荒川 衛

OBJECTIVE: The predissection aortic diameter is the best reference for determining the size of the frozen elephant trunk in aortic dissection. We aimed to develop a new prediction method to estimate the predissection diameter of proximal descending aorta. Furthermore, we evaluated the accuracy of the estimated predissection proximal descending aortic diameters calculated using 3 prediction methods. METHODS: A total of 39 patients with acute type A aortic dissection who underwent predissection computed tomography were included in derivation sets. We measured the aortic dimensions at 3 levels of the proximal descending aorta: 5, 10, and 15 cm from zone 2. We developed a new prediction method-postdissection aortic diameter divided by 1.13 (AoDNew factor)-and estimated the predissection aortic diameter using the new and previously proposed methods by Rylski (AoDRylski) and Yamauchi (EquationYamauchi). Furthermore, we validated the new prediction method using a validation dataset with 24 patients. RESULTS: The rate of bias ≤2 mm was significantly greater with EquationYamauchi and AoDNew factor than with AoDRylski in the derivation group at each level of the proximal descending aorta (P < .001). In the validation group, the rate of bias ≤2 mm was significantly greater with EquationYamauchi and AoDNew factor than with AoDRylski at 10 cm and 15 cm from zone 2 (10 cm: P = .014, 15 cm: P < .001). CONCLUSIONS: These results suggest that the new prediction method can be used as a simple and accurate estimation method for the predissection aortic diameter at the proximal descending aorta.

OBJECTIVES: Zone 2 anastomosis with total cervical branch reconstruction for acute type A aortic dissection and aortic arch aneurysms became possible after stent-graft introduction. This may be an easier procedure and reduce the risk of recurrent laryngeal nerve palsy. Therefore, this study aimed to compare the outcomes between Zone 2 and Zone 3 distal anastomoses. METHODS: After evaluating the patient data in our institute between April 2016 and April 2022, the patients in whom distal anastomosis was performed at Zone 2 with a stent-graft were defined as the Zone 2 group (n = 70). The patients in whom distal anastomosis was performed at Zone 3 were defined as the Zone 3 group (n = 24). RESULTS: The incidence of new-onset recurrent nerve palsy was one patient (1.4%) in the Zone 2 group and six patients (25.0%) in the Zone 3 group (p < 0.001). The lower body perfusion arrest time was 44.3 ± 9.1 min in the Zone 2 group and 52.9 ± 12.8 min in the Zone 3 group (p = 0.005). There were no significant differences in in-hospital mortality and morbidities. Multivariable analysis showed that only age was an independent predictor of overall mortality. CONCLUSIONS: Performing distal anastomosis at Zone 2 with a frozen elephant trunk or stent-graft reduced the lower body perfusion arrest time and possibly prevented recurrent nerve palsy.

Malignant cardiac tumor is a rare tumor with extremely poor prognosis, and metastatic cardiac tumor causes superior vena cava( SVC) syndrome. A 52-year-old man visited a clinic with a chief complaint of facial edema. Contrast-enhanced computed tomography( CT) revealed a mass in the right atrium( RA)obstructing the SVC. Echocardiography revealed a mass about to incarcerate the tricuspid valve orifice. The patient was transferred to our institution for emergency surgery. Tumor resection was performed under general anesthesia. A cardiopulmonary bypass was established with cannulate in the ascending aorta, in the RA through the right femoral vein, and in the left ventricle for venting. The RA was incised, and the tumor was resected. The SVC was incised, and the tumor and blood clots were removed. Because adhesion between vessel wall and the mass was tight, complete mass removal and recanalization of the SVC was not attempted. Pathological diagnosis was metastatic squamous cell carcinoma. All imaging studies failed to identify primary lesions. The clinical course was uneventful, and the patient was discharged on postoperative day 17. Four months postoperatively, chemotherapy for squamous cell carcinoma was initiated. The patient is alive at approximately 28 months postoperatively.

A 78-year-old man presented with severe stage 3 (Fontaine IV, Rutherford 5, W1 I3 FI0) right limb ischemia. Although his artery was completely occluded from below the right external iliac to the popliteal artery, collateral circulation from the right lateral femoral circumflex artery was well developed and supplied the lower extremity arteries. We selected an uncommon crossover bypass strategy with the left common femoral artery to the right lateral femoral circumflex artery to improve lower extremity perfusion via indirect revascularization. Bypass using the lateral femoral circumflex artery as an outflow is an option for patients with major lower extremity artery occlusions.

