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Shiraki T., Ichibori Y., Ohtani T., et al. Pathophysiological evaluations of initial plaque development after heart transplantation via serial multimodality imaging and cytokine assessments. Journal of Heart and Lung Transplantation 41, 877 (2022); https://doi.org/10.1016/j.healun.2022.03.007., Background: Detailed morphological characteristics of de novo and donor-transmitted plaques and the association of serum T-lymphocyte cytokine levels with plaque progression of coronary allograft vasculopathy within 1 year after heart transplantation are unknown. Methods: In this retrospective analysis of data in a prospectively maintained database, 40 heart transplant recipients were included. We performed serial 3 vessel optical coherence tomography and intravascular ultrasound analyses, at the 8 week (baseline) and 12 month post-transplantation follow-ups, and serum cytokine measurements (n = 23). The correlation between serum cytokines and Δplaque burden (between baseline and follow-up) was evaluated depending on plaque morphology. Results: Thirteen de novo plaques (maximum intimal thickness ≥0.5 mm at the 12 month follow-up without plaques at baseline) were identified in 8 recipients, and 31 donor-transmitted plaques (maximum intimal thickness ≥0.5 mm at baseline) were detected in 17 recipients. Compared with donor-transmitted plaques, the Δplaque burden in the de novo plaques, with mainly fibrous morphology, was high (38.8% [29.6%–41.2%] vs 8.7% [1.33%–13.6%], p < 0.001). Stratification of the morphology of donor-transmitted plaques revealed that the Δplaque burden in fibrous plaques (10.6% [7.0%–18.0%]) was similar to that in fibroatheroma (10.3% [8.7%–23.8%]). Serum interleukin-31 levels at baseline correlated with fibrous plaque proliferation (r = 0.73, p = 0.007) even under immunosuppressive conditions, whereas other cytokines (interleukin-1β, interleukin-17, and interferon-gamma) were mostly undetectable. Conclusions: Intimal fibrous proliferation contributed to the progression of donor-transmitted and de novo plaques. Serum interleukin-31 levels at baseline may contribute to intimal fibrous proliferation within 1 year after heart transplantation.

Acute calcineurin inhibitor (CNI) nephrotoxicity is a common complication associated with CNI exposure. However, it can be difficult to diagnose. Herein, we report a case of acute CNI nephrotoxicity after heart transplant that was visualized using kidney Doppler ultrasonography.A 38-year-old female patient underwent heart transplant 5 years after the use of left ventricular assist device support because of advanced heart failure due to ischemic cardiomyopathy. Corticosteroids, tacrolimus, and mycophenolate mofetil were administered as immunosuppressive regimens postoperatively. The patient gradually developed kidney dysfunction despite a favorable perioperative clinical course and hemodynamics. Serum creatinine increased to 1.89 mg/dL on postoperative day (POD) 9, and the kidney Doppler ultrasonography examination showed severely reduced blood flow in the renal and renal segmental arteries, indicating acute CNI nephrotoxicity due to vasoconstriction of the renal arterioles. After the cessation of tacrolimus, kidney function returned to baseline levels within 2 days, and the kidney Doppler ultrasonography examination on POD 19 revealed a significant increase in blood flow in the renal and renal segmental arteries. Basiliximab followed by everolimus were administered as alternative immunosuppressants. No organic stenosis of the renal artery was detected on the kidney magnetic resonance angiography, and the patient was discharged on POD 51, without any other adverse events, including rejection.Although CNIs are widely used after heart transplant, acute nephrotoxicity should always be considered. After heart transplant, a kidney Doppler ultrasonography should be performed routinely and promptly if there are any clinical manifestations related to kidney function.

OBJECTIVES Limited data are available for use of the HeartMate 3 (HM 3) left ventricular assist device in patients with a small body surface area (BSA). Because the HM 3 is currently the sole device available worldwide, we conducted a single-centre retrospective study of patients with a small BSA ( METHODS This study enrolled 64 consecutive patients who had undergone HM 3 implantation from August 2018 to July 2021. The patients were divided into 2 groups based on their BSA before the operation: BSA of RESULTS The average BSA was 1.38 m2 in the small BSA group. The overall event-free survival rate at 12 months was 100% and 86.7% in the small BSA group and regular BSA group, respectively, and no significant difference was found between the 2 groups (log-rank P = 0.2). The number of cumulative adverse events of death, stroke of any severity, driveline infection, pump infection, ventricular arrhythmia, gastrointestinal Haemorrhage and pump failure was similar between the 2 groups. CONCLUSIONS The HM 3 was safely implanted in patients with a small BSA, and postoperative outcomes were acceptable regardless of BSA. However, further research is needed to confirm the indications for HM 3 implantation in even smaller patients.

