Nardilysin in vascular smooth muscle cells controls blood pressure via the regulation of calcium dynamics.

Blood pressure is a crucial physiological parameter and its abnormalities can cause a variety of health problems. We have previously reported that mice with systemic deletion of nardilysin (NRDC), an M16 family metalloprotease, exhibit hypotension. In this study, we aimed to clarify the role of NRDC in vascular smooth muscle cell (VSMC) by generating VSMC-specific Nrdc knockout (VSMC-KO) mice. Our findings reveal that VSMC-KO mice also exhibit hypotension. Aortas isolated from VSMC-KO mice exhibited a weakened contractile response to phenylephrine, accompanied by reduced phosphorylation of myosin light chain 2 and decreased rhoA expression. VSMC isolated from VSMC-KO aortas showed a reduced increase in intracellular Ca2+ concentration induced by α-stimulants. These findings suggest that NRDC in VSMC regulates vascular contraction and blood pressure by modulating Ca2+ dynamics.

Location of the False Lumen Within the Medial Layer in Acute Intramural Hematoma.

BACKGROUND: We compared the location of the false lumen within the medial layer between acute intramural hematoma (AIH) and acute aortic dissection (AAD) using microscopic images of aortic specimens and examined the associations with patient characteristics, CT findings, and late outcomes.Methods and Results: Among 293 patients undergoing surgery for Stanford type A acute aortic syndrome between 2008 and 2018, 45 patients had neither an identifiable intimal tear, flow to the false lumen on preoperative CT or intimal tear by intraoperative observation (AIH group), and 98 patients with patent false lumen were enrolled (AAD group). The AIH group had a significantly thinner outer media thickness (OMT) than the AAD group. The AIH group showed more pericardial effusion, but distal progression of dissection and branch vessel involvement were limited. The change in aortic diameter after surgery was insignificant in the AIH group, whereas in the AAD group it continued to increase. Cumulative incidence of aortic adverse events was significantly higher among AAD patients, but no significant difference was observed in survival between groups. CONCLUSIONS: The AIH group had a significantly thinner OMT than the AAD group, which was significantly associated with a large amount of pericardial effusion, greater false lumen diameter, and limited progression of aortic dissection.

Left Atrial Appendage Closure During Coronary Bypass Surgery in Patients on Hemodialysis.

BACKGROUND: Patients with end-stage renal disease on hemodialysis (ESRD-HD) have a lifelong risk of atrial fibrillation-related stroke. We compared clinical outcomes in ESRD-HD patients undergoing coronary artery bypass grafting (CABG) with and without concomitant left atrial appendage (LAA) closure.Methods and Results: Of 2,783 consecutive patients undergoing isolated CABG between 2002 and 2020, 242 patients had ESRD-HD with sinus rhythm. The primary outcome was a composite of death and stroke. An inverse probability (IP)-weighted cohort was created based on the propensity score. The 2 IP-weighted groups had well-balanced baseline and surgical backgrounds, with an equivalent follow-up. Five-year stroke-free survival was significantly higher in patients with LAA closure (log-rank test, P=0.035). The adjusted hazard ratio of LAA closure for death and stroke was 0.43 (95% confidence interval [CI] 0.20-0.92; P=0.023). Competing risk analysis showed that LAA closure was significantly associated with a risk reduction of stroke (subhazard ratio 0.26; 95% CI 0.08-0.96; P=0.028). No significant difference was observed in adjusted risk ratios for reoperation for bleeding, new atrial fibrillation, 30-day mortality, and readmission for heart failure. CONCLUSIONS: Concomitant LAA closure during CABG can reduce the risk of death and stroke in ESRD-HD patients with normal sinus rhythm.

Hyperlactatemia as a Risk Stratification for Postinfarction Ventricular Septal Rupture.

