Neurohormonal Changes Research Articles

The Dual Burden of Frailty and Heart Failure.

Frailty is highly prevalent among patients with heart failure (HF) and independently predicts adverse outcomes. However, optimal frailty definitions, assessments, and management in HF remain unclear. Frailty is common in HF, affecting up to 80% of patients depending on population characteristics. Even pre-frailty doubles mortality risk versus robust patients. Frailty worsens HF prognosis through systemic inflammation, neurohormonal changes, sarcopenia, and micronutrient deficiency. Simple screening tools like gait speed and grip strength predict outcomes but lack HF-specificity. Comprehensive geriatric assessment is ideal but not always feasible. Exercise, nutrition, poly-pharmacy management, and multidisciplinary care models can help stablize frailty components and improve patient-centred outcomes. Frailty frequently coexists with and exacerbates HF. Routine frailty screening should guide supportive interventions to optimize physical, cognitive, and psychosocial health. Further research on HF-specific frailty assessment tools and interventions is warranted to reduce this dual burden.

Pemeriksaan Status Gizi dan Edukasi Pencegahan Diabetes Melitus terhadap Lansia di Wilayah Putukrejo, Desa Peniwen, Kabupaten Malang

The number of elderly people in Indonesia is increasing from year to year. The increasing age of the elderly, as well as the increasing prevalence of diabetes mellitus in the elderly, are the result of neurohormonal changes, lifestyle changes, decreased physical activity, changes in body composition, and increased oxidative stress. The goal of this community service is to provide health services in the form of nutritional assessments for the elderly and education to increase the elderly's knowledge in Peniwen Village, Malang Regency. Community service activities begin with screening Upper Arm Circumference, Abdominal Circumference, Height, Weight, Body Mass Index, Blood Pressure, and Random Blood Sugar levels in the elderly. Counseling was then provided to 20 people using powerpoint media, brochures, and booklets. The information provided included diabetes mellitus, risk factors, random blood sugar levels, and diabetes mellitus prevention. The level of knowledge of respondents is assessed using pre-test and post-test instruments. According to the results of the pre-test and post-test conducted by the elderly in Putukrejo Hamlet, educational methods in the form of presentations, booklets, and brochures containing material about Diabetes Mellitus, risk factors for events, measurement of blood sugar levels in the elderly, and diabetes mellitus prevention went as expected, namely a 40% increase.

Psychiatric comorbidities, quality of life, and cardiovascular risk factors in patients with heart failure

Background: Heart failure (HF) leads to various changes including physiological (neurohormonal) changes and an increase in stress level, which can become a risk factor for the development of various psychiatric disorders, further worsening quality of life (QOL). Methods: Patients of HF between 18 and 60 years of age attending the outpatient department of the Department of Cardiology were enrolled. Patients were screened for psychiatric illness by applying Mini International Neuropsychiatric Interview 7.0.2. The diagnosis was made through the Diagnostic and Statistical Manual of Mental Disorders-5. The severity of anxiety and depression was assessed by applying the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. Sleep quality was measured by applying the Pittsburgh Sleep Quality Index. Subsyndromal symptoms were assessed via SADS-CB. QOL was measured by the World Health Organization QOL-BREF. Data were statistically analyzed. Results: Out of 70 enrolled patients, 32 patients did not have any psychiatric illness (Group A), 20 patients were in the subsyndromal group (Group B), and 18 patients had psychiatric disorders (Group C). Tobacco use and the number of risk factors of HF present were significantly higher in Group C. A significantly higher number of patients in Group C were lying in the New York Heart Association (NYHA) II class (patients lying in NYHA III and NYHA IV classes were excluded) than in other groups. In addition, sleep and QOL (especially among patients under NYHA I class) were significantly impaired in Group C. Conclusion: Psychiatric illness is common in patients with HF. Despite guidelines to screen for them, clinicians either do not screen for them or otherwise miss the psychiatric illness. These psychiatric illnesses may further impair the outcome of heart diseases and worsen QOL.

Angiotensin-Converting Enzyme and Heart Failure.

Pharmacotherapy is the cornerstone treatment for patients with heart failure (HF) that uses drugs targeting the renin-angiotensin-aldosterone system (RAAS), including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan. This article reviews the pathophysiology of the RAAS and the neurohormonal changes seen in patients with HF as well as the targets and the mode of action of these drugs. We also assess the role of ACE in ventricular remodeling and summarize the main evidence for the use of ACE-related drugs in HF patients.