A bridging strategy from extracorporeal life support (ECLS) is effective in salvage and a bridge to recovery or to a durable left ventricular assist device (LVAD) for acute refractory heart failure. However, the correlation of this strategy with adverse events after durable LVAD implantation has not been fully investigated. This study enrolled 158 consecutive patients who had either the HeartMate II or HeartMate 3 and were implanted for bridge-to-transplantation. These devices were implanted as the primary mechanical support device in 115 patients, whereas the remaining 43 underwent LVAD implantation as the bridge from central ECLS. The primary study endpoint was all-cause mortality and cerebrovascular accidents (CVAs) after durable LVAD implantation, and the secondary endpoints were adverse events. Overall survival was not significantly different between the two groups. In contrast, the probability of CVAs was significantly greater in the bridge group than in the primary group (probability of CVAs,P = 0.002; log-rank test). In Cox multivariate logistic regression analysis, a bridge from central ECLS was an independent predictive factor of CVAs (hazard ratio 4.27, 95% confidence interval 1.43–12.8;P = 0.0095). Patients who are bridged from central ECLS are more frequently complicated by CVAs compared with those who undergo primary implantation of a durable LVAD, but survival is not significantly different between the two groups. A bridge from central ECLS is an independent predictive factor of CVAs post-implantation of an LVAD.

This study sought to investigate whether elevated liver stiffness (LS) values at discharge reflect residual liver congestion and are associated with worse outcomes in patients with heart failure (HF).Transient elastography is a newly developed, noninvasive method for assessing LS, which can be highly reflective of right-sided filling pressure associated with passive liver congestion in patients with HF.LS values were determined for 171 hospitalized patients with HF before discharge using a Fibroscan device.The median LS value was 5.6 kPa (interquartile range: 4.4 to 8.1 kPa; range 2.4 to 39.7 kPa) and that of right-sided filling pressure, which was estimated based on LS, was 5.7 mm Hg (interquartile range: 4.1 to 8.2 mm Hg; range 0.1 to 18.9 mm Hg). The patients in the highest LS tertile (6.9 kPa, corresponding to an estimated right-sided filling pressure of7.1 mm Hg) had advanced New York Heart Association functional class, high prevalence of jugular venous distention and moderate/severe tricuspid regurgitation, large inferior vena cava (IVC) diameter, low hemoglobin and hematocrit levels, high serum direct bilirubin level, and a similar left ventricular ejection fraction compared with the lower tertiles. During follow-up periods (median: 203 days), 8 (5%) deaths and 33 (19%) hospitalizations for HF were observed. The patients in the highest LS group had a significantly higher mortality rate and HF rehospitalization (hazard ratio: 3.57; 95% confidence interval: 1.93 to 6.83; p 0.001) compared with the other tertiles. Although LS correlated with IVC diameter and serum direct bilirubin and brain natriuretic peptide levels, LS values were predictive of worse outcomes, even after adjustment for these indices.These data suggest that LS is a useful index for assessing systemic volume status and predicting the severity of HF, and that the presence of liver congestion at discharge is associated with worse outcomes in patients with HF.

Background: Left ventricular reverse remodeling (LVRR) is a favorable response in non-ischemic, non-valvular cardiomyopathy (NICM) patients. Recently, 18-lead body surface electrocardiography (ECG), the standard 12-lead ECG with synthesized right-sided/posterior chest leads, has been developed, but its predictive value for LVRR has not been evaluated. Methods and Results: Of 216 consecutive hospitalized NICM patients with LV ejection fraction (LVEF) ≤35%, we studied 125 who received optimization of their heart failure treatment and had 18-lead ECG and echocardiography data available for evaluating LVRR, defined as an absolute increase in LVEF ≥10% concomitant with LVEF ≥35% after 1-year optimized treatment. Most 18-lead ECG parameters in the NICM patients differed from those in 312 age- and body mass index-matched subjects with normal echocardiography. LVRR occurred in 59 NICM patients and they had a larger QRS amplitude in the limb leads (I, II, aVR, and aVF), precordial leads (V3–V6), and synthesized leads (syn-V4R–5R), decreased QRS axis and duration, and lower prevalence of fragmented QRS than those without LVRR. The ECG score using 3 selected parameters (QRS amplitude in aVR ≥675 µV; QRS duration

BACKGROUND Treatment decisions in dilated cardiomyopathy (DCM) patients with severe heart failure (HF) and short clinical history are challenging because of the difficulty of determining HF stage or prognosis in the acute HF phase. We hypothesized that persistent decreased systemic or increased pulmonary arterial pressure , including in the sub-clinical phase, might affect the main pulmonary artery diameter (PAD), ascending aortic diameter (AoD), and their ratio (PAD/AoD). This study assessed AoD, PAD, and PAD/AoD by non-contrast computed tomography scans in DCM patients in the acute phase of HF and examined the association of these parameters with their clinical course. METHODS Of 261 screened individuals, we studied 110 consecutive hospitalized patients with DCM suspected of being in advanced stage of HF and 45 age-matched controls, assessing clinical data and later events (cardiac death or left ventricular assist device implantation). RESULTS Compared with controls, DCM patients had smaller AoD (26.6 ± 4.4 vs 30.6 ± 2.7 mm) and larger PAD (27.7 ± 3.5 vs 25.4 ± 2.8 mm) and PAD/AoD (1.05 ± 0.14 vs 0.83 ± 0.08; all p 1.05) had more frequent past HF hospitalizations, lower blood pressure, stroke volume, and ejection fraction , higher brain natriuretic peptide levels, smaller AoD, and similar PAD compared with patients with a low PAD/AoD. A higher PAD/AoD was associated with poorer outcomes even after adjusting for age, blood pressure, ejection fraction, or number of hospitalizations. CONCLUSION Assessment of AoD and PAD may have important clinical implications in determining whether DCM patients are in an advanced stage of HF with a poorer prognosis.