Thoracic endovascular aortic repair is widely used for type B aortic dissection. However, there is no favorable stent-graft for type A aortic dissection. A significant limitation for device development is the lack of an experimental model for type A aortic dissection. We developed a novel three-dimensional biomodel of type A aortic dissection for endovascular interventions. Based on Digital Imaging and Communication in Medicine data from the computed tomography image of a patient with a type A aortic dissection, a three-dimensional biomodel with a true lumen, a false lumen, and an entry tear located at the ascending aorta was created using laser stereolithography and subsequent vacuum casting. The biomodel was connected to a pulsatile mock circuit. We conducted four tests: an endurance test for clinical hemodynamics, wire insertion into the biomodel, rapid pacing, and simulation of stent-graft placement. The biomodel successfully simulated clinical hemodynamics; the target blood pressure and cardiac output were achieved. The guidewire crossed both true and false lumens via the entry tear. The pressure and flow dropped upon rapid pacing and recovered after it was stopped. This simulation biomodel detected decreased false luminal flow by stent-graft placement and detected residual leak. The three-dimensional biomodel of type A aortic dissection with a pulsatile mock circuit achieved target clinical hemodynamics, demonstrated feasibility for future use during the simulated endovascular procedure, and evaluated changes in the hemodynamics.

Negative impact of prosthesis-patient mismatch on long-term survival after valve replacement has been reported. However, the effect of prosthesis-patient mismatch after bioprosthetic mitral valve replacement has not yet been well examined. The purpose of this study was to investigate the effect of prosthesis-patient mismatch on late outcomes after bioprosthetic mitral valve replacement for mitral regurgitation. A total of 181 patients underwent bioprosthetic mitral valve replacement between April 2008 and December 2016. After excluding patients with mitral stenosis and those with incomplete data, 128 patients were included in the study. Postoperative transthoracic echocardiography was performed before discharge for all patients and the effective orifice area of bioprosthetic mitral valve was calculated using the formula: 220/pressure half-time, and the effective orifice area index was calculated by the formula: effective orifice area/body surface area. Prosthesis-patient mismatch was defined as a postoperative effective orifice area index ≤ 1.2 cm2/m2. The characteristics and outcomes were compared between the groups. There were 34 patients (26.6%) with prosthesis-patient mismatch and 94 patients (73.4%) without prosthesis-patient mismatch. There were no significant differences in the in-hospital mortality and morbidities. Multivariable analysis showed that prosthesis-patient mismatch was an independent predictor of late mortality (hazard ratio 3.38; 95% confidence interval 1.69-6.75; p = 0.001) and death from heart failure (hazard ratio 31.03, 95% confidence interval 4.49-214.40, p < 0.001). Prosthesis-patient mismatch at discharge after mitral valve replacement for mitral regurgitation was associated with long-term mortality and death from heart failure.

PURPOSE: We describe a pull-through pull-back technique to revascularize the left common carotid artery (LCCA) that was unintentionally covered during thoracic endovascular aortic repair (TEVAR). CASE REPORT: A 69-year-old man presented with back pain secondary to acute type B aortic dissection with an intimal tear in the proximal descending aorta. Serial computed tomography (CT) revealed an enlarged descending aorta and proximal progression of the aortic dissection. He underwent left carotid-subclavian artery bypass and TEVAR, 10 days after admission. The Valiant Navion stent graft without a bare stent was deployed proximally; however, the LCCA was unintentionally covered by the stent graft during this procedure. A pull-through form was created between the left axillary and femoral arteries using a 0.035-inch guide wire. The pull-through guide wire was gently pulled, and the greater curvature of the proximal end of the stent graft was displaced distally. Angiography confirmed restoration of antegrade blood flow into the LCCA. The patient's postoperative course was uneventful. Follow-up CT performed 6 months postoperatively confirmed preserved blood flow into the LCCA without endoleak nor stent migration. CONCLUSION: The pull-through pull-back technique is a feasible troubleshooting strategy for accidental coverage of supra-aortic vessels during TEVAR.

OBJECTIVES: We investigated the outcomes of a fenestrated frozen elephant trunk (FET) technique performed without reconstruction of one or more supra-aortic vessels for aortic repair in patients with acute type A aortic dissection. METHODS: We investigated 22 patients who underwent the fenestrated FET technique for acute type A aortic dissection at our hospital between December 2017 and April 2020. The most common symptom was chest pain and/or back pain. Nine patients presented with malperfusion and 1 with cardiac arrest, preoperatively. A FET was deployed under hypothermic circulatory arrest and manually fenestrated under direct vision. Single fenestration was made in the FET in 15 patients, 2 fenestrations in 5 patients and a total fenestrated technique in 2 patients. Concomitant procedures were performed in 5 patients. RESULTS: The cardiopulmonary bypass, aortic cross-clamp and hypothermic circulatory arrest times were 181 ± 49, 106 ± 43 and 37 ± 7 min, respectively. In-hospital mortality, stroke, or recurrent nerve injury did not occur in any patient. One patient developed paraparesis, which completely recovered at discharge. During the follow-up period (mean 18 ± 7 months), 1 patient died of heart failure. Fenestration site occlusion did not occur. Follow-up computed tomography (mean 12 ± 6 months postoperatively) revealed that the maximal aortic diameter remained unchanged at the levels of the distal end of the FET, the 10th thoracic vertebra and the coeliac artery; however, the aortic diameter was significantly reduced at the level of the pulmonary artery bifurcation. CONCLUSIONS: The fenestrated FET technique is a simple, safe and effective procedure for selected patients with acute type A aortic dissection.