Adrenomedullin peptides and precursor levels in relation to haemodynamics and prognosis after heart transplantation.

Heart failure (HF) is a frequent condition in the elderly, further complicated by associated pulmonary hypertension (PH), with impact on morbidity and mortality. Plasma proteins associated with cardiovascular disease, related to inflammation, neurohormonal changes, and myocyte stress, pathways recognized in the pathophysiology of HF, may provide information on disease severity and prognosis. We aimed to investigate such cardiovascularproteins and their relationship to haemodynamics before and 1year after heart transplantation (HT), as well as their prognostic value in advanced HF with PH. In 20 healthy controls and 67 patients with HF and PH, before and 1year after HT, N-terminal pro-brain natriuretic peptide (NT-proBNP) and 18 cardiovascular proteins were analysed with proximity extension assay. Right heart catheterization was used to measure the haemodynamics of the HF patients pre-operatively and at 1year follow-up after HT. Prognosis was estimated using Kaplan-Meier and Cox regression analyses. Out of 18 plasma proteins, 11 proteins including adrenomedullin peptides and precursor levels (ADM) and protein suppression of tumourigenicity 2 receptor were elevated before HT compared with healthy controls and had decreased 1year after HT. The decrease in plasma levels 1year after HT was towards the healthy controls' levels. The decrease in ADM levels before vs. after HT correlated with decreased mean right atrial pressure (rs =0.61; P=0.0077), decreased NT-proBNP (rs =0.75; P=0.00025), and decreased stroke volume index (rs =-0.52; P=0.022). High levels of pre-operative plasma ADM were associated with worse event-free survival (HT or death), as well as survival compared with low ADM levels (log-rank P value=0.023 and 0.0225, respectively). Univariable Cox regression analysis demonstrated that ADM levels were associated with survival, hazard ratio (HR) 1.007 (95% confidence interval (CI): 1.00-1.015, P=0.049), and the association remained after adjusting for NT-proBNP, HR 1.01 (95% CI: 1.00-1.021, P=0.041). Elevated plasma levels of ADM may be a marker of pressure/volume overload in HF patients with PH, as well as long-term prognosis after HT. In line with previous studies, our findings additionally confirm that ADM may be a marker of venous congestion in HF. Further studies are encouraged to establish a deeper understanding of the properties of ADM and its relationship with HF and PH, in order to potentially facilitate clinical management of HF and associated PH.

Mechanisms of Atrial Fibrillation: How Our Knowledge Affects Clinical Practice.

Atrial fibrillation (AF) is a very common arrhythmia that mainly affects older individuals. The mechanism of atrial fibrillation is complex and is related to the pathogenesis of trigger activation and the perpetuation of arrhythmia. The pulmonary veins in the left atrium arei confirm that onfirm the most common triggers due to their distinct anatomical and electrophysiological properties. As a result, their electrical isolation by ablation is the cornerstone of invasive AF treatment. Multiple factors and comorbidities affect the atrial tissue and lead to myocardial stretch. Several neurohormonal and structural changes occur, leading to inflammation and oxidative stress and, consequently, a fibrotic substrate created by myofibroblasts, which encourages AF perpetuation. Several mechanisms are implemented into daily clinical practice in both interventions in and the medical treatment of atrial fibrillation.

Women’s experience of early labour in a free-standing birth centre: Midwifing embodied labour

IssueWomen who present at hospital labour wards in early labour must often meet measurable diagnostic criteria before admission. BackgroundEarly labour is a phase of neurohormonal, emotional, and physical changes that are often not measurable. When admission to birthplace is based on results of diagnostic procedures, women’s embodied knowledge may be disregarded. AimTo describe the early labour experience of women with spontaneous onset of labour in a free-standing birth centre, as well as midwifery care when women arrived in labour. MethodologyAn ethnographic study was conducted in 2015 in a free-standing birth centre after receiving ethics approval. The findings for this article were drawn from a secondary analysis of the data, which included interview data with women and detailed field notes of midwives’ activities related to early labour. FindingsThe women in this study were instrumental in the decision-making process to stay at the birth centre. Observational data showed that vaginal exams were rarely conducted when women arrived at the birth centre and were not a deciding factor in admission. DiscussionThe women and midwives co-constructed early labour based on the lived experience of women and the meaning that this experience held for both. ConclusionGiven the growing concern about the need for respectful maternity care, this study provides examples of good practice in listening to women, as well as an illustration of the consequences of not doing so.

