Pioglitazone treatment mitigates cardiovascular bioprosthetic degeneration in a chronic kidney disease model.

Aims: Chronic kidney disease (CKD) is a risk factor for the development of cardiovascular diseases, e.g., atherosclerosis and calcific aortic valve disease, leading inevitably to valve replacement surgery. CKD patients with bioprosthetic cardiovascular grafts, in turn, have a higher risk of premature graft degeneration. Peroxisome proliferator-activated receptor gamma (PPARγ) activation by pioglitazone has cardio-renal protective properties, and research using a heterotopic valve implantation model has shown anti-degenerative effects of PPARγ activation on bioprosthetic valved grafts (BVG) in rats. The present work aims to analyze a potential protective effect of pioglitazone treatment on BVG in an adenine-induced rat model of CKD. Methods and Results: BVG of Sprague Dawley rats were heterotopically implanted in Wistar rats in an infrarenal position for 4 and 8 weeks. Animals were distributed into three groups for each time point: 1) control group receiving standard chow, 2) CKD group receiving 0.25% adenine and 3) CKD + pioglitazone group (300 mg per kg of 0.25% adenine chow). BVG function was analyzed by echocardiography. Plasma analytes were determined and explanted grafts were analyzed by semi-quantitative real-time PCR, Western blot analysis, histology and immunohistology.PPARγ activation significantly reduced CKD-induced calcification of aortic and valvular segments of BVG by 44% and 53%, respectively. Pioglitazone treatment significantly also reduced CKD-induced intima hyperplasia by 60%. Plasma analysis revealed significantly attenuated potassium and phosphate levels after pioglitazone treatment. Moreover, PPARγ activation led to significantly decreased interleukin-6 gene expression (by 57%) in BVG compared to CKD animals. Pioglitazone treatment leads to functional improvement of BVG. Conclusion: This study broadens the understanding of the potential value of PPARγ activation in cardio-renal diseases and delineates pioglitazone treatment as a valuable option to prevent bioprosthetic graft failure in CKD. Further mechanistic studies, e.g., using small molecules activating PPARγ signaling pathways, are necessary for the evaluation of involved mechanisms. Additionally, the translation into pre-clinical studies using large animals is intended as the next research project.

New rat model of spinal cord infarction with long-lasting functional disabilities generated by intraspinal injection of endothelin-1.

BACKGROUND: The current method for generating an animal model of spinal cord (SC) infarction is highly invasive and permits only short-term observation, typically limited to 28 days. OBJECTIVE: We aimed to establish a rat model characterised by long-term survival and enduring SC dysfunction by inducing selective ischaemic SC damage. METHODS: In 8-week-old male Wistar rats, a convection-enhanced delivery technique was applied to selectively deliver endothelin-1 (ET-1) to the anterior horn of the SC at the Th13 level, leading to SC infarction. The Basso, Beattie and Bresnahan (BBB) locomotor score was assessed for 56 days. The SC was examined by a laser tissue blood flowmeter, MRI, immunohistochemistry, triphenyl tetrazolium chloride (TTC) staining, Western blots and TUNEL staining. RESULTS: The puncture method was used to bilaterally inject 0.7 µL ET-1 (2.5 mg/mL) from the lateral SC into the anterior horns (40° angle, 1.5 mm depth) near the posterior root origin. Animals survived until day 56 and the BBB score was stably maintained (5.5±1.0 at day 14 and 6.2±1.0 at day 56). Rats with BBB scores ≤1 on day 1 showed stable scores of 5-6 after day 14 until day 56 while rats with BBB scores >1 on day 1 exhibited only minor dysfunction with BBB scores >12 after day 14. TTC staining, immunostaining and TUNEL staining revealed selective ischaemia and neuronal cell death in the anterior horn. T2-weighted MR images showed increasing signal intensity at the SC infarction site over time. Western blots revealed apoptosis and subsequent inflammation in SC tissue after ET-1 administration. CONCLUSIONS: Selective delivery of ET-1 into the SC allows for more precise localisation of the infarcted area at the targeted site and generates a rat SC infarction model with stable neurological dysfunction lasting 56 days.

