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This study was designed to evaluate the role of biologically active adrenomedullin (bio-ADM) in congestion assessment and risk stratification in acute dyspnea.This is a sub-analysis of the Lithuanian Echocardiography Study of Dyspnea in Acute Settings. Congestion was assessed by means of clinical (peripheral edema, rales) and sonographic (estimated right atrial pressure) parameters. Ninety-day mortality was chosen for outcome analysis.There were 1188 patients included. Bio-ADM concentration was higher in patients with peripheral edema at admission (48.2 [28.2-92.6] vs 35.4 [20.9-59.2] ng/L, P.001). There was a stepwise increase in bio-ADM concentration with increasing prevalence of rales: 29.8 [18.8-51.1], 38.5 [27.5-67.1], and 51.1 [33.1-103.2] ng/L in patients with no rales, rales covering less than one-half, and greater than or equal to one-half of the pulmonary area, respectively (P0.001). Bio-ADM concentration demonstrated gradual elevation in patients with normal, moderately, and severely increased estimated right atrial pressure: 25.1 [17.6-42.4] ng/L, 36.1 [23.1-50.2], and 47.1 [30.7-86.7] ng/L, respectively (P.05). Patients with bio-ADM concentration35.5 ng/L were at more than twofold increased risk of dying (P.001). Survival in those with high bio-ADM was significantly modified by neurohormonal blockade at admission (P.05), especially if NT-proBNP levels were lower than the median (P = .002 for interaction).Bio-ADM reflects the presence and the degree of pulmonary, peripheral, and intravascular volume overload and is strongly related to 90-day mortality in acute dyspnea. Patients with high bio-ADM levels demonstrated survival benefit from neurohormonal blockade.

BackgroundDelayed enhancement cardiac magnetic resonance (DE-CMR) is the reference standard for the non-invasive assessment of myocardial fibrosis. DE-CMR is able to distinguish ischaemic from non-ischaemic aetiologies based on differences in hyperenhancement distribution patterns. Hyperenhancement caused by ischaemic injury typically involves the endocardium, while hyperenhancement confined to the mid- and epicardial layers of the myocardium suggests a non-ischaemic aetiology.Case summaryThis is a case of a 20-year-old male with an unremarkable medical history with an acute ST-elevation myocardial infarction. DE-CMR revealed two distinct patterns of hyperenhancement: (i) a ‘normal’ wavefront-ischaemic pattern, and (ii) multiple atypical mid-wall and epicardial areas of focal hyperenhancement. Invasive coronary angiography (ICA) and coronary computed tomographic angiography (CCTA) showed multiple intracoronary thrombi and distal emboli in the left anterior descending, ramus circumflexus, and in smaller branches of the LCA. All hyperenhancement patterns observed on DE-CMR perfectly matched the distribution territories of the affected coronary arteries.DiscussionThis case with an acute myocardial infarction showed intracoronary thrombi and emboli on ICA and CCTA. Interestingly, DE-CMR showed two different patterns of hyperenhancement in the same territories of the coronary thrombi. This observation may challenge the concept that these non-endocardial areas of hyperenhancement on DE-CMR are always of non-ischaemic aetiology. It is hypothesized that occlusion of smaller distal branches of the coronary arteries may result in mid-wall or epicardial fibrosis as opposed to subendocardial fibrosis commonly found in patients with a large epicardial coronary occlusion. Clinicians should be aware of these atypical patterns to be able to initiate adequate medical therapy.

Highly complex and irregular atrial activation patterns during atrial fibrillation (AF) can occasionally be interrupted by repetitive atrial activation patterns (RAAPs). These patterns are thought to be generated by mechanisms that initiate or maintain AF episodes are therefore, might be more diverse in patients with more complex forms of AF We quantified RAAP diversity by the half decay time of the ratio of the unprecedented RAAPs to the total num{###} ber of RAAPs in a goat model with different durations of sustained AF[3 weeks (3wkAF, n=8) and 22 weeks (22wkAF, n=8)]. 32 recordings from left and right atria (LA/RA) of each goat were analyzed. 24 out of 32 curves could be modeled as exponential decay functions with adjusted R-squared > 0.75 while others presented more irregular decaying patterns (3wkAF LA:2 RA:3,22wkAF LA: 1 RA:2). Half decay rates were significantly shorter in LAs of 3wkAF goats (δ3wkAF=23.67s vs. δ22wkAF=32.86s,p < 0.05, Mann-Whitney U-test). There was no significant difference in RA.

ObjectivesTo evaluate the potential of soluble cluster of differentiation 146 (sCD146) in the detection and grading of congestion in patients with acute dyspnoea.DesignSubanalysis of the prospective observational Lithuanian Echocardiography Study of Dyspnoea in Acute Settings (LEDA) cohort.SettingTwo Lithuanian university centres.ParticipantsAdult patients with acute dyspnoea admitted to the emergency department.MethodsCongestion was assessed using clinical and sonographic parameters. All patients underwent sCD146 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing.ResultsThe median value of sCD146 concentration in the study cohort (n=437) was 405 (IQR 315–509) ng/mL. sCD146 was higher in patients with peripheral oedema than in those without (median (IQR) 472 (373–535) vs 400 (304–501) ng/mL, p=0.009) and with pulmonary rales than in those without (439 (335–528) vs 394 (296–484) ng/mL, p=0.001). We found a parallel increase of estimated right atrial pressure (eRAP) and sCD146 concentration: sCD146 was 337 (300–425), 404 (290–489) and 477 (363–572) ng/mL in patients with normal, moderately elevated and high eRAP, respectively (p=0.001). In patients with low NT-proBNP, high sCD146 distinguished a subgroup with a higher prevalence of oedema as compared with patients with low levels of both biomarkers (76.0% vs 41.0%, p=0.010). Moreover, high sCD146 indicated a higher prevalence of elevated eRAP, irrespective of NT-proBNP concentration (pConclusionsCD146 concentration reflects the degree of intravascular and tissue congestion assessed by clinical and echocardiographic indices, with this association maintained in patients with low NT-proBNP. Our data support the notion that NT-proBNP might represent heart stretch while sCD146 rather represents peripheral venous congestion.

