Monitoring of myocardial injury by serial measurements of QRS area and T area: The MaastrICCht cohort.

BACKGROUND: Manually derived electrocardiographic (ECG) parameters were not associated with mortality in mechanically ventilated COVID-19 patients in earlier studies, while increased high-sensitivity cardiac troponin-T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were. To provide evidence for vectorcardiography (VCG) measures as potential cardiac monitoring tool, we investigated VCG trajectories during critical illness. METHODS: All mechanically ventilated COVID-19 patients were included in the Maastricht Intensive Care Covid Cohort between March 2020 and October 2021. Serum hs-cTnT and NT-proBNP concentrations were measured daily. Conversion of daily 12-lead ECGs to VCGs by a MATLAB-based script provided QRS area, T area, maximal QRS amplitude, and QRS duration. Linear mixed-effect models investigated trajectories in serum and VCG markers over time between non-survivors and survivors, adjusted for confounders. RESULTS: In 322 patients, 5461 hs-cTnT, 5435 NT-proBNP concentrations and 3280 ECGs and VCGs were analyzed. Non-survivors had higher hs-cTnT concentrations at intubation and both hs-cTnT and NT-proBNP significantly increased compared with survivors. In non-survivors, the following VCG parameters decreased more when compared to survivors: QRS area (-0.27 (95% CI) (-0.37 to -0.16, p < .01) µVs per day), T area (-0.39 (-0.62 to -0.16, p < .01) µVs per day), and maximal QRS amplitude (-0.01 (-0.01 to -0.01, p < .01) mV per day). QRS duration did not differ. CONCLUSION: VCG-derived QRS area and T area decreased in non-survivors compared with survivors, suggesting that an increase in myocardial damage and tissue loss play a role in the course of critical illness and may drive mortality. These VCG markers may be used to monitor critically ill patients.

A single-centre prospective evaluation of left bundle branch area pacemaker implantation characteristics.

BACKGROUND: Left bundle branch area pacing (LBBAP) has recently been introduced as a physiological pacing technique with synchronous left ventricular activation. It was our aim to evaluate the feasibility and learning curve of the technique, as well as the electrical characteristics of LBBAP. METHODS AND RESULTS: LBBAP was attempted in 80 consecutive patients and electrocardiographic characteristics were evaluated during intrinsic rhythm, right ventricular septum pacing (RVSP) and LBBAP. Permanent lead implantation was successful in 77 of 80 patients (96%). LBBAP lead implantation time and fluoroscopy time shortened significantly from 33 ± 16 and 21 ± 13 min to 17 ± 5 and 12 ± 7 min, respectively, from the first 20 to the last 20 patients. Left bundle branch (LBB) capture was achieved in 54 of 80 patients (68%). In 36 of 45 patients (80%) with intact atrioventricular conduction and narrow QRS, an LBB potential (LBBpot) was present with an LBBpot to onset of QRS interval of 22 ± 6 ms. QRS duration increased significantly more during RVSP (141 ± 20 ms) than during LBBAP (125 ± 19 ms), compared to 130 ± 30 ms without pacing. An even clearer difference was observed for QRS area, which increased significantly more during RVSP (from 32 ± 16 µVs to 73 ± 20 µVs) than during LBBAP (41 ± 15 µVs). QRS area was significantly smaller in patients with LBB capture compared to patients without LBB capture (43 ± 18 µVs vs 54 ± 21 µVs, respectively). In patients with LBB capture (n = 54), the interval from the pacing stimulus to R­wave peak time in lead V6 was significantly shorter than in patients without LBB capture (75 ± 14 vs 88 ± 9 ms, respectively). CONCLUSION: LBBAP is a safe and feasible technique, with a clear learning curve that seems to flatten after 40-60 implantations. LBB capture is achieved in two-thirds of patients. Compared to RVSP, LBBAP largely maintains ventricular electrical synchrony at a level close to intrinsic (narrow QRS) rhythm.

Visualisation of coronary venous anatomy by computed tomography angiography prior to cardiac resynchronisation therapy implantation.