We demonstrate a 1-read/1-write two-port (2P) embedded static random access memory macro based on 8T SRAM bitcell with an effective scheme for design of testability. To achieve a smaller macro area, a differential sense amplifier is introduced to read out the data, where the reference voltage for reading 0/1 data is generated by an unselected bitcell array. In addition, we propose a screening test circuit for read disturbance and wordline coupling noise. A 512-kbit 2P SRAM macro using 28-nm high-K/metal gate bulk CMOS technology has been designed, confirming experimentally that the worst minimum operation voltage ( $V_{\text {min}}$ ) can be reproduced by our test circuit. Bit density of 3.16 Mb/mm2 was achieved.

Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.

A 34-year-old man underwent heart transplantation because of ischemic cardiomyopathy. Coronary angiography after the transplantation showed no significant stenosis in his coronary trees except for mild stenosis in the proximal left anterior descending (LAD) artery. However, 6 years later, coronary

In the era where electromigration (EM) resistance is degraded by the continuous process advancement, we provide a solution to improve this EM resistance by 60% using our ternary content-addressable memory (TCAM). We designed the high-density TCAM macro in a 7nm Fin-FET process which includes novel circuitry: far-side driver of match and search line, and self-adjust reference match amplifier. Measurement shows that total active power in our proposed macro is 15 % less than that in the conventional one. A 4.04 Mb/mm2 marks the world highest memory density at this time.

Background Research suggests that heart failure with reduced ejection fraction (HFrEF) is a state of systemic inflammation that may be triggered by microbial products passing into the bloodstream through a compromised intestinal barrier. However, whether the intestinal microbiota exhibits dysbiosis in HFrEF patients is largely unknown.Methods and Results:Twenty eight non-ischemic HFrEF patients and 19 healthy controls were assessed by 16S rRNA analysis of bacterial DNA extracted from stool samples. After processing of sequencing data, bacteria were taxonomically classified, diversity indices were used to examine microbial ecology, and relative abundances of common core genera were compared between groups. Furthermore, we predicted gene carriage for bacterial metabolic pathways and inferred microbial interaction networks on multiple taxonomic levels.Bacterial communities of both groups were dominated by the Firmicutes and Bacteroidetes phyla. The most abundant genus in both groups wasBacteroides. Although α diversity did not differ between groups, ordination by β diversity metrics revealed a separation of the groups across components of variation.StreptococcusandVeillonellawere enriched in the common core microbiota of patients, whileSMB53was depleted. Gene families in amino acid, carbohydrate, vitamin, and xenobiotic metabolism showed significant differences between groups. Interaction networks revealed a higher degree of correlations between bacteria in patients. Conclusions Non-ischemic HFrEF patients exhibited multidimensional differences in intestinal microbial communities compared with healthy subjects.

Objective The authors examined the effect of prolonged support with continuous-flow ventricular assist devices (CF-VADs) and other related factors on the severity of infections within 30 days of heart transplantation (HTx). Design A retrospective analysis of consecutive HTx procedures. Setting University hospital, between 2010 and 2016. Participants A cohort of 53 heart transplantation recipients (median age, 38.5 yr; interquartile range [IQR], 30.3-49.2 yr; women, 34%). Interventions Forty-nine patients required CF-VAD support (median duration, 946 d; IQR, 600-1,132 d). Measurements and Main Results Severity of postoperative infections was categorized as follows: no infection, minor infection (resolved within 14 days), major infection (resolved after >14 days), and severe infection (septic shock). Results were expressed as number (frequency) and median with IQR. Potential risk factors for increased infection severity were expressed as odds ratio (OR) with 95% confidence interval (CI). Postoperatively, no infection, minor infection, major infection, and severe infection occurred in 32 (60.4%), 8 (15.1%), 8 (15.1%), and 5 patients (9.4%), respectively. Active ventricular assist device (VAD)-specific infections at the time of HTx occurred in 37.7% of patients. Moderate-to-severe primary graft dysfunction occurred in 26.4% of the patients. Multivariable analysis indicated that risk factors for increased infection severity included active VAD-specific infection (OR 4.8; 95% CI 2.3-11.2) and moderate-to-severe primary graft dysfunction (OR 8.8; 95% CI 2.1-42.5) but not duration of CF-VAD support (OR 1.0; 95% CI 1.0-1.0). Conclusion Active VAD-specific infection and poor graft function likely contribute to the severity of early postoperative infections after HTx.

BACKGROUND Advanced left heart failure (HF) often accompanies post-capillary pulmonary hypertension related to RV afterload. Although pulmonary arterial capacitance (PAC), a measure of pulmonary artery compliance, reflects right ventricular (RV) afterload, the clinical utility of PAC obtained by echocardiography (echo-PAC) is not well established in advanced HF.Methods and Results:We performed right heart catheterization in advanced HF patients (n=30), calculating echo-PAC as stroke volume/(tricuspid regurgitation pressure gradient-pulmonary regurgitation pressure gradient). The difference between the echo-PAC and catheter-measured PAC values was insignificant (0.21±0.17 mL/mmHg, P=0.23). Echo-PAC values predicted both pulmonary arterial wedge pressure (PAWP) ≥18 mmHg and pulmonary vascular resistance ≥3 Wood units (P=0.02, area under the curve: 0.88, cutoff value: 1.94 mL/mmHg). Next, we conducted an outcome study with advanced HF patients (n=72). Patients with echo-PAC

