Synthesis of purine derivatives of Me-TaNA and properties of Me-TaNA-modified oligonucleotides.

We previously reported that pyrimidine derivatives of methylated 2'-O,4'-C-methyleneoxy-bridged nucleic acid (Me-TaNA), a unique consecutive three-acetal-containing nucleic acid, are promising building blocks for chemically modified oligonucleotides. Herein, purine derivatives of Me-TaNA (Me-TaNA-A and -G) were synthesized and introduced into oligonucleotides. During the synthesis, we found stereoselective introduction of a substituent on the 4' carbons by using 2',3'-carbonate compounds as substrates. When forming duplexes with single-stranded RNA, the modified oligonucleotides, including purine derivatives of Me-TaNA, showed higher duplex stability than the natural oligonucleotide. This study enabled the use of Me-TaNA for the chemical modification of various oligonucleotide sequences because synthesis of Me-TaNAs with all four nucleobases was achieved.

Comparison between conventional and compressed sensing cine cardiovascular magnetic resonance for feature tracking global circumferential strain assessment.

BACKGROUND: Feature tracking (FT) has become an established tool for cardiovascular magnetic resonance (CMR)-based strain analysis. Recently, the compressed sensing (CS) technique has been applied to cine CMR, which has drastically reduced its acquisition time. However, the effects of CS imaging on FT strain analysis need to be carefully studied. This study aimed to investigate the use of CS cine CMR for FT strain analysis compared to conventional cine CMR. METHODS: Sixty-five patients with different left ventricular (LV) pathologies underwent both retrospective conventional cine CMR and prospective CS cine CMR using a prototype sequence with the comparable temporal and spatial resolution at 3 T. Eight short-axis cine images covering the entire LV were obtained and used for LV volume assessment and FT strain analysis. Prospective CS cine CMR data over 1.5 heartbeats were acquired to capture the complete end-diastolic data between the first and second heartbeats. LV volume assessment and FT strain analysis were performed using a dedicated software (ci42; Circle Cardiovasacular Imaging, Calgary, Canada), and the global circumferential strain (GCS) and GCS rate were calculated from both cine CMR sequences. RESULTS: There were no significant differences in the GCS (- 17.1% [- 11.7, - 19.5] vs. - 16.1% [- 11.9, - 19.3; p = 0.508) and GCS rate (- 0.8 [- 0.6, - 1.0] vs. - 0.8 [- 0.7, - 1.0]; p = 0.587) obtained using conventional and CS cine CMR. The GCS obtained using both methods showed excellent agreement (y = 0.99x - 0.24; r = 0.95; p < 0.001). The Bland-Altman analysis revealed that the mean difference in the GCS between the conventional and CS cine CMR was 0.1% with limits of agreement between -2.8% and 3.0%. No significant differences were found in all LV volume assessment between both types of cine CMR. CONCLUSION: CS cine CMR could be used for GCS assessment by CMR-FT as well as conventional cine CMR. This finding further enhances the clinical utility of high-speed CS cine CMR imaging.

Feasibility of contrast-enhanced coronary artery magnetic resonance angiography using compressed sensing.

BACKGROUND: Coronary magnetic resonance angiography (CMRA) is a promising technique for assessing the coronary arteries. However, a disadvantage of CMRA is the comparatively long acquisition time. Compressed sensing (CS) can considerably reduce the scan time. The aim of this study was to verify the feasibility of CS CMRA scanning during the waiting time between contrast injection and late gadolinium enhancement (LGE) scan in a clinical protocol. METHODS: Fifty clinical patients underwent contrast-enhanced CS CMRA and conventional CMRA on a 3 T CMR scanner. After contrast injection, CS CMRA was scanned during the waiting time for LGE CMR. A conventional CMRA scan was performed after LGE CMR. We assessed acquisition times and coronary artery image quality for each segment on a 4-point scale. Visible vessel length, sharpness and diameter of right (RCA), left anterior descending (LAD), and left circumflex (LCX) coronary arteries were also quantitatively compared among the scans. RESULTS: All CS CMRA scans were successfully performed within the LGE waiting time. The median total scan time was 207 s (163, 259 s) for CS and 785 s (698, 975 s) for conventional CMRA (p < 0.001). No significant differences were observed in image quality scores, vessel length measurements, sharpness, and diameter between CS and conventional CMRA. CONCLUSIONS: We could achieve all CS CMRA scans within the LGE waiting time. Contrast-enhanced CS CMRA could considerably shorten the scan time while maintaining image quality compared with conventional CMRA.

