Evaluation of fractional flow reserve and atherosclerotic plaque characteristics on coronary non-contrast T1-weighted magnetic resonance imaging.

BACKGROUND AND AIMS: The relationship between high-risk coronary plaque characteristics regardless of the severity of lesion stenosis and myocardial ischemia remains unsettled. High-intensity plaques (HIPs) on non-contrast T1-weighted magnetic resonance imaging (T1WI) have been characterized as high-risk coronary plaques. We sought to elucidate whether the presence of coronary HIPs on T1WI influences fractional flow reserve (FFR) in the distal segment of the vessel. METHODS: We retrospectively analyzed 281 vessels in 231 patients with chronic coronary syndrome who underwent invasive FFR measurement and coronary T1WI using a multicenter registry. The plaque-to-myocardial signal intensity ratio (PMR) of the most stenotic lesion was evaluated; a coronary plaque with PMR ≥1.4 was defined as a HIP. RESULTS: The median PMR of coronary plaques on T1WI in vessels with FFR ≤0.80 was significantly higher than that of plaques with FFR >0.80 (1.17 [interquartile range (IQR): 0.99-1.44] vs. 0.97 [IQR: 0.85-1.09]; p < 0.001). Multivariable analysis showed that an increase in PMR of the most stenotic segment was associated with lower FFR (beta-coefficient, -0.050; p < 0.001). The presence of coronary HIPs was an independent predictor of FFR ≤0.80 (odds ratio (OR), 6.18; 95% confidence interval (CI), 1.93-19.77; p = 0.002). Even after adjusting for plaque composition characteristics based on computed tomography angiography, the presence of coronary HIPs was an independent predictor of FFR ≤0.80 (OR, 4.48; 95% CI, 1.19-16.80; p = 0.026). CONCLUSIONS: Coronary plaques with high PMR are associated with low FFR in the corresponding vessel, indicating that plaque morphology might influence myocardial ischemia severity.

Outcomes of patients with cerebral microbleeds undergoing percutaneous coronary intervention and dual antiplatelet therapy.

INTRODUCTION: Cerebral microbleeds (CMBs) on brain magnetic resonance imaging (MRI) are predictive of intracerebral hemorrhage (ICH). However, the risk of ICH in patients with CMBs who undergo percutaneous coronary intervention (PCI) while receiving dual antiplatelet therapy (DAPT) is unclear. MATERIALS AND METHODS: We conducted a study on 329 consecutive patients with coronary artery disease who underwent PCI and were evaluated using a 3T MRI scanner. Based on T2*-weighted imaging, patients were classified into three groups: no CMBs, < 5 CMBs, or ≥ 5 CMBs. We determined the occurrence of ICH during follow-up. RESULTS: At least 1 CMB was found in 109 (33%) patients. The mean number of CMBs per patient was 2.9 ± 3.6. Among the 109 patients with CMBs, 16 (15%) had ≥ 5 CMBs. Coronary stent implantation was performed in 321 patients (98%). DAPT was prescribed for 325 patients (99%). During a mean follow-up period of 2.3 years (interquartile range, 1.9-2.5 years), ICH occurred in one patient (1.1%) with four CMBs. There were no significant differences in the incidence of ICH (0% vs. 1.1% vs. 0%; p = 0.28). However, the rate of DAPT at 6 months of follow-up was significantly lower in patients with ≥ 5 CMBs than in patients with no CMBs or < 5 CMBs (89% vs. 91% vs. 66%, p = 0.026). Furthermore, there were no significant differences in systemic blood pressure during follow-up (123 ± 16 vs. 125 ± 16 vs. 118 ± 11 mmHg; p = 0.40). CONCLUSION: Although a substantial number of patients who underwent PCI had cerebral microbleeds, at approximately two years of follow-up, intracerebral hemorrhage was very rare in our study population.

Stronger positive correlation of the left ventricular mass index and extracellular volume fraction with diastolic function in diabetic patients without myocardial infarction.

