Left Ventricular Subendocardium Research Articles

Electrophysiological characteristics of lead-position-dependent electrogram uninterrupted transition during left bundle branch pacing

BackgroundThe interrupted technique of left bundle branch pacing (LBBP) limits the continuous monitoring of paced electrocardiogram (ECG) and intracardiac electrogram (EGM) transitions, which may result in overlooked or misinterpreted subtle transitions. ObjectivesThis study aimed to explore the electrophysiological characteristics of lead position-dependent EGM continuous transition to evaluate lead depth and investigate the clinical significance of transseptal pacing modalities. MethodsA continuous pacing and recording technique enabled by a rotatable connector was employed to allow the real-time monitoring of progressive changes in paced EGM and ECG morphology. Careful observations were conducted to evaluate whether there were significant changes in the amplitude and morphology of the ventricular current of injury (COI), R-wave peak times of V1 and V6, QRS duration, and impedance at different interventricular septal depths. ResultsThe study included 105 patients. Nonselective LBBP was achieved in 94 (89.5 %) patients, of whom 88 (83.8%) achieved selective LBBP (SLBBP). Left ventricular septal pacing was confirmed in 11 (11.5 %) patients. The amplitude of ventricular EGM predictably changed with radial septum depth and peaked in the interventricular septum (26.3±11.3 mV). As the lead was inserted into the left ventricular subendocardium, the ventricular COI declined to a level approximating that of the right septum (11.7 ± 6.3 mV for SLBBP versus 10.4 ± 5.8 mV for right ventricular septal pacing). When selective LBB capture occurred, significant morphological transitions in the ventricular COI were observed in the unfiltered EGM. ConclusionsThe continuous recording technique provides a more detailed understanding of pacing lead radial depth throughout implantation. COI amplitude and morphology variations can identify different pacing modalities, particularly in recognizing SLBBP.

Animal study on left bundle branch current of injury and anatomic location of leads in His-purkinje conduction system pacing

Objective: Explore the relationship between tip of the left bundle branch pacing lead and anatomic location of left bundle branch as well as the mechanism of left bundle branch current of injury. To clarify the clinical value of left bundle branch current of injury during operation. Methods: The pacing leads were implanted in the hearts of two living swines. Intraoperative electrophysiological study confirmed that the left bundle branch or only the deep left ventricular septum was captured at low output. Immediately after operation, the gross specimen of swine hearts was stained with iodine to observe the gross distribution of His-purkinje conduction system on the left ventricular endocardium and its relationship with the leads. Subsequently, the swine hearts were fixed with formalin solution, and the pacing leads were removed after the positions were marked. The swine hearts were then sectioned and stained with Masson and Goldner trichrome, and the relationship between the anatomic location of the conduction system and the tip of the lead was observed under a light microscope. Results: After iodine staining of the specimen, the His-purkinje conduction system was observed with the naked eye in a net-like distribution, and the lead tip was screwed deeply and fixed in the left bundle branch area of the left ventricular subendocardium in the ventricular septum. Masson and Goldner trichrome staining showed that left bundle branch pacing lead directly passed through the left bundle branch when there was left bundle branch potential with left bundle branch current of injury, while it was not directly contact the left bundle branch when there was left bundle branch potential without left bundle branch current of injury. Conclusion: The left bundle branch current of injury observed on intracardiac electrocardiogram during His-purkinje conduction system pacing suggests that the pacing lead directly contacted the conduction bundle or its branches, therefore, the captured threshold was relatively low. Left bundle branch current of injury can be used as an important anatomic and electrophysiological evidence of left bundle branch capture.

