Acute Dapagliflozin Administration Ameliorates Cardiac Surgery-Associated Acute Kidney Injury in a Rabbit Model.

BACKGROUND: Several studies have shown that sodium-glucose cotransporter-2 inhibitors have a renoprotective effect on acute kidney injury (AKI), but their effect on cardiac surgery-associated AKI is unknown.Methods and Results: AKI was induced in 25 rabbits without diabetes mellitus by cardiopulmonary bypass (CPB) for 2 h and they were divided into 5 groups: sham; dapagliflozin-treated sham; CPB; dapagliflozin-treated CPB; and furosemide-treated CPB (n=5 in each group). Dapagliflozin was administered via the femoral vein before initiating CPB. Kidney tissue and urine and blood samples were collected after the surgical procedure. There were no differences in the hemodynamic variables of each group. Dapagliflozin reduced serum creatinine and blood urea nitrogen concentrations, and increased overall urine output (all P<0.05). Hematoxylin and eosin staining showed that the tubular injury score was improved after dapagliflozin administration (P<0.01). Dapagliflozin administration mitigated reactive oxygen species and kidney injury molecule-1 as assessed by immunohistochemistry (both P<0.0001). Protein expression analysis showed improvement of inflammatory cytokines and apoptosis, and antioxidant enzyme expression was elevated (all P<0.05) through activation of the nuclear factor erythroid 2-related factor 2 pathway (P<0.01) by dapagliflozin. CONCLUSIONS: Acute intravenous administration of dapagliflozin protects against CPB-induced AKI. Dapagliflozin may have direct renoprotective effects in renal tubular cells.

"Kyushu-style" collaboration between the implantable ventricular assist device implantation and management centers: a republication of the article published in Japanese journal of artificial organs.

Collaboration between the implantation centers, management centers, and regional core hospitals is a key factor in securing long-term implantable ventricular assist device (VAD) management. In Kyushu, a management system for patients with implantable VADs has been established at the prefectural and regional levels. Presently, six implantable VAD implantation centers and seven management centers exists in the eight prefectures of Kyushu and Okinawa, with at least one specialized VAD centers in each prefecture. This collaborative management system allows patients with VADs to receive seamless treatment based on the same management concept wherever they live. In fact, approximately half of the present outpatients treated at our center reside outside the prefecture and are managed in collaboration with management centers and regional core hospitals. Among our patients, there were no significant differences in survival or rehospitalization-free rates between patients with VADs in and out of the prefecture, suggesting that the place of residence did not affect the outcome. With the increase in the number of patients with VADs and the diversification of patients, patient management has become more complex. Mutual collaboration between the implantation centers, management centers, and regional core hospitals, is essential to improve the quality of VAD management. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2023 (Vol. 52, No. 1, pp. 85-88), with some modifications.

Necrostatin-1 Attenuates Delayed Paraplegia after Transient Spinal Cord Ischemia in Rabbits by Inhibiting the Upregulation of Receptor-Interacting Protein Kinase 1 and 3.

