Physiological research最新文献

Although the heart atria have a lesser functional importance than the ventricles, atria play an important role in the pathophysiology of heart failure and supraventricular arrhythmias, particularly atrial fibrillation. In addition, knowledge of atrial morphology recently became more relevant as cardiac electrophysiology and interventional procedures in the atria gained an increasingly significant role in the clinical management of patients with heart disease. The atrial chambers are thin-walled, and several vessels enter at the level of the atria. The left and right atrium have different structures and shape. In general, both atrial chambers have the venous part, the appendage, and the vestibule; different aspects of each part allow us to distinguish morphologically between the left and right atrium. The human atrial conduction system consists of the sinus node and the atrioventricular node with no histologically specialized conduction pathways in the atrial chamber and an interatrial connection. The data show that the propagation of the impulse depends mainly on the myocardial architecture in the atria and the orientation of the myocytes plays a significant role in conduction. To complete the picture, it is also important to know how the atria develop and what is the embryonic origin of its different structures, as this may play a role in the development of some pathological conditions such as atrial fibrillation or certain types of congenital heart defects. Functional impairment of the atria can in some situations severely compromise heart pumping function, and conversely, can support it if other areas are damaged, balancing the blood flow to the body for some time. Key words Morphology of atrial chambers, Pectinate muscles, Atrial function.

Adverse events during the perinatal period are associated with an increased risk to develop cardiometabolic diseases later in life. We established a murine model to study long-term effects of perinatal hypoxia (PH) on the pulmonary circulation. We previously demonstrated that PH led to an impaired regulation of pulmonary vascular tone in adulthood, linked to alterations in K+ channels in males and in the nitric oxide (NO)/cyclic guanosine monophosphate pathway in females. Moreover, simultaneous administration of inhaled NO (iNO) during PH exposure prevented adverse effects of PH on adult pulmonary vasculature in females. The present study showed that PH induced a significant increase in right ventricular pressure in males and females, and an enhanced sensitivity to acute hypoxia in females. PH significantly reduced acetylcholine-induced relaxation in pulmonary artery, to a greater extent in females than in males. PH led to right ventricular hypertrophy in adulthood, appearing earlier in males than in females. Morphometric measurements showed a significant increase in the number of 25-75-µm pulmonary vessels in male lungs following PH, probably resulting in increased pulmonary vascular resistance. The effects of prolonged hypoxia in adulthood differed between males and females. Perinatal iNO during PH prevented PH-induced alterations in the cardiopulmonary system, whereas perinatal iNO alone could have some adverse effects. Therefore, PH led to long-lasting alterations in the regulation of adult pulmonary circulation, which vary between males and females. In males, the increased pulmonary vascular resistance was associated with morphological changes besides functional alterations, whereas females showed an important pulmonary vascular dysfunction. Keywords: Perinatal hypoxia, Pulmonary circulation, Endothelium-dependent relaxation, Phosphodiesterases, Sex differences.

Pulmonary hypertension is a complex and heterogeneous condition with five main subtypes (groups). This review focuses on pulmonary hypertension caused by chronic hypoxia (hypoxic pulmonary hypertension, HPH, group 3). It is based mainly on our own experimental work, especially our collaboration with the group of Professor Herget, whose fifth anniversary of death we commemorate. We have found that oxidation and degradation of the extracellular matrix (ECM) in vitro, in either the presence or the absence of pro-inflammatory cells, activate vascular smooth muscle cell (VSMC) proliferation. Significant changes in the ECM of pulmonary arteries also occurred in vivo in hypoxic rats, namely a decrease in collagen VI and an increase in matrix metalloproteinase 9 (MMP-9) in the tunica media, which may also contribute to the growth activation of VSMCs. The proliferation of VSMCs was also enhanced in their co-culture with macrophages, most likely due to the paracrine production of growth factors in these cells. However, hypoxia itself has a dual effect: on the one hand, it can activate VSMC proliferation and hyperplasia, but on the other hand, it can also induce VSMC hypertrophy and increased expression of contractile markers in these cells. The influence of hypoxia-inducible factors, microRNAs and galectin-3 in the initiation and development of HPH, and the role of cell types other than VSMCs (endothelial cells, adventitial fibroblasts) are also discussed. Keywords: Vasoconstriction, Remodeling, Oxidation, Degradation, Extracellular matrix, Collagen, Proteolytic enzymes, Metalloproteinases, Macrophages, Mast cells, Smooth muscle cells, Endothelial cells, Fibroblasts, Mesenchymal stem cells, Hypoxia-inducible factor, microRNA, Galectins, Hyperplasia, Hypertrophy, Therapy of hypoxic pulmonary hypertension.

