Transmural Regions Research Articles

An ECG generative model of myocardial infarction

Background and Objective Computer-aided diagnosis (CAD) of Myocardial Infarction (MI) using machine learning depends on a large amount of clinical Electrocardiogram (ECG) data. Existing infarct ECG databases face the problem of class imbalance. Data augmentation using generative simulation models is a new approach to effectively address this problem.Methods A multiscale ECG generative model was established for ECG data augmentation. In the cellular layer, an ischemic Action Potential (AP) model was established to generate APs in cardiomyocytes with different transmural regions of infraction or different ischemic durations. In the tissue layer, a probability-driven cellular automata excitation propagation model was established to simulate the propagation speed and direction of excitation. An infarct tissue model and a coronary artery model were established to describe the spatiotemporal diversity of MI. A ventricle model, a human torso model, and a computational model of surface ECG based on field source theory were established in the heart-torso layer.Results The model generated pathological 12-lead ECGs of MI with different topography and different extent. When simulating different ventricular wall infarction, the lesions appear in the same leads as the clinical 12-lead ECG. The ST-segment decreases and the T-wave amplitude decreases, similar to the clinical ECG features when simulating subendocardial ischemia. The average fidelity of the 12-lead ECG the model generated is 95.6%, according to the designed DTW-GRA distance algorithm.Conclusions The generative model considers the electrophysiological properties of the natural heart, the pathology of myocardial infarction, and the diversity of clinical ECGs. The model can provide many reliable samples for machine learning of MI.

Cardiovascular magnetic resonance imaging characteristics in patients with methamphetamine-associated cardiomyopathy

BackgroundMethamphetamine-associated cardiomyopathy (MA-CMP) is an increasingly recognised aetiology of cardiomyopathy. Cardiovascular magnetic resonance (CMR) is a specialised cardiac imaging modality commonly used in assessment of cardiomyopathy. We aimed to identify specific CMR features associated with MA-CMP.MethodsA retrospective cohort study of CMR scans was performed in a single centre between January 2015 and December 2020. Thirty patients with MA-CMP who had undergone CMR were identified. MA-CMP was defined as those with a history of significant methamphetamine use hospitalised with acute decompensated heart failure (other causes of cardiomyopathy excluded). A retrospective analysis of index admission CMRs was performed. All studies were performed on a 1.5 T CMR scanner.ResultsThe mean age of MA-CMP patients was 43.7 ± 7.5 years, and 86.7% were male. The mean left ventricular (LV) volume obtained in this cohort was consistent with severe LV dilatation (LV end-diastolic volume (334 ± 99 ml); LV end-systolic volume: 269 ± 98 ml), whilst the right ventricular (RV) volume indicated moderate-to-severe dilatation (RV end-diastolic volume: 272 ± 91 ml; RV end-systolic volume: 173 ± 82 ml). Mean LV ejection fraction (20.9 ± 9.2%) indicated severe LV dysfunction, with moderate-to-severe RV dysfunction also detected (RV ejection fraction: 29.4 ± 13.4%). 22 patients (73.3%) had myocardial late gadolinium enhancement (LGE), of which 59.1% were located in the mid-wall, with all of these involving the interventricular septum. 22.7% displayed localised regions of sub-endocardial LGE in a variety of locations, and 18.2% had transmural regions of LGE that were located in the inferior and inferolateral segments. 6 patients (20%) had intracardiac thrombus (4 LV, 2 both LV and RV).ConclusionMA-CMP was associated with severe biventricular dilatation and dysfunction, with a high prevalence of intraventricular thrombus. This cohort study highlights that MA-CMP patients have a high prevalence of CMR findings.

Transmural Remodeling of Cardiac Microstructure in Aged Spontaneously Hypertensive Rats by Diffusion Tensor MRI.

