Efficacy and safety of remote cardiac rehabilitation in the recovery phase of cardiovascular diseases (RecRCR study): A multicenter, nonrandomized, and interventional trial in Japan.

Backgrounds: Remote cardiac rehabilitation has proven useful in patients with cardiovascular disease; however, the methodology had not been fully validated. This study aimed to investigate the efficacy and safety of remote cardiac rehabilitation (RCR) with real-time monitoring and an ergometer using a bidirectional communication tool during the recovery phase of cardiovascular diseases. Methods: This multicenter, nonrandomized, interventional study was conducted at 29 institutions across Japan and enrolled patients with cardiovascular diseases who met indications for cardiac rehabilitation (CR) after receiving in-hospital treatment. The RCR group exercised at home using an ergometer and was monitored in real-time using interactive video and monitoring tools for 2-3 months. Educational instructions were provided concurrently through e-learning approaches. The safety of the RCR protocol and the improvement in peak oxygen consumption (VO2) were compared with those of the historical control group that participated in center-based CR. Results: Fifty-three patients from the RCR group were compared with 103 historical controls having similar background characteristics. No patients in RCR experienced significant cardiovascular complications while engaging in exercise sessions. After 2-3 months of RCR, