Epicardial Layer Research Articles

Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles

Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies.

A case of Takotsubo cardiomyopathy with apical hypertrophic cardiomyopathy-like morphological changes during recovery.

Objective: Few cases of Takotsubo cardiomyopathy with apical hypertrophic cardiomyopathy (APH)-like morphological changes during the recovery process have been reported.Patient: A 56-year-old woman diagnosed with Takotsubo cardiomyopathy showed a morphology similar to that of APH during recovery. We examined this patient using 2D speckle-tracking echocardiography based on the method used for hypertrophic cardiomyopathy, which suggested that the circumferential strain (CS) of the middle wall indicated myocardial function of the left ventricle, and the CS of the inner wall was associated with left ventricular chamber function.Results: We measured the CS of the endocardial, middle, and epicardial layers and found that the apical inner layer CS (CSinner), middle layer CS, and outer layer CS were all decreased at the onset. CSinner showed a strong tendency to recover on echocardiography performed when APH-like morphology was observed.Conclusion: The morphology of the apex in our case likely contributed to the maintenance of chamber function.

The Interventricular Septum Is Biomechanically Distinct from the Ventricular Free Walls.

The interventricular septum contributes to the pumping function of both ventricles. However, unlike the ventricular wall, its mechanical behavior remains largely unknown. To fill the knowledge gap, this study aims to characterize the biaxial and transmural variation of the mechanical properties of the septum and compare it to the free walls of the left and right ventricles (LV/RV). Fresh hearts were obtained from healthy, adult sheep. The septal wall was sliced along the mid-line into two septal sides and compared to the epicardial layers of the LV- and RV-free walls. Biaxial tensile mechanical tests and constitutive modeling were performed to obtain the passive mechanical properties of the LV- and RV-side of the septum and ventricular walls. We found that both sides of the septum were significantly softer than the respective ventricular walls, and that the septum presented significantly less collagen than the ventricular walls. At low strains, we observed the symmetric distribution of the fiber orientations and a similar anisotropic behavior between the LV-side and RV-side of the septum, with a stiffer material property in the longitudinal direction, rather than the circumferential direction. At high strains, both sides showed isotropic behavior. Both septal sides had similar intrinsic elasticity, as evidenced by experimental data and constitutive modeling. These new findings offer important knowledge of the biomechanics of the septum wall, which may deepen the understanding of heart physiology.

Abstract 13887: Cardio-Oncology in a Dish: Cardiovascular Tissue Engineering Strategies for Modeling Cancer Therapy Related Cardiac Dysfunction

Cardio-oncology in a dish: cardiovascular tissueengineering strategies for modeling cancer therapyrelated cardiac dysfunction.Over the recent years, there was a robust proliferation of oncological therapies leading to asignificant reduction in cancer related death. Unfortunately, there was a parallel increase in thenumber of patients developing cardiotoxicity & heart failure making it the main cause of deathamong cancer survivors. Current strategies for predicting cardio-toxic side effects are limitedand robust pre-clinical, personalized platforms for assessing both harmful drugs and protectiveagents are lacking.In the current study by using human pluripotent stem cells technology, we developed a uniquehuman-engineered cardiac tissue (ECT) platform generated from cardiomyocytes, endothelialcells and authentic cardiac fibroblasts derived from the epicardial cell layer. Using this platform,we are examined the ability of the model to recapitulate the cardio-toxic effects of Doxorubicinand the cardio protective capabilities of Dexrazoxane and SGLT2i; a novel agent, that wasrecently shown to prevent heart failure in patients with diabetes and high risk forcardiovascular diseases.p<0.001 Results: Paired, long-term, consecutive force evaluations of the ECTs demonstrated the cardio-toxiceffect of Doxorubicin resulting in a lower total active force for each preload compared toBaseline control. Moreover, concomitant exposure to Doxorubicin and the cardio-protectiveagents (Dexrazoxane and SGLT2 inhibitor ‘Empagliflozin’) resulted in considerable recovery ofthe active force generation compared to control. Conclusion: This report is an initial proof of concept demonstrating the ability of ECTs to serve as a modelfor functional evaluation induced by cardio toxic drugs as well as the effect of cardio-protective agents. High-throughput based on this platform may be used for identifying novel cardio-protective agents as well as for evaluating patient-specific cardio-toxic effects.

