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In meiotic cells, chromosomes are organized as chromatin loop arrays anchored to a protein axis. This organization is essential to regulate meiotic recombination, from DNA double-strand break (DSB) formation to their repair. In mammals, it is unknown how chromatin loops are organized along the genome and how proteins participating in DSB formation are tethered to the chromosome axes. Here, we identify three categories of axis-associated genomic sites: PRDM9 binding sites, where DSBs form; binding sites of the insulator protein CTCF; and H3K4me3-enriched sites. We demonstrate that PRDM9 promotes the recruitment of MEI4 and IHO1, two proteins essential for DSB formation. In turn, IHO1 anchors DSB sites to the axis components HORMAD1 and SYCP3. We discovered that IHO1, HORMAD1, and SYCP3 are associated at the DSB ends during DSB repair. Our results highlight how interactions of proteins with specific genomic elements shape the meiotic chromosome organization for recombination.
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Roturas del ADN de Doble Cadena , N-Metiltransferasa de Histona-Lisina , Meiosis , Meiosis/genética , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Animales , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Histonas/metabolismo , Histonas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Sitios de Unión , Cromosomas/genética , Cromosomas/metabolismo , Cromatina/metabolismo , Cromatina/genética , Factor de Unión a CCCTC/metabolismo , Factor de Unión a CCCTC/genética , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Recombinación Genética , MasculinoRESUMEN
OBJECTIVES: Serum angiotensin-converting enzyme (ACE) is the only biomarker routinely used in the laboratory diagnostics of sarcoidosis, and ACE inhibitor (ACEi) drugs are among the most prescribed drugs worldwide. Taking ACEi can mislead medical teams by lowering ACE activity, delaying diagnosis and giving a false impression of disease activity of sarcoidosis. We aimed to develop a simple method to detect the presence of ACEi drugs in samples, to investigate the ACEi medication-caused interference and consequences in a retrospective study. METHODS: ACE activity and the level of ACE inhibition were determined for 1823 patients with suspected sarcoidosis. These values were compared with the therapeutic information at the first and follow-up visits. RESULTS: A total of 302 patients had biochemical evidence of an ACEi drug effect during diagnostic ACE activity testing. In their case, ACE activity was significantly lower (median(IQR): 4.41â¯U/L(2.93-6.72)) than in patients not taking ACEi (11.32â¯U/L(8.79-13.92), p<0.01). In 62 sarcoidosis patients, the ACEi reduced ACE activity to the reference range or below. Only in 40â¯% of the cases was the medication list recorded in the outpatient chart and only in 3 cases was low ACE activity associated with ACEi use. 67â¯% of the repeated ACE activity measurements were also performed during ACEi therapy. CONCLUSIONS: Our study revealed that the use of ACEi is common in patients with suspected sarcoidosis. The ACE activity lowering effect of ACEi drugs may escape the attention of medical teams which can lead to diagnostic errors and unnecessary tests. Nevertheless, these pitfalls can be avoided by using a method suggested by our team.
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Inhibidores de la Enzima Convertidora de Angiotensina , Peptidil-Dipeptidasa A , Sarcoidosis , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/diagnóstico , Sarcoidosis/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Peptidil-Dipeptidasa A/sangre , Adulto , Biomarcadores/sangreRESUMEN
Background: Atrial fibrillation (AF) is accompanied by inflammation and fibrosis to variable extent. The biomarkers of fibrosis were measured in patients with different forms of AF and cardiac status. Herein, we assessed the associations of the baseline concentrations of different biomarkers with the long-term success of pulmonary vein isolation (PVI) in patients with a structurally normal heart. Furthermore, we compared biomarker levels before and 3 years after ablation to gain further insights into the AF mechanism. Methods: Patients, undergoing PVI for paroxysmal/persistent AF were enrolled prospectively. Blood samples were obtained 24 hours before and 3 years after ablation. Serum cancer antigen 125 (CA-125), plasma Caspase-3, Galectin-3 and Cathepsin L concentrations were measured. Follow-up visits every 6 months included 12-lead electrocardiogram, 24-hour Holter, trans-telephonic monitoring as well as transthoracic echocardiography after ablation. Biomarker levels, left ventricular ejection fraction and left atrial (LA) diameters at baseline and at the 3-year follow-up were compared in patients with versus without AF recurrence. Results: A total of 63 patients were enrolled (23 women; age 61.4 ( ± 8.8) years). The acute isolation of all pulmonary veins was achieved in all patients. During a mean follow-up of 36.3 ± 6.3 months, AF recurrence was demonstrated in 26 (41.3%) patients. No significant differences were demonstrated in the levels of CA-125, Galectin-3, Caspase-3 and Cathepsin L pre- and post-ablation in patients with versus without AF recurrence. A significant decrease was detected in the concentrations of Caspase-3, Galectin-3 and Cathepsin L during follow-up with no difference in patients with versus without AF recurrence. A positive correlation was found between Caspase-3 levels and LA diameters in the AF recurrence group both before (r = 0.477; p = 0.018) and after the procedure (r = 0.533; p = 0.019). Conclusions: Our results demonstrated that the levels of CA-125, Caspase-3, Cathepsin L and Galectin-3 are not associated with AF recurrence after PVI in patients with a structurally normal heart and mainly paroxysmal AF. Except for CA-125, all the other biomarkers demonstrated a significant decrease during a 3-year follow-up post-ablation. Furthermore, Caspase-3 levels demonstrated a positive correlation with LA dimensions in patients with AF recurrence.
