Real-life experience of a stent-less revascularization strategy using a combination of excimer laser and drug-coated balloon for patients with acute coronary syndrome.

OBJECTIVES: We aimed to test a novel stent-less revascularization strategy using a combination of excimer laser coronary angioplasty (ELCA) and drug-coated balloon (DCB) for patients with acute coronary syndrome (ACS). BACKGROUND: Percutaneous coronary intervention with drug eluting stents is a standard invasive treatment for ACS. Some unsolved issues however remain, such as stent thrombosis and bleeding risks associated with dual antiplatelet therapy. METHODS: Consecutive ACS patients were planned to receive either a DCB application following ELCA without a stent implantation or conventional revascularization with a coronary stent. The endpoints were (i) major cardiac adverse events (MACEs), defined as the composite of cardiac death, myocardial infarctions, and target lesion revascularization; (ii) target vessel revascularization (TVR); and (iii) angiographic outcome. RESULTS: Since a greater than expected number of patients allocated to the stent-less treatment arm eventually received a bailout stenting, the following 3 as-treated groups were compared; DCB with ELCA group (N = 60), Stent with ELCA group (N = 23), and Stent without ELCA group (N = 85). During a mean follow-up period of 420 ± 137 days, and with angiographic 6- and 12-month-follow-up rates of 96.7%, 87%, and 81.2%, and 50%, 65.2%, and 45.9%, respectively, the MACE rate did not differ across the groups (10%, 4.3%, and 3.5%; P = 0.22) while an incidence of TVR was more common (15%, 0, and 4.7%; P = 0.02) and the diameter stenosis at 6-months of follow-up was greater (25.7 ± 18.2, 14.9 ± 13.1 and 16.2 ± 15.4%; P = 0.002) in the DCB with ELCA group. CONCLUSIONS: The stent-less revascularization strategy with DCB and ELCA was associated with a higher occurrence of restenosis in ACS patients.

Primary cardiac lymphoma diagnosed by endomyocardial biopsy using transthoracic echocardiography in the substernal window.

We report a case of a 56-year-old man with a cardiac tumor, which grew and spread rapidly in the right heart. Using transthoracic echocardiography (TTE) in the substernal window, a transvenous biopsy of the tumor was performed safely. The tissue diagnosis revealed a diffuse large B cell lymphoma. After undergoing chemotherapy, the tumor was completely cured and the patient continues to be in good health. A biopsy using TTE in the substernal window may be a useful method to diagnose right-sided extensive tumors.

Determining the fate of seeded cells in venous tissue-engineered vascular grafts using serial MRI.

A major limitation of tissue engineering research is the lack of noninvasive monitoring techniques for observations of dynamic changes in single tissue-engineered constructs. We use cellular magnetic resonance imaging (MRI) to track the fate of cells seeded onto functional tissue-engineered vascular grafts (TEVGs) through serial imaging. After in vitro optimization, murine macrophages were labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles and seeded onto scaffolds that were surgically implanted as inferior vena cava interposition grafts in SCID/bg mice. Serial MRI showed the transverse relaxation times (T(2)) were significantly lower immediately following implantation of USPIO-labeled scaffolds (T(2) = 44 ± 6.8 vs. 71 ± 10.2 ms) but increased rapidly at 2 h to values identical to control implants seeded with unlabeled macrophages (T(2) = 63 ± 12 vs. 63 ± 14 ms). This strongly indicates the rapid loss of seeded cells from the scaffolds, a finding verified using Prussian blue staining for iron containing macrophages on explanted TEVGs. Our results support a novel paradigm where seeded cells are rapidly lost from implanted scaffolds instead of developing into cells of the neovessel, as traditionally thought. Our findings confirm and validate this paradigm shift while demonstrating the first successful application of noninvasive MRI for serial study of cellular-level processes in tissue engineering.

Tissue-engineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel.

We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.

Association between plasma high-molecular-weight adiponectin and coronary plaque characteristics assessed by computed tomography angiography in conditions of visceral adipose accumulation.

BACKGROUND: Our group has previously reported that visceral adipose tissue (VAT) accumulation was associated with the extent and vulnerable characteristics of coronary plaques using coronary computed tomography angiography (CTA). An investigation of the associations between these coronary lesions with plasma adiponectin and leptin was performed. METHODS AND RESULTS: A total of 394 patients (220 men and 174 women) in the study were referred for CTA. Plain abdominal scanning was simultaneously performed to evaluate VAT areas. The median level of plasma high-molecular-weight (HMW) adiponectin in patients with CTA-based obstructive coronary artery disease was significantly lower than that in patients without (men: 1.45 vs. 1.88 µg/ml, P=0.002; women: 2.49 vs. 3.44 µg/ml, P<0.001). Multivariate analyses revealed that a lower HMW adiponectin concentration was significantly associated with the presence (men: P=0.019; women: P=0.018) and involved segment numbers (men: P=0.001; women: P=0.003) of coronary plaques. Furthermore, it was significantly related to coronary plaque with all 3 vulnerable characteristics of positive remodeling, low CT density (≤38 Hounsfield units), and adjacent spotty calcium (men: P=0.019; women: P=0.016). These associations were also observed with VAT areas, but not with plasma leptin concentrations, in both genders. CONCLUSIONS: Lower plasma HMW adiponectin is associated with the presence, extent, and vulnerable characteristics of coronary plaques assessed by CTA in both genders.