A 38-year-old man underwent thoracic endovascular aortic repair for impending rupture of acute type B aortic dissection. Computed tomography revealed abscess formation around the proximal descending aorta 4 weeks after endovascular treatment. He underwent one-stage total arch and descending aorta replacement and omental wrapping via left thoracotomy. At the 6-month follow-up, his postoperative course was uneventful.

An 85-year-old man with appetite loss, lightheadedness, and leg edema was referred to our institution. Computed tomography and transthoracic echocardiography revealed a left ventricular pseudoaneurysm with a maximal diameter of 80 mm and severe mitral regurgitation. Coronary angiography showed 90% stenosis and total occlusion of the left circumflex artery at segments 11 and 12, respectively. He was diagnosed with postinfarction left ventricular pseudoaneurysm and underwent patch repair using two bovine pericardium patches and biological glue, mitral valve replacement, and coronary artery bypass grafting. His postoperative course was uneventful.

A 77-year-old woman who presented with chest pain was diagnosed with acute anterior myocardial infarction. Echocardiography revealed pericardial effusion, and she underwent sutureless repair for postinfarction left ventricular free wall rupture. Echocardiography performed 2 days postoperatively revealed ventricular septal rupture and left ventricular acute dilatation. Hemodynamic instability with ventricular tachycardia and rapid decline of kidney function developed. Four days after the primary surgery, we performed successful sandwich repair for ventricular septal rupture and the dilatation. Her postoperative course was uneventful, and postoperative evaluation did not show a residual shunt or left ventricular dilatation.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype-phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin αV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.

BACKGROUND: Decision-making regarding the operability of thoracic aortic disease in nonagenarian patients remains controversial because outcomes of open surgical repair of the thoracic aorta are unclear. We investigated the surgical and nonsurgical outcomes of acute thoracic aortic syndrome treatment in nonagenarians. METHODS: After evaluating data in our institute from April 2016 to March 2020, we included 10 nonagenarians who needed surgical intervention on the thoracic aorta via a median sternotomy for acute thoracic aortic syndrome. The mean age of the cohort was 91.9 ± 2.1 years. Five patients underwent open surgical repair of the thoracic aorta (surgical group), and 5 refused surgery (nonsurgical group). All patients in the surgical group performed activities of daily living independently, with a mean clinical frailty scale of 3.2 ± 0.4. The surgical group included 4 patients with type A aortic dissection and one with a ruptured thoracic aortic aneurysm. Hemiarch replacement was performed in 3 patients and total arch replacement in 2. The mean follow-up period was 17.8 ± 5.1 months. RESULTS: Hospital mortality rates were 0% in the surgical and 80% in the nonsurgical group. The mean length of hospitalization was 28.4 ± 6.7 days in the surgical group. The 1-year survival rates were 100% in the surgical group and 20% in the nonsurgical group. CONCLUSION: Open surgical repair for acute thoracic aortic syndrome via median sternotomy is a reasonable treatment option even in nonagenarians. Involvement of family members is important for decision-making to devise the optimal treatment strategy (surgical vs. medical).

BACKGROUND: Limited data is available on the use of a polyester graft limb with a helical stent configuration deployed in the external iliac artery (EIA) during endovascular aneurysm repair (EVAR), so we prospectively analyzed the efficacy of the Zenith Spiral-Z limb deployed in the EIA. METHODS AND RESULTS: Patients undergoing EVAR using a Zenith stent-graft and Spiral-Z limb deployed in the EIA were prospectively registered in 24 Japanese institutions from June 2017 to November 2017. In total, 65 patients (74 limbs) (mean age: 77.1±8.0 years, 87.7% men, mean abdominal aortic aneurysm (AAA) diameter: 51.9±7.2 mm, mean iliac artery aneurysm (IAA) diameter: 38.3±10.0 mm) were registered and followed up. The most common reason for deployment in the EIA was a common IAA (43 limbs, 58.1%), and 8 limbs (10.8%) had a bare nitinol stent placed at the Spiral-Z limb. A total of 61 patients (70 limbs) completed a 24-month follow-up. There were 2 Spiral-Z limb stenoses and 1 occlusion, leading to a primary patency of 95.5% and a secondary patency of 100%, at 24 months. Buttock claudication occurred in 24.3% of the limbs treated at 1 month but decreased to 4.3% at 24 months. CONCLUSIONS: Our multicenter prospective study showed that Spiral-Z limb deployed in the EIA was associated with satisfactory results and seems to be a durable option, even in the era of iliac branch devices.

