Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern

Aims Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism. Methods and Results Optical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001). In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411±266ms versus compact: 354±38ms, p < 0.001). DiF (n = 11) exhibited an intermediately organised VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs. Conclusion The degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organisation in VF, ranging between globally organised fibrillation sustained by stable RAs and disorganised, possibly multiple-wavelet driven fibrillation with no RAs. Translational perspective Multiple competing mechanisms have been proposed for sustaining VF. We reframed conflicting mechanisms reported in sustaining fibrillation and defined them as part of a continuum of varying global organisation, with some sustained by stable rotationalactivities. The underlying cardiac electroarchitecture, namely gap junction coupling and fibrosis, were important determinants of the VF mechanism. Characterising the VF mechanism and its relationship to the cardiac electroarchitecture may facilitate a patient-tailored treatment approach towards VF prevention in VF survivors. Organised fibrillation sustained by stable rotational activities could be considered for targeted ablation. Disorganised fibrillation dynamics may be better suited for conventional pharmacotherapy

Plasma Level’s of Neuregulin-1 in Healthy People

Aim. To determine the median levels of neuregulin-1 (NRG-1; endothelium-derived growth factor and the natural agonist of the ERBB3 and ERBB4 receptors) NRG-1 in healthy volunteers and to study the associations of NRG-1 levels with gender and age.Material and Methods. Ninety seven healthy participants were enrolled (median age of 44 [32-54], men 45 men [46.4%]). The following age groups were identified: 20-29 y.о. (n=20, men – 50.0%),  30-39  y.о.  (n=21,  men  –  52.4%),  40-49  y.о.  (n=22,  men  –  45.5%),  50-59  y.о. (n=22, men – 36.4%); 60-69 y.о. (n=12, men – 50.0%). Peripheral blood samples were collected at the time of enrolment, standard laboratory tests were performed, and NRG-1 levels were determined in the plasma samples by ELISA.Results. In the cohort of 97 healthy participants the median value of NRG-1 was 0.3 [0.121-2.24] ng/ml. NRG-1 levels did not differ significantly between men and women (p=0.145), indicating that NRG-1 levels are not influenced by gender. The levels of NRG-1 were similar in the different age groups: age 20-29 years=0.26 [0.17-0.37] ng/ml; age 30-39=0.24 [0.1-0.39] ng/ml; age 40-49=0.31 [0.19-1.15] ng/ml; age 50-59=0.37  [0.19-1.0] ng/ml; age 60-69=0.4 [0.13-0.81] ng/ml. Correlation analysis between NRG-1 levels and route blood measurements (haemoglobin, lipids, glucose, creatinine, and uretic acid) did not show significant associations.Conclusions. In this study, the median value of NRG-1 plasma levels were determined. The results of the study show that age and gender had no influence on NRG-1 values

Neuregulin-1β, Biomarkers of Inflammation and Myocardial Fibrosis in Heart Failure Patients

Neuregulin-1β (NRG-1) is an emerging biomarker of heart failure (HF). The mechanisms of its action in HF patients are yet  to be investigated. Cardioprotective and anti-inflammatory  effects of NRG-1 have been reported.Aim. To assess NRG-1 levels in HF patients and investigate the association between NRG-1 and biomarkers of inflammation and myocardial fibrosis.Material and Methods. NRG-1, biomarkers of inflammation and fibrosis (hsCRP, IL-6, sVCAM-1, MMP-9, Galectin-3, ST2, TGF-β) were assessed in 47 patients with HF and preserved ejection fraction (HFpEF); 39 patients with HF and reduced ejection  (HFrEF) and 40 healthy participants. The associations between  NRG-1 and biomarkers of inflammation and fibrosis, as well as  the composite outcomes of cardiovascular death and HF  hospitalisations were assessed.Results. Median NRG-1 levels in HFpEF were 0.969 (0.348; 1.932) ng/ml, in HFrEF – 0.63 (0.348; 1.932), in healthy participants 0.379 (0.195; 0.861) ng/ml, and was significantly higher in HFpEF compared to healthy volunteers (р=0.004). There was no  difference in NRG-1 concentration between HFpEF and HFrEF. In  HF patients, all biomarkers of inflammation and fibrosis were  higher than in controls. ST2, IL-6 and TGF-β were significantly higher in HFrEF compared to HFpEF patients, while hsCRP,  sVCAM-1, MMP-9, and Galectin-3 levels were comparable. In  HFpEF, NRG-1 was associated with hsCRP (rs=0.378, p=0.023) and IL-6 (rs=0.378, p=0.014). Median follow-up time in patients with HFpEF and in patients was 312 (236; 388) days, in HFrEF – 147 (98; 237) days. In HFpEF, 2 patients died and 19 were  hospitalized due to HF. In HFrEF, 10 deaths and 19  hospitalizations were registered. Kaplan-Mayer analysis showed that HFpEF patients with increased NRG-1 and IL-6 had higher  levels of HF hospitalisation (log rank test, р=0.046 and р=0.012, respectively). In a multivariable cox proportional hazard model,  the association between the NRG-1 and outcomes remained significant after adjustment for age, gender and NTproBNP but diminished when hsCRP and IL-6 were included in the model.Conclusion. NGR-1 level significantly higher in HFpEF compared to healthy participants, and comparable with NRG-1 concentrations in HFrEF. In HFpEF, NRG-1 was associated with biomarkers of inflammation and fibrosis. The prognostic value of NRG-1 in HF requires further investigations