This paper presents an analysis of impact of local bias temperature instability (BTI) by measuring Ring-Oscillators (RO) with short stage and its impact on Logic circuit and SRAM. The evaluation result of local BTI variation based on measuring RO at a test chip fabricated in 7 nm FinFET process shows that the standard deviation of NBTI $\boldsymbol{Vth}$ degradation is proportional to the square root of the mean value ( $\boldsymbol{\mu}(\mathbf{\Delta} \boldsymbol{Vthp})$ ) at any stress time, $\boldsymbol{Vth}$ flavors and various recovery condition. Based on these measurement result, we present an analysis of its impact on logic circuit with considering measured $\boldsymbol{Vth}$ dependency on global NBTI. We also analyze its impact on SRAM minimum operation voltage ( $\boldsymbol{V_{min}}$ ) of static noise margin (SNM) and shows nonnegligible $\boldsymbol{V_{min}}$ degradation due to local NBTI.

This paper presents an analysis methodology of the impact of Local Layout Effect (LLE) of bias temperature instability (BTI) on logic circuits by measuring Ring-Oscillators (RO) consist of many kinds of standard cells and shows its measurement result in a 10nm FinFET process. The measured delay degradations of all ROs are well correlated with estimated one without considering LLE of BTI and its maximum error rates is −16% and +13%. The LLE on BTI recovery effect is also evaluated and there is no obvious standard cell type dependency. This analysis would be useful for more accurate guideline to design BTI guard-band on logic circuits for high reliability required applications.

We propose an on-chip bias temperature instabilities (BTI) monitor by using standard cell based unbalanced ring-oscillator (RO). The monitor consists of NAND and NOR with extremely large difference in drive strength, which enables 4.2x sensitivity to BTI compared with normal INV based RO. This originates not only from accentuation of the degraded stage with small drive strength by the dominant delay but also from ΔVth sensitivity improvement of stacked transistors with increasing output transition time. In addition, our proposal allows to monitor either one of negative BTI (NBTI) or positive BTI (PBTI) selectively by making use of the Miller effect caused by the size combination of NOR and NAND. A test chip is implemented in a 28 nm High-k Metal-Gate (HKMG) CMOS technology. We successfully observed that measured results of each RO were well matched with simulations. Owing to this high sensitivity and successful NBTI/PBTI separation, we can detect variations and outliers of BTI at time of testing, and optimize guard band (GB) while considering NBTI/PBTI sensitivity difference of each circuit.

Fulminant myocarditis is one of the most challenging diseases. We sought to examine the outcomes of our multidisciplinary treatment strategy for fulminant myocarditis. A retrospective review of consecutive 30 patients with fulminant myocarditis was conducted. Of the 30 patients, 25 required mechanical circulatory support (MCS). Percutaneous extracorporeal membrane oxygenation (ECMO) was the first-line therapy to rescue the patients and inserted in 23 of them. The other 2 were implanted with temporary ventricular assist device (t-VAD) with extracorporeal centrifugal pump(s). Sixteen of the ECMO-supported patients were later transitioned to t-VAD. Of the 18 patients who underwent t-VAD support, heart function recovered and the VAD was explanted in 10. Four patients were bridged to long-term VAD and the other 4 died on t-VAD. Two patients were directly bridged to long-term VAD by ECMO. Heart function recovered only with ECMO in 4 patients and 1 died on ECMO. Overall survival rate was 83.3%. The duration of ECMO support significantly correlated with total bilirubin level, which was a significant risk factor for mortality. Pathologically, 7 patients (23.3%) had eosinophilic myocarditis and 1 (3.3%) had giant-cell myocarditis, and all the 8 patients underwent immunosuppressive therapy including steroids. Heart function recovered to normal level in 7 of them (87.5%). Timely conversion from the percutaneous ECMO to the temporary VAD before elevation of total bilirubin level is crucial for improving the clinical outcomes. Endomyocardial biopsy is needed to be done as soon as possible, because immunosuppressive therapy carries promising outcomes in certain etiologies.

Background The prevalence of atrial fibrillation (AF) is high in elder subjects. Our previous observational study suggested that vitamin K antagonist (VKA) promotes aortic valve degeneration, a principal cause of aortic stenosis in the elderly, and that angiotensin receptor blocker (ARB) attenuates its progression. This study aimed to prospectively investigate these observations in non-valvular AF patients. Methods Of enrolled 430 patients with calcification on no or one aortic valve leaflet, all of the planned 4-year follow-up data were obtained in 122 non-valvular AF patients treated with warfarin (warfarin group) and 101 patients with cardiovascular diseases and without AF and prescription of warfarin (non-warfarin group). Results Despite higher atherosclerotic risks in the non-warfarin group, 2 or 3 newly calcified leaflets emerged during 4 years in 18.0% of patients in the warfarin group and in 6.9% in the non-warfarin group (p = 0.014). Aortic valve area (AVA) did not significantly change in the non-warfarin group during the follow-up, but tended to decrease in the warfarin group (p = 0.057). Non-vitamin K antagonist oral anticoagulant got available in Japan after this study started, and warfarin was discontinued in 15 patients of the warfarin group. The reduction of AVA was significant in the remaining 107 patients on the continuous warfarin treatment (p = 0.002). The effects of ARB on AVA were obscure. Conclusion Major bleeding associated with VKA is well recognized. This study suggests that the development of aortic valve degeneration is another risk of long-term use of VKA in non-valvular AF patients with no or mild aortic valve degeneration.