Median sternotomy is the standard approach for coronary artery bypass grafting. Herein, we performed off-pump coronary artery bypass grafting via left anterior thoracotomy from the 4th costal space in an unstable angina pectoris patient with total laryngectomy and a permanent tracheostoma. In this patient, median sternotomy had high risks of surgical-site infection and tracheal injury. To avoid these risks, we selected left anterior thoracotomy. Initially, it was difficult to expose the ascending aorta and postdescending branch. With extension of the skin incision to the median area and division of the 5th and 6th ribs and costal arch, we could expose the anastomotic sites, including the ascending aorta and postdescending branch, without median sternotomy conversion. We performed multiple coronary artery bypass graft procedures safely. This approach might be an additional surgical option in patients with total laryngectomy and a permanent tracheostoma.

UNLABELLED: Figure 4. OBJECTIVES: We investigated the clinical and haemodynamic outcomes in elderly patients undergoing composite aortic root replacement. METHODS: Between 2005 and 2017, 135 patients underwent aortic root surgery at our hospital. Of these 135 patients, 47 patients aged ≥65 years were included in this study. Pathologies included aneurysms in 31, chronic aortic dissection in 6, acute aortic dissection in 4 and other causes in 6 patients. A bioprosthesis was used in 27 and a mechanical valve in 20 patients. The mean age was 71.0 ± 4.3 years. The mean follow-up period was 61 ± 35 months. Follow-up echocardiographic data (average 48 months after surgery) were collected in 35 patients (74%). RESULTS: The in-hospital mortality rate was 2.1% (1 patient). Seven late deaths occurred during follow-up. The 1-, 5- and 8-year overall survival was 93.6%, 82.9% and 82.9%, respectively. Infective endocarditis, Marfan syndrome and diabetes were independent predictors of poorer survival. During the follow-up, thromboembolism occurred in 1 patient, major bleeding events in 5 patients, or proximal reoperation for prosthetic valve endocarditis in 1 patient. The type of valve, mechanical or biological valve, did not affect late mortality and morbidity. Follow-up echocardiography revealed significantly improved left ventricular ejection fraction compared with that at discharge. CONCLUSIONS: Composite aortic root replacement provided satisfactory midterm outcomes in patients aged ≥65 years. Further studies with a longer follow-up are warranted to evaluate late valve-related events.

BACKGROUND: An aortic pseudoaneurysm after cardiovascular surgery can be fatal. METHODS/RESULTS: Here, we describe the staged successful treatments of three pseudoaneurysms in a 77-year-old female patient who underwent total arch replacement and coronary artery bypass grafting 5 years ago. Computed tomography revealed three pseudoaneurysms: in the distal anastomosis of the total arch replacement, in the anastomosis of the left common carotid artery, and in the proximal anastomosis of the saphenous vein graft. Endovascular treatment and surgical repair were performed to treat these three pseudoaneurysms. DISCUSSION: An aortic pseudoaneurysm is a rare complication after cardiac or aortic surgery. Here, we present a case of combined endovascular and surgical repairs of three pseudoaneurysms in one patient.

OBJECTIVE: Postoperative atrial fibrillation (POAF) after open heart surgery is associated with a high risk of mortality and morbidity. Although oral β-blockers are usually recommended to prevent POAF, the efficacy of a transdermal β-blocker patch in preventing POAF is unclear. We compared the incidence of POAF between users of oral and transdermal bisoprolol. METHODS: We investigated 108 patients who underwent cardiac and/or thoracic aortic surgery between April 2016 and February 2018. We compared perioperative clinical and hemodynamic variables between 49 patients treated with a transdermal bisoprolol patch and 59 patients treated with an oral bisoprolol fumarate. RESULTS: POAF occurred in 24% of patients in the transdermal and in 46% of patients in the oral bisoprolol groups (p = 0.027). No intergroup difference was observed in in-hospital mortality, perioperative blood pressures and heart rates, and other morbidities. Multivariable logistic regression analysis revealed that the use of transdermal bisoprolol was independently associated with a lower rate of POAF (odds ratio 0.21, 95% confidence interval 0.05-0.84, p = 0.027). CONCLUSIONS: A transdermal bisoprolol patch is an effective and safe β-blocker drug delivery system. The incidence of POAF in this group was lower than that in users of oral bisoprolol.