Layer-Specific Global Longitudinal Strain Predicts Arrhythmic Risk in Arrhythmogenic Cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (AC) is a life-threatening disease which predispose to malignant arrhythmias and sudden cardiac death (SCD) in the early stages of the disease. Risk stratification relies on the electrical, genetic, and imaging data. Our study aimed to investigate how myocardial deformation parameters may identify the subjects at risk of known predictors of major ventricular arrhythmias.Methods: A cohort of 45 subjects with definite or borderline diagnosis of AC was characterized using the advanced transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) and divided into the groups according to the potential arrhythmic risk markers, such as non-sustained ventricular tachycardia (NSVT), late gadolinium enhancement (LGE), and genetic status. Layer-specific global longitudinal strain (GLS) by TTE 2D speckle tracking was compared in patients with and without these arrhythmic risk markers.Results: In this study, 23 (51.1%) patients were men with mean age of 43 ± 16 years. Next-generation sequencing identified a potential pathogenic mutation in 39 (86.7%) patients. Thirty-nine patients presented LGE (73.3%), mostly located at the subepicardial-to-mesocardial layers. A layer-specific-GLS analysis showed worse GLS values at the epicardial and mesocardial layers in the subjects with NSVT and LGE. The epicardial GLS values of −15.4 and −16.1% were the best cut-off values for identifying the individuals with NSVT and LGE, respectively, regardless of left ventricular ejection fraction (LVEF).Conclusions: The layer-specific GLS assessment identified the subjects with high-risk arrhythmic features in AC, such as NSVT and LGE. An epicardial GLS may emerge as a potential instrument for detecting the subjects at risk of SCD in AC.

Multilayer global longitudinal strain assessment of subclinical myocardial dysfunction related to insulin resistance

Abstract Myocardial tissue is sensitive to insulin resistance (IR) due to its interactions with insulin levels. Previous studies demonstrated that heart failure prevalence was higher in IR patients. Evaluation of myocardial deformation by multilayer global longitudinal strain (MGLS) might provide more information about IR related left ventricular dysfunction. In this study, we aimed to investigate subclinical LV dysfunction with MGLS in patients with IR. The study was designed as a prospective cross-sectional study. The present study included 64 patients with IR(+), and 54 subjects without IR(−) prospectively. The homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. Specific analysis for endocardial, mid-myocardial and epicardial layers were performed by two-dimensional (2D) speckle tracking echocardiography (STE) for multilayer global longitudinal strain. MGLS (Endocard-Mid-myocard-Epicard) values were significantly lower in the IR(+) group compared to IR(−) group ((GLS-endocard; −15.1±1.5 vs. −18.7±1.3, p<0.001), (GLS-mid-myocard; −16.0±2.0 vs. −18.0±2.0, p<0.001), (GLS-epicard; −17.0±1.7 vs. −18.01±1.94, p=0.004)). GLS-endocard levels were significantly and positively correlated with HOMA-IR levels (r=0.643, p<0.001). HOMA-IR and age were found to be independent factors in detecting a decrease in GLS-endocard level in regression analysis. In conclusion, our data reveal that IR(+) patients had significantly lower strain values compared to IR(−) group. Besides, we presented that the HOMAIR value was an independent predictor of subclinical left ventricular dysfunction. Funding Acknowledgement Type of funding sources: None.

Epicardial Contribution to the Developing and Injured Heart: Exploring the Cellular Composition of the Epicardium.

The epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it secretes paracrine factors that support cardiac tissue formation. In the adult heart the epicardium is a quiescent layer of cells which can be reactivated upon ischemic injury, initiating an embryonic-like response in the epicardium that contributes to post-injury repair processes. Therefore, the epicardial layer is considered an interesting target population to stimulate endogenous repair mechanisms. To date it is still not clear whether there are distinct cell populations in the epicardium that contribute to specific lineages or aid in cardiac repair, or that the epicardium functions as a whole. To address this putative heterogeneity, novel techniques such as single cell RNA sequencing (scRNA seq) are being applied. In this review, we summarize the role of the epicardium during development and after injury and provide an overview of the most recent insights into the cellular composition and diversity of the epicardium.

B-PO03-087 ATRIAL UNIPOLAR VOLTAGE MAPPING FOR DETECTION OF INTRAMURAL ABLATION GAPS

Endocardial bipolar voltage is primarily influenced by superficial muscle layers. Thus, endocardial scar with surviving intramural/epicardial layers may exhibit low bipolar voltage. Alternatively, intramural/epicardial scar with preserved endocardium may exhibit normal voltage. To examine the value of unipolar voltage for assessing atrial tissue. In a chronic swine model of transcaval ablation line with intentional gap (7.9-14.8mm), the RA was mapped after a survival period of 6 weeks using a multielectrode catheter (Pentaray, Biosense Webster). Unipolar and bipolar voltage maps were compared with histopathology. In 10 swine, the transcaval ablation line was transmural in 4 and non-transmural in 6. Four gaps exhibited endocardial scar with preserved mid-myocardial and epicardial layers; 1 gap showed preserved endocardium with mid-myocardial scar, and 1 gap showed a fully preserved atrial wall. Bipolar voltage (using a 0.50mV cutoff) performed well for detecting all endocardial gaps (0.64mV, IQR: 0.36-1.52, PPV=100%) but failed to detect intramural gaps (0.28mV, IQR:0.13-0.52, p=0.004; PPV=0%;). Lowering the bipolar voltage cutoff to 0.2mV did not significantly improve its sensitivity to detect intramural gaps (PPV=25%). In contrast, unipolar voltage was higher in sites of intramural gaps (1.37mV, IQR:1.12-1.93) compared to regions of transmural scar (0.74mV, IQR:0.58-0.94, p<0.001; PPV=100%) without false positive gap detection (NPV=100%); Figure. Unipolar voltage mapping may be useful for detecting intramural surviving muscle. The clinical utility and specific cutoff values require further investigation.

Effects of Different Systolic Blood Pressure Targets on Myocardial Function: A One-Year Follow-Up in Geriatric Hypertension.

BackgroundA lower systolic blood pressure (SBP) target reduces major cardiovascular events and mortality from any cause of geriatric hypertension. However, the effect of different SBP targets on myocardial function remains unclear. This study aimed to determine changes in left ventricular (LV) strain in older hypertensive patients after 1 year of different SBP goals, and to evaluate its effects on myocardial mechanics in this population.MethodsWe studied 313 hypertensive adults aged 60 years or older after 1 year of the Systolic Blood Pressure Intervention Trial. They were divided into the intensive group (target SBP: 110–130 mmHg) and the standard group (target SBP: 130–150 mmHg). All participants underwent echocardiography within 1 week after enrollment and 1 year after participating in the study. Global longitudinal strain (GLS) of the LV (endocardial, middle, and epicardial layer: GLS-end, GLS-mid, and GLS-epi, respectively) and the improvement of GLS at 1 year (ΔGLS-end, ΔGLS-mid, and ΔGLS-epi) were measured.ResultsAt 1 year, GLS-end in the intensive group was slightly improved compared with that before the trial (−23.78%±3.10% vs −22.58%±3.11%, P<0.05). The ΔGLS-end and ΔGLS-mid in the intensive group were higher than those in the standard group (1.20±0.23 vs 0.58±0.59% and 0.70±0.21 vs 0.52±0.17, P<0.05). Moreover, SBP at 1 year and an angiotensin II type 1 receptor antagonist were independent factors that affected ΔGLS-end (β= −0.005, P=0.004; β= 0.080, P<0.001, respectively).ConclusionThese trial results suggest that a lower SBP target can slightly improve myocardial function in older hypertensive patients at 1 year.