BACKGROUND: Surgical repair for postinfarction ventricular septal rupture (VSR) is a challenging operation, especially in the acute phase with unstable hemodynamics. We retrospectively examined the value of measuring lactate, which can be a quantitative indicator of end-organ ischemia caused by multiple factors including ineffective cardiac output, for risk stratification in patients undergoing surgical repair. METHODS: From April 2008 to December 2018, 33 consecutive patients were admitted to our hospital with a diagnosis of VSR and underwent VSR repair surgery within 24 hours of admission. We categorized patients into 3 groups based on the distribution of preoperative blood lactate level: <5 mmol/L (n = 16), 5 to 10 mmol/L (n = 11), and >10 mmol/L (n = 6). RESULTS: There was no intraoperative death, but the prognosis for patients with lactate >10 mmol/L was extremely poor, with a median postoperative survival time of only 23 days [25th percentile 6, 75th percentile 30]. Five of 6 patients (83%) died within 30 days after surgery. The risk-adjusted hazard ratio (95% confidence interval) for mortality per 1 SD (0.41-unit) increase in log-transformed preoperative lactate level (equivalent to a 4.10-fold increase) was 2.85 (1.57 to 5.19). Patients with lactate 5 to 10 mmol/L had 3.95-fold and those with lactate >10 mmol/L had 6.03-fold higher risk of mortality than those with lactate <5 mmol/L. CONCLUSION: Elevation of preoperative serum lactate is significantly associated with mortality in patients who underwent VSR repair. The findings of this study highlight the value of measuring lactate level for risk stratification.

[Stanford Type A Aortic Dissection with Tricuspid Regurgitation in a Patient with Situs Inversus Totalis].

Situs inversus totalis is a congenital anomaly characterized by a mirror image transposition of the normal visceral organs, which makes it difficult to perform aortic surgery accurately. Stanford type A aortic dissection in patients with this condition is very rare and difficult to assess and manage. We report a case of Stanford type A aortic dissection with situs inversus totalis. The patient presented with severe tricuspid regurgitation with annulus enlargement due to chronic atrial fibrillation, requiring ascending aortic replacement and tricuspid annuloplasty. These procedures were performed after the operator swapped the left and right positions during the operation. Postoperative course was uneventful. By carefully checking the preoperative computed tomography images and changing the operator's position during the operation, it is possible to safely perform Stanford type A aortic dissection surgery in patients with situs inversus totalis.

[A Rapidly Growing Cardiac Calcified Amorphous Tumor in a Peritoneal Dialysis Patient:Report of a Case].

A calcified amorphous tumor( CAT) is a non-neoplastic cardiac tumor, which has been reported to be associated with hemodialysis dependent end-stage renal disease. We report a case of CAT attached to mitral annular calcification (MAC) in the posterior leaflet annulus of the mitral valve in a 56-year-old man who had been receiving peritoneal dialysis for three years. The CAT grew to 10 mm long in a half year. Peritoneal dialysis dependent end-stage renal disease is associated with MAC. Additionally, MAC-related CAT has been reported growing rapidly. We should perform periodic echocardiography not only for hemodialysis patients but also for peritoneal dialysis patients. When CAT is diagnosed, operation should be performed early to prevent embolism such as cerebral infarction.

Bilateral Internal Thoracic Artery Grafting in Hemodialysis Patients.

BACKGROUND: We compared postoperative outcomes in hemodialysis (HD) patients who underwent isolated coronary artery bypass grafting (CABG) for multivessel disease using either bilateral or single skeletonized internal thoracic artery.Methods and Results:Among 1,486 patients who underwent isolated CABG between 2002 and 2020, 145 HD patients were retrospectively analyzed. After inverse probability of treatment weighting, there were no significant differences in the preoperative characteristics. No significant differences in 30-day mortality (P=0.551) or postoperative deep sternal wound infection (P=0.778) were observed. However, the bilateral internal thoracic artery grafting group had a lower postoperative stroke rate (0% vs. 4.0%, P=0.019). No significant differences in freedom from all-cause death (P=0.760) and cardiac death (P=0.863) were found. In the multivariate Cox proportional hazards models, bilateral internal thoracic artery grafting was not associated with all-cause death (P=0.246) or cardiac death (P=0.435). CONCLUSIONS: Bilateral internal thoracic artery grafting in HD patients did not improve mid-term outcomes, but it was also not associated with worse postoperative outcomes. Use of the bilateral internal thoracic artery may be an important option in patients with limited conduits to prevent postoperative complications.

Total arch replacement in patients with chronic kidney disease.