BACKGROUND: Delayed-onset paraplegia is a disastrous complication after thoracoabdominal aortic open surgery and thoracic endovascular aortic repair. Studies have revealed that transient spinal cord ischemia caused by temporary occlusion of the aorta induces delayed motor neuron death owing to apoptosis and necroptosis. Recently, necrostatin-1 (Nec-1), a necroptosis inhibitor, has been reported to reduce cerebral and myocardial infarction in rats or pigs. In this study, we investigated the efficacy of Nec-1 in delayed paraplegia after transient spinal cord ischemia in rabbits and assessed the expression of necroptosis- and apoptosis-related proteins in motor neurons. METHODS: This study used rabbit transient spinal cord ischemia models using a balloon catheter. They were divided into a vehicle-treated group (n = 24), Nec-1-treated group (n = 24), and sham-controls (n = 6). In the Nec-1-treated group, 1 mg/kg of Nec-1 was intravascularly administered immediately before ischemia induction. Neurological function was assessed using the modified Tarlov score, and the spinal cord was removed 8 hr and 1, 2, and 7 days after reperfusion. Morphological changes were examined using hematoxylin and eosin staining. The expression levels of necroptosis-related proteins (receptor-interacting protein kinase [RIP] 1 and 3) and apoptosis-related proteins (Bax and caspase-8) were assessed using western blotting and histochemical analysis. We also performed double-fluorescence immunohistochemical studies of RIP1, RIP3, Bax, and caspase-8. RESULTS: Neurological function significantly improved in the Nec-1-treated group compared with that in the vehicle-treated group 7 days after reperfusion (median 3 and 0, P = 0.025). Motor neurons observed 7 days after reperfusion were significantly decreased in both groups compared with the sham group (vehicle-treated, P < 0.001; Nec-1-treated, P < 0.001). However, significantly more motor neurons survived in the Nec-1-treated group than in the vehicle-treated group (P < 0.001). Western blot analysis revealed RIP1, RIP3, Bax, and caspase-8 upregulation 8 hr after reperfusion in the vehicle-treated group (RIP1, P = 0.001; RIP3, P = 0.045; Bax, P = 0.042; caspase-8, P = 0.047). In the Nec-1-treated group, the upregulation of RIP1 and RIP3 was not observed at any time point, whereas that of Bax and caspase-8 was observed 8 hr after reperfusion (Bax, P = 0.029; caspase-8, P = 0.021). Immunohistochemical study revealed the immunoreactivity of these proteins in motor neurons. Double-fluorescence immunohistochemistry revealed the induction of RIP1 and RIP3, and that of Bax and caspase-8, in the same motor neurons. CONCLUSIONS: These data suggest that Nec-1 reduces delayed motor neuron death and attenuates delayed paraplegia after transient spinal cord ischemia in rabbits by selectively inhibiting necroptosis of motor neurons with minimal effect on their apoptosis.

Veno-venous extracorporeal membrane oxygenation support of pulmonary insufficiency using Avalon Elite® cannula in pediatric patients.

The "Avalon Elite®" cannula is a double-lumen cannula used to establish veno-venous extracorporeal membrane oxygenation support. The reported advantages are that extracorporeal circulation can be established by cannulating through the right internal jugular vein only, and there is less re-circulation than with a two-cannula technique. It is available in a wide range of cannula sizes and can be used in a variety of patients, from children to adults. We herein report three pediatric cases in which an Avalon Elite® cannula was useful. The first was a case of acute mitral regurgitation due to idiopathic chordal rupture for postoperative severe lung injury and atelectasis due to cardiogenic pulmonary edema. The second was a case of end-stage radiation pneumonitis for safe transfer to facility of lung transplantation. The third was a convalescent case of fulminant myocarditis with severe atelectasis due to cardiogenic pulmonary edema. In each case, veno-venous extracorporeal membrane oxygenation using an Avalon Elite® cannula was established, the expected sufficient support was secured, and a good clinical course was obtained without major complications associated with an Avalon Elite® cannula.

[The Trend of Minimally Invasive Cardiac Surgery:Where Robot-assisted Cardiac Surgery in Japan is Now].

The trend in cardiac surgery is moving toward minimally invasive procedures worldwide. In Japan, robot-assisted cardiac surgery has started simultaneously with the insurance coverage of minimally invasive cardiac surgery in April 2018. Technology innovations such as the miniaturization of the robot arm, the development of various type of instruments have improved operability and has contributed to the spread of robot-assisted cardiac surgery. On the other hand, there are several issues that may be barriers to its widespread use. The number of facilities for robot-assisted cardiac surgery has not increased as expected probably due to the current insurance system, that is still being developed, the requirement for implementation, and the cost. The current status and issues of robot-assisted cardiac surgery in Japan will be discussed.

Investigating the cause of hemolysis in patients supported by a pulsatile ventricular assist device.

A survey conducted by Abiomed, Inc. revealed that 10 of 60 patients who received ventricular assistance via the AB5000 ventricular assist device (VAD) experienced hemolysis. The present study was conducted to investigate which factors influence hemolysis under pulsatile-flow VADs such as the AB5000. We compared the specificity of the AB5000 and its driving console with those of the NIPRO-VAD and VCT50χ under severe heart failure conditions using a mock circulatory system with a glycerol water solution. We used the mock circuit with bovine blood to confirm which pump conditions were most likely to cause hemolysis. In addition, we measured the shear velocity using particle image velocimetry by analyzing the seeding particle motion for both the AB5000 and NIPRO-VAD under the same conditions as those indicated in the initial experiment. Finally, we analyzed the correlation between negative pressure, exposure time, and hemolysis by continuously exposing fixed vacuum pressures for fixed times in a sealed device injected with bovine blood. Applying higher vacuum pressure to the AB5000 pump yielded a larger minimum inlet pressure and a longer exposure time when the negative pressure was under - 10 mmHg. The plasma-free hemoglobin increased as more negative pressure was driven into the AB5000 pump. Moreover, the negative pressure interacted with the exposure time, inducing hemolysis. This study revealed that negative pressure and exposure time were both associated with hemolysis.