A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery.

To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and metabolic changes in isoflurane-anesthetized cats undergoing ovariohysterectomy or castration. 72 client-owned mixed-breed cats undergoing ovariohysterectomy or castration between October 4, 2018, and January 10, 2020. For each type of surgery, cats were assigned to 1 of 6 premedication protocols groups, with 6 cats/group: physiologic saline (0.9% NaCl) solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IV); physiologic saline solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IM); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IV); medetomidine (50 μg/kg, IM) and alfaxalone (5 mg/kg, IM); midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IV); or midazolam (0.5 mg/kg, IM), medetomidine (50 μg/kg, IM), and alfaxalone (5 mg/kg, IM). Venous blood was taken before pretreatment, pre- and postoperatively during anesthesia with isoflurane and oxygen, and during early and complete recovery. Compared with baseline concentrations, plasma adrenaline and noradrenaline concentrations decreased during anesthesia in cats premedicated with alfaxalone alone and in combination with medetomidine. The combination of medetomidine, midazolam, and alfaxalone prevented an excessive increase in catecholamines during anesthesia and surgery in cats. Postoperative plasma cortisol concentration after ovariohysterectomy was lower for cats premedicated with the combination of medetomidine and alfaxalone or the combination of medetomidine, midazolam, and alfaxalone, compared with cats premedicated with alfaxalone alone. Cats treated with combinations that included medetomidine and midazolam had hyperglycemia during anesthesia. Cats treated with medetomidine or medetomidine and midazolam in combination with alfaxalone, compared with alfaxalone alone, had lower concentrations of nonesterified fatty acids during anesthesia. Behavioral recovery scores were lower (better) for cats that received medetomidine in addition to alfaxalone, compared with alfaxalone alone. Results indicated that pretreatments with medetomidine and alfaxalone or with medetomidine, midazolam, and alfaxalone were useful for preventing stress-related hormonal and metabolic responses, other than hyperglycemia, during isoflurane anesthesia and surgery in cats.

Hepatogenous diabetes: Knowledge, evidence, and skepticism.

The diabetogenic potential of liver cirrhosis (LC) has been known for a long time, and the name "hepatogenous diabetes" (HD) was coined in 1906 to define the condition. Diabetes mellitus (DM) that develops as a consequence of LC is referred to as HD. In patients with LC, the prevalence rates of HD have been reported to vary from 21% to 57%. The pathophysiological basis of HD seems to involve insulin resistance (IR) and pancreatic β-cell dysfunction. The neurohormonal changes, endotoxemia, and chronic inflammation of LC initially create IR; however, the toxic effects eventually lead to β-cell dysfunction, which marks the transition from impaired glucose tolerance to HD. In addition, a number of factors, including sarcopenia, sarcopenic obesity, gut dysbiosis, and hyperammonemia, have recently been linked to impaired glucose metabolism in LC. DM is associated with complications and poor outcomes in patients with LC, although the individual impact of each type 2 DM and HD is unknown due to a lack of categorization of diabetes in most published research. In fact, there is much skepticism within scientific organizations over the recognition of HD as a separate disease and a consequence of LC. Currently, T2DM and HD are being treated in a similar manner although no standardized guidelines are available. The different pathophysiological basis of HD may have an impact on treatment options. This review article discusses the existence of HD as a distinct entity with high prevalence rates, a strong pathophysiological basis, clinical and therapeutic implications, as well as widespread skepticism and knowledge gaps.

Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure.

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.

FORENSIC PERSPECTIVES OF PCOS AND ADOLESCENT SUICIDE: A CASE REPORT

Suicide is the second cause of death among adolescents worldwide. Besides neurohormonal changes following puberty, a constellation of risk factors such as academic failure, relationship issues, nancial stress, peer pressure, increasing life responsibilities, and family issues stir up suicidal emotions. However, the impact of polycystic ovary syndrome (PCOS) and gynecological pathologies are rarely encountered and considered in medicolegal autopsies. We present a case of a 16-year-old adolescent girl who committed suicide by swallowing an organophosphate compound following a minor argument with her sister. At autopsy, besides poisoning, dual pathology of the ovary that includes right polycystic ovary and left ovarian mature cystic teratoma was discovered. The psychophysiological characteristics of PCOS and its prospective association with depression vis-à-vis suicidal tendencies are discussed.