The purpose of this study was to observe and clarify the interventricular dysscynchrony caused by continuous-flow left ventricular assist device (CF-LVAD) support using the conductance method. During CF-LVAD support, the systolic phase of the left ventricle (LV) becomes shorter than that of the right ventricle (RV). Accordingly, timing of the systole and diastole during the cardiac cycle is not synchronous between the LV and RV. In this study, we evaluated this phenomenon in a normal heart model using the adult goat (n = 5, body weight 44.5 ± 2.9 kg). A centrifugal LVAD was implanted under general anesthesia. We inserted the conductance catheter into the RV and LV to obtain the pressure-volume relationship of the two ventricles simultaneously. We defined the dyssynchronous status as the sign (plus or minus) of the LV volume-change opposite to that of RV volume-change. Dyssynchronous phase of the cardiac cycle was observed in 5.6 ± 0.65% of hearts under LVAD pump-off and 25.3 ± 3.3% under LVAD full bypass, respectively (p < 0.05). To the best of our knowledge, this is the first experimental report clarifying interventricular dyssynchrony during CF-LVAD support using the conductance method. Quantification of this phenomenon under various support conditions and assessment of influences on the right ventricular function will be studied in future studies.

Papillary muscle rupture is a rare but life-threatening complication of myocardial infarction (MI). Here, we describe a case of papillary muscle rupture caused by a microscopic MI. A 76-year-old woman was referred to our institution, where she developed cardiac arrest upon admission. Severe mitral regurgitation was noted without significant coronary artery lesions. Emergency surgery was performed, and posteromedial papillary muscle rupture was observed. Postoperatively, cardiac magnetic resonance imaging revealed a microscopic MI of the posteromedial papillary muscle.

OBJECTIVE: Preoperative frailty affects the progression of cardiac rehabilitation (CR) after cardiovascular surgery. Different frailty assessment measures are available. However, it remains unclear which tool most likely predicts the progress of CR. Our aim was to evaluate preoperative frailty using different methods and to identify the predictors in the progress of postoperative CR. METHODS: Eighty-nine patients underwent elective cardiovascular surgery at our institution between May 2016 and April 2018. Mortality cases and patients without evaluation of preoperative frailty were excluded. This study included the remaining 78 patients. We divided the patients into two groups: 47 patients who achieved 100 m walking within 7 days after surgery (successful CR group) and 31 patients who achieved 100 m walking later than 8 days after surgery (delayed CR group). Preoperative frailty was assessed using the Kaigo-Yobo Check-List, Cardiovascular Health Study, Short Physical Performance Battery, and Clinical Frailty Scale. RESULTS: The prevalence of frailty defined by these four measures was higher in the delayed CR group. The delayed CR group had lower nutritional status, serum hemoglobin level, serum albumin level, and psoas muscle index. Multivariable analysis demonstrated the Kaigo-Yobo Check-List score as an independent predictor for delayed CR (odds ratio 1.53, 95% confidence interval 1.18-1.98, p = 0.001) and Clinical Frailty Scale as an independent predictor for discharge to a health care facility (odds ratio 3.70, 95% confidence interval 1.30-10.51, p = 0.014). CONCLUSIONS: Among the various tools for assessing frailty, the Kaigo-Yobo Check-List was most likely to predict the progress of postoperative CR after elective cardiovascular surgery.

Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-β antibody, angiotensin II (AngII), anti-TGF-β antibody + AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-β dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-β dependent.

Ventricular septal rupture is an uncommon fatal complication of acute myocardial infarction. In rare cases, the rupture can extend into the right ventricular free wall and cause intramyocardial dissection. We describe the case of a patient who developed postinfarction right ventricular free wall dissection with left-to-right shunting and successfully underwent patch repair.

Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane-bound G-protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and -2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal-regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras-dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA -treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c-Raf and phosphorylated ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras-dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin-treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras-dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

OBJECTIVE: Progression of cardiac rehabilitation after cardiovascular surgery can be affected by frailty. The nutritional status of the patient has been proposed as an indicator of frailty. In this study, we aimed to evaluate the influence of preoperative nutritional status on the progress of postoperative cardiac rehabilitation. METHODS: This study included 146 patients (82 males, 64 females, average age 71.9 ± 12.0 years) who underwent elective cardiovascular surgery. In-hospital mortality cases were excluded to focus on postoperative cardiac rehabilitation. We classified patients with a Geriatric Nutritional Risk Index of 92 or higher as the good nutrition group and those with a Geriatric Nutritional Risk Index less than 92 as the malnutrition group. Preoperative patient characteristics and postoperative cardiac rehabilitation progress were compared between the good nutrition (n = 93) and malnutrition (n = 53) groups. RESULTS: The patients in the good nutrition group had an earlier progression to walking after postoperative rehabilitation (p = 0.002), a shorter postoperative hospital stay (p = 0.004), and a higher rate of discharge home (p = 0.028) than those in the malnutrition group. Multivariable analysis demonstrated preoperative malnutrition to be an independent predictor for the day to 100 m walking (p = 0.010). CONCLUSIONS: Preoperative nutritional status was associated with progression of postoperative cardiac rehabilitation.

The mechanisms underlying aortic dissection remain to be fully elucidated. We aimed to identify key molecules driving dissection through gene expression profiling achieved by microarray analysis and subsequent in vitro experiments using human aortic endothelial cells (HAECs) and aortic vascular smooth muscle cells (AoSMCs). Total RNA, including microRNA (miRNA), was isolated from the intima-media layer of dissected ascending aorta obtained intraoperatively from acute type A aortic dissection (ATAAD) patients without familial thoracic aortic disease (n = 8) and that of non-dissected ascending aorta obtained from transplant donors (n = 9). Gene expression profiling was performed with mRNA and miRNA microarrays, and results were confirmed by quantitative polymerase chain reaction (qPCR). Target genes and miRNA were identified by gene ontology analysis and a literature search. To reproduce the in silico results, HAECs and AoSMCs were stimulated in vitro by upstream cytokines, and expression of target genes was assessed by qPCR. Microarray analysis revealed 1536 genes (3.6%, 1536/42 545 probes) and 41 miRNAs (3.0%, 41/1368 probes) that were differentially expressed in the ATAAD group (versus donor group). The top 15 related pathways included regulation of inflammatory response, growth factor activity and extracellular matrix. Gene ontology analysis identified JAK2 (regulation of inflammatory response), PDGFA, TGFB1, VEGFA (growth factor activity) and TIMP3, TIMP4, SERPINE1 (extracellular matrix) as the target genes and miR-21-5p, a TIMP3 repressor, as target miRNA that interacts with the target genes. Validation qPCR confirmed the altered expression of all 7 target genes and miR-21-5p in dissected aorta specimens (all genes, P &lt; 0.05). Ingenuity pathway analysis showed TNF-alpha and TGF-beta to be upstream cytokines for the target genes. In vitro experiments showed these cytokines inhibit TIMP3 expression (P &lt; 0.05) and enhance VEGFA expression (P &lt; 0.01) in AoSMCs but not HAECs. miR-21-5p expression increases in AoSMCs under TNF-alpha and TGF-beta stimulation (fold change: 1.36; P = 0.011). Results of our novel approach, integrating in vitro assessment into gene expression profiling, implicated chronic inflammation characterized by MMP-TIMP dysregulation, increased VEGFA expression, and TGF-beta signalling in the development of dissection. Further investigation may reveal novel diagnostic biomarkers and uncover the mechanism(s) underlying ATAAD.

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1C1039G/+ Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1C1039G/+ Marfan mice were treated with retro-orbital LNA-anti-miR-29b inhibitor or scrambled-control-miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1C1039G/+ mice at 14.5 days post-coitum) (n = 8-10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8-10, each group). To determine if miR-29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4-6, each group). miR-29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA-anti-miR-29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR-29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR-29b inhibition significantly reduces aneurysm development long-term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR-29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.

Continuous-flow left ventricular assist devices (LVADs) have improved the prognosis of end-stage heart failure. However, continuous-flow LVADs diminish pulsatility, which possibly result in bleeding, aortic insufficiency, and other adverse effects. We previously developed a novel control system for a continuous-flow LVAD (EVAHEART®; Sun Medical), and demonstrated that we could create sufficient pulsatility by increasing its rotational speed (RS) in the systolic phase (Pulsatile Mode) in the normal heart model. Here, we aimed to evaluate differences between systolic assist with advanced and delayed loads by shifting the timing of increased RS. We implanted EVAHEART in six goats (55.3 ± 4.3 kg) with normal hearts. We reduced their heart rates to <60 bpm using propranolol and controlled the heart rates at 80 and 120 bpm using ventricular pacing. We shifted the timing of increasing RS from -60 to +60 ms in the systolic phase. We found significant increases in all the following parameters when assessments of delayed timing (+60 ms) were compared with assessments of advanced timing (-60 ms): pulse pressure, mean dP/dt max of aortic pressure, and energy-equivalent pulse pressure. During continuous-flow LVAD support, pulsatility can be controlled using a rotary pump. In particular, pulsatility can be shifted by delaying increased RS.

