Left Ventricular Anterior Wall Research Articles

Myocardial deformation imaging by 2D speckle tracking echocardiography for assessment of diastolic dysfunction in murine cardiopathology

Diastolic dysfunction is increasingly identified as a key, early onset subclinical condition characterizing cardiopathologies of rising prevalence, including diabetic heart disease and heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction characterization has important prognostic value in management of disease outcomes. Validated tools for in vivo monitoring of diastolic function in rodent models of diabetes are required for progress in pre-clinical cardiology studies. 2D speckle tracking echocardiography has emerged as a powerful tool for evaluating cardiac wall deformation throughout the cardiac cycle. The aim of this study was to examine the applicability of 2D speckle tracking echocardiography for comprehensive global and regional assessment of diastolic function in a pre-clinical murine model of cardio-metabolic disease. Type 2 diabetes (T2D) was induced in C57Bl/6 male mice using a high fat high sugar dietary intervention for 20 weeks. Significant impairment in left ventricle peak diastolic strain rate was evident in longitudinal, radial and circumferential planes in T2D mice. Peak diastolic velocity was similarly impaired in the longitudinal and radial planes. Regional analysis of longitudinal peak diastolic strain rate revealed that the anterior free left ventricular wall is particularly susceptible to T2D-induced diastolic dysfunction. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of cardiopathology and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies.

Relationship between left ventricular mechanical dyssynchrony with cardiac resynchronization therapy response in chronic heart failure patients with left bundle branch block

Aim. To investigate the relationship between left ventricular (LV) mechanical dyssynchrony with cardiac resynchronization therapy (CRT) response in chronic heart failure (CHF) pts with left bundle branch block.Methods. Forty-nine pts (male - 34 [69.4%], average age 58.3±11.4 years) with sinus rhythm, permanent left bundle branch block with QRS duration ≥150 ms and New York Heart Association (NYHA) II-III functional class of CHF were included in the study. In addition to full examination, myocardial perfusion scintigraphy (MPS) and gated blood pool single-photon emission computed tomography (gBPS) were performed before and 6 months after CRT devices with cardioverter-defibrillator function implantation. Pts were considered as responders to CRT if they fulfilled after 6-month follow-up the following combined criteria: NYHA FC improvement ≥1 class + LV end systolic volume decrease >15% or NYHA FC improvement ≥1 class + LV ejection fraction improvement >5%.Results. The 1st and 2nd groups included 35 (71.4%) and 14 (28.6%) pts with and without response to CRT respectively. Groups were comparable in terms of pre-CRT implantation clinical and instrumental parameters, except for MPS and gBPS parameters. The multivariate logistic regression had shown that only ∆interventricular dyssynchrony (adjusted odds ratio [OR] 1,0349; 95% confidence interval [CI] 1.0075-1,0631; р=0.01) and phase standard deviation of the anterior LV wall (OR 1.0669; 95% CI 1.0118-1.1251; p=0.01) were independently related with CRT response. An increase in the prognostic coefficient, calculated using the ∆interventricular dyssynchrony and phase standard deviation of the anterior LV wall, more than 0.67 was a predictor of CRT response (area under the curve 0.918; sensitivity 85.71; specificity 85.71; p <0.001).Conclusion. The mechanical dyssynchrony assessed by MPS and gBPS is associated with CRT response. According to our predictive model, an increase in prognostic coefficient more than 0.67 is a predictor of CRT response.

Dose additive maternal and offspring effects of oral maternal exposure to a mixture of three PFAS (HFPO-DA, NBP2, PFOS) during pregnancy in the Sprague-Dawley rat

Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14–18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.