An important complication of prolonged support of the left ventricle with an assist device when implanted in patients with heart failure is unloading-induced cardiac atrophy. Our recent study suggested that sex-linked differences in the development of atrophy induced by heterotopic heart transplantation (HTX) do exist, however, the role of the environmental conditions dependent on plasma concentrations of sex hormones remains elusive. We aimed to compare the course of HTX-induced cardiac atrophy in male and female rats after gonadectomy with substitution of steroid hormones of the opposite sex. In a separate series of experiments, we evaluated the course of unloading-induced cardiac atrophy in the female heart transplanted into a male recipient and vice versa. Cardiac atrophy was assessed as the ratio of the transplanted heart weight to native heart weight (HW), which was determined 14 days after HTX. In female rats, studied in both experimental variants, HTx resulted in significantly smaller decreases in whole HW when compared to those observed in male rats exposed to the same experimental conditions (-9 ± 1 and - 11 + 1 vs. -44 ± 2 and -42 ± 2 %, p?0.05 in both cases). The dynamic of changes in left and right ventricle was similar as in the whole HW. Our results show that the process of unloading-induced cardiac atrophy exhibits important sex-linked differences and that attenuation of this process in female rats cannot be simply ascribed to the protective effects of estradiol or to the absence of deleterious actions of testosterone. Keywords: Cardiac atrophy, Sex differences, Gonadectomy, Hormonal substitution, Heterotopic heart transplantation, Mechanical heart unloading.

Hypoxic pulmonary vasoconstriction (HPV) rapidly and reversibly matches lung ventilation (V) and perfusion (Q), optimizing oxygen uptake and systemic oxygen delivery. HPV occurs in small pulmonary arteries (PA), which uniquely constrict to hypoxia. Although HPV is modulated by the endothelium the core mechanism of HPV resides in PA smooth muscle cells (PASMC). The PASMC's mitochondrial oxygen sensor lies within the electron transport chain (ETC) and includes NDUFS2 in ETC Complex-I. PASMC mitochondria respond to hypoxia by varying production of reactive oxygen species (ROS) and hydrogen peroxide in proportion to alveolar oxygen tension. Hypoxic ROS inhibition results in a state of reduction which triggers a redox-mediated inhibition of oxygen-sensitive, voltage-gated, potassium channels, including Kv1.5 and Kv2.1. Kv channel inhibition depolarizes the PASMC, opening of large-conductance calcium channels (CaL), elevating cytosolic calcium and activating the contractile apparatus. HPV is strongest in small PAs where sensors (hypoxia-responsive mitochondria) and effectors (oxygen-sensitive K+ channels) are enriched. Oxygenation at birth reverses fetal HPV, contributing to the rapid neonatal drop in pulmonary vascular resistance (PVR). A similar mitochon-drial-K+ channel sensor-effector mechanism exists in the ductus arteriosus (DA), however in DASMC it is oxygen-induced increases in mitochondrial ROS that inhibit DASMC K+ channels, causing DA constriction. Atelectasis and pneumonia elicit HPV, which optimises V/Q matching, increasing systemic oxygenation. Whilst HPV in response to localized hypoxia in a single lung lobe does not increase PA pressure; global airway hypoxia, as occurs with altitude or sleep apnea, causes pulmonary hypertension. HPV can be inhibited by drugs, including calcium channel blockers, or used to maintain a dry operative field during single lung anesthesia for lung surgery. HPV does not normally cause lung edema but excessive, heterogenous HPV contributes to high altitude pulmonary edema. HPV is suppressed in COVID-19 pneumonia by a SARS-CoV-2 mitochondriopathy. HPV is a component of the body's homeostatic oxygen sensing system. Keywords: Ductus arteriosus, Redox, NDUFS2, Oxygen sensitive potassium, Channels, High altitude pulmonary edema (HAPE), Mitochondrial electron transport chain, COVID-19 pneumonia, Atelectasis.

