Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease.

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifier Sap130 , and adhesion protein Pcdha9, revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating memory and synaptic plasticity, and impaired neurovascular coupling modulating cerebral blood flow. Many neurodevelopmental/neurobehavioral disease pathways were recovered, including autism and cognitive impairment. These same pathways emerged from genome-wide DNA methylation and Sap130 chromatin immunoprecipitation sequencing analyses, suggesting epigenetic perturbation. Mice with Pcdha9 mutation or forebrain-specific Sap130 deletion without CHD showed learning/memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation and suggest new avenues for therapy.

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. One Sentence Summary: Mitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.

Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction.

Introduction: The prevalence of ischemic heart disease has reached pandemic levels worldwide. Early revascularization is currently the most effective therapy for ischemic heart diseases but paradoxically induces myocardial ischemia/reperfusion (MI/R) injury. Cardiac inflammatory reaction and oxidative stress are primarily involved in the pathology of MI/R injury. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to reduce cell injury by protecting against inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury. Methods: This study was designed to clarify whether LIPUS alleviates MI/R injury by alleviating inflammatory reaction and oxidative stress. Simultaneously, we have also tried to confirm which intensity of the LIPUS might be more suitable to ameliorate the MI/R injury, as well as to clarify the signaling mechanisms. MI/R and simulated ischemia/reperfusion (SI/R) were respectively induced in Sprague Dawley rats and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). LIPUS treatment, biochemical measurements, cell death assay, estimation of cardiac oxidative stress and inflammatory reaction, and protein detections by western blotting were performed according to the protocol. Results: In our study, both in vivo and in vitro, LIPUS of 0.1 W/cm2 (LIPUS0.1) and 0.5 W/cm2 (LIPUS0.5) make no significant difference in the cardiomyocytes under normoxic condition. Under the hypoxic condition, MI/R injury, inflammatory reaction, and oxidative stress were partially ameliorated by LIPUS0.5 but were significantly aggravated by LIPUS of 2.5 W/cm2 (LIPUS2.5) both in vivo and in vitro. The activation of the apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway in cardiomyocytes with MI/R injury was partly rectified LIPUS0.5 both in vivo and in vitro. Conclusion: Our study firstly demonstrated that LIPUS of different intensities differently affects MI/R injury by regulating cardiac inflammatory reaction and oxidative stress. Modulations on the ASK1/JNK pathway are the signaling mechanism by which LIPUS0.5 exerts cardioprotective effects. LIPUS0.5 is promising for clinical translation in protecting against MI/R injury. This will be great welfare for patients suffering from MI/R injury.

Ultrasound-controlled nano oxygen carriers enhancing cell viability in 3D GelMA hydrogel for the treatment of myocardial infarction.

Heart failure is a critical and ultimate phase of cardiovascular ailment that leads to a considerable incidence of disability and mortality. Among various factors contributing to heart failure, myocardial infarction is one of the most frequent and significant causes, which is still difficult to manage effectively. An innovative therapeutic strategy, namely a 3D bio-printed cardiac patch, has recently emerged as a promising approach to substitute damaged cardiomyocytes in a localized infarct region. Nevertheless, the efficacy of this treatment primarily relies on the long-term viability of the transplanted cells. In this study, we aimed to construct acoustically sensitive nano oxygen carriers to improve cell survival inside the bio-3D printed patch. In this study, we initially created nanodroplets capable of phase transition triggered by ultrasound and integrated them into GelMA (Gelatin Methacryloyl) hydrogels, which were then employed for 3D bioprinting. After adding nanodroplets and ultrasonic irradiation, numerous pores appeared inside the hydrogel with improved permeability. We further encapsulated hemoglobin into nanodroplets (ND-Hb) to construct oxygen carriers. Results of in vitro experiments showed the highest cell survival within the patch of ND-Hb irradiated by the low-intensity pulsed ultrasound (LIPUS) group. The genomic analysis discovered that the increased survival of seeded cells within the patch might be related to the protection of mitochondrial function owing to the improved hypoxic state. Eventually, in vivo studies revealed that the LIPUS+ND-Hb group had improved cardiac function and increased revascularization after myocardial infarction. To summarize, our study successfully improved the permeability of the hydrogel in a non-invasive and efficient manner, facilitating the exchange of substances in the cardiac patch. Moreover, ultrasound-controlled oxygen release augmented the viability of the transplanted cells and expedited the repair of infarcted tissues.