Sustained high-fat diet increases ventricular susceptibility to arrhythmias and impairs myocardial calcium cycling

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Medizinische Fakultät, Heinrich Heine Universität Düsseldorf Background – Obesity is one of the most relevant factors for cardiovascular disease in western societies. Independent of coronary heart disease, obesity promotes a multimodal arrhythmic substrate and increases the susceptibility to ventricular arrhythmias (VA) eventually leading to sudden cardiac death. Purpose – Aim of the present study was to develop an ex vivo mouse model to characterize obesity-mediated VAs and left ventricular (LV) myocardial disruption of calcium homeostasis. Methods – All experiments were performed ex vivo in retrogradely perfused hearts from 32 – 36 week-old C57Bl/6J mice (n=14). Five mice received a normal chow diet (NCD), 9 mice were fed a sustained high-fat diet (HFD) over a 6-month period to generate diet-induced-obesity (DIO). We combined an endocardial catheter-based technique to assess VA susceptibility with an epicardial dual fluorescence imaging approach employing a potentiometric (Rh237) and a calcium sensitive (Rhod2) dye to assess action potential and calcium cycling characteristics. Optical mapping data was analysed using a MATLAB-based algorithm. VA susceptibility was quantified by an established scoring system. Results – Mice receiving a sustained HFD were significantly heavier than those receiving NCD (NCD: 34.8±2.1g, HFD: 53.3±3.2g, P<0.0001). The number of induced VAs and VA susceptibility were increased in HFD compared to NCD (number of induced VAs: NCD: 1.4±0.7, HFD: 6.3±0.8, P=0.005, Figure 1A; VA susceptibility: NCD: 1.4±0.7, HFD: 18.1±2.3, P=0.001, Figure 1B). Ventricular tachycardias (VT) were only inducible in HFD, additionally, those hearts presented mostly polymorphic VTs (VT inducibility: NCD: 0.0 %, HFD: 88.9 %, P=0.003, Figure 1C; VT morphology: monomorphic VT: 25 %, polymorphic VT: 75 %). Epicardial optical mapping of the anterior LV wall showed a prolonged action potential duration (APD) and prolonged calcium transient duration (CaTD) in HFD (APD90 at CL 100 ms: NCD: 45.1±1.5 ms, HFD: 50.8±1.8 ms, P=0.03; CaTD90 at 100 ms pacing cycle length (PCL): NCD: 61.0±2.3 ms, HFD: 66.6±0.6 ms, P=0.02, Figure 2A). Furthermore, CaT alternans (ALT) threshold defined as amplitude alternans > 10 % of two consecutive beats was decreased (PCL ALT threshold: NCD: 60.0±1.6 ms, DIO: 67.8±1.2 ms, P=0.006, Figure 2B), with mean ALT being increased in HFD (mean ATL at 60 ms PCL: NCD: 15.4±2.4 %, HFD: 25.7±3.0 %, P=0.04). Conclusions – Our findings show that sustained HFD in mice increases ventricular susceptibility to VTs, especially polymorphic VTs indicating heterogeneity in wave propagation. DIO leads to disruption of LV myocardial calcium homeostasis as demonstrated by a decreased ALT threshold and increased mean ALT. Our data suggest that LV calcium mishandling may be a driver for arrhythmogenesis in DIO and modulation may present a perspective therapeutical approach. Further experiments will address molecular mechanisms and identify potential targets of modulation.

Xuesaitong promotes myocardial angiogenesis in myocardial infarction mice by inhibiting MiR-3158-3p targeting Nur77.

This study aims to investigate the regulatory effect of Xuesaitong (XST) and miR-3158-3p on angiogenesis. All mice were randomly assigned into Sham group, Model group, XST group, XST + miR-3158-3P-overexpression (miRNA-OE) group. XST was found to increase the left ventricular anterior wall thickness at end diastole and end systole (LVAWd and LVAWs), left ventricular internal dimension at end diastole and end systole (LVIDd and LVIDs), fractional shortening (FS), and ejection fraction (EF) and decrease the proportion of fibrotic areas in mice. In contrast to those in Sham group, the protein expressions of Nur77, p-PI3K, HIF-1α, VEGFs, COX-2 in the heart tissues of mice in Model group were elevated and further increased after XST treatment in comparison with those in Model group. Nur77-/- mice were utilized. It was found that XST enhanced cell viability through a methyl thiazolyl tetrazolium assay and facilitated angiogenesis in each group, as assessed by a catheter formation assay. Specifically, XST was shown to promote the formation of blood vessels. Moreover, the protein expression levels of Associated proteins in the heart tissues of Nur77-/- mice were dramatically reduced in mice in Model and XST group compared with those in WT mice. Additionally, the above-mentioned protein expressions in the heart tissues of Nur77-/- mice did not change significantly in mice in Model + miRNA-OE + XST group compared with those in WT mice, suggesting that miR-3158-3p can specifically inhibit the expression of Nur77. In conclusion, XST inhibits miR-3158-3p targeting Nur77 to facilitate myocardial angiogenesis in mice with myocardial infarction.

