Long-Term Changes in the Biomarkers of Left Atrial Fibrosis after Pulmonary Vein Isolation for Paroxysmal and Persistent Atrial Fibrillation.

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.

Therapeutic Aspects of Prunus cerasus Extract in a Rabbit Model of Atherosclerosis-Associated Diastolic Dysfunction.

This study evaluates the potential therapeutic effects of anthocyanin-rich Prunus cerasus (sour cherry) extract (PCE) on atherosclerosis-associated cardiac dysfunction, described by the impairment of the NO-PKG (nitric oxide-protein kinase G) pathway and the antioxidant capacity. Initially, a rabbit model of atherosclerotic cardiovascular disease was established by administering a cholesterol-rich diet, enabling the examination of the impact of 9 g/kg PCE on the pre-existing compromised cardiovascular condition. After that, the animals were divided into four groups for 12 weeks: the (1) untreated control group; (2) PCE-administered healthy rabbits; (3) hypercholesterolemic (HC) group kept on an atherogenic diet; and (4) PCE-treated HC group. Dyslipidemia, impaired endothelial function, and signs of diastolic dysfunction were evident in hypercholesterolemic rabbits, accompanied by a reduced cardiac expression of eNOS (endothelial nitric oxide synthase), PKG, and SERCA2a (sarco/endoplasmic reticulum calcium ATPase 2a). Subsequent PCE treatment improved the lipid profile and the cardiac function. Additionally, PCE administration was associated with elevated myocardial levels of eNOS, PKG, and SERCA2a, while no significant changes in the vascular status were observed. Western blot analysis further revealed hypercholesterolemia-induced increase and PCE-associated reduction in heme oxygenase-1 expression. The observed effects of anthocyanins indicate their potential as a valuable addition to the treatment regimen for atherosclerosis-associated cardiac dysfunction.

Changes in the Composition of Unstimulated and Stimulated Saliva Due to Chewing Sour Cherry Gum and a Toothbrush Change.

BACKGROUND: Our previous studies demonstrated that sour cherry anthocyanins (AC) reduce the salivary count of Streptococcus mutans and inhibit salivary amylase activity within 30 minutes after chewing AC gum. AC gum and changing toothbrushes after scaling reduced the Gram-negative species in the unstimulated salivary microbiota. The present study examined the effect of AC gums on salivary factors, including changes in microbiome. METHODS: The study was conducted over three weeks with two groups; young adults (18-30) and adults (30-45). Ten participants changed their toothbrushes, while the other 10 participants did not change after the control period. After scaling, all participants received three doses of AC gum daily. The salivary mRNA and protein levels of cytokines, mucins, melatonin, and the microbiota of unstimulated and stimulated saliva were determined by polymerase chain reaction, enzyme-linked immunosorbent assay, and 16S rRNA gene sequencing. RESULTS: Significantly higher levels of tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), mucin5B (MUC5B), mucin7 (MUC7), and melatonin were detected in stimulated saliva. Correlation analysis of these factors with the microbiota showed positive correlations with the genera Lachnospiraceae, Eikenella, Saccharibacteria_(TM7), Streptococcus, Prevotella, and Haemophilus. CONCLUSIONS: AC chewing gum has a beneficial effect on the composition of the oral microbiome, and toothbrush replacement leads to changes in the levels of salivary pro-inflammatory cytokines.

Ultrasonication affects the melatonin and auxin levels and the antioxidant system in potato in vitro.

Melatonin is an ancient hormone whose physiological effects have been extensively studied in animals and human. We now know that it also plays a prominent role in the growth and development of plants. In our present experiment, the relationship between endogenous melatonin and the antioxidant system was investigated in potato plant grown in vitro. Changes in redox homeostasis under ultrasound stress were examined. The concentration of small molecule antioxidants and enzymes of the three-level antioxidant pathway was measured. ELISA method was used to determine the melatonin levels in plant tissues at each growth stage (0 h, 24 h, 48 h, 1 week, and 4 weeks after subculturing the explants) both in control and ultrasound-treated plants. Ultrasound stress activated the three-level defense system and decreased the endogenous melatonin levels. Melatonin was able to provide protection against membrane damage caused by drastic ultrasound treatment. Melatonin at the heart of the redox network is a key component regulating various biochemical, cellular, and physiological responses. It has a dual role, as it is able to act both as a growth regulator and an antioxidant. A close relationship was evidenced between the plant hormone indole-3-acetic acid and melatonin and ascorbic acid.

