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.

Cannula to Femoral Artery Diameter Ratio Predicts Potential Lower-Limb Ischemia in Minimally Invasive Cardiac Surgery With Femoral Cannulation.

OBJECTIVE: Lower-limb ischemia is a complication of minimally invasive cardiac surgery with femoral cannulation. Herein, we verified our strategy using distal perfusion cannulation (DPC) against this complication. METHODS: We retrospectively assessed 91 cases of aortic valve replacement with femoral cannulation between January 2019 and March 2023. DPC was applied when lower-limb tissue oxygenation index declined by ≥20%. The cannula to femoral artery diameter ratio (C/FA) was calculated by dividing the cannula size (Fr) divided by 3 by the femoral artery inner diameter (mm). Postoperative maximum creatinine kinase (CKmax), lactate dehydrogenase (LDHmax), and lactate levels were analyzed, and univariable logistic regression and receiver operating characteristic curve analyses were employed to determine DPC predictors and the cutoff C/FA for DPC, respectively. Patients without DPC were divided into 2 subgroups based on the cutoff C/FA for further comparisons. RESULTS: DPC was required in 9 patients. Symptomatic ischemia was not observed. All laboratory data were similar in the DPC and non-DPC groups. C/FA was significantly associated with DPC (odds ratio = 1.27, 95% confidence interval: 1.09 to 1.47, P = 0.002), and the cutoff C/FA was 0.70 (sensitivity = 0.89, specificity = 0.80). In the non-DPC group, CKmax (P = 0.027) and LDHmax (P = 0.041) were significantly higher in patients with C/FA ≥0.7 (n = 16) than in those with C/FA <0.7 (n = 66). CONCLUSIONS: Our strategy for preventing symptomatic ischemia is reasonable and could be almost achieved without DPC when C/FA is <0.7. C/FA also predicts asymptomatic potential ischemia, and proactive DPC is preferable when C/FA is ≥0.7.

Efficacy of Sac Coil Embolization in Endovascular Aortic Repair for Sac Shrinkage in Patients at a High Risk of Type II Endoleak from Lumbar Arteries.

BACKGROUND: In endovascular aortic repair (EVAR), preemptive embolization of sac branch vessels is effective in preventing postoperative type II endoleak (T2EL). However, this technique has not been widely adopted especially for lumbar arteries (LAs) because of technical difficulties and time constraints. This study aimed to investigate the efficacy of nonselective sac coil embolization, which is a simpler surgical method, in postoperative sac shrinkage for patients at a high risk of T2EL from LAs. METHODS: We retrospectively assessed 76 patients who underwent elective EVAR for abdominal aortic aneurysm with 4 or more patent LAs or at least 1 patent LA of ≥2 mm at our hospital between January 2014 and December 2022. The patients who underwent sac coil embolization were included in Group Ⅰ (n = 20), and the others were divided into 2 groups: those with an inferior mesenteric artery that was originally occluded or embolized by coils or stent graft bodies (Group Ⅱ, n = 21), and those without that (Group Ⅲ, n = 35). In Group Ⅰ, 0.035-inch coils were inserted into the sac after complete stent graft deployment. The cumulative incidence of sac shrinkage (≥5 mm) was compared between the groups. Further, univariable and multivariable Cox regression analyses were used to determine the predictors of sac shrinkage. RESULTS: Sac shrinkage (≥5 mm) was observed more frequently in Group Ⅰ (50%) than in Group Ⅱ (19%) and Group Ⅲ (17%) (P = 0.052 and 0.043, respectively). The cumulative incidence of sac shrinkage was significantly higher in Group Ⅰ than in Group Ⅱ (log-rank P = 0.039) and Group Ⅲ (log-rank P = 0.024). Multivariable Cox regression analyses revealed that sac embolization was a significant predictor of sac shrinkage (hazard ratio, 4.23; 95% confidence interval, 1.66-10.8; P = 0.003). CONCLUSIONS: Nonselective sac coil embolization in EVAR is potentially effective for sac shrinkage in the early postoperative phase in patients at high risk of T2EL from LAs. This simple procedure may improve prognosis after EVAR.

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.

Potential of the EVAHEART 2 Double-Cuff Tipless Inflow Cannula for Prevention of Thromboembolic Events.

A 32-year-old man, who had developed fulminant myocarditis leading to asystole, underwent implantation of an EVAHEART 2 left ventricular assist system with a double-cuff tipless inflow cannula and a concurrent Fontan operation. Approximately 2 years after the simultaneous EVAHEART 2 implantation and the Fontan operation, the patient underwent heart transplantation. There was no device-related thromboembolism or pump malfunction under adequate antithrombotic management during the postoperative support period. Computed tomography showed no malposition of the inflow cannula irrespective of the left ventricular chamber size. Macroscopically, the left ventricular cavity of the excised heart revealed a smooth inflow ostium with appropriate intimal proliferation and without pannus or wedge thrombus formation. These findings suggest the utility of the double-cuff tipless inflow cannula for long-term clinical applications, which may lead to favorable outcomes during long-term patient management. The double-cuff tipless inflow cannula, which does not protrude into the left ventricular cavity, potentially contributes to the prevention of suction events and the collision of the inflow cannula with the interventricular septum and left ventricular free wall. Further investigation is required to confirm the role of the unique EVAHEART 2 inflow cannula in reducing thromboembolic events.