We propose a new 2T mask read only memory (ROM) with dynamic column source bias control technique, which enables achieving both high-speed operation and low power consumption. It is also possible to overcome the inherent problem of crosstalk between the bitlines. The fabricated 128-kb ROM macro using 28-nm high- k and metal-gate CMOS bulk technology realizes 0.72 ns read access time at the typical 0.85-V supply voltage, which is comparable to that of recent high-speed embedded static random access memories. The measured dynamic power dissipation is reduced by 50% compared to the conventional 2T ROM. The standby leakage can also be reduced to half that of conventional macros.

Background: Endovascular aortic repair (EVAR) is performed in patients with thoracic or abdominal aortic aneurysm because it is less invasive than conventional open repair. However, the effects of EVAR on vascular and cardiac function remain to be clarified. Methods and Results: We studied the effects of EVAR on several outcome variables in 40 consecutive patients undergoing EVAR for abdominal and/or thoracic aneurysm with preserved ejection fraction. Echocardiography and brachial–ankle pulse wave velocity (baPWV) data were collected before, 1 week, and 1 year after EVAR. Although no changes in blood pressure were found, baPWV, left ventricular mass index (LVMI), and left atrial volume index were significantly elevated at both post-op time periods after EVAR compared with baseline data. The changes in LVMI correlated with those in baPWV (R=0.32, P

We propose pseudo dual-port (DP) SRAM by using 6T single-port (SP) SRAM bitcell with double pumping circuitry, which enables 2-read/write (2RW) operation within a clock cycle. The data sequencer for address/data latch and double output sense amplifier realize the simulations read-read or write-write operation. We designed and implemented a 512-kb pseudo DP SRAM macro based on 28-nm low-power bulk CMOS technology. Our design achieved the bit density of 5.92 Mb/mm2, which is the highest ever reported. Measured data at 1.0 V supply voltage shows 1.05 ns read-access-time for one port and 2.37 ns for another port, respectively. Area overhead of the proposed circuitry is only 3.2% compared to the original SP SRAM macro.

We demonstrate SRAM circuit design techniques for enhancing performance, power and area (PPA) in 16 nm FinFET technology. The wordline overdrive (WLOD) assist circuitries with dual power rail are introduced for not only 6T single-port SRAM bitcell but also for 8T dual-port bitcell, improving minimum operating voltage (Vmin) by enhancing write-abilities. The read access times are also improved by WLOD. We also implement a high-density 2-port SRAM using 6T bitcell with double pumping scheme, enabling about 2× higher density than conventional 8T bitcell design. The resume standby circuit, which is adoptively controlled the bias of VSS source lines in cell arrays, is introduced for reducing leakage power. The measured silicon data show that the Vmin, read access time, and standby power are improved by up to 45%, 50%, and 80%, respectively.

Although the mouse heart failure (HF) model of hypertensive heart disease (HHD) is useful to investigate the pathophysiology and new therapeutic targets for HHD, the model using simple experimental procedures and stable phenotypes has not been established. This study aimed to develop a novel mouse HF model of HHD by combining salt loading and uninephrectomy with ANG II infusion. Eight-week-old C57BL/6 male mice were treated with ANG II infusion (AT), ANG II infusion and uninephrectomy (AN), ANG II infusion and salt loading (AS), or ANG II infusion, uninephrectomy, and salt loading (ANS). Systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was found in AT, AN, AS, and ANS mice, and there were no significant differences in those parameters between the four groups. At 6 wk after the procedures, only ANS mice showed significant decreases in LV fractional shortening and increases in lung weight with a high incidence. This phenotype was reproducible, and there were few perioperative or early deaths in the experimental procedures. Severe LV fibrosis was found in ANS mice. Oxidative stress was enhanced and small GTPase Rac1 activity was upregulated in the hearts of ANS mice. After the addition of salt loading and uninephrectomy to the ANG II infusion mouse model, cardiac function was significantly impaired, and mice developed HF. This might be a novel and useful mouse HF model to study the transition from compensated LV hypertrophy to HF in HHD.

We propose low-leakage current embedded SRAMs with high-performance for mobile applications. The proposed SRAM has two standby modes depending on temperature; one is a low-voltage resume-standby mode to reduce the standby current (ISTBY) more effectively at room temperature, and the other is the conventional resume-standby to reduce ISTBY effectively at high temperature. These schemes are implemented in a single SRAM macro with an all-digital current comparator (ADCC) that chooses either mode by monitoring ISTBY automatically. ADCC has a time to digital converter (TDC) which is suitable for leakage measurement. Moreover, the proposed monitoring sequence can compensate the error of the measurement caused by the variation of the MOSFETs. A test chip was fabricated using 28 nm HKMG CMOS technology. The proposed 32 kb SRAM achieves 0.41 μA standby leakage which is half of the conventional value. This SRAM also realizes a high-speed operation with an access time of 420 ps.