Despite advances in management, the long-term prognosis of heart failure patients remains poor. Fluid accumulation in the human body is called congestion, and the phenomenon is known to attribute significantly to adverse events in the context of heart failure. Congestion is difficult to detect and diuretics – the cornerstone of congestion management – have no high-quality efficacy and safety evidence. Even more, observational data indicates potential harm of diuretic treatment. The present research analyses the complex relationship between congestion, its treatment and heart failure outcome. The results indicate that persistent congestion is deleterious, and treatment with intensive diuretic regimen might be beneficial. Novel tools of congestion detection and grading were identified. All of them have the potential to be translated from the research field to daily clinical practice, after their impact on hard outcome is investigated in appropriate interventional trials.

In this thesis, the studies’ aimed to investigate the technical feasibility of laser energy in the treatment of cardiac arrhythmias. Several arrhythmias can be treated by ablation therapy, selectively destroying abnormal tissue to inhibit cardiac arrhythmia. In the past, laser energy was already explored as feasible energy source for this treatment of cardiac arrhythmias. The linear laser catheter developed and investigated in this thesis could provide an alternative to the existing ablation devices, by delivering the necessary energy to the tissue, achieving the required tissue coagulation. The technical feasibility, laser interaction and preliminary safety of the catheter design was tested in lab conditions with freshly excised animal tissue (ex vivo) and later confirmed during animal studies (in vivo). In vivo studies showed good results in energy applications from inside (endocardial) and from outside (epicardial) the heart suggesting suitability as alternative to existing treatment devices.

Aims Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients. Methods and results A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41–72) vs. persAF: 39% (0–51), P Conclusion High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.

Background Invasive coronary angiography (ICA) is still the reference test in suspected non-ST elevation myocardial infarction (NSTEMI), although a substantial number of patients do not have obstructive coronary artery disease (CAD). Early cardiovascular magnetic resonance (CMR) may be a useful gatekeeper for ICA in this setting. The main objective was to investigate the accuracy of CMR to detect obstructive CAD in NSTEMI. Methods This study is a sub-analysis of a randomized controlled trial investigating whether a non-invasive imaging-first strategy safely reduced the number of ICA compared to routine clinical care in suspected NSTEMI (acute chest pain, non-diagnostic electrocardiogram, high sensitivity troponin T > 14 ng/L), and included 51 patients who underwent CMR prior to ICA. A stepwise approach was used to assess the diagnostic accuracy of CMR to detect (1) obstructive CAD (diameter stenosis ≥ 70% by ICA) and (2) an adjudicated final diagnosis of acute coronary syndrome (ACS). First, in all patients the combination of cine, T2-weighted and late gadolinium enhancement (LGE) imaging was evaluated for the presence of abnormalities consistent with a coronary etiology in any sequence. Hereafter and only when the scan was normal or equivocal, adenosine stress-perfusion CMR was added. Results Of 51 patients included (63 ± 10 years, 51% male), 34 (67%) had obstructive CAD by ICA. The sensitivity, specificity and overall accuracy of the first step to diagnose obstructive CAD were 79%, 71% and 77%, respectively. Additional vasodilator stress-perfusion CMR was performed in 19 patients and combined with step one resulted in an overall sensitivity of 97%, specificity of 65% and accuracy of 86%. Of the remaining 17 patients with non-obstructive CAD, 4 (24%) had evidence for a myocardial infarction on LGE, explaining the modest specificity. The sensitivity, specificity and overall accuracy to diagnose ACS (n = 43) were 88%, 88% and 88%, respectively. Conclusion CMR accurately detects obstructive CAD and ACS in suspected NSTEMI. Non-obstructive CAD is common with CMR still identifying an infarction in almost one-quarter of patients. CMR should be considered as an early diagnostic approach in suspected NSTEMI. Trial registration. The CARMENTA trial has been registered at ClinicalTrials.gov with identifier NCT01559467.

Aims Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF. Methods and results Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed. Conclusions Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.