Non-invasive pressure-volume analysis by 3-dimensional echocardiography: a novel method for left ventricular stroke work estimation

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Institute for Surgical Research, Oslo University Hospital. Introduction Left ventricular pressure-volume analysis is a powerful method to quantify left ventricular function. A major limitation of its clinical utility, however, is the need for invasive pressure and volume measurements. We hypothesized that accurate non-invasive left ventricular (LV) stroke work analysis is feasible by combining continuous 3-dimensional (3D) echocardiographic LV volume measurements with non-invasive LV pressure curve estimation. Purpose To investigate if LV stroke work can be estimated non-invasively by combining 3D echocardiographic volume measurements with non-invasive pressure curve estimation. Methods In 21 open-chest anesthetized canines, piezoelectric crystals were placed in the LV subendocardium for volume measurements and a micromanometer catheter was placed in the LV cavity for pressure measurements. Echocardiography was performed directly on the heart to acquire 3D LV volumes and timings of mitral and aortic valve events. The estimated LV pressure curve was obtained by adjusting the cardiac phases of an LV reference pressure curve to these valve events and adjusting its amplitude to measured peak LV pressure. Stroke work was calculated as the area under the pressure-volume curve from mitral valve closure to mitral valve opening. Non-invasively estimated and invasively measured stroke work were compared. Recordings were done during baseline, aortic constriction, dobutamine infusion and after induction of left bundle branch block by ablation. Results Panel A in the Figure illustrates non-invasive (left) and invasive (right) pressure-volume loops from a representative experiment. Baseline and the different interventions are colour-coded allowing visual comparison of the similar non-invasive and invasive stroke work. Panel B shows the pooled data from all experiments. There was a strong correlation (r=0.98, p<0.0001) and good agreement between the non-invasive and invasive stroke work. Furthermore, the non-invasive method captured similar changes in stroke work during interventions as compared to the invasive method (Panel C). Conclusions Non-invasive pressure-volume analysis by combining 3D echocardiography and estimated pressure for stroke work evaluation, is feasible and accurate.

Electrophysiological characteristics of septal perforation during left bundle branch pacing.

Left bundle branch pacing (LBBP) provides a low and stable threshold by direct capture of left bundle fibers on the left ventricular subendocardium. As the procedure involves the deployment of the pacing lead deep inside the septum, septal perforation is a potential complication. The purpose of this study was to analyze the morphology of intracardiac electrograms and unipolar pacing parameters to identify septal perforation in patients undergoing LBBP. Patients who had undergone successful LBBP between January 2020 to November 2021 were retrospectively included in the study. LBBP was attempted in 219 patients and was successful in 212 (96.8% success rate). Septal perforation during lead deployment was identified in 30 patients (14.1%). Peak troponin release was 188 ± 162 pg/mL. Mean unipolar impedance during septal perforation was 404.6 ± 19.9 Ω (400-450 Ω in 16 patients [53.3%]; <400 Ω in 14 patients [46.7%]). A cutoff <450 Ω for diagnosing septal perforation had high sensitivity (100%) and specificity (96.6%). Current of injury amplitude reduced from 15.4 ± 11.6 mV just before perforation to 0.9 ± 0.6 mV after perforation. Based on morphology, unfiltered unipolar electrograms were classified into 2 patterns: (1) type I (QS) seen in 20 patients (67%) due to complete perforation (mean unipolar impedance 402.5 ± 20.4 Ω); and (2) type II (RS/rS) seen in 10 patients (33%) due to partial perforation, with 80% showing capture (mean impedance 411 ± 21.3 Ω). All 30 patients underwent successful reimplantation at a new site. No patient developed lead dislodgment during mean follow-up of 9.9 ± 6.7 months. Although considered one of the concerns of LBBP, septal perforation, when recognized promptly during implantation by unipolar parameters and treated by reimplantation, would be benign and not associated with an unfavorable outcome.

Stimulation and propagation of activation in conduction tissue: Implications for left bundle branch area pacing