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The estrus cycle in female rodents has been shown to affect a variety of physiological functions. However, little is known about its presumably thorough effect on auditory processing during the sleep-wake cycle and sleep deprivation. Vertex auditory evoked potentials (vAEPs) were evoked by single click tone stimulation and recorded during different stages of the estrus cycle and sleep deprivation performed in metestrus and proestrus in female rats. vAEPs showed a strong sleep-dependency, with the largest amplitudes present during slow wave sleep while the smallest ones during wakefulness. Higher amplitudes and longer latencies were seen in the light phase during all vigilance stages. The largest amplitudes were found during proestrus (light phase) while the shortest latencies were seen during estrus (dark phase) compared to the 2nd day diestrus baseline. High-amplitude responses without latency changes were also seen during metestrus with increased homeostatic sleep drive. More intense and faster processing of auditory information during proestrus and estrus suggesting a more effective perception of relevant environmental cues presumably in preparation for sexual receptivity. A 4-h sleep deprivation resulted in more pronounced sleep recovery in metestrus compared to proestrus without difference in delta power replacement suggesting a better tolerance of sleep deprivation in proestrus. Sleep deprivation decreased neuronal excitability and responsiveness in a similar manner both during metestrus and proestrus, suggesting that the negative consequences of sleep deprivation on auditory processing may have a limited correlation with the estrus cycle stage.
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Estro , Privación de Sueño , Ratas , Femenino , Animales , Metestro , Proestro , DiestroRESUMEN
(1) Background: The effects of short-term social isolation during adulthood have not yet been fully established in rats behaviourally, and not at all transcriptomically in the medial prefrontal cortex (mPFC). (2) Methods: We measured the behavioural effects of housing adult male rats in pairs or alone for 10 days. We also used RNA sequencing to measure the accompanying gene expression alterations in the mPFC of male rats. (3) Results: The isolated animals exhibited reduced sociability and social novelty preference, but increased social interaction. There was no change in their aggression, anxiety, or depression-like activity. Transcriptomic analysis revealed a differential expression of 46 genes between the groups. The KEGG pathway analysis showed that differentially expressed genes are involved in neuroactive ligand-receptor interactions, particularly in the dopaminergic and peptidergic systems, and addiction. Subsequent validation confirmed the decreased level of three altered genes: regulator of G protein signalling 9 (Rgs9), serotonin receptor 2c (Htr2c), and Prodynorphin (Pdyn), which are involved in dopaminergic, serotonergic, and peptidergic function, respectively. Antagonizing Htr2c confirmed its role in social novelty discrimination. (4) Conclusions: Social homeostatic regulations include monoaminergic and peptidergic systems of the mPFC.
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Corteza Prefrontal , Transducción de Señal , Aislamiento Social , Animales , Corteza Prefrontal/metabolismo , Masculino , Ratas , Monoaminas Biogénicas/metabolismo , Ratas Sprague-Dawley , Conducta Animal , Receptor de Serotonina 5-HT2C/metabolismo , Receptor de Serotonina 5-HT2C/genética , Encefalinas/metabolismo , Encefalinas/genética , Precursores de Proteínas/metabolismo , Precursores de Proteínas/genética , Transcriptoma/genética , Regulación de la Expresión GénicaRESUMEN
BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.