Mortality in type 2 diabetes, is determined not only by classical complications, but also by comorbidities, and is linked to hyperglycaemia and apparent even in prediabetes. We aimed to comprehensively investigate, in a population-based cohort, health burden defined as the presence of comorbidities in addition to classical complications and cardiometabolic risk factors, in not only type 2 diabetes but also prediabetes. Such population-based study has not been performed previously. Extensive phenotyping was performed in 3,410 participants of the population-based Maastricht Study (15.0% prediabetes and 28.6% type 2 diabetes) to assess presence of 17 comorbidities, six classical complications, and ten cardiometabolic risk factors. These were added up into individual and combined sum scores and categorized. Group differences were studied with multinomial regression analyses adjusted for age and sex. Individuals with type 2 diabetes and prediabetes, as compared to normal glucose metabolism (NGM), had greater comorbidities, classical complications, cardiometabolic risk factors and combined sum scores (comorbidities sum score ≥ 3: frequencies (95% CI) 61.5% (57.6;65.4) and 41.2% (36.5;45.9) vs. 25.4% (23.5;27.4), p-trend P P = 0.065 vs NGM) vs. 8.0% (6.9;9.3)); cardiometabolic risk factors ≥ 6 (39.7% (35.9;43.4) and 28.5% (24.5;32.6) vs. 14.0% (12.5;15.6); p-trend

AimThis proof-of-concept study aimed to investigate atrial and ventricular lesion formation by a 20-mm linear laser ablation catheter, regarding lesion depth and tissue damage.MethodsIn total, 6 female swines underwent standard femoral vein access to introduce a novel 20-mm linear laser ablation catheter in the right atrium to perform endocardial cavotricuspid isthmus (CTI) ablations. The navigation took place under fluoroscopy with additional visualization by intracardiac echocardiograph. Via a sternotomy, epicardial ablations were performed on the surface of the left ventricle (LV), right ventricle (RV), and right atrial appendage (RAA). Procedural safety was assessed by registration of intraprocedural adverse events and by macroscopic examination of the excised hearts for the presence of charring or tissue disruption at the lesion site.ResultsAltogether 39 lesions were created, including 8 endocardial CTI (mean lesion length 20.6 ± 1.65 mm), 26 epicardial ventricle (mean lesion length LV: 25.3 ± 1.35 mm, RV: 24.9 ± 2.40 mm), and 5 epicardial appendage ablations (mean lesion length RAA: 26.0 ± 3.16 mm). Transmurality was achieved in all CTI and atrial appendage ablations, in 62% of the RV ablations and in none of the LV ablations. No perforation or steam pop occurred, and no animal died during the procedure.ConclusionIn this porcine study, the 20-mm linear laser ablation catheter has shown excellent results for endocardial cavotricuspid isthmus ablation, and it resulted in acceptable lesion depth during atrial and ventricular epicardial ablation. The absence of tissue charring, steam pops, or microbubbles under the experimental conditions suggests a high degree of procedural safety.

Frontiers in physiology 13, 779826 (2022). doi:10.3389/fphys.2022.779826 special issue: "How Can a Better Understanding of Mechanisms Enable Phenotyping of Human Atrial Fibrillation and Improve Clinical Treatments?", Published by Frontiers Research Foundation, Lausanne

In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Phosphatidylinositol-4-kinase-IIIβ (PI4KIIIβ) is a lipid kinase downstream of protein kinase D1 (PKD1) that mediates Golgi-to-plasma membrane vesicular trafficking in HeLa-cells. In this study, we evaluated whether PI4KIIIβ is involved in myocellular GLUT4 translocation induced by contraction or oligomycin (an F1F0-ATP synthase inhibitor that activates contraction-like signaling). Pharmacological targeting, with compound MI14, or genetic silencing of PI4KIIIβ inhibited contraction/oligomycin-stimulated GLUT4 translocation and glucose uptake in cardiomyocytes but did not affect CD36 translocation nor LCFA uptake. Addition of the PI4KIIIβ enzymatic reaction product phosphatidylinositol-4-phosphate restored oligomycin-stimulated glucose uptake in the presence of MI14. PI4KIIIβ activation by PKD1 involves Ser294 phosphorylation and altered its localization with unchanged enzymatic activity. Adenoviral PI4KIIIβ overexpression stimulated glucose uptake, but did not activate hypertrophic signaling, indicating that unlike PKD1, PI4KIIIβ is selectively involved in GLUT4 translocation. Finally, PI4KIIIβ overexpression prevented insulin resistance and contractile dysfunction in lipid-overexposed cardiomyocytes. Together, our studies identify PI4KIIIβ as positive and selective regulator of GLUT4 translocation in response to contraction-like signaling, suggesting PI4KIIIβ as a promising target to rescue defective glucose uptake in diabetics. Electronic supplementary material The online version of this article (10.1007/s00018-020-03669-7) contains supplementary material, which is available to authorized users.

Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200–500 mg/dL in steps of 100 mg/dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.

Background Challenges to cardiac PET-CT include patient motion, prolonged image acquisition and a reduction of counts due to gating. We compared two analytical tools, FusionQuant and OsiriX, for quantification of gated cardiac 18F-sodium fluoride (18F-fluoride) PET-CT imaging. Methods Twenty-seven patients with aortic stenosis were included, 15 of whom underwent repeated imaging 4 weeks apart. Agreement between analytical tools and scan-rescan reproducibility was determined using the Bland-Altman method and Lin's concordance correlation coefficients (CCC). Results Image analysis was faster with FusionQuant [median time (IQR) 7:10 (6:40-8:20) minutes] compared with OsiriX [8:30 (8:00-10:10) minutes,p = .002]. Agreement of uptake measurements between programs was excellent, CCC = 0.972 (95% CI 0.949-0.995) for mean tissue-to-background ratio (TBRmean) and 0.981 (95% CI 0.965-0.997) for maximum tissue-to-background ratio (TBRmax). Mean noise decreased from 11.7% in the diastolic gate to 6.7% in motion-corrected images (p = .002); SNR increased from 25.41 to 41.13 (p = .0001). Aortic valve scan-rescan reproducibility for TBR(max)was improved with FusionQuant using motion correction compared to OsiriX (error +/- 36% vs +/- 13%,p < .001) while reproducibility for TBR(mean)was similar (+/- 10% vs +/- 8%p = .252). Conclusion 18F-fluoride PET quantification with FusionQuant and OsiriX is comparable. FusionQuant with motion correction offers advantages with respect to analysis time and reproducibility of TBR(max)values.