Characterizing wavefront generation and impulse conduction in left bundle (LB) has implications for left bundle branch area pacing (LBBAP). The purpose of this study was to describe the pacing characteristics of LB and to study the role of pacing pulse width (PW) in overcoming left bundle branch block. Twenty fresh ovine heart slabs containing well-developed and easily identifiable tissues of the conduction system were used for the study. LB stimulation, activation, and propagation were studied under baseline conditions, simulated conduction slowing, conduction block, and fascicular block. The maximum radius of the LB early activation increased up to 13.4 ± 2.4 mm from the pacing stimulus, and the time from stimulus to evoked potential shortened when pacing PW was increased from 0.13 to 2 ms at baseline. Conduction slowing and block induced by cooling could be resolved by increasing pacing PW from 0.25 to 1.5 ms over a distance of 10 ± 1.5 mm from the pacing stimulus. The LB strength-duration (SD) curve was shifted to the left of the myocardial SD curve. Increasing PW resolved conduction slowing and block and bypassed the experimental model of fascicular block in LB. Precise positioning of the LB lead in left ventricular subendocardium is not mandatory in LBBAP, as the SD curve of LB was shifted to the left of the myocardium SD curve and could be captured from a distance by optimizing PW.

Layer-specific speckle tracking analysis of left ventricular systolic function and synchrony in maintenance hemodialysis patients

BackgroundThis study investigated the value of layer-specific strain analysis by two-dimensional speckle tracking echocardiography (2D-STE) for evaluating left ventricular (LV) systolic function and synchrony in maintenance hemodialysis (MHD) patients.MethodsA total of 34 MHD patients and 35 healthy controls were enrolled in this study. Dynamic images were collected at the LV apical long-axis, the four- and two- chamber, and the LV short-axis views at the basal, middle, and apical segments. The layer-specific speckle tracking (LST) technique was used to analyze the longitudinal strain (LS) and circumferential strain (CS) of LV sub-endocardium, mid-myocardium, sub-epicardium, global longitudinal strain (GLS), global circumferential strain (GCS), the LV 17 segment time to peak LS (TTP), and the peak strain dispersion (PSD). The differences in these parameters were compared between control and MHD groups, and the correlation between PSD and each LS parameter was examined. The receiver operator characteristic (ROC) curve was used to evaluate the efficacy of three myocardial layer LS and CS in the assessment of LV systolic dysfunction in MHD patients.ResultsMHD patients had comparable left ventricular ejection fraction (LVEF), but significantly smaller LV GLS, GCS, and three-layer LS and CS compared to the control group. The three myocardial layer LS of the basal segment, middle segment, and apex segment was significantly reduced in the MHD patients compared to the normal subjects, while the three myocardial layer CS of the basal segment, middle segment, and apex segment was significantly reduced in the MHD patients compared to the normal subjects, except for the sub-endocardium of the middle and apex segment. MHD patients had significantly higher TTP of LV 17 segments and PSD compared to controls, and had delayed peak time in most segments. In addition, PSD of MHD patients was positively correlated with sub-endocardial and mid-myocardial LS and GLS, but not with sub-epicardial LS. The area under the curves (AUCs) of sub-endocardial, mid-myocardial, and sub-epicardial LS in MHD patients were 0.894, 0.852, and 0.870, respectively; the AUCs of sub-epicardial, mid-myocardial, and sub-endocardial CS were 0.852, 0.837, and 0.669, respectively.ConclusionsLST may detect early changes of all three-layer LS and CS and PSD in MHD patients, and is therefore a valuable tool to diagnose LV systolic dysfunction in MHD patients.

Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial.

Organ protective management during aortic arch surgery comprises deep hypothermic (18°C) circulatory arrest (DHCA), or moderate hypothermia (28°C/ 'tepid') with regional cerebral perfusion (TRCP). The aim of this experimental study was to evaluate the effect of distinct organ protective management on hemodynamic performance and myocardial integrity. Ten male piglets were randomized to group DHCA (n = 5) or TRCP (n = 5) group and operated on cardiopulmonary bypass (CPB) with 60 min of aortic cross-clamping. Blood gas analysis was performed throughout the experiment. Haemodynamic assessment was performed using a thermodilution technique before and after CPB. Myocardial biopsies were taken 2 h after CPB and evaluated using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling assay and western blot analysis. At reperfusion, levels of central venous saturation were significantly higher (P = 0.016) and levels of lactate significantly lower (P = 0.029) in the DHCA group. After CPB, thermodilution measurements revealed higher stroke volume and lower peripheral resistance in the TRCP group (P = 0.012 and 0.037). At the end of the experiment, no significant differences regarding laboratory and haemodynamic parameters were evident. All specimens showed enrichment of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling-positive cells exclusively at the left ventricular subendocardium with no difference between groups and equal concentrations of cyclo-oxygenase-2. TRCP is associated with decreased peripheral resistance and higher stroke volume immediately after CPB. However, this beneficial effect is contrasted by signs of lower body hypoperfusion, which is expressed by lower central venous saturations and higher lactate levels. Distinct strategies of organ protection did not seem to affect apoptotic/necrotic and inflammatory changes in the left ventricular myocardium.