Development of modified laser Doppler flowmetry device for real-time monitoring of esophageal mucosal blood flow: a preclinical assessment with an animal model.

This study aimed to modify a laser Doppler flowmeter designed and assembled at our institute. After measuring sensitivity evaluation in ex vivo experiments, we confirmed the efficacy of this new device for monitoring real-time esophageal mucosal blood flow changes after thoracic stent graft implantation by simulating various clinical situations in an animal model. Thoracic stent graft implantation was performed in a swine model (n = 8). Esophageal mucosal blood flow decreased significantly from baseline (34.1 ± 18.8 ml/min/100 g vs. 16.7 ± 6.6 ml/min/100 g, P < 0.05) in the lower esophagus (Th6-Th8) where the stent graft covered the aorta. In the hemorrhagic shock model (shock index ≥ 1.0), esophageal mucosal blood flow showed a remarkable change from baseline in the upper esophagus (Th1-Th3), where the stent graft did not cover the aorta (20.8 ± 9.8 ml/min/100 g vs. 12.9 ± 8.6 ml/min/100 g, P < 0.01); however, it returned to the baseline value within a 30-min period. Mucosal blood flow remained stable in the esophagus, where the stent graft did not cover the aorta. After elevating the mean blood pressure to > 70 mmHg with continuous intravenous noradrenaline infusion, esophageal mucosal blood flow increased significantly in both regions; however, the reaction was different between the two regions. Our newly developed laser Doppler flowmeter could measure real-time esophageal mucosal blood flow changes in various clinical situations during thoracic stent graft implantation in a swine model. Hence, this device can be applied in many medical fields by downsizing it.

Percutaneous Cannulation of Femoral Vessels in Minimally Invasive Cardiac Surgery.

OBJECTIVE: Despite the recent trend of access miniaturization in minimally invasive cardiac surgery (MICS) surgical "cut down (CD)" for femoral cannulation remains the standard at many centers. Percutaneous vascular closure (PVC) devices have recently been introduced for minimizing invasiveness during interventional diagnostic and therapy. This report summarizes the initial experience with this new approach in the setting of MICS, with a special focus on safety and advantages. METHODS: Percutaneous cannulation with a standard protocol including preoperative computer tomography imaging and intraoperative point-of-care ultrasound guidance was performed in 93 consecutive patients from September 2018 until February 2020, while conventional "CD" procedure performed in 218 patients in the previous period. We analyzed patients' characteristics and compared access site complications of PVC group versus conventional "CD" group. RESULTS: As far as operative/postoperative outcome, the duration of intensive care unit stay as well as hospital stay was statistically shorter in PVC compared with CD (CD vs. PVC: 2.74 ± 3.83 vs. 2.16 ± 2.01 days, p < 0.01, 16.7 ± 8.75 vs. 13.0 ± 4.96 days, p < 0.001, respectively). Further, we found no femoral infection or lymphocele in the PVC group, whereas 4 cases of wound complications were observed in the CD group. CONCLUSION: According to our results, percutaneous closure system for femoral vessels in MICS seems to be beneficial with the assist of preoperative computed tomography and intraoperative Doppler guidance.

Coronary artery bypass grafting under sole Impella 5.0 support for patients with severely depressed left ventricular function.

Selection of the ideal surgical procedure for coronary revascularization in patients with severe cardiac dysfunction at times may represent a challenge. In recent years, with the advent of surgical large microaxial pumps, e.g., Impella 5.0 (Abiomed Inc., Boston, USA), specific support and effective unloading of the left ventricle has become available. In the interventional field, good results have been achieved with smaller microaxial pumps in the setting of so-called protected percutaneous coronary intervention. In this study, we would like to share our early experience with surgical coronary revascularization under the sole support of Impella 5.0, omitting the use of heart-lung machine in three cases of severe cardiac dysfunction due to complex ischemic heart disease. Effective circulatory support intraoperatively and postoperatively speaks in favor of this technique in selected patients.

