Progression Of Cardiovascular Pathology Research Articles

Cardiac Remodeling in Aged Rats after Early-life Chronic Stress: Sex-specific Outcomes and Associations with Metabolic Parameters

Cardiovascular disease is the leading cause of death worldwide. Additionally, the incidence of cardiovascular disease varies both across the lifespan and between sexes. While multiple factors influence the development and progression of cardiovascular pathology, prolonged stress is a prominent risk factor for adverse cardiac events. However, the interactions between stress, sex, and aging that impact cardiac susceptibility remain to be determined. To this end, we examined hypertrophy of the aged myocardium in a sex- and stress-specific manner. We hypothesized that sex and stress history would interact to predict cardiac outcomes and that susceptibility/resilience would associate with behavioral, endocrine, and metabolic parameters assessed across the lifespan. In this study, rats were either exposed to chronic variable stress (CVS) in late adolescence (n = 36/sex) or remained as unstressed controls (n = 24/sex). Rats were subsequently challenged with a forced swim test (FST) and glucose tolerance test (GTT) before ageing to 15 months. The FST and GTT were then repeated prior to tissue collection. Cardiac tissue was processed for histological analysis and quantification of ventricular morphology. The data indicated that early-life chronic stress had sex-specific consequences on the aged left ventricle as CVS females had greater concentric hypertrophy. Based on the level of inward remodeling, rats were then classified as susceptible or resilient. Multiple behavioral and endocrine factors in young and aged animals significantly interacted with hypertrophy, including coping behaviors and glucocorticoid responses to hyperglycemia. However, correlations with hypertrophy were only present in males. Male rats that were not exposed to CVS had a positive association between baseline corticosterone and hypertrophy. Alternatively, CVS males had a positive correlation between visceral adiposity and hypertrophy. Thus, sex-specific cardiac susceptibility/resilience relates to endocrine and metabolic measures depending on stress history. This outcome suggests that adverse experiences can have lasting impacts on homeostatic adaptation. Ultimately, these results highlight the importance of sex and prior stress exposure for disparities in cardiovascular risk. NIH R01 HL 150559 (B Myers) NIHH F30 OD032120 (C Dearing) Pilot Translation Research Program grant from the University of Cincinnati (B Myers). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The multifaceted actions of the lncRNA H19 in cardiovascular biology and diseases.

Cardiovascular diseases are the leading cause of death and debility worldwide. Various molecular mechanisms have been studied to better understand the development and progression of cardiovascular pathologies with hope to eradicate these diseases. With the advancement of the sequencing technology, it is revealed that the majority of our genome is non-coding. A growing body of literature demonstrates the critical role of long non-coding RNAs (lncRNAs) as epigenetic regulators of gene expression. LncRNAs can regulate cellular biological processes through various distinct molecular mechanisms. The abundance of lncRNAs in the cardiovascular system indicates their significance in cardiovascular physiology and pathology. LncRNA H19, in particular, is a highly evolutionarily conserved lncRNA that is enriched in cardiac and vascular tissue, underlining its importance in maintaining homeostasis of the cardiovascular system. In this review, we discuss the versatile function of H19 in various types of cardiovascular diseases. We highlight the current literature on H19 in the cardiovascular system and demonstrate how dysregulation of H19 induces the development of cardiovascular pathophysiology.

Risks of developing cardiovascular diseases and modern approaches to their reduction

The risks of developing diseases of the cardiovascular system were analyzed. The causes of cardiovascular risks and arterial hypertension can be diseases of the kidneys, central nervous system, endocrine system, vascular disease. The use of nutrient complexes aimed at the prevention of diseases of the cardiovascular system can be used to regulate metabolic disorders, control body weight, normalize fat metabolism, regulate blood pressure and progression of cardiovascular pathology and improve the quality of life in different age groups.