Compliance mismatch between an arteriovenous dialysis graft (AVG) and the connected vein is believed to result in disturbed haemodynamics around the graft–vein anastomosis and increased mechanical loading of the vein. Both phenomena are associated with neointimal hyperplasia development, which is the main reason for AVG patency loss. In this study, we use a patient-specific fluid structure interaction AVG model to assess whether AVG haemodynamics and mechanical loading can be optimised by using novel electrospun polyurethane (ePU) grafts, since their compliance can be better tuned to match that of the native veins, compared to gold standard, expanded polytetrafluoroethylene (ePTFE) grafts. It was observed that the magnitude of flow disturbances in the vein and the size of anastomotic areas exposed to highly oscillatory shear ($$\hbox {OSI} >0.25$$OSI>0.25) and very high wall shear stress ($$>40 \hbox { Pa}$$>40Pa) were largest for the ePTFE graft. Median strain and von Mises stress in the vein were similar for both graft types, whereas highest stress and strain were observed in the anastomosis of the ePU graft. Since haemodynamics were most favourable for the ePU graft simulation, AVG longevity might be improved by the use of ePU grafts.

Objective: Arteriovenous grafts (AVGs) typically lose patency within two years of creation due to venous neointimal hyperplasia, which is initiated by disturbed haemodynamics after AVG surgery. Haemodialysis needle flow can further disturb haemodynamics and thus impact AVG longevity. In this computational study it was assessed how dialysis flow and venous needle positioning impacts flow at the graft-vein anastomosis. Furthermore, it was studied how negative effects of dialysis needle flow could be mitigated.Methods: Non-physiological wall shear stress and disturbed blood flow were assessed in an AVG model with and without dialysis needle flow. Needle distance to the venous anastomosis was set to 6.5, 10.0, or 13.5 cm, whereas dialysis needle flow was set to 200, 300 or 400 mL/min. Intraluminal needle tip depth was varied between superficial, central, or deep. The detrimental effects of dialysis needle flow were summarised by a haemodynamic score (HS), ranging from 0 (minimal) to 5 (severe).Results: Dialysis needle flow resulted in increased disturbed flow and/or non-physiological wall shear stress in the venous peri-anastomotic region. Increasing cannulation distance from 6.5 to 13.5 cm reduced the HS by a factor 4.0, whereas a central rather than a deep or superficial needle tip depth reduced the HS by a maximum factor of 1.9. Lowering dialysis flow from 400 to 200 mL/min reduced the HS by a factor 7.4.Conclusion: Haemodialysis needle flow, cannulation location, and needle tip depth considerably increase the amount of disturbed flow and non-physiological wall shear stress in the venous anastomotic region of AVGs. Negative effects of haemodialysis needle flow could be minimised by more upstream cannulation, by lower dialysis flow and by ensuring a central needle tip depth. Since disturbed haemodynamics are associated with neointimal hyperplasia development, optimising dialysis flow and needle positioning during haemodialysis could play an important role in maintaining AVG patency.

Objective: The aim of the study was to observe the natural haemodynamic changes after arteriovenous fistula (AVF) creation in haemodialysis patients with and without a previous ipsilateral vascular access.Methods: This was a retrospective, single centre cohort study. Patient demographics were registered and preand post-operative vessel ultrasound examinations were performed at regular follow up intervals. Arteriovenous fistula outcomes in terms of vessel diameter and access flow enhancement were determined for radiocephalic, brachiocephalic, and brachiobasilic AVFs.Results: In total, 331 patients (median age 66 years, 60% male) with 366 new autologous AVFs were studied, of whom 112 patients had a previous ipsilateral vascular access (VA). Patients with a previous ipsilateral VA had a statistically significantly greater pre-operative brachial artery diameter (4.4 mm) and flow (106 mL/min), and basilic vein diameter (4.9 mm), compared with patients without a previous ipsilateral VA (4.0 mm, 54 mL/min, and 4.3 mm, respectively). For all AVF configurations these differences gradually disappeared over three months after AVF creation. The haemodynamic changes reached a plateau at three months, and were statistically significantly accelerated in patients with a previous ipsilateral VA. There were no differences in primary failure or high flow complications between both groups.Conclusion: Arteriovenous fistulae show haemodynamic and remodelling changes up to three months post-operatively. Previous ipsilateral VAs may initiate vessel preconditioning, and accelerate the observed haemodynamic changes after AVF creation. However, this preconditioning does not result in a beneficial or detrimental effect on VA function.