BACKGROUND: The purpose of this study was to illustrate the additive value of computed tomography angiography (CTA) for visualisation of the coronary venous anatomy prior to cardiac resynchronisation therapy (CRT) implantation. METHODS: Eighteen patients planned for CRT implantation were prospectively included. A specific CTA protocol designed for visualisation of the coronary veins was carried out on a third-generation dual-source CT platform. Coronary veins were semi-automatically segmented to construct a 3D model. CTA-derived coronary venous anatomy was compared with intra-procedural fluoroscopic angiography (FA) in right and left anterior oblique views. RESULTS: Coronary venous CTA was successfully performed in all 18 patients. CRT implantation and FA were performed in 15 patients. A total of 62 veins were visualised; the number of veins per patient was 3.8 (range: 2-5). Eighty-five per cent (53/62) of the veins were visualised on both CTA and FA, while 10% (6/62) were visualised on CTA only, and 5% (3/62) on FA only. Twenty-two veins were present on the lateral or inferolateral wall; of these, 95% (21/22) were visualised by CTA. A left-sided implantation was performed in 13 patients, while a right-sided implantation was performed in the remaining 2 patients because of a persistent left-sided superior vena cava with no left innominate vein on CTA. CONCLUSION: Imaging of the coronary veins by CTA using a designated protocol is technically feasible and facilitates the CRT implantation approach, potentially improving the outcome.

Pathophysiology of dyssynchrony: of squirrels and broken bones.

The genesis of cardiac resynchronisation therapy (CRT) consists of 'bedside' research and 'bench' studies that are performed in series with each other. In this field, the bench studies are crucial for understanding the pathophysiology of dyssynchrony and resynchronisation. In a way, CRT started with the insight that abnormal ventricular conduction, as caused by right ventricular pacing, has adverse effects. Out of this research came the ground-breaking insight that 'simple' disturbances in impulse conduction, which were initially considered innocent, proved to result in a host of molecular and cellular derangements that lead to a vicious circle of remodelling processes that facilitate the development of heart failure. As a consequence, CRT does not only correct conduction abnormalities, but also improves myocardial properties at many levels. Interestingly, corrections by CRT do not exactly reverse the derangements, induced by dyssynchrony, but also activate novel pathways, a property that may open new avenues for the treatment of heart failure.

Identifying delayed left ventricular lateral wall activation in patients with non-specific intraventricular conduction delay using coronary venous electroanatomical mapping.

BACKGROUND: Delayed left ventricular (LV) lateral wall activation is considered the electrical substrate that characterises patients suitable for cardiac resynchronisation therapy (CRT). Although typically associated with left bundle branch block, delayed LV lateral wall activation may also be present in patients with non-specific intraventricular conduction delay (IVCD). We assessed LV lateral wall activation in a cohort of CRT candidates with IVCD using coronary venous electroanatomical mapping, and investigated whether baseline QRS characteristics on the ECG can identify delayed LV lateral wall activation in this group of patients. METHODS: Twenty-three consecutive CRT candidates with IVCD underwent intra-procedural coronary venous electroanatomical mapping using EnSite NavX. Electrical activation time was measured in milliseconds from QRS onset and expressed as percentage of QRS duration. LV lateral wall activation was considered delayed if maximal activation time measured at the LV lateral wall (LVLW-AT) exceeded 75 % of the QRS duration. QRS morphology, duration, fragmentation, axis deviation, and left anterior/posterior fascicular block were assessed on baseline ECGs. RESULTS: Delayed LV lateral wall activation occurred in 12/23 patients (maximal LVLW-AT = 133 ± 20 ms [83 ± 5 % of QRS duration]). In these patients, the latest activated region was consistently located on the basal lateral wall. QRS duration, and prevalence of QRS fragmentation and left/right axis deviation, and left anterior/posterior fascicular block did not differ between patients with and without delayed LV lateral wall activation. CONCLUSION: Coronary venous electroanatomical mapping can be used at the time of CRT implantation to determine the presence of delayed LV lateral wall activation in patients with IVCD. QRS characteristics on the ECG seem unable to identify delayed LV lateral wall activation in this subgroup of patients.

Cardiac resynchronization: insight from experimental and computational models.