Low-intensity pulsed ultrasound promotes cell viability and inhibits apoptosis of H9C2 cardiomyocytes in 3D bioprinting scaffolds via PI3K-Akt and ERK1/2 pathways.

The aim of this study was to investigate whether low-intensity pulsed ultrasound (LIPUS) promotes myocardial cell viability in three-dimensional (3D) cell-laden gelatin methacryloyl (GelMA) scaffolds. Cardiomyoblasts (H9C2s) were mixed in 6% (w/v) GelMA bio-inks and printed using an extrusion-based 3D bioprinter. These scaffolds were exposed to LIPUS with different parameters or sham-irradiated to optimize the LIPUS treatment. The viability of H9C2s was measured using Cell Counting Kit-8 (CCK8), cell cycle, and live and dead cell double-staining assays. Western blot analysis was performed to determine the protein expression levels. We successfully fabricated 3D bio-printed cell-laden GelMA scaffolds. CCK8 and live and dead cell double-staining assays indicated that the optimal conditions for LIPUS were a frequency of 0.5 MHz and an exposure time of 10 min. Cell cycle analysis showed that LIPUS promoted the entry of cells into the S and G2/M phases from the G0/G1 phase. Western blot analysis revealed that LIPUS promoted the phosphorylation and activation of ERK1/2 and PI3K-Akt. The ERK1/2 inhibitor (U0126) and PI3K inhibitor (LY294002) significantly reduced LIPUS-induced phosphorylation of ERK1/2 and PI3K-Akt, respectively, which in turn reduced the LIPUS-induced viability of H9C2s in 3D bio-printed cell-laden GelMA scaffolds. A frequency of 0.5 MHz and exposure time of 10 min for LIPUS exposure can be adapted to achieve optimized culture effects on myocardial cells in 3D bio-printed cell-laden GelMA scaffolds via the ERK1/2 and PI3K-Akt signaling pathways.

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Histone Methylation and Oxidative Stress in Cardiovascular Diseases.

Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.

Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease.

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease.

Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39-50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD. Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue. Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR. Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.

Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomal MicroRNA-18b-3p Inhibits the Occurrence of Preeclampsia by Targeting LEP.

Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) expressing microRNAs have been highlighted in human diseases. However, the detailed molecular mechanism of hucMSCs-derived exosomal miR-18b-3p on preeclampsia (PE) remains further investigation. We aimed to investigate the effect of exosomes and miR-18b-3p/leptin (LEP) on occurrence of PE. The morphology of the hucMSC and hucMSC-exosomes (Exos) was identified. The exosomes were infected with different lentivirus expressing miR-18b-3p to explore the role of miR-18b-3p in PE. The PE rat model was established by intraperitoneal injection of N-nitro-L-arginine methyl ester. The expression of LEP and miR-18b-3p was tested in PE rat placenta tissues. Also, the effect of exosomes on LEP and miR-18b-3p expression was detected. The systolic blood pressure (SBP), proteinuria, inflammatory factors, the weight of fetal rat and placenta and cell apoptosis in PE rats were detected. Finally, the relationship between miR-18b-3p and LEP was verified using dual-luciferase reporter gene assay and RNA pull-down assay. Exosomes, restoring miR-18b-3p or inhibiting LEP reduced SBP and proteinuria of PE rats as well as increased the weight of fetal rat and placenta, decreased serum levels of inflammatory factors as well as suppressed apoptotic cells of PE rats, exerting a suppressive effect on PE progression. miR-18b-3p was decreased and LEP was increased in placenta tissues of PE rats. LEP was the direct target gene of miR-18b-3p. Upregulation of miR-18b-3p or treatment of the exosomes suppressed LEP expression and reduced PE occurrence, while downregulation of miR-18b-3p had contrary effects. Downregulated LEP reversed the effect of miR-18b-3p reduction on PE rats. HucMSCs-derived exosomal miR-18b-3p targets LEP to participate in the occurrence and development of PE. This study may provide a novel theoretical basis for the mechanism and investigation of PE.