Two case reports: clinical experience with fixed combinations of indapamide/perindopril and amlodipine/perindopril in patients with arterial hypertension during the COVID-19 pandemic

The article, using the example of two clinical cases, discusses the severity of the course of COVID-19 depending on the presence of cardiovascular diseases and the effectiveness of their treatment. Randomized clinical trials and meta-analyses of the coronavirus infection indicate a greater likelihood of developing severe forms of COVID-19 in patients with high and very high cardiovascular risk, in older age groups, with comorbid pathology, especially with arterial hypertension (AH), coronary heart disease (CHD), chronic heart failure (CHF), diabetes mellitus (DM). Considering effectiveness, safety and influence on the prognosis, an adequately selected therapy for concomitant diseases can reduce the number of adverse outcomes of the coronavirus infection. A key role in the development and progression of cardiovascular pathology is played by the renin-angiotensin-aldosterone system (RAAS), so RAAS blockers remain the first-line medicine in the treatment of cardiac patients. The experts of the European Society of Cardiology, the American College of Cardiology and the Russian Society of Cardiology confirm the importance of continuing therapy with this class of medicine in patients having already received RAAS blockers according to such indications as AH, CHD and CHF during COVID-19 and emphasize the danger of their cancellation in high-risk patients. Most patients need to take several groups of medicine which affect complementary pathogenetic mechanisms. It is shown that the reason for the lack of achieving blood pressure control in clinical practice is monotherapy or non-optimally combined therapy of free acceptable but not rational combinations of antihypertensive medicine. Optimization of the therapeutic regimen using fixed combinations of indapamide/perindopril and amlodipine/perindopril has made it possible to achieve an effective reduction in blood pressure according to routine measurement and ambulatory blood pressure monitoring, to reduce blood pressure variability, to increase patients’ adherence to the treatment. The use of such medicine is becoming the most relevant during the COVID-19 pandemic.

Endothelial function status in hypogonadal men

Background: Type 2 diabetes mellitus (T2DM) and hypogonadism are mutually aggravating diseases associated with the development and progression of cardiovascular pathology. The status of endothelial function in men with T2DM and hypogonadism hasn’t been studied.Aims: To assess the effect of hypogonadism on endothelial function in men with T2DM.Materials and methods: Patients underwent clinical studies, assessment of carbohydrate and lipid metabolism, the content of sex hormones (total testosterone (T), sex hormones binding globulin, free T, luteinizing hormone) and markers of endothelial function (nitric oxide (NO), endothelial nitric oxide synthase type 3 (eNOS3), endothelin, adhesion molecules ICAM-1, VCAM-1, p- and e-selectins, cadherin), ultrasound examinations of endothelium-dependent vasodilation (EDVD) of the brachial artery (BA) and carotid arteries with an assessment of the thickness of intima-media complex (TIM) were performed.Results: The study included 276 men with T2DM (age 54.0[49;60] years), who were divided into 2 groups: 1–124 patients with hypogonadism; 2–152 eugonadal patients. Reduction of the endothelial vasomotor function was detected in 32.4% of patients in the 2st group and in 55.3% of the 1nd group (χ2=6.1; p=0.01), which was associated with a decrease in EDVD by 29.8 % (p<0.001) and an increase in the time of development of maximal BA vasodilation by 30 seconds in patients with hypogonadism (p<0.001). The TIM of the carotid arteries was 10% more in group 1 compared with group 2 (p=0.03). The ­level of NO in the 1st group was reduced by 1.6 times (p=0.001), eNOS3–by 1.5 times (p=0.038) compared with the 2nd group. The concentrations of adhesion molecules were higher in group 1 compared to group 2: VCAM-1 by 32.5% (p<0.001), ICAM-1 by 43.5% (p<0.001), p-selectin–by 19.3% (p=0.004), cadherin–6 times (p<0.001).Conclusion: Hypogonadism in men with T2DM is associated with the development of endothelial dysfunction, which manifests in a weakening of the EDVD and a slowdown in its development, as well as disturbances of the secretory activity of endothelium–a decrease in NO synthesis and activation of the adhesion molecules expression, which can be regarded as an universal pathogenetic mechanism of the development of cardiovascular diseases in combination of T deficiency and T2DM.

Resilience, Cardiological Outcome, and Their Correlations With Anxious-Depressive Symptoms and Quality of Life in Patients With an Implantable Cardioverter Defibrillator.