Left atrial myxoma resection through right mini-thoracotomy in a patient with retrosternal gastric tube.

We report a case with a retrosternal gastric tube after oesophagectomy, who required left atrial myxoma resection, pulmonary vein isolation and left atrial appendage closure. A right mini-thoracotomy approach was adopted to avoid neo-oesophagus injury, and nitric oxide inhalation was useful to facilitate one-lung ventilation while dissecting the pleural adhesion.

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.

Transgenic Expression of the Formin Protein Fhod3 Selectively in the Embryonic Heart: Role of Actin-Binding Activity of Fhod3 and Its Sarcomeric Localization during Myofibrillogenesis.

Fhod3 is a cardiac member of the formin family proteins that play pivotal roles in actin filament assembly in various cellular contexts. The targeted deletion of mouse Fhod3 gene leads to defects in cardiogenesis, particularly during myofibrillogenesis, followed by lethality at embryonic day (E) 11.5. However, it remains largely unknown how Fhod3 functions during myofibrillogenesis. In this study, to assess the mechanism whereby Fhod3 regulates myofibrillogenesis during embryonic cardiogenesis, we generated transgenic mice expressing Fhod3 selectively in embryonic cardiomyocytes under the control of the ß-myosin heavy chain (MHC) promoter. Mice expressing wild-type Fhod3 in embryonic cardiomyocytes survive to adulthood and are fertile, whereas those expressing Fhod3 (I1127A) defective in binding to actin die by E11.5 with cardiac defects. This cardiac phenotype of the Fhod3 mutant embryos is almost identical to that observed in Fhod3 null embryos, suggesting that the actin-binding activity of Fhod3 is crucial for embryonic cardiogenesis. On the other hand, the ß-MHC promoter-driven expression of wild-type Fhod3 sufficiently rescues cardiac defects of Fhod3-null embryos, indicating that the Fhod3 protein expressed in a transgenic manner can function properly to achieve myofibril maturation in embryonic cardiomyocytes. Using the transgenic mice, we further examined detailed localization of Fhod3 during myofibrillogenesis in situ and found that Fhod3 localizes to the specific central region of nascent sarcomeres prior to massive rearrangement of actin filaments and remains there throughout myofibrillogenesis. Taken together, the present findings suggest that, during embryonic cardiogenesis, Fhod3 functions as the essential reorganizer of actin filaments at the central region of maturating sarcomeres via the actin-binding activity of the FH2 domain.

Left ventricular pacing can be a complementary solution for systolic anterior motion after mitral valve plasty.

A 54-year old man underwent redo mitral valve (MV) plasty because of recurrent mitral regurgitation (MR). Intraoperative transoesophageal echocardiography revealed severe MR and turbulent flow at the left ventricular (LV) outflow tract associated with systolic anterior motion of the MV. Various medical treatments, additional surgical correction, and atrial and right ventricular pacing had failed to resolve the MR associated with systolic anterior motion. LV pacing, however, markedly attenuated MR. Temporary LV pacing was discontinued on postoperative day 2, and subsequently MR associated with systolic anterior motion has not recurred. LV dyssynchrony resulting from conduction disturbances might cause systolic anterior motion immediately after MV plasty. We speculate that LV pacing eliminated LV dyssynchrony and improved the MR associated with systolic anterior motion. Temporary LV pacing can be performed easily and safely at the time of MV plasty. LV pacing can be a complementary treatment for systolic anterior motion and resultant MR.

Immunoglobulin G4-related multiple cardiovascular lesions successfully treated with a combination of open surgery and corticosteroid therapy.

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.

Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis.

Heart development requires organized integration of actin filaments into the sarcomere, the contractile unit of myofibrils, although it remains largely unknown how actin filaments are assembled during myofibrillogenesis. Here we show that Fhod3, a member of the formin family of proteins that play pivotal roles in actin filament assembly, is essential for myofibrillogenesis at an early stage of heart development. Fhod3(-/-) mice appear normal up to embryonic day (E) 8.5, when the developing heart, composed of premyofibrils, initiates spontaneous contraction. However, these premyofibrils fail to mature and myocardial development does not continue, leading to embryonic lethality by E11.5. Transgenic expression of wild-type Fhod3 in the heart restores myofibril maturation and cardiomyogenesis, which allow Fhod3(-/-) embryos to develop further. Moreover, cardiomyopathic changes with immature myofibrils are caused in mice overexpressing a mutant Fhod3, defective in binding to actin. These findings indicate that actin dynamics, regulated by Fhod3, participate in sarcomere organization during myofibrillogenesis and thus play a crucial role in heart development.

Expression and subcellular localization of mammalian formin Fhod3 in the embryonic and adult heart.