Aortic Insufficiency Causes Symptomatic Heart Failure during Left Ventricular Assist Device Support.

De novo aortic insufficiency is often documented during long-term left ventricular assist device (LVAD) support, despite the absence of aortic insufficiency at the time of LVAD implantation. However, whether aortic insufficiency affects long-term mortality and symptomatic heart failure in LVAD-supported patients remains controversial. We aimed to examine whether aortic insufficiency development influenced mortality and symptomatic heart failure following LVAD implantation. Fifty-three patients who underwent durable LVAD implantation between January 1, 2008 and April 31, 2017 were retrospectively examined in a single center institute. After discharge, we performed the echocardiographic examination in accordance with the Japanese registry for the mechanically assisted circulatory support protocol. Aortic insufficiency was graded on an interval scale (severe = 4, moderate = 3, mild = 2, trivial or none = 1). Kaplan-Meier estimates for long-term mortality at the follow-up were generated. We used a logistic regression model to identify risk factors for symptomatic heart failure. The overall median duration of LVAD support was 856.3 ± 430.8 days (range, 12-1,744 days). We did not observe a significant difference in long-term mortality in patients with aortic insufficiency ≥ 3 grade compared with patients with aortic insufficiency < 3 grade (P = 0.767; log-rank). Aortic insufficiency was associated with an increased risk for heart failure event after discharge (odds ratio, 4.12; confidence interval, 1.48-16.93; P = 0.005). Aortic insufficiency was an independent risk factor for symptomatic heart failure and was not associated with long-term mortality. Aortic insufficiency progression was associated with symptomatic heart failure.

Transplantation after Mustard operation for transposition of the great arteries.

As long-term outcomes of congenital heart diseases improve, the probability of adult patients presenting for heart transplantation for late failure of congenitally corrected heart disease also increases. In patients with dextro-transposition of the great arteries (d-TGA) who were initially treated in the era of Mustard or Senning procedures and before Jatene procedure was introduced, progressive systemic right ventricular failure represents a problem in the very long-term follow-up. We report a rare case of heart transplantation as a third operation 36 years after Mustard procedure in a patient with d-TGA experiencing late failure of the systemic right ventricle.

PPAR-Gamma Activation May Inhibit the In Vivo Degeneration of Bioprosthetic Aortic and Aortic Valve Grafts under Diabetic Conditions.

BACKGROUND: We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). METHODS: DM was induced in male Wistar rats by high-fat diet with an intraperitoneal streptozotocin (STZ) injection. The experimental group received additional pioglitazone, and controls received normal chow without STZ (n = 20 each group). Cryopreserved aortic donor grafts including the aortic valve were analyzed after 4 weeks and 12 weeks in vivo for analysis of calcific bioprosthetic degeneration. RESULTS: DM led to a significant media proliferation at 4 weeks. The additional administration of pioglitazone significantly increased circulating adiponectin levels and significantly reduced media thickness at 4 and 12 weeks, respectively (p = 0.0002 and p = 0.0107, respectively). Graft media calcification was highly significantly inhibited by pioglitazone after 12 weeks (p = 0.0079). Gene-expression analysis revealed a significant reduction in relevant chondro-osteogenic markers osteopontin and RUNX-2 by pioglitazone at 4 weeks. CONCLUSIONS: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM.

Initial experience covering 50 consecutive cases of large Impella implantation at a single heart centre.