Cardiac resynchronization therapy (CRT) is a promising therapy for heart failure patients with a conduction disturbance, such as left bundle branch block. The aim of CRT is to resynchronize contraction between and within ventricles. However, about 30% of patients do not respond to this therapy. Therefore, a better understanding is needed for the relation between electrical and mechanical activation. In this paper, we focus on to what extent animal experiments and mathematical models can help in order to understand the pathophysiology of asynchrony to further improve CRT.

Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy.

BACKGROUND: Left bundle branch block (LBBB) morphology is associated with improved outcome of cardiac resynchronisation therapy (CRT) and is an important criterion for patient selection. There are, however, multiple definitions for LBBB. Moreover, applying these definitions seems subjective. We investigated the inter- and intraobserver agreement in the determination of LBBB using available definitions, and clinicians' judgement of LBBB. METHODS: Observers were provided with 12­lead ECGs of 100 randomly selected CRT patients. Four observers judged the ECGs based on different LBBB-definitions (ESC, AHA/ACC/HRS, MADIT, and Strauss). Additionally, four implanting cardiologists scored the same 100 ECGs based on their clinical judgement. Observer agreement was summarized through the proportion of agreement (P) and kappa coefficient (k). RESULTS: Relative intra-observer agreement using different LBBB definitions, and within clinical judgement was moderate (range k 0.47-0.74 and k = 0.76 (0.14), respectively). The inter-observer agreement between observers using LBBB definitions as well as between clinical observers was minimal to weak (range k 0.19-0.44 and k = 0.35 (0.20), respectively). The probability of classifying an ECG as LBBB by available definitions varied considerably (range 0.20-0.76). The agreement between different definitions of LBBB ranged from good (P = 0.95 (0.07)) to weak (P = 0.40 (0.22)). Furthermore, correlation between the different LBBB definitions and clinical judgement was poor (range phi 0.30-0.55). CONCLUSION: Significant variation in the probability of classifying LBBB is present in using different definitions and clinical judgement. Considerable intra- and inter-observer variability adds to this variation. Interdefinition agreement varies significantly and correlation of clinical judgement with LBBB classification by definitions is modest at best.

A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data.

BACKGROUND: Cardiac Resynchronization Therapy (CRT) is one of the few effective treatments for heart failure patients with ventricular dyssynchrony. The pacing location of the left ventricle is indicated as a determinant of CRT outcome. OBJECTIVE: Patient specific computational models allow the activation pattern following CRT implant to be predicted and this may be used to optimize CRT lead placement. METHODS: In this study, the effects of heterogeneous cardiac substrate (scar, fast endocardial conduction, slow septal conduction, functional block) on accurately predicting the electrical activation of the LV epicardium were tested to determine the minimal detail required to create a rule based model of cardiac electrophysiology. Non-invasive clinical data (CT or CMR images and 12 lead ECG) from eighteen patients from two centers were used to investigate the models. RESULTS: Validation with invasive electro-anatomical mapping data identified that computer models with fast endocardial conduction were able to predict the electrical activation with a mean distance errors of 9.2 ±â€¯0.5 mm (CMR data) or (CT data) 7.5 ±â€¯0.7 mm. CONCLUSION: This study identified a simple rule-based fast endocardial conduction model, built using non-invasive clinical data that can be used to rapidly and robustly predict the electrical activation of the heart. Pre-procedural prediction of the latest electrically activating region to identify the optimal LV pacing site could potentially be a useful clinical planning tool for CRT procedures.

Sensitivity analysis of ventricular activation and electrocardiogram in tailored models of heart-failure patients.

Cardiac resynchronization therapy is not effective in a variable proportion of heart failure patients. An accurate knowledge of each patient's electroanatomical features could be helpful to determine the most appropriate treatment. The goal of this study was to analyze and quantify the sensitivity of left ventricular (LV) activation and the electrocardiogram (ECG) to changes in 39 parameters used to tune realistic anatomical-electrophysiological models of the heart. Electrical activity in the ventricles was simulated using a reaction-diffusion equation. To simulate cellular electrophysiology, the Ten Tusscher-Panfilov 2006 model was used. Intracardiac electrograms and 12-lead ECGs were computed by solving the bidomain equation. Parameters showing the highest sensitivity values were similar in the six patients studied. QRS complex and LV activation times were modulated by the sodium current, the cell surface-to-volume ratio in the LV, and tissue conductivities. The T-wave was modulated by the calcium and rectifier-potassium currents, and the cell surface-to-volume ratio in both ventricles. We conclude that homogeneous changes in ionic currents entail similar effects in all ECG leads, whereas the effects of changes in tissue properties show larger inter-lead variability. The effects of parameter variations are highly consistent between patients and most of the model tuning could be performed with only ~10 parameters.

Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging.

OBJECTIVES: The purpose of this study was to determine the spatial distribution of myocardial function (myofiber shortening and work) within the left ventricular (LV) wall during ventricular pacing. BACKGROUND: Asynchronous electrical activation, as induced by ventricular pacing, causes various abnormalities in LV function, perfusion and structure. These derangements may be caused by abnormalities in regional contraction patterns. However, insight into these patterns during pacing is as yet limited. METHODS: In seven anesthetized dogs, high spatial and temporal resolution magnetic resonance-tagged images were acquired in three orthogonal planes. Three-dimensional deformation data and LV cavity pressure and volume were used to determine midwall circumferential strain and external and total mechanical work at 192 sites around the left ventricle. RESULTS: During ventricular pacing, systolic fiber strain and external work were approximately zero in regions near the pacing site, and gradually increased to more than twice the normal value in the most remote regions. Total mechanical work, normalized to the value during right atrial pacing, was 38 +/- 13% (right ventricular apex [RVapex] pacing) and 61 +/- 23% (left ventricular base [LVbase] pacing) close to the pacing site, and 125 +/- 48% and 171 +/- 60% in remote regions, respectively (p < 0.05 between RVapex and LVbase pacing). The number of regions with reduced work was significantly larger during RVapex than during LVbase pacing. This was associated with a reduction of global LV pump function during RVapex pacing. CONCLUSIONS: Ventricular pacing causes a threefold difference in myofiber work within the LV wall. This difference appears large enough to regard local myocardial function as an important determinant for abnormalities in perfusion, metabolism, structure and pump function during asynchronous electrical activation. Pacing at sites that cause more synchronous activation may limit the occurrence of such derangements.

Estimates of regional work in the canine left ventricle.

Assessment of the magnitude of regional myocardial work requires knowledge of regional fiber stress and fiber shortening. The theoretical development and experimental validation of a method is presented which used values of estimated active and passive fiber stress according to a fluid-fiber model, and measured fiber strain values. This enables the construction of regional stress-strain diagrams, a regional analog of the pressure-volume area model by Suga and co-investigators, which can be linked to regional oxygen consumption. In the left ventricle, either normally or asynchronously activated, the method yields reliable data on strain and active and passive fiber stress. The relation between estimated regional work and myocardial oxygen demand is in quantitative agreement with previously reported relations between global oxygen demand and measured pressure-volume area. During coronary artery occlusion, however, these values were less reliable, which might be due to inaqdequate knowledge of the (passive) material properties of the myocardium.

Developments in non-radioactive microsphere techniques for blood flow measurement.

Considerable progress is being made in the development of non-radioactive microsphere methods. Validation studies of the three commercially available non-radioactive microspheres are promising. In most experimental conditions the use of non-radioactive microspheres saves money. Avoiding the use of radioactivity facilitates the use of microspheres in chronic animal experiments and when blood flow and chemical measurements are performed in the same sample. Moreover, using histological techniques, distributions of coloured or fluorescent microspheres in subunits of organs could be quantified, opening new scientific possibilities. Currently, the fluorescent microsphere technique seems to be the most promising non-radioactive microsphere method. Due to the high sensitivity and good spectral separation, the number of microspheres injected can be as small as that used, for radioactive microspheres, at least six labels can be used, and the relatively large volume in which fluorescence is measured (approximately 1-3 ml) enables the use of time saving microsphere isolation techniques. Development of these methods and further automation of the quantification process (using either automised spectrometry or FACS analysis) will considerably increase interest in the non-radioactive microsphere techniques. To accelerate these developments, investigators are encouraged to share their experiences.

Blood flow distributions by microsphere deposition methods.