BACKGROUND: We investigated the effect of preoperative renal dysfunction on postoperative outcomes in patients undergoing elective isolated total arch replacement (TAR) with mild hypothermic lower body circulatory arrest with antegrade selective cerebral perfusion (SCP). METHODS: One hundred and forty-four patients who had undergone elective isolated TAR between January 2002 and December 2019 were retrospectively analyzed. Patients were divided into two groups according to whether their preoperative estimated glomerular filtration rate (eGFR) was lower than or higher than 60 ml/min/1.73 m2 . We compared perioperative data and mid-term outcomes after adjusting for patients' baseline characteristics using weighted logistic regression analysis and inverse probability of treatment weighting. RESULTS: More patients underwent postoperative stroke in the chronic kidney disease group compared with the normal group (2.8% vs. 0%, respectively; p = .049). Overall 30-day mortality and hospital mortality were 0% in both groups, and there was no significant difference in overall survival between the two groups (log-rank test, p = .129). Multivariate Cox proportional hazard analysis showed that eGFR < 60 ml/min/1.73 m2 was not an independent predictor (hazard ratio: 1.636, 95% confidence interval 0.829-3.231; p = .156). CONCLUSIONS: Preoperative eGFR <60 ml/min/1.73 m2 was not associated with worse outcomes after elective isolated TAR with mild hypothermic lower body circulatory arrest with antegrade SCP.

Garcinielliptone G from Garcinia subelliptica Induces Apoptosis in Acute Leukemia Cells.

Cytotoxicity and apoptosis-inducing properties of compounds isolated from Garcinia subelliptica leaves were investigated. The hexane-soluble portion of MeOH extracts of G. subelliptica leaves that showed cytotoxic activity was separated to yield seven compounds 1-7. Chemical structure analysis using NMR spectroscopy and mass spectrometry confirmed that compound 1 was canophyllol, and compounds 2-7 were garcinielliptones N, O, J, G, F, and garcinielliptin oxide, respectively. Among them, garcinielliptone G (5) showed growth inhibition by causing apoptosis in THP-1 and Jurkat cells derived from human acute monocytic leukemia and T lymphocyte cells, respectively. Apoptosis induced by garcinielliptone G (5) was demonstrated by the detection of early apoptotic cells with fluorescein-labeled Annexin V and increases in cleaved caspase-3 and cleaved PARP protein levels. However, the addition of caspase inhibitor Z-VAD-FMK did not affect growth arrest or apoptosis induction. These results suggest that garcinielliptone G (5) can induce both caspase-3 activation and caspase-independent apoptosis. Therefore, garcinielliptone G (5) may be a potential candidate for acute leukemia treatment.

Caspase-7 mediates caspase-1-induced apoptosis independently of Bid.

Inflammasomes are innate immune mechanisms that activate caspase-1 in response to a variety of stimuli, including Salmonella infection. Active caspase-1 has a potential to induce two different types of cell death, depending on the expression of the pyroptosis mediator gasdermin D (GSDMD); following caspase-1 activation, GSDMD-sufficient and GSDMD-null/low cells undergo pyroptosis and apoptosis, respectively. Although Bid, a caspase-1 substrate, plays a critical role in caspase-1 induction of apoptosis in GSDMD-null/low cells, an additional mechanism that mediates this cell death independently of Bid has also been suggested. This study investigated the Bid-independent pathway of caspase-1-induced apoptosis. Caspase-1 has been reported to process caspase-6 and caspase-7. Silencing of caspase-7, but not caspase-6, significantly reduced the activation of caspase-3 induced by caspase-1, which was activated by chemical dimerization, in GSDMD/Bid-deficient cells. CRISPR/Cas9-mediated depletion of caspase-7 had the same effect on the caspase-3 activation. Moreover, in the absence of GSDMD and Bid, caspase-7 depletion reduced apoptosis induced by caspase-1 activation. Caspase-7 was activated following caspase-1 activation independently of caspase-3, suggesting that caspase-7 acts downstream of caspase-1 and upstream of caspase-3. Salmonella induced the activation of caspase-3 in GSDMD-deficient macrophages, which relied partly on Bid and largely on caspase-1. The caspase-3 activation and apoptotic morphological changes seen in Salmonella-infected GSDMD/Bid-deficient macrophages were attenuated by caspase-7 knockdown. These results suggest that in addition to Bid, caspase-7 can also mediate caspase-1-induced apoptosis and provide mechanistic insights into inflammasome-associated cell death that is one major effector mechanism of inflammasomes.