Abstract 11490: Increased Late Sodium Current Contributes to Excess Prolongation of Canine Ventricular Repolarization Induced by Dofetilide

Introduction: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict QT prolongation and proarrhythmic potential, but recent in vitro cell studies have shown chronic exposure (hours) to some IKr blockers (e.g. dofetilide, D) prolongs repolarization by increasing late sodium current (INa-L) via PI3 kinase inhibition. Hypothesis: Chronic D administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. Methods: We continuously infused D into 6 dogs (6-9 μg/kg bolus+6-9 μg/kg/h IV infusion) for 7h, maintaining D plasma levels within the therapeutic range(2.4±0.2 to 5.2±0.6ng/ml). Acute and chronic D effects on action potential duration (APD) were studied in canine left ventricular (LV) subendocardial slabs using microelectrode techniques. Results: D infusion increased QTc and repolarization time (RT) continuously from baseline to 7h (Table). The INa-L blocker lidocaine (2mg/kg bolus) reduced all variables at 6.5h&gt;0.5h (Table) (e.g. QTc: 19±2% vs 8±1%, P&lt;.05). Chronic, but not acute, D increased apico-basal dispersion of RT, and lidocaine significantly attenuated this effect (Table). In LV subendocardium in vitro, D superfusion (0.2 μM) increased APD at 90% repolarization (APD90) from 232±8ms at baseline to 303±7 at 0.5h (P&lt;.05) and 372±6 at 6.5h (P&lt;.05 vs .5h)(n=6). Lidocaine (20 μM) decreased APD90 by 8±1% at 0.5h and 23±1% at 6.5h (P&lt;.05). In comparison, moxifloxacin (100 μM), an IKr blocker with no effect on INa-L increased APD90 from 216±3ms to 282±5 at 1h (P&lt;.05), and 289±5 at 6.5h (P&gt;.05 vs 1h). Lidocaine reduced APD90 equally by 8% at both 1h and 6.5h (P&gt;.05 for 1h vs 6.5h). Conclusions: Chronic D prolongs ventricular repolarization by blocking Ikr and increasing INa-L. Acquired LQT during chronic D dosing may be attributable to the INa-L increase, highlighting the need to include time and INa-L in evaluating the PI3K inhibition-derived proarrhythmic potential of new drugs.

The relationship between left ventricular scar and ventricular repolarization in patients with coronary artery disease: insights from late gadolinium enhancement magnetic resonance imaging

The markers of ventricular repolarization corrected QT interval (QTc), QT dispersion (QTD) and Tpeak-to-Tend interval (Tpeak-end) have shown an association with sudden cardiac death (SCD) in the general population. However, their mechanistic relationship with SCD is unclear. The study aim was to evaluate the relationship between QTc, QTD, and Tpeak-end, and the extent and distribution of left ventricular (LV) scar in patients with coronary artery disease at high SCD risk. We included 64 consecutive implantable cardioverter defibrillator (ICD) recipients (66 ± 11 years, 80% male, median left ventricular ejection fraction 30%) who had undergone late gadolinium enhancement cardiac magnetic resonance (CMR) imaging prior to device implantation over 4 years. Scar was quantified using the CMR images and characterized in terms of percent LV scar and number of LV segments with subendocardial/transmural scar. Repolarization parameters were measured on an electrocardiogram performed prior to ICD implantation. After adjustment for potential confounders there was a strong association between the number of limited subendocardial (1-25% transmurality) scar segments and QTc (P = 0.003), QTD (P = 0.002), and Tpeak-end (P = 0.008). However, there was no association between the repolarization parameters and percent LV scar or the amount of transmural scar. During a mean follow-up of 19 ± 10 months 19 (30%) patients received appropriate ICD therapy, but none of the repolarization parameters were associated with its occurrence. In this pilot study there was a strong association between limited subendocardial LV scar and prolonged QTc, QTD, and Tpeak-end. However, there was no association between any of these repolarization markers and the delivery of appropriate ICD therapy.