We have previously developed a native heart load control system for a continuous-flow left ventricular assist device (LVAD) ((EVAHEART®; Sun Medical) and demonstrated that the rotational speed (RS) in synchronization with the cardiac cycle can alter pulsatility and left ventricular (LV) load under general anesthesia. In this study, we assessed the effects of different levels of increase in RS on pulsatility and LV load in the chronic awake phase. We implanted the EVAHEART via left thoracotomy in 7 normal goats (59.3 ± 4.6 kg). Two weeks after implantation, we examined the effects of co-pulse mode (increased RS in the systolic phase) and counter-pulse mode (increased RS in the diastolic phase), as well as shifting the change in RS from 250 to 500 rpm, and 750 rpm in both modes on pulsatility and LV load. Pulsatility was assessed using pulse pressure and mean dP/dt max of aortic pressure. LV load was assessed using stroke work and left ventricle end-diastolic volume determined from LV pressure-volume loops. In the co-pulse mode, pulsatility values increased as the change in RS increased. By contrast, in the counter-pulse mode, these values decreased as the change in RS increased. LV load increased significantly in the co-pulse mode compared with the counter-pulse mode, but there were no significant differences among the three levels of RS increase in either mode. Increasing RS to varying degrees with our newly developed system could contribute to pulsatility. However, it appeared to have little effect on LV load in normal hearts.

UNLABELLED: Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. METHODS: Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe. RESULTS: Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P < 0.005 and P < 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model. CONCLUSION: We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

We previously developed a novel control system for a continuous-flow left ventricular assist device (LVAD), the EVAHEART, and demonstrated that sufficient pulsatility can be created by increasing its rotational speed in the systolic phase (pulsatile mode) in a normal heart animal model. In the present study, we assessed this system in its reliability and ability to follow heart rate variability. We implanted an EVAHEART via left thoracotomy into five goats for the Study for Fixed Heart Rate with ventricular pacing at 80, 100, 120 and 140 beats/min and six goats for the Study for native heart rhythm. We tested three modes: the circuit clamp, the continuous mode and the pulsatile mode. In the pulsatile mode, rotational speed was increased during the initial 35 % of the RR interval by automatic control based on the electrocardiogram. Pulsatility was evaluated by pulse pressure and dP/dt max of aortic pressure. As a result, comparing the pulsatile mode with the continuous mode, the pulse pressure was 28.5 ± 5.7 vs. 20.3 ± 7.9 mmHg, mean dP/dt max was 775.0 ± 230.5 vs 442.4 ± 184.7 mmHg/s at 80 bpm in the study for fixed heart rate, respectively (P < 0.05). The system successfully determined the heart rate to be 94.6 % in native heart rhythm. Furthermore, pulse pressure was 41.5 ± 7.9 vs. 27.8 ± 5.6 mmHg, mean dP/dt max was 716.2 ± 133.9 vs 405.2 ± 86.0 mmHg/s, respectively (P < 0.01). In conclusion, our newly developed the pulsatile mode for continuous-flow LVADs reliably provided physiological pulsatility with following heart rate variability.

Both left ventricular assist device and left ventricular reconstruction are treatment choices for severe heart failure conditions. Our institution performed a left ventricular assist device installation following a left ventricular reconstruction procedure on a 42-year-old male patient who presented with dilated cardiomyopathy and low cardiac output syndrome. A mitral valve plasty was used to correct the acute mitral valve regurgitation and we performed a Nipro extra-corporeal left ventricular assist device installation on post-operative day 14. Due to the left ventricular reconstruction that the patient had in a previous operation, we needed to attach an apical cuff on posterior apex, insert the inflow cannula with a large curve, and shift the skin insertion site laterally to the left. We assessed the angle between the cardiac longitudinal axis and the inflow cannula using computed tomography. The patient did not complain of any subjective symptoms of heart failure. Although Nipro extra-corporeal left ventricular assist device installation after left ventricular reconstruction has several difficulties historically, we have experienced a successful case.

In-body tissue architecture--a novel and practical regeneration medicine technology--can be used to prepare a completely autologous heart valve, based on the shape of a mold. In this study, a three-dimensional (3D) printer was used to produce the molds. A 3D printer can easily reproduce the 3D-shape and size of native heart valves within several processing hours. For a tri-leaflet, valved conduit with a sinus of Valsalva (Biovalve type VII), the mold was assembled using two conduit parts and three sinus parts produced by the 3D printer. Biovalves were generated from completely autologous connective tissue, containing collagen and fibroblasts, within 2 months following the subcutaneous embedding of the molds (success rate, 27/30). In vitro evaluation, using a pulsatile circulation circuit, showed excellent valvular function with a durability of at least 10 days. Interposed between two expanded polytetrafluoroethylene grafts, the Biovalves (N = 3) were implanted in goats through an apico-aortic bypass procedure. Postoperative echocardiography showed smooth movement of the leaflets with minimal regurgitation under systemic circulation. After 1 month of implantation, smooth white leaflets were observed with minimal thrombus formation. Functional, autologous, 3D-shaped heart valves with clinical application potential were formed following in-body embedding of specially designed molds that were created within several hours by 3D printer.