Localized AF drivers with repetitive activity are candidate ablation targets for patients with persistent atrial fibrillation (AF). High-density mapping electrodes cover only a fraction of the atria but combining sequential recordings could provide a more comprehensive picture of common repetitive atrial conduction characteristics and enable AF driver localization. We developed a novel algorithm to merge overlapping local activation maps into larger composite maps using recurrence plots. The proposed algorithm was applied to atrial recordings in a goat model of AF (249-electrode mapping array, 2.4 mm inter-electrode distance, n=16). Sequential, overlapping recordings were generated by segmenting the mapping region into four spatially overlapping regions. Repetitive activation patterns were detected from recurrence plots generated from the recorded electrograms, and reconstructed with the proposed algorithm. Reconstruction quality was measured as the Pearson correlation between original and reconstructed activation patterns. The average correlation was 0.86. Among pattern properties, such as duration, area, complexity and cycle length, only duration was significantly correlated with the composite map quality (r=0:126, p < 0:05). The percentage of the cases where a composite map could be generated was 75.30% which was significantly higher for larger patterns (p

The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing in vitro thrombin generation (TG). We describe the customization of the CAT assay in goat platelet‐poor plasma (PPP) and in factor Xa (FXa)‐inhibitor‐anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom‐factor X activator (RVV‐X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV‐X method. To obtain FXa‐inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV‐X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV‐X methods were comparable in triggering TG in goat plasma. The RVV‐X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.

RATIONALE: Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.METHODS AND RESULTS: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.CONCLUSION: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.

Objective The diabetic heart is characterized by extensive lipid accumulation which often leads to cardiac contractile dysfunction. The underlying mechanism involves a pivotal role for vacuolar-type H+-ATPase (v-ATPase, functioning as endosomal/lysosomal proton pump). Specifically, lipid oversupply to the heart causes disassembly of v-ATPase and endosomal deacidification. Endosomes are storage compartments for lipid transporter CD36. However, upon endosomal deacidification, CD36 is expelled to translocate to the sarcolemma, thereby inducing myocardial lipid accumulation, insulin resistance, and contractile dysfunction. Hence, the v-ATPase assembly may be a suitable target for ameliorating diabetic cardiomyopathy. Another function of v-ATPase involves the binding of anabolic master-regulator mTORC1 to endosomes, a prerequisite for the activation of mTORC1 by amino acids (AAs). We examined whether the relationship between v-ATPase and mTORC1 also operates reciprocally; specifically, whether AA induces v-ATPase reassembly in a mTORC1-dependent manner to prevent excess lipids from entering and damaging the heart. Methods Lipid overexposed rodent/human cardiomyocytes and high-fat diet-fed rats were treated with a specific cocktail of AAs (lysine/leucine/arginine). Then, v-ATPase assembly status/activity, cell surface CD36 content, myocellular lipid uptake/accumulation, insulin sensitivity, and contractile function were measured. To elucidate underlying mechanisms, specific gene knockdown was employed, followed by subcellular fractionation, and coimmunoprecipitation. Results In lipid-overexposed cardiomyocytes, lysine/leucine/arginine reinternalized CD36 to the endosomes, prevented/reversed lipid accumulation, preserved/restored insulin sensitivity, and contractile function. These beneficial AA actions required the mTORC1–v-ATPase axis, adaptor protein Ragulator, and endosomal/lysosomal AA transporter SLC38A9, indicating an endosome-centric inside-out AA sensing mechanism. In high-fat diet-fed rats, lysine/leucine/arginine had similar beneficial actions at the myocellular level as in vitro in lipid-overexposed cardiomyocytes and partially reversed cardiac hypertrophy. Conclusion Specific AAs acting through v-ATPase reassembly reduce cardiac lipid uptake raising the possibility for treatment in situations of lipid overload and associated insulin resistance., Graphical abstract Image 1, Highlights • High physiological concentrations of specific AAs (K/L/R) activate v-ATPase. • The KLR mix activates v-ATPase by mutually dependent activation of mTORC1. • KLR-induced v-ATPase activation enables endosomes to retain lipid transporter CD36. • KLR mends lipid-induced insulin resistance and cardiomyocytic contractile dysfunction. • KLR reverses v-ATPase disassembly and cardiac hypertrophy in high-fat diet-fed rats.

Aims Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145. Methods and results Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred. Conclusion AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of F2R (PAR-1) and F2RL1 (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of Ccl2 (MCP-1, &gt, 30-fold at 4 h in atrial and ventricular CF) and Il6 (IL-6, ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of CCL2 (&gt, 3-fold) and IL6 (&gt, 4-fold) at 4 h. Silencing of F2R (PAR-1 gene), but not F2RL1 (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased CCL2 and IL6 gene expression, this was prevented by F2R (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.

Aims Vascular calcification is a hallmark of atherosclerotic burden and can predict the cardiovascular outcome. Vitamin K antagonists (VKA) are widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis but are also associated with increase vascular calcification progression. We aim to unravel the paradox that VKA suppresses plasma coagulation but promotes vascular calcification and subsequent atherosclerosis-dependent coagulability of the vessel wall. Methods and results Apoe −/− mice were placed on western-type diet enriched with the VKA warfarin for 18 weeks to measure atherosclerotic plaque burden, calcification, and coagulation. Patients (n = 54) displaying paroxysmal atrial fibrillation with a low cardiovascular risk, who were treated with VKA were included to measure pre-thrombotic state. Finally, primary vascular smooth muscle cells (VSMC) derived from human tissue explants were used for in vitro experiments. In Apoe−/− mice, VKA increases both atherosclerotic plaque size and calcification. Higher plaque calcification was associated with increased plasma levels of thrombin-antithrombin and factor IXa-antithrombin complexes in mice and patients treated with VKA. Mechanistically, phenotypic switching of VSMC into synthetic VSMC promotes thrombin generation, which is enhanced in a tissue-factor (TF)-dependent manner by VSMC calcification. Moreover, calcified VSMC exposed to whole blood under flow significantly enhanced platelet deposition and TF-dependent fibrin formation. Conclusions Oral anticoagulation with VKA aggravates vascular calcification and atherosclerosis. VSMC phenotype differentiation impacts coagulation potential in a TF-dependent manner. VKA-induced vascular calcification increases hypercoagulability and could thereby potentially positively affect atherothrombosis.

