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Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Aims
Neprilysin degrades natriuretic peptides in circulation and is also suggested to degrade the gut hormones gastrin and cholecystokinin. Neprilysin inhibition has become a therapeutic strategy and thus a regimen in need of further testing in terms of other hormonal axes besides natriuretic peptides. The aim of this study was to examine whether acute inhibition of neprilysin affects meal-induced responses in gastrin and cholecystokinin concentrations in healthy individuals.
Methods and results
Nine healthy young men were included in an open-labelled, randomized cross-over clinical trial. The participants received a standardized meal (25 g fat, 26 g protein, 42 g carbohydrate) on two separate days with or without a one-time dosage of sacubitril ((194 mg)/valsartan (206 mg)). Blood pressure, heart rate and blood samples were measured and collected during the experiment. Statistical differences between groups were assessed using area under the curve together with an ANOVA with a Bonferroni post hoc test. Sacubitril/valsartan increased the postprandial plasma concentrations of both gastrin and cholecystokinin (80% (AUC0-270 min, P = 0.004) and 60% (AUC0-270 min, P = 0.003), respectively) compared with the control meal. No significant hemodynamic effects were noted (blood pressure, AUC0-270 min, P = 0.86, heart rate, AUC0-270 min, P = 0.96).
Conclusion
Our study demonstrates that sacubitril/valsartan increases the postprandial plasma concentrations of gastrin and cholecystokinin in healthy individuals. The results thus suggest that neprilysin-mediated degradation of gastrin and cholecystokinin is physiologically relevant and may have a role in heart failure patients treated with sacubitril/valsartan.
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Porto, Portugal
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Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Porto, Portugal
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Thyroid hormones have a central role in cardiovascular homeostasis. In myocardium, these hormones stimulate both diastolic myocardial relaxation and systolic myocardial contraction, have a pro-angiogenic effect and an important role in extracellular matrix maintenance. Thyroid hormones modulate cardiac mitochondrial function. Dysfunction of thyroid axis impairs myocardial bioenergetic status. Both overt and subclinical hypothyroidism are associated with a higher incidence of coronary events and an increased risk of heart failure progression. Endothelial function is also impaired in hypothyroid state, with decreased nitric oxide-mediated vascular relaxation. In heart disease, particularly in ischemic heart disease, abnormalities in thyroid hormone levels are common and are an important factor to be considered. In fact, low thyroid hormone levels should be interpreted as a cardiovascular risk factor. Regarding ischemic heart disease, during the late post-myocardial infarction period, thyroid hormones modulate left ventricular structure, function and geometry. Dysfunction of thyroid axis might even be more prevalent in the referred condition since there is an upregulation of type 3 deiodinase in myocardium, producing a state of local cardiac hypothyroidism. In this focused review, we summarize the central pathophysiological and clinical links between altered thyroid function and ischemic heart disease. Finally, we highlight the potential benefits of thyroid hormone supplementation as a therapeutic target in ischemic heart disease.
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The concept of the heart as an endocrine organ arises from the observation that the atrial cardiomyocytes in the mammalian heart display a phenotype that is partly that of endocrine cells. Investigations carried out between 1971 and 1983 characterised, by virtue of its natriuretic properties, a polypeptide referred to atrial natriuretic factor (ANF). Another polypeptide isolated from brain in 1988, brain natriuretic peptide (BNP), was subsequently characterised as a second hormone produced by the mammalian heart atria. These peptides were associated with the maintenance of extracellular fluid volume and blood pressure. Later work demonstrated a plethora of other properties for ANF and BNP, now designated cardiac natriuretic peptides (cNPs). In addition to the cNPs, other polypeptide hormones are expressed in the heart that likely act upon the myocardium in a paracrine or autocrine fashion. These include the C-type natriuretic peptide, adrenomedullin, proadrenomedullin N-terminal peptide and endothelin-1. Expression and secretion of ANF and BNP are increased in various cardiovascular pathologies and their levels in blood are used in the diagnosis and prognosis of cardiovascular disease. In addition, therapeutic uses for these peptides or related substances have been found. In all, the discovery of the endocrine heart provided a shift from the classical functional paradigm of the heart that regarded this organ solely as a blood pump to one that regards this organ as self-regulating its workload humorally and that also influences the function of several other organs that control cardiovascular function.
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Background
A prolonged heart rate-corrected QT interval (QTc) has been associated with peripheral artery disease (PAD) in the general population. However, no study to date has identified a link between prolonged QTc and the severity of PAD in patients with diabetes mellitus and foot ulcers (DFUs). This study aimed to investigate this relationship.
Methods
This multicenter study enrolled 281 patients with DFUs. The severity of PAD was classified into no severe PAD group (without stenosis or occlusion) and severe PAD group (with stenosis or occlusion) based on duplex ultrasonography. The association of prolonged QTc with severe PAD was evaluated in a multivariable mixed-effect logistic regression model, with the hospital as a random effect. Directed acyclic graphs were used to drive the selection of variables to fit the regression model.
Results
Patients with severe PAD had longer QTc than those without. Based on the multivariable mixed-effect logistic regression model, a prolonged QTc was positively associated with severe PAD (odds ratio (OR) = 2.61; 95% CI: 1.07–6.35) and severe DFUs (Wagner grade score ≥ 3) (OR = 2.87; 95% CI: 1.42–5.81).
Conclusions
A prolonged QTc was associated with severe PAD in patients with DFUs. Further research is required to ascertain whether the association is causal.