Cardiac rehabilitation in heart failure with severely reduced ejection fraction: effects on mortality.

Thirty years ago, patients with low ejection fraction (EF) have often been excluded from rehabilitation programs due to concern about possibility of sudden death or other adverse cardiovascular events during exercise sessions. Recent studies have highlighted the fact that cardiac rehabilitation could improve exercise capacity, cardiac function, and health-related quality of life in congestive heart failure patients. This encouraged us to write a review article and update our latest knowledge about the outcome of rehabilitation program in patients with severely depressed cardiac function. We were particularly interested in effect of cardiac rehabilitation on exercise capacity, quality of life, vascular effects, neuro-hormonal changes, and mortality. We also conducted a mini-systematic review and meta-analysis on randomized controlled trials comparing exercise training with usual care in patients with severely reduced left ventricular ejection fraction, for the mortality subsection to obtain precise estimates of overall treatment benefit on mortality. It is our privilege to submit our manuscript for possible publication in your prestigious journal.

Neurohormonal Changes in the Gut-Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery.

Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut–brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut–brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed.

Long Term Impact of Epicardial Left Atrial Appendage Ligation on Systemic Hemostasis: LAA HOMEOSTASIS-2.

Background: Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. Objective: To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. Methods: In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. Results: In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. Conclusions: Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction.

Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction

ABSTRACT Introduction Sacubitril/valsartan is the first-in-class angiotensin-receptor neprilysin inhibitor approved in 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF). On 16 February 2021, the Food and Drug Administration acknowledged that “Benefits are most clearly evident in patients with left ventricular ejection fraction below normal,” thus potentially extending the use in subjects with heart failure and preserved ejection fraction (HFpEF). Areas covered The authors outline the regulatory history, pharmacokinetics, pharmacodynamics, and risk-benefit profile of sacubitril/valsartan in HFrEF and HFpEF. A critical cross-trial comparison is presented, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), together with an insight into the latest European Society of Cardiology guidelines, where the new category of heart failure with mildly reduced ejection fraction is introduced. Expert opinion Sacubitril/valsartan is a foundation of the pharmacological armamentarium in HFrEF to counteract the neuro-hormonal changes and reverse cardiac remodeling, together with beta-blockers, SGLT2i and mineralocorticoid receptor antagonists. The optimal sequence algorithm is an evolving issue, and the authors provide the reader with their personal perspective. A multidisciplinary management is encouraged to minimize the therapeutic inertia and manage tolerability issues, thus supporting adherence. Pragmatic trials, pharmacovigilance, and high-quality real-world evidence are crucial toward personalized safe prescribing of sacubitril/valsartan.

Neurobiology of phenotypic plasticity in the light of climate change

Abstract Phenotypic plasticity describes the ability of an organism with a given genotype to respond to changing environmental conditions through the adaptation of the phenotype. Phenotypic plasticity is a widespread means of adaptation, allowing organisms to optimize fitness levels in changing environments. A core prerequisite for adaptive predictive plasticity is the existence of reliable cues, i.e. accurate environmental information about future selection on the expressed plastic phenotype. Furthermore, organisms need the capacity to detect and interpret such cues, relying on specific sensory signalling and neuronal cascades. Subsequent neurohormonal changes lead to the transformation of phenotype A into phenotype B. Each of these activities is critical for survival. Consequently, anything that could impair an animal’s ability to perceive important chemical information could have significant ecological ramifications. Climate change and other human stressors can act on individual or all of the components of this signalling cascade. In consequence, organisms could lose their adaptive potential, or in the worst case, even become maladapted. Therefore, it is key to understand the sensory systems, the neurobiology and the physiological adaptations that mediate organisms’ interactions with their environment. It is, thus, pivotal to predict the ecosystem-wide effects of global human forcing. This review summarizes current insights on how climate change affects phenotypic plasticity, focussing on how associated stressors change the signalling agents, the sensory systems, receptor responses and neuronal signalling cascades, thereby, impairing phenotypic adaptations.