The feasibility of baroreflex sensitivity measurements in heart failure subjects: The role of slow-patterned breathing.

INTRODUCTION: Increased muscle sympathetic nerve activity (MSNA) indicates an adverse outcome in heart failure. Decreased baroreflex modulation of MSNA is a well-known feature of the disease. The determinability of cardiovagal baroreflex sensitivity (BRS) in heart failure is low, however, the determinability of sympathetic BRS is not known. METHODS: We have assessed the spontaneous, MSNA burst incidence-based baroreflex index (BRSsymp) in 33 stable heart failure patients and in 10 healthy controls using the traditional r ≥ .5 cutoff for acceptable individual diastolic pressure-burst incidence slopes, and also a more stringent r ≥ .7 cutoff. We have also assessed the influence of 6/min breathing. RESULTS: The determinability of BRSsymp in heart failure patients was 64% during spontaneous breathing with r ≥ .5 cutoff, and 39% using the r ≥ .7 cutoff. The determinability of these indices further decreased during 6/min breathing, dropping to 29% with the r ≥ .7 cutoff. In contrast, the determinability of the cardiovagal BRS indices increased significantly with 6/min breathing (from 24% to 66%; p < .001). Patients who still had determinable BRSsymp at the r ≥ .7 cutoff had a significantly lower baseline burst incidence than those with an undeterminable index (70 ± 14 vs. 89 ± 10 burst/100 cycles; p < .002). Neither the 6/min breathing, nor the r ≥ .7 cutoff limit influenced the high availability of BRSsymp in healthy subjects. CONCLUSION: The determinability of BRSsymp in heart failure patients is limited, especially with the 0.7 limit for correlation. Undeterminable BRSsymp in patients is associated with higher sympathetic activity. 6/min breathing improves the determinability of cardiovagal BRS indices, but not that of BRSsymp.

Cardiovagal and sympathetic baroreflex regulation in heart failure / Cardiovagalis és szimpatikus artériás baroreflex szabályozásának vizsgálata szívelégtelenségben.