We developed a novel controller for a continuous-flow left ventricular assist device (EVAHEART) that can change the pump's rotational speed (RS) in synchronization with a patient's myocardial electrocardiogram (ECG) with the aim of facilitating cardiac recovery. We previously presented various applications of this system in animal models, but there remained a concern that the repeated acceleration and deceleration of the impeller may induce additional hemolysis. In this study, we evaluated the blood trauma and motor power consumption induced by our system in a mock circulation. We evaluated our system with a 60-bpm pulse frequency and a variance between the high and low RSs of 500 rpm (EVA-P; n = 4). The continuous modes of EVAHEART (EVA-C; n = 4) and ROTAFLOW (n = 4) were used as controls. The pumps were examined at a mean flow rate of 5.0 ± 0.2 L/min against a mean pressure head of 100 ± 3 mmHg for a 4-h period. As a result, the normalized indexes of the hemolysis levels of EVA-P and EVA-C were 0.0023 ± 0.0019 and 0.0023 ± 0.0025, respectively, and their difference was not significant. The estimated mean motor power consumptions of EVA-C and EVA-P were 6.24 ± 0.33 and 7.19 ± 0.93 W, respectively. When a novel ECG-synchronized RS-change system was applied to EVAHEART, the periodic RS change with a 500-rpm RS variance did not affect the hemolysis at a 60-bpm pulse frequency.

OBJECTIVE: We previously developed a native heart load control system for a continuous-flow left ventricular assist device and demonstrated that the rotational speed synchronized with the cardiac cycle can alter left ventricular preload and myocardial oxygen consumption. In the present study, we assessed this system in a conscious goat model of chronic heart failure. METHODS: Chronic heart failure was induced by coronary microsphere embolization of the left ascending artery and subsequent rapid ventricular pacing in 6 goats. After 4 to 6 weeks of rapid pacing, the goats showed a decreased ejection fraction (from 89.7% ± 3.1% to 53.3% ± 5.4%) measured during sinus rhythm. The assist device was implanted by way of a left thoracotomy, and we examined the effects of the continuous, co-pulse, and counterpulse mode on the end-diastolic volume and stroke work, determined from the left ventricular pressure-volume loops. RESULTS: Significant decreases were found in the end-diastolic volume and stroke work in the counterpulse mode relative to the values observed with 0% bypass (63.4% ± 15.2% and 39.1% ± 18.2%, respectively; P < .01). Furthermore, both increased in the co-pulse mode (82.1% ± 17.6% and 68.3% ± 22.2%; P < .01) compared with those in the continuous mode (69.6% ± 15.4% and 54.6% ± 21.6%) with 100% bypass. CONCLUSIONS: The system offers the possibility to control the left ventricular load by changing the rotational speed of a continuous-flow assist device in synchronization with the cardiac cycle. This system should provide the most favorable left ventricular loading conditions for recovery of the native heart.

BACKGROUND: Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome. The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using MRI with a gadolinium-based elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) mice. METHODS AND RESULTS: Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (n=9 and n=10, respectively) using 7-T MRI with a T1 mapping sequence. Significantly lower enhancement (ie, lower R1 values, where R1=1/T1) was detected post-elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) compared with wild-type ascending aortas (1.15±0.07 versus 1.36±0.05; P<0.05). Post-elastin-specific magnetic resonance contrast agent R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (P=0.006). CONCLUSIONS: Herein, we demonstrate that MRI with elastin-specific magnetic resonance contrast agent accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared with wild-type controls. This approach has translational potential for noninvasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.

OBJECTIVE: Since drug-eluting stents (DESs) appeared in Japan, coronary artery bypass grafting (CABG) has been indicated for more severe lesions. To understand the implications of this trend, we compared SYNTAX scores in two groups of patients treated with CABG before and after DESs approval. METHODS: Consecutive CABG patients during January 2001-July 2003 (pre-DES era patients, n = 160) and January 2008-July 2010 (DES era patients, n = 103) were included. The SYNTAX scores of both groups were compared and a cardiologist retrospectively re-evaluated coronary angiograms to determine whether CABG or percutaneous coronary intervention (PCI) would be recommended under current standards. RESULTS: SYNTAX scores were significantly higher in DES era group compared with pre-DES era group (33.3 ± 10.6 vs. 28.1 ± 10.6, p < 0.01). Percutaneous coronary intervention would be the preferred treatment option in 66 (41 %) of pre-DES patients, whose SYNTAX scores were significantly lower than those of patients who were considered good candidates for CABG (21.9 ± 9.3 vs. 32.5 ± 9.1, p < 0.01). CONCLUSIONS: Although CABG is now being performed in intermediate-to-highly complex cases, DES era outcomes, including operative mortality and early graft failure, have not worsened in comparison to the pre-DES era.