Left Atrium Involvement in Lymphoma Patients: Single Center Observational Study

Aim. To assess the structure and performance of left atrium (LA) before and after 3 cycles of anticancer treatment in lymphoma patients, as well as the incidences of supraventricular arrhythmia (SVA) and the levels of biomarkers of inflammation.Material and Methods. This is a prospective observational study of patients with confirmed diagnosis of lymphoma [n=23; 57% men; median age 52 (34;64) years], who had no prior polychemotherapy. The comparison group included persons without lymphoma [n=18; 50% men; median age 43 (37; 54) years] comparable with the main group in terms of sex, age and risk factors for cardiovascular diseases. Patients with lymphoma underwent 24h-ECG monitoring and advanced transthoracic echocardiography at baseline and after 3 cycles (within 3 months) of anticancer treatment. Biomarkers of inflammation were measured. The results were compared with the data of the comparison group.Results. In lymphoma patients, LA reservoir, conduit, and booster function were found to be impaired at baseline but were comparable with these in matched controls. After 3 cycles of anticancer treatment, a trend to reduction of LA booster and conduit strain was found. The proportion of those with SVA was significantly higher in lymphoma patients before chemotherapy compared to those after anti-cancer treatment or controls: 57% vs 10% and 33% respectively (p&lt;0.05). Lymphoma patients had a higher number of premature ventricular beats at baseline than after treatment or in control [183 (14;841) vs 38 (14;94) and 9 (4;38) respectively]. There were no associations found between the parameters of LA structure and function and SVA. Moderate positive correlation between ESR and supraventricular premature complexes was found (rS=0.44; p&lt;0.05). A positive correlation between LA contractile function and inflammatory biomarkers were revealed: LA active ejection fraction (LA EFact) and ESR (rS=0.42, p&lt;0.05); LA volume index and β-globulin (rS=0.43, p&lt;0.05); LA EFact and neuregulin-1β (rS=0.42, p&lt;0.05); LA expansion index and neuregulin-1β (rS=0.55, p&lt;0.05).Conclusions. In lymphoma patients, LA phasic strain parameters were impaired regardless of anticancer treatment. The associations between inflammatory biomarkers with SVA and parameters of LA performance were found

Advanced Heart Failure and Angiotensin System Fascinating Complexities

International audienceNo abstract availabl

VASCULAR INJURY CORRECTION IN ARTERIAL HYPERTENSION: FOCUS ON PERINDOPRIL

Risk factors are the cornerstone of the cardiovascular continuum concept. Arterial hypertension is one of major risk factors, which accounts for a substantial proportion of cardiovascular morbidity and mortality due to cardiovascular complications (CVC). The latter develop due to, among other reasons, the damage of the vascular component of cardiovascular system (CVS). Presently, the aims of antihypertensive treatment include not only control of blood pressure levels, but also CVC prevention. Antihypertensive medications of choice include the agents which also possess vasoprotective qualities

INFLUENCE OF THE COMBINATION DRUG PRESTANS (PERINDOPRIL A, AMLODIPINE) ON MORPHO-FUNCTIONAL PARAMETERS OF ARTERIAL BED IN ESSENTIAL HYPERTENSION