“Rehospitalization Prognostic Factors In Patients with Heart Failure”

Introduction: The prognosis of chronic heart failure (CHF) is determined by the complex relationship of neurohormonal, mechanical and polyorgan pathological changes emerging in the course and progression of the disease.
 Objective: To assess the risk and rate of rehospitalisation due to decompensation of chronic heart failure (CHF) in relation to certain biologic, clinical and instrumental characteristics.
 Material and Methods: This study conducted in the Department of Cardiology, Community Based Medical College & Hospital, Bangladesh. Prospective study on 228 consecutive CHF patients. The follow-up period was 12 to 24 months. The primary endpoint was rehospitalization due to HF decompensation. The risk values were calculated using the Cox regression models. 
 Results: Median survival time was 8 months. The total number of rehospitalizations was 86 (37.7%). Rehospitalization risk values were insignificantly lower in women (HR 0.7, 95% CI 0.4-1.1, р >0.05) and higher in older age groups (HR 1.4 95% CI 0.8-2.2, р>0.05). Univariate regression analysis showed a higher rehospitalization risk in patients with survived myocardial infarction, clinical signs of CHF, high functional class and pulmonary pressure. Multivariate regression analyses revealed the leading role of functional class on rehospitalization risk. 
 Conclusion: rehospitalization rates due to decompensation of CHF are high. Age and gender are insignificant predictors for rehospitalization in our study. Functional class is the prognostic factor with an independent effect on rehospitalization risk over the defined follow-up period among the examined group of patients.

Diagnosis and Management of Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes. We reviewed available literature from MEDLINE for randomized controlled trials, cohort studies, cross-sectional studies, and real-world outcomes using the search terms "cirrhotic cardiomyopathy," "left ventricular diastolic dysfunction," "heart failure in cirrhosis," "liver transplantation," and "coronary artery disease". Cirrhotic cardiomyopathy is associated with increased risk of complications such as hepatorenal syndrome, refractory ascites, impaired response to stressors including sepsis, bleeding or transplantation, poor health-related quality of life and increased morbidity and mortality. The evaluation of cirrhotic cardiomyopathy should also guide the feasibility of procedures such as transjugular intrahepatic portosystemic shunt, dose titration protocol of betablockers, and liver transplantation. The use of targeted heart rate reduction is of interest to improve cardiac filling and improve the cardiac output using repurposed heart failure drugs such as ivabradine. Liver transplantation may also reverse the cirrhotic cardiomyopathy; however, careful cardiac evaluation is necessary to rule out coronary artery disease and improve cardiac outcomes in the perioperative period. More data are needed on the new diagnostic criteria, molecular and biochemical changes, and repurposed drugs in cirrhotic cardiomyopathy. The use of advanced imaging techniques should be incorporated in clinical practice.

Circadian regulation of cardiac metabolism.

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day-dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock - through a network of a core clock, slave clock, and effectors - exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.

Seasonal variation in neurohormones, mood and sleep in patients with primary open angle glaucoma – implications of the ipRGC-system

ABSTRACT Primary open angle glaucoma is associated with an increased risk of mood and sleep disorders. These adversities have been suggested to relate to a disrupted function of the intrinsically photosensitive retinal ganglion cells (ipRGCs). The ipRGCs are key components in the nonvisual photoreceptive system that mediates light effects on mood, sleep and circadian rhythm. We assessed the diurnal hormone levels, pupillary responses and mood and sleep under seasons with different photoperiods in 24 patients with glaucoma and 24 age- and sex-matched healthy controls to investigate responses to naturalistic seasonal changes in daylight. The patients had moderate-to-advanced glaucoma with substantial visual field defects and reductions in the ipRGC-mediated pupillary responses (p < .001). In winter, compared with summer, patients with glaucoma had higher daytime melatonin concentration (p < .001) and lower nighttime cortisol (p = .002). In winter, the daytime melatonin level was inversely correlated with the ipRGC-mediated pupillary responses in the control group (p = .04). In the control group, there were no significant changes in hormone levels between seasons or any correlations between neurohormone levels and the ipRGC-mediated responses. The two groups showed a similar response to season with lower depression scores in summer compared with winter. In between-group comparison, the nocturnal melatonin level (area under curve from 20:00 h to 08:00 h) in summer was lower in glaucoma compared with controls (p = .03). In winter, nocturnal cortisol (at 04:00 h) was lower (p = .004) and daytime cortisol (12:00 h and 16:00 h) was higher (p = .007) in glaucoma compared with controls. In conclusion, we found that patients with glaucoma displayed a seasonal variation in diurnal hormone levels that was not present in healthy controls. Such neurohormonal changes may contribute to the increased risk of mood and sleep disorders seen in patients with glaucoma.