On-Site Computed Tomography-Derived Fractional Flow Reserve Using a Machine-Learning Algorithm　- Clinical Effectiveness in a Retrospective Multicenter Cohort.

BACKGROUND: This study evaluated the diagnostic capability of on-site coronary computed tomography-derived computational fractional flow reserve (CT-FFR) determinations for detecting coronary artery disease (CAD), as assessed by invasive fractional flow reserve (FFR).Methods and Results:Seventy-four patients with coronary artery calcium scores <1,500 who underwent coronary CT angiography (CTA) and invasive FFR measurements within 90 days were retrospectively reviewed. CT-FFR was computed using a prototype machine-learning (ML) algorithm in 91 vessels; 47 vessels of 42 patients were determined to have significant CAD (FFR ≤0.8). Correlation between CT-FFR and FFR was good (r=0.786, P<0.001). Per-vessel area under the curve was significantly larger for CT-FFR (0.907, 95% confidence interval: 0.828-0.958) than for CTA stenosis ≥50% (0.595, 0.487-0.697) or ≥70% (0.603, 0.495-0.705) (both P<0.001). Standard coronary CTA classifications recommended further functional tests in 57 patients with moderate or worse stenosis on CTA. CT-FFR analysis (mean analysis time: 16.4±7.5 min) corrected the standard coronary CTA classification in 18 of 74 patients and confirmed it in 45 of 74 patients. Thus, the per-patient diagnostic accuracy of the classifications was improved from 66% (54-77%) to 85% (75-92%). CONCLUSIONS: On-site CT-FFR based on a ML algorithm can provide good diagnostic performance for detecting hemodynamically significant CAD, suggesting the high value of coronary CTA for selected patients in clinical practice.

Assessment of Second- and Third-Generation Drug-Eluting Stents on Chronic Coronary Angioscopy　- Multicenter Study on Intra-Coronary AngioScopy After Stent (MICASA) Prospective Data Analysis.

BACKGROUND: The vascular response, in terms of quality and quantity, of the second- and third-generation drug-eluting stents (2G- and 3G-DES, respectively) was assessed prospectively on coronary angioscopy (CAS).Methods and Results:The Multicenter study on Intra-Coronary AngioScopy After Stent (MICASA) is a multicenter CAS registry. A total of 107 DES (71 2G- and 36 3G-DES) were prospectively observed on CAS 8.7±2.7 months after percutaneous coronary intervention. Neointimal coverage (NC) grade was evaluated using a 4-point grading scale, from 0 (no coverage) to 3 (complete coverage). Plaque yellow color (YC) was also assessed using a 4-point grading system, from 0 (white) to 3 (bright yellow). Max-NC (2G-DES vs. 3G-DES: 2.14±0.68 vs. 2.44±0.73, P=0.023); min-NC (1.07±0.48 vs. 1.39±0.60, P=0.002), and dominant-NC (1.57±0.69 vs. 2.08±0.84, P=0.002) were significantly higher and the YC grade (1.23±0.82 vs. 0.86±0.76, P=0.031) significantly lower in the 3G-DES group than in the 2G-DES group. There was no significant difference in the presence of thrombus (28.2% vs. 22.2%, P=0.51) between the 2G- and 3G-DES groups. CONCLUSIONS: The higher NC grade and lower YC grade in 3G-DES than in 2G-DES might be associated with better long-term clinical outcome, which remains to be determined in future studies.

The effect of blood pressure on non-invasive fractional flow reserve derived from coronary computed tomography angiography.