During the development of medicines, people try to minimize the risk of unwanted side effects. In particular, the “torsades de pointes” side effect (TdP; a chamber rhythm disorder) is feared. Patients with the hereditary long QT syndrome are particularly sensitive. They may unexpectedly faint or sometimes suddenly die. In this research, a unique model was developed to study the development of TdP in detail. The studies were done in narcotized dogs so that the animals did not experience any pain or stress. We identified a groundbreaking new parameter, the electromechanical window (EMW). This parameter has the potential to more adequately determine the risk of TdP during drug development. Currently EMW measurements are successfully evaluated by means of computer models and safety studies in cells by the pharmaceutical industry and in clinical studies with different patient populations by academic specialists worldwide.

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart., Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.

Background This cross‐sectional study evaluated associations between structural and functional measures of left ventricular diastolic function and cardiorespiratory fitness (CRF) in a well‐characterized population‐based cohort stratified according to glucose metabolism status. Methods and Results Six hundred seventy‐two participants from The Maastricht Study (mean±SD age, 61±9 years; 17.4% prediabetes and 25.4% type 2 diabetes mellitus) underwent both echocardiography to determine left atrial volume index, left ventricular mass index, maximum tricuspid flow regurgitation, average e′ and E/e′ ratio; and submaximal cycle ergometer test to determine CRF as maximum power output per kilogram body mass. Associations were examined with linear regression adjusted for cardiovascular risk and lifestyle factors, and interaction terms. After adjustment, in normal glucose metabolism but not (pre)diabetes, higher left atrial volume index (per 1 mL/m 2 ), left ventricular mass index (per 1 g/m 2.7 ), maximum tricuspid regurgitation flow (per 1 m/s) were associated with higher CRF (maximum power output per kilogram body mass; β in normal glucose metabolism 0.015 [0.008–0.023], P interaction (pre)diabetes P interaction type 2 diabetes mellitus P interaction >0.10; for left atrial volume index, left ventricular mass index, maximum tricuspid regurgitation flow, respectively). Furthermore, after adjustment, in all individuals, higher average E/e′ ratio (per unit), but not average e′, was associated with lower CRF (normal glucose metabolism −0.044 [−0.071 to −0.016]), P interaction >0.10). Conclusions In this population‐based study, structural and functional measures of left ventricular diastolic function were independently differentially associated with CRF over the strata of glucose metabolism status. This suggests that deteriorating left ventricular diastolic function, although of small effect, may contribute to the pathophysiological process of impaired CRF in the general population. Moreover, the differential effects in these structural measures may be the consequence of cardiac structural adaptation to effectively increase CRF in normal glucose metabolism, which is absent in (pre)diabetes.

A 32-year-old male, known to have atopic eczema, presented with a 3-day history of acute pleuritic chest pain and shortness of breath. No traumatic event had occurred. The pain was described as sharp and posture dependent, and was worse when leaning backwards. The patient had no palpitations, oedema or radiated pain. Dyspnoea was present both at rest and during exercise, without the presence of wheezing, haemoptysis or purulent sputum. He had no history of fever, cold shivers, weight loss or perspiration. His nutritional state was normal and he had no symptoms of nausea, vomiting or diarrhoea. For 3 days he had experienced dysphagia during meals. The patient was working full-time as a national courier and did not visit foreign countries for his work and did not travel outside Europe. The patient owned a dog but he had no specific contact with (farm) animals. He never smoked and never consumed alcohol. His physical condition, before the start of the present symptoms, was excellent due to daily exercises. On clinical examination our patient was conscious and orientated. He had a normal temperature of 36.9 °C, a respiratory rate of 16 breaths·min−1, blood pressure of 115/75 mmHg, heart rate of 68 beats·min−1 and an oxygen saturation of 95% on room air. Both percussion and respiratory sounds were reduced over the right hemithorax, without crackles or rhonchi. He had no pitting oedema around the ankles. A chest radiograph was performed (figure 1)., Most bronchogenic cysts are found incidentally and clinicians should be aware of an atypical case presentation. Total surgical resection is the treatment of choice of a bronchogenic cyst, especially in symptomatic patients. https://bit.ly/3uQrFXo

Background: Atrial Fibrillation (AF) in patients without concomitant cardiovascular pathophysiological disease, is called idiopathic Atrial Fibrillation (iAF). Nonetheless, iAF patients have often times subclinical coronary (micro) vascular dysfunction and, particularly in women, a higher prevalence of subsequent cardiovascular comorbidities. Previously, we identified a plasma miRNA association with diabetes and microvascular injury in Diabetic Nephropathy (DN) patients. Therefore, in this study we assessed whether plasma levels of these diabetic, microvascular injury associated miRNAs reflect microvascular integrity in iAF patients, associated with the presence of paroxysmal arrhythmia or instead are determined by concealed coronary artery disease. Methods: Circulating levels of a pre-selected set of diabetic, (micro) vascular injury associated miRNAs, were measured in 59 iAF patients compared to 176 Sinus Rhythm (SR) controls. Furthermore, the presence of coronary artery and aortic calcification in each patient was assessed using Cardiac Computed Tomography Angiography (CCTA). Results: Paroxysmal arrhythmia in iAF patients did not result in significant miRNA expression profile differences in iAF patients compared to SR controls. Nonetheless, coronary artery calcification (CAC) was associated with higher levels of miRNAs-103, -125a-5p, -221 and -223 in men. In women, CAC was associated with higher plasma levels of miRNA-27a and miRNA-126 and correlated with Agatston scores. Within the total population, ascending Aortic Calcification (AsAC) patients displayed increased plasma levels of miRNA-221, while women, in particular, demonstrated a Descending Aorta Calcification (DAC) associated increase in miRNA-212 levels. Conclusions: Diabetic microvascular injury associated miRNAs in iAF are associated with subclinical coronary artery disease in a sex-specific way and confirm the notion that biological sex identifies iAF subgroups that may require dedicated clinical care.