Prognostic Value of Multilayer Left Ventricular Global Longitudinal Strain in Patients with ST-segment Elevation Myocardial Infarction with Mildly Reduced Left Ventricular Ejection Fractions

Multilayer (epi-, mid- and endocardium) left ventricular (LV) global longitudinal strain (GLS) reflects the extent of myocardial damage after ST-segment myocardial infarction (STEMI). However, the prognostic implications of multilayer LV GLS remain unclear. We studied the association between multilayer LV GLS and prognosis in patients with mildly reduced or preserved LV ejection fraction (EF) after STEMI. Patients with first STEMI and LVEF>45% were evaluated retrospectively. Baseline multilayer (endocardial, mid-myocardial and epicardial) LV GLS were measured on 2-dimensional speckle tracking echocardiography. Patients were followed up for of all-cause mortality. A total of 569 patients (77% male, 60 ± 11 years) were included. After a median follow-up of 117 (interquartile range 106-132) months, 95 (17%) patients died. We observed no differences in baseline LVEF and peak troponin levels between survivors and non-survivors. However, non-survivors showed more impaired GLS at all layers (epicardium: -11.9 ± 2.8% vs. -13.4 ± 2.8%; mid-myocardium: -14.2 ± 3.2% vs. -15.6 ± 3.2%; endocardium: -16.5 ± 3.7% vs. -17.7 ± 3.6%, p <0.05, for all). On multivariable analysis, increasing age (hazard ratio 1.095; p<0.001) and impaired LV GLS of the epicardial layer (hazard ratio 1.085; p=0.047) were independently associated with higher risk of all-cause mortality. In addition, LV GLS at the epicardium had incremental prognostic value for all-cause mortality (χ2=114, p=0.044). In conclusion, in contemporary STEMI patients with mildly reduced or preserved LVEF, ageing and reduced LV GLS of the epicardium (reflecting transmural scar formation) were independently associated with all-cause mortality after adjusting for clinical and echocardiographic variables.

Left ventricle longitudinal strain of the endocardial and epicardial layers and left ventricle remodelling in children born with low and extremely low body weight aged from one to five years old

Background. In last decades, the number of babies born preterm has increased significantly. Premature newborns are more susceptible to cardiovascular disease in the long-term. To identify subclinical myocardial impairment in premature infants, an assessment of of the left ventricle (LV) deformation could be used.Objective. The aim of the study was to study the left ventricle (LV) Longitudinal Strain of the endocardial, middle and epicBardial layers in children born with very low and extremely low body weight, at the age from one to five years.Design and methods. The study included 88 children aged from one to 5 years old, born very premature with very low and extremely low body weight. The comparison group consisted of 43 healthy children of the same age, born full-term. The LV Longitudinal Strain of the endocardial, middle and epicardial layers was studied using the Speckle Tracking Imaging-2D Strain.Results. In children aged 1 to 5 years, born with very low and extremely low body weight, changes in the gradient of transmural wall Strain and a decrease in LV segments longitudinal strain were detected in 15.90 % and 14.77 % of cases, respectively. Mothers of children born prematurely and who subsequently registered disturbance of the transmural gradient of left ventricular strain in 10 cases (71.43 %) had a history of threatened termination of pregnancy. The threat of termination of pregnancy was noted in all women whose children had a decrease in LV segmental strain. In children who have normal of LV segmental strain, the threat of termination of pregnancy in mothers was registered in 16 cases (26.23 %). LV remodeling is observed in children with a change in the gradient of transmural wall strain or and with a decrease in LV longitudinal segment strain. Conclusion. Changes in the transmural gradient of wall deformation or reduction of segmental LV deformation in the longitudinal direction in premature infants require correction of the conventional algorithm of dispensary observation in an outpatient setting.