Background: Resilience is proven as a protective factor against the development of psychiatric disorders, and it has gained clinical relevance in the development and progression of cardiovascular pathology. The authors performed a longitudinal study on patients with implantable cardioverter defibrillator (ICD) with the primary aim to highlight the possible existence of a correlation between individual resilience capacity, depressive and anxiety symptoms, and quality of life in terms of outcomes. The secondary aim was to analyze the differences between patients with major cardiac events in the follow-up and patients without cardiac events with respect to the previous variables.Materials and Methods: A total of 80 patients enrolled in the Cardiology Unit were evaluated at T0 and during the follow-up through the following scales: the 14-item Resilience Scale (RS-14), the Hospital Anxiety and Depression Scale (HADS), and the World Health Organization Quality of Life-Brief Version (WHOQOL-Bref).Results: A significant linear correlation between resilience and all the areas of quality of life at T0, T1, and T2 emerged. A negative correlation between resilience and anxiety and depressive symptoms emerged, as well as between depression and anxiety and quality of life. Patients with cardiac events during the follow up have shown a worse quality of life and the onset of anxiety-depressive symptoms over time, without changes to the resilience scores. Patients without cardiac events showed an increasing trend in resilience scores.Discussion: Given the speed and simplicity of use of the RS-14 scale, it seems promising to further investigate the real clinical usefulness of this instrument in the cardiology field.

Coexistent rheumatoid arthritis and hyperuricemia: clinical and immunological features

BACKGROUND: Currently, the negative role of asymptomatic hyperuricemia (HU) in the development and progression of cardiovascular pathology, metabolic disorders and chronic kidney disease is generally recognized. There is not much data in the literature on the effect of HU on the course of rheumatoid arthritis (RA), therefore, the study of the relationship of HU with clinical, radiological and immunological features of RA seems relevant.
 AIM: To study the relationship between HU with the clinical, radiological and immunological features of RA.
 MATERIALS AND METHODS: The data of 262 patients with RA and HU and 262 with RA without HU (comparison group) included in the city register from January 2000 to April 2020 have been analyzed. The information included demographic features (gender, age), diagnosis, presence and duration of HU, duration of observation, disease activity, laboratory, immunological, radiological and functional parameters, therapy of the underlying disease. HU was understood as a recorded 1-fold increase in the level of uric acid (UA) in the blood serum 360 mmol/l. The study has been approved by the local ethics committee.
 RESULTS: The data of 524 patients with rheumatoid arthritis for the period from January 2000 to April 2020 have been analyzed. The study included 440 women and 84 men. The average age of the patients was 60.0 13.6 y. The patients with HU have been divided into two subgroups: the first with the level of UA less than 500 mmol/l, the second with the level of UA more than 500 mmol/l. The number of males was significantly higher among the patients with high HU than among the patients with low HU and the comparison group. Every third patient had significant structural changes in the joints (radiological stage III-IV) and 98% of the patients had moderate and pronounced functional limitations (functional class 2-3). The patients with HU were older, had more follow-up visits, were observed for a longer period of time, had a lower frequency of radiological progression, a greater number of painful and swollen joints, less often and at a smaller dose had methotrexate and more often sulfasalazine in comparison with the patients without HU (p 0.05).
 CONCLUSIONS: 1) Thus, we can emphasize the negative impact of hyperuricemia on the course of rheumatoid arthritis: if it is present, there are direct (more PJ, SJ) and indirect signs of a more severe course (longer duration of observation and the number of visits). 2) Immunosuppressive therapy is associated with the absence of differences with the generally recognized markers of disease activity (ESR, CRP, DAS28), the immunological profile (RF, ACCP) and the ambiguous relationship with radiological progression and functional insufficiency of the joints, as well as unreliable relationship with a higher frequency of bone density reduction.

MODERN ASPECTS OF FREE RADICAL PATHOLOGY (LITERATURE REVIEW AND OWN RESEARCH)

Today, there have been numerous studies that show the emergence and development of various pathologies accompanied by the activation of free radical reactions. It should be noted that the current clinical experience and results of experimental studies indicate the important role of oxidative stress in the formation and progression of cardiovascular pathology, and a series of reports are devoted to the study and comparison of the distinctive features of free radical lipid oxidation and proteins in patients with endothelial dysfunction and various functional classes of angina. Despite the considerable period that has elapsed since the Chernobyl disaster, the medical and biological problems of long-term effects of ionizing radiation are remaining relevant. However, it should be noted that according to some authors, the ideas of lipid peroxidation, mainly based on in vitro studies, do not meet the requirements for recognizing the existence of a metabolic process or metabolic pathway. In recent years, the Department of Internal Medicine # 3 with Phthisiology has conducted the number of multidirectional studies focused on various aspects of free radical pathology in experimental and clinical medicine on cardiology, nephrology, immunology, haematology, pulmonology, and gastroenterology. According to the results of the literature review and comprehensive analysis of the conducted research, we can point out that the study of the role of free radical processes in experimental and clinical medicine is still remaining quite relevant. The scientific search and practical value of these studies can lead to new insight in the context of an overall deterioration of the environment and exposure to negative environmental factors.

