Improvement in left atrial strain following ferric carboxymaltose in heart failure: an analysis of the Myocardial-IRON trial.

AIMS: Iron deficiency (ID) is associated with an impaired cardiac function and remodelling in heart failure (HF). Treatment with ferric carboxymaltose (FCM) has been showed recently to improve biventricular systolic function and ventricular strain parameters in patients with HF with reduced ejection fraction and ID, but there is no evidence on the benefit of FCM on the left atrium (LA). In this study, we aimed to evaluate the effect of FCM on LA longitudinal strain (LA-LS). METHODS AND RESULTS: This is a post hoc subanalysis of a double-blind, placebo-controlled, randomized clinical trial that enrolled 53 ambulatory patients with HF, left ventricular ejection fraction (LVEF) < 50%, and ID [Myocardial-IRON trial (NCT03398681)], treated with FCM or placebo. Cardiac magnetic resonance-featured tracking (CMR-FT) strain changes were evaluated before and 7 and 30 days after randomization using linear mixed regression analysis. The median age of the sample was 68 years (interquartile range: 64-76), and 20 (69%) were men. Mean ± standard deviation of LVEF was 39 ± 11%, and most (97%) were in stable New York Heart Association class II. At baseline, mean LA-LS was -8.9 ± 3.5%. At 30 days, and compared with placebo, LA-LS significantly improved in those allocated to FCM treatment arm (LA-LS = -12.0 ± 0.5 and -8.5 ± 0.6, respectively; - ∆ 3.55%, P < 0.001). CONCLUSIONS: In patients with stable HF, LVEF < 50%, and ID, treatment with FCM was associated with short-term improvements in LA-LS assessed by CMR-FT. Future works should assess the potential benefit of iron repletion on LA function.

Detection and Classification of Myocardial Infarction Transmurality Using Cardiac MR Image Analysis and Machine Learning Algorithms.

The presence of abnormalities when the left ventricle is deformed is related to the patients' prognosis after a first myocardial infarction. These deformations can be detected by performing a cardiac magnetic resonance (CMR) study. Currently, late gadolinium enhancement (LGE) is considered to be the gold standard when performing CMR imaging. However, CMR with LGE overestimates infarct size and underestimates recovery of dysfunctional segments after myocardial infarction. Based on this statement, the objective is to detect, characterize, and quantify the extent of myocardial infarction in patients with cardiac pathologies, using parameters derived from CMR, in order to obtain greater precision in patients' recovery predictions than when only studying LGE images. For this purpose, we studied the infarct presence and extension from a total of 105 images from 35 patients, and calculated myocardium strain and torsion to characterize and quantify the affected tissue. A total of twenty-one parameters were selected to create predictive models. Moreover, we compared two feature extraction methods, and the performance of five machine learning algorithms. Results show that both temporal and strain parameters are the most relevant to detect and characterize the extent of myocardial infarction. The use of imaging techniques and machine learning algorithms have great potential and show promising results when it comes to detecting the presence and extent of myocardial infarction. The current study proposes a novel approach to detect, quantify, and characterize cardiac infarction by using strain and torsion parameters from different CMR images and different Machine Learning algorithms. This would potentially overcome LGE, the current state of the art technique, in estimating the extension of damaged tissue and enable an objective diagnosis and clinical decision.

Short-Term Changes in Left and Right Ventricular Cardiac Magnetic Resonance Feature Tracking Strain Following Ferric Carboxymaltose in Patients With Heart Failure: A Substudy of the Myocardial-IRON Trial.