Objectives Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. Methods and results Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. Conclusions L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

We examine appropriate bitcell layouts for two read/write (2RW) 8T dual-port (DP) SRAM in advanced planar/FinFET technologies. 256-kbit 2RW DP SRAM macros with highly symmetrical 8T DP bitcell were designed and fabricated using 16 nm FinFET technology. The read/write assist with wordline overdrive reduces Vmln by 120 mV, achieving successful operation at below 0.5 V.

Showing that the worst minimum operating voltage (Vmin) of an 8T dual-port (DP) SRAM is determined by the write/read-disturbing condition with a finite clock skew, we propose a circuit technique to detect the worst Vmin in asynchronous clock operation. This circuitry allows us to screen the worst bit in an array that is conventionally obtained by a costly and time-consuming test procedure. For instance, we can at least realize 400x speed-up for the test time compared to the conventional method. We designed and fabricated a 512-kb DP-SRAM macro using 28-nm low-power CMOS technology, and confirmed experimentally that the worst Vmin can be successfully reproduced within 6% discrepancy by our proposed circuit.

The performance and threshold voltage variability of quasi-planar bulk MOSFETs are compared against those of conventional bulk MOSFETs, via three-dimensional (3-D) device simulations with gate line-edge roughness and atomistic doping profiles, at 25 nm gate length. The nominal performance of six transistor (6-T) SRAM cells is studied via 3-D simulation of full cell structures. Compact (analytical) modeling is used to estimate SRAM cell yields. As compared to conventional bulk CMOS technology, quasi-planar bulk CMOS technology provides for enhanced SRAM cell performance and yield, and hence facilitates reductions in cell area and operating voltage. It also enables a notchless 6-T SRAM cell design which is advantageous for improved lithographic printability and either smaller area or lower standby power, and is projected to achieve 6-sigma cell yields at operating voltages down to ~0.8 V.

Aims The prevalence of heart failure with preserved ejection fraction (HFpEF) has increased in the past two decades, and diabetes mellitus (DM) is frequently associated with HFpEF. Although it has been demonstrated that left ventricular (LV) diastolic and vascular functional abnormalities are generally observed in HFpEF, it remains to be clinically elucidated how an asymptomatic stage progresses to symptomatic HFpEF in DM patients. We aimed to identify risk factors associated with incident HFpEF in DM patients and to evaluate the contribution of LV relaxation and compliance to the development of HFpEF. Methods and results The study included 544 consecutive Japanese DM patients with ejection fraction ≥50%. Patients with coronary artery disease or serum creatinine ≥2.0 mg/dL were excluded. Multiple logistic regression analysis revealed that obesity, female gender, anaemia, and impaired LV compliance were independently associated with the prevalence of HFpEF, and that age, LV mass index, an index of LV relaxation, estimated glomerular filtration rate, and history of hypertension were not. There was no difference in haemoglobin A1c or brachial-ankle pulse wave velocity between the DM patients with and without HFpEF. Conclusions This study suggests that exacerbation of LV compliance impairment, rather than of relaxation abnormality or vascular stiffening, plays a crucial role in the induction of HFpEF in DM patients regardless of the severity of DM and renal dysfunction. Anaemia and obesity may also contribute to the transition from asymptomatic stage to symptomatic HFpEF even without further progression of LV diastolic dysfunction.

Aims Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na+/K+-ATPase and activate the Ca2+ entry mode of Na+/Ca2+ exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. Methods and results (i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague–Dawley rats. (iii) Ouabain elevated intracellular Ca2+ concentration through the entry of extracellular Ca2+, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening. Conclusion Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

Background: Systolic abnormality, as well as diastolic dysfunction, is observed in patients with heart failure with preserved ejection fraction (HFPEF). However, the role of these 2 conditions in the transition from asymptomatic diastolic dysfunction to symptomatic heart failure remains unclear. We recently demonstrated that diastolic wall strain (DWS) inversely correlates to the myocardial stiffness constant. Methods and Results: This study consisted of 127 subjects: 52 consecutive HFPEF patients (HFPEF group), 50 asymptomatic hypertensive patients with ejection fraction ≥50% whose age, gender and left ventricular (LV) mass index matched those of the HFPEF group (HT group) and 25 normal volunteers (Normal group). The tissue Doppler-derived peak systolic and early diastolic velocities of the mitral annulus were significantly decreased in groups HFPEF and HT than in group Normal, but were not significantly different between groups HFPEF and HT. DWS was significantly lower in group HFPEF than in group HT. Conclusions: The transition from asymptomatic diastolic dysfunction stage to HFPEF stage is not attributed to progression of systolic abnormality, and exacerbation of LV distensibility rather than relaxation plays a crucial role in the development of HFPEF. (Circ J 2011; 75: 596-602)

The performance and threshold voltage variability of fully depleted silicon-on-insulator (FD-SOI) MOSFETs are compared against those of conventional bulk MOSFETs via 3-D device simulation with atomistic doping profiles. Compact (analytical) modeling is then used to estimate six-transistor SRAM cell performance metrics (i.e., read and write margins, and read current) at the 22 nm CMOS technology node. The dependences of these metrics on cell ratio, pull-up ratio, and operating voltage are analyzed for FD-SOI versus bulk SRAM cells. Iso-area and iso-yield comparisons are then made to determine the yield and cell-area benefits of FD-SOI technology, respectively. Finally, the minimum operating voltages required for FD-SOI and bulk SRAM cells to meet the six-sigma yield requirement are compared.