P75 neurotrophin receptor is a regulatory factor in sudden cardiac death with myocardial infarction

Sudden cardiac death (SCD) is a major cause of morbidity and mortality in patients with coronary artery diseases and myocardial infarction (MI). Sympathetic stimulation and sympathetic neural remodeling are important in the generation of SCD in diseased heart. The balance of nerve growth factor (NGF) and semaphoring 3A determines the sympathetic innervation patterning. Recently studies showed that P75 neurotrophin receptor (P75 NTR) is the main receptor for NGF mediates sympathetic hyperinnervation in the heart, and also interacts with semaphoring 3A. Sympathetic axons lacking P75 NTR are more sensitive to semaphoring 3A in vitro than control neurons, resulting in decreased sympathetic innervation in the left ventricular subendocardium. P75 NTR−/− mice had increased sympathetic heterogeneity and more spontaneous ventricular arrhythmias. Based on current studies, we present a hypothesis that P75 NTR plays an important regulatory role in sudden cardiac after myocardial infarction and hope to find new therapeutic target for SCD.

Pressure overload-induced mild cardiac hypertrophy reduces left ventricular transmural differences in mitochondrial respiratory chain activity and increases oxidative stress

Objective: Increased mechanical stress and contractility characterizes normal left ventricular (LV) subendocardium (Endo) but whether Endo mitochondrial respiratory chain complex activities is reduced as compared to subepicardium (Epi) and whether pressure overload-induced LV hypertrophy (LVH) might modulate transmural gradients through increased reactive oxygen species (ROS) production is unknown. Methods: LVH was induced by 6 weeks abdominal aortic banding and cardiac structure and function were determined with echocardiography and catheterization in sham-operated and LVH rats (n = 10 for each group). Mitochondrial respiration rates, coupling, content and ROS production were measured in LV Endo and Epi, using saponin-permeabilized fibers, Amplex Red fluorescence and citrate synthase activity. Results: In sham, a transmural respiratory gradient was observed with decreases in endo maximal oxidative capacity (−36.7%, P < 0.01) and complex IV activity (−57.4%, P < 0.05). Mitochondrial hydrogen peroxide (H2O2) production was similar in both LV layers. Aortic banding induced mild LVH (+31.7% LV mass), associated with normal LV fractional shortening and end diastolic pressure. LVH reduced maximal oxidative capacity (−23.6 and −33.3%), increased mitochondrial H2O2 production (+86.9 and +73.1%), free radical leak (+27.2% and +36.3%) and citrate synthase activity (+27.2% and +36.3%) in Endo and Epi, respectively. Transmural mitochondrial respiratory chain complex IV activity was reduced in LVH (−57.4 vs. −12.2%; P = 0.02). Conclusions: Endo mitochondrial respiratory chain complexes activities are reduced compared to LV Epi. Mild LVH impairs mitochondrial oxidative capacity, increases oxidative stress and reduces transmural complex IV activity. Further studies will be helpful to determine whether reduced LV transmural gradient in mitochondrial respiration might be a new marker of a transition from uncomplicated toward complicated LVH.