Background The mechanisms explaining the clinical benefits of ferric carboximaltose (FCM) in patients with heart failure, reduced or intermediate left ventricular ejection fraction, and iron deficiency remain not fully clarified. The Myocardial-IRON trial showed short-term cardiac magnetic resonance (CMR) changes suggesting myocardial iron repletion following administration of FCM but failed to find a significant increase in left ventricular ejection fraction in the whole sample. Conversely, the strain assessment could evaluate more specifically subtle changes in contractility. In this subanalysis, we aimed to evaluate the effect of FCM on the short-term left and right ventricular CMR feature tracking derived strain. Methods and Results This is a post hoc subanalysis of the double-blind, placebo-controlled, randomized clinical trial that enrolled 53 ambulatory patients with heart failure and left ventricular ejection fraction <50%, and iron deficiency [Myocardial-IRON trial (NCT03398681)]. Three-dimensional left and 2-dimensional right ventricular CMR tracking strain (longitudinal, circumferential, and radial) changes were evaluated before, 7 and 30 days after randomization using linear mixed-effect analysis. The median (interquartile range) age of the sample was 73 years (65-78), and 40 (75.5%) were men. At baseline, there were no significant differences in CMR feature tracking strain parameters across both treatment arms. At 7 days, the only global 3-dimensional left ventricular circumferential strain was significantly higher in the FCM treatment-arm (difference: -1.6%, P=0.001). At 30 days, and compared with placebo, global 3-dimensional left ventricular strain parameters significantly improved in those allocated to FCM treatment-arm [longitudinal (difference: -2.3%, P<0.001), circumferential (difference: -2.5%, P<0.001), and radial (difference: 4.2%, P=0.002)]. Likewise, significant improvements in global right ventricular strain parameters were found in the active arm at 30 days (longitudinal [difference: -3.3%, P=0.010], circumferential [difference: -4.5%, P<0.001], and radial [difference: 4.5%, P=0.027]). Conclusions In patients with stable heart failure, left ventricular ejection fraction <50%, and iron deficiency, treatment with FCM was associated with short-term improvements in left and right ventricular function assessed by CMR feature tracking derived strain parameters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

The impact of prolonged frozen storage on the preparation quality of bird skins and skeletons in zoological collections.

Specimens from zoological collections play a pivotal role in improving scientific knowledge in many natural science disciplines. To guarantee an optimum state of conservation and ensure their usefulness, the preparation process employed is crucial. Skins and skeletons are key elements in vertebrate scientific collections and, ideally, are prepared from recently deceased animals; however, specimens are often stored in a frozen state for a long time (years) prior to preparation. Whether the duration of this frozen state has a deleterious effect on preparation quality has rarely been studied. The main objective of this study was thus to contribute towards research into zoological preparation by testing to see whether prolonged frozen storage hinders the preparation of bird skins and skeletons. We used the common buzzard (Buteo buteo) and the barn owl (Tyto alba) as biological models. Our results showed that long-term frozen storage led to weight loss, bone marrow acidification and solidification, and hampered skin preparation. The necropsy affected weight loss and decreased the skin tear resistance, probably due to tissue dehydration. Thus, prolonged frozen storage appears to have a harmful effect on the preparation quality of vertebrate specimens. Since frozen storage could ultimately have an impact on the conservation and scientific use of museum specimens, practices should be implemented to minimise the amount of time specimens are frozen or to mitigate any detrimental effects. More importance should be attached to research on zoological preparation since it is fundamental for optimising the quality, conservation status, and value of museum collections.

Development and Long-Term Follow-Up of an Experimental Model of Myocardial Infarction in Rabbits.

A chronic model of acute myocardial infarction was developed to study the mechanisms involved in adverse postinfarction ventricular remodeling. In an acute myocardial infarction (AMI), the left circumflex coronary artery of New Zealand White rabbits (n = 9) was occluded by ligature for 1 h, followed by reperfusion. A specific care protocol was applied before, during, and after the intervention, and the results were compared with those of a sham operated group (n = 7). After 5 weeks, programmed stimulation and high-resolution mapping were performed on isolated and perfused hearts using the Langendorff technique. The infarct size determined by 2,3,5-triphenyltetrazolium chloride inside of the area at risk (thioflavin-S) was then determined. The area at risk was similar in both groups (54.33% (experimental infarct group) vs. 58.59% (sham group), ns). The infarct size was 73.16% as a percentage of the risk area. The experimental infarct group had a higher inducibility of ventricular arrhythmias (100% vs. 43% in the sham group, p = 0.009). A reproducible chronic experimental model of myocardial infarction is presented in which the extent and characteristics of the lesions enable the study of the vulnerability to develop ventricular arrhythmias because of the remodeling process that occurs during cardiac tissue repair.

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers.