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Bromocriptina , Agonistas de Dopamina , Ciclo Estral , Periodo Posparto , Ratas Wistar , Receptores de Dopamina D2 , Sueño , Animales , Bromocriptina/farmacología , Femenino , Periodo Posparto/efectos de los fármacos , Ratas , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacología , Ciclo Estral/efectos de los fármacos , Sueño/efectos de los fármacos , Vigilia/efectos de los fármacos , ProlactinaRESUMEN
Angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated ACE expression in tissues (which is generally reflected by blood ACE levels) is associated with an increased risk of cardiovascular diseases. Elevated blood ACE is also a marker for granulomatous diseases. Decreased blood ACE activity is becoming a new risk factor for Alzheimer's disease. We applied our novel approach-ACE phenotyping-to characterize pairs of tissues (lung, heart, lymph nodes) and serum ACE in 50 patients. ACE phenotyping includes (1) measurement of ACE activity with two substrates (ZPHL and HHL); (2) calculation of the ratio of hydrolysis of these substrates (ZPHL/HHL ratio); (3) determination of ACE immunoreactive protein levels using mAbs to ACE; and (4) ACE conformation with a set of mAbs to ACE. The ACE phenotyping approach in screening format with special attention to outliers, combined with analysis of sequencing data, allowed us to identify patient with a unique ACE phenotype related to decreased ability of inhibition of ACE activity by albumin, likely due to competition with high CCL18 in this patient for binding to ACE. We also confirmed recently discovered gender differences in sialylation of some glycosylation sites of ACE. ACE phenotyping is a promising new approach for the identification of ACE phenotype outliers with potential clinical significance, making it useful for screening in a personalized medicine approach.
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Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article.
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Síndrome Metabólico , Proteínas de la Leche , Obesidad , Síndrome Metabólico/metabolismo , Síndrome Metabólico/epidemiología , Animales , Obesidad/metabolismo , Humanos , Proteínas de la Leche/metabolismo , Péptidos , Búfalos , Bovinos , Comida Rápida/efectos adversos , Leche/química , Leche/metabolismoRESUMEN
Fatty acids (FAs) play important roles as membrane components and signal transduction molecules. Changes in short chain FA (SCFA) composition are associated with gut microbiota modifications. However, the effect of bacteria-driven changes on the detailed FA spectrum has not been explored yet. We investigated the effect of antibiotics (ABx) and/or probiotics, in four treatment groups on rat stool FA composition. Principal component analysis indicated that the chromatogram profiles of the treatment groups differ, which was also observed at different time points. Linear mixed effects models showed that in the parameters compared (sampling times, treatments. and their interactions), both the weight percentage and the concentration of FAs were affected by ABx and probiotic administration. This study found that the gut microbiome defines trans and branched saturated FAs, most saturated FAs, and unsaturated FAs with less carbon atoms. These results are among the first ones to demonstrate the restoring effects of a probiotic mixture on a substantial part of the altered total FA spectrum, and also revealed a previously unknown relationship between gut bacteria and a larger group of FAs. These findings suggest that intestinal bacteria produce not only SCFAs but also other FAs that may affect the host's physiological processes.
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Ácidos Grasos , Probióticos , Ratas , Animales , Ácidos Grasos/análisis , Antibacterianos/farmacología , Heces/microbiología , Ácidos Grasos Insaturados/análisis , Probióticos/farmacología , Bacterias , Ácidos Grasos VolátilesRESUMEN
The RFamide peptide family is a group of proteins that share a common C-terminal arginine-phenylalanine-amide motif. To date, the family comprises five groups in mammals: neuropeptide FF, LPXRFamides/RFamide-related peptides, prolactin releasing peptide, QRFP, and kisspeptins. Different RFamide peptides have their own cognate receptors and are produced by different cell populations, although they all can also bind to neuropeptide FF receptors with different affinities. RFamide peptides function in the brain as neuropeptides regulating key aspects of homeostasis such as energy balance, reproduction, and cardiovascular function. Furthermore, they are involved in the organization of the stress response including modulation of pain. Considering the interaction between stress and various parameters of homeostasis, the role of RFamide peptides may be critical in the development of stress-related neuropathologies. This review will therefore focus on the role of RFamide peptides as possible key hubs in stress and stress-related psychopathologies. The neurotransmitter coexpression profile of RFamide-producing cells is also discussed, highlighting its potential functional significance. The development of novel pharmaceutical agents for the treatment of stress-related disorders is an ongoing need. Thus, the importance of RFamide research is underlined by the emergence of peptidergic and G-protein coupled receptor-based therapeutic targets in the pharmaceutical industry.