Segmental Difference in Vasoreactivity of the Human Right Gastroepiploic Artery.

BACKGROUND: The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.Methods and Results:The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end). Concentration-response curves for vasoconstrictors (phenylephrine, prostaglandin F2α, and endothelin-1) and vasodilators (carperitide, nitroglycerin, and nifedipine) were then established using organ baths. All the vasoconstrictors and vasodilators produced concentration-dependent responses in each section. As the concentration of the vasoconstrictors increased, segments at the distal section showed a significantly greater contraction than those at the middle and proximal sections regardless of the type of vasoconstrictor. The effective concentration of drugs that caused 50% of the maximal response for endothelin-1 was significantly greater in the distal section than that in the proximal sections. No significant difference was found in vasodilators-induced relaxation. CONCLUSIONS: The contractility increases toward to the end of the GEA. Clinically, the distal portion of the GEA should be trimmed off and not be used as an anastomotic site wherever possible.

Responsiveness of internal thoracic arteries to nitroglycerin in patients with renal failure.

Nitroglycerin is commonly used as an antispasmodic for treating spasm of coronary artery bypass grafts. This study investigated whether the presence of renal failure affects reactivity to nitroglycerin in internal thoracic arteries obtained from patients undergoing coronary bypass surgery. The patients were divided into three groups according to estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): without renal failure (60 ≤ eGFR, n = 13), with moderate renal failure (30 ≤ eGFR < 60, n = 10), and with severe renal failure (eGFR < 30, n = 10). Organ chamber technique was used to evaluate concentration-related responses of isolated internal thoracic arteries to vasodilators. Nitroglycerin induced a concentration-dependent relaxation, which was significantly augmented in patients with severe but not moderate renal failure than in those without renal failure. In addition, there was a negative correlation between eGFR and the relaxant efficacy of nitroglycerin (P = 0.016). On the other hand, relaxant responses to BAY 60-2770 (which enhances cGMP generation as with nitroglycerin) were similar among three grades of renal function. An inverse relationship of eGFR to the relaxant efficacy of BAY 60-2770 was not observed, either (P = 0.314). These findings suggest that severe renal failure specifically potentiates nitroglycerin-induced relaxation in internal thoracic artery grafts.

[Cor Triatriatum in an Adult Patient Conbined with Mitral Regurgitation and Coronary Artery Disease;Report of a Case].

A 71-year-old female, who had been diagnosed with cor triatriatum 30 years before, presented with complains of worsening dyspnea and fatigue. She was diagnosed with a combination of cor triatriatum, mitral valve disease and coronary artery disease. She underwent removal of the left atrial membrane, repair of the mitral valve and coronary artery bypass grafting. This combination of cor triatriatum, mitral valve disease and coronary artery disease is exceedingly rare. She remains well at 3 years' follow-up.

Vitamin B6 Prevents IL-1ß Protein Production by Inhibiting NLRP3 Inflammasome Activation.

Vitamin B6 includes six water-soluble vitamers: pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), and their phosphorylated forms. Pyridoxal 5'-phosphate (PLP) is an important cofactor for many metabolic enzymes. Several lines of evidence demonstrate that blood levels of PLP are significantly lower in patients with inflammation than in control subjects and that vitamin B6 has anti-inflammatory effects, with therapeutic potential for a variety of inflammatory diseases. Although one of our group previously demonstrated that PL inhibits the NF-κB pathway, the molecular mechanism by which vitamin B6 suppresses inflammation is not well understood. Here, we showed that both PL and PLP suppressed the expression of cytokine genes in macrophages by inhibiting Toll-like receptor (TLR)-mediated TAK1 phosphorylation and the subsequent NF-κB and JNK activation. Furthermore, PL and PLP abolished NLRP3-dependent caspase-1 processing and the subsequent secretion of mature IL-1ß and IL-18 in LPS-primed macrophages. In contrast, PM and PN had little effect on IL-1ß production. PLP, but not PL, markedly reduced the production of mitochondrial reactive oxygen species (ROS) in peritoneal macrophages. Importantly, PL and PLP reduced IL-1ß production induced by LPS and ATP, or by LPS alone, in mice. Moreover, PL and PLP protected mice from lethal endotoxic shock. Collectively, these findings reveal novel anti-inflammatory activities for vitamin B6 and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome.

