Thrombocytopenia Following Perceval Sutureless Aortic Valve Replacement in Asian Patients.

BACKGROUND: This study analyzed the safety and performance of the Perceval valve for aortic valve replacement (AVR) in patients at 1 year after undergoing aortic stenosis (AS) treatment, and its effect on significant declines in the platelet count during the immediate postoperative period.Methods and Results: Data were collected retrospectively for the initial 121 patients (median age 77 years; 47.1% females) who underwent Perceval sutureless AVR between May 2019 and July 2022. Implantation was successful in all (100%), with median cross-clamp and CPB times of 59 and 100 min, respectively. Postoperative thrombocytopenia (platelet count <50×103/µL) was noted in 80 (66.1%) patients. Multivariate analysis showed advanced age (>80 years), preoperative low platelet count (<200×103/µL), and a sternotomy approach as significant risk factors for postoperative thrombocytopenia. One (0.8%) patient died within 30 days after the procedure. The 2-year site-reported event rate was 14% (n=17) for all-cause mortality, 0.8% (n=1) for cardiac mortality, 4.1% (n=5) for stroke, and 1.7% (n=2) for endocarditis and valve-related reoperation; there were no instances of paravalvular leakage or structural valve deterioration. CONCLUSIONS: Thrombocytopenia was common after Perceval sutureless AVR, although its impact was not significant. Although Perceval sutureless AVR was found to be a safe and effective option, preoperative assessment of potential bleeding should be performed and the Perceval valve should not be used for patients with a high bleeding risk.

An elderly case of aortic stenosis associated with double-chambered right ventricle.

Double-chambered right ventricle (DCRV) caused by right ventricular outflow tract obstruction, is a developmental cardiac anomaly in which the anomalous muscle bundles divide the right ventricular cavity into two chambers. Few cases with DCRV coexisting with severe aortic stenosis (AS) have been reported. Moreover, adult cases are extremely uncommon.We report an elderly case of a heavy DCRV with severe AS detected by transthoracic echocardiography and catheterization study. An 85-year-old woman with dyspnea on effort and right-sided heart failure was diagnosed with DCRV and severe AS by echocardiography. She underwent a resection of the anomalous muscle of the right ventricle and aortic valve replacement. Her symptoms disappeared postoperatively and was discharged home. At 2 years postoperatively, she was generally well without recurrence of DCRV. In conclusion, the case of DCRV with AS is rare and surgery is useful to relieve the heart failure symptoms and improve the prognosis of both young and adult patients. Learning objective: Double-chambered right ventricle (DCRV) is uncommon in the older population; however, clinicians should consider DCRV in patients with right-sided heart failure as a differential diagnosis. The case of DCRV with aortic stenosis is rare, surgical treatment is particularly useful for these patients to relieve the heart failure symptoms and improve the prognosis in young and adult cases.

Chronic expanding intrapericardial hematoma associated with blunt chest trauma 50 years earlier.

Chronic expanding intrapericardial hematoma can be treated surgically; however, a correct diagnosis is not always established, thus the condition remains untreated. A 76-year-old man was referred to us with a diagnosis of congestive heart failure. The patient had experienced blunt trauma to the chest 50 years earlier (during bar practice). Cardiac computed tomography revealed a cystic mass wrapped in a calcified membrane that was impeding inflow to the right atrium and ventricle. Cardiac catheterization revealed that the right ventricular pressure had a dip and plateau pattern. We diagnosed the patient with constrictive pericarditis-induced chronic expanding intrapericardial hematoma and agreed upon surgical management. We removed the hematoma and performed a pericardiectomy. The postoperative course was uneventful. In conclusion, chronic expanding intrapericardial hematoma can develop after blunt chest trauma and can be diagnosed precisely with cardiac computed tomography. Learning objective: A 76-year-old man presented with congestive heart failure. The patient had experienced blunt trauma to the chest 50 years earlier. Cardiac computed tomography (CT) revealed a cystic mass within a calcified membrane that was impeding inflow in the right atrium and ventricle. We diagnosed chronic expanding intrapericardial hematoma (CEIH). We successfully removed the hematoma and performed a pericardiectomy. CEIH can develop after blunt chest trauma and could be diagnosed earlier with cardiac CT.

Collapse of Najuta endograft (aortic arch graft) in patient with intermittent paraparesis.

A 50-year-old male underwent thoracic endovascular aortic repair (TEVAR) for distal arch traumatic aortic dissection. Following placement of a Najuta endograft (Kawasumi Laboratories, Inc., Tokyo, Japan) from zone 0 to zone 4, patency of the three vessels was confirmed. Later, the patient suddenly experienced complete intermittent loss of motor and sensory functions in the bilateral lower extremities. Contrast computed tomography (CT) findings indicated endograft stenosis. Following an additional TEVAR procedure, the paraparesis state was temporarily improved. Thereafter, he was readmitted due to congestive heart failure with intermittent paraparesis and contrast CT findings indicated endograft collapse. An emergency procedure for re-expansion of the collapsed endograft and urgent surgery for replacement of the aortic arch was successful. In cases with intermittent paraparesis, endograft collapse should be considered.

