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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.

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.

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.

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.

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.

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

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. 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. 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). 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.

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.

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).

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.

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. 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. 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). Preoperative nutritional status was associated with progression of postoperative cardiac rehabilitation.

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.

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 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.

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

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.

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.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.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).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.

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 Fbn1 C1039G/+ 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 Fbn1 C1039G/+ 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 Fbn1 C1039G/+ smooth muscle cells (n=5 per group). Fbn1 C1039G/+ 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 Fbn1 C1039G/+ 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.

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.

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.

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

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.

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 14.5days post-coitum) (n=8-10, each group) or (2) postnatally every other week, from 2 to 22weeks of age, and sacrificed at 24weeks (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 8weeks 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 32weeks, whereas postnatal treatment was effective up to 16weeks. 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.

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 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.

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.

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.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.SYNTAX scores were significantly higher in DES era group compared with pre-DES era group (33.3 ± 10.6 vs. 28.1 ± 10.6, p0.01). 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, p0.01).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.

Aiming the ‘Bridge to Recovery’ course, we have developed a novel left ventricular assist device (LVAD) controlling system. It can change the rotational speed of the continuous flow LVAD, EVAHEART, synchronized with the cardiac beat. Employing this system, we have already demonstrated that myocardial oxygen consumption (MVO2), which is considered to be equivalent to native heart load, changes in the hearts of normal goats. Herein, we examined changes in goats with acute ischemic heart failure. We studied 14 goats (56.1 ± 6.9 kg) with acute ischemic heart failure due to coronary microsphere embolization. We installed the EVAHEART and drive in four modes: “circuit-clamp”, “continuous support”, “counter-pulse”, and “co-pulse”, with 50 and 100 % bypass. In comparison to the circuit-clamp mode, MVO2 was reduced to 70.4 ± 17.9 % in the counter-pulse mode and increased to 90.3 ± 14.5 % in the co-pulse mode, whereas it was 80.0 ± 14.5 % in the continuous mode, with 100 % bypass (p

Caregiver Perspectives on End-of-Life Experiences of PatientsWith Left Ventricular Assist Devices To the Editor In an article published in a recent issue of JAMA Internal Medicine, McIlvennan et al1 found that the bereaved caregivers of patients with left ventricular assist devices (LVADs) reported feelingsofconfusionandabandonment.How to support patients with LVADs and their caregivers in endof-life issues in an era of increasing destination therapy (DT) is a crucial issue. When considering end-of-life issues of LVAD-DT, McIlvennan et al1 should have mentioned the importance of the informed consent process. As the endpoint of LVAD-DT is patient death, patients, caregivers, and VAD teams must anticipate end-of-life issues at the beginning of therapy, including device discontinuation. Before introducing LVAD-DT, the VAD teamshouldprovide specific information regarding caregiver burden,2 in addition to information related to the procedure, risks, benefits, and alternative treatment options. As not all patients (and caregivers) who provide consent to the LVAD treatment fully understand it, even after implantation.3 Informed consent should not be a single event where patientsare informedandtheir consentobtainedbut ratheraprocess that continues for the duration of wearing a VAD. In a research participation context, a continuing consent process could address the factors relevant to an individual’s decisionmaking process; the nature of the research itself, participants’medical conditions, or participants’ preferences and interests may change unexpectedly after the initial informed consent.4 This would apply to the clinical situation of LVADDT.ThemedicalconditionandothercircumstancesofLVAD-DT patients and caregivers could change during the long treatmentperiod. Patientswhoconsent toLVAD-DTand their caregivers are facedwithday-to-daydecisions in the context of an extended period in which increasing symptoms adversely affect their daily lives. The IC process encompasses providing information via the IC form and signing the letter of consent. Patients and caregivers can reconsider both their daily liveswithanLVADandtheendpointof the therapybeforesigning; the VAD team can understand the concerns of patients and caregivers regarding therapy and partake in the treatment path, step-by-step, when providing information. Moreover, the processes via an IC form can record the decisionmakinghistory of bothpatients and caregivers. Continuing to progressively provide information will lead to better education asMcIlvennan et almentioned.1 The ethical and psychosocial needs of both patients and caregivers will change with thechronicprogressive illness trajectory.Thisgradual andcontinuous approach5 IC process could contribute to preparing patients and caregivers for the end of life with an LVAD.