BACKGROUND: The structural and functional characteristics of the heart in patients with diabetes mellitus (DM) and without myocardial infarction (MI) are not fully understood. METHODS: We retrospectively analysed the data of patients with left ventricular ejection fraction (LVEF) ≥ 40% who underwent contrast-enhanced cardiac magnetic resonance imaging (CMR), which was also used to exclude MI, at two hospitals. Volumetric data and extracellular volume fraction (ECVf) of the myocardium evaluated using CMR were compared between patients with and without DM, and their association with diastolic function was evaluated. RESULTS: Among 322 analysed patients, 53 had DM. CMR revealed that the left ventricular mass index (LVMi) and ECVf were increased while LVEF was decreased in patients with DM after adjusting for patient characteristics (all P < 0.05). A stronger positive correlation was observed between LVMi and the early diastolic transmitral flow velocity to early diastolic mitral annular velocity ratio (E/e') in patients with DM than in those without DM (correlation coefficient [R] = 0.46, p = 0.001; R = 0.15, p = 0.021, respectively; p for interaction = 0.011). ECVf correlated with E/e' only in patients with DM (R = 0.61, p = 0.004). CONCLUSIONS: Patients with DM have increased LVMi and ECVf. Importantly, there was a difference between patients with and without DM in the relationship between these structural changes and E/e', with a stronger relationship in patients with DM. Furthermore, DM is associated with mildly reduced LVEF even in the absence of MI.

Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024.

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Can right ventricular endomyocardial biopsy predict left ventricular fibrosis beforehand in dilated cardiomyopathy?

AIMS: Myocardial fibrosis of the left ventricle (LV) is a prognostic factor in dilated cardiomyopathy (DCM). This study aims to evaluate whether fibrosis of right ventricular (RV) endomyocardial biopsy (EMB) can predict the degree of LV fibrosis beforehand in DCM. METHODS AND RESULTS: Fibrosis extent in 70 RV-EMB specimens of DCM diagnosis was compared with that in the whole cross-sectional LV of excised hearts in the same patients (52 explanted hearts for transplant and 18 autopsied hearts). The median interval between biopsy and excision was 4.1 (0.13-19.3) years. The fibrosis area ratio of the EMBs and excised hearts were evaluated via image analysis. The distribution of cardiovascular magnetic resonance-late gadolinium enhancement (LGE) in the intraventricular septum was classified into four quartile categories. The fibrosis area ratio in RV-EMB correlated significantly with that in the short-axis cut of the LV of excised hearts (r = 0.82, P < 0.0001) and with a diffuse pattern of LGE (r = 0.71, P = 0.003). In a multivariate model, after adjusting for the interval between biopsy performance and heart excision, the fibrosis area ratio in RV-EMB was associated with that in LV-excised heart (regression coefficient, 0.82; 95% confidence interval, 0.68-0.95; P < 0.0001). CONCLUSIONS: The fibrosis observed in RV-EMB positively correlated with the extent of fibrosis in the LV of excised hearts in patients with DCM. The study findings may help predict LV fibrosis, considered a prognostic factor of DCM through relatively accessible biopsy techniques.

Post hoc analysis of patients with rheumatoid arthritis under clinical remission in two Japanese Phase 3 trials of peficitinib treatment (RAJ3 and RAJ4).

OBJECTIVE: We evaluated remission rates and their relationship with baseline characteristics in patients with rheumatoid arthritis treated with the oral Janus kinase inhibitor peficitinib. METHODS: This post hoc analysis of data from two Phase 3 studies (RAJ3 and RAJ4) of peficitinib (100 and 150 mg/day) in Asian rheumatoid arthritis patients investigated clinical disease activity index (CDAI) remission and low disease activity rates from baseline to Week 52. CDAI, Health Assessment Questionnaire-Disability Index, and van der Heijde-modified total Sharp score remission/low disease activity rates at Week 52 were evaluated among patients achieving CDAI remission at Weeks 12/28. Logistic regression analyses explored the relationship between baseline characteristics and CDAI remission/low disease activity rates. RESULTS: CDAI remission rates increased over time in a dose-dependent manner in both peficitinib-treated groups. Most patients achieving CDAI remission at Weeks 12/28 also achieved remission at Week 52. Following the multivariate analysis of demographic and baseline characteristics, factors associated with the achievement of CDAI remission at Week 28 included male sex, low baseline prednisone dose (RAJ3 only), and low baseline Disease Activity Score 28-C-reactive protein (RAJ4 only). CONCLUSIONS: Peficitinib demonstrated persistent efficacy in clinical remission to Week 52. Baseline characteristics associated with CDAI remission were mostly consistent with previous studies using other disease-modifying antirheumatic drugs.

Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Safety and effectiveness of peficitinib 100 mg/day in patients achieving clinical remission from a long-term open-label extension study in Japan, Korea, and Taiwan (RAJ2).