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes, (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed, (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations, (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF.Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407.Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.

Highlights • Persistent atrial fibrillation is associated with increased fibroblast accumulation. • Six weeks of persistent AF is not associated with structural remodeling. • Fibroblasts are potentially contributing to alteration in atrial electrophysiology., Background Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF. Material and methods Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics. Results Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation p = 0.0295). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins (p

Background: Microvascular obstruction (MO) is a pathophysiologic complication of acute myocardial infarction that portends poor prognosis; however, it is transient and disappears with infarct healing. Much remains unknown regarding its pathophysiology and whether there are predictors of MO that could function as stable surrogates. We tested for clinical and cardiovascular magnetic resonance predictors of MO to gain insight into its pathophysiology and to find a stable surrogate. Methods: Three hundred two consecutive patients from 2 centers underwent cardiovascular magnetic resonance within 2 weeks of first acute myocardial infarction. Three measures of infarct morphology: infarct size, transmurality, and a new index—the epicardial surface area (EpiSA) of full-thickness infarction—were quantified on delayed-enhancement cardiovascular magnetic resonance. Results: Considering all clinical characteristics, only measures of infarct morphology were independent predictors of MO. EpiSA was the strongest predictor of MO and provided incremental predictive value beyond that of infarct size and transmurality ( P P =0.045). Conclusions: The EpiSA of infarction is a novel index of infarct morphology which accurately predicts MO during the first 2 weeks of MI, but unlike MO, does not disappear with infarct healing. This index has potential as a stable surrogate of the presence of acute MO and may be useful as a predictor of adverse remodeling and outcome which is less dependent on the time window of patient assessment.

Objective. Presence of a patent ductus arteriosus (PDA) in neonates is assessed by echocardiography. Echocardiographic assessment has disadvantages, primarily its discontinuous nature. We hypothesize that the continuously measured ratio of arterial blood pressures (ABP) at the borders of a window surrounding the systolic peak ratio discriminates non-PDA from PDA patients. Approach. Preterm infants (gestational age n = 8) and PDA patients (n = 22), the latter with a subset of patients with closed PDA after three doses Ibuprofen (n = 10). For each patient, a six-hour ABP segment from 12 AM to 6 AM on the day of echocardiographic assessment patency or closure of the DA was selected. The mean ratio of the ABP values a samples before and p samples after the systolic peak (R ABP) was calculated for each segment. If R ABP a and p with the least misclassifications were selected (−64 and +104 ms). Main results. R ABP was significantly lower in PDA patients (median 0.95, IQR 0.06) compared to controls (median 1.05, IQR 0.10; p = 0.0024). R ABP correctly predicted 19 out of 22 patients (86.4%) and six out of eight controls (75%). R ABP increased after closure in nine out of 10 patients (median 1.01, IQR 0.04; p = 0. 0182). Significance. R ABP may discriminate preterm PDA patients from non-PDA patients and can be calculated continuously from clinical data measured during standard of care.

Objective: Chronic renal failure patients with arteriovenous hemodialysis access may exhibit pain and neurological complaints due to local nerve compression by the access conduit vessels of autogenous arteriovenous fistulas or the prosthesis of arteriovenous grafts. In this study, we have examined the results of surgical intervention for vascular access–related nerve compression in the upper extremity. Methods: A single center retrospective study was performed of all patients referred for persistent pain and neurological complaints after vascular access surgery for hemodialysis. There were four brachial-cephalic, three brachial-basilic upper arm arteriovenous fistulas, and three prosthetic arteriovenous grafts. All patients had pain and sensory deficits in a distinct nerve territory (median nerve: 6; median + ulnar nerve: 1; medial cutaneous nerve: 1), and two patients had additional motor deficits (median nerve). Results: A total of 10 patients (mean age: 59 years; range: 25–73 years; 2 men; 4 diabetics) were treated by surgical nerve release alone (2 patients) or in combination with access revision (8 patients). Mean follow-up was 23 months (range: 8–46 months). Direct complete relief of symptoms was achieved in six patients. Three patients had minor complaints, and one patient had a reoperation with good success. Conclusion: Vascular access–related nerve compression is an uncommon cause for pain, sensory and motor deficits after vascular access surgery. Surgical nerve release and access revision have good clinical outcome with relief of symptoms and maintenance of the access site in the majority of patients.