With M-protein positive, could transthyretin amyrodosis be easily excluded? Not necessarily! Wild-type transthyretin amyrodosis with Waldenström's macroglobulinaemia: a case report.

Background: Generally, it is said that amyloid light-chain (AL) develops not only in multiple myeloma but also in Waldenström's macroglobulinemia. We experienced a case of M-protein positive and diagnosed as wild-type transthyretin amyrodosis (ATTRwt) accompanied with Waldenström's macroglobulinemia. Case summary: The patient was 72-year-old male, and the main complaint was dyspnoea in April 2020 and visited a nearby doctor. He was introduced to the Department of Haematology at our hospital for high levels of serum immunoglobulin M, M-protein positivity, and cardiac hypertrophy with a suspect of AL amyloidosis. Duodenal mucosal biopsy and abdominal skin biopsy showed no amyloid deposits, and left iliac bone marrow biopsy diagnosed Waldenström's macroglobulinemia and with no amyloid, and Kumamoto criteria score 1. Last of all, ATTRwt was diagnosed for endocardial biopsy. Discussion: This is a very rare case of ATTRwt with Waldenström's macroglobulinaemia.

Coronary calcium score as a predictor for coronary artery disease and cardiac events in Japanese high-risk patients.

BACKGROUND: Although the coronary artery calcium (CAC) score as measured with computed tomography (CT) is associated with cardiovascular mortality and morbidity in Western countries, little is known in Asian populations. METHODS AND RESULTS: Three hundred and seventeen Japanese patients (205 men and 112 women) were followed in the study and they underwent both coronary angiography and CT for CAC measurements. The frequencies of angiographic coronary artery disease (CAD) were 5%, 36%, 76%, 80%, and 94% (P<0.001) and the needs for revascularization were 5%, 26%, 53%, 59%, and 69% (P<0.001) in patients with CAC scores of 0 (n=64), 1-100 (n=58), 101-400 (n=76), 401-1,000 (n=70), and >1,000 (n=49), respectively. In the average of 6.0 (range, 1-10) years follow-up period, 34 patients died including 13 from reasons of cardiac disease. In a Cox proportional hazard model after adjustment for age and sex, traditional coronary risk factors, previous myocardial infarction, and the need for revascularization, the hazard ratio for cardiac mortality in patients with a CAC score >1,000 was 2.98 (95% confidence interval: 1.15-9.40) compared with those with a CAC score=0-100. CONCLUSIONS: The CAC score has a predictive value for angiographical CAD and long-term mortality from cardiac disease in Japanese high-risk patients who undergo coronary angiography.

Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients.

In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

A case in which SGLT2 inhibitor is a contributing factor to takotsubo cardiomyopathy and heart failure.

SGLT2 inhibitors are reported to have advantages in protecting against heart failure events. However, there are also reports of concerns when given to older persons or persons with geriatric syndrome. Our case is an example of a patient with a history of chronic thyroiditis where the SGLT2 inhibitor triggered a thyroid crisis, and blood catecholamine overload caused takotsubo cardiomyopathy and heart failure. .

Local tenomodulin absence, angiogenesis, and matrix metalloproteinase activation are associated with the rupture of the chordae tendineae cordis.

BACKGROUND: Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture. METHODS AND RESULTS: We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner. CONCLUSIONS: These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.

Therapeutic angiogenesis using tissue engineered human smooth muscle cell sheets.

OBJECTIVE: Peripheral arterial disease (PAD) can have severe consequences on patient mortality and morbidity. In contrast to approaches using growth factor administration or isolated cell transplantation, we attempted to develop an alternative method for ischemic therapy using the transplantation of tissue engineered cell sheets with angiogenic potential. METHODS AND RESULTS: Human smooth muscle cell (SMC) and fibroblast cell (FbC) sheets were harvested from temperature-responsive culture dishes and transplanted into ischemic hind limbs of athymic rats. ELISA showed significantly increased in vitro secretion of angiogenic factors by SMCs in comparison to FbCs. Twenty-one days after transplantation, laser doppler analysis demonstrated significantly increased blood perfusion in the SMC group. Perfusion with Indian ink and immunohistochemistry also revealed significantly greater numbers of functional capillaries in the SMC group. Finally, cell tracing experiments revealed that some SMCs from the transplanted cell sheets migrated into the ischemic tissues, contributing to newly formed vessels. CONCLUSIONS: SMC sheet transplantation allows for controlled and localized delivery of cells that possess angiogenic potential directly to ischemic tissues. Through the secretion of angiogenic factors, as well as cell migration and integration with newly formed vessels, SMC sheet transplantation provides an effective method for the revascularization of ischemic tissues.