Aim. Recently, the problem of endothelial dysfunction is in high interest. It was proved that microcirculatory disorders play main role in development and progression of target organ damage in essential arterial hypertension (EAH). Microcirculatory bed itself should be the target of EAH. Modern antihypertension drugs, despite of normalization of blood pressure (BP), should fulfill the prevention of target organ damage. In our study, the influence was evaluated, of treatment with the fixed combination of perindopril A and amlodipine (Prestans®, “Les Laboratoires Servier”, France) on structural and functional parameters of the heart and vessels.Material and methods. In the study, 30 patients with grade II-III EAH included, mean age 54,12±9,15 y.o., duration of EAH — 12,6 (4;21) years. For the assessment of endothelial function and structural and functional condition of capillary net of a finger skin, photopletysmography were applied and videocapillroscopy, respectively.Results. Therapy with Prestans® led to improvement of functioning of the middle sized vessels and microcirculatory vessels (MC) (increase of occlusion index on MC level from 1,5 to 1,8, p&lt;0,006); on the large vessels level led to phase shift from 6,0 to 10,3 (р&lt;0,00005). There was influence of Prestans® on the parameters characterizing vascular bed remodelling on the levels of cappilars: density of capillary net in the skin at rest (cap/mm2) increased from 47 cap/mm2 to 51 cap/mm2 (р&lt;0,00005), and the density of capillar net after venous occlusion test — from 53 cap/mm2 to 60 cap/mm2 (р&lt;0,006).Conclusion. Prestans® is a medication of choice not only for AH treatment, but for prevention of target organs damage, that is based on correction of endothelial dysfunction and morphofunctional parameters at the level of MC

Heart Failure with Perserved Ejection Fraction Current Diagnostic and Therapeutic Approaches

Heart failure with preserved ejection fraction (HFpEF) is a syndrome associated with high morbidity and mortality rates. Little progress has been in the treatment of this condition since its introduction some 30 years ago. It's accepted that HFpEF is heterogeneous in many ways, ethologically and phenotypically. The underlying mechanisms of the syndrome are not clear. Recently, it has been shown that the diagnostic criteria for HFpEF lacks sensitivity and specificity. Novel treatment approaches, which were developed based on current HFpEF pathophysiological concepts, did not show either clinical or prognostic benefit for patients. Therefore, there is an urgent need to revise current diagnostic approaches and to further investigate the underlying mechanisms. Recently, two novel diagnostic score systems were proposed: H2PEF and HFA-PEFF. Recently, a number of phase II and III randomized control trials have been completed. Here, the authors discuss the potential novel diagnostic approaches to HFpEF and treatment perspectives

Sequencing and titrating approach of therapy in heart failure with reduced ejection fraction following the 2021 European Society of Cardiology guidelines: an international cardiology survey

Aims In symptomatic patients with heart failure and reduced ejection fraction (HFrEF), recent international guidelines recommend initiating four major therapeutic classes rather than sequential initiation. It remains unclear how this change in guidelines is perceived by practicing cardiologists versus heart failure (HF) specialists.Methods and results An independent academic web-based survey was designed by a group of HF specialists and posted by email and through various social networks to a broad community of cardiologists worldwide 1 year after the publication of the latest European HF guidelines. Overall, 615 cardiologists (38 [32-47] years old, 63% male) completed the survey, of which 58% were working in a university hospital and 26% were HF specialists. The threshold to define HFrEF was <= 40% for 61% of the physicians. Preferred drug prescription for the sequential approach was angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors first (74%), beta-blockers second (55%), mineralocorticoid receptor antagonists third (52%), and sodium-glucose cotransporter 2 inhibitors (53%) fourth. Eighty-four percent of participants felt that starting all four classes was feasible within the initial hospitalization, and 58% felt that titration is less important than introducing a new class. Age, status in training, and specialization in HF field were the principal characteristics that significantly impacted the answers.Conclusion In a broad international cardiology community, the 'historical approach' to HFrEF therapies remains the preferred sequencing approach. However, accelerated introduction and uptitration are also major treatment goals. Strategy trials in treatment guidance are needed to further change practices.[GRAPHICS]