Introduction Electrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF. Methods Repetitive conduction patterns recorded by a multi-electrode array were detected and visualized using recurrence plots. Recurrence plots were constructed by first transforming atrial electrograms to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent recurrence threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were delineated by an algorithm that locates square blocks in a recurrence plot with a high recurrence rate. Intervals that contained repetitive patterns representing similar patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF (3 weeks AF (3wkAF, n=8) and 22 weeks AF (22wkAF, n=8)), using a 249-electrode mapping array (2.4mm inter-electrode distance). Results Recurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration (mean maximum duration 3wkAF: 74 cycles, 95% confidence interval [54-94] vs. 22wkAF: 41 cycles [21-62], p=0.03), and smaller recurrent regions within repetitive patterns (3wkAF 1.7cm2 [1.0-2.3] vs. 22wkAF 0.5cm2 [0.0-1.2], p=0.02). Both breakthrough patterns and re-entry were identified as repetitive conduction patterns. Conclusions Recurrence plots provide a novel way to delineate high-density contact mapping of atrial fibrillation. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.

Highlights • The MINOCA prevalence is 5.2% in the total ACS population. • MINOCA occurs predominantly in the NSTE-ACS population and in females. • MINOCA show an ‘intermediate’ risk profile with mortality rates in between those of SV-ACS and MV-ACS., Aims Whether patients with MINOCA (myocardial infarction with non-obstructive coronary arteries) have better outcomes than patients with obstructive coronary artery disease remains contradictory. The current study focussed on the clinical profile and prognosis of MINOCA patients. Methods and results We performed a retrospective analysis of patients with acute coronary syndrome (ACS) admitted to the Isala hospital in Zwolle, the Netherlands, between 2006 and 2014. A total of 7693 patients were categorized into three groups: MINOCA, single-vessel obstructive ACS (SV-ACS), and multi-vessel obstructive ACS (MV-ACS). MINOCA patients (5.2% of the total population) were more likely to be female (51.5% vs. 30.3% and 26.0% in SV-ACS and MV-ACS, respectively, p

Backgrounds The role of right ventricular (RV) and atrial (RA) structure and function, in the increased heart failure risk in (pre)diabetes is incompletely understood. The purpose of this study is to investigate the associations between (pre)diabetes and RV and RA structure and function, and whether these are mediated by left ventricular (LV) alterations or pulmonary pressure. Methods Participants of the Maastricht Study; a population-based cohort study (426 normal glucose metabolism (NGM), 142 prediabetes, 224 diabetes), underwent two-dimensional and tissue Doppler echocardiography. Multiple linear regression analyses with pairwise comparisons of (pre)diabetes versus NGM, adjusted for cardiovascular risk factors, and mediation analyses were used. Results In general, differences were small. Nevertheless, in individuals with prediabetes and diabetes compared to NGM; RA volume index was lower (both p trend trend trend = 0.04), TDI S′RV was lower (p = 0.08 and p trend trend = 0.01) and TDI A′RV was lower (p trend = 0.04). Only the differences in RA volume index (7.8%) and RV diameter (6.2%) were mediated by the maximum tricuspid gradient, but no other LV structure and function measurements. Conclusions (Pre)diabetes is associated with structural RA and RV changes, and impaired RV systolic and diastolic function, independent of cardiovascular risk factors. These associations were largely not mediated by indices of LV structure, LV function or pulmonary pressure. This suggests that (pre)diabetes affects RA and RV structure and function due to direct myocardial involvement.

Chest pain is a common symptom and can be caused by both cardiac and non-cardiac disorders. Non-invasive diagnostics is increasingly regarded as an essential part of the diagnostic evaluation in patients with chest pain, but inefficient and excessive use must be prevented. This dissertation describes the role of non-invasive diagnostics in patients with acute and chronic chest pain. In short, non-invasive diagnostics: 1) has no role in low risk acute chest pain, 2) can improve selection for invasive heart catheterizations in acute chest pain and suspicion of a heart attack, 3) can identify low risk patients if the test result is "negative" in patients with chronic chest pain, 4) cardiac MRI can identify an acute heart attack.

BackgroundThe course of the disease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in mechanically ventilated patients is unknown. To unravel the clinical heterogeneity of the SARS-CoV-2 infection in these patients, we designed the prospective observational Maastricht Intensive Care COVID cohort;MaastrICCht. We incorporated serial measurements that harbour aetiological, diagnostic and predictive information. The study aims to investigate the heterogeneity of the natural course of critically ill patients with SARS-CoV-2 infection.Study populationMechanically ventilated patients admitted to the Intensive Care with SARS- CoV-2 infection.Main messageWe will collect clinical variables, vital parameters, laboratory variables, mechanical ventilator settings, chest electrical impedance tomography, electrocardiograms, echocardiography as well as other imaging modalities to assess heterogeneity of the natural course of SARS-CoV-2 infection in critically ill patients. TheMaastrICChtcohort is, also designed to foster various other studies and registries and intends to create an open-source database for investigators. Therefore, a major part of the data collection is aligned with an existing national Intensive Care data registry and two international COVID-19 data collection initiatives. Additionally, we create a flexible design, so that additional measures can be added during the ongoing study based on new knowledge obtained from the rapidly growing body of evidence.ConclusionThe spread of the COVID-19 pandemic requires the swift implementation of observational research to unravel heterogeneity of the natural course of the disease of SARS- CoV-2 infection in mechanically ventilated patients. Our design is expected to enhance aetiological, diagnostic and prognostic understanding of the disease. This paper describes the design of theMaastrICChtcohort.Strengths and limitations of this studySerial measurements that characterize the disease course of SARS-CoV-2 infection in mechanically ventilated patientsData collection and analysis according to a predefined protocolFlexible, evolving design enabling the study of multiple aspects of SARS-CoV-2 infection in mechanically ventilated patientsSingle centre, including only ICU patients