The formin family proteins play pivotal roles in actin filament assembly via the FH2 domain. The mammalian formin Fhod3 is highly expressed in the heart, and its mRNA in the adult heart contains exons 11, 12, and 25, which are absent from non-muscle Fhod3 isoforms. In cultured neonatal cardiomyocytes, Fhod3 localizes to the middle of the sarcomere and appears to function in its organization, although it is suggested that Fhod3 localizes differently in the adult heart. Here we show, using immunohistochemical analysis with three different antibodies, each recognizing distinct regions of Fhod3, that Fhod3 localizes as two closely spaced bands in middle of the sarcomere in both embryonic and adult hearts. The bands are adjacent to the M-line that crosslinks thick myosin filaments at the center of a sarcomere but distant from the Z-line that forms the boundary of the sarcomere, which localization is the same as that observed in cultured cardiomyocytes. Detailed immunohistochemical and immuno-electron microscopic analyses reveal that Fhod3 localizes not at the pointed ends of thin actin filaments but to a more peripheral zone, where thin filaments overlap with thick myosin filaments. We also demonstrate that the embryonic heart of mice specifically expresses the Fhod3 mRNA isoform harboring the three alternative exons, and that the characteristic localization of Fhod3 in the sarcomere does not require a region encoded by exon 25, in contrast to an essential role of exons 11 and 12. Furthermore, the exon 25-encoded region appears to be dispensable for actin-organizing activities both in vivo and in vitro, albeit it is inserted in the catalytic FH2 domain.

Mammalian formin fhod3 regulates actin assembly and sarcomere organization in striated muscles.

Actin filament assembly in nonmuscle cells is regulated by the actin polymerization machinery, including the Arp2/3 complex and formins. However, little is known about the regulation of actin assembly in muscle cells, where straight actin filaments are organized into the contractile unit sarcomere. Here, we show that Fhod3, a myocardial formin that localizes to thin actin filaments in a striated pattern, regulates sarcomere organization in cardiomyocytes. RNA interference-mediated depletion of Fhod3 results in a marked reduction in filamentous actin and disruption of the sarcomeric structure. These defects are rescued by expression of wild-type Fhod3 but not by that of mutant proteins carrying amino acid substitution for conserved residues for actin assembly. These findings suggest that actin dynamics regulated by Fhod3 are critical for sarcomere organization in striated muscle cells.

Clinical results of commissure plication annuloplasty for mitral regurgitation in children.

PURPOSE: We evaluated the clinical results of commissure plication annuloplasty for mitral regurgitation (MR) in children. METHODS: Twenty-eight patients underwent a valve repair with commissure plication annuloplasty for MR from 1988 to 2005. The mean age was 2.7 +/- 3.3 years. Several appropriate techniques were combined (cleft closure in 5 patients, chordal shortening in 2 patients, artificial chordal replacement in 4 patients, leaflet fixation in 2 patients, and so on). The mean follow-up period was 6.2 years. RESULTS: There was one operative death (3.6%) and no late deaths. Two patients underwent a second repair 19 and 23 months after their initial repairs. The actuarial freedom from the reoperation rate was 90.4% +/- 0.6% at 10 years. The freedom from moderate MR or more was shown to decrease over time, 87.8% +/- 0.7% at 5 years and 78.0% +/- 11.0% at 10 years. Furthermore, the 10-year freedom from mild MR or more was 56.5% +/- 11.9%. A progression of MR was seen. Most of the residual or recurrent MR cases weighed less than 10 kg at operation. CONCLUSIONS: The combination of commissure plication annuloplasty and several appropriate techniques provided adequate results for MR in children. Since a progression of MR was observed, a careful follow-up is therefore needed in such cases.

Surgical results of anomalous origin of the right pulmonary artery from the ascending aorta including reoperation for infrequent complications.

BACKGROUND: We evaluated the results of surgery for an anomalous origin of the right pulmonary artery from the ascending aorta. METHODS: From August 1986 to December 2005, 8 children (6 neonates) aged 7 to 180 days (mean, 35 +/- 59 days) with anomalous origin of the right pulmonary artery from the ascending aorta underwent surgical repair at our institute. All except one child, who had the distal form, had the proximal form. Cardiac catheterization showed that the left pulmonary artery to systemic pressure ratio was 1.0 or more. Surgery was performed by direct anastomosis in 7 patients and by graft interposition in 1. RESULTS: There were no operative or late deaths. All patients postoperatively underwent cardiac catheterization that showed decreased left pulmonary artery to systemic pressure ratio ranging from 0.2 to 0.6. Follow-up periods ranged from 2 months to 13 years. We undertook reoperations for two infrequent postoperative causes. One patient exhibited significant supravalvar aortic stenosis and required patch enlargement of the ascending aorta 3 years after operation. The other patient (with the distal form) needed a reoperation after 1 month because of progressive stenosis at the anatomic site. Graft interposition was performed, and histopathologic examination showed that the tissue from the stenotic region looked like that of a ductus. CONCLUSIONS: We undertook surgical repair for anomalous origin of the right pulmonary artery from the ascending aorta. Pulmonary hypertension was improved in all patients. Careful follow-up was necessary to detect supravalvar aortic and anastomotic stenosis early and late after operation.