Összefoglaló. Bevezetés: Az artériás baroreflex-érzékenységi (BRS-) indexek egységnyi nyomásváltozásra adott élettani válaszokat írnak le. Az RR-intervallum gyors válaszait a cardiovagalis BRS-indexekkel, a vasomotorválaszokat az izom szimpatikus idegi aktivitás (MSNA) válaszain alapuló szimpatikus-BRS-indexekkel jellemezzük. Szívelégtelenségben kórosan csökkent értékeik kedvezotlen kimenetelt jeleznek. Betegek és módszerek: A BRS-indexek meghatározhatóságát 52, szívelégtelenségben szenvedo betegben (kor: 59 ± 10 év; EF: 37 ± 11%) és 11, kor szerint illesztett egészséges önkéntesben vizsgáltuk. EKG- és vérnyomásfelvételekbol három cardiovagalis BRS-indexet számítottunk; a növekvo, illetve csökkeno spontán szekvenciák módszerén alapuló up-BRS-t és down-BRS-t, továbbá az alacsony frekvenciatartomány-beli 'cross-spectralis ' indexet, az LF-alfát. Egy perifériás ideg (nervus peroneus) perkután punkciójával detektáltuk az MSNA szimpatikus csúcs incidenciáját (csúcs/100 szívciklus), s ezt korreláltattuk a diastolés nyomás 3 Hgmm sávokba rendezett értékeivel. Így nyertük a szimpatikus BRS jellemzoit, a BRSSY-incidencia-értékeket. Eredmények: Az up- és down-BRS-szekvenciák csak a betegek 19%-ában voltak meghatározhatók, az LF-alfa a 69%-ukban. Azok, akiknél cardiovagalis BRS nem volt meghatározható, szignifikánsan csökkent RR-intervallum-ingadozást és magasabb NT-proBNP-értékeket mutattak. A meghatározható cardiovagalis BRS-indexek nem különítették el a betegeket és a kontrollszemélyeket. A BRSSY-incidencia-érték 58%-ban állt rendelkezésre, s csakúgy, mint maga a "csúcs" incidencia, jól elkülönítette a betegeket és az önkénteseket. A hiányzó baroreflexérték a magas "csúcs" incidenciával állt összefüggésben. Következtetés: A cardiovagalis BRS-értékek csak korlátozottan alkalmasak egészséges önkéntesek és szívelégtelen betegek elkülönítésére, a meghatározhatatlan értékek súlyosabb betegségre utalnak. A BRSSY-incidencia elkülöníti az egészséges és a beteg csoportokat; a hiányzó érték a fokozott szimpatikus aktivitással áll összefüggésben. Orv Hetil. 2021; 162(3): 91-98. INTRODUCTION: Arterial baroreflex sensitivity (BRS) is characterized by the magnitude of physiological responses to arterial pressure changes. Rapid RR interval responses are quantified by cardiovagal BRS parameters, sympathetic responses could be assessed by changes in muscle sympathetic nerve activity (MSNA). Abnormal indices in heart failure are associated with poor outcome. PATIENTS AND METHODS: 52, heart failure patients (age 59 ± 10 years, EF 37 ± 11%), and 11, age-matched healthy volunteers were studied. From ECG and arterial pressure recordings up-BRS and down-BRS values were determined using the method of spontaneous sequences. The low frequency cross-spectral gain, the LF alpha was also determined. Percutaneous puncture of the peroneal nerves allowed determination of MSNA burst incidence (burst/100 cycles), which was correlated to corresponding diastolic pressure bins of 3 mmHg, yielding a sympathetic BRS, the BRSSY-incidence. RESULTS: Up- and down-BRS could be calculated in 19% of the patients, LF alpha was determined in 69%. Those with missing cardiovagal BRS values showed diminished RR interval variation, and higher levels of NT-proBNP. The measurable cardiovagal BRS indices did not separate patients and healthy volunteers. BRSSY-incidence could be determined in 58% of the patients. The sympathetic gain as well as the burst incidence differed significantly between patients and healthy volunteers. Missing BRSSY-incidence was associated with higher burst incidence. CONCLUSION: Cardiovagal BRS indices have limited value in differentiating healthy and heart failure subjects. Incalculable values among patients indicate more severe disease state. BRSSY-incidence does separate healthy and diseased population, the missing BRSSY-incidence values are related to increased sympathetic activity. Orv Hetil. 2021; 162(3): 91-98.

Sympathetic activation in heart failure with reduced and mildly reduced ejection fraction: the role of aetiology.