Cardiac involvement in Wegener’s granulomatosis resistant to induction therapy

ObjectivesThe aim of the study was to assess cardiac involvement in patients with Wegener’s granulomatosis (WG), who failed to achieve remission following >6 months induction therapy for life or organ threatening disease.MethodsEleven WG patients (eight males, mean age 47 ± 13 years), who failed to achieve remission despite >6 months induction therapy, underwent transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR).ResultsCardiac involvement was present in 9 (82%) patients. Regional wall motion abnormalities were found in two individuals, but none had left ventricular (LV) ejection fraction <50%. Nine patients had late gadolinium enhancement (LGE) lesions involving LV myocardium and right ventricle free wall was involved in four patients. LGE lesions were found in subepicardial, midwall and subendocardial LV myocardial layers. CMR revealed myocarditis in six patients. Patients with myocarditis had a higher number of LV segments with LGE (5.2 ± 3.4 vs 1.0 ± 1.2, p = 0.03) and more frequent diastolic dysfunction by TTE (5 vs 0, p = 0.02) than those without. Pericardial effusion was observed in five patients, while localized pericardial thickening in six patients.ConclusionsIn WG resistant to >6 months induction therapy cardiac involvement is frequent and is characterized by foci of LGE lesions and signs of myocardial inflammatory process.

Evaluation of the difference of rotation between subendocardium and subepicardium in diastolic heart failure patients by two-dimensional speckle tracking imaging

Objective To observe the rotation of subendocardium and subepidium by two-dimensional speckle tracking imaging(2D-STI),and to evaluate its performance in diastolic heart failure patients(DHF)with a normal left ventricular ejection fraction. Methods Ninety-seven consecutive clinically stable patients were enrolled in this study [41 healthy controls,36 with diastolic heart failure,20 with systolic heart failure (SHF)]. High frame rate dynamic two-dimensional images were recorded at the left ventricular short-axis view,including basal, papillary muscle and apical planes. Subendocardial and subepicardial global rotation were measured using Q-lab 7.0 software offline. Results ① In all the subjects, the rotation of the subendocardium was obviously greater than that of subepicardium. ②As seen from the apex,left ventricular subendocardium and subepicardium performed a wringing motion with a clockwise rotation at the base and countclockwise rotation at the apex. ③In the apical plane, subendocardial rotation was significantly lower in both heart failure groups than in controls,and was depressed to a larger extent in SHF patients than in those with DHF. Subepicardial rotation was no significant difference between the DHF group and the control group, though it was significantly lower in patients with SHF. ④At the base, the rotation of subendocardium and subepicardium were not different between DHF and control groups, but it was significantly reduced in patients with SHF. Conclusions The subendocardial rotation is reduced, but subepicardial rotation is normal in DHF patients. On the other hand, in patients with SHF, subendocardial and subepicardial rotation are both reduced. The left ventricular systolic properties are impaired in DHF patients. Key words: Echocardiography; Heart failure,congestive; Ventricular function,left; Speckle tracking imaging

Cardioscopic Observation of Subendocardial Microvessels in Patients With Coronary Artery Disease

Coronary microvessels play a direct and critical role in determining the extent and severity of myocardial ischemia and cardiac function. However, because direct observation has never been performed in vivo, the functional properties of the individual microvesssels in patients with coronary artery disease remain unknown. Subendocardial coronary microvessels were observed by cardioscopy in 149 successive patients with coronary artery disease (81 with stable angina and 68 with old myocardial infarction). Twenty-four arterial microvessels (AMs) and 27 venous microvessels (VMs) were observed in the left ventricular subendocardium. All 12 AMs and 13 of 14 VMs that were located in normokinetic-to-hypokinetic left ventricular wall segments were filled with blood during diastole and were collapsed during systole. In contrast, 8 of 12 AMs and 9 of 13 VMs that were located in akinetic-to-dyskinetic wall segments were filled with blood during systole and were collapsed during diastole. There were no significant correlations between the timing of blood filling and the severity of coronary stenosis and collateral development. In patients with coronary artery disease, the timing of blood filling of AMs and VMs was dependent on the regional left ventricular contractile state; during diastole when contraction was preserved and during systole when it was not. It remains to be elucidated whether and how blood filling is disturbed in other categories of heart disease.