Determinants of Changes in Arterial Stiffness after Thoracic Endovascular Aortic Repair.

BACKGROUND: Aortic stent grafting can cause aortic stiffening and increase pulse wave velocity (PWV), which can potentially affect long-term cardiovascular outcomes. The aim of this study was to clarify the factors contributing to increases in PWV after thoracic endovascular aortic repair (TEVAR). METHODS: We included 64 patients with thoracic aortic pathology (51 men; mean age, 73 years) who underwent elective TEVAR, in this study. TEVAR was performed for degenerative aortic aneurysm (n = 43) or aortic dissection (n = 21), and the treatment length was 175 ± 52 mm. Brachial-ankle PWV (baPWV) was obtained before and 1 week after TEVAR. Univariable and multivariable logistic regression analyses were used to determine the predictors of increases in baPWV of ≥100 cm/sec after TEVAR. RESULTS: baPWV increased from 1,851 ± 392 cm/sec to 2,047 ± 479 cm/sec, and the change in baPWV (ΔbaPWV) was 195 ± 339 cm/sec (95% confidence interval, 111-280). Thirty-seven patients (58%) had ΔbaPWV ≥100 cm/sec after TEVAR. In the multivariable analysis, in addition to Δheart rate and Δsystolic blood pressure, age (odds ratio, 1.21/year; 95% confidence interval, 1.05-1.40) and coronary artery disease (odds ratio, 12.0; 95% confidence interval, 1.20-121) were independent determinants of ΔbaPWV ≥100 cm/sec after TEVAR, whereas ΔbaPWV ≥100 cm/sec was not associated with treatment length or device type. CONCLUSIONS: TEVAR was associated with PWV progression, especially in older patients with coronary artery disease, whereas treatment length or device type was not a predictor of PWV progression after TEVAR.

Interaction between cardiac myosin-binding protein C and formin Fhod3.

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C-binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C-null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C-related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C-mediated regulation of cardiac function via direct interaction.

Successful papillary muscle approximation for severe mitral regurgitation via apical cuff hole in HeartMate 3 implantation via left anterior thoracotomy.

We herein report a case of successful papillary muscle approximation for severe mitral regurgitation and HeartMate 3 left ventricular assist device implantation via left anterior thoracotomy in a 39-year-old man diagnosed with dilated cardiomyopathy. He underwent papillary muscle approximation in the mitral valve for severe functional regurgitation via the apical cuff hole. The postoperative course was uneventful. Echocardiography revealed that mitral regurgitation has disappeared. He was awaiting heart transplantation while working.

A therapeutic concept to resolve a possible coronary desaturation under Ecpella support and maximize the potential for myocardial recovery: combination of veno-arteriovenous extracorporeal membrane oxygenation and Impella (VAVEcpella).

INTRODUCTION: Ecpella, a combination of veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) and Impella, may result in the differential hypoxia in patients with cardiogenic shock and severe lung dysfunction. Here, we report a solution of this Ecpella-induced unfavorable phenomenon. CASE REPORT: A 70-year-old man developed cardiogenic shock from fulminant myocarditis. As we established Ecpella but immediately significant differential hypoxia became apparent, the ECMO configuration was switched from V-A to veno-arteriovenous (V-AV): a combination of V-AV ECMO and Impella, newly termed VAVEcpella, was instituted. The differential hypoxia resolved, and he was successfully weaned from mechanical circulatory support. DISCUSSION AND CONCLUSION: VAVEcpella is an effective configuration to resolve Ecpella-induced differential hypoxia and may contribute to restoration of normal cardiac function.

Fatal Pulmonary Hemorrhagic Infarction Caused by Pulmonary Vein Thrombotic Occlusion During Venoarterial Extracorporeal Membrane Oxygenation.