AIM: While sympathetic overactivity in heart failure (HF) with reduced ejection fraction (HFrEF; EF < 40%) is well-documented, it is ill-defined in patients with mildly reduced EF (HFmrEF; EF 40-49%). Furthermore, the significance of ischaemic versus non-ischaemic aetiology in sympathetic activation is also unclear and has yet to be studied in HF. Our goal was to compare muscle sympathetic nerve activity (MSNA) in HFmrEF and HFrEF patients and in healthy subjects, as well as to elucidate the influence of the underlying disease. METHODS AND RESULTS: Twenty-three HFrEF (age 58 ± 10 years), 33 HFmrEF patients (age 61 ± 10 years), including 11 subjects with non-ischaemic cardiomyopathy in each HF groups and 10 healthy controls (age 55 ± 10 years), were studied. MSNA-detected by peroneal microneurography, continuous arterial pressure, and ECG-was recorded. MSNA frequency (burst/min) and incidence (burst/100 cycles) were calculated. Association with the patients' characteristics were assessed, and aetiology-based comparisons were performed. Burst frequency demonstrated a significant stepwise increase in both HFmrEF (41 ± 11 burst/min) and HFrEF (58 ± 17 burst/min, P < 0.001) patients as compared with controls (27 ± 9; P < 0.001 for both HF groups). Similarly, burst incidences were 66 ± 17, 82 ± 15, and 36 ± 10 burst/100 cycles in HFmrEF, HFrEF patients, and in healthy controls, respectively (P < 0.001 for all). Burst frequencies in HF patients showed significant correlation with NT-proBNP levels, and significant inverse correlations with the subjects' mean RR intervals, stroke volumes, pulse pressures, and EF. CONCLUSIONS: Muscle sympathetic nerve activity parameters indicated significant sympathetic activation in both HFmrEF and HFrEF patients as compared with healthy controls with no difference in relation to ischaemic versus non-ischaemic aetiology.

Theory and history of the study of muscle sympathetic nerve activity / Az izom szimpatikus idegaktivitás vizsgálatának elméleti alapjai és története

Heart failure is a rapidly growing epidemic in developed countries. It has been well documented that heart failure is associated with abnormal neurohumoral activation. The autonomic regulation is characterized by decreased parasympathetic and elevated sympathetic activity. While the cardiovagal activity could be easily assessed by various heart rate variability parameters, markers of the sympathetic activity are not readily available. Percutaneous insertion of microelectrodes in a peripheral nerve allows recording of the muscle sympathetic vasomotor nerve activity (MSNA). MSNA shows good correlation with the cardiac sympathetic activity, and also with the levels of circulating catecholamines. Besides determination of the baseline sympathetic activity, rapid sympathetic responses to various stimuli can be also described by changes of MSNA. Elevated MSNA has been documented in several diseases, including hypertension, obesity, myocardial ischemia and renal failure. In heart failure, the elevated MSNA is well correlated to the clinical severity of the patient's conditions, and serves as a prognostic marker of mortality. In our paper, we give a short account of the history of MSNA studies, describe its physiological background and clinical relevance with special regard to heart failure. Orv Hetil. 2020; 161(29): 1190-1199.

Quantification of peripheral whole blood, cell-free plasma and exosome encapsulated mitochondrial DNA copy numbers in patients with atrial fibrillation.

Mitochondrial DNA (mtDNA) copy number changes have been associated with various diseases. Several studies showed that mtDNA content in peripheral blood was associated with oxidative stress and cardiovascular disease. Atrial fibrillation (AF) is one of the severe cardiovascular diseases. We aimed to determine the mtDNA copy numbers in peripheral blood, in cell-free plasma and in exosomes of AF patients and healthy controls. Peripheral blood was drawn from 60 AF patients and 72 healthy controls. DNA was isolated from EDTA blood and plasma. Exosomes were isolated from cell-free plasma and then exosome encapsulated DNA (exoDNA) was extracted. Quantitative-real-time PCR was performed with Human Mitochondrial DNA (mtDNA) Monitoring Primer Set. Statistical analysis of the data was performed. We found statistically significant difference in mtDNA copy numbers in DNA isolated from peripheral whole blood, cell-free plasma and exosome samples of controls' (44.4 ± 18.0, 27.2 ± 30.1, 11.5 ± 8.7), and patients' group (43.4 ± 13.6, 26.2 ± 26.4, 14.5 ± 12.3). However there was no significant difference in mtDNA copy number between the two study groups either in peripheral blood, in cell-free plasma and in exosomes, and even in different sexes and ages. We found the highest copy number of mtDNA in peripheral blood, followed by plasma and exosomes. We did not find differences between patients and controls, neither age nor gender had effect on the mtDNA copy number. According to our results the mtDNA copy numbers did not differ in AF patients.