OBJECTIVES: This post hoc analysis of the RAJ2 study assessed long-term safety and effectiveness of peficitinib 100 mg/day for treatment of rheumatoid arthritis. METHODS: Eligible patients previously completed two Phase 3 (RAJ3 and RAJ4) studies of peficitinib in Asia. All patients received peficitinib 100 mg/day at RAJ2 Week (W)0; dose change to 50 mg/day or 150 mg/day was permitted. Safety endpoints included treatment-emergent adverse events and laboratory test results. Effectiveness endpoints included peficitinib exposure pattern, achievement of Clinical Disease Activity Index (CDAI) remission by peficitinib exposure pattern at W0 and W48, and association of demographics/characteristics with CDAI remission at W0 and W48. RESULTS: Overall, no new safety findings were reported at W48, and renal function was unaffected. Of patients included in effectiveness analyses at W48, 70.9% (451/636) had maintained peficitinib 100 mg/day since W0. Of patients who achieved CDAI remission at W0 and maintained peficitinib 100 mg/day to W48, 50.3% (79/157) maintained CDAI remission to W48. Low disease activity and a lower number of prior disease-modifying antirheumatic drugs were significantly associated with CDAI remission at W48. CONCLUSIONS: Long-term peficitinib treatment at a dose of 100 mg/day was generally well tolerated and, following induction therapy, maintained effectiveness through to W48.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

OBJECTIVE: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. METHODS: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. RESULTS: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018). SIGNIFICANCE: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline.

Transthyretin derived amyloid deposits in the atrium and the aortic valve: insights from multimodality evaluations and mid-term follow up.

BACKGROUND: Recent studies have reported atrial involvement and coexistence of aortic stenosis in transthyretin (ATTR) cardiac amyloidosis (CA). However, pathological reports of extraventricular ATTR amyloid deposits in atrial structures or heart valves are limited, and the clinical implications of ATTR amyloid deposits outside the ventricles are not fully elucidated. CASE PRESENTATION: We report 3 cases of extraventricular ATTR amyloid deposits confirmed in surgically resected aortic valves and left atrial structures, all of which were unlikely to have significant ATTR amyloidosis infiltrating the ventricles as determined by multimodality evaluation including 99mtechnetium-pyrophosphate scintigraphy, cardiac magnetic resonance, endomyocardial biopsy and their mid-term clinical course up to 5 years. These findings suggested that these were extraventricular ATTR amyloid deposits localized in the aortic valve and the left atrium. CONCLUSIONS: While long-term observation is required to fully clarify whether these extraventricular ATTR amyloid deposits are truly localized outside the ventricles or are early stages of ATTR-CA infiltrating the ventricles, our 3 cases with multimodality evaluations and mid-term follow up suggest the existence of extraventricular ATTR amyloid deposits localized in the aortic valve and left atrial structures.

Deep Learning-based Post Hoc CT Denoising for the Coronary Perivascular Fat Attenuation Index.

RATIONALE AND OBJECTIVES: Coronary inflammation related to high-risk hemorrhagic plaques can be captured by the perivascular fat attenuation index (FAI) using coronary computed tomography angiography (CCTA). Since the FAI is susceptible to image noise, we believe deep learning (DL)-based post hoc noise reduction can improve diagnostic capability. We aimed to assess the diagnostic performance of the FAI in DL-based denoised high-fidelity CCTA images compared with coronary plaque magnetic resonance imaging (MRI) delivered high-intensity hemorrhagic plaques (HIPs). MATERIALS AND METHODS: We retrospectively reviewed 43 patients who underwent CCTA and coronary plaque MRI. We generated high-fidelity CCTA images by denoising the standard CCTA images using a residual dense network that supervised the denoising task by averaging three cardiac phases with nonrigid registration. We measured the FAIs as the mean CT value of all voxels (range of -190 to -30 HU) located within a radial distance from the outer proximal right coronary artery wall. The diagnostic reference standard was defined as HIPs (high-risk hemorrhagic plaques) using MRI. The diagnostic performance of the FAI in the original and denoised images was assessed using receiver operating characteristic curves. RESULTS: Of 43 patients, 13 had HIPs. The denoised CCTA improved the area under the curve (0.89 [95% confidence interval (CI) 0.78-0.99]) of the FAI compared with that in the original image (0.77 [95% CI, 0.62-0.91], p = 0.008). The optimal cutoff value for predicting HIPs in denoised CCTA was -69 HU with 0.85 (11/13) sensitivity, 0.79 (25/30) specificity, and 0.80 (36/43) accuracy. CONCLUSION: DL-based denoised high-fidelity CCTA improved the AUC and specificity of the FAI for predicting HIPs.

Optimization of null point in Look-Locker images for myocardial late gadolinium enhancement imaging using deep learning and a smartphone.