Modern approaches to the diagnosis and treatment of cardiac sarcoidosis: results of a cohort study

Aim. To analyze clinical and paraclinical data in patients with documented cardiac sarcoidosis, outlining the key points of diagnosis and selection of the optimal treatment.Material and methods. For the period from 2016 to 2021, 63 patients (50,4±14,1 years) were included in the cohort study on negotiability. Based on a standard examination, 15 patients (41±13 years old) were selected, who continued the examination to confirm the diagnosis of cardiac sarcoidosis. Contrast-enhanced cardiac magnetic resonance imaging (MRI) was performed in 10 patients, while endomyocardial biopsy in 7 patients. All patients underwent 18F-fluorodeoxyglucose positron emission tomography (PET).Results. The most common (53%) electrocardiographic abnormality was right bundle branch block. Ventricular arrhythmias and high-grade atrioventricular block were recorded mainly in patients with documented activity. Regional contractility disorders were predominantly detected in patients with cardiac fibrosis. Delayed contrast enhancement according to cardiac MRI was recorded mainly intramurally in the interventricular septum and subepicardial area of left ventricular (LV) lateral wall. When analyzing the PET results, we found the predominant radiopharmaceutical accumulation in the interventricular septum (56%), lateral (44%) and anterior (33%) LV walls. There was no significant improvement in global LV contractility against the background of immunosuppressive therapy, especially in patients with reduced ejection fraction: initially 49,2±10,1% vs 46,9±14,9% during therapy (p=0,658).Conclusion. A certain apprehensive attitude of the doctor and adherence to the algorithm for early diagnosis of cardiac sarcoidosis allows minimizing the risks of fatal cardiovascular events. On the contrary, in the case of late diagnosis, even the use of aggressive immunosuppressive therapy does not lead to an improvement in global myocardial contractility, and fibrosis zones can cause life-threatening bradyarrhythmias and ventricular arrhythmias.

L-carnitine attenuated hyperuricemia-associated left ventricular remodeling through ameliorating cardiomyocytic lipid deposition.

Hyperuricemia (HUA) is associated with left ventricular remodeling (LVR) and thereby causes the initiation and development of a large number of cardiovascular diseases. LVR is typically accompanied by cardiomyocyte energy metabolic disorder. The energy supply of cardiomyocytes is provided by glucose and fatty acid (FA) metabolism. Currently, the effect of HUA on cardiomyocytic FA metabolism is unclear. In this study, we demonstrate that UA-induced cardiomyocyte injury is associated with cytoplasmic lipid deposition, which can be ameliorated by the FA metabolism-promoting drug L-carnitine (LC). UA suppresses carnitine palmitoyl transferase 1B (CPT1B), thereby inhibiting FA transport into the mitochondrial inner matrix for elimination. LC intervention can ameliorate HUA-associated left ventricular anterior wall thickening in mice. This study showed that FA transport dysfunction plays is a critical mechanism in both cardiomyocytic injury and HUA-associated LVR and promoting cytoplasmic FA transportation through pharmacological treatment by LC is a valid strategy to attenuate HUA-associated LVR.