Transmural differences in respiratory capacity across the rat left ventricle in health, aging, and streptozotocin-induced diabetes mellitus: evidence that mitochondrial dysfunction begins in the subepicardium

In diabetic cardiomyopathy, ventricular dysfunction occurs in the absence of hypertension or atherosclerosis and is accompanied by altered myocardial substrate utilization and depressed mitochondrial respiration. It is not known if mitochondrial function differs across the left ventricular (LV) wall in diabetes. In the healthy heart, the inner subendocardial region demonstrates higher rates of blood flow, oxygen consumption, and ATP turnover compared with the outer subepicardial region, but published transmural respirometric measurements have not demonstrated differences. We aim to measure mitochondrial function in Wistar rat LV to determine the effects of age, streptozotocin-diabetes, and LV layer. High-resolution respirometry measured indexes of respiration in saponin-skinned fibers dissected from the LV subendocardium and subepicardium of 3-mo-old rats after 1 mo of streptozotocin-induced diabetes and 4-mo-old rats following 2 mo of diabetes. Heart rate and heartbeat duration were measured under isoflurane-anesthesia using a fetal-Doppler, and transmission electron microscopy was employed to observe ultrastructural differences. Heart rate decreased with age and diabetes, whereas heartbeat duration increased with diabetes. While there were no transmural respirational differences in young healthy rat hearts, both myocardial layers showed a respiratory depression with age (30-40%). In 1-mo diabetic rat hearts only subepicardial respiration was depressed, whereas after 2 mo diabetes, respiration in subendocardial and subepicardial layers was depressed and showed elevated leak (state 2) respiration. These data provide evidence that mitochondrial dysfunction is first detectable in the subepicardium of diabetic rat LV, whereas there are measureable changes in LV mitochondria after only 4 mo of aging.

Left ventricular rotational mechanics in patients with coronary artery disease: differences in subendocardial and subepicardial layers

ObjectiveSubendocardial and subepicardial layers have opposite orientation of the myofibres and they are differently affected by coronary artery disease. This study investigated the differences in subendocardial and subepicardial left ventricular...

Effect of Cardiac Resynchronization Therapy on Subendo- and Subepicardial Left Ventricular Twist Mechanics and Relation to Favorable Outcome

The analysis of left ventricular (LV) mechanics provides novel insights into the effects of cardiac resynchronization therapy (CRT) on LV performance. Currently, advances in speckle-tracking echocardiographic analysis have permitted the characterization of subendocardial and subepicardial LV twist. The aim of this study was to investigate the role of the acute changes in subendocardial and subepicardial LV twist for the prediction of midterm beneficial effects of CRT. A total of 84 patients with heart failure scheduled for CRT were recruited. All patients underwent echocardiography before and <48 hours after CRT implantation and at 6-month follow-up. The assessment of LV volumes, ejection fractions, and mechanical dyssynchrony (systolic dyssynchrony index) was performed with real-time 3-dimensional echocardiography. The assessment of subendocardial and subepicardial LV twist was performed with 2-dimensional speckle-tracking echocardiography. A favorable outcome was defined as the occurrence of a reduction > or =15% in LV end-systolic volume associated with an improvement of > or =1 New York Heart Association functional class at 6-month follow-up. At 6-month follow-up, 53% of the patients showed favorable outcomes. Ischemic cause of heart failure, baseline systolic dyssynchrony index, immediate improvement in the LV ejection fraction, immediate improvement in systolic dyssynchrony index, and immediate improvement in subendocardial and subepicardial LV twist were significantly related to favorable outcomes. However, in multivariate logistic regression analysis, only the immediate improvement of subepicardial LV twist was independently related to favorable outcomes (odds ratio 2.31, 95% confidence interval 1.29 to 4.15, p = 0.005). Furthermore, the immediate improvement of subepicardial LV twist had incremental value over established parameters. In conclusion, the immediate improvement of subepicardial LV twist (but not subendocardial LV twist) is independently related to favorable outcomes after CRT.

