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Trimethylamine N-oxide (TMAO), a metabolite derived from the gut microbiota, is proatherogenic and associated with cardiovascular events. However, the change in TMAO with secondary prevention therapies for ST-segment elevation acute myocardial infarction (STEMI) remains unclear. The purpose of this study was to investigate the sequential change in TMAO levels in response to the current secondary prevention therapies in patients with STEMI and the clinical impact of TMAO levels on cardiovascular events We included 112 STEMI patients and measured plasma TMAO levels at the onset of STEMI and 10 months later (chronic phase). After the chronic-phase assessment, patients were followed up for cardiovascular events. Plasma TMAO levels significantly increased from the acute phase to the chronic phase of STEMI (median: 5.63 to 6.76 μM, P = 0.048). During a median period of 5.4 years, 17 patients experienced events. The chronic-phase TMAO level independently predicted future cardiovascular events (adjusted hazard ratio for 0.1 increase in log chronic-phase TMAO level: 1.343, 95% confidence interval 1.122–1.636, P = 0.001), but the acute-phase TMAO level did not. This study demonstrated the clinical importance of the chronic-phase TMAO levels on future cardiovascular events in patients after STEMI.

Background Cachexia, characterized by loss of muscle with or without loss of fat mass, is a poor prognostic factor in patients with heart failure (HF). However, there is limited investigation on the prognostic impact of muscle and fat mass separately in HF. We hypothesized that muscle and fat mass have different effects on the prognosis of HF. Methods This was an observational cohort study of 418 patients (59% were men) admitted with a diagnosis of HF (71 ± 13 years [mean ± standard deviation]), with left ventricular ejection fraction (LVEF) of 39 ± 16%, including 31.3%, 14.8%, and 53.8% of patients with preserved LVEF (LVEF ≥ 50%), mid‐range LVEF (40–50%), and reduced (<40%) LVEF, respectively. Dual‐energy X‐ray absorptiometry was performed with the patients in the stable state after decongestion therapy. Results The mean body mass index of patients was 22.1 ± 4.6 kg/m2, and the mean appendicular skeletal mass (ASM) index was 6.88 ± 1.23 kg/m2 in men and 5.59 ± 0.92 in women; 54.1% of the patients showed reduced muscle mass defined by the international cut‐off value (7.0 kg/m2 for men and 5.4 for women). The mean fat mass was 20.4 ± 7.2% in men and 27.2 ± 8.6% in women. During a median follow‐up of 37 months, 92 (22.0%) of 418 patients with HF died (1 and 3 year mortality: 8.4% and 17.3%, respectively). Lower values of both skeletal muscle and fat mass were independently associated with increased risk of mortality adjusted for age, sex, haemoglobin, New York Heart Association functional class, and height squared (hazard ratio with 95% confidence interval of 0.825 [0.747–0.908] per 1 kg increase of ASM, P < 0.001, and 0.954 [0.916–0.993] per 1 kg increase of fat mass, P = 0.018, respectively). Conclusions More than half of the patients with HF showed reduced muscle mass. Lower values of both muscle and fat mass were associated with higher mortality in HF.

No medications have been reported to inhibit the progression of aortic valve stenosis (AS). The present study aimed to investigate whether evolocumab use is related to the slow progression of AS evaluated by serial echocardiography. This was a retrospective observational study from 2017 to 2022 at Yokohama City University Medical Center. Patients aged ≥ 18 with moderate AS were included. Exclusion criteria were (1) mild AS; (2) severe AS defined by maximum aortic valve (AV) velocity ≥ 4.0 m/s; and/or (3) no data of annual follow-up echocardiography. The primary endpoint was the association between evolocumab use and annual changes in the maximum AV-velocity or peak AV-pressure gradient (PG). A total of 57 patients were enrolled: 9 patients treated with evolocumab (evolocumab group), and the other 48 patients assigned to a control group. During a median follow-up of 33 months, the cumulative incidence of AS events (a composite of all-cause death, AV intervention, or unplanned hospitalization for heart failure) was 11% in the evolocumab group and 58% in the control group ( P  = 0.012). Annual change of maximum AV-velocity or peak AV-PG from the baseline to the next year was 0.02 (− 0.18 to 0.22) m/s per year or 0.60 (− 4.20 to 6.44) mmHg per year in the evolocumab group, whereas it was 0.29 (0.04–0.59) m/s per year or 7.61 (1.46–16.48) mmHg per year in the control group (both P  < 0.05). Evolocumab use was associated with slow progression of AS and a low incidence of AS events in patients with moderate AS.