AIMS: Pre-operative or post-operative heart failure (HF) and cardiogenic shock of various natures frequently remain refractory to conservative treatment and require mechanical circulatory support. We report our clinical experience with large Impella systems (5.0 or 5.5; i.e. Impella 5+) (Abiomed Inc., Boston, USA) and evaluate the parameters that determined patient outcome. METHODS AND RESULTS: The initial 50 cases of Impella 5+ implanted for acute HF between November 2018 and August 2020 at a single centre were enrolled in this study. Data, including preoperative characteristics, perioperative clinical course information, and post-operative outcomes, were retrospectively collected from the hospital data management and quality assurance system. Descriptive and univariate analyses were performed. Among the 49 patients in this study, 28 (56.0%) survived in the first 30 days post-operatively, and 3 died of non-cardiac reasons later. In-hospital mortality was significantly higher in patients with biventricular failure [P < 0.01, odds ratio (OR) 5.63] or dilated cardiomyopathy (DCM) (P = 0.02, OR 15.8), whereas ischaemic cardiomyopathy (ICM) was associated with lower mortality (P = 0.03, OR 0.24). Interestingly, the mortality was comparable between the 'solo' Impella group and the veno-arterial extracorporal membrane oxygenation (va-ECMO) plus Impella (ECMELLA) group, despite the severity of the patients' profile in the ECMELLA group ('solo' vs. ECMELLA; 55.6% vs. 52.6%, P = 1.00). All patients who received an additional temporary right ventricular assist device (tRVAD) were successfully weaned from va-ECMO. CONCLUSIONS: Our results suggest that biventricular failure and DCM are predictors of higher mortality in patients with Impella. Considering the pathophysiology of HF, implantation of a large Impella system seems to be promising, especially for ICM patients. The large Impella system might be more effective for better prognosis of patients under va-ECMO, and combination therapy with tRVAD seems to be a promising strategy for early weaning from va-ECMO.

Combined heart transplantation and replacement of atheromatous proximal arch.

Concomitant surgery on the aortic arch with hypothermic cardiac arrest in the setting of heart transplantation (HTX) is extremely rare. Herein, we report a case of combined HTX and proximal arch replacement at our institution.

New hemostatic technique with combined use of Hydrofit® and Surgicel®: an in vitro and in vivo study.

We developed an effective hemostatic technique using Hydrofit® and Surgicel® simultaneously. The aim of this study was to demonstrate the hemostatic efficacy of the Hydrofit® and Surgicel® combination technique through an in vitro experiment and to elucidate mid-term consequences of the combined components through an in vivo experiment. For the in vitro experiment, a closed circuit using a heparin-coated cardiopulmonary bypass circuit and a prosthetic graft was created. The amount of bleeding from the prosthetic graft was measured, and the following three hemostatic methods were applied: only gauze compression in control group, Hydrofit® application in Hydrofit group, Surgicel® spread Hydrofit® application in Hydrofit and Surgicel (HS) group, respectively. In the in vivo experiment, Hydrofit® and/or Surgicel® were implanted under skin on the back of rats (n = 10) at 4 points. In the control group, only an incision was made; in the Hydrofit, Surgicel, and HS groups, Hydrofit® and/or Surgicel® was implanted. One and three months later, each of the five rats were killed and in each section histopathologic examination was carried out. In the in vitro experiment, the amount of bleeding was 7.84 ± 1.08, 2.26 ± 1.02, and 0.87 ± 0.38 ml in the control, Hydrofit, and HS groups, respectively. The amount of bleeding in the HS group was more suppressed than in the Hydrofit group (p = 0.012). In the in vivo experiment, the maximal depth diameter of each remaining hemostatic sealant was measured. After 3 months, the diameter was 0, 2289.0 ± 768.2, 3850.3 ± 935.8 µm in Surgicel, Hydrofit and HS groups, respectively. The diameter was significantly increased in the HS group compared with the Surgicel and Hydrofit groups (p < 0.001, respectively,). In conclusion, the combination of Hydrofit® and Surgicel® was effective in achieving hemostasis. The remnants of Hydrofit® and Surgicel® were present for a long time in the tissues which could compress the surrounding tissue.

Less Invasive Left Ventricular Assist Device Implantation With the Furoshiki Technique.