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Encéfalo , Neuropéptidos , Estrés Psicológico , Humanos , Neuropéptidos/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Estrés Psicológico/metabolismoRESUMEN
Bioimpedance spectrum (BIS) measurements have a great future in in vitro experiments, meeting all the requirements for non-destructive and label-free methods. Nevertheless, a real basic research can provide the necessary milestones to achieve the success of the method. In this paper a self-developed technology-based approach for in vitro assays is proposed. Authors invented a special graphene-based measuring plate in order to assess the high sensitivity and reproducibility of introduced technique. The design of the self-produced BIS plates maximizes the detection capacity of qualitative changes in cell culture and it is robust against physical effects and artifacts. The plates do not influence the viability and proliferation, however the results are robust, stable and reproducible regardless of when and where the experiments are carried out. In this study, physiological saline concentrations, two cancer and stem cell lines were utilized. All the results were statistically tested and confirmed. The findings of the assays show, that the introduced BIS technology is appropriate to be used in vitro experiments with high efficacy. The experimental results demonstrate high correlation values across the replicates, and the model parameters suggested that the characteristic differences among the various cell lines can be detected using appropriate hypothesis tests.
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Impedancia Eléctrica , Humanos , Reproducibilidad de los Resultados , Grafito/química , Línea Celular Tumoral , Supervivencia Celular , Espectroscopía Dieléctrica/métodos , Proliferación CelularRESUMEN
Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.
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Proteínas de Ciclo Celular , Roturas del ADN de Doble Cadena , Ratones , Animales , Proteínas de Ciclo Celular/metabolismo , ADN , Meiosis/genética , Complejo Sinaptonémico/metabolismo , Recombinación Genética , Recombinación HomólogaRESUMEN
INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.
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Insuficiencia Cardíaca , Hipertensión , Miocitos Cardíacos , Ratas Transgénicas , Remodelación Ventricular , Animales , Masculino , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Hipertensión/metabolismo , Hipertensión/fisiopatología , Ratas , Remodelación Ventricular/fisiología , Factores Sexuales , Miocitos Cardíacos/metabolismo , Conectina/metabolismo , Modelos Animales de Enfermedad , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ecocardiografía , Fosforilación , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologíaRESUMEN
Angiotensin-converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. GOAL: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. METHODS: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. RESULTS: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. CONCLUSION: The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.
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BACKGROUND: Regional functional left ventricular (LV) assessment using current imaging techniques remains limited. Inward displacement (InD) has been developed as a novel technique to assess regional LV function via measurement of the regional displacement of the LV endocardial border across each of the 17 LV segments. Currently, normal ranges for InD are not available for clinical use. The aim of this study was to validate the normal reference limits of InD in healthy adults across all LV segments. METHODS: InD was analyzed in 120 healthy subjects with a normal LV ejection fraction, using the three standard long-axis views obtained during cardiac MRI that quantified the degree of inward endocardial wall motion towards the true LV center of contraction. For all LV segments, InD was measured in mm and expressed as a percentage of the theoretical degree of maximal segment contraction towards the true LV centerline. The arithmetic average InD was obtained for each of the 17 segments. The LV was divided into three regions, obtaining average InD at the LV base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). RESULTS: Average InD was 33.4 ± 4.3%. InD was higher in basal and mid-cavity LV segments (32.8 ± 4.1% and 38.1 ± 5.8%) compared to apical LV segments (28.6 ± 7.7%). Interobserver variability correlations for InD were strong (R = 0.80, p < 0.0001). CONCLUSIONS: We provide clinically meaningful reference ranges for InD in subjects with normal LV function, which will emerge as an important screening and assessment imaging tool for a range of HFrEF therapies.