Two Cases of Aortic Root Replacement After Fontan Completion.

Aortic root dilatation is a well-known complication in patients with congenital aortic valve malformation, tetralogy of Fallot, or a double outlet right ventricle. We report two rare patients who underwent composite graft replacement of the aortic root with a mechanical valve, the so-called Bentall-type operation, after Fontan completion. The pathological examination on the resected aortic wall revealed mucoid degeneration in tunica media and elastic fiber fragmentation. Our report emphasizes the need for close observation of these patients over a long-term period.

Subaortic stenosis associated with systolic anterior motion.

Left ventricular outflow tract obstruction in children is classified according to the site of the obstruction into a supra-aortic type, valvular type, and subaortic type (subaortic stenosis). Subaortic stenosis, in turn, is classified into two major subtypes, i.e., a discrete type, which accounts for most cases and a tunnel type, and one minor subtype, the accessory mitral tissue type, which is rare. Systolic anterior motion (SAM) is a phenomenon that is commonly observed in hypertrophic cardiomyopathy. We report a rare case of subaortic stenosis associated with SAM, which was caused by cleft anterior mitral leaflet and an accessory papillary muscle. Surgical treatment was successful, and there were no complications.

Clinical results of staged repair with complete unifocalization for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVE: Our treatment strategy for pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collateral arteries is a staged repair that comprises the first complete unifocalization (UF) with 'unification' of intrapulmonary arteries and then the definitive repair. The purpose of this study is to evaluate the outcome of our staged repair strategy with complete UF and to determine the results of our current management strategy. METHODS: From 1982 to 2004, 113 consecutive patients were treated with staged repair at our institute. We evaluated the risk of definitive repair failure or death in the 3 years after definitive repair using logistic regression. Furthermore, we compared the early group (patients who underwent UF before December 1995) and the late group (patients who underwent UF after January 1996). RESULTS: The mean follow-up interval was 8.8 years (0.8 months to 23.3 years), and Kaplan-Meier-estimated overall survival rates after first UF were 80.9, 73.8, and 69.9% at 5, 10, and 15 years, respectively. Survival in patients with an absent central pulmonary artery (PA) was significantly lower than in those with a central PA (p<0.05), and the factor that was significantly associated with definitive repair failure or death in the 3 years after definitive repair was central PA morphology (p<0.05). Higher mean PA pressure after UF was detected in patients with hypoplastic central PA, compared with those without hypoplastic PA (30.9 mmHg vs 23.3 mmHg, p<0.05). In the late group, age (in years) at first UF (3.9 vs 8.4, p<0.01), second UF (4.3 vs 9.2, p<0.01), and definitive repair (5.8 vs 9.1, p<0.01) was significantly younger than in early group, and the survival rate after first UF in the late group was 96.2 and 91.3% at 3 and 7 years, respectively. Systolic right ventricular pressure and the pressure ratio between the right and the left ventricles after definitive repair in the late group were significantly lower than in the early group (53.6 mmHg vs 75.0 mmHg, p<0.01; 61.7% vs 75.9%, p<0.05). CONCLUSIONS: Hypoplastic central PA was a significant risk factor in this disease. The overall survival was improved by our current management strategy. Improved RV pressure after definitive repair appears to affect the long-term outcome.

Primary cardiac rhabdomyosarcoma developed after receiving radiotherapy for left breast cancer 18 years prior.

The heart is an organ where primary malignant tumors rarely develop. In particular, the incidence of cardiac rhabdomyosarcoma (RMS) is extremely low. It has been reported that the risk of second malignant tumors in mediastinum is increased by radiotherapy in women with breast cancer. However, little is known about the association between irradiation to heart and cardiac RMS. Here, we report a case of a 68-year-old woman with primary cardiac RMS. She suddenly presented syncope at a workplace, and was taken to the emergency room at our hospital. Several imaging tests, including echocardiogram and cine magnetic resonance imaging, detected two tumors in the right ventricle (RV) and its outflow tract, which had almost obstructed the main trunk of the pulmonary artery (PA). To avoid sudden PA occlusion by the tumor, we emergently performed surgical excision of the tumors from the RV. Pathological analysis revealed that these tumors were embryonal type RMS. She had received radiotherapy after mastectomy for left breast cancer 18 years previously, and no recurrence of breast cancer had been detected. This cardiac RMS is considered as a second malignant tumor related to radiotherapy for breast cancer. .