The art and science of the use of deposition markers for the estimation of blood flow distributions throughout the body and within organs is reviewed. Development of diffusible tracer techniques started 50 years ago. Twenty years later, radioactive 15 micron microspheres became the standard marker. Early studies on small animals, fetal sheep in 1967 and rats in 1976, provoked much of the technical development. Needs for avoiding the use of radioactivity, for having long lasting labels, and for providing higher spatial resolution, are driving the continuing exploration of newer techniques using colored and fluorescent microspheres and molecular deposition markers. Strengths and weaknesses of the various methods are compared.

Cardiac output distribution in the chick embryo from stage 36 to 45.

OBJECTIVE: The distribution of cardiac output to different organs is well described in the mammalian fetus. Chick embryos are not often used in perinatal cardiovascular research and therefore it is not known whether they can serve as an animal model for this purpose. In this study we documented cardiac output distribution in chick embryos at increasing incubation time. METHODS: Fertilized eggs from day 10 to 19 with an incubation time of 21 days were studied in 3 increasing incubation time groups (10-13, 14-16 and 17-19 days). For the experiment, the egg was placed in a holder in an incubator. The egg was opened at the air cell and a small vein of the chorioallantoic membrane was catheterized. Twenty thousand fluorescent 15 microns microspheres in 0.2 ml were injected. After 5 min, the embryo was sacrificed and the different organs were dissected and digested for microsphere isolation and subsequent fluorescence analysis. RESULTS: The chorioallantoic membrane, which is the placenta equivalent of the chick embryo, received a relatively large fraction of the combined cardiac output: 52.08% (interquartile range [IQR] 12.67%) on days 10-13 and 40.95% (IQR 27.24%) on days 17-19. Relatively small fractions were distributed: to the heart 2.03% (IQR 1.58) on days 10-13 and 3.18% (IQR 1.95) on days 17-19, and to the brain 3.20% (IQR 1.80) on days 10-13 and 5.02% (IQR 3.39) on days 17-19. As incubation time advanced, the fraction of the combined cardiac output to the chorioallantoic membrane and yolk-sac decreased significantly in favor of the heart and brain. CONCLUSION: This distribution shows great similarity to the one found in the mammalian fetus. The chick embryo is an attractive model for perinatal cardiovascular research.

Remodeling by ventricular pacing in hypertrophying dog hearts.

OBJECTIVE: Asynchronous electrical activation of the left ventricle (LV), induced by ventricular pacing (VP), reduces mechanical load in early- and enhances it in late-activated regions. Consequently, chronic VP leads to asymmetric hypertrophy. We investigated whether such locally induced myocardial hypertrophy also occurs in the presence of pressure overload hypertrophy (POH). METHODS: POH was induced by aortic banding in puppies. At age 9 months, seven dogs were paced at the right ventricular (RV) apex at physiological heart rate for 6 months (POH-pace group), while four POH dogs served as POH-control group. Changes in volume of the LV cavity and the total LV wall and of five LV wall sectors were measured by means of 2D-echocardiography and X-ray marker detection. RESULTS: During the last 6 months of the protocol the volume of the five LV wall sectors increased in the POH-control group, ranging from 27+/-9 to 30+/-5% (mean+/-S.D.). In POH-pace animals sector wall volume in the four sectors at intermediate to long distance from the pacing site increased to a similar extent (ranging from 31+/-16 to 35+/-17%), but wall volume in the early-activated apical septum increased significantly less (17+/-21%). In these hearts myocyte diameter was significantly smaller in the apical septum than in the lateral LV wall. The regional difference in wall volume changes (19+/-21%) was significantly smaller in the POH-pace group than in chronically paced, non-hypertrophic, canine hearts in a previous study from our laboratory (43+/-14%). CONCLUSIONS: In hypertrophying hearts chronic pacing at the RV apex suppresses the development of hypertrophy in the early-activated apical septum but does not cause additional hypertrophy in late-activated regions, as is the case in non-hypertrophic hearts. The latter suggests that the local growth response is reduced in hypertrophying hearts.

The effect of diltiazem on myocardial recovery after regional ischemia in dogs.