OBJECTIVES: The aim of this study is to assess the effect of blood pressure (BP) on coronary computed tomography angiography (CTA) derived computational fractional flow reserve (CTA-FFR). MATERIALS AND METHODS: Twenty-one patients who underwent coronary CTA and invasive FFR were retrospectively identified. Ischemia was defined as invasive FFR ≤0.80. Using a work-in-progress computational fluid dynamics algorithm, CTA-FFR was computed with BP measured before CTA, and simulated BPs of 60/50, 90/60, 110/70, 130/80, 150/90, and 180/100 mmHg respectively. Correlation between CTA-FFR and invasive FFR was assessed using Pearson test. The repeated measuring test was used for multiple comparisons of CTA-FFR values by simulated BP inputs. RESULTS: Twenty-nine vessels (14 with invasive FFR ≤0.80) were assessed. The average CTA-FFR for measured BP (134 ± 20/73 ± 12 mmHg) was 0.77 ± 0.12. Correlation between CTA-FFR by measured BP and invasive FFR was good (r = 0.735, P < 0.001). For simulated BPs of 60/50, 90/60, 110/70, 130/80, 150/90, and 180/100 mmHg, the CTA-FFR increased: 0.69 ± 0.13, 0.73 ± 0.12, 0.75 ± 0.12, 0.77 ± 0.11, 0.79 ± 0.11, and 0.81 ± 0.10 respectively (P < 0.05). CONCLUSION: Measurement of the BP just before CTA is preferred for accurate CTA-FFR simulation. BP variations in the common range slightly affect CTA-FFR. However, inaccurate BP assumptions differing from the patient-specific BP could cause misinterpretation of borderline significant lesions. KEY POINTS: • The blood pressure (BP) affects the CTA-FFR computation. • Measured BP before CT examination is preferable for accurate CTA-FFR simulation. • Inaccurate BP assumptions can cause misinterpretation of borderline significant lesions.

Assessment of Left Ventricular Function and Mass on Free-Breathing Compressed Sensing Real-Time Cine Imaging.

BACKGROUND: Compressed sensing (CS) cine magnetic resonance imaging (MRI) has the advantage of being inherently insensitive to respiratory motion. This study compared the accuracy of free-breathing (FB) CS and breath-hold (BH) standard cine MRI for left ventricular (LV) volume assessment.Methods and Results:Sixty-three patients underwent cine MRI with both techniques. Both types of images were acquired in stacks of 8 short-axis slices (temporal/spatial resolution, 41 ms/1.7×1.7×6 mm3) and compared for ejection fraction, end-diastolic and systolic volumes, stroke volume, and LV mass. Both BH standard and FB CS cine MRI provided acceptable image quality for LV volumetric analysis (score ≥3) in all patients (4.7±0.5 and 3.7±0.5, respectively; P<0.0001) and had good agreement on LV functional assessment. LV mass, however, was slightly underestimated on FB CS cine MRI (median, IQR: BH standard, 83.8 mL, 64.7-102.7 mL; FB CS, 79.0 mL, 66.0-101.0 mL; P=0.0006). The total acquisition times for BH standard and FB CS cine MRI were 113±7 s and 24±4 s, respectively (P<0.0001). CONCLUSIONS: Despite underestimation of LV mass, FB CS cine MRI is a clinically useful alternative to BH standard cine MRI in patients with impaired BH capacity.

Compressed sensing real-time cine cardiovascular magnetic resonance: accurate assessment of left ventricular function in a single-breath-hold.