OBJECTIVES: To determine the optimal inversion time (TI) from Look-Locker scout images using a convolutional neural network (CNN) and to investigate the feasibility of correcting TI using a smartphone. METHODS: In this retrospective study, TI-scout images were extracted using a Look-Locker approach from 1113 consecutive cardiac MR examinations performed between 2017 and 2020 with myocardial late gadolinium enhancement. Reference TI null points were independently determined visually by an experienced radiologist and an experienced cardiologist, and quantitatively measured. A CNN was developed to evaluate deviation of TI from the null point and then implemented in PC and smartphone applications. Images on 4 K or 3-megapixel monitors were captured by a smartphone, and CNN performance on each monitor was determined. Optimal, undercorrection, and overcorrection rates using deep learning on the PC and smartphone were calculated. For patient analysis, TI category differences in pre- and post-correction were evaluated using the TI null point used in late gadolinium enhancement imaging. RESULTS: For PC, 96.4% (772/749) of images were classified as optimal, with under- and overcorrection rates of 1.2% (9/749) and 2.4% (18/749), respectively. For 4 K images, 93.5% (700/749) of images were classified as optimal, with under- and overcorrection rates of 3.9% (29/749) and 2.7% (20/749), respectively. For 3-megapixel images, 89.6% (671/749) of images were classified as optimal, with under- and overcorrection rates of 3.3% (25/749) and 7.0% (53/749), respectively. On patient-based evaluations, subjects classified as within optimal range increased from 72.0% (77/107) to 91.6% (98/107) using the CNN. CONCLUSIONS: Optimizing TI on Look-Locker images was feasible using deep learning and a smartphone. KEY POINTS: • A deep learning model corrected TI-scout images to within optimal null point for LGE imaging. • By capturing the TI-scout image on the monitor with a smartphone, the deviation of the TI from the null point can be immediately determined. • Using this model, TI null points can be set to the same degree as that by an experienced radiological technologist.

Sequential detection rates of intramural hematoma for diagnosing spontaneous intracranial artery dissection.

BACKGROUND AND PURPOSE: Spontaneous intracranial artery dissection (IAD) can be definitively diagnosed by detecting intramural hematoma (IMH) on arterial wall imaging. However, evidence of a time-dependent natural history for the development of radiological findings is lacking. Therefore, this study aimed to determine when imaging detects IAD. METHODS: We obtained data from our cohort databases between March 2011 and August 2018 on consecutive patients who had definite, probable, or possible IAD based on the multidisciplinary expert consensus criteria. We assessed IMH on initial and follow-up high-resolution three-dimensional T1-weighted imaging (HR-3D-T1WI). We retrospectively investigated the association between IMH detection and days from symptom onset to initial HR-3D-T1WI and compared the IMH detection rate with other definitive diagnostic arterial dissection findings. RESULTS: We analyzed 106 patients (mean age = 51 ± 13 years, 31 women) with at least initial HR-3D-T1WI data. The final diagnoses were definite, probable, and possible IAD in 83, 18, and 5 patients, respectively. IMHs were observed in 63 patients (59%, 95% confidence interval [CI] = 49%-69%). Overall IMH detection rate was 55% (95% CI = 45%-64%), 20% (95% CI = 3%-60%), 40% (95% CI = 21%-64%), and 50% (95% CI = 37%-63%) on the initial HR-3D-T1WI and Days 3, 7, and 13, respectively. Among 68 patients evaluated with digital subtraction angiography and HR-3D-T1WI, IMH was confirmed more frequently than other definitive diagnostic arterial dissection findings. CONCLUSIONS: The overall IMH detection rate on HR-3D-T1WI was >50% and peaked in 1-2 weeks. IMH was a frequently detectable finding for the diagnosis of IAD compared to other radiological findings.

Multimodality assessments of wild-type transthyretin cardiac amyloidosis with no ventricular hypertrophy.

While patients with transthyretin cardiac amyloidosis (ATTR-CA) typically present with concentric or asymmetric hypertrophy, a small percentage of ATTR-CA is known to present with 'atypical' cardiac morphologies such as eccentric hypertrophy or even no hypertrophy. However, detailed report of multimodality assessments of ATTR-CA with no ventricular hypertrophy is lacking. Herein, we report detailed multimodality assessments of an 81-year-old Japanese woman with heart failure and history of carpal tunnel syndrome and lumbar canal stenosis, presenting no ventricular hypertrophy and negative 99m technetium-pyrophosphate scintigraphy, who was eventually diagnosed as having wild-type ATTR-CA. Our case highlights the role of multimodality assessments for early diagnosis of ATTR-CA in patients with atypical cardiac morphologies and also emphasizes the limitations of bone scintigraphy and the importance of considering ATTR-CA in patients with non-cardiac manifestations of ATTR amyloidosis.

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs  = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.