CARDIOPSYCHIATRY. PROBLEMS OF TRANSLATION

Cardiopsychiatry is relatively new field in medicine that studies psychic disorders (PD) having common pathological pathways with cardiovascular pathology (CVP). Most of them are related to stress and present with disordered neuronal activity. A working classification is proposed for PD in cardiopsychiatry. PD might be caused by: threat from actual CVP (type 1), other threatening situation (type 2a — in persons without CVP, type 2b — if CVP), “causal” non-threatening situation or even not known factors (type 3a — if without CVP, type 3b — with CVP). Literature data suggest that 2a PD does increase (though temporarily) the risk of CVP. Also the 2b PD enforces progression of CVP (possible only in specific pathogenetic variant of disease). Studies of other PD types are demanded. The review includes tables that make visible the relations of multiple terms used for PD. Information on rational selection of psychotropic drugs is provided.

The role of mineral and bone disorders in the development and progression of cardiac and renal pathology in patients with type 1 diabetes mellitus of long duration

AimsThe objective of our study was to evaluate the role of mineral and bone metabolism disorders associated with chronic kidney disease (MBD-CKD) in the development and progression of cardiac and renal pathology in patients with type 1 diabetes mellitus (T1DM) of long duration. MethodsWe investigated 96 patients with T1DM of long duration, with CKD at different stages (0–5), including patients on hemodialysis (HD) and with kidney transplantation (KT). Along with overall clinical examination, we assessed markers of MBD (calcium, phosphorus, parathormone, vitamin D, fibroblast growth factor (FGF) 23) and levels of cardiac injury marker (atrial natriuretic peptide, NT-proBNP). Multispiral computer tomography with Agatston index calculation was also included. ResultsDecreased kidney function was associated with increased of levels phosphorus, parathormone, FGF 23, and vitamin D deficiency, with the highest deviation from the reference ranges seen in patients on HD with a very high risk of cardiovascular events. In KT patients with satisfactory graft function, these parameters were at the same levels as in patients with CKD stages 0–4. Progression of cardiovascular pathology was accompanied by elevation of NT-proBNP levels as CKD duration increased, decreased glomerular filtration rate, and were correlated with the main parameters of mineral homeostasis. The severity of coronary arteries calcification was associated with patient age and duration of T1DM and arterial hypertension. ConclusionsDevelopment and progression of kidney dysfunction is accompanied by MBD, a significant factor in progression of cardiac pathology, which remains a major cause of mortality in this patient population.

Mitochondrial dynamics, mitophagy and cardiovascular disease.

Cardiac hypertrophy is often initiated as an adaptive response to haemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As the myocardium is a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. 'Mitochondrial dynamics', the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality and abundance have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischaemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases.

Abstract 619: Blockage Of Toll-Like Receptor 4 Inhibits Renin Stimulation Of NF-KB-Mediated Cytokine Signaling In Brain Neurons

Toll-like receptor 4 (TLR4) has been shown to play an important role in inflammation and initiation and progression of cardiovascular pathologies. This, coupled with the observation that activation of the brain (pro)renin receptor (PRR) initiates NF-Kappa B (KB) -cytokine signaling to induce neurogenic hypertension has led us to hypothesize that brain PRR activation, in part, stimulates TLR4 to induce NF-KB-cytokine signal pathway. Thus, blockage of TLR4 should attenuate the expression of NF-KB and proinflammatory cytokines induced by PRR activation. To test this hypothesis, we harvested neuronal cells from neonatal Sprague Dawley rat brain that abundantly express PRR, and incubated with 20 nM of renin for 6 hours. Real time PCR was performed to analyze expression of NF-KB and other inflammatory mediators. Renin treatment resulted in significant increases in interleukin-1 β (IL-1β, 1200-fold), IL-6 (33-fold), tumor necrosis factor (TNF-α, 17-fold), leukemia inhibitory factor (LIF, 18-fold) and C-C ligand 5 (CCL5, 330-fold). In addition, the mRNA levels of P50, a subunit of NF-KB was increased by 5-fold, and nfkbia, a subunit of I-kappa B kinase (IKK), was increased by 7-fold. Furthermore, mRNA levels of inducible nitric oxide synthase (iNOS) was increased by 8000-fold, and a neuronal activation maker, c-FOS was increased by 28 fold as compared with control neurons. However, Quinazoline (10μM), a NF-KB activation inhibitor, effectively blocked renin-induced increases in IL-1β, IL-6, TNF-α, CCL5, iNOS and P50 by more than 85%, but failed to inhibit LIF, nfkbia and c-FOS. In contrast, renin stimulation of all the above genes (IL-1β, IL-6, TNF-α, CCL5, iNOS, LIF, P50, nfkbia and c-FOS) was almost entirely blocked (>90%) by the TLR4 inhibitor, TAK-242 (2 μM), indicating a novel PRR mediated activation of TLR4 signaling. This PRR regulation of neuronal inflammatory mediators and neuronal activity was not affected by AT1 receptor antagonist losartan, demonstrating that the effect is not mediated by PRR-induced Ang-II generation. Our studies suggest that PRR plays a central role in the development of inflammatory mediated neurogenic hypertension through activation of TLR4.