Left ventricular noncompaction\u2014a rare cause of triad: heart failure, ventricular arrhythmias, and systemic embolic events: a\xa0case report\xa0

BackgroundLeft ventricular noncompaction is a rare cardiomyopathy characterized by a thin, compacted epicardial layer and a noncompacted endocardial layer, with trabeculations and recesses that communicate with the left ventricular cavity. In the advanced stage of the disease, the classical triad of heart failure, ventricular arrhythmia, and systemic embolization is common. Segments involved are the apex and mid inferior and lateral walls. The right ventricular apex may be affected as well.Case presentationA 29-year-old Caucasian male was hospitalized with dyspnea and fatigue at minimal exertion during the last months before admission. He also described a history of edema of the legs and abdominal pain in the last weeks. Physical examination revealed dyspnea, pulmonary rales, cardiomegaly, hepatomegaly, and splenomegaly. Electrocardiography showed sinus rhythm with nonspecific repolarization changes. Twenty-four-hour Holter monitoring identified ventricular tachycardia episodes with right bundle branch block morphology. Transthoracic echocardiography at admission revealed dilated left ventricle with trabeculations located predominantly at the apex but also in the apical and mid portion of lateral and inferior wall; end-systolic ratio of noncompacted to compacted layers > 2; moderate mitral regurgitation; and reduced left ventricular ejection fraction. Between apical trabeculations, multiple thrombi were found. The right ventricle had normal morphology and function. Speckle-tracking echocardiography also revealed systolic left ventricle dysfunction and solid body rotation. Abdominal echocardiography showed hepatomegaly and splenomegaly. Abdominal computed tomography was suggestive for hepatic and renal infarctions. Laboratory tests revealed high levels of N-terminal pro-brain natriuretic peptide and liver enzymes. Cardiac magnetic resonance evaluation at 1 month after discharge confirmed the diagnosis. The patient received anticoagulants, antiarrhythmics, and heart failure treatment. After 2 months, before device implantation, he presented clinical improvement, and echocardiographic evaluation did not detect thrombi in the left ventricle. Coronary angiography was within normal range. A cardioverter defibrillator was implanted for prevention of sudden cardiac death.ConclusionsLeft ventricular noncompaction is rare cardiomyopathy, but it should always be considered as a possible diagnosis in a patient hospitalized with heart failure, ventricular arrhythmias, and systemic embolic events. Echocardiography and cardiac magnetic resonance are essential imaging tools for diagnosis and follow-up.

Left and Right Myocardial Functionality Assessed by Two-Dimensional Speckle-Tracking Echocardiography in Cats with Restrictive Cardiomyopathy.

Simple SummaryThe endomyocardial form of restrictive cardiomyopathy, a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. While two-dimensional speckle-tracking echocardiography has been known to identify myocardial deformations, its function relative to cats with the endomyocardial form of restrictive cardiomyopathy has yet to be characterized. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with the endomyocardial form of restrictive cardiomyopathy, causing this disease pathophysiology and clinical status. In the current study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography. Our study indicated that cats with restrictive cardiomyopathy have reduced left ventricular myocardial function. Notably, left ventricular systolic circumferential endocardial strain and circumferential endocardial-to-epicardial strain ratio were lower in cats with restrictive cardiomyopathy. Furthermore, some right ventricular myocardial deformations were also differerent in cats with restrictive cardiomyopathy. Myocardial function assessed by two-dimensional speckle-tracking echocardiography could reveal left and right myocardial dysfunction.The endomyocardial form of restrictive cardiomyopathy (EMF-RCM), a primary disorder of the myocardium, is one of the diseases with poor prognosis in cats. We hypothesized that both the left and right myocardial functional abnormalities may occur in cats with EMF-RCM, causing this disease pathophysiology and clinical status. Out of the 25 animals included in this study, 10 were client-owned cats with EMF-RCM, and 15 were healthy cats. In this study, cats were assessed for layer-specific myocardial function (whole, endocardial, and epicardial) in the left ventricular longitudinal and circumferential directions, and right ventricular longitudinal direction, via two-dimensional speckle-tracking echocardiography (2D-STE). Cats with EMF-RCM had depressed left ventricular myocardial deformations both in systole (whole longitudinal strain, epicardial longitudinal strain, and endocardial circumferential strain) and diastole (early and late diastolic longitudinal strain rates, and late diastolic circumferential strain rate) compared to controls. Furthermore, some right ventricular myocardial deformations (systolic longitudinal strain in epicardial layers, and endocardial-to-epicardial strain ratio) were significantly differerent in cats with EMF-RCM. Myocardial function assessed by 2D-STE could reveal left and right myocardial dysfunction.