The effect of diltiazem on post-ischemic metabolic and functional recovery was investigated in regionally ischemic dog hearts. The duration of ischemia was 60 min, followed by 60 min of reperfusion. Diltiazem (bolus injection of 0.1 mg X kg-1 body weight prior to ischemia, followed by a continuous infusion of 0.1 mg X kg-1 X h-1) had no effect on residual coronary flow in the centre of the ischemic area, but blunted the reactive hyperemia response after restoration of flow. The drug partially prevented the depletion of ATP and glycogen in the severely underperfused subendocardial layers, i.e. when residual flow was below 0.1 ml X min-1 X g-1. Reduction of the content of these substances in the subepicardial layers was moderate and not influenced by diltiazem. Segment shortening in the subepicardial layers disappeared whereas segment lengthening was observed in the subendocardial layers during the ischemic period. Diltiazem did not prevent the loss of contractile function. Despite an initial restoration of contractile function within 10 min after reperfusion, no significant beneficial effect of diltiazem treatment on mechanical function of the reperfused area was present thereafter.

Mapping of epicardial deformation using a video processing technique.

A method has been developed to measure deformation of the canine epicardium during the cardiac cycle simultaneously in a number (eight) of small regions (1 X 1 cm2). Approximately 50 white markers (diameter 1.5 mm) are attached to the epicardium and their motion is recorded on tape by a video camera. Marker positions are detected by computer processing of the digitized images. In each region the three deformation parameters are calculated from the displacements of all markers in that region by means of a least-squares criterium. In the experimental situation in the center of the area of the epicardium analyzed the accuracy of measuring circumferential strain, base-to-apex strain and shear is +/- 0.005, +/- 0.005 and +/- 0.002 rad, respectively. The method has been applied in an experiment in which local ischemia of the left ventricular wall was induced by occluding the anterior descending branch of the left coronary artery. Healthy and ischemic regions could clearly be distinguished by the differences in deformation.

Fiber shortening in the inner layers of the left ventricular wall as assessed from epicardial deformation during normoxia and ischemia.

A mathematical model of left ventricular mechanics predicts that fiber shortening in the inner layers of the left ventricular wall can be estimated (eendo, est) from the magnitude of minimal (emin, o) and maximal shortening (emax, o) of the outer surface (= epicardium) of this wall. To evaluate this prediction, eendo, est and emin, o were compared with the shortening in the inner layers approximately along the fiber direction (eendo) as measured directly, before and during one minute of coronary artery occlusion. Deformation of the epicardium and the inner layers was determined by measuring mutual motion and angulation of three needles pierced into the myocardial wall, using an electromagnetic inductive technique. The proposed linear relations of eendo, est and emin, o with eendo were found to be significant. The needles hardly influenced wall deformation since similar values of epicardial deformation were found in separate, comparable, experiments (n = 13) using a triplet of epicardial coils. So eendo, est and emin, o are useful estimates of fiber shortening in the inner layers during normoxia and ischemia, especially when the time course of events is followed in the same animal.

Relation between torsion and cross-sectional area change in the human left ventricle.

During the ejection phase, motion of the left ventricular (LV) wall is such that all myocardial fibers shorten to the same extent. In a mathematical model of LV mechanisms it was found that this condition could be satisfied only if torsion around the long axis followed a unique function of the ratio of cavity volume to wall volume. When fiber shortening becomes non-uniform due to cardiac pathology, this pathology may be reflected in aberration of the torsional motion pattern. In the present study we investigated whether the predicted regular motion pattern could be found in nine healthy volunteers, using Magnetic Resonance Tagging. In two parallel short-axis cross-sections, displacement, rotation, and area ejection were derived from the motion of tags, attached non-invasively to the myocardium. Information from both sections was combined to determine area ejection, quantified as the change in the logarithm of the ratio of cavity area to wall area, and torsion, represented by the shear angle on the epicardium. Linear regression was applied to torsion as a function of area ejection. The slope thus found (-0.173 +/- 0.024 rad, mean +/- S.D.) was similar to the slope as predicted by the model of LV mechanics (-0.194 +/- 0.026 rad). In conclusion, the relation between area ejection and torsion could be assessed noninvasively in humans. In healthy volunteers, the relation was close to what was predicted by a mathematical model of LV mechanics, and also close to what was found earlier in experiments on animals.