A 20-year-old man with arrhythmogenic right ventricular cardiomyopathy (ARVC) was resuscitated from ventricular fibrillation. He was transferred to our hospital because of progressive multiorgan dysfunction despite mechanical circulatory support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pump (IABP). At admission to our hospital, chest X-ray showed bilateral complete lung opacification, and echocardiography revealed a massive thrombus occupying the left atrium (LA) and left ventricle (LV). Conversion to central ECMO with transapical LV venting and thrombectomy were performed. The huge LA thrombus occluded all pulmonary veins (PVs). Despite the surgery and intensive care, complete lung opacity remained, and he died of multiorgan failure associated with sepsis. Autopsy demonstrated bilateral pulmonary multiple red infarctions, and histopathology showed alveolar wall necrosis with extensive hemorrhage, confirming a diagnosis of pulmonary hemorrhagic infarction. Extensive pulmonary infarction was attributable to PV occlusion due to massive LA thrombus. PV thrombosis should be considered when refractory lung opacities are encountered during VA-ECMO and necessitates early intervention.

Pneumopericardium suggesting left ventricular assist device-related gastrointestinal complication.

We report an uncommon case of ventricular assist device-related infection and resultant fistula formation into the gastrointestinal tract. A 69-year-old man, who had undergone implantation of a HeartMate II 1 year earlier secondary to ischemic cardiomyopathy, presented to our hospital with a high fever. Computed tomography showed unusual gas collection around the heart apex (i.e., pneumopericardium), which had not been detected before. The patient developed sudden melena with fresh blood without abdominal symptoms 1 month after beginning antibiotic therapy. Emergent colonoscopy showed that the HeartMate II strain relief of the inflow conduit had penetrated the transverse colon. We immediately performed laparoscopy-assisted left-sided hemicolectomy and found intraoperatively that a fistula had formed between the splenic flexure and the pericardial cavity. Subsequently, the HeartMate II system was totally explanted and replaced with an Impella 5.0 for alternative hemodynamic support. In our patient, pneumopericardium might have been an early sign of a hidden gastrointestinal complication. Our experience is a caution for clinicians who manage patients with ventricular assist device support via the apex.

The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice.

Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifen-induced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.

Single-stage hybrid total arch replacement for extended arch aneurysms.

OBJECTIVE: The therapeutic strategy for extended aortic arch aneurysms remains controversial and has changed substantially since thoracic endovascular aortic repair was introduced. We applied single-stage hybrid (s-hybrid) total arch replacement (TAR), which involved ascending aorta replacement and debranching of arch vessels, consecutively performed with thoracic endovascular aortic repair for extended arch aneurysms. The aim of this study was to investigate the short-term results of s-hybrid TAR and to clarify the benefit of this method. METHODS: We reviewed the operative results of 62 patients who underwent elective s-hybrid TAR or conventional TAR (c-TAR) through the median approach from 2008 to 2017. We used the s-hybrid approach in 15 patients and the c-TAR approach in 47 patients. In both groups, axillary arterial perfusion and selective antegrade cerebral perfusion under moderate hypothermia were applied for brain protection. We compared the perioperative outcomes of the two groups. RESULTS: We completed s-hybrid TAR in all 15 patients with extended aneurysms. The s-hybrid group required shorter times for myocardial ischemia, selective antegrade cerebral perfusion, and circulatory arrest of the lower body compared with the c-TAR group. The patients with complicated recurrent laryngeal nerve palsy and long ventilation support times were fewer in the s-hybrid group. No patient had substantial endoleaks or permanent paraplegia. The in-hospital mortality rates were 6.7% in the s-hybrid group and 0% in the c-TAR group. CONCLUSIONS: The s-hybrid TAR has the same or better perioperative outcomes compared with the c-TAR approach. For extended aneurysms, this technique could resolve the problem of respiratory failure induced by left thoracotomy and also resolve the problem of rupture during the waiting period in staged surgery.

[The Role of Extracorporeal Ventricular Assist Device is Changing in the Era of Implantable Ventricular Assist Device].

In the era of implantable ventricular assist device (VAD), the role of extracorporeal VAD is changing. The extracorporeal VAD was ever the mainstream of treatment for severe heart failure. Now, it is mainly applied to patients with severe cardiogenic shock. Recently the centrifugal pump available for cardiopulmonary bypass system has been often used as the extracorporeal VAD because of its simplicity of management. Although the implantable VAD plays the pivotal role for bridge to transplantation since its clinical introduction in 2011, the extracorporeal VAD still has the important role for end-stage heart failure and cardiogenic shock. We have experienced 47 cases of the extracorporeal VAD until now. Here, based on our experience, we describe the "past and present" role of the extracorporeal VAD and mention the future aspect of the extracorporeal VAD.

