Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Reduction of left ventricular diastolic pressure as a key regulator of infarct coronary flow under mechanical left ventricular support.

Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Acute mechanical left ventricular (LV) support has been suggested to improve infarct tissue perfusion. However, its regulatory mechanism remains unclear. We investigated the physiological mechanisms in six Yorkshire pigs, which were subjected to 90-min balloon occlusion of the left anterior descending artery. During the acute reperfusion phase, LV support using an Impella heart pump was initiated. LV pressure, coronary flow and pressure of the infarct artery were simultaneously recorded to evaluate the impact of LV support on coronary physiology. Coronary wave intensity was calculated to understand the forces regulating coronary flow. Significant increases in coronary flow velocity and its area under the curve were found after mechanical LV support. Among the coronary flow-regulating factors, coronary pressure was increased mainly during the late diastolic phase with less pulsatility. Meanwhile, LV pressure was reduced throughout diastole resulting in significant and consistent elevation of coronary driving pressure. Interestingly, the duration of diastole was prolonged with LV support. In the wave intensity analysis, the duration between backward suction and pushing waves was extended, indicating that earlier myocardial relaxation and delayed contraction contributed to the extension of diastole. In conclusion, mechanical LV support increases infarct coronary flow by extending diastole and augmenting coronary driving pressure. These changes were mainly driven by reduced LV diastolic pressure, indicating that the key regulator of coronary flow under mechanical LV support is downstream of the coronary artery, rather than upstream. Our study highlights the importance of LV diastolic pressure in infarct coronary flow regulation. KEY POINTS: Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Although mechanical left ventricular (LV) support has been suggested to improve infarct coronary flow, its specific mechanism remains to be clarified. LV support reduced LV pressure, and elevated coronary pressure during the late diastolic phase, resulting in high coronary driving pressure. This study demonstrated for the first time that mechanical LV support extends diastolic phase, leading to increased infarct coronary flow. Future studies should evaluate the correlation between improved infarct coronary flow and resulting infarct size.

Negative Impact of Acute Reloading after Mechanical Left Ventricular Unloading.

Mechanical LV unloading for acute myocardial infarction (MI) is a promising supportive therapy to reperfusion. However, no data is available on exit strategy. We evaluated hemodynamic and cellular effects of reloading after Impella-mediated LV unloading in Yorkshire pigs. First, we conducted an acute study in normal heart to observe effects of unloading and reloading independent of MI-induced ischemic effects. We then completed an MI study to investigate optimal exit strategy on one-week infarct size, no-reflow area, and LV function with different reloading speeds. Initial studies showed that acute reloading causes an immediate rise in end-diastolic wall stress followed by a significant increase in cardiomyocyte apoptosis. The MI study did not result in any statistically significant findings; however, numerically smaller average infarct size and no-reflow area in the gradual reloading group prompt further examination of reloading approach as an important clinically relevant consideration.

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Endobronchial Aerosolized AAV1.SERCA2a Gene Therapy in a Pulmonary Hypertension Pig Model: Addressing the Lung Delivery Bottleneck.

A disappointing number of new therapies for pulmonary hypertension (PH) have been successfully translated to the clinic. Adeno-associated viral (AAV) gene therapy has the potential to treat the underlying pathology of PH, but the challenge remains in efficient and safe delivery. The aims of this study were (1) to test the efficacy of endobronchial aerosolization delivery for AAV1-mediated sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) gene therapy in a PH pig model and (2) to identify the most efficient airway administration modality for in-lung gene therapy in PH. We hypothesized that delivery to the distal bronchi increases lung viral uptake and avoids virus loss in off-target compartments. In part 1 of the study, PH was induced in pigs by surgically banding the pulmonary veins. Two months postsurgery, 1 × 1013 viral genomes (vg) of AAV1.SERCA2a or saline was endobronchially aerosolized using a bronchoscope. Two months after aerosolization, high vg copies (vgc) were detected in the lungs, accompanied by functional and morphometrical amelioration of PH. In part 2 of the study, we directly compared the endobronchial aerosolization gene delivery to the intratracheal aerosolization in PH pigs. Endobronchial delivery demonstrated higher viral expression (6,719 ± 927 vs. 1,444 ± 402 vgc/100 ng DNA, p = 0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH.