The fetus develops normally in a hypoxic environment but exaggerated hypoxia late in pregnancy is a worrisome sign often observed in hypertensive disorders of pregnancy, placental insufficiency, or fetal growth restriction (FGR). Serial fetal biometry and the cerebroplacental ratio (CPR, calculated as the middle cerebral artery [MCA] / the umbilical artery [UmbA] pulsatility indices [PI]), are commonly used to indicate fetal "brain sparing" resulting from exaggerated fetal hypoxia. But unclear is the extent to which a low CPR indicates pathology or is a physiological response for maintaining cerebral blood flow. We studied 31 appropriate for gestational age (AGA) pregnancies at low (LA, 1670 m) or high (HA, 2879 m) altitude, given the chronic hypoxia imposed by HA residence, and 54 LA women with a clinical diagnosis of FGR. At week 34, the MCA PI was lower in the LA-FGR than the LA-AGA group but lower still in the HA-AGA compared to either LA groups due to a trend toward higher end-diastolic velocity (EDV). We concluded that the lower MCA PI was likely due to greater cerebral vasodilation in the HA AGA group and an indication of physiological versus pathological fetal hypoxia. Future reporting of serial MCA and UmbA values and their determinants along with the CPR could improve our ability to distinguish between physiological and pathological fetal brain sparing. Keywords: Birth weight, Cerebroplacental ratio, Fetal physiology, HDP, High altitude.

Pulmonary arterial hypertension is characterized by perivascular and systemic inflammation. The gut microbiome influences the host immune system. Here we review the emerging preclinical and clinical evidence that strongly suggests that alterations in the gut microbiome may either initiate or facilitate progression of established pulmonary arterial hypertension by modifying the systemic immune responses. We also briefly review the relationship between the gut microbiome and preeclampsia, a vascular disease also characterized by inflammation. Key words: Dysbiosis, Right ventricle, Inflammation.

Chronic heart failure (CHF) is a rare entity in children but carries a burden of high mortality and morbidity. Medical treatment of pediatric CHF is largely based on guidelines for the adult population. In contrast to adults, evidence for the efficacy of medications in treating CHF in children is sparse. This may be due to the difficulty of conducting high-powered studies in children or to true differences in the mechanisms of CHF pathophysiology. Recent observations suggest that CHF in children differs from adults at the molecular and cellular levels. Different pathways are involved, leading to less fibrosis and hypertrophy than in adults, with potential implications for therapy. The main pathophysiological goals of medical treatment of pediatric CHF due to systemic left ventricular dysfunction are discussed in this review. These include preload and afterload optimization, diminishing cardiomyocyte apoptosis and necrosis as well as interstitial fibrosis, and optimizing myocardial oxygen consumption. The pediatric myocardium should be provided with optimal conditions to achieve its regenerative potential. The cornerstones of medical CHF therapy are angiotensin converting enzyme inhibitors (ACEI), beta blockers and mineralocorticoid receptor antagonists. There are potential benefits of tissue ACEI and ?1-selective beta blockers in children. Angiotensin receptor blockers are an alternative to ACEI and their slightly different mechanism of action may confer certain advantages and disadvantages. Diuretics are employed to achieve a euvolemic state. Digoxin is used more frequently in children than in adults. Promising new drugs already routinely used in adults include angiotensin receptor-neprilysin inhibitors and sodium-glucose contransporter 2 inhibitors. Key words: Pediatric heart failure, Heart failure with reduced ejection fraction (HFrEF), ACE inhibitor, Beta blocker, Digoxin.

The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction. Keywords: Secretory cells, Motile cilia, Epithelial barrier, Oxygenation, Obstructive respiratory diseases.

Schizophrenia, a severe psychiatric, neurodevelopmental disorder affecting about 0.29-1 % of the global population, is characterized by hallucinations, delusions, cognitive impairments, disorganized thoughts and speech, leading to significant social withdrawal and emotional blunting. During the 1980s, considerations about diseases that result from complex interactions of genetic background and environmental factors started to appear. One of the critical times of vulnerability is the perinatal period. Concerning schizophrenia, obstetric complications that are associated with hypoxia of the fetus or neonate were identified as a risk. Also, maternal infections during pregnancy were linked to schizophrenia by epidemiological, serologic and genetic studies. Research efforts then led to the development of experimental models testing the impact of perinatal hypoxia or maternal immune activation on neurodevelopmental disorders. These perinatal factors are usually studied separately, but given that the models are now validated, it is feasible to investigate both factors together. Inclusion of additional factors, such as metabolic disturbances or chronic stress, may need to be considered also. Understanding the interplay of perinatal factors in schizophrenia's etiology is crucial for developing targeted prevention and therapeutic strategies.