In recent years, a less invasive approach has progressively become the first choice for left ventricular assist device (LVAD) implantation. However, in the setting of bridge to transplantation, device-related dense adhesions, particularly at the thoracotomy site, still remain a cumbersome problem at the time of heart transplantation. We propose a technique termed "Furoshiki" with the double wrapping of the LVAD at the primary less invasive implantation consisting of complete wrapping of the LVAD with expanded polytetrafluoroethylene as the first step and complete closure of the pericardial continuity with bovine pericardial patch plasty as the second step.

Valve-Sparing Root Replacement Without Cusp Repair for Regurgitant Quadricuspid Aortic Valve.

Quadricuspid aortic valve (QAV) is a relatively rare valve abnormality. Patients with aortic valve regurgitation or stenosis associated with congenital abnormalities often require surgery at a relatively young age. In most cases, patients with QAV undergo aortic valve replacement. We report on a 58-year-old patient with QAV and aortic insufficiency due to enlarged aortic root. Valve-sparing aortic root replacement was performed without any procedure on the aortic leaflets.

The analysis of left ventricular ejection fraction after minimally invasive surgery for primary mitral valve regurgitation.

BACKGROUND: Although minimally invasive mitral valve surgery (MIMVS) has become the first choice for primary mitral regurgitation (MR) in recent years, clinical evidence in this field is yet limited. The main focus of this study was the analysis of preoperative (Pre), postoperative (Post), and 1-year follow-up (Fu) data in our series of MIMVS to identify factors that have an impact on the left ventricular ejection fraction (LVEF) evolution after MIMVS. METHODS: We reviewed the perioperative and 1-year follow-up data from 436 patients with primary MR (338 isolated MIMVS und 98 MIMVS combined with tricuspid valve repair) to analyze patients' baseline characteristics, the change of LV size, the postoperative evolution of LVEF and its factors, and the clinical outcomes. RESULTS: The overall mean value of ejection fraction (EF) slightly decreased at 1-year follow-up (mean change of LVEF: -2.63 ± 9.00%). A significant correlation was observed for preoperative EF (PreEF) und EF evolution, the higher PreEF the more pronounced decreased EF evolution (in all 436 patients; r = -.54, p < .001, in isolated MIMVS; r = -.54, p < .001, in combined MIMVS; r = -.53, p < .001). Statistically significant differences for negative EF evolution were evident in patients with mild or greater tricuspid valve regurgitation (TR) (in all patients; p < .05, odds ratio [OR] = 1.64, in isolated MIMVS; p < .01, OR = 1.93, respectively). Overall clinical outcome in New York Heart Association classification at 1 year was remarkably improved. CONCLUSIONS: Our results suggest an excellent clinical outcome at 1 year, although mean LVEF slightly declined over time. TR could be a predictor of worsened follow-up LVEF in patients undergoing MIMVS.

Preventive effect of low-dose landiolol on postoperative atrial fibrillation study (PELTA study).

OBJECTIVE: To investigate the efficacy of prophylactic administration of low-dose landiolol on postoperative atrial fibrillation (POAF) in patients after cardiovascular surgery. METHODS: Consecutive 150 patients over 70 years of age who underwent cardiovascular surgery for valvular, ischemic heart, and aortic diseases were enrolled in this single-center prospective randomized control study from 2010 to 2014. They were assigned to three treatment groups: 1γ group (landiolol at 1 µg/kg/min), 2γ group (landiolol at 2 µg/kg/min), or control group (no landiolol). In the two landiolol groups, landiolol hydrochloride was intravenously administered for a period of 4 days postoperatively. Electrocardiography was continuously monitored during the study period, and cardiologists eventually assessed whether POAF occurred or not. RESULTS: POAF occurred in 24.4% of patients in the control group, 18.2% in 1γ group, and 11.1% in 2γ group (p = 0.256). Multivariate logistic regression analysis showed that the incidence of POAF tended to decrease depending on the dose of landiolol (trend-p = 0.120; 1γ group: OR = 0.786, 95% CI 0.257-2.404; 2γ group: OR = 0.379, 95% CI 0.112-1.287). Subgroup analysis showed a significant dose-dependent reduction in POAF among categories of female sex, non-use of angiotensin II receptor blockers (ARBs) before surgery, and valve surgery (each trend-p = 0.02, 0.03, and 0.004). CONCLUSIONS: These findings indicate that prophylactic administration of low-dose landiolol may not be effective for preventing the occurrence of POAF in overall patients after cardiovascular surgery, but the administration could be beneficial to female patients, patients not using ARBs preoperatively, and those after valvular surgery.