Midkine-a Regulates the Formation of a Fibrotic Scar During Zebrafish Heart Regeneration.

Unlike the hearts of mammals, the adult zebrafish heart regenerates after injury. Heart cryoinjury in zebrafish triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression was induced at 1-day post-cryoinjury (dpci) throughout the epicardial layer, whereas by 7 dpci expression had become restricted to the epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in an arrest in heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and intense TGFβ signaling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.

The impact of chronic alcohol overuse on heart function and prognosis: layer-specific longitudinal strain and mid-term outcome analysis.

The exact effects of alcohol drinking on cardiac function are not clear. This study aimed to determine the relationship between consumed amount of alcohol, myocardial injury, and prognosis. Myocardial function and cardiac outcomes were examined in subjects with chronic alcoholism by classical and strain echocardiographic parameters, including global (GLS) and layer-specific longitudinal strain of the endocardial (GLSendo) and epicardial (GLSepi) layer. One group of 65 alcohol-overusers (ALC), median (IQR, interquartile range) age 44 (38-51) years, was compared with 30 controls (CG). Median (IQR) alcohol dose (in alcohol units, 1 AU = 1 g of ethanol) per week was 30 (12-51) AU in ALC and 0 in CG; P <0.001, and the mean (SD, standard deviation) drinking period was 16 (9) years. ALC patients demonstrated higher left ventricular (LV) mass and impaired diastolic function. The ALC group demonstrated lower median (IQR) LV ejection fraction (EF): 52% (37%-57%) vs 60% (55%-63%) (P <0.001); GLS: 17% (9%-20%) vs 19% (18%-21%) (P = 0.01); absolute layer-specific strain values. GLSendo <19% and GLSepi <15% predicted worsened mid-term prognosis, as did elevated N-terminal brain natriuretic peptide (NT-proBNP) and lower EF and GLS. Long-term alcohol overuse, even with a rather low reported median (IQR) dose of 4 (2-7) AU per day resulted in LV hypertrophy, diastolic and systolic dysfunction. Diminished GLS <18%, endocardial <19% and epicardial <15% layer strain predicted combined endpoints but did not significantly improve the prognostic power of tested models, based on NT-proBNP and EF in follow-up.

Speckle tracking derived strain in neonates: planes, layers and drift

The aims of this study was to assess the effect of using a four chamber versus a three plane model on speckle tracking derived global longitudinal strain, the effects of drift compensation, the effect of assessing strain in different layers and finally the interplay between these aspects for the assessment of strain in neonates. Speckle tracking derived longitudinal strain was obtained from 22 healthy neonates. ANOVA, Bland–Altman analyses, coefficients of variation and assessment of intraclass correlation coefficients were conducted to assess the effect of the abovementioned aspects as well as assess both inter-observer and intra-observer variability. Neither the use of the three plane model versus the four chamber model nor the use of drift compensation had a substantial effect on global longitudinal strain (less than 1%, depending on which layer was being assessed). A gradient was seen with increasing strain from the epicardial to endocardial layers, similar to what is seen in older subjects. Finally, drift compensation introduced more discrepancy in segmental strain values compared to global longitudinal strain. Global longitudinal strain in healthy neonates remains reasonably consistent regardless of whether the three plane or four chamber model is used and whether drift compensation is applied. Its value increases when one moves from the endocardial to the epicardial layer. Finally, drift compensation introduces more discrepancy for regional measures of longitudinal strain compared to global longitudinal strain.