Sutureless Aortic Valve Replacement Through Lateral Mini-Thoracotomy　- Feasibility and Effectiveness.

BACKGROUND: Minimally invasive sutureless aortic valve replacement with the Perceval bioprosthetic heart valve (MISUAVR) is commonly performed through a right anterior thoracotomy (AT). However, a lateral thoracotomy (LT) may be superior as it does not require rib and right internal thoracic artery (RITA) cutting.Methods and Results: In total, 38 MISUAVRs performed from May 2019 to approximately August 2021 were retrospectively reviewed; 21 through LT (Group L), and 17 through AT (Group A). In Group L, the skin incision was made on the right anterior axillary line and third intercostal space, and in group A, on the right anterior chest and second or third intercostal space. All other surgical techniques were the same. Age, body surface area, EuroSCORE II, and ejection fraction were similar between the patients. Cardiopulmonary bypass (L: 82±19 vs. A: 93±28 min, P=0.19) and cross-clamp times (L: 57±13, vs. A: 64±23 min, P=0.19) were similar. Rib and/or RITA cutting were required in 94.6% of patients in group A and in none of group L (P<0.001). Surgical visualization score was better in group L (L: 1.19±0.40 vs. A: 1.94±0.69, P<0.01). Total amount of intraoperative bleeding was lower in group L (L: 623±141 vs. A: 838±316 mL, P<0.01). Duration of hospital stay was similar (P=0.30). CONCLUSIONS: MISUAVR through LT has multiple advantages over AT.

Surgical outcomes of minimally invasive aortic valve replacement via right mini-thoracotomy for hemodialysis patients.

OBJECTIVES: Minimally invasive valve surgery has become increasingly accepted as an alternative to conventional median sternotomy in low-risk patients. However, there have been no reports regarding the outcomes of this procedure on high-risk hemodialysis patients. The purpose of this investigation was to assess the surgical outcomes of minimally invasive aortic valve replacement (AVR) via right mini-thoracotomy (MIAVR) in hemodialysis patients compared with those of conventional AVR (CAVR) via full sternotomy. METHODS: Two hundred and seventy-four patients underwent isolated AVR for severe AS, and 42 hemodialysis patients were included in this study. MIAVR was performed in 17 cases and CAVR in 25 cases. We compared the short-term surgical outcome among the two groups. RESULTS: There was no difference in the aortic cross-clamp or cardiopulmonary bypass time. However, the procedure time was significantly shorter in the MIAVR group. Patients in the MIAVR group had less bleeding and a smaller amount of transfused red blood cells. There were four hospital deaths (18.2%) in the CAVR group. For postoperative complications, there were 2 (9.1%) cerebrovascular incidents, 2 (9.1%) cases of respiratory failure, 1 (4.5%) re-exploration for bleeding in CAVR group. The postoperative ventilation time was significantly shorter in the MIAVR group. There was no difference in the length of postoperative intensive care unit stay or of postoperative hospital stay. CONCLUSION: The surgical outcomes of MIAVR in hemodialysis patients were acceptable, with a low incidence of morbidity, reasonable lengths of hospital stay, and no mortality among the patients studied.

Cell Size Critically Determines Initial Retention of Bone Marrow Mononuclear Cells in the Heart after Intracoronary Injection: Evidence from a Rat Model.

Intracoronary injection of bone marrow mononuclear cells (BMMNC) is an emerging treatment for heart failure. Initial donor cell retention in the heart is the key to the success of this approach, but this process remains insufficiently characterized. Although it is assumed that cell size of injected cells may influence their initial retention, no scientific evidence has been reported. We developed a unique model utilizing an ex-vivo rat heart perfusion system, enabling quantitative assessment of retention of donor cells after intracoronary injection. The initial (5 minutes after intracoronary injection) retention rate of BMMNC was as low as approximately 20% irrespective of donor cell doses injected (1×106, 8×106, 4×107). Quantitative cell-size assessment revealed a positive relationship between the size of BMMNC and retention ratio; larger subpopulations of BMMNC were more preferentially retained compared to smaller ones. Furthermore, a larger cell type-bone marrow-derived mesenchymal stromal cells (median size = 11.5µm versus 7.0µm for BMMNC)-had a markedly increased retention rate (77.5±1.8%). A positive relationship between the cell size and retention ratio was also seen in mesenchymal stromal cells. Flow-cytometric studies showed expression of cell-surface proteins, including integrins and selectin-ligands, was unchanged between pre-injection BMMNC and those exited from the heart, suggesting that biochemical interaction between donor cells and host coronary endothelium is not critical for BMMNC retention. Histological analyses showed that retained BMMNC and mesenchymal stromal cells were entrapped in the coronary vasculature and did not extravasate by 60 minutes after transplantation. Whilst BMMNC did not change coronary flow after intracoronary injection, mesenchymal stromal cells reduced it, suggesting coronary embolism, which was supported by the histological finding of intravascular cell-clump formation. These data indicate that cell-size dependent, passive (mechanical), intravascular entrapment is responsible for the initial donor cell retention after intracoronary injection of BMMNC in the heart having normal vasculatures (at least).

