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.

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. .

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.

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 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. .

Prognostic value of coronary artery calcium and epicardial adipose tissue assessed by non-contrast cardiac computed tomography.

OBJECTIVE: Epicardial adipose tissue (EAT) accumulation is believed to be associated with development of coronary atherosclerosis. We investigated whether EAT volume as assessed by computed tomography (CT) has value in prediction of future cardiac events. METHODS: We studied 722 patients without proven coronary artery disease (CAD) who underwent non-contrast cardiac CT. EAT volume and coronary artery calcium (CAC) score were measured simultaneously. Patients were followed as to the occurrence of coronary events (cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, and late coronary revascularization≥3 months after CT examination). RESULTS: During a 3.7±1.7 years follow-up period, 37 coronary events were documented. Annual event rates increased across CAC score categories (0.3%, 1.0%, 2.4%, and 4.3%, in 0, 1-99, 100-399, and ≥400, respectively, p<0.001); these were significantly higher in the higher EAT volume group (>median; 107.2 mL, 0.7% vs., 2.1%, adjusted hazard ratio; 2.65, p=0.0090). Cox-proportional hazard analysis demonstrated that a combination of CAC score≥100 and high EAT volume had a significantly higher event rate than CAC score<100 and low EAT volume group (adjusted hazard ratio 11.6, p<0.0001). Using Cox regression models, incremental prognostic values were identified by adding high EAT volume to clinical risks plus CAC score≥100 (global χ2, 6.7; p=0.059). CONCLUSION: We suggest that high EAT volume may be an independent predictor of future coronary events and increases predictive values of CAC score in patients without proven CAD.

Beyond burst pressure: initial evaluation of the natural history of the biaxial mechanical properties of tissue-engineered vascular grafts in the venous circulation using a murine model.

We previously developed and validated a murine model for investigating neotissue formation in tissue-engineered vascular grafts (TEVGs). Herein, we present the first longitudinal assessment of both the microstructural composition and the mechanical properties of a TEVG through the process of neovessel formation (total scaffold degradation). We show that when (poly)glycolic acid-based biodegradable scaffolds were used as inferior vena cava interposition grafts in mice, the evolving neovessel developed biaxial properties that approached those of the native vein within 24 weeks of implantation. Further, we found that these changes in biaxial properties related temporally to extracellular matrix production and remodeling, including deposition of collagen (types I and III), elastic fibers (elastin and fibrillin-1), and glycosaminoglycans in addition to changes in matrix metalloproteinase (MMP)-2 and -9 activity. Improving our understanding of the mechanobiological principles underlying vascular neotissue formation in TEVGs holds great promise for improving the design of TEVGs and enabling us to continue the translation of this technology from the bench to the clinic.

Noncalcified atherosclerotic lesions with vulnerable characteristics detected by coronary CT angiography and future coronary events.

BACKGROUND: The ability of coronary CT angiography (CTA) findings such as plaque characteristics to predict future coronary events remains controversial. OBJECTIVE: We investigated whether noncalcified atherosclerotic lesions (NCALs) detected by coronary CTA were predictive of future coronary events. METHODS: A total of 511 patients who underwent coronary CTA were followed for cardiovascular events over a period of 3.3 ± 1.2 years. The primary end point was defined as hard events, including cardiac death, nonfatal myocardial infarction, or unstable angina that required urgent hospitalization. Early elective coronary revascularizations (n = 58) were excluded. The relationship between features of NCALs and outcomes is described. RESULTS: A total of 15 hard events (2 cardiac deaths, 7 myocardial infarctions, 6 cases of unstable angina that required urgent hospitalization) were documented in the remaining 453 patients with modest risks during a follow-up period of 3.3 ± 1.2 years. For these hard events, a univariate Cox proportional hazard model showed that the hazard ratio for the presence of >50% stenosis was 7.27 (95% CI, 2.62-21.7; P = .0002). Although the presence of NCAL by itself was not statistically significant, NCALs with low attenuation and positive remodeling (low-attenuation plaque [LAP] and positive remodeling [PR]; plaque CT number ≤ 34 HU and remodeling index ≥ 1.20) showed an adjusted hazard ratio of 11.2 (95% CI, 3.71-36.7; P < .0001). With C-statistics analysis, when both LAP and PR and >50% stenosis were added, the C-statistic was significantly improved compared with the basal model adjusted for age, sex, and log2 (Agatston score +1) (0.900 vs 0.704; P = .0018). CONCLUSIONS: Identification of NCALs with LAP and PR characteristics by coronary CTA provides additional prognostic information to coronary stenosis for the prediction of future coronary events.

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.

Association between aortic valve calcification and myocardial ischemia, especially in asymptomatic patients.