Global, segmental and layer specific analysis of myocardial involvement in Duchenne muscular dystrophy by cardiovascular magnetic resonance native T1 mapping

BackgroundProgressive cardiomyopathy accounts for almost all mortality among Duchenne muscular dystrophy (DMD) patients.‍ Thus, our aim was to comprehensively characterize myocardial involvement by investigating the heterogeneity of native T1 mapping in DMD patients using global and regional (including segmental and layer-specific) analysis across a large cohort.MethodsWe prospectively enrolled 99 DMD patients (8.8 ± 2.5 years) and 25 matched male healthy controls (9.5 ± 2.5 years). All subjects underwent cardiovascular magnetic resonance (CMR) with cine, T1 mapping and late gadolinium enhancement (LGE) sequences. Native T1 values based on the global and regional myocardium were measured, and LGE was defined.ResultsLGE was present in 49 (49%) DMD patients. Global native T1 values were significantly longer in LGE-positive (LGE +) patients than in healthy controls, both in basal slices (1304 ± 55 vs. 1246 ± 27 ms, p < 0.001) and in mid-level slices (1305 ± 57 vs. 1245 ± 37 ms, p < 0.001). No significant difference in global native T1 was found between healthy controls and LGE-negative (LGE−) patients. In segmental analysis, LGE + patients had significantly increased native T1 in all analyzed segments compared to the healthy control group. Meanwhile, the comparison between LGE− patients and healthy controls showed significantly elevated values only in the basal anterolateral segment (1273 ± 62 vs. 1234 ± 40 ms, p = 0.034). Interestingly, the epicardial layer had a significantly higher native T1 in LGE− patients than in healthy controls (p < 0.05), whereas no such pattern was noticed in the global myocardium. Epicardial layer native T1 resulted in the highest diagnostic performance for distinguishing between healthy controls and DMD patients in receiver operating curve analyses (area under the curve [AUC] 0.84 for basal level and 0.85 for middle level) when compared to global native T1 and endocardial layer native T1.ConclusionsMyocardial regional native T1, particularly epicardial native T1, seems to have potential as a novel robust marker of very early cardiac involvement in DMD patients.Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) ChiCTR1800018340, 09/12/2018, Retrospectively registered.

Association between microvascular dysfunction and impaired myocardial deformation in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Objective To analyze the relationship between coronary microvascular dysfunction (MCD) and left ventricular (LV) myocardial deformation in hypertrophic cardiomyopathy (HCM). Methods Prospectively inclusion of HCM patients (P). MCD was assessed by CMR, during regadenoson-induced hyperemia. For perfusion assessment, the myocardium was divided into 32 subsegments (16 AHA segments subdivided into an endocardial and epicardial layer). Ischemic burden was calculated as the number of involved subsegments, assigning 3% of myocardium to each subsegment. Epicardial coronary artery disease was excluded by computed tomography or invasive coronary angiography. LV myocardial deformation was evaluated by 2D and 3D speckle-tracking echocardiography (STE), including global longitudinal strain (GLS), peak systolic dispersion (PDS), global circumferential strain (GCS), global radial strain (GRS), area strain, twist and torsion. Results 31 P enrolled (51%male,age57.8 ± 15.5years). Asymmetric septal hypertrophy was seen in 55%, apical in 29%, concentric in 16%,maximal wall thickness (MWT) of 20.5 ± 4.9mm; 26% with LVOT obstruction; LV ejection fraction 67.9 ± 7.9%. In 2DSTE analysis, P with more ischemia (&amp;gt;20%of LV) presented more severe impaired GLS and greater PDS, comparing with patients with ≤20% of ischemia. Similarly, 3DSTE imaging showed worse LV performance in P with greater ischemic burden, expressed by significant difference in GLS, GRS and area strain. GCS also trended to be worse in the presence of &amp;gt;20% of ischemia. The stronger correlation was found between 2D GLS and ischemic burden (Pearson correlation factor 0.545; p = 0.002). Conclusion In HCM, the severity of ischemia secondary to MCD was associated with impairment in LV myocardial deformation evaluated by 2D and 3D STE. Table 1. Echocardiography Ischemic burden (% of LV) 2D parameters ≤ 20% (n = 15) &amp;gt; 20% (n = 16) p-value GLS (%) -15.6 ± 2.7 -12.1 ± 4.7 0.016 PSD (ms) 73.2 ± 25.6 102.1 ± 57.6 0.150 3D parameters GLS (%) -10.3 ± 4.5 -7.3 ± 3.0 0.010 GCS (%) -12.6 ± 3.0 -10.1 ± 4.5 0.079 GRS (%) 30.8 ± 8.5 22.8 ± 11.4 0.035 Area strain(%) -20.8 ± 4.9 -15.8 ± 6.3 0.020 Twist (deg) 6.0 ± 4.8 4.1 ± 4.0 0.175 Torsion (deg/cm) 1.2 ± 0.9 0.8 ± 0.7 0.232