Item does not contain fulltext 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.

Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance preprandial acid output, possibly through stimulation of the cephalic phase. The present study was designed to clarify the dynamics of ghrelin in H(2) receptor (H(2)R)-null mice by genetic H(2)R knockout.Fifteen-week- and 54-week-old H(2)R-null mice and their littermates were used. After evaluating the levels of food intake and body-weight increments, mice were killed, and the plasma and gastric active and total ghrelin levels were examined by radioimmunoassay, and gastric preproghrelin mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction. Furthermore, each stomach specimen was evaluated by immunohistochemistry and transmission electron microscopy for ghrelin.The levels of food intake and body-weight gain of the H(2)R-null mice were higher than those of wild-type mice. The gastric pH of the 54-week-old H(2)R-null mice was lower than that of the 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level, and density of ghrelin-immunoreactive cells in the gastric mucosa of the H(2)R-null mice were significantly increased compared with those of the wild-type mice. Ghrelin-positive immunogold density seen in the electron micrograph was significantly reduced in A-like cells of the H(2)R-null mouse stomach.Ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in H(2)R-null mice, a genetic H(2)R knockout model.

Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H2 receptor-knockout (H2R-null) mice and an acid exposure model. Age-matched H2R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H2R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H2R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Introduction: Enhanced TGF-β signaling drives aortic root aneurysm development in Marfan syndrome (MFS) via the non-canonical (ERK) pathway in murine models, but ERK not been studied in human tissue. Conversely, blockade of canonical (Smad) TGF-β signaling is detrimental in MFS mice. Recently, TGF-β-induced increases in smooth muscle cell (SMC) contractile genes and collagen I (COL1) expression have been proposed to lead to aortic stiffness and dilatation in MFS. Hypothesis: We hypothesized that ERK signaling is enhanced in human MFS tissue and dictates the predilection of the aortic root to develop aneurysm by altering SMC gene expression. Methods and Results: Western blot of aortic root tissue from MFS patients with root aneurysms (4.67±0.09 cm) revealed 3.1-fold increased ERK activation relative to control aortic root (p=0.03, n=8). When compared to non-dilated MFS ascending (ASC) aorta (2.94±0.14 cm), there was no difference in ERK activation between the two regions. While RT-PCR of MFS root showed increased expression of the contractile gene regulator myocardin (2.4±0.07 fold, p=0.01), and of MYH11 (3.05±0.13 fold, p=0.03) ACTA2 (2.93±0.10 fold, p Conclusions: ERK signaling is uniformly enhanced in MFS aortic root and ASC tissue, indicating that further study into aortic region-specific responses to cellular signals is needed to assess the development of focal aortic root aneurysm in MFS. Increased contractile gene expression is Smad-dependent and non-focal and thus does not clarify focal root aneurysm. COL1, while focally enhanced in the MFS root, is Smad-driven and suppressed by ERK, and may represent a compensatory response.