Ventricular fibrillation during carotid endarterectomy and bailout stenting: a case report.

BACKGROUND: Carotid artery manipulation is not a special technique but reports of intraoperative ventricular fibrillation are rare. The risk of fatal arrhythmias may be hidden behind routine surgical techniques and anesthetic management. We focused on QT prolongation and QT dispersion. CASE PRESENTATION: A 77-year-old man underwent carotid endarterectomy and bailout stenting. Although there were no obvious preoperative risk factors for intraoperative ventricular tachyarrhythmia, ventricular fibrillation (VF) had occurred during a maneuver of the carotid artery under hypercapnia. QTc was prolonged from 317 ms before surgery to 458 ms before the onset of VF. QTc dispersion between leads II and III was also increased to 50 ms. Hypomagnesemia was noted after resuscitation by electrical defibrillation, adrenaline, and noradrenaline. CONCLUSIONS: We considered that the combination of multiple risk factors led to the development of ventricular fibrillation. It should be noted that carotid artery manipulation has the potential to cause arrhythmias.

Impact of ischemia on left atrial remodeling and dysfunction in swine models of mitral regurgitation.

Left atrial (LA) dysfunction is one of the predictive factors of worse outcomes after mitral valve surgery for mitral regurgitation (MR). We aimed to investigate the effect of MR etiology on progression of LA remodeling in swine MR models. MR was induced in 14 Yorkshire pigs using catheter-based procedures. Seven pigs underwent simultaneous occlusions of the left circumflex artery and the diagonal branch, which resulted in ischemic mitral regurgitation (IMR group). The other seven pigs underwent chordal severing to induce leaflet prolapse simulating degenerative mitral regurgitation (DMR group). Changes in LA volume and function were assessed at baseline, 1 mo, and 3 mo using echocardiography and hemodynamic evaluations. Histopathological assessments were conducted to evaluate LA hypertrophy and fibrosis. At 3 mo, quantitative MR severity was comparable and severe in both groups. Despite the similar degree of MR, minimum LA volume index increased significantly more in the IMR group (IMR: 11.9 ± 6.4 to 73.2 ± 6.4 mL/m2, DMR: 10.7 ± 6.4 to 29.5 ± 6.4 mL/m2, Pinteraction = 0.004). Meanwhile, increase in maximum LA volume index was similar between the groups, resulting in lower LA emptying function in the IMR group (IMR: 60.1 ± 3.1 to 29.4 ± 3.1%; DMR: 62.4 ± 3.1 to 58.2 ± 3.1%, Pinteraction = 0.0003). LA reservoir strain assessed by echocardiography was also significantly lower in the IMR group. Histological analyses revealed increased LA cellular hypertrophy and fibrosis in the IMR group. In conclusion, ischemic MR is associated with aggressive remodeling and reduced emptying function compared with the MR due to leaflet prolapse. Earlier intervention might be necessary for ischemic MR to prevent LA remodeling.NEW & NOTEWORTHY We show different LA structural and functional remodeling patterns between ischemic MR and MR due to leaflet prolapse. Severe ischemic MR was accompanied by extensive LA remodeling, which may be associated with poor clinical outcomes. Our data suggest that detailed structural and functional LA remodeling assessment is important for managing IMR and to determine the presence of LA ischemia.

The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure.

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α+/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α-/- hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG-PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.

TEE image quality improvement with our devised probe cover.

