The Sympathetic Nervous System in Heart Failure Physiology, Pathophysiology, and Clinical Implications

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta1-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta2-ARs and alpha1-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome

A Holistic View of Advanced Heart Failure

Advanced heart failure (HF) may occur at any level of left ventricular (LV) ejection fraction (LVEF). The latter, which is widely utilized for the evaluation of LV systolic performance and treatment guidance of HF patients, is heavily influenced by LV size and geometry. As the accurate evaluation of ventricular systolic function and size is crucial in patients with advanced HF, the LVEF should be supplemented or even replaced by more specific indices of LV function such as the systolic strain and cardiac power output and size such as the LV diastolic diameters and volumes. Conventional treatment (cause eradication, medications, devices) is often poorly tolerated and fails and advanced treatment (mechanical circulatory support [MCS], heart transplantation [HTx]) is required. The effectiveness of MCS is heavily dependent on heart size, whereas HTx which is effective in the vast majority of the cases is limited by the small donor pool. Expanding the MCS indications to include patients with small ventricles as well as the HTx donor pool are major challenges in the management of advanced HF

Chronic Obstructive Pulmonary Disease as a Main Factor of Premature Aging

(1) Background: Chronic obstructive pulmonary disease (COPD) is defined as an inflammatory disorder that presents an increasingly prevalent health problem. Accelerated aging has been examined as a pathologic mechanism of many chronic diseases like COPD. We examined whether COPD is combined with accelerated aging, studying two hormones, dehydroepiandrosterone (DHEA) and growth hormone (GH), known to be characteristic biological markers of aging. (2) Methods: Data were collected from 119 participants, 70 (58.8%) COPD patients and 49 (41.2%) from a health control group over the period of 2014⁻2016 in a spirometry program. Information about their medical history, tobacco use, and blood tests was obtained. (3) Results: The average age of the health control patients was 73.5 years (SD = 5.5), and that of the COPD patients was 75.4 years (SD = 6.9). Both groups were similar in age and sex. A greater proportion of smokers were found in the COPD group (87.1%) versus the control group (36.7%). The majority of COPD patients were classified as STAGE II (51.4%) and STAGE III (37.1%) according to GOLD (Global Initiative for Chronic Obstructive Pulmonary Disease). Levels of DHEA (SD = 17.1) and GH (SD = 0.37) were significantly lower in the COPD group (p < 0.001) compared to those in the controls (SD = 26.3, SD = 0.79). DHEA and GH were more significant and negatively correlated with age. The regression equation of DHEA with age produced a coefficient equal to 1.26. In this study, the difference in DHEA between COPD patients and controls was, on average, 30.2 μg/dL, indicating that the biological age of a COPD patient is on average about 24 years older than that of a control subject of the same age. Similarly, the difference in GH between COPD patients and controls was, on average, 0.42 ng/mL, indicating that the biological age of a COPD patient is on average about 13.1 years older than that of a control subject of the same age. (4) Conclusions: The findings of our study strongly suggest the presence of premature biological aging in COPD patients. Their biological age could actually vary from 13 to 23 years older than non-COPD controls according to DHEA and GH variation

Red Blood Cell Distribution Width in Heart Failure: Pathophysiology, Prognostic Role, Controversies and Dilemmas

Red blood cell distribution width (RDW), an integral parameter of the complete blood count (CBC), has been traditionally used for the classification of several types of anemia. However, over the last decade RDW has been associated with outcome in patients with several cardiovascular diseases including heart failure. The role of RDW in acute, chronic and advanced heart failure is the focus of the present work. Several pathophysiological mechanisms of RDW’s increase in heart failure have been proposed (i.e., inflammation, oxidative stress, adrenergic stimulation, undernutrition, ineffective erythropoiesis, reduced iron mobilization, etc.); however, the exact mechanism remains unknown. Although high RDW values at admission and discharge have been associated with adverse prognosis in hospitalized heart failure patients, the prognostic role of in-hospital RDW changes (ΔRDW) remains debatable. RDW has been incorporated in recent heart failure prognostic models. Utilizing RDW as a treatment target in heart failure may be a promising area of research

ACE2, the Counter-Regulatory Renin-Angiotensin System Axis and COVID-19 Severity

Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin-angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1-7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin-angiotensin-aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1-7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed

Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device: A Systematic Review and Meta-Analysis

Background: Despite the improvement in left ventricular assist device (LVAD) technology and the advent of third-generation LVADs, hemocompatibility-related events remain a significant issue. Therefore, new pharmacological treatments are necessary to optimize patient management and to further reduce hemocompatibility-related events. The purpose of the present systematic review and meta-analysis was to summarize the existing data regarding the safety and efficacy of post-implant phosphodiesterase-5 inhibitors (PDE-5i) on hemocompatibility-related events. Methods: Among the 258 articles in Pubmed, Scopus, and CENTRAL that were retrieved (1990–2022), 15 studies were included in the qualitative synthesis, and 9 studies were included in the quantitative synthesis. The fixed-effects model was used because it is statistically sound for combining a very small number of studies. The primary endpoint of the study was all-cause mortality, whereas the secondary endpoints were ischemic stroke, pump thrombosis, and gastrointestinal bleeding. Results: Mortality was significantly lower in the PDE-5i group vs. the control group (OR: 0.92 [95% CI: 0.85, 0.98]; p = 0.02). The secondary endpoints ischemic stroke (OR: 0.87 [95% CI: 0.78, 0.98]; p = 0.02) and pump thrombosis (OR: 0.90 [95% CI: 0.82, 0.99]; p = 0.04) were also lower in the PDE-5i group. The incidence of gastrointestinal bleeding was significantly higher in patients with LVAD receiving PDE-5i (OR: 1.26 [95% CI: 1.11, 1.44]; p < 0.01). In the overall analysis, the heterogeneity of outcomes was low, except for pump thrombosis. Conclusions: The use of PDE-5i post-implant was associated with lower mortality and thrombotic events but with a higher risk of gastrointestinal bleeding