Bone marrow-derived mesenchymal stem cells for the treatment of heart failure.

Heart failure remains a major cause of death and disability, requiring rapid development of new therapies. Bone marrow-derived mesenchymal stem cell (MSC)-based therapy is an emerging approach for the treatment of both acute and chronic heart failure. Following successful experimental studies in a range of models, more than 40 clinical trials of MSC-based therapy for heart failure have now been registered, and the results of completed clinical trials so far have shown feasibility and safety of this approach with therapeutic potential suggested (though preliminarily). However, there appear to be several critical issues to be solved before this treatment could become a widespread standard therapy for heart failure. In this review, we comprehensively and systemically summarize a total of 73 preclinical studies and 11 clinical trial reports published to date. By analyzing the data in these reports, (1) improvement in the cell delivery method to the heart in order to enhance donor cell engraftment, (2) elucidation of mechanisms underpinning the therapeutic effects of the treatment differentiation and/or treatment secretion, and (3) validation of the utility of allogeneic MSCs which could enhance the efficacy and expand the application/indication of this therapeutic approach are highlighted as future perspectives. These important respects are further discussed in this review article with referencing latest scientific and clinical information.

Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study.

Transplantation of bone marrow mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure. We have reported that epicardial placement of MSC-sheets generated using temperature-responsive dishes markedly increases donor MSC survival and augments therapeutic effects in an acute myocardial infarction (MI) model, compared to intramyocardial (IM) injection. This study aims to expand this knowledge for the treatment of ischemic cardiomyopathy, which is likely to be more difficult to treat due to mature fibrosis and chronically stressed myocardium. Four weeks after MI, rats underwent either epicardial MSC-sheet placement, IM MSC injection, or sham treatment. At day 28 after treatment, the cell-sheet group showed augmented cardiac function improvement, which was associated with over 11-fold increased donor cell survival at both days 3 and 28 compared to IM injection. Moreover, the cell-sheet group showed improved myocardial repair, in conjunction with amplified upregulation of a group of reparative factors. Furthermore, by comparing with our own previous data, this study highlighted similar dynamics and behavior of epicardially placed MSCs in acute and chronic stages after MI, while the acute-phase myocardium may be more responsive to the stimuli from donor MSCs. These proof-of-concept data encourage further development of the MSC-sheet therapy for ischemic cardiomyopathy toward clinical application.

Surgery without Blood Transfusion for Giant Paraganglioma in a Jehovah's Witness Patient.

A retroperitoneal tumor was identified in a 57-year-old female belonging to Jehovah's Witnesses during a health check. Subsequent examination led to the suspicion of a right pheochromocytoma. The patient wished to be treated by bloodless surgery and consulted our hospital after being refused surgery by several hospitals. She signed a liability waiver for blood transfusion refusal. After obtaining consent for diluted autotransfusion and preoperative administration of erythropoietin, the surgery was scheduled. The tumor was attached to the inferior vena cava and left renal vein and engulfed the right renal artery and vein. The tumor and right kidney were removed en bloc. Operative time was 8 h and 18 min, with 1,770 ml of blood loss. The histopathological diagnosis was paraganglioma with the normal adrenal gland within the border of the tumor. The patient was discharged from the hospital with no postoperative complications.

Extracellular high mobility group box 1 plays a role in the effect of bone marrow mononuclear cell transplantation for heart failure.