Effect of Temporal and Spatial Smoothing on Speckle\u2013Tracking-Derived Strain in Neonates

Clinical application of strain in neonates requires an understanding of which image acquisition and processing parameters affect strain values. Previous studies have examined frame rate, transmitting frequency, and vendor heterogeneity. However, there is a lack of human studies on how user-regulated spatial and temporal smoothing affect strain values in 36 neonates. This study examined nine different combinations of spatial and temporal smoothing on peak systolic left ventricular longitudinal strain in 36 healthy neonates. Strain values were acquired from four-chamber echocardiographic images in the software-defined epicardial, midwall, and endocardial layers in the six standard segments and average four-chamber stain. Strain values were compared using repeated measure ANOVAs. Overall, spatial smoothing had a larger impact than temporal smoothing, and segmental strain values were more sensitive to smoothing settings than average four-chamber strain. Apicoseptal strain decreased by approximately 4% with increasing spatial smoothing, corresponding to a 13–19% proportional change (depending on wall layer). Therefore, we recommend clinicians be mindful of smoothing settings when assessing segmental strain values.

Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans.

Ca2+ alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca2+ transients that frequently occur during tachycardia, ischemia, or hypothermia that can lead to sudden cardiac death. Ca-Alts appear to result from a variation in the amount of Ca2+ released from the sarcoplasmic reticulum (SR) between two consecutive heartbeats. This variable Ca2+ release has been attributed to the alternation of the action potential duration, delay in the recovery from inactivation of RYR Ca2+ release channel (RYR2), or an incomplete Ca2+ refilling of the SR. In all three cases, the RYR2 mobilizes less Ca2+ from the SR in an alternating manner, thereby generating an alternating profile of the Ca2+ transients. We used a new experimental approach, fluorescence local field optical mapping (FLOM), to record at the epicardial layer of an intact heart with subcellular resolution. In conjunction with a local cold finger, a series of images were recorded within an area where the local cooling induced a temperature gradient. Ca-Alts were larger in colder regions and occurred without changes in action potential duration. Analysis of the change in the enthalpy and Q10 of several kinetic processes defining intracellular Ca2+ dynamics indicated that the effects of temperature change on the relaxation of intracellular Ca2+ transients involved both passive and active mechanisms. The steep temperature dependency of Ca-Alts during tachycardia suggests Ca-Alts are generated by insufficient SERCA-mediated Ca2+ uptake into the SR. We found that Ca-Alts are heavily dependent on intra-SR Ca2+ and can be promoted through partial pharmacologic inhibition of SERCA2a. Finally, the FLOM experimental approach has the potential to help us understand how arrhythmogenesis correlates with the spatial distribution of metabolically impaired myocytes along the myocardium.