Down regulation of immuno-detectable cardiac connexin-43 in BALB/c mice following acute fasting

Acute starvation effects for connexin-43 protein expression, in the heart, had not been previously explored. Hence we examined acute fasting on the myocardial immuno-histochemical expression of connexin-43 in 3 groups of 8-week old female BALB/c mice. Groups consisted of control mice ( n = 5), fasting for 24 h ( N = 5) and 48 h ( N = 3). Under light microscopy all control fed cases revealed the presence of some immuno-detectable staining for connexin-43 that is either present or weakly observed in some or all of the regions of interest, that include the cross-sectional left ventricular sub-endocardium, mid-myocardium and papillary muscle. Whereas mice that underwent 24 or 48 h of acute starvation, connexin-43 expression was either difficult to detect visually ( N = 3) or was completely absent ( N = 5) at 40× magnification using a light microscope. In starved mice with no membrane staining for connexin-43 we observed an increase in the intracellular accumulation of cytoplasmic connexin-43 expression.

Heterogeneous Expression of NO-Activated Soluble Guanylyl Cyclase in Mammalian Heart: Implications for NO- and Redox-Mediated Indirect Versus Direct Regulation of Cardiac Ion Channel Function

Nitrogen oxides exert significant but diverse regulatory effects on cardiac myocytes. Many of these effects are due to modulation of voltage-sensitive ion channel function. The redox-status of NO-related compounds is a critical factor in determining whether indirect (cGMP-dependent) versus direct (cGMP-independent) effects are dominant. However, molecular mechanisms by which different cardiac myocyte types, and associated different ion channel types expressed within them, could achieve selectivity between NO-related indirect versus direct effects are unclear We have previously demonstrated heterogeneous expression gradients of Type III NO synthase (eNOS) and sarcolemmal superoxide dismutase (ECSOD) in ferret and human ventricle, with both enzymes being highly expressed in right ventricle and left ventricular subepicardium but markedly reduced in left ventricular subendocardium. In this study we extend this previous analysis by analyzing NO-activated soluble guanylyl cyclase (sGC) expression in the heart (ferret and human). We demonstrate that, at both tissue and single myocyte levels, sGC protein expression is heterogeneous, being high in sinoatrial node, right atrium, right ventricle and left ventricular subepicardium, but markedly reduced to absent in left atrium and left ventricular subendocardium. Thus, there is a significant overlap in expression gradients of sGC, eNOS, and ECSOD among distinct cardiac tissue and myocyte types. These gradients positively correlate with both: i) experimentally measured basal NO production levels; and ii) expression gradients of specific voltage-gated ion channels (particularly Kv1 and Kv4 channels). Our results provide the first demonstration in the heart of an expressed coupled multienzymatic system for selective regulation of indirect (sGC-dependent) versus direct (sGC-independent) NO- and redox-related modulation of voltage-gated ion channel function in different myocyte types. Our results also have functional implications for NO. / redox - related modulation of ion channels expressed in other cell types, including neurons, skeletal muscle and smooth muscle.

Activation of the Cardiac Proteasome During Pressure Overload Promotes Ventricular Hypertrophy

The adaptation of cardiac mass to hemodynamic overload requires an adaptation of protein turnover, ie, the balance between protein synthesis and degradation. We tested 2 hypotheses: (1) chronic left ventricular hypertrophy (LVH) activates the proteasome system of protein degradation, especially in the myocardium submitted to the highest wall stress, ie, the subendocardium, and (2) the proteasome system is required for the development of LVH. Gene and protein expression of proteasome subunits and proteasome activity were measured separately from left ventricular subendocardium and subepicardium, right ventricle, and peripheral tissues in a canine model of severe, chronic (2 years) LVH induced by aortic banding and then were compared with controls. Both gene and protein expressions of proteasome subunits were increased in LVH versus control (P<0.05), which was accompanied by a significant (P<0.05) increase in proteasome activity. Posttranslational modification of the proteasome was also detected by 2-dimensional gel electrophoresis. These changes were found specifically in left ventricular subendocardium but not in left ventricular subepicardium, right ventricle, or noncardiac tissues from the same animals. In a mouse model of chronic pressure overload, a 50% increase in heart mass and a 2-fold increase in proteasome activity (both P<0.05 versus sham) were induced. In that model, the proteasome inhibitor epoxomicin completely prevented LVH while blocking proteasome activation. The increase in proteasome expression and activity found during chronic pressure overload in myocardium submitted to higher stress is also required for the establishment of LVH.