OBJECTIVE(S): Our hypothesis was that our devised transesophageal echocardiography probe cover with the capacity for pinpoint suction would improve image quality. DESIGN: Prospective cohort study. SETTING: Single tertiary medical center. PARTICIPANTS: Patients undergoing surgery requiring intraoperative transesophageal echocardiography. INTERVENTIONS: Suctioning with inserted orogastric tube. MEASUREMENTS AND MAIN RESULTS: Changes in image quality with suctioning were assessed by 2 methods. In method #1, investigators categorized the quality of all acquired images on a numeric scale based on each investigator's impression (1: very poor, 2: poor, 3: acceptable, 4: good, and 5: very good). In method #2, the reproducibility of the left ventricular fraction area change (LV FAC) was assessed, assuming that improved transgastric midpapillary short-axis view image quality would yield better LV FAC reproducibility. With method #1, for midesophageal views, 26.5%, 70.5%, and 3.0% of images showed improved, the same, and worsened image quality, respectively. For transgastric views, 55.3%, 43.3%, and 1.4% showed improved, the same, and worsened image quality, respectively. For deep transgastric views, 60.0%, 38.0%, and 2.0% showed improved, the same, and worsened image quality, respectively. With method #2, the presuction group had an ICC of 0.942 (95% CI: 0.91, 0.965). The postsuction group had an ICC of 0.988 (95% CI: 0.981, 0.993). CONCLUSIONS: Our investigation validates the potential image quality improvement withour devised TEE probe cover. However, its clinical validity needs to be confirmed by further studies.

Corrigendum: Novel Porcine Model of Coronary Dissection Reveals the Impact of Impella on Dissected Coronary Arterial Hemodynamics.

[This corrects the article DOI: 10.3389/fcvm.2020.00162.].

Effects of Therapeutic Hypothermia on Normal and Ischemic Heart.

Therapeutic hypothermia has been used for treating brain injury after out-of-hospital cardiac arrest. Its potential benefit on minimizing myocardial ischemic injury has been explored, but clinical evidence has yet to confirm positive results in preclinical studies. Importantly, therapeutic hypothermia for myocardial infarction is unique in that it can be initiated prior to reperfusion, in contrast to its application for brain injury in resuscitated cardiac arrest patients. Recent advance in cooling technology allows more rapid cooling of the heart than ever and new clinical trials are designed to examine the efficacy of rapid therapeutic hypothermia for myocardial infarction. In this review, we summarize current knowledge regarding the effect of hypothermia on normal and ischemic hearts and discuss issues to be solved in order to realize its clinical application for treating acute myocardial infarction.

Hepatic Vein Flow Index During Orthotopic Liver Transplantation as a Predictive Factor for Postoperative Early Allograft Dysfunction.

OBJECTIVES: The authors devised a hepatic vein flow index (HVFi), using intraoperative transesophageal echocardiography and graft weight, and investigated its predictive value for postoperative graft function in orthotopic liver transplant. DESIGN: Prospective clinical trial. SETTING,: Single-center tertiary academic hospital. PARTICIPANTS: Ninety-seven patients who had orthotopic liver transplant with the piggy-back technique between February 2018 and December 2019. MEASUREMENTS AND MAIN RESULTS: HVFi was defined with HV flow/graft weight. Patients who developed early graft dysfunction (EAD) had low HVFi in systole (HVFi sys, 1.23 v 2.19 L/min/kg, p < 0.01), low HVFi in diastole (HVFi dia, 0.87 v 1.54 L/min/kg, p < 0.01), low hepatic vein flow (HVF) in systole (HVF sys, 2.04 v 3.95 L/min, p < 0.01), and low HVF in diastole (HVF dia, 1.44 v 2.63 L/min, p < 0.01). More cardiac death, more vasopressors at the time of measurement, more acute rejection, longer time to normalize total bilirubin (TIME t-bil), longer surgery time, longer neohepatic time, and more packed red blood cell transfusion were observed in the EAD patients. All HVF parameters were negatively correlated with TIME t-bil (HVFi sys R = -0.406, p < 0.01; HFVi dia R = -0.442, p < 0.01; HVF sys R = -0.44, p < 0.01; HVF dia R = -0.467, p < 0.01). The receiver operating characteristic curve analysis determined the best cut-off levels of HVFi to predict occurrence of EAD (HVFi sys <1.608, HVFi dia <0.784 L/min/kg), acute rejection (HVFi sys <1.388, HVFi dia <1.077 L/min/kg), and prolonged high total bilirubin (HVFi sys <1.471, HVFi dia <1.087 L/min/kg). CONCLUSIONS: The authors' devised HVFi has the potential to predict the postoperative graft function.