584 AN UNUSUAL CASE OF A STRESSED HEART

Abstract A 53-year-old woman was admitted to our emergency department complaining severe stabbing and oppressive retrosternal pain radiating posteriorly to left scapulae and left arm The onset was followed by general malaise, nausea, vomiting which she attributed to a period of intense emotional stress. She denied common cardiovascular risk factors, but in 2019 had a suspected acute coronary syndrome with subsequent finding of normal coronary artery at angiography in another institute. Her past medical history included severe asthma on multiple drug therapy with regular follow-up. Physical exam was normal. Electrocardiogram (ECG) showed subtle diphasic-negative T wave in anterior leads with mild ST depression in V4-V5, with patient still symptomatic. Lab examinations showed significantly increased troponins levels (hsTnI 664 ng/L, reference < 34 ng/L) with other lab values within normal range. A transthoracic echocardiogram at the bedside revealed mildly reduced systolic function with hypo-akinesis of the mid-apical anteroseptal and anterior left ventricular myocardial wall. Therefore, acute coronary syndrome was suspected and heparin and aspirin at a loading dose were administered. Still symptomatic, the patient was admitted in the ICU. In the same day a left heart catheterization revealed normal aspect of epicardial coronary arteries and ventriculography showed preserved basal and apical myocardial wall motion but hypo-akinesis of mid-cavitary walls, suggesting a possible mid-ventricular variant of Takotsubo syndrome (Figure 1). The patient was still symptomatic for stabbing chest pain after coronarography. To rule out the suspicion of acute aortic syndrome and pulmonary embolism, she also underwent a contrast-enhanced chest CT scan, that was fortunately normal. During her hospital stay, the patient had no arrhythmic and hemodynamic complications. Peak troponin level was 5027 ng/L. At serial ECGs, she developed diffuse deep T-wave inversion and a mild prolonged QT interval. Echocardiogram was repeated after 4 days showing complete normalization of left ventricular wall motion and restored ejection fraction also. From the traditional “apical ballooning” Takotsubo Syndrome with apical akinesia and basal hypercontractility, different variants have been described. The mid-ventricular variant, seen in our patient was found in only 14.6% of the cases in the International Takotsubo Registry, followed by basal “reverse” and focal variants (2.2% and 1.5%, respectively).

652 SUCCESSFUL SURGICAL REPAIR OF LEFT VENTRICULAR PSEUDOANEURYSM IN A PATIENT WITH SUBACUTE ST-ELEVATION MYOCARDIAL INFARCTION

Abstract A 65-year-old man was admitted to the emergency department for abdominal pain begun 4 days before. Past medical history consisted of ischemic stroke and diabetes mellitus. Of note, he was not taking any medication. Vital signs: blood pressure 90/50 mmHg, heart rate 50/minute, respiratory rate 18/minute, body temperature 36.5°C; saturation oxygen level 93%. High-sensitivity cardiac troponin was mildly elevated (121 pg/mL). Electrocardiogram showed sinus bradycardia, Q waves with ST elevation in antero-lateral leads consistent with subacute STEMI. Transthoracic echocardiogram (TTE) revealed aneurysmatic expansion of apical left ventricular (LV) walls (ejection fraction 30%) with a large apical thrombus (35×15 mm). Coronary angiography showed complete occlusion of proximal left anterior descending artery and a critical stenosis of right coronary artery; percutaneous coronary intervention with stent implantation on right coronary artery was performed. He received triple antithrombotic therapy with aspirin, clopidogrel, intravenous heparin first and then oral anticoagulation with warfarin. During coronary care unit stay, the patient was asymptomatic and hemodynamically stable. However, a control TTE (day 6) in cardiology ward revealed the presence of pseudoaneurysm with an oval out-pouching (23 × 13 mm) from the apical aspect of LV septum, communicating with the LV chamber through a passage measuring 1.6 cm. Partially organized pericardial effusion was evident around right ventricular free wall (Figure 1). Thus, the patient was immediately transferred to the cardiac surgery department for urgent surgical repair. The LV anterior wall rupture with pseudoaneurysm was then treated with endoaneurysmectomy of the LV with dacron patch and freewall reconstruction with prolene sutures and teflon felt stripes. The patient was finally discharged 3 weeks after surgery with betablockers, ace- inhibitors, diuretics, statins and dual antiplatelet therapy with aspirin and clopidogrel. At one month follow-up visit, the patient was hemodynamically stable with acceptable functional capacity. Figure 1Modified five chamber view (a, b) and three chamber view (c, d) showing apical LV pseudoaneurysm (arrows) with moderate pericardial effusion (arrowhead); color Doppler through the passage (arrow) in 3 chamber view (d). LV, left ventricular.

Tropoelastin Improves Post-Infarct Cardiac Function.

Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI. We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. RNA sequencing (RNAseq) analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using RNA-seq we also demonstrated the tropoelastin gene ELN is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment. We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.

Abstract 11965: Cellular Senescence Produces Diastolic Dysfunction and Cardiac Hypertrophy With Aging in Mice

Background: Age is a major risk factor for heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are poorly understood. Cellular senescence is an aging and stress related response; senescent cells (SCs) secrete bioactive substances that produce a variety of pathological changes. The role of senescence in HFpEF is unknown. Objectives: To study the effect of targeted deletion of SCs on cardiac function, structure and left ventricular (LV) pressure in an aging mouse model of HFpEF. Methods: We studied INK ATTAC mice, in which SCs undergo targeted clearance following treatment with a dimerizing agent, AP20187 (AP). Mice were treated with blinded AP or vehicle from 12 months to 18 months of age. Cardiac function and structure were studied with echocardiography. Contractility parameters were measured with a Millar catheter. The percentage of SCs in different cardiac-cell populations was analyzed with the use of Fluorescence-Activated Cell Sorting (FACS). Results: From 12 to 18 months, LV mass/LV diameter at end diastole (LVDd) and the LV anterior wall thickness at end diastole (LVAWd) increased in the vehicle group while they decreased in the AP group (LV mass/LVDd: %Δvehicle=+7.9± 3%, %ΔAP=-2±1.2%, P=0.005; LVAWd: %Δvehicle=+5.3±2.5%, %ΔAP=-3.5±1.6%, P=0.007) (Fig1A, B). E/e’ (echo) and isovolumic relaxation time indicated diastolic dysfunction in vehicle mice, and improved with AP (Fig1C, D). GFP bicistronic with p16 indicated SCs; FACS-purified fibroblasts (FBs) showed reduced GFP fluorescence (P=0.056) in the AP group, whereas immune and endothelial cells were not affected, suggesting that the anti-HFpEF effects of SC-clearance might be mediated through the clearance of senescent FBs (Fig1E). Conclusions: Our study points to a significant role of SCs, likely senescent FBs, in the pathophysiology of HFpEF. Modulating senescence might provide the basis for novel therapeutic approaches to HFpEF prevention and/or therapy.

Mechanism of Kaixin Powder prescriptions Buxin Decoction regulating PI3K/AKT signaling pathway to protect cardiovascular system: based on network pharmacology and experimental verification

This study established the EA.hy926 cell myocardial ischemia model to compare the effects of two Kaixin Powder prescriptions, Buxin Decoction(BXD) and Dingzhi Pills(DZP), at three dosages(500, 200, and 100 μg·mL~(-1)) on the cell viability. Further, the public databases(TCMSP, TCMID, SYMMAP, and STRING) and the network pharmacology methods such as KEGG pathway enrichment were employed to decipher the possible molecular mechanism of BXD in exerting the cardioprotective effect. The pharmacological effect of BXD was evaluated with the rat model of isoprenaline(ISO)-induced myocardial ischemia. The expression levels of proteins involved in the phosphatidylinositol-3-kinase/protein kinase B(PI3 K/AKT) signaling pathway were measured by Western blot. BXD significantly increased the viability of EA.hy926 cells, showing the performance superior to DZP. The network pharmacology analysis predicted that BXD might exert cardiac protection through the PI3 K/AKT signaling pathway. The in vivo experiment on rats showed that BXD treatment significantly increased the cardiac ejection fraction(EF), fractional shortening(FS), diastolic left ventricular anterior wall(LVAWd), systolic left ventricular anterior wall(LVAWs), and diastolic left ventricular posterior wall(LVPWd), significantly decreased the beat per minute(BPM) and diastolic left ventricular internal diameter(LVIDd), and significantly improved the ST segment in the electrocardiogram. The pathological results(Masson staining) showed that BXD restored the myocardial thickness, decreased the collagen fiber, increased the muscle fiber, and reduced the infarct area to alleviate myocardial ischemia. Furthermore, BXD lowered the serum levels of inflammatory cytokines [tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6)] and myocardial enzymes [creatine kinase(CK) and lactate dehydrogenase(LDH)], increased the p-AKT/AKT ratio, up-regulated the protein levels of PI3 K, NF-κB, IKK-α, and Bcl-xl, and down-regulated that of the apoptotic protein Bax. In conclusion, BXD may exert cardiac protection effect by regulating the PI3 K/AKT signaling pathway.