Progression of vascular remodeling in pulmonary vein obstruction.

OBJECTIVES: Pulmonary vein obstruction (PVO) frequently occurs after repair of total anomalous pulmonary vein connection with progression of intimal hyperplasia from the anastomotic site toward upstream pulmonary veins (PVs). However, the understanding of mechanism in PVO progression is constrained by lack of data derived from a physiological model of the disease, and no prophylaxis has been established. We developed a new PVO animal model, investigated the mechanisms of PVO progression, and examined a new prophylactic strategy. METHODS: We developed a chronic PVO model using infant domestic pigs by cutting and resuturing the left lower PV followed by weekly hemodynamic parameter measurement and angiographic assessment of the anastomosed PV. Subsequently, we tested a novel therapeutic strategy with external application of rapamycin-eluting film to the anastomotic site. RESULTS: We found the pig PVO model mimicked human PVO hemodynamically and histopathologically. This model exhibited increased expression levels of Ki-67 and phospho-mammalian target of rapamycin in smooth muscle-like cells at the anastomotic neointima. In addition, contractile to synthetic phenotypic transition; that is, dedifferentiation of smooth muscle cells and mammalian target of rapamycin pathway activation in the neointima of upstream PVs were observed. Rapamycin-eluting films externally applied around the anastomotic site inhibited the activation of mammalian target of rapamycin in the smooth muscle-like cells of neointima, and delayed PV anastomotic stenosis. CONCLUSIONS: We demonstrate the evidence on dedifferentiation of smooth muscle-like cells and mammalian target of rapamycin pathway activation in the pathogenesis of PVO progression. Delivery of rapamycin to the anastomotic site from the external side delayed PV anastomotic stenosis, implicating a new therapeutic strategy to prevent PVO progression.

A novel diagnostic system for Doppler ultrasound of the peripheral arteries to detect the presence of thoracic aortic aneurysm.

OBJECTIVE: We aimed to develop a novel ultrasound system and examine its feasibility for noninvasively detecting thoracic aortic aneurysm (TAA) in clinical settings. METHODS: We developed a novel ultrasound system consisting of a modified console and data analysis algorithm. The exploratory study included 100 patients hospitalized for elective cardiovascular surgery. After admission, the arterial pulse waveform at the left carotid artery was acquired using the novel system. Based on these data, we inferred the presence of TAA based on arterial viscoelasticity and instability, which are reflected into the time-averaged trajectory of deformation of the blood vessel wall caused by disturbance of blood flow. Meanwhile, all patients underwent computed tomography as preoperative screening to confirm the presence of TAA. The sensitivity and specificity of TAA detection using the novel ultrasound system were calculated. RESULTS: The datasets from 37 patients were not suitable for analysis and were thus discarded. Based on computed tomography findings, 40 patients were categorized into the aneurysm group while 23 were judged not to have and aortic aneurysm. On the other hand, 44 patients were diagnosed as having TAA based on ultrasound findings obtained using the novel system. The overall sensitivity and specificity of the ultrasound system were 0.83 and 0.52, respectively. CONCLUSION: We successfully developed a novel system for noninvasive, ultrasound-based evaluation of the left carotid artery to detect TAA. Although improvements to the probe and diagnostic algorithm are warranted, this device has potential utility for mass screening to detect asymptomatic TAA as part of community-level healthcare programs.