Transthoracic ultrasound-guided percutaneous intramyocardial injection combined with ultrasound-targeted microbubble destruction-mediated angiogenin 1 gene therapy in canine myocardial infarction model.

BACKGROUND: Intravenous (IV) ultrasound-targeted microbubble destruction (UTMD) has made distinct but limited progress in gene transfected therapy. Intramyocardial (IM) injection also has some effect. In this study, IM injection could be performed under the guidance of transthoracic ultrasound without thoracotomy. We aimed to evaluate the effect of combination transthoracic ultrasound-guided percutaneous IM injection and UTMD for mediating the angiogenin 1 (Ang1) gene therapy in myocardial infarction (MI) canines. METHODS: Forty-two canines were divided into four groups: IM-UTMD group (intramyocardial injection of the negative control plasmid with UTMD as the sham group); IM-Ang1 group (intramyocardial injection of the Ang1 plasmid without UTMD); IM-Ang1-UTMD group (intramyocardial injection of the Ang1 plasmid with UTMD); and IV-Ang1-UTMD group (intravenous injection of the Ang1 plasmid with UTMD). The FITC green fluorescence and Ang1 protein in myocardial tissue were used for the distribution of Ang1 gene. Left ventricular dimension and systolic function were observed by echocardiography. The Masson's and Sirius Red's staining were used for evaluating the collagen fiber. The immunohistochemistry for CD31 and alpha-smooth muscle actin (α-SMA) were as the indicators of microvasculature. Myocardial contrast echocardiography was used to reflect the microvascular perfusion. RESULTS: More FITC-labeled plasmid was observed in the three IM injection groups than in the IV-Ang1-UTMD group, and the Ang1 protein expression was higher in the IM-Ang1-UTMD group. One month later, no significant differences in survival rate and complications were observed among all four groups. Although there were no differences in the left ventricular end-diastolic diameter among the 4 groups, the left ventricular end-systolic diameter was lower in the IM-Ang1-UTMD group than in the other groups. Then, the left ventricular ejection fraction was increased in the IM-Ang1-UTMD group, with lower collagen fiber percentage, higher blood vessel density and myocardial reperfusion intensity than those in the other groups (P<0.05). CONCLUSIONS: Transthoracic ultrasound-guided percutaneous IM injection combined with UTMD is a safe and effective method for mediating Ang1 plasmid therapy in MI canines.

Layer-Specific Strain for Long-Term Outcome Prediction After First-Onset Myocardial Infarction.

Many studies have reported the prognostic value of global strain obtained with speckle tracking echocardiography (STE) in patients with acute myocardial infarction (AMI). However, as a novel method derived from STE, layer-specific strain has seldom been evaluated with respect to prediction of AMI outcomes. We sought to investigate the predictive value of layer-specific strain and whether it has incremental value compared with conventional parameters, such as left ventricular ejection fraction and wall motion score index, and STE parameters. Our study was prospective. Ninety-two patients with first-onset AMI were enrolled and underwent echocardiography before coronary intervention for analysis of global and layer-specific strain. Cox proportional hazard ratio (HR) and receiver operating characteristic curve analyses were performed for the prediction of cardiac events and cardiac death. Fifty-three patients have had cardiac events during follow-up. Endocardial longitudinal strain has received relatively higher HRs for risk predictions of both cardiac events (HR = 1.69) and cardiac death (HR = 3.21) adjusted with clinical data. The areas under the receiver operating characteristic curves of the longitudinal strain at the endocardial layer from layer-specific strain were higher than those of global strain and conventional parameters for cardiac event prediction (p ˂ 0.05, all). Layer-specific strain is valuable for cardiac risk prediction after infarction and has incremental values in addition to conventional and global STE parameters. Myocardial damage at the endocardial layer was closely related to outcomes of AMI patients at long-term follow-ups.