Abstract Background and objectives Initially described as a benign acute cardiomyopathy, Takotsubo syndrome has been linked to elevated mortality rates. Emerging evidence suggests that unresolved myocardial inflammation may contribute to this adverse prognosis. This study aimed to evaluate the incremental prognostic utility of C-reactive protein (CRP) in conjunction with the InterTAK prognosis score for stratifying long-term mortality in Takotsubo syndrome. Methods A retrospective analysis was conducted from a multicentre registry encompassing 307 patients diagnosed with Takotsubo syndrome between 2008 and 2020. Patients were stratified into quartiles based on the InterTAK prognosis score. The discriminatory potential of CRP in predicting long-term mortality was assessed. The primary endpoint was defined as all-cause mortality within 1 year. Results A stepwise increase of CRP at discharge that corresponds to INTERTAK quartiles was observed: 9.5 mg/L (25th percentile) in the first quartile, 15.8 mg/L (median) in the second quartile, 25.3 mg/L (75th percentile) in the third quartile and 41.2 mg/L (maximum) in the fourth quartile. Receiver operating-characteristic curves analysis revealed that CRP value at discharge was predictive of 1 year mortality (area under the curve = 0.81; 95% confidence interval = 0.68–0.90) with an optimal threshold set at 33 mg/L (sensitivity: 65%; specificity: 87%). When considering the InterTAK score, the incorporation of CRP at discharge with a cut-off of 33 mg/L exhibited a significant enhancement in the prediction of 1 year mortality in ‘intermediate’ risk (25% vs. 1%; P = 0.008) or ‘very high’ risk (40% vs. 10%; P = 0.02) patients. Conclusions In Takotsubo syndrome, the persistence of inflammatory burden at hospital discharge emerged as an independent predictor of 1 year mortality, augmenting the predictive capacity of the conventional InterTAK prognosis score.

Aims Reduced skeletal muscle mass is a major component of sarcopenia, associated with impaired exercise capacity and poor prognosis in patients with heart failure (HF). Measurement of skeletal muscle mass by dual‐energy X‐ray absorptiometry may be affected by fluid retention, typically in the patients' lower extremities. The aim of the present study was to elucidate the association between upper and lower extremity skeletal muscle mass (USM and LSM) and all‐cause mortality in hospitalized patients with HF, after discharge. Methods This was a single‐centre observational cohort study of 418 patients (59% were men) admitted with a diagnosis of HF (71 ± 13 years), with a left ventricular ejection fraction of 39 ± 16%. USM and LSM were measured by dual‐energy X‐ray absorptiometry with patients in a stable state after decongestion therapy. Results The USM and LSM were 5.29 ± 1.18 and 13.78 ± 3.20 kg for men and 3.37 ± 0.68 and 9.19 ± 1.80 kg for women. A positive correlation was obtained between USM and LSM with mid‐upper arm circumference (r = 0.684, P < 0.001) and calf circumference (r = 0.822, P < 0.001), respectively. During a median follow‐up of 37 months, 92 (22.0%) of the 418 patients died. A Kaplan–Meier analysis revealed that sex‐specific quartiles of USM/height2 and LSM/height2 were associated with all‐cause mortality (both P < 0.001 by the log‐rank test). In Cox models adjusted by age, sex, creatinine, haemoglobin, NYHA class, and height2, the hazard ratio with 95% confidence intervals for all‐cause mortality was 0.557 [0.393–0.783] (P < 0.001) for USM per 1 kg, and 0.783 [0.689–0.891] (P < 0.001) for LSM per 1 kg. The receiver‐operator‐characteristic curve analysis showed a comparable area under the curve between the USM/height2 and LSM/height2 (0.557 vs. 0.568, P = 0.562) in predicting all‐cause mortality. The ratio of USM to LSM was significantly lower in 37 patients with residual leg oedema than in the 360 patients without oedema (36.1% vs. 38.1%, P = 0.004), suggesting the influence of oedema on measured LSM. Conclusions Both USM and LSM had a prognostic implication on mortality after discharge in HF, even though LSM may have been affected by leg oedema. These findings indicate that clinicians should not ignore a patient's USM or LSM in the prognostication of patients with HF.