Rationale: Aortic root aneurysm formation and subsequent dissection remain the major cause of death in patients with Marfan syndrome (MFS). HMG-CoA reductase inhibitors (statins) have been reported to reduce aneurysm growth in MFS mouse models, although the mechanism is unknown. In addition to reducing cholesterol, statins block both farneslyation and geranylgeranylation, which participate in membrane bound G-protein signaling, including Ras. The Ras signaling pathway (via ERK) has been shown to be important in MFS aneurysm formation. Objective: Systematically dissect the prenylation pathway to better define the mechanism behind the beneficial effect of statins on aneurysm reduction in MFS and anticipate this will help elucidate the pathophysiology of aneurysm formation. Method and results: Fbn1 C1039G/+ mice (4 week old) were treated subcutaneously with either (a) Pravastatin (PS) (HMG-Co Reductase inhibitor) (100 mg/kg per day); (b) Manumycin A (MA) (FPT inhibitor) (2.5 mg/kg/every other day); (c) Perillyl Alcohol (PA) (GGPT-1 and -2 inhibitor) (5.0 mg/kg/every other day); or (d) vehicle control Fbn1 C1039G/+ mice from age 4-8 weeks. PS and MA significantly reduced aneurysm growth compared to vehicle control (PS:1.57 ± 0.03 mm; MA: 1.55 ± 0.06 mm; vehicle: 1.77 ± 0.05 mm, respectively: p < 0.05). There was no significant difference between PS and MA treated groups. In contrast, PA did not significantly decrease aneurysm size (PA: 1.81 ± 0.06 mm). Elastin staining illustrated reduced elastin breakdown in MA treated mice compared to vehicle control treated groups (MA: 2.2 ± 0.3, vehicle: 4.2 ± 0.6, respectively: p < 0.05). After identifying that the Ras pathway is important, we measured the relative expression of pRaf-1 and pErk1/2, downstream enzymes in transforming growth factor- β (TGF-β) signaling pathway with Western blot. Although elevated in control Marfan mice, both pRaf-1 and pErk 1/2 were significantly reduced in MA treated mice, corresponding with a reduction in aneurysm growth (pRaf-1: MA: 5.1 ± 1.3, vehicle: 8.8 ± 0.8, p = 0.08, pErk1/2: MA: 2.3 ± 0.1, vehicle: 3.2 ± 0.1, p < 0.05, respectively). Conclusion: Statins reduce aortic aneurysm growth in Fbn1 C1039G/+ Marfan mice by decreasing both Ras activation and downstream ERK signaling.

Rationale: Marfan syndrome patients typically develop aortic root aneurysms with ensuing aortic dissection remaining the leading cause of death. Although losartan (Angiotensin 1 receptor blocker) has been shown to reduce aneurysms in mice, the role Angiotensin II (AngII) plays during aneurysm formation in MFS remains unknown. Objective: We hypothesized that AngII may exacerbate aneurysm growth in Fbn1 C1039G/+ mice. Moreover, we predicted AngII would induce abdominal aneurysms, creating a novel model to study the pathophysiology of aneurysm formation with two different embryonic origins. Method and results: Fbn1 C1039G/+ mice (n = 7) were treated with either (a) AngII (500 ng/min/kg) or (b) vehicle control and compared to ApoE-/- mice treated with Ang II (1000 ng/min/kg). Aortic root, ascending and abdominal diameters are measured with echo on POD 3, 7 and 14. Following dose-response curve experiments, optimal survival rate is 70%, 14 days after treatment. The average aortic root/ascending (AS) aortic diameter in Ang II Fbn1 C1039G/+ mice was 2.08 ± 0.31 mm, compared to 1.48 ± 0.25 mm in vehicle control Fbn1 C1039G/+ mice (pC1039G/+ mice were due to either AS or abdominal aneurysm dissection. Immunohistochemistry on POD 14 showed severe elastic layer disruption in aneurysmal tissue from both aneurysms. Quantitative PCR was performed to measure the expression of matrix-metalloproteinase (MMP) gene expression. When comparing AS and abdominal aneurysms in AngII Fbn1 C1039G/+ mice, MMP-2 was highly up-regulated in AS aneurysms (Fold change: 3.03 ± 0.69, p Conclusions: Fbn1 C1039G/+ mice treated with AngII develop severe aortic root/ascending aortic aneurysms. Ang II treatment results in abdominal aneurysm formation. Interestingly, gene expression analyses suggest different mechanisms of aneurysm development in aortic segments of different embryonic origin.