BACKGROUND: Cardiovascular cine magnetic resonance (CMR) accelerated by compressed sensing (CS) is used to assess left ventricular (LV) function. However, it is difficult for prospective CS cine CMR to capture the complete end-diastolic phase, which can lead to underestimation of the end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF), compared to retrospective standard cine CMR. This prospective study aimed to evaluate the diagnostic quality and accuracy of single-breath-hold full cardiac cycle CS cine CMR, acquired over two heart beats, to quantify LV volume in comparison to multi-breath-hold standard cine CMR. METHODS: Eighty-one participants underwent standard segmented breath-hold cine and CS real-time cine CMR examinations to obtain a stack of eight contiguous short-axis images with same high spatial (1.7 × 1.7 mm(2)) and temporal resolution (41 ms). Two radiologists independently performed qualitative analysis of image quality (score, 1 [i.e., "nondiagnostic"] to 5 [i.e., "excellent"]) and quantitative analysis of the LV volume measurements. RESULTS: The total examination time was 113 ± 7 s for standard cine CMR and 24 ± 4 s for CS cine CMR (p < 0.0001). The CS cine image quality was slightly lower than standard cine (4.8 ± 0.5 for standard vs. 4.4 ± 0.5 for CS; p < 0.0001). However, all image quality scores for CS cine were above 4 (i.e., good). No significant differences existed between standard and CS cine MR for all quantitative LV measurements. The mean differences with 95 % confidence interval (CI), based on Bland-Altman analysis, were 1.3 mL (95 % CI, -14.6 - 17.2) for LV end-diastolic volume, 0.2 mL (95 % CI, -9.8 to10.3) for LV end-systolic volume, 1.1 mL (95 % CI, -10.5 to 12.7) for LV stroke volume, 1.0 g (95 % CI, -11.2 to 13.3) for LV mass, and 0.4 % (95 % CI, -4.8 - 5.6) for LV ejection fraction. The interobserver and intraobserver variability for CS cine MR ranged from -4.8 - 1.6 % and from -7.3 - 9.3 %, respectively, with slopes of the regressions ranging 0.88-1.0 and 0.86-1.03, respectively. CONCLUSIONS: Single-breath-hold full cardiac cycle CS real-time cine CMR could evaluate LV volume with excellent accuracy. It may replace multi-breath-hold standard cine CMR.

Comparison of Chronic Angioscopic Findings of Bare Metal Stents, 1st-Generation Drug-Eluting Stents and 2nd-Generation Drug-Eluting Stents　- Multicenter Study of Intra-Coronary Angioscopy After Stent (MICASA).

BACKGROUND: No previous study has reported a comprehensive comparison of the chronic angioscopic findings after bare metal stent (BMS), and 1st- and 2nd-generation drug-eluting stents (DES). METHODS AND RESULTS: The Multicenter Study on Intra-Coronary Angioscopy after Stent (MICASA) is a multicenter registry of coronary angioscopy. A total of 264 stents were observed by coronary angioscopy 1 year after PCI. There were 15 BMS, 90 1st-generation DES, and 159 2nd-generation DES. Neointimal coverage (NC) of the stent was classified into 4 grades from 0 (no coverage) to 3 (complete coverage). Yellow color (YC) of plaque at the stented segment was graded from 0 (white) to 3 (bright yellow). Minimum (Min-) and Maximum (Max-) NC grade were significantly lower with 1st- and 2nd-generation DES than with BMS. Although the Max-NC grade was similar, the Min-NC grade was significantly higher for 2nd-generation DES than for 1st-generation DES. Both the YC grade and the incidence of thrombus with 2nd-generation DES were lower than with the 1st-generation DES and were comparable to BMS. Multivariate analysis showed that low-density lipoprotein, 1st-generation DES, and acute coronary syndrome were independent factors for yellow plaque (YG2 or 3), and that hypertension and 1st-generation DES were independent factors for the incidence of thrombus. CONCLUSIONS: Coronary angioscopy revealed more homogeneous coverage with white neointima and less thrombus after 2nd-generation DES as compared with 1st-generation DES. These findings may explain the favorable clinical outcomes observed for patients treated with 2nd-generation DES. (Circ J 2016; 80: 1916-1921).

Fast and Stable Responses during Decision Making Require Strong Inhibitory Processes in Soccer Players.

Quick decision making is a vital factor for a successful pass in soccer games. Many previous studies of decision making in soccer focused on motor execution, but inhibitory processing has remained unclear. This study aimed to clarify the differences in motor execution and inhibitory among Japanese collegiate soccer players with different skill levels. We evaluated the behavioral data and event-related potentials in the high-skilled, low-skilled, and novice groups during the Go/No-go and pass choice reaction tasks. The reaction time (RT) was significantly shorter in the high group than in the novice group, and RT variability was small in the high group. The amplitude of the N2 component was significantly larger in the high group than in the low and novice groups, and the latency of the P3 component was significantly shorter in the high and low groups than in the novice group during the pass choice reaction task. The subtracted No-go N2 amplitude was also significantly larger in the high and low groups than in the novice group, and correlations existed between the RT, RT variability, and the subtracted No-go N2 amplitude during these tasks. These data indicate that soccer players' behavioral responses and inhibition processing decision-making activities are associated with skill levels.