Abstract Background The present article describes two cases of patients with coronary arteritis (CA) whose identification of CA diagnosis (late vs. early) resulted in different clinical courses and outcomes. Case summary Case 1 is a 53-year-old woman with multiple coronary risk factors who was admitted with acute coronary syndrome (ACS) and significant stenosis in the left main trunk (LMT). Although clues suggested arteritis (LMT lesion without any other stenosis, occlusion of left internal thoracic artery, etc.), the diagnosis of CA (coronary involvement of unclassified arteritis) was delayed and revascularization, including coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), was performed under uncontrolled inflammatory status. As a result, Case 1 experienced repeated ACS episodes due to graft failure and in-stent restenosis, and repeatedly underwent PCI. Case 2 is a 76-year-old woman with no significant coronary risk factors who was admitted with ACS. This patient was successfully diagnosed with coronary involvement of Takayasu arteritis before revascularization. Coronary artery bypass grafting was performed after stabilizing inflammation with prednisolone, and the patient remains angina-free beyond 1-year post-CABG. In both cases, intravascular imaging clearly identified the localization and degree of inflammation related to CA by demonstrating specific findings (ambiguous typical three-layer structure of arterial wall and extended low-echoic areas within adventitia). Discussion Accurate and early diagnosis with meticulous diagnostic and therapeutic strategies appear to be important for favourable clinical outcomes in the medical treatment of patients with coronary involvement of arteritis. Intravascular imaging has the potential to contribute to optimizing clinical management of CA.

Objective The purpose of this study is to evaluate whether prone myocardial perfusion single-photon emission computed tomography (MPS) with thallium-201 acquired through a variable-focus collimator (IQ-SPECT) can correct for soft-tissue attenuation. Methods Thirty-nine patients underwent thallium-201 stress MPS with IQ-SPECT. Delayed images acquired with the patients in the prone position were compared with delayed images obtained with the patients in the supine position with computed tomography-derived attenuation correction (CTAC) (S-CTAC images) or without CTAC (S-NCTAC images). Quantitative tracer uptake (QTU) and semi-quantitative defect scores were determined for the 17 standard myocardial segments. Segments were categorized into anterior–anteroseptal, lateral, inferior, and apex, and areas with defect decision were determined by using the defect scores. Results Image quality in the prone images was similar to that of S-NCTAC and S-CTAC images. In male patients, QTU in prone images was equivalent to that in S-CTAC images in the anterior–anteroseptal area, but was significantly lower than that in S-CTAC images in the inferior area. In female patients, QTU in prone images was similar to that in S-CTAC images in the anterior–anteroseptal, lateral, and inferior areas. In male and in female patients, QTU in the apex was significantly greater in the prone images than that in the S-CTAC images. In the combined male and female patient group, the defect decision for prone images was similar to that for S-CTAC images in the anterior–anteroseptal, lateral, and inferior areas. Apical defects were observed more frequently in S-CTAC images than in prone or S-NCTAC images. Conclusions Fewer artificial defects were observed in the apex of images acquired by prone imaging than by S-CTAC imaging. Prone images improved attenuation and had similar defect decision as S-CTAC images in the anterior–anteroseptal, lateral, and inferior areas.

This thesis consists of essays on technology and trade. In Chapter 1, I study how technology in the 21st century has changed the pattern of trade. I document that skill-abundant countries no longer have a comparative advantage in skill-intensive sectors. While this empirical relationship was strong in the 1980s, it weakened in the 1990s and disappeared by the 2000s. The decline is more pronounced in countries and sectors with higher automation. I find no such heterogeneous effects among countries and sectors more exposed to offshoring. Using a quantitative trade model incorporating automation and offshoring, I confirm that the observed changes in automation can account for the evolution of comparative advantage while observed changes in offshoring cannot. I conclude by revisiting the relationships between globalization, technology, and inequality through this model. Automation increases skill premia in developed countries with high automation and also raises welfare globally, whereas offshoring leads to smaller, more evenly distributed welfare gains.In Chapter 2 (joint with Daniel G. O'Connor), we turn to the geographic consequences of technology and trade by analyzing the role of granularity—the dominance of a few large firms in local labor markets. We propose a new economic geography model featuring granular firms subject to idiosyncratic shocks. We show that average wages increase in the size of the local labor market due to that granularity, and provide a sufficient statistic for the contribution of our mechanism. We further prove that too few firms enter in equilibrium. Using Japanese administrative data on manufacturing, we provide evidence consistent with our mechanism and quantify it. Our mechanism implies that markets with around 2 firms per sector have an elasticity of wages to population of 0.05 and firms capture only 85% of their contribution to production in profits. In large markets like Tokyo, the elasticity is around 0.001, and firm entry is approximately efficient. Enacting optimal place-based industrial policy would increase the number of firms in modest-sized cities by more than 30% and actually decrease the number of firms and people in Tokyo.In Chapter 3 (joint with Sagiri Kitao), we study the distributional consequences of technological and trade-induced polarization—wage and employment losses of middle-class workers relative to low- and high-skill groups. We build a model of overlapping generations who choose consumption, savings, labor supply, and occupations over their life-cycles, and accumulate human capital. We simulate a wage shift observed since the early 1980s and investigate individuals' responses. Polarization improves welfare of young individuals that are high-skilled, while it hurts low-skilled individuals across all ages and especially younger ones. The gain of the high-skilled is larger for generations entering in later periods, who can fully exploit the rising skill premium.