Curative effect of zinc-selenium tea on rat's cardiotoxicity induced by long-term exposure to nonylphenol.

This study aimed to explore whether zinc-selenium tea has an curative effect on the cardiotoxicity induced by nonylphenol (NP), and to compare the effect of zinc-selenium tea and green tea. After drinking of zinc-selenium tea or green tea, compared with the control group, the left ventricular anterior wall became thinner, and the left ventricular end-diastolic diameter increased, the anterior wall of the left ventricle became thin at the end of diastole in the NP group. The serum myocardial enzymes aspartate aminotransferase, creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase in the NP group were significantly increased, and the serum myocardial enzymes were significantly decreased after the intervention of zinc-selenium tea. Proteins and mRNA expressions of Collagen I and Collagen III in the tea groups were lower than those in the NP group. In the green tea and zinc-selenium tea intervention groups, the disorder and degree of myocardial fiber were alleviated to varying degrees. The disturbance, breakage, and inflammatory cell infiltration of myocardial fibers in zinc-selenium tea and green tea groups were less than that of NP group. After tea intervention, collagen I and collagen III in the myocardium decreased. The intervention effect of zinc-selenium tea was better than that of green tea. Zinc-selenium tea and green tea could interfere with the cardiotoxicity indued by NP, which would alleviate the myocardial fibrosis by reducing expressions of collagen I and collagen III. Moreover, the curative effect of zinc-selenium tea was better than that of green tea.

Acute myocardial infarction induces remodeling of the murine superior cervical ganglia and the carotid body.

A role for cardiac sympathetic hyperinnervation in arrhythmogenesis after myocardial infarction (MI) has increasingly been recognized. In humans and mice, the heart receives cervical as well as thoracic sympathetic contributions. In mice, superior cervical ganglia (SCG) have been shown to contribute significantly to myocardial sympathetic innervation of the left ventricular anterior wall. Of interest, the SCG is situated adjacent to the carotid body (CB), a small organ involved in oxygen and metabolic sensing. We investigated the remodeling of murine SCG and CB over time after MI. Murine SCG were isolated from control mice, as well as 24 h, 3 days, 7 days and 6 weeks after MI. SCG and CBs were stained for the autonomic nervous system markers β3-tubulin, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), as well as for the neurotrophic factors brain derived neurotropic factor (BDNF), nerve growth factor (NGF) and their tyrosine receptor kinase (pan TRK). Results show that after MI a significant increase in neuron size occurs, especially in the region bordering the CB. Co-expression of TH and ChAT is observed in SCG neuronal cells, but not in the CB. After MI, a significant decrease in ChAT intensity occurs, which negatively correlated with the increased cell size. In addition, an increase of BDNF and NGF at protein and mRNA levels was observed in both the CB and SCG. This upregulation of neurotropic factors coincides with the upregulation of their receptor within the SCG. These findings were concomitant with an increase in GAP43 expression in the SCG, which is known to contribute to axonal outgrowth and elongation. In conclusion, neuronal remodeling toward an increased adrenergic phenotype occurs in the SCG, which is possibly mediated by the CB and might contribute to pathological hyperinnervation after MI.

Necklace Pattern Left Ventricular Noncompaction Cardiomyopathy with Plethora of Paradoxic Septal Premature Ventricular Complexes: A Case Report and Literature Review

We report an extremely rare case of left ventricular noncompaction (LVNC) cardiomyopathy sparing the anterior ventricular wall in an interesting “necklace” pattern in parasternal short axis view in a 76-year-old female with frequent palpitation and shortness of breath for the last 6 months. Interestingly, the patient had a plethora of basal septal premature ventricular complexes (PVCs) both from the anterior and posterior aspects of the paradoxically thinned-out basal septum and they were not from the segment of noncompacted (NC) myocardium. Our case is unique and the first to describe the LVNC in an interesting shape of “necklace” sparing the left ventricular anterior, anteroseptal, and anterolateral wall and paradoxically arising plethora of septal PVCs from the thinned-out basal septum deteriorating the left ventricular function rapidly in an elderly female in her seventh decade of life. Although commonly in LVNC, the PVCs arise from the NC segment, in this unique case plethora of PVCs paradoxically arising from the basal septum were contributing toward rapid deterioration of left ventricular systolic function in an elderly patient in her seventh decade of life without the presence of conventional risk factors.