Comparison of the effect of combination therapy with an angiotensin II receptor blocker and either a low-dose diuretic or calcium channel blocker on cardiac hypertrophy in patients with hypertension.

Left ventricular hypertrophy (LVH) regression is an important issue in hypertensive patients. Patients with LVH who had received the angiotensin receptor blocker (ARB) treatment for 8 weeks and had not reached the target blood pressure level were enrolled in the study. Patients were assigned to either losartan (50 mg)/hydrochlorothiazide (HCTZ, 12.5 mg) group or ARB + CCB group (usual dose of ARB and calcium channel blocker, CCB). After 48 weeks, LV mass index was found to be reduced significantly in the losartan/HCTZ group but not in the ARB + CCB group. These results suggest that combination therapy of an ARB and diuretic has greater potential to cause regression compared with an ARB and CCB.

Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)-based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a cancer-specific conformational epitope in a ubiquitous protein, which cannot be identified by transcriptome or proteome analyses, can be found by extensive screening of primary human tumor samples.

Diagnostic Performance of Dynamic Myocardial Perfusion Imaging Using Dual-Source Computed Tomography.

BACKGROUND: Single-center studies indicated a high diagnostic accuracy of dynamic computed tomography perfusion (CTP) imaging in the diagnosis of coronary artery disease (CAD). OBJECTIVES: This prospective multicenter study determined the diagnostic performance of combined coronary computed tomography angiography (CTA) and CTP for detecting hemodynamically significant CAD defined by invasive coronary angiography (ICA) with fractional flow reserve (FFR). METHODS: Seven centers enrolled 174 patients with suspected or known CAD who were clinically referred for ICA. CTA and dynamic CTP were performed using dual-source CT before ICA. FFR was done as part of ICA in the case of 26% to 90% coronary diameter stenosis. Hemodynamically significant stenosis was defined as FFR of <0.8 or >90% stenosis on ICA. RESULTS: The study protocol was completed in 157 participants, and hemodynamically significant stenosis was detected in 76 of 157 patients (48%) and 112 of 442 vessels (25%). According to receiver-operating characteristic curve analysis, adding dynamic CTP to CTA significantly increased the area under the curve from 0.65 (95% CI: 0.57-0.72) to 0.74 (95% CI: 0.66-0.81; P = 0.011) on the patient level, with decreased sensitivity (93% vs 72%; P < 0.001), improved specificity (36% vs 75%; P < 0.001), and improved overall accuracy (64% vs 74%; P < 0.001). CONCLUSIONS: In this prospective multicenter study on dynamic CTP, the combination of anatomic assessment with coronary CTA and functional evaluation with dynamic CTP allowed more accurate identification of hemodynamically significant CAD compared with CTA alone. However, the clinical significance of this approach needs to be further investigated, including its usefulness in improving prognosis. (Assessment of Myocardial Perfusion Linked to Infarction and Fibrosis Explored With Dual-Source CT [AMPLIFiED]; UMIN000016353).

Comparison of compressed sensing and conventional coronary magnetic resonance angiography for detection of coronary artery stenosis.

PURPOSE: This study aimed to compare the efficacy of compressed sensing (CS) and conventional coronary magnetic resonance angiography (CMRA) in detecting coronary artery stenosis. METHOD: Twenty-eight patients underwent 3 T contrast-enhanced CS and conventional CMRA; for late gadolinium enhancement (LGE) imaging, 0.1 mmol/kg gadolinium medium was infused. CS CMRA was scanned within the LGE waiting time. After the LGE image acquisition, conventional CMRA was performed. The diagnostic performance of both CMRA for the detection of significant stenosis was evaluated using coronary angiography as a reference. The analysis was conducted to examine the three main coronary artery vessels: left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). These arteries were subdivided into 8 segments (LAD; main, proximal, and middle, LCX; proximal and distal, RCA; proximal, middle, and distal). Of these, hypoplastic segments and vessels after coronary stent implantation were excluded. The acquisition time of CS CMRA was compared with that of conventional CMRA. RESULTS: The coronary arteries were evaluated in 197 segments. The sensitivity, specificity, and accuracy of CS CMRA in detecting significant stenosis were 85.2 %, 82.5 %, and 83.2 %, respectively, on a per-segment basis. Those of conventional CMRA were 85.2 %, 86.7 %, and 86.3 %, respectively. The acquisition time was 207 s (range, 144-258 s) for CS and 975 s (range, 787-1226s) for conventional CMRA (p < 0.001). CONCLUSIONS: Similar to conventional CMRA, CS CMRA has shown potential for the detection of significant coronary artery stenosis.

Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome.

BACKGROUND: The endoplasmic reticulum (ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. METHODS AND RESULTS: Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells and macrophages in the fibrous caps of thin-cap atheroma and ruptured plaques, but not in the fibrous caps of thick-cap atheroma and fibrous plaques, showed a marked increase of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP (a transcription factor induced by ER stress)-dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells. CONCLUSIONS: Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.

Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.

BACKGROUND: Patients who have acute myocardial infarction remain at major risk of cardiovascular events. We aimed to assess the effects of either human atrial natriuretic peptide or nicorandil on infarct size and cardiovascular outcome. METHODS: We enrolled 1216 patients who had acute myocardial infarction and were undergoing reperfusion treatment in two prospective, single-blind trials at 65 hospitals in Japan. We randomly assigned 277 patients to receive intravenous atrial natriuretic peptide (0.025 microg/kg per min for 3 days) and 292 the same dose of placebo. 276 patients were assigned to receive intravenous nicorandil (0.067 mg/kg as a bolus, followed by 1.67 microg/kg per min as a 24-h continuous infusion), and 269 the same dose of placebo. Median follow-up was 2.7 (IQR 1.5-3.6) years for patients in the atrial natriuretic peptide trial and 2.5 (1.5-3.7) years for those in the nicorandil trial. Primary endpoints were infarct size (estimated from creatine kinase) and left ventricular ejection fraction (gauged by angiography of the left ventricle). FINDINGS: 43 patients withdrew consent after randomisation, and 59 did not have acute myocardial infarction. We did not assess infarct size in 50 patients for whom we had fewer than six samples of blood. We did not have angiographs of left ventricles in 383 patients. Total creatine kinase was 66,459.9 IU/mL per h in patients given atrial natriuretic peptide, compared with 77,878.9 IU/mL per h in controls, with a ratio of 0.85 between these groups (95% CI 0.75-0.97, p=0.016), which indicated a reduction of 14.7% in infarct size (95% CI 3.0-24.9%). The left ventricular ejection fraction at 6-12 months increased in the atrial natriuretic peptide group (ratio 1.05, 95% CI 1.01-1.10, p=0.024). Total activity of creatine kinase did not differ between patients given nicorandil (70 520.5 IU/mL per h) and controls (70 852.7 IU/mL per h) (ratio 0.995, 95% CI 0.878-1.138, p=0.94). Intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases. 29 patients in the atrial natriuretic peptide group had severe hypotension, compared with one in the corresponding placebo group. INTERPRETATION: Patients with acute myocardial infarction who were given atrial natriuretic peptide had lower infarct size, fewer reperfusion injuries, and better outcomes than controls. We believe that atrial natriuretic peptide could be a safe and effective adjunctive treatment in patients with acute myocardial infarction who receive percutaneous coronary intervention.

Non-contrast compressed sensing whole-heart coronary magnetic resonance angiography at 3T: A comparison with conventional imaging.