Targeted delivery of therapeutic agents to the heart.

For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical force of the blood flow, the endothelial barrier, the cellular barrier and the immune response. Various vectors and delivery methods have been proposed to improve the cardiac-specific uptake of materials to modify gene expression. Viral and non-viral vectors are widely used to deliver genetic materials, but each has its respective advantages and shortcomings. Adeno-associated viruses have emerged as one of the best tools for heart-targeted gene delivery. In addition, extracellular vesicles, including exosomes, which are secreted by most cell types, have gained popularity for drug delivery to several organs, including the heart. Accumulating evidence suggests that extracellular vesicles can carry and transfer functional proteins and genetic materials into target cells and might be an attractive option for heart-targeted delivery. Extracellular vesicles or artificial carriers of non-viral and viral vectors can be bioengineered with immune-evasive and cardiotropic properties. In this Review, we discuss the latest strategies for targeting and delivering therapeutic materials to the heart and how the knowledge of different vectors and delivery methods could successfully translate cardiac gene therapy into the clinical setting.

Left Ventricular Assist Devices for Acute Myocardial Infarct Size Reduction: Meta-analysis.

We conducted a meta-analysis of preclinical studies that tested left ventricular assist device (LVAD) therapy for reducing myocardial infarct size in experimental acute myocardial infarction (AMI). Twenty-six articles were included with a total of 488 experimental animal subjects. The meta-analysis showed that infarct size was significantly decreased by LVAD support compared to control animals (SDM, - 2.19; 95% CI, - 2.70 to - 1.69; P < 0.001). The meta-regression analysis demonstrated a high degree of heterogeneity associated with time from coronary artery occlusion to LVAD support, which correlated positively with infarct size. Subgroup analysis suggested smaller infarct size in LVAD therapies that withdrew blood from left heart than those from right heart. The proportion of left ventricular support relative to total cardiac output was positively correlated with infarct size reduction in Impella studies. Thus, early initiation of LVAD after ischemia and effective left ventricular venting may be important factors to reduce infarct size in AMI.

Rapid spread of COVID-19 in New York and the response of the community.

The first COVID-19 patient in New York (NY) was reported on March 1, 2020. Since then NY has become one of the largest epicenters in the world where the disease has been overwhelming the healthcare system. Here I report how rapidly COVID-19 spread, and how the community responded during the first 30 days in NY. Gathering reliable information quickly was important in the evolving situation. Shortage of beds, personal protective equipment, ventilators, and staffing was observed. Reducing the number of infections and increasing the efficiency of medical resource allocation have been two major strategies taken in NY. It is important for Japan to accurately analyze the current situation, refer to answers in other parts of the world, and quickly establish strategy for clear goals that will lead to a "New Normal".

Novel Porcine Model of Coronary Dissection Reveals the Impact of Impella on Dissected Coronary Arterial Hemodynamics.