BACKGROUND: Mechanical stretch increases Na+ inflow into myocytes, related to mechanisms including stretch-activated channels or Na+/H+ exchanger activation, involving Ca2+ increase that leads to changes in electrophysiological properties favoring arrhythmia induction. Ranolazine is an antianginal drug with confirmed beneficial effects against cardiac arrhythmias associated with the augmentation of I NaL current and Ca2+ overload. OBJECTIVE: This study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine. METHODS: Confluent HL-1 cells were cultured in silicone membrane plates and were stretched to 110% of original length. The characteristics of in vitro fibrillation (dominant frequency, regularity index, density of phase singularities, rotor meandering, and rotor curvature) were analyzed using optical mapping in order to study the mechanoelectric response to stretch under control conditions and ranolazine action. RESULTS: HL-1 cell stretch increased fibrillatory dominant frequency (3.65 ± 0.69 vs. 4.35 ± 0.74 Hz, p < 0.01) and activation complexity (1.97 ± 0.45 vs. 2.66 ± 0.58 PS/cm2, p < 0.01) under control conditions. These effects were related to stretch-induced changes affecting the reentrant patterns, comprising a decrease in rotor meandering (0.72 ± 0.12 vs. 0.62 ± 0.12 cm/s, p < 0.001) and an increase in wavefront curvature (4.90 ± 0.42 vs. 5.68 ± 0.40 rad/cm, p < 0.001). Ranolazine reduced stretch-induced effects, attenuating the activation rate increment (12.8% vs. 19.7%, p < 0.01) and maintaining activation complexity-both parameters being lower during stretch than under control conditions. Moreover, under baseline conditions, ranolazine slowed and regularized the activation patterns (3.04 ± 0.61 vs. 3.65 ± 0.69 Hz, p < 0.01). CONCLUSION: Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.

Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart.

A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1µM), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78±10 vs. 68±10 ms) and after atropine (76±8 vs. 67±10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53±8 vs. 42±7 ms and 50±6 vs. 40±6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5±1.5% vs. 15.1±3.8%) and, decreased after atropine (15.1±3.8% vs. 12.2±2.4%) in the control group. The trained group showed higher NE values before (0.40±0.04 vs. 0.36±0.05) and after atropine (0.37±0.04 vs. 0.34±0.06; p = 0.08). Training decreased the CV of NE both before (23.3±2% vs. 25.2±4%; p = 0.08) and after parasympathetic blockade (22.6±1% vs. 26.1±5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34±8 vs. 41±5), and increased after atropine in the control group (41±5 vs. 48±9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology.

PURPOSE: Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch. METHODS: Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n = 28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 µM). RESULTS: On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 µM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 µM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p < 0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p < 0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p < 0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p < 0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03 µM = 33%, 0.1 µM = 33%, 0.3 µM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03µM = 41%, 0.1 µM = 32%, 0.3 µM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration. CONCLUSIONS: GS967 attenuates stretch-induced changes in cardiac electrophysiology.

Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback.

Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca2+ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n = 10); (b) S-nitrosoglutathione 10 µM (n = 11); and (c) S-nitrosoglutathione 50 µM (n = 11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 µM did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6 ± 1.7 vs. 21.3 ± 3.8 Hz; p < 0.0001) and reduction of percentile 5 of the activation intervals (42 ± 3 vs. 38 ± 4 ms; p < 0.05) induced by stretch. In contrast, at baseline using the 50 µM concentration, percentile 5 was shortened (38 ± 6 vs. 52 ± 10 ms; p < 0.005) and the complexity index increased (1.77 ± 0.18 vs. 1.27 ± 0.13; p < 0.0001). The greatest complexity indices (1.84 ± 0.17; p < 0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 µM attenuates the effects of mechanoelectric feedback, while at a concentration of 50 µM the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.

Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback.

JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca2+ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca2+ overload. Mechanical stretch increases cellular Na+ inflow, activates the reverse mode of the Na+ /Ca2+ exchanger, and modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 µmol/L (n=9) and 1 µmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 µmol/L=11.1±1.1 Hz, P<.01; JTV 1 µmol/L=6.6±1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 µmol/L (19.8%) and abolished by JTV 1 µmol/L (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 µmol/L=1.13±0.3, P<.0001; JTV 1 µmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=-.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback.

Ranolazine Attenuates the Electrophysiological Effects of Myocardial Stretch in Langendorff-Perfused Rabbit Hearts.

