects on norepinephrine-mediated hypertrophic responses in H9c2 cardiac myoblasts. CST alone regulated the expression of a number of fetal genes that are induced during hypertrophy. When cells were pre-treated CST, it blunted the modulation of those genes by norepinephrine. Norepinephrine (2 µM) treatment also increased cell size and enhanced the level of Troponin T in the sarcomere. These effects were attenuated by the treatment with CST. CST attenuated the immediate generation of ROS and the increase in glutathione peroxidase activity induced by norepinephrine treatment. Expression of fosB and AP-1 promoter–reporter constructs was used as the endpoint readout for the interaction between the CST and adrenergic signals at the gene level. It showed that CST largely attenuates the stimulatory effects of norepinephrine and other mitogenic signals through the modulation of the gene regulatory modules in a characteristic manner. Depending upon the dose, the signaling by CST appears to be disparate, and at 10–25 nM doses, it primarily moderated the signaling by the β1/2-adrenoceptors. This study, for the first time, provides insights into the modulation of adrenergic signaling in the heart by CST.

Shyamal K. Goswami

Papers

Catestatin reverses the hypertrophic effects of norepinephrine in H9c2 cardiac myoblasts by modulating the adrenergic signaling.