Toll-like receptors in cardiovascular diseases.

The Toll-like receptor family recognizes mostly exogenous ligands like bacterial lipopolysaccharides or DNA and activates the inflammatory cell. Evidence is accumulating that these Toll-like receptors are important in cardiovascular pathologies. Recently, expression of Toll-like receptors in arterial and myocardial cells has been shown and mouse knockout and human studies on polymorphisms point to a role of Toll-like receptor 4 in neointima formation and atherosclerosis. It is now becoming clear that these receptors not only serve as receptors for pathogen-associated molecular patterns but are also involved in the initiation and progression of cardiovascular pathologies.

Cardiac autonomic reactivity and salivary cortisol in men and women exposed to social stressors: relationship with individual ethological profile

The degree of cardiovascular stress responsivity and its possible implications for the onset and progression of cardiovascular pathologies seem to be linked to the individual strategy of behavioral coping with stressors. This study was designed to investigate the relationship among cardiac autonomic, endocrine and behavioral responses to real-life stress episodes. Thirty university students were exposed to two brief social challenges (stress interviews), during which the state of sympathovagal balance (time-domain indexes of heart rate variability) and a number of non-verbal behaviors were quantified. Psychometric measurements were also obtained via SPRAS questionnaire, administered just after each stress interview. Samples of saliva were collected for cortisol determination immediately prior and after the experimental session. Subjects showing higher levels of sympathetic dominance were characterized by higher scores of submissive behavior, larger cortisol increments, and higher perception of psychophysiological arousal. A clear consistency in the individual response to the two stress interviews was found, at the behavioral, physiological and psychophysiological level. Finally, the gender of the subjects did not clearly influence their stress responsivity. These results support the hypothesis of a close relationship between the degree of physiological arousal and the style of behavioral adaptation to social stressors.

The wnt-frizzled cascade in cardiovascular disease.

Time for primary review 31 days. Wnt-proteins constitute a family of secreted cystein-rich glycosylated proteins, involved in a variety of modeling and remodeling processes including cell proliferation, differentiation, apoptosis and the control of cell orientation [1–3]. Malfunctioning of the wnt-frizzled pathway has been implied in diseases as divergent as cancer and Alzheimer's disease [1,4]. The wnt-frizzled signal transduction pathway plays an important role during non-vertebrate and vertebrate development [5]. Several studies have shown the importance of wnts in the control of processes such as patterning of the body axis and development of the central nervous system and the limbs [6,7]. Moreover, interventions in wnt signaling have been described to affect cardiac morphogenesis [8,9] and several members of the wnt-frizzled signal transduction pathway were found to be expressed during cardiac development in vertebrates [10–14]. In cardiovascular pathology, re-expression of a fetal gene expression pattern is a generally observed phenomenon [15]. The study of gene expression during development may therefore provide clues about the expression profile during cardiovascular pathology. Recently, considerable progress has been made concerning the role of the wnt-frizzled signal transduction pathway in the development and progression of cardiovascular pathology. This review will focus on the possible role of the wnt-frizzled signal transduction pathway in cardiovascular diseases. The family of wnt proteins consists of 16 members [5]. These proteins are extremely difficult to purify because they tend to bind to the extracellular matrix [16], which hampers the study of their characteristics. An overview of the wnt proteins and their proposed function during development, derived from the study of null mutants, is provided in Table 1. Based on functional differences, wnt proteins can be divided into two classes, the wnt1 class and the wnt5a class. Members of the wnt1 class are able … * Corresponding author. Tel.: +31-43-388-1417; fax: +31-43-388-4149 wm.blankesteijn{at}farmaco.unimaas.nl