Objective IQ-SPECT (Siemens AG, Munich, Germany) is a highly sensitive single-photon-emission computed tomography (SPECT) myocardial perfusion imaging (MPI) system that uses a multifocal collimator. We searched for a suitable protocol for short-time imaging by IQ-SPECT in thallium-201 (Tl-201) MPI by evaluating phantom images and also by comparing human IQ-SPECT images with conventional SPECT images as reference standards. Methods We assessed the image quality using the normalized mean square error (NMSE) and drew up count profiles in Tl-201 SPECT images acquired with IQ-SPECT in a phantom study. We also performed Tl-201 stress myocardial SPECT/CT in 21 patients and compared delayed images acquired by using IQ-SPECT with 36 or 17 views per head with images obtained by using conventional SPECT. Results The NMSE of SPECT images from IQ-SPECT with 36 views was approximately one-fifth of that with 17 views. The myocardial count profile of images with 17 views was lower than those of images with 36 or 104 views in some regions. Defect scores were significantly lower, and image quality scores higher, in images from conventional SPECT than in those from IQ-SPECT with 17 views. Defect scores and image quality scores were equivalent in images from conventional SPECT and those from IQ-SPECT with 36 views. Agreement with the results of conventional SPECT in terms of coronary artery territory-based defect judgment was the best in IQ-SPECT with 36 views with computed tomography-derived attenuation correction (CTAC): the kappa values for IQ-SPECT with 36 views were 0.76 (without CTAC) and 0.83 (with CTAC), and those for IQ-SPECT with 17 views were 0.62 (without CTAC) and 0.59 (with CTAC). The difference in quantitative tracer uptake between conventional SPECT images and IQ-SPECT images was significantly greater for IQ-SPECT images with 17 views than for those with 36 views. Conclusions Scanning with 36 views per head with CTAC may be appropriate for Tl-201 MPI using IQ-SPECT, because it provides images equivalent to those using conventional SPECT.

•Severe aortic atheroma was an independent risk factor for 2-year MACCE following TAVR.•Severe aortic atheroma was associated with periprocedural ischemic stroke and CV death (≤30 d), and late stroke (>1 y post-TAVR).•Severe aortic atheroma constitutes a major harmful factor associated with periprocedural events and can affect late stroke post-TAVR. Although aorta atheroma morphology is associated with acute outcomes post-transcatheter aortic valve replacement (TAVR), its association with long-term outcomes post-TAVR remains unknown. This study evaluates the impact of severe aortic atheroma on long-term outcomes following TAVR. We enrolled 977 patients who underwent TAVR between February 2010 and May 2019, with available contrast-enhanced computed tomography data. Severe aortic atheroma was defined as protruding atheroma of ≥3mm thickness with protruding components, ulcerated atheroma with ulcer-like intimal disruption, and atheroma of ≥5mm thickness. The primary endpoint was 2-year major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of cardiovascular death, myocardial infarction, ischemic stroke, and heart failure, events classified as periprocedural (≤30 days), early (30 days to 1 year), and late (>1-year post-TAVR). Patients with severe aortic atheroma (n = 274, 28%) had a higher cumulative incidence of 2-year MACCE than those without (40.6% vs 28.9%, log-rank p = 0.0002), which was attributed to increased risks of ischemic stroke (13.8% vs 6.8%, log-rank p = 0.0012) and cardiovascular death (18.6% vs 10.8%, log-rank p = 0.0009). Severe aortic atheroma was an independent risk factors for 2-year MACCE (adjusted hazard ratio [aHR], 1.49, 95% CI 1.16 to 1.90). In the landmark analysis, severe aortic atheroma was independently associated with periprocedural ischemic stroke and cardiovascular death (aHR, 2.12, 95% CI 1.15 to 3.90 and aHR, 3.29, 95% CI 1.70 to 6.37, respectively), and late ischemic stroke (aHR, 3.71, 95% CI 1.35 to 10.2). Patients with severe aortic atheroma have an increased risk of 2-year MACCE post-TAVR.