The long-standing high blood pressure (also known as hypertension) overworks the heart. Microstructural remodeling is a key factor of hypertensive heart disease progression. Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful tool for the rapid noninvasive nondestructive delineation of the cardiomyocyte organization. The spontaneously hypertensive rat (SHR) is a well-established model of genetic hypertension. The goal of this study was to employ high-resolution DT-MRI and the SHR animal model to assess the transmural layer-specific remodeling of myocardial microstructure associated with hypertension. Ex vivo experiments were performed on excised formalin-fixed hearts of aged SHRs (n = 4) and age-matched controls (n = 4). The DT-MRI-derived fractional anisotropy (FA), longitudinal diffusivity (λL), transversal diffusivity (λT), and mean diffusivity (MD) served as the readout parameters investigated at three transmural zones (i.e., endocardium, mesocardium, and epicardium). The helix angles (HAs) of the aggregated cardiomyocytes and the orientation of laminar sheetlets were also studied. Compared with controls, the SHRs exhibited decreased epicardial FA, while FA changes in the other two transmural regions were insignificant. No substantial differences were observed in the diffusivity parameters and the transmural course of HAs between the two groups. A consistent distribution pattern of laminar sheetlet orientation was not identified for either group. Our findings are in line with the known cellular microstructure from early painstaking histological studies. Biophysical explanations of the study outcomes are provided. In conclusion, our experimental findings indicate that the epicardial microstructure is more vulnerable to high blood pressure leading to more pronounced changes in this region during remodeling. DT-MRI is well-suited for elucidating these alterations. The revealed transmural nonuniformity of myocardial reorganization may shed light on the mechanisms of the microstructure-function relationship in hypertension progression. Our results provide insights into the management of patients with systemic arterial hypertension, thus prevent the progression toward heart failure. The findings of this study should be acknowledged by electromechanical models of the heart that simulate the specific cardiac pathology.

The effects of load on transmural differences in contraction of isolated mouse ventricular cardiomyocytes

Mechanical properties of cardiomyocytes from different transmural regions are heterogeneous in the left ventricular wall. The cardiomyocyte mechanical environment affects this heterogeneity because of mechano-electric feedback mechanisms. In the present study, we investigated the effects of the mechanical load (preload and afterload) on transmural differences in contraction of subendocardial (ENDO) and subepicardial (EPI) single cells isolated from the murine left ventricle. Various preloads imposed via axial stretch and afterloads (unloaded and heavy loaded conditions) were applied to the cells using carbon fiber techniques for single myocytes. To simulate experimentally obtained results and to predict mechanisms underlying the cellular response to change in load, our mathematical models of the ENDO and EPI cells were used.Our major findings are the following. Our results show that ENDO and EPI cardiomyocytes have different mechanical responses to changes in preload to the cells. Under auxotonic contractions at low preload (unstretched cells), time to peak contraction (Tmax) and the time constant of [Ca2+]i transient decay were significantly longer in ENDO cells than in EPI cells. An increase in preload (stretched cells) prolonged Tmax in both cell types; however, the prolongation was greater in EPI cells, resulting in a decrease in the transmural gradient in Tmax at high preload. Comparing unloaded and heavy loaded (isometric) contractions of the cells we found that transmural gradient in the time course of contraction is independent of the loading conditions. Our mathematical cell models were able to reproduce the experimental results on the distinct cellular responses to changes in the mechanical load when we accounted for an ENDO/EPI difference in the parameters of cooperativity of calcium activation of myofilaments.

Effects of cellular electromechanical coupling on functional heterogeneity in a one-dimensional tissue model of the myocardium

Based on the experimental evidence, we developed a one-dimensional (1D) model of heterogeneous myocardial tissue consisting of in-series connected cardiomyocytes from distant transmural regions using mathematical models of subendocardial and subepicardial cells. The regional deformation patterns produced by our 1D model are consistent with the transmural regional strain patterns obtained experimentally in the normal heart in vivo. The modelling results suggest that the mechanical load may essentially affect the transmural gradients in the electrical and mechanical properties of interacting myocytes within a tissue, thereby regulating global myocardial output.

Myocardial hypertrophy reduces transmural variation in mitochondrial function.

Myocardial hypertrophy reduces transmural variation in mitochondrial function.

(449) - Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that tissue samples from the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces region-specific changes in contractile function.

Transmural heterogeneity of cellular level power output is reduced in human heart failure

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function.Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06μWmg−1) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33kNm−2) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain-1.Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.