Rare combined variations of accessory left hepatic artery and accessory right hepatic artery: a case report and literature review.

Variations in the hepatic artery are commonly described in the literature, which is vital for the success procedure of all hepatobiliary surgery. Usually a variation occurs in either the accessory right hepatic artery (aRHA) or the accessory left hepatic artery (aLHA). However, we report an extremely rare case where the variation occurs in both simultaneously. We over served the aRHA arising from the gastroduodenal artery and branching into the superior pancreatic duodenum artery, while the aLHA arose from the common hepatic artery and branched into right gastric artery. This situation has never been reported in literature. We will discuss the meaning of this hepatic artery variation in a clinical setting.

Carotid baroreceptor stimulation improves cardiac performance and reverses ventricular remodelling in canines with pacing-induced heart failure.

AIMS: Carotid baroreceptor stimulation (CBS) has potential protective effects on chronic heart failure (CHF). The aim of our study was to investigate the effects of CBS on more detailed aspects of ventricular remodelling and the underlying mechanisms in a CHF canine model. MAIN METHODS: Twenty-four beagles were randomised into Con (n = 8), CHF (n = 8), and CHF-CBS (n = 8) groups. The CHF and CHF-CBS groups underwent 6 weeks of rapid ventricular pacing (RVP) at 250 beats per minute to establish a CHF model. Concomitant CBS was delivered together with RVP in the CHF-CBS group. KEY FINDINGS: RVP for 6 weeks caused typical heart failure in the CHF group. CBS significantly reversed the decrease in the high-frequency heart rate variability component and increase in low-frequency/high-frequency ratio induced by RVP. CBS significantly reduced cardiac dilation, improved left ventricle ejection fraction, and inhibited the increase in natriuretic peptide mRNA expression of LV tissue. CBS alleviated collagen volume fraction and reduced protein expression of transforming growth factor ß1, matrix metallopeptidase 2, and matrix metallopeptidase 9, as well as decreased the percentage of TUNEL-positive nuclei and protein expression of Caspase-3 in LV tissue. The intracellular PKA signalling pathway and cardiac inflammation of LV tissue were upregulated in the CHF group, and markedly inhibited by CBS. SIGNIFICANCE: Our study found that CBS improved cardiac performance and reversed ventricular remodelling in CHF canines by rebalancing the autonomic nervous system; the suppression of the intracellular PKA signalling pathway and cardiac inflammation might underly the mechanisms.

Imbalance of cardiac autonomic nervous activity and increase of ventricular repolarization dynamicity induced by thyroid hormones in hyperthyroidism.

OBJECTIVE: To investigate the effects of thyroid hormones on cardiac autonomic nervous activity and ventricular repolarization dynamicity in hyperthyroidism. METHODS: 57 consecutive patients first diagnosed of hyperthyroidism (HT group) and 55 age and sex-matched healthy volunteers (Control group) from March 2012 to March 2013 in our center were enrolled. All subjects underwent standard 12­lead ECG and 24 h Holter recording at baseline. For the HT group, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were monitored, and after they returned to normal all the examinations were redone. Heart rate variability (HRV) was assessed to determine the cardiac autonomic nervous activity. QTe/RR slope (QT end) and QTp/RR slope (QT apex) were calculated to evaluate the ventricular repolarization dynamicity. RESULTS: The HT patients before treatment had significantly higher LF/HF, QTe/RR slope and QTp/RR slope, and larger QT dispersion than the controls and after treatment (P < 0.05 for all). Correlation analyses revealed that FT3 was positively correlated with QTe/RR and QTp/RR slopes (r = 0.689 and 0.665 respectively, P < 0.001 for both), and similarly in FT4 (r = 0.665 and 0.668 respectively, P < 0.001 for both). While TSH was negatively correlated with QTe/RR and QTp/RR slopes (r = -0.660 and -0.680 respectively, P < 0.001 for both). FT3 and FT4 levels were independent predictors of QTe/RR slopes (P < 0.001, ß = 0.007; P = 0.017, ß = 0.001, respectively) and QTp/RR slopes (P < 0.001, ß = 0.008; P = 0.002, ß = 0.001, respectively). CONCLUSIONS: High-level thyroid hormones induce the cardiac sympathetic overactivity and increases ventricular repolarization dynamicity, and the impact can be attenuated after euthyroidism restored.

Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction.

OBJECTIVE: This study aimed to develop a gene delivery system using ultrasound-targeted microbubbles destruction (UTMD) combined with nuclear localization signal (NLS) and investigate its efficacy and safety for therapeutic angiogenesis in canine myocardial infarction (MI) model. METHODS: Fifty MI dogs were randomly divided into 5 groups and transfected with Ang-1 gene plasmid: (i) group A: only injection of microbubbles and Ang-1 plasmid; (ii) group B: only UTMD mediated gene transfection; (iii) group C: UTMD combined with classical NLS mediated gene transfection; (iv) group D: UTMD combined with mutational NLS mediated transfection; and (v) group E: UTMD combined with classical NLS in the presence of a nucleus transport blocker. The mRNA and protein expression of Ang-1 gene, microvessel density (MVD) cardiac troponin I (cTnI), and cardiac function were determined after transfection. RESULTS: The expression of mRNA and protein of Ang-1 gene in group C was significantly higher than that of the other groups (all P < 0.01). The MVD of group C was 10.2-fold of group A and 8.1-fold of group E (P < 0.01). The cardiac function in group C was significant improvement without cTnI rising. CONCLUSIONS: The gene delivery system composed of UTMD and NLS is efficient and safe.

Evaluating the morphology of the left atrial appendage by a transesophageal echocardiographic 3-dimensional printed model.

The novel 3-dimensional printing (3DP) technique has shown its ability to assist personalized cardiac intervention therapy. This study aimed to determine the feasibility of 3D-printed left atrial appendage (LAA) models based on 3D transesophageal echocardiography (3D TEE) data and their application value in treating LAA occlusions.Eighteen patients with transcatheter LAA occlusion, and preprocedure 3D TEE and cardiac computed tomography were enrolled. 3D TEE volumetric data of the LAA were acquired and postprocessed for 3DP. Two types of 3D models of the LAA (ie, hard chamber model and flexible wall model) were printed by a 3D printer. The morphological classification and lobe identification of the LAA were assessed by the 3D chamber model, and LAA dimensions were measured via the 3D wall model. Additionally, a simulation operative rehearsal was performed on the 3D models in cases of challenging LAA morphology for the purpose of understanding the interactions between the device and the model.Three-dimensional TEE volumetric data of the LAA were successfully reprocessed and printed as 3D LAA chamber models and 3D LAA wall models in all patients. The consistency of the morphological classifications of the LAA based on 3D models and cardiac computed tomography was 0.92 (P < .01). The differences between the LAA ostium dimensions and depth measured using the 3D models were not significant from those measured on 3D TEE (P > .05). A simulation occlusion was successfully performed on the 3D model of the 2 challenging cases and compared with the real procedure.The echocardiographic 3DP technique is feasible and accurate in reflecting the spatial morphology of the LAA, which may be promising for the personalized planning of transcatheter LAA occlusion.

Low-Level Tragus Stimulation for the Treatment of Ischemia and Reperfusion Injury in Patients With ST-Segment Elevation Myocardial Infarction: A Proof-of-Concept Study.

OBJECTIVES: The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The authors' previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia. METHODS: Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation [n = 48]). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro-B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated. RESULTS: The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro-B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS. CONCLUSIONS: LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.