Long-term results after treatment of the ascending aorta for bicuspid aortic valve patients.

PURPOSE: We evaluated the long-term results of aortic valve replacement for bicuspid aortic valve patients with or without surgical treatment of the ascending aorta. METHODS: A total of 145 bicuspid aortic valve patients had undergone aortic valve replacement since 1974 at our institution. No surgical treatment (Group-N; n = 115) was performed in the ascending aorta if the diameter was less than 40 mm. We wrapped an ascending aorta of 40-50 mm with an artificial graft (Group-W; n = 19), and performed replacement (Group-R; n = 11) if the ascending aorta measured more than 50 mm. Follow-up was completed for 144 patients (99.3 % of the cases). RESULTS: The hospital mortality rate was 1.4 %. There were no significant differences among Groups N, W and R in the freedom from valve-related death and cardiac death at 10 years after surgery. The rates of freedom from aorta-related events in the three groups at 10 years after surgery were 98.3 % (Group-N), 100 % (Group-W) and 100 % (Group-R). CONCLUSIONS: The long-term survival was equivalent among the three groups, and the rates of freedom from aorta-related death or events were low. Our surgical protocol for the treatment of the enlarged ascending aorta associated with BAV is appropriate.

Cardiac energetics analysis after aortic valve replacement with 16-mm ATS mechanical valve.

The 16-mm ATS mechanical valve is one of the smallest prosthetic valves used for aortic valve replacement (AVR) in patients with a very small aortic annulus, and its clinical outcomes are reportedly satisfactory. Here, we analyzed the left ventricular (LV) performance after AVR with the 16-mm ATS mechanical valve, based on the concept of cardiac energetics analysis. Eleven patients who underwent AVR with the 16-mm ATS mechanical valve were enrolled in this study. All underwent echocardiographic examination at three time points: before AVR, approximately 1 month after AVR, and approximately 1 year after AVR. LV contractility (end-systolic elastance [Ees]), afterload (effective arterial elastance [Ea]), and efficiency (ventriculoarterial coupling [Ea/Ees] and the stroke work to pressure-volume area ratio [SW/PVA]) were noninvasively measured by echocardiographic data and blood pressure measurement. Ees transiently decreased after AVR and then recovered to the pre-AVR level at the one-year follow-up. Ea significantly decreased in a stepwise manner. Consequently, Ea/Ees and SW/PVA were also significantly improved at the one-year follow-up compared with those before AVR. The midterm LV performance after AVR with the 16-mm ATS mechanical valve was satisfactory. AVR with the 16-mm ATS mechanical valve is validated as an effective treatment for patients with a very small aortic annulus. The cardiac energetics variables, coupling with the conventional hemodynamic variables, can contribute to a better understanding of the patients' clinical conditions, and those may serve as promising indices of the cardiac function.

Operative modification for the prevention of device-related infection during NIPRO extracorporeal left ventricular assist device implantation.

An operative modification in which the NIPRO left ventricular assist device (LVAD) cannulas are passed through the intraperitoneal cavity is performed as the first-choice standard technique in our institution. Eighteen consecutive patients who underwent NIPRO LVAD implantation as heart transplantation candidates were enrolled in this study. The cannulas were passed through the intraperitoneal cavity in 11 patients (Group IP) and the extraperitoneal space in 7 patients (Group EP). A device-related major infection was defined as bloodstream infection and/or abscess formation in the deep tissue space. Device-related major infection occurred in 6 patients in Group IP and in 6 patients in Group EP. Of these patients, 3 patients in Group IP and 5 patients in Group EP suffered from uncontrollable bloodstream infection and finally died of development into multiple organ failure and/or cerebrovascular accidents. The actuarial rates of freedom from device-related major infection at 6 months after LVAD implantation were 100 % in Group IP and 38 % in Group EP, respectively (p = 0.02). Moreover, the actuarial survival rates after the initial device-related major infection in Group IP could be significantly higher than in Group EP (83 and 67 % at 6 months, p = 0.03). We demonstrated that this operative modification can contribute to prevention of progression of superficial skin infection to critical infection and to extension of the survival duration after the initial device-related major infection.