Background: Coronary artery dissection (CAD) sometimes accompanies unstable hemodynamics and requires mechanical cardiac support. Meanwhile, mechanical cardiac support may influence coronary hemodynamics in CAD. No study has examined the impact of Impella left ventricular (LV) support on CAD. Materials and Methods: CAD was induced in eight Yorkshire pigs by injuring the left anterior descending artery (LAD) using a 0.018-in. stiff guidewire and/or deep engagement of a blunt-cut coronary guiding catheter. After the creation of CAD, hemodynamic parameters, coronary pressure, and flow as well as coronary angiograms were acquired before and after maximum LV support using the Impella CP. Result: CADs with a large flap were successfully created by deep engagement of a blunt-tip guiding catheter with forceful contrast injection. One animal (#8) exhibited thrombolysis in myocardial infarction (TIMI)-1 flow, while the others (animals #1-#7) showed TIMI-2/3 flow. In TIMI-2/3 animals, maximal Impella support increased mean coronary pressure (108.4 ± 22.5 to 124.7 ± 28.0 mmHg, P < 0.001) with unchanged mean coronary flow velocity (63.50 ± 28.66 to 48.32 ± 13.30 cm/s, P = 0.17) of the LAD distal to the dissection. The LV end-diastolic pressure (20.6 ± 6.6 vs. 12.0 ± 3.4 mmHg, P = 0.032), LV end-diastolic volume (127 ± 32 vs. 97 ± 26 ml, P = 0.015), stroke volume (68 ± 16 vs. 48 ± 14 ml, P = 0.003), stroke work (5,744 ± 1,866 vs. 4,424 ± 1,650 mmHg·ml, P = 0.003), and heart rate (71.4 ± 6.6 vs. 64.9 ± 9.3/min, P = 0.014) were all significantly reduced by Impella support, indicating effective unloading of the LV. In the TIMI-1 animal (animal #8), maximal Impella support resulted in further delay in angiographic coronary flow and reduced distal coronary pressure (22.9-17.1 mmHg), together with increased false-lumen pressure. Conclusion: Impella support effectively unloaded the LV and maintained the hemodynamics in a novel porcine model of CAD. Coronary pressure distal to the dissection was increased in TIMI-2/3 animals after Impella support but decreased in the animal with initial TIMI-1 flow.

Impaired left ventricular global longitudinal strain is associated with elevated left ventricular filling pressure after myocardial infarction.

Left ventricular (LV) global longitudinal strain (GLS) has emerged as a significant prognostic marker in patients after myocardial infarction (MI). Although elevated LV filling pressure after MI might alter GLS, direct evidence for this is lacking. This study aimed to clarify the association between GLS and LV filling pressure in a large animal MI model. A total of 104 Yorkshire pigs underwent both echocardiographic and hemodynamic assessments 1-4 wk after induction of large anterior MI. GLS was measured in the apical four-chamber view using a semiautomated speckle-tracking software. LV pressure-volume relationship was invasively measured using a high-fidelity pressure-volume catheter. GLS >-14% was considered impaired. Compared with pigs with LV ejection fraction (LVEF) >40% and preserved GLS (n = 29), those with LVEF >40% and impaired GLS (n = 37) and those with LVEF ≤40% (n = 38) had significantly higher LV end-diastolic pressure (15.5 ± 5.5 vs. 19.7 ± 5.8 and 19.6 ± 6.6 mmHg; P = 0.008 and P = 0.026, respectively) and higher LV mean diastolic pressure (7.1 ± 2.9 vs. 10.4 ± 4.5 and 11.1 ± 5.4 mmHg; P = 0.013 and P = 0.002, respectively). GLS was modestly correlated with τ (r = 0.21, P = 0.039) and slope of LV end-diastolic pressure-volume relationship (r = 0.43, P < 0.001). Impaired GLS was associated with higher LV end-diastolic and mean-diastolic pressures after adjusting for LVEF and baseline characteristics (P = 0.026 and P = 0.001, respectively). Impaired GLS assessed by speckle-tracking echocardiography was associated with elevated LV filling pressure after MI. GLS has an incremental diagnostic value for detecting elevated LV filling pressure and may be particularly useful for evaluating post-MI patients with preserved LVEF.NEW & NOTEWORTHY Strain analysis was performed in 104 pigs after MI, and its relationship to invasive hemodynamic measurements was studied. Impaired longitudinal strain was associated with high ventricular filling pressure independent of LVEF in post-MI setting. Global longitudinal strain is a potential prognostic marker after MI.

Bronchovenous Fistula During Adult Cardiac Surgery: A Case Report.

Bronchovenous fistula (BVF) associated with adult cardiac surgery is a rarely reported life-threatening condition. We present a 75-year-old woman who developed a BVF during cardiac surgery. Dense adhesion in the pleural and pericardial cavities was noted. Restrictive pulmonary pathology required high airway pressure. Transesophageal echocardiography and hemoglobin measurement were helpful for the timely diagnosis of BVF, which was controlled by transection of the right upper pulmonary vein where a vent catheter had been inserted. Injuries around the cannulated site presumably initiated the BVF, which was worsened by high-pressure ventilation. Therefore, cannulation site might be a risk factor for BVF.