Effects of Transmural Region and Heart Failure on the Contractile Properties of Human Myocardium

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that tissue samples from the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces region-specific changes in contractile function. Chemically permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricle of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was ∼20% higher in non-failing mid-myocardial samples (0.59 ± 0.06 μW mg−1) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced ∼20% more isometric force (14.3 ± 1.33 kN m−2) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected mid-myocardial samples more than sub-epicardial and sub-endocardial tissue. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than the matching sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Myocardial power output was correlated with the relative content of actin (p=0.012), and the relative content (p=0.034) and phosphorylation (p=0.006) of myosin light chain-1. Passive force correlated with the phosphorylation of TnI at Ser23/24 (p=0.006) while shortening velocity increased in proportion with the phosphorylation of cMyBP-C at Ser282 (p=0.001). In conclusion, non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in mid-myocardial tissue. Targeting collagen deposition and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.

Abstract 290: Long Term Safety and Efficacy of Renal Nerve Ablation in Swine with the First Prototype of the Boston Scientific Renal Ablation System

Introduction: Early splanchnicectomy and radical sympathectomy research demonstrated that reducing sympathetic nerve activity achieved blood pressure reductions and improved long-term outcomes in hypertensive patients. These methods were abandoned due to high perioperative morbidity and mortality. A minimally invasive approach to inhibition of renal sympathetic nerves represents an attractive treatment of essential hypertension. Methods: Swine were evaluated at 7, 30, 60, 90 or 180 days post treatment. At each time point, 4 animals treated with bilateral renal artery radiofrequency (RF) ablation and 3 sham treated animals were assessed. A single point ablation catheter was positioned within each renal artery of anesthetized animals and 4-6 ablations/artery were delivered in a spiral pattern. At baseline and termination, urinalysis, blood chemistry and QVA was performed. Right and left kidneys and renal arteries were harvested from all animals. Renal arteries were processed for histological evaluation. Kidneys were weighed, frozen, and used for the analysis of norepinephrine levels. Results: No injuries were seen in tissues surrounding the renal arteries and no safety concerns were identified in the histological evaluation of the renal arteries. RF treated renal arteries showed segmental, transmural regions of minimal vessel wall injury with SMC loss. These regions showed progression of healing and complete recellularization by 60 days. All vessels had complete endothelial cell coverage at all timepoints. Minimal intimal hyperplasia was seen. There were no instances of EEL injury. Mural and adventitial inflammation were seen at 30 days, but both resolved by 60 days. No abnormalities in renal function were identified by urinalysis or serum chemistry. Efficacy of nerve ablation was determined by renal norepinephrine levels (pg/mg) and a significant decrease was seen in ablation groups relative to sham groups at every timepoint (7 days: 69% p&lt; 0.0001, 30 days: 46% p =0.044; 60 days: 59% p&lt;0.004; 90 days: 53% p&lt; 0.0001; 180 days: 56% p&lt;0.001). Conclusions: Renal ablation with the BSC catheter in a healthy swine model demonstrated safety and efficacy as assessed by renal artery histology and renal norepinephrine levels out to 6 months.

Transmural Distribution of Myocyte Contractile Properties in Aging F344 Rats

Age-associated diastolic heart failure occurs when the amount of blood filling the heart between beats is reduced due to slow relaxation and increased passive stiffness of the left ventricle. We are testing the hypothesis that slowed active relaxation in diastolic heart failure is caused in part by age-dependent alterations in the contractile function of different transmural regions of the myocardium. Cardiac myocytes from endocardial, midmyocardial, and endocardial regions of the left ventricular free wall were isolated from hearts of 6, 18, and 22-month-old female Fischer 344 rats (n = 2 at each age). Cells were placed in a superfusion chamber controlled at 25oC and field stimulated at 0.5 Hz. Unloaded sarcomere shortening was measured in an average of 27 cells per myocardial region per animal. In five of the six animals, significant differences in relaxation (time from peak shortening to 50% re-lengthening, tp50) were observed among cell subtypes (p < 0.05, ANOVA). Analysis of collated data showed that tp50 was significantly affected by age, tending to increase in older animals (p < 0.01, two-way ANOVA). Aging appeared to have the greatest effect on relaxation of epicardial and midmyocardial cells.

Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model

The mechanical properties of myocardium vary across the transmural aspect of the left ventricular wall. Some of these functional heterogeneities may be related to differences in excitation–contraction coupling characteristics that have been observed in cells isolated from the epicardial, mid-myocardial and endocardial regions of the left ventricle of many species, including canine. Integrative models of coupled myocyte electromechanics are reviewed and used here to investigate sources of heterogeneous electromechanical behaviour in these cells. The simulations (i) illustrate a previously unrecognized role of the transient outward potassium current in mechanical function and (ii) suggest that there may also exist additional heterogeneities affecting crossbridge cycling rates in cells from different transmural regions.

Transmural variation of myocardial attenuation measured with a clinical imager

The objective of this study was to quantify the transmural variation in attenuation for the septal and lateral walls of the heart. Our approach was to utilize a commercially available ultrasonic imaging system to acquire images of excised sections of eight sheep hearts with an orientation similar to that encountered in the apical four-chamber view. The measured values (mean ± SE) of the slope of attenuation for the transmural regions of the septum are: 1.40 ± 0.11, 0.99 ± 0.09, and 1.85 ± 0.16 (dB/cm/MHz) for the left subendocardial, midmyocardial, and right subendocardial zones, respectively. The analogous data from the lateral wall are: 1.42 ± 0.11, 0.83 ± 0.07, and 1.20 ± 0.16 (dB/cm/MHz) for the subendocardial, midmyocardial, and subepicardial zones, respectively. These data demonstrate that ultrasonic attenuation associated with the septum and the lateral wall, when imaged in a manner similar to that of the apical four-chamber view, is anisotropic. (E-mail: jgm@howdy.wustl.edu)

Contractile reserve and contrast uptake pattern by magnetic resonance imaging and functional recovery after reperfused myocardial infarction

OBJECTIVESWe hypothesized that contrast-enhanced and dobutamine tagged magnetic resonance imaging (MRI) could investigate microvascular integrity and contractile reserve of reperfused myocardial infarction (MI) in one examination.BACKGROUNDIn reperfused MI, microvascular integrity and contractile reserve are important determinants of functional recovery.METHODSTwenty-three patients with a reperfused first MI were studied. On day 3 ± 1 after MI, patients underwent tagged MRI at baseline and during infusion of 5 and 10 μg/kg/min of dobutamine followed by contrast-enhanced MRI (first pass and delayed imaging) after a bolus infusion of gadolinium-diethylenetriaminepenta-acetic acid. Tagged MRI was performed 9 ± 1 weeks later (follow-up). Eighty-four transmural regions with hyperenhancement on delayed contrast-enhanced images were defined as COMB (first pass hypoenhancement) or HYPER (normal first pass signal enhancement). Percent circumferential segment shortening was measured within the subendocardium and subepicardum of each region of HYPER or COMB at baseline, peak dobutamine and follow-up.RESULTSShortening improved in COMB regions from 4 ± 1% at baseline to 10 ± 1% at peak dobutamine and 10 ± 1% at follow-up, respectively (p < 0.0003 vs. baseline for both). The HYPER regions likewise improved from 10 ± 1% at baseline to 16 ± 1% and 17 ± 1%, respectively (p < 0.0004 vs. baseline for both). Function within COMB regions was less than that of HYPER at baseline, peak dobutamine and follow-up (p < 0.0003 for all).CONCLUSIONSDobutamine magnetic resonance tagging and contrast enhanced MRI are complementary in assessing functional recovery after reperfused MI. Regions of delayed contrast hyperenhancement demonstrate both contractile reserve and late functional recovery. However, if these regions demonstrate first pass contrast hypoenhancement, they are associated with greater myocardial damage.

Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs

Angiogenic response of the myocardial capillary bed to long-term (7 mo) renovascular hypertension (one-kidney, one-clip) was assessed in eight mongrel dogs and compared with seven control dogs. Image analyses of histological sections from four transmural specimen sites of left ventricular (LV) free wall were performed. While mean cross-sectional cardiocyte area increased in all transmural layers (epi-endo) in dogs with LV hypertrophy (LVH), the greatest increases occurred in the inner layers. Although capillary length density was significantly lower in two of the four transmural regions of LVH dogs, these decrements were much less than the lateral expansion of cardiocytes as indicated by cross-sectional areas. Calculations of total capillary length indicate that approximately one-fifth of the capillary bed in LVH dogs was formed during the 7-mo period of hypertension in hypertrophied hearts. Capillary volume and surface densities in LVH dogs decreased to a greater extent due to a larger population of capillaries with lumen diameters less than 4 microns. Capillary volume density in LVH dogs was remarkably similar across the wall despite large transmural differences in cardiocyte hypertrophy. LVH did not alter the log SD of capillary domains, a measure of the heterogeneity of spacing, or capillary orientation (degree or anisotropy). These data support several important conclusions regarding long-term hypertension-induced LVH in dogs. First, although capillary growth does not fully compensate for the increase in LV mass, a myriad of new capillaries are formed as indicated by a substantial increase in total capillary length. This growth minimizes the increase in intercapillary distance characteristic of LVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated coronary vascular resistance in the presence of reduced resting blood flow distal to a severe coronary stenosis.

Vascular reserve in underperfused myocardium has recently been described. This seemingly paradoxical observation conflicts with older concepts of the coronary circulation which hold that flow deficits do not develop until reserve is fully exhausted. To examine this phenomenon in greater detail in an animal model mimicking a fixed human coronary artery stenosis, we analysed the records of 25 carefully selected, sedated pigs all instrumented with a rigid intralumenal coronary stenosis (82% lumenal diameter reduction). Each animal satisfied the following criteria: 1) perfused myocardial mass beyond the stenosis was within a narrow weight range (16 to 24 g); and 2) post stenosis (distal) epicardial (Epi) and endocardial (endo) flows were less than or equal to 90% of respective flows in a region perfused by the non-stenosed circumflex (CX) coronary artery. Accordingly, distal flow was reduced compared to circumflex zone flow (p less than 0.01) in the Epi (173 +/- 51 to 113 +/- 32 ml . 100g-1 . min-1), Endo (146 +/- 39 to 116 +/- 27) and transmural (Tm) regions (164 +/- 45 to 124 +/- 31). Despite a flow deficit and constant severity of stenosis, distal zone Tm resistance (0.55 +/- 0.21 mmHg/ml . 100 g-1 . min-1) exceeded the minimum level achievable with intravenous infusion of adenosine (0.25 +/- 0.07) in a separate group of eight animals without a stenosis. Distal transmural resistance also varied over a five fold range (0.27 to 1.33) and in 20/25 animals exceeded the highest level (0.37) seen in non-stenosis animals during adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

High energy phosphate depletion and lactate accumulation in the interventricular septum and left ventricular free wall of the dog after total coronary occlusion.

We measured indices of energy metabolism in tissue samples taken from the interventricular septum and left ventricular free wall of open-chest dogs under control conditions and after a 20-second period of no coronary inflow. The heart was paced at 150 beats/min, and arterial pressure was controlled by aortic constriction. Each tissue sample was divided into three transmural regions and analyzed for creatine phosphate, adenosine triphosphate, and lactate. Data were also obtained in animals subjected to ventricular fibrillation, with ventricular pressures reduced to atmosphere and sampling delayed to 70 seconds, and with the pulmonary artery constricted prior to coronary artery occlusion. In control animals, there were no metabolite differences between the free wall and septum. Coronary occlusion produced a lactate gradient across both the free wall and septum, with the highest lactate concentrations occurring in the regions adjacent to the left ventricular cavity. The increase in tissue lactate above control was greater in the septum than in the free wall. Coronary occlusion decreased tissue creatine phosphate but not adenosine triphosphate. The decrease in creatine phosphate was greater in the septum than in the free wall. Coronary occlusion and ventricular fibrillation, or coronary occlusion and ventricular pressures reduced to atmosphere, produced neither transmural metabolite differences nor differences between the free wall and septum. Pulmonary artery constriction increased right and decreased left ventricular pressures.(ABSTRACT TRUNCATED AT 250 WORDS)