UNLABELLED: Aortic valve calcification (AVC) is recognized as a manifestation of systemic arteriosclerosis. However, it is unclear whether AVC is associated with myocardial ischemia. Stress myocardial perfusion SPECT (MPS) is widely used for the diagnosis of myocardial ischemia. However, routine MPS is not recommended, particularly in asymptomatic patients. Accordingly, we investigated the hypothesis that the presence of AVC is strongly associated with inducible myocardial ischemia, even among asymptomatic patients. METHODS: We investigated 669 consecutive patients who underwent both adenosine stress (201)Tl MPS and echocardiography. We evaluated the extent and severity of myocardial ischemia by the summed difference score (SDS). We defined the presence of myocardial ischemia as SDS ≥ 3 and moderate to severe ischemia as SDS ≥ 8. We classified the severity of AVC according to the number of affected aortic leaflets. We also compared the mean SDS and the prevalence of SDS ≥ 3 and SDS ≥ 8 among patients stratified by the severity of AVC. RESULTS: The presence of AVC was significantly associated with myocardial ischemia (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.10-2.23; P = 0.013) and moderate to severe ischemia (OR, 2.16; 95% CI, 1.26-3.80; P = 0.0061). In 311 asymptomatic patients, AVC was strongly associated with moderate to severe ischemia (OR, 4.31; 95% CI, 1.67-12.8; P = 0.0043). However, the SDS value and the prevalence of SDS ≥ 3 and SDS ≥ 8 did not increase with increasing number of affected aortic leaflets. CONCLUSION: The presence of AVC may be associated with the presence of myocardial ischemia, particularly in asymptomatic patients. However, we found no association between the extent of AVC and inducible myocardial ischemia. The presence of AVC may be a useful anatomic marker to help identify patients at high risk of myocardial ischemia, particularly asymptomatic patients.

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.

Association between epicardial adipose tissue volume and characteristics of non-calcified plaques assessed by coronary computed tomographic angiography.

BACKGROUND: The aim of this study was to investigate whether high epicardial adipose tissue (EAT) volume is related to the presence of vulnerable coronary plaque components as assessed by computed tomography (CT). METHODS: We evaluated 357 patients referred for 64-slice CT, and assessed coronary plaque components and EAT volume. Vulnerable coronary plaque components were defined as the presence of non-calcified plaque (NCP), including low-density plaque (LDP: <39 HU) and positive remodeling (PR: remodeling index>1.05). In accordance with a previous report, patients were assigned to two groups: low (<100 ml) or high (≥100 ml) EAT volume. RESULTS: Compared to the low EAT volume group, the high EAT volume group had a higher prevalence of NCP (74% vs. 59%, p=0.003). Additionally, the high EAT volume group had a higher prevalence of LDP with PR than the low EAT volume group (46% vs. 25%, p<0.001). Interestingly, a high EAT volume was an independent predictor of LDP with PR (odds ratio 2.56, 95% confidence interval 1.38-4.85, p=0.003) after adjusting for age, gender, traditional cardiovascular risk factors, body mass index (BMI), abdominal visceral adipose tissue (VAT), and coronary artery calcium (CAC) scores. CONCLUSIONS: A high EAT volume was associated with the presence of vulnerable plaque components, independent of obesity measurements (BMI and VAT) and CAC scores.

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.

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.

Comparison of human bone marrow mononuclear cell isolation methods for creating tissue-engineered vascular grafts: novel filter system versus traditional density centrifugation method.

INTRODUCTION: We created the first tissue-engineered vascular graft (TEVG) to be successfully used in humans. The TEVG is made by seeding autologous bone marrow-derived mononuclear cells (BM-MNCs) onto a biodegradable tubular scaffold fabricated from polyglycolic-acid mesh coated with a 50:50 copolymer of poly-L-lactide and-ɛ-caprolactone. In the initial clinical study, the BM-MNCs were isolated using a Ficoll density centrifugation method. Use of this cell isolation technique is problematic in that it is performed using an open system and therefore is susceptible to contamination. As a first step toward creating a closed system for assembling a TEVG, we evaluated the use of a filter-based method for isolating BM-MNCs and compared it to density centrifugation in Ficoll. METHODS: BM-MNCs were isolated from human BM using density centrifugation in Ficoll or a filter-based method. BM-MNCs were seeded onto biodegradable tubular scaffold and incubated for 24 h before implantation. The TEVG were implanted as inferior vena cava interposition grafts in SCID/bg mice (n=24) using microsurgical technique. Grafts were followed with ultrasonography and computed tomography-angiography. Ten weeks after implantation the TEVG were explanted and examined using histology and immunohistochemistry. RESULTS: Both methods isolated similar number of cells (Ficoll: 8.5±6.6×10(6)/mL, Filter: 6.6±3.5×10(6)/mL; p=0.686) with similar viability as assayed using fluorescence-activated cell sorting (FACS) (Ficoll: 97.0%±1.5%, Filter: 95.9%±3.0%; p=0.339). FACS analysis demonstrated that the fraction of lymphocytes and monocytes to total cells was lower in the filter group (CD4 in Ficoll: 8.9%±1.1%, CD4 in Filter: 3.5%±0.8%; p=0.002, CD8 in Ficoll: 9.4%±2.1%, CD8 in Filter: 3.9%±1.4%; p=0.021, Monocyte in Ficoll: 6.9%±1.0%, Monocyte in Filter: 2.7%±1.0%; p=0.008), consistent with granulocyte contamination (Ficoll: 46.6±2.7×10(6)/mL, Filter: 58.1±5.2×10(6)/mL; p<0.001). The ratio of stem cells to BM-MNCs was comparable between groups. There were no statistically significant differences with regard to TEVG patency and morphology between groups. Both methods of cell isolation produced neovessels with similar histology. CONCLUSION: Filter-based BM-MNC isolation is comparable to BM-MNC isolation using density centrifugation in Ficoll for TEVG assembly. The filter-based cell isolation technique has the added advantage of the potential to create a closed disposable system.

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.