PURPOSE: Mechanical stretch is an arrhythmogenic factor found in situations of cardiac overload or dyssynchronic contraction. Ranolazine is an antianginal agent that inhibits the late Na (+) current and has been shown to exert a protective effect against arrhythmias. The present study aims to determine whether ranolazine modifies the electrophysiological responses induced by acute mechanical stretch. METHODS: The ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n = 9) or during perfusion of the late Na(+) current blocker ranolazine 5 µM (n = 9). Spectral and mapping techniques were used to establish the ventricular fibrillation dominant frequency, the spectral concentration and the complexity of myocardial activation in three situations: baseline, stretch and post-stretch. RESULTS: Ranolazine attenuated the increase in ventricular fibrillation dominant frequency produced by stretch (23.0 vs 40.4 %) (control: baseline =13.6 ± 2.6 Hz, stretch = 19.1 ± 3.1 Hz, p < 0.0001; ranolazine: baseline = 1.4 ± 1.8 Hz, stretch =14.0 ± 2.4 Hz, p < 0.05 vs baseline, p < 0.001 vs control). During stretch, ventricular fibrillation was less complex in the ranolazine than in the control series, as evaluated by the lesser percentage of complex maps and the greater spectral concentration of ventricular fibrillation. These changes were associated to an increase in the fifth percentile of VV intervals during ventricular fibrillation (50 ± 8 vs 38 ± 5 ms, p < .01) and in the wavelength of the activation (2.4 ± 0.3 vs 1.9 ± 0.2 cm, p < 0.001) under ranolazine. CONCLUSIONS: The late inward Na(+) current inhibitor ranolazine attenuates the electrophysiological effects responsible for the acceleration and increase in complexity of ventricular fibrillation produced by myocardial stretch.

Characterization of normal regional myocardial function by MRI cardiac tagging.

PURPOSE: The aim of this study was to establish reference values for segmental myocardial strain measured by magnetic resonance (MR) cardiac tagging in order to characterize the regional function of the heart. MATERIAL AND METHODS: We characterized the left ventricular (LV) systolic deformation in 39 subjects (26 women and 13 men, age 58.8 ± 11.6 years) whose cardiological study had not revealed any significant abnormality. The deformation was measured from MR-tagged (Siemens 1.5T MR) images using an algorithm based on sine wave modeling. Circumferential and radial peak systolic strain values along with the torsion angle and circumferential-longitudinal (CL) shear were determined in 16 LV segments in order to settle the reference values for these parameters. RESULTS: Circumferential strain was highest at the anterior and lateral walls (-20.2 ± 4.0% and -21.8 ± 4.3%, respectively; P < 0.05) and was lowest at the base level (-17.2 ± 3.1% vs. -20.1 ± 3.1% "mid level," P < 0.05; -17.2 ± 3.1% vs. -20.3 ± 3.0% "apical level," P < 0.05). Radial strain highest values were from inferior and lateral walls (13.7 ± 7.4% and 12.8 ± 7.8%, respectively; P < 0.05) and it was lowest medially (9.4 ± 4.1% vs. 13.1 ± 4.1% "base level," P < 0.05; 9.4 ± 4.1% vs. 12.1 ± 4.4% "apical level," P < 0.05). Torsion angle (counterclockwise when viewed from the apex) increased with the distance from the base (7.9 ± 2.4° vs. 16.8 ± 4.4°, P < 0.05), and the highest and lowest values were found at lateral (medial lateral: 12.0 ± 4.4°, apical lateral: 25.1 ± 6.4°, P < 0.05) and septal wall (medial septal: 3.6 ± 2.1°, apical septal: 8.3 ± 5.3°, P < 0.05), respectively. These differences were found again in CL shear values, around the LV circumference. However, CL shear remained constant with increasing distance from the base (9.1 ± 2.6°, medium and 9.8 ± 2.4°, apex). CONCLUSION: In summary, this study provides reference values for the assessment of regional myocardial function by MR cardiac tagging. Comparison of patient deformation parameters with normal deformation patterns may permit early detection of regional systolic dysfunction.

Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study.

INTRODUCTION AND OBJECTIVES: An experimental model is used to analyze the characteristics of ventricular fibrillation in situations of variable complexity, establishing relationships among the data produced by different methods for analyzing the arrhythmia. METHODS: In 27 isolated rabbit heart preparations studied under the action of drugs (propranolol and KB-R7943) or physical procedures (stretching) that produce different degrees of change in the complexity of myocardial activation during ventricular fibrillation, use was made of spectral, morphological, and mapping techniques to process the recordings obtained with epicardial multielectrodes. RESULTS: The complexity of ventricular fibrillation assessed by mapping techniques was related to the dominant frequency, normalized spectral energy, signal regularity index, and their corresponding coefficients of variation, as well as the area of the regions of interest identified on the basis of these parameters. In the multivariate analysis, we used as independent variables the area of the regions of interest related to the spectral energy and the coefficient of variation of the energy (complexity index=-0.005×area of the spectral energy regions -2.234×coefficient of variation of the energy+1.578; P=.0001; r=0.68). CONCLUSIONS: The spectral and morphological indicators and, independently, those derived from the analysis of normalized energy regions of interest provide a reliable approach to the evaluation of the complexity of ventricular fibrillation as an alternative to complex mapping techniques.