We propose an access scheme for a synchronous dual- port (DP) SRAM that minimizes the 8T-DP-cell area and maintains cell stability. A priority row decoder circuit and shifted bit- line access scheme eliminates access conflict issues. Using 65 nm CMOS technology (hp90) with the proposed scheme, we fabricated 32 kB DP-SRAM macros. We obtained a 0.71 mum2 8T-DP-cell for which the cell size is only 1.44 times larger than a 6T-single-port (SP)- cell. The bit-density of the fabricated 32 kB DP-RAM macro is 667 kbit/mm2, which is 25% larger than a conventional 8T SRAM. The standby leakage is 27% less because of the small drive-NMOS transistor of the proposed 8T-DP-cell.

Objectives We prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG), heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF). Background Cardiac MIBG imaging predicts prognosis of CHF patients. However, the long-term predictive value of MIBG imaging for SCD in this population remains to be elucidated. Methods At entry, cardiac MIBG imaging, SAECG, 24-h Holter monitoring, and standard 12-lead electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients with a radionuclide left ventricular ejection fraction (LVEF) Results During a follow-up period of 65 ± 31 months, 18 of 106 patients died suddenly. A multivariate Cox analysis revealed that WR and LVEF were significantly and independently associated with SCD, whereas the SAECG, HRV parameters, or QT dispersion were not. Patients with an abnormal WR (>27%) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95% confidence interval: 1.55 to 14.76). Even when confined to the patients with LVEF >35%, SCD was significantly more frequently observed in the patients with than without an abnormal WR (p = 0.02). Conclusions Cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.

This paper presents that advanced actively body-bias controlled (Advanced ABC) technology contributes to enhancing operation margins of static random access memory (SRAM). For the first time, significant enhancement of static noise margin (SNM) is successfully realized by using a body bias of load, access, and driver transistors while suppressing threshold-voltage variations. In this technology, well taps control the body potential of the load transistor and word lines also control the body potential of the access and driver transistors. It is demonstrated that the write and read margins of 65-nm-node silicon-on-insulator (SOI) SRAMs are improved by the Advanced ABC technology. Furthermore, it is found that the SNM is enhanced by 27% for 32 nm and 49% for 22 nm node. It is summarized that this technology is one of countermeasures for emerging generations.

We propose a new 2-port SRAM with a single read bit line (SRBL) eight transistors (8 T) memory cell for a 45 nm system-on-a-chip (SoC). Access time tends to be slower as a fabrication is scaled down because of threshold voltage (Vt) random variations. A divided read bit line scheme with shared local amplifier (DBSA) realizes fast access time without increasing area penalty. We also show an additional important issue of a simultaneous read and write (R/W) access at the same row by using DBSA with the SRBL-8T cell. A rise of the storage node causes misreading. A read end detecting replica circuit (RER) and a local read bit line dummy capacitance (LDC) are introduced to solve this issue. A 128 bit lines - 512 word lines 64 kb 2-port SRAM macro using these schemes was fabricated by a 45 nm bulk CMOS low-standby-power (LSTP) CMOS process technology [1]. The memory cell size is 0.597 mum2. This 2-port SRAM macro achieves 7 times faster access time without misreading.

An actively body-bias controlled (ABC) silicon-on-insulator (SOI) static random access memory (SRAM) connecting the bodies of the access and the driver transistors with the word line is proposed to realize high-speed and low-voltage operation. We developed the direct body contact to apply forward biases to the bodies without increases in the area penalty and the parasitic gate capacitance. An increase of the standby current does not occur because the body biases are not applied when the word-line voltage is low level. It is demonstrated that a significant speed improvement and a reduction of performance variations for the SRAM are achieved by applying the body bias. Neutron-accelerated soft-error tests reveal that the ABC structure suppresses soft-error events due to the body-tied SOI structure. In summary, the ABC SOI technology is one of the countermeasures for emerging generations.

The variation tolerant assist circuits of an SRAM against process and temperature are proposed. Passive resistances are introduced to the read assist circuit with replica memory transistors to lower the wordline voltage accurately reflecting the process and temperature variations. For the sake of not only enlarging the write margin but also reducing power consumption and speed overhead, the divided dynamic power-line scheme based on a charge sharing is adopted. Test chips of 512-Kb SRAM macros and isolated memory cell TEGs are fabricated using 45-nm bulk CMOS technology. Two types of 6-T SRAM cells, whose sizes were 0.245 mum2 and 0.327 mum2 were designed and evaluated. From the measurement results, we achieved over 100-mV improvement for static noise margin, and 35 mV for write margin for both SRAM cells at 1.0-V worst condition by using assist circuitry. It enables the wordline level to keep higher voltage at the slowest condition than the typical process condition, which results in 83% improvement of the cell current compared with the conventional assist circuit. Furthermore, the minimum operating voltage in the worst case condition was improved by 170 mV, confirming a high immunity against process and temperature variations with less than 10% area overhead.