Effect of WenXin KeLi on Improvement of Arrhythmia after Myocardial Infarction by Intervening PI3K-AKT-mTOR Autophagy Pathway.

Background Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart. Methods The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot. Results After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1. Conclusion WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role.

Ventricular stabilization with a customized decellularized cardiac ECM-based scaffold after myocardial infarction alters gene expression in a rodent LAD-ligation model.

Objectives: Decellularized extracellular matrix (dECM) is increasingly used in a wide range of regenerative medicine applications and may also offer the potential to support injured myocardium. Here, we evaluated the myocardial gene expression pattern after myocardial infarction (MI) in a standardized rodent LAD-ligation model with and without ventricular stabilization with a customized, cardiac dECM-based scaffold (cdECM). Methods: MI was induced in male Wistar rats by standard LAD-ligation and confirmed 14 days post-intervention by echocardiographic parameters (FAS<40%). Cardiac ECM from donor rats was used to generate individual cdECM-scaffolds (tissue engineered myocardial sleeve, TEMS), which were epicardially implanted after confirmed MI for ventricular stabilization. After 4 and 8 weeks heart function was assessed by echocardiography, rats were sacrificed and explanted hearts were analyzed. In addition to histological analysis, standardized anterior left ventricular wall myocardial tissue samples were assessed by quantitative real-time PCR evaluating the specific gene expression pattern for immunomodulatory (IL-10, TGFBR2, TNFα), pro-angiogenic (VEGFA, FGF2, PGF, PDGFB), pro-survival (HGF, SDF1, IGF1, AKT1), remodeling-associated (TIMP1, MMP2, MMP9) and infarction-specific (NPPA, NPPB) markers. Results: Ventricular stabilization led to integration of the TEMS-scaffold into the myocardial scar with varying degrees of cellular infiltration, as well as significantly improved echocardiographic parameters demonstrating attenuation of maladaptive cardiac remodeling. Further, TEMS implantation after MI altered the myocardial gene expression pattern. Differences in gene expression were most striking after 4 weeks with significantly reduced expression of NPPA (0.36 ± 0.26 vs 0.75 ± 0.40; p < 0.05), NPPB (0.47 ± 0.25 vs 0.91 ± 0.429; p < 0.01), TGFBR2 (0.68 ± 0.16 vs 0.90 ± 0.14; p < 0.01) and PDGFB (0.81 ± 0.13 vs 1.06 ± 0.14; p < 0.01) as well as increased expression of IL-10 (5.93 ± 5.67 vs 1.38 ± 0.60; p < 0.05), PGF (1.48 ± 0.38 vs 1.09 ± 0.25; p < 0.05) and IGF1 (1.67 ± 0.70 vs 1.03 ± 0.42; p < 0.05). However, after 8 weeks differences in the gene expression patterns of remodeling-associated, and pro-angiogenic markers could still be observed between groups. Conclusion: Ventricular stabilization via TEMS implantation after MI did not only led to biological integration of the cdECM-scaffolds into the host tissue and improved functional cardiac parameters, but also altered 4 and 8 week gene expression of infarcted myocardium, possibly contributing to reducing chronic deteriorating effects while increasing the potential for myocardial regeneration.

Assessment of the influence on left ventricle by potassium oxonate and hypoxanthine-induced chronic hyperuricemia.