Valve Phenotype and Risk Factors of Aortic Dilatation After Aortic Valve Replacement in Japanese Patients With Bicuspid Aortic Valve.

BACKGROUND: The aim of this study was to assess the risk factors for dilatation of the aorta over time in Japanese patients with bicuspid aortic valve (BAV) undergoing aortic valve replacement (AVR), focusing on the possible impact of valve fusion phenotype. METHODS AND RESULTS: Of 167 BAV patients undergoing AVR (24% of overall AVR patients, n=702), 135 patients in whom surgical intervention for the aorta was not undertaken were focused on (74 had right-left fusion and 61 non-right-left fusion type). During a mean follow up of 5.2 years, aortic growth rate (mm/year) of the ascending aorta was similar between the valve phenotype. In multivariate logistic regression, the presence of aortic regurgitation > moderate was significantly associated with a rapid dilatation of the ascending aorta, defined as >0.7 mm/year (odds ratio 2.1, 95% confidence interval 1.2-3.7, P=0.03). Independent predictors of dilatation of the aorta up to more than 45 mm were: a diameter of the ascending aorta >40 mm at the time of surgery (odds ratio 3.7, 95% confidence interval 1.2-11.4, P=0.02) and length of follow up (odds ratio 1.3-increase per year, 95% confidence interval 1.0-1.5, P=0.04). CONCLUSIONS: The presence of aortic regurgitation and the ascending aorta of >40 mm at the time of surgery emerged as significant predictors of dilatation of the aorta after AVR but valve fusion phenotype was not. (Circ J 2016; 80: 1356-1361).

Reoperative median sternotomy following the use of a right internal mammary artery pedicle graft crossing the midline to the left anterior descending artery.

BACKGROUND AND AIM: The purpose of the present study was to examine the outcomes of cardiac reoperations for the patients with a previously placed pedicled graft of the right internal thoracic artery (RITA) to the left anterior descending artery (LAD). METHODS: Of 1002 consecutive patients who underwent isolated coronary bypass surgery, 612 patients received pedicled grafts of skeletonized RITA to the LAD crossing the midline over the aorta. Of this cohort, seven patients underwent cardiac reoperations via a median resternotomy including aortic valve replacement, mitral valve plasty, and total arch replacement. Covering the RITA with pericardium and mediastinal tissue had been routinely performed in the initial operation. RESULTS: Preoperative computed tomography (CT) angiography showed the RITA at a safe distance from the sternum in six patients. No graft injury occurred during dissection. The patient who underwent emergent total arch replacement died from global brain ischemia at postoperative day 11. The remaining six patients recovered well without major complication and survived at 7.5 ± 4.5 years after reoperations. CONCLUSIONS: Cardiac reoperation via a median sternotomy can be performed at acceptable risk in patients with the RITA graft crossing the midline. Specific maneuvers should be applied in the first coronary artery bypass grafting to keep the RITA at the level of the aortic plane and prevent migration toward the sternum. Preoperative CT angiography is an important tool to understand the surgical anatomy and determine the safety of reoperation.

Surgical repair of Kommerell's diverticulum and an aberrant subclavian artery.