Transplantation of unfractionated bone marrow mononuclear cells (BMCs) repairs and/or regenerates the damaged myocardium allegedly due to secretion from surviving BMCs (paracrine effect). However, donor cell survival after transplantation is known to be markedly poor. This discrepancy led us to hypothesize that dead donor BMCs might also contribute to the therapeutic benefits from BMC transplantation. High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes nucleosomes, and also acts as a multi-functional cytokine when released from damaged cells. We thus studied the role of extracellular HMGB1 in the effect of BMC transplantation for heart failure. Four weeks after coronary artery ligation in female rats, syngeneic male BMCs (or PBS only as control) were intramyocardially injected with/without anti-HMGB1 antibody or control IgG. One hour after injection, ELISA showed that circulating extracellular HMGB1 levels were elevated after BMC transplantation compared to the PBS injection. Quantitative donor cell survival assessed by PCR for male-specific sry gene at days 3 and 28 was similarly poor. Echocardiography and catheterization showed enhanced cardiac function after BMC transplantation compared to PBS injection at day 28, while this effect was abolished by antibody-neutralization of HMGB1. BMC transplantation reduced post-infarction fibrosis, improved neovascularization, and increased proliferation, while all these effects in repairing the failing myocardium were eliminated by HMGB1-inhibition. Furthermore, BMC transplantation drove the macrophage polarization towards alternatively-activated, anti-inflammatory M2 macrophages in the heart at day 3, while this was abolished by HMGB1-inhibition. Quantitative RT-PCR showed that BMC transplantation upregulated expression of an anti-inflammatory cytokine IL-10 in the heart at day 3 compared to PBS injection. In contrast, neutralizing HMGB1 by antibody-treatment suppressed this anti-inflammatory expression. These data suggest that extracellular HMGB1 contributes to the effect of BMC transplantation to recover the damaged myocardium by favorably modulating innate immunity in heart failure.

The use of scaffold-free cell sheet technique to refine mesenchymal stromal cell-based therapy for heart failure.

Transplantation of bone marrow-derived mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure based on their secretion-mediated "paracrine effects". Feasibility of the scaffoldless cell sheet technique to enhance the outcome of cell transplantation has been reported using other cell types, though the mechanism underpinning the enhancement remains uncertain. We here investigated the role of this innovative technique to amplify the effects of MSC transplantation with a focus on the underlying factors. After coronary artery ligation in rats, syngeneic MSCs were grafted by either epicardial placement of MSC sheets generated using temperature-responsive dishes or intramyocardial (IM) injection. Markedly increased initial retention boosted the presence of donor MSCs persistently after MSC sheet placement although the donor survival was not improved. Most of the MSCs grafted by the cell sheet technique remained resided on the epicardial surface, but the epicardium quickly regressed and new vessels sprouted into the sheets, assuring the permeation of paracrine mediators from MSCs into the host myocardium. In fact, there was augmented upregulation of various paracrine effect-related genes and signaling pathways in the early phase after MSC sheet therapy. Correspondingly, more extensive paracrine effects and resultant cardiac function recovery were achieved by MSC sheet therapy. Further development of this approach towards clinical application is encouraged.

The use of cell-sheet technique eliminates arrhythmogenicity of skeletal myoblast-based therapy to the heart with enhanced therapeutic effects.

BACKGROUND: Clinical application of skeletal myoblast transplantation has been curtailed due to arrhythmogenicity and inconsistent therapeutic benefits observed in previous studies. However, these issues may be solved by the use of a new cell-delivery mode. It is now possible to generate "cell-sheets" using temperature-responsive dishes without artificial scaffolds. This study aimed to validate the safety and efficacy of epicardial placement of myoblast-sheets (myoblast-sheet therapy) in treating heart failure. METHODS AND RESULTS: After coronary artery ligation in rats, the same numbers of syngeneic myoblasts were transplanted by intramyocardial injection or cell-sheet placement. Continuous radio-telemetry monitoring detected increased ventricular arrhythmias, including ventricular tachycardia, after intramyocardial injection compared to the sham-control, while these were abolished in myoblast-sheet therapy. This effect was conjunct with avoidance of islet-like cell-cluster formation that disrupts electrical conduction, and with prevention of increased arrhythmogenic substrates due to exaggerated inflammation. Persistent ectopic donor cells were found in the lung only after intramyocardial injection, strengthening the improved safety of myoblast-sheet therapy. In addition, myoblast-sheet therapy enhanced cardiac function, corresponding to a 9.2-fold increase in donor cell survival, compared to intramyocardial injection. Both methods achieved reduced infarct size, decreased fibrosis, attenuated cardiomyocyte hypertrophy, and increased neovascular formation, in association with myocardial upregulation of a group of relevant molecules. The pattern of these beneficial changes was similar between two methods, but the degree was more substantial after myoblast-sheet therapy. CONCLUSION: The cell-sheet technique enhanced safety and therapeutic efficacy of myoblast-based therapy, compared to the current method, thereby paving the way for clinical application.

Calcineurin splicing variant calcineurin Aß1 improves cardiac function after myocardial infarction without inducing hypertrophy.

BACKGROUND: Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin Aß (CnAß) gene generates the CnAß1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAß1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown. METHODS AND RESULTS: We generated transgenic mice overexpressing CnAß1 in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAß1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnAß1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnAß1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation. CONCLUSIONS: Calcineurin Aß1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAß1 an attractive candidate for the development of future therapeutic approaches.