Meiotic recombination is initiated by the introduction of DNA double-strand breaks (DSBs) at recombination hotspots. DSB ends are resected to yield ssDNA, which is used in a homology search. Sae2p, which is involved in the resection of DSB ends, is phosphorylated by the Mec1p and Tel1p kinases during meiosis. To clarify the role of Sae2p phosphorylation in meiotic recombination, three mutants with alanine substitutions (at two putative Mec1/Tel1 phosphorylation sites near the N terminus, at three sites near the C terminus or at all five sites) were constructed. Analysis of DSB ends during meiotic recombination demonstrated that phosphorylation of the three C-terminal phosphorylation sites is necessary for DSB end resection and that phosphorylation of the two N-terminal phosphorylation sites is required for the efficient initiation of DSB end resection. Sae2p was localized on meiotic chromosomes in the rad50S and mre11-H125R mutants, which accumulate DSB ends. Alanine substitutions of all phosphorylation sites did not affect localization of Sae2p on meiotic chromosomes. Although colocalization of Sae2p with Mre11p and recombinant formation were observed in the N-terminally mutated and the C-terminally mutated strains, these processes were drastically impaired in the quintuple mutant. These results indicate that phosphorylation of Sae2p is required to initiate resection and to improve the efficiency of resection through cooperation with the Mre11-Rad50-Xrs2 complex.

We propose a wafer level burn-in (WLBI) mode, a leak-bit redundancy and a small, highly reliable Cu E-trim fuse repair for an embedded 6T-SRAM to achieve a known good die (KGD) SoC. We fabricated a 16 Mb SRAM with these techniques using 65 nm LSTP technology, and confirmed the efficient operations of these techniques. The WLBI mode enables simultaneous write operation for 6T-SRAM, and has no area penalty and a speed penalty of only 50 ps. The leak-bit redundancy for 6T-SRAM can reduce the infant mortality of the bare die, and improves the standby current distribution. The area penalty is less than 2%. The Cu E-trim fuse can be used beyond the 45 nm advanced process technology. The fuse requires no additional wafer process steps. Using only 1.2 V core transistors will allow CMOS technology scaling to enable fuse circuit size reduction. The trimming transistor is placed under the fuse due to there being no cracking around the trimmed position. We achieve the small fuse circuit size of 6 x 36 mum2 using 65 nm technology.

Objective: To evaluate the usefulness of cardiac iodine-123 ( 123 I) metaiodobenzylguanidine (MIBG) imaging as a predictor of sudden death in patients with chronic heart failure (CHF). Design and setting: Prospective cohort study in a tertiary referral centre. Patients: 97 outpatients with CHF with a radionuclide left ventricular ejection fraction Interventions: At study entry, cardiac I-123 MIBG imaging was performed. The cardiac MIBG heart-to-mediastinum ratio (H/M) and washout rate (WR) were obtained from MIBG imaging. Main outcome measures: Patients were assigned to two groups based upon 27% of WR, which was the mean (2SD) control WR. 48 of 97 patients with CHF had abnormal WR (⩾27%), whereas the remaining 49 patients had normal WR ( Results: During the mean (SD) follow-up period of 65 (29) months, 12 (25%) patients in the abnormal WR group and 2 (4%) patients in the normal WR group died suddenly. Kaplan–Meier analysis revealed that sudden death was more often observed in patients with abnormal WR than those with normal WR (p = 0.001). On Cox regression analysis, MIBG WR, H/M on the delayed image and H/M on the early image were significantly associated with sudden death. Conclusion: Cardiac MIBG imaging would be useful for predicting sudden death in patients with CHF.

In the case of an emergency coronary procedure where the risk of contrast-induced nephropathy is especially high, there are few reliable methods to attenuate renal injury. We examined the efficacy of sodium bicarbonate for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure. We enrolled 59 patients who were scheduled to undergo an emergency coronary angiography or intervention. These patients were randomized to receive a 154-mEq/L infusion of sodium bicarbonate (n = 30) or sodium chloride (n = 29), as a bolus of 3 ml/kg/hour for 1 hour before the administration of contrast, followed by an infusion of 1 ml/kg/hour for 6 hours during and after the procedure. In the sodium bicarbonate group, serum creatinine concentration remained unchanged within 2 days of contrast administration (1.31 +/- 0.52 to 1.31 +/- 0.59 mg/dl), whereas it increased in the sodium chloride group (1.32 +/- 0.65 to 1.52 +/- 0.92 mg/dl, p = 0.01). The incidence of contrast-induced nephropathy (an increase0.5 mg/dl or25% in serum creatinine concentration within 2 days of contrast) was significantly lower in the sodium bicarbonate group than in the sodium chloride group (7% vs 35%, p = 0.01, risk ratio 0.19, 95% confidence interval 0.046 to 0.80). In conclusion, hydration with sodium bicarbonate is more effective than with sodium chloride for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure.

In the sub-100-nm CMOS generation, a large local Vth variability degrades the 6T-SRAM cell stability, so that we have to consider this local variability as well as the global variability to achieve high-yield SRAM products. Therefore, we need to employ some assist circuits to expand the SRAM operating margin. We propose a variability-tolerant 6T-SRAM cell layout and new circuit techniques to improve both the read and the write operating margins in the presence of a large Vth variability. By applying these circuit techniques to a 0.494-mum2 SRAM cell with a beta ratio of 1, which is an extremely small cell size, we can achieve a high-yield 8M-SRAM for a wide range of Vth values using a 65-nm low stand-by power (LSTP) CMOS technology