Evaluation of tissue-engineered vascular autografts.

This study evaluated the endothelial function and mechanical properties of tissue-engineered vascular autografts (TEVAs) constructed with autologous mononuclear bone marrow cells (MN-BMCs) and a biodegradable scaffold using a canine inferior vena cava (IVC) model. MN-BMCs were obtained from a dog and seeded onto a biodegradable tubular scaffold consisting of polyglycolide fiber and poly(L-lactide-co-epsilon-caprolactone) sponge. This scaffold was implanted in the IVC of the same dog on the day of surgery. TEVAs were analyzed biochemically, biomechanically, and histologically after implantation. When TEVAs were explanted and stimulated with acetylcholine at 1 month, they produced nitrates and nitrites dose dependently. N(G)-nitro-L-arginine methylester significantly inhibited these reactions. With stimulation by acetylcholine, factor VIII-positive cells of TEVAs produced endothelial nitric oxide synthase proteins, and the ratio of endothelial nitric oxide synthase/s17 mRNA was similar among native IVC and TEVAs 1 and 3 months after implantation. TEVAs had biochemical properties and wall thickness similar to those of native IVC at 6 months after implantation, and tolerated venous pressure well without any problems such as calcification. The number of inflammatory cells in TEVAs and the ratio of CD4/s17 mRNA decreased significantly with time. These results indicate that TEVAs are a biocompatible material with functional endothelial cells and biomechanical properties and do not have unwanted side effects.

First evidence that bone marrow cells contribute to the construction of tissue-engineered vascular autografts in vivo.

BACKGROUND: Materials commonly used to repair complex cardiac defects lack growth potential and have other unwanted side effects. We designed and tested a bone marrow cell (BMC)-seeded biodegradable scaffold that avoids these problems. METHODS AND RESULTS: To demonstrate the contribution of the BMCs to histogenesis, we labeled them with green fluorescence, seeded them onto scaffolds, and implanted them in the inferior vena cava of dogs. The implanted grafts were analyzed immunohistochemically at 3 hours and subsequently at 2, 4, and 8 weeks after implantation using antibodies against endothelial cell lineage markers, endothelium, and smooth muscle cells. There was no stenosis or obstruction caused by the tissue-engineered vascular autografts (TEVAs) implanted into the dogs. Immunohistochemically, the seeded BMCs expressing endothelial cell lineage markers, such as CD34, CD31, Flk-1, and Tie-2, adhered to the scaffold. This was followed by proliferation and differentiation, resulting in expression of endothelial cells markers, such as CD146, factor VIII, and CD31, and smooth muscle cell markers, such as alpha-smooth muscle cell actin, SMemb, SM1, and SM2. Vascular endothelial growth factor and angiopoietin-1 were also produced by cells in TEVAs. CONCLUSIONS: These results provide direct evidence that the use of BMCs enables the establishment of TEVAs. These TEVAs are useful for cardiovascular surgery in humans and especially in children, who require biocompatible materials with growth potential, which might reduce the instance of complications caused by incompatible materials and lead to a reduced likelihood of further surgery.

The tissue-engineered vascular graft using bone marrow without culture.

OBJECTIVE: To overcome the shortcomings of current vascular grafts, tissue-engineering methods have been applied to cardiovascular regions. We previously reported the creation of a tissue-engineered vascular graft by using vascular mixed cells. However, the cost and manpower for harvesting and culturing the cells was too burdensome. To overcome these drawbacks, we have developed a new method for creating a tissue-engineered vascular graft by using bone marrow cells, which can be obtained easily and used immediately, without cell culture. METHODS: Biodegradable polymers seeded with different types of cells (group V, cultured venous cells; group B, bone marrow cells without culture; and group C, non-cell-seeded graft [as control]) were implanted into the inferior venae cavae of dogs. The grafts were explanted at 4 weeks and assessed histologically and biochemically. RESULTS: In the histologic examination, a regular layer of Masson-staining collagen fiber and a layer of factor VII-stained endothelial and ant-alpha-smooth muscle cell antigen-immunoreactive cells stained in groups V and B like native vascular tissue, whereas no such stained regular lining was detected in group C. A 4-hydroxyproline assay in group C showed significantly lower levels than in groups V and B or native tissue ( P < .05). The DNA content of the tissue-engineered vascular graft tended to be higher in group C than in groups V and B or in native tissue. CONCLUSIONS: In the creation of tissue-engineered vascular grafts, the method of using bone marrow cells seems to be useful and superior to that of using vascular cells because bone marrow cells can be used directly, without culture.