Cellular cytoplasmic xanthine oxidase (XO)-mediated uric acid synthesis and extracellular excess uric acid exposure are both causes of cardiomyocytic injury under the condition of hyperuricemia (HUA). Potassium oxonate suppresses uric acid degradation to increase extracellular concentration, while hypoxanthine is the catalytic substrate of XO. We aimed to observe cardiac damage in a chronic HUA mouse model induced by potassium oxonate and hypoxanthine. The mouse model was established by the co-administration of potassium oxonate and hypoxanthine for eight weeks. Then, left ventricular parameters were examined by echocardiographic evaluation, and the heart tissues were harvested for further histopathological analysis. The results showed that plasma uric acid was persistently elevated in the model mice, which demonstrated the stable establishment of chronic HUA. The left ventricular anterior wall was significantly thickened in the model group compared with the blank control group. After the end of modeling, the left ventricular anterior wall thickness of the hyperuricemic mice increased compared with that of blank group. The histological analysis showed and myocardial structure disorganization in the model group compared with the blank control. The above cardiac impairment changes could be attenuated by allopurinol pretreatment. This study systematically assessed cardiac damage in a chronic HUA mouse model. In addition, it provides useful information for future HUA-associated heart injury mechanism investigation and therapeutic treatment evaluation.

Piezo2 is not an indispensable mechanosensor in murine cardiomyocytes

A short-term increase in ventricular filling leads to an immediate (Frank-Starling mechanism) and a slower (Anrep effect) rise in cardiac contractility, while long-term increased cardiac load (e.g., in arterial hypertension) decreases contractility. Whether these answers to mechanical tension are mediated by specific sensors in cardiomyocytes remains elusive. In this study, the piezo2 protein was evaluated as a potential mechanosensor. Piezo2 was found to be upregulated in various rat and mouse cardiac tissues upon mechanical or pharmacological stress. To investigate its function, C57BL/6J mice with homozygous cardiomyocyte-specific piezo2 knockout [Piezo2-KO] were created. To this end, α-MHC-Cre mice were crossed with homozygous “floxed” piezo2 mice. α-MHC-Cre mice crossed with wildtype mice served as controls [WT-Cre+]. In cardiomyocytes of Piezo2-KO mice, piezo2 mRNA was reduced by > 90% and piezo2 protein was not detectable. Piezo2-KO mice displayed no morphological abnormalities or altered cardiac function under nonstressed conditions. In a subsequent step, hearts of Piezo2-KO or WT-Cre+-mice were stressed by either three weeks of increased afterload (angiotensin II, 2.5 mg/kg/day) or one week of hypercontractility (isoprenaline, 30 mg/kg/day). As expected, angiotensin II treatment in WT-Cre+-mice resulted in higher heart and lung weight (per body weight, + 38%, + 42%), lower ejection fraction and cardiac output (− 30%, − 39%) and higher left ventricular anterior and posterior wall thickness (+ 34%, + 37%), while isoprenaline led to higher heart weight (per body weight, + 25%) and higher heart rate and cardiac output (+ 24%, + 54%). The Piezo2-KO mice reacted similarly with the exception that the angiotensin II-induced increases in wall thickness were blunted and the isoprenaline-induced increase in cardiac output was slightly less pronounced. As cardiac function was neither severely affected under basal nor under stressed conditions in Piezo2-KO mice, we conclude that piezo2 is not an indispensable mechanosensor in cardiomyocytes.

Effect of p-Tyrosol on the Process of Left-Ventricular Remodeling in the Long Period after Myocardial Infarction.

The effect of p-tyrosol on the main hemodynamic parameters and contractile function of the heart was studied and a morphometric assessment of left-ventricular remodeling was performed in Wistar rats 2 months after acute 1-h myocardial ischemia followed by reperfusion. p-Tyrosol in a dose of 20 mg/kg was injected intraperitoneally 5 times: 20 min before the start of reperfusion, 4 h after the start of reperfusion, and then once a day over the next 3 days. Administration of p-tyrosol to animals in the acute period of myocardial infarction slowed down the formation of systolic and diastolic myocardial dysfunction, improved the pumping function of the heart, maintained the hemodynamic parameters at a significantly higher level, and reduced left-ventricular remodeling in the late period of myocardial infarction. In 2 months after acute myocardial ischemia modeling, the dimensions of the left-ventricular cavity, the area of the postinfarction focus, and the area of connective tissue in rats treated with p-tyrosol were significantly lower than in the control group. In the group treated with p-tyrosol, no anterior left-ventricular wall aneurysms were found.