OBJECTIVES: Whole-heart coronary magnetic resonance angiography (MRA) is a promising non-contrast, radiation-free technique for assessing the coronary artery. Yet, a disadvantage of coronary MRA is the relatively long acquisition time. The purpose of this study was to evaluate the scan time and image quality of compressed sensing (CS) coronary MRA compared with conventional coronary MRA. MATERIALS AND METHODS: Twenty healthy volunteers underwent navigator-gated coronary MRA with a CS prototype sequence and conventional navigator-gated coronary MRA on a clinical 3T MRI scanner without contrast medium. The spatial resolutions were 1.33 × 1.33 × 1.20 mm3 for CS and 1.33 × 1.33 × 1.48 mm3 interpolated to 0.70 × 0.70 × 1.20 mm3 for conventional, respectively. We compared acquisition times, rated image quality on a 4-point scale (RCA; proximal, middle, and distal, LAD; main, proximal, middle, and distal, LCX; proximal and distal), and measured the visualized vessel lengths of three vessels. RESULTS: The mean acceptance rates were 44.9% for CS coronary MRA and 48.7% for conventional coronary MRA (p = .39). The mean effective scan time was 3 min 45 s for CS coronary MRA and 15 min 6 s for conventional coronary MRA (p < 0.001). Image quality scores were significantly lower for CS coronary MRA than for conventional coronary MRA (3.4 ±â€¯0.7 for CS vs. 3.8 ±â€¯0.4 for conventional; p < 0.0001). Conventional coronary MRA images were scored >3.4 in all segments on average, while CS coronary MRA images were scored >3.2 (good quality for diagnosis) in almost all segments, with only the distal RCA segment graded 2.9 on average. The average visible vessel lengths for CS and conventional coronary MRA were as follows: 11.5 ±â€¯4.4 cm and 12.5 ±â€¯4.8 cm for the RCA, respectively (p < 0.05, 95% limits of agreement [LOA]; -3.6 to 1.6 cm); 10.6 ±â€¯3.0 cm and 11.1 ±â€¯2.9 cm for the LAD, respectively (p = .15, 95% LOA -4.0 to 2.8 cm); and 7.1 ±â€¯2.2 cm and 8.2 ±â€¯2.5 cm for the LCX, respectively (p < 0.05, 95% LOA -4.0 to 1.7 cm). CONCLUSIONS: Non-contrast coronary MRA using CS could largely shorten acquisition time, compared with conventional navigator-gated coronary MRA, while maintaining acceptable visualization at 3T.

Long-term oral administration of dipyridamole improves both cardiac and physical status in patients with mild to moderate chronic heart failure: a prospective open-randomized study.

Adenosine is known as an endogenous cardioprotectant. We previously reported that plasma adenosine levels increase in patients with chronic heart failure (CHF), and that a treatment that further elevates plasma adenosine levels may improve the pathophysiology of CHF. Therefore, we performed a prospective, open-randomized clinical trial to determine whether or not exposure to dipyridamole for 1 year improves CHF pathophysiology compared with conventional treatments. The study enrolled 28 patients (mean+/-SEM: 66+/-4 years of age) attending specialized CHF outpatient clinics with New York Heart Association (NYHA) class II or III, no major complications, and stable CHF status during the most recent 6 months under fixed medications. They were randomized into three groups with or without dipyridamole (Control: n=9; 75 mg/day: n=9; 300 mg/day: n=10) in addition to their original medications and were followed up for 1 year. The other drugs were not altered. Among the enrolled patients, 100%, 4%, 100%, and 79% received angiotensin-converting enzyme inhibitors, aldosterone analogue, loop diuretics, and beta-adrenoceptor blocker, respectively. Fifteen patients suffered from dilated cardiomyopathy, and 7/3/3 patients suffered from ischemic/valvular/hypertensive heart diseases, respectively. Mean blood pressure was comparable among the groups. While the baseline conditions were comparable, we found that echocardiographic ejection fraction (p<0.01 vs. baseline, p<0.01 vs. Control), left ventricular systolic diameter (p<0.05, p<0.05), Specific Activity Scale (SAS) score (p<0.05, p<0.01), maximal oxygen consumption (p<0.05, p<0.05) and plasma B-type natriuretic peptide level (p<0.01, p<0.01) were significantly improved in patients with dipyridamole after 1 year, generally in a dose-dependent manner. Therefore, we suggest that an additional administration of dipyridamole further improves CHF pathophysiology.

The activated conformation of integrin ß7 is a novel multiple myeloma-specific target for CAR T cell therapy.

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin ß7 molecules. The MMG49 epitope, in the N-terminal region of the ß7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin ß7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin ß7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.