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Department of Internal Medicine, Section of Metabolic Vascular Medicine, Division of Diabetes and Nutritional Sciences, Cardiovascular Endocrinology Laboratory, Faculty of Medicine, Hospital de Urgencias, National University of Córdoba, X5000 Córdoba, Argentina
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Since their discovery in 1981, the cardiac natriuretic peptides (cNP) atrial natriuretic peptide (also referred to as atrial natriuretic factor) and brain natriuretic peptide have been well characterised in terms of their renal and cardiovascular actions. In addition, it has been shown that cNP plasma levels are strong predictors of cardiovascular events and mortality in populations with no apparent heart disease as well as in patients with established cardiac pathology. cNP secretion from the heart is increased by humoral and mechanical stimuli. The clinical significance of cNP plasma levels has been shown to differ in obese and non-obese subjects. Recent lines of evidence suggest important metabolic effects of the cNP system, which has been shown to activate lipolysis, enhance lipid oxidation and mitochondrial respiration. Clinically, these properties lead to browning of white adipose tissue and to increased muscular oxidative capacity. In human association studies in patients without heart disease higher cNP concentrations were observed in lean, insulin-sensitive subjects. Highly elevated cNP levels are generally observed in patients with systolic heart failure or high blood pressure, while obese and type-2 diabetics display reduced cNP levels. Together, these observations suggest that the cNP system plays a role in the pathophysiology of metabolic vascular disease. Understanding this role should help define novel principles in the treatment of cardiometabolic disease.
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Medical Microbiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Physiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Objective
Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.
Design
A total of 16 females and 40 males, ages 23–68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort.
Results
Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.
Conclusions
This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
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High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
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Cardiovascular disease is the leading cause of death in general population. Besides well-known risk factors such as hypertension, impaired glucose tolerance and dyslipidemia, growing evidence suggests that hormonal changes in various endocrine diseases also impact the cardiac morphology and function. Recent studies highlight the importance of ectopic intracellular myocardial and pericardial lipid deposition, since even slight changes of these fat depots are associated with alterations in cardiac performance. In this review, we overview the effects of hormones, including insulin, thyroid hormones, growth hormone and cortisol, on heart function, focusing on their impact on myocardial lipid metabolism, cardiac substrate utilization and ectopic lipid deposition, in order to highlight the important role of even subtle hormonal changes for heart function in various endocrine and metabolic diseases.
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Thyroid hormone stimulates cardiac inotropy and chronotropy via direct genomic and non-genomic mechanisms. Hyperthyroidism magnifies these effects, resulting in an increase in heart rate, ejection fraction and blood volume. Hyperthyroidism also affects thrombogenesis and this may be linked to a probable tendency toward thrombosis in patients with hyperthyroidism. Patients with hyperthyroidism are therefore at higher risk for atrial fibrillation, heart failure and cardiovascular mortality. Similarly, TSH suppressive therapy for differentiated thyroid cancer is associated with increased cardiovascular risk. In this review, we present the latest insights on the cardiac effects of thyroid suppression therapy for the treatment of thyroid cancer. Finally, we will show new clinical data on how to implement this knowledge into the clinical practice of preventive medicine.
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark
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Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
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Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Objective
The aim was to examine the association between hospital-diagnosed overweight/obesity and incident CVD according to the time period of the overweight/obesity diagnosis.
Design
This is a cohort study.
Methods
From Danish national health registries, we identified all residents with a first-time hospital-based overweight/obesity diagnosis code, 1977–2018 (n = 195,221), and an age and sex-matched general population comparison cohort (n = 1,952,210). We computed adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox regression. We adjusted for comorbidities and educational level and applied 10 years of follow-up.
Results
The overall incidence rate was 10.1 (95% CI 10.0–10.1) per 1000 person-years for the comparison cohort and 25.1 (95% CI 24.8–25.4) per 1000 person-years for the overweight/obesity cohort, corresponding to an aHR of 2.5 (95% CI 2.4–2.5). The aHR was elevated for all subtypes of CVD: heart failure: 3.9 (95% CI 3.7–4.1), bradyarrhythmia: 2.9 (95% CI 2.7–3.1), angina pectoris: 2.7 (95% CI 2.7–2.8), atrial fibrillation or flutter: 2.6 (95% CI 2.5–2.6), acute myocardial infarction: 2.4 (95% CI 2.3–2.4), revascularization procedure: 2.4 (95% CI 2.2–2.5), valvular heart disease: 1.7 (95% CI 1.6–1.8), ischemic stroke: 1.6 (95% CI 1.4–1.7), transient ischemic attack: 1.6 (95% CI 1.5–1.7), and cardiovascular death: 1.6 (95% CI 1.5–1.6). The 1–10-year aHR of any CVD associated with an overweight/obesity diagnosis decreased from 2.8 (95% CI 2.7–2.9) in 1977–1987 to 1.8 (95% CI 1.8–1.9) in 2008–2018.
Conclusion
Patients with hospital-diagnosed overweight/obesity had high rates of ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and death, although the strength of the association decreased in recent years.
Significance statement
Obesity is linked to metabolic abnormalities that predispose individuals to an increased risk of subtypes of CVD. In this population-based nationwide 40-year cohort study, we found that of 195,221 patients with an overweight/obesity diagnosis, more than 31,000 (15.9%) were admitted to hospital within 10 years because of CVD; corresponding to a 2.5-fold greater relative risk of any CVD associated with overweight/obesity than in the general population. We observed an increased risk for most CVD subtypes, including ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and cardiovascular death, although the strength of the association decreased in recent years. Our study emphasizes the importance of improved clinical handling of obesity and underscores the need to prevent associated complications to alleviate the burden of obesity.