PURPOSE: The coexistence of Kommerell's diverticulum and an aberrant subclavian artery (ASCA) is a rare congenital variation of the vascular structure. We report our experience of treating aneurysms associated with these anomalies. METHODS: Between June 2007 and November 2011, five consecutive patients underwent repair of an aneurysm associated with Kommerell's diverticulum and an ASCA at Shiga University Hospital. Four of the five patients had a right-sided aortic arch associated with the ASCA. One patient underwent emergency surgery for a ruptured thoracic aneurysm. The operations performed were descending aorta replacement through right thoracotomy in one patient and total arch replacement through a median thoracotomy, under deep hypothermic circulatory arrest and selective cerebral perfusion, in four patients. No staged operation was required. RESULTS: One patient died of mediastinitis, subsequent to a ruptured Kommerell's diverticulum, 45 days postoperatively. There were no other deaths in the early or late (6-58 months) postoperative period. One patient required re-exploration for bleeding, but none of the patients suffered neurologic complications. CONCLUSIONS: Aortic disease with an ASCA and Kommerell's diverticulum can be repaired safely under elective conditions.

Long-Term Outcomes of Coronary Artery Bypass Grafting Using an Internal Thoracic Artery versus a Radial Artery as a Second Arterial Graft.

PURPOSE: To compare the outcomes of left circumflex artery (LCx) revascularization using an internal thoracic artery (ITA) or radial artery (RA) as the second arterial graft. METHODS: Patients who underwent primary isolated coronary artery bypass grafting with left anterior descending artery revascularization using an ITA and LCx revascularization using another bilateral ITA (BITA group) or an RA (ITA-RA group) were included. All-cause mortality (primary endpoint), cardiac death, major adverse cardiac events, in-hospital death, and deep sternal wound infection (secondary endpoints) were evaluated. RESULTS: Among 790 patients (BITA, n = 548 (69%); ITA-RA, n = 242 (31%)), no significant difference in all-cause mortality between the groups was observed (hazard ratio (HR): 0.87; 95% confidence interval (CI): 0.67-1.12; p = 0.27) during follow-up (mean, 10 years). Multivariate analysis revealed that the BITA group exhibited significantly lower rates of long-term all-cause mortality (HR: 0.63; 95% CI: 0.48-0.84; p = 0.01). In the propensity-matched cohort (n = 480, 240 pairs), significantly fewer all-cause deaths occurred in the BITA group (HR: 0.66; 95% CI 0.47-0.93; p = 0.02). There were no significant differences in secondary outcomes. CONCLUSIONS: When used as second grafts for LCx revascularization, ITA grafts may surpass RA grafts in reducing all-cause mortality 10 years postoperatively.

Abietane diterpenoids and a sesquiterpene pyridine alkaloid from Euonymus lutchuensis.

Four new abietane diterpenoids (1-4), a new 9(10→20)-abeo-abietane diterpenoid (5), and a new sesquiterpene pyridine alkaloid (6) were isolated from the roots of Euonymus lutchuensis along with 19 known compounds. The structures of the new compounds were elucidated by interpretation of the spectroscopic data.

Place attachment among rural migrants and returnees: case of Shuangfeng County, China.

In the mobile era, place attachment among rural migrants and returnees has become dynamic and diversified. However, research on place attachment to native place among rural migrants and returnees is limited. The focus of previous research has primarily been on the destination place attachment of rural migrants, which makes it difficult to gain a comprehensive understanding of the place attachment among both rural migrants and returnees. This study aims to investigate the state of place attachment to both native and destination places among rural migrants and returnees originating from the same birthplace. It explores their place attachment after migrating from rural areas to cities. A quantitative research approach was adopted, garnering questionnaire responses from 274 rural migrants and returnees, all born in Shuangfeng County, Hunan Province. The questionnaire encompassed a Likert scale for measuring place attachment, as well as sociodemographic statistical information. Exploratory factor analysis and confirmatory factor analysis were conducted to ascertain the reliability and validity of the questionnaire. Based on the factor scores of place attachment to both places from migrants and returnees, a two-step cluster analysis identified three types of migrants and two types of returnees. Chi-square tests revealed significant differences among migrants in terms of property ownership, educational level, marital status, presence of children, age at departure, and time away from hometown. The study discovered that, regardless of being a migrant or returnee, the overall attachment to hometown was stronger than that to the current or previously inhabited city. In the context of existing literature primarily concerned with the integration of rural migrants into urban areas, this paper offers a fresh research perspective, highlighting the significance of emotional ties to one's hometown for rural migrants. The findings of this paper provide direction and a theoretical basis for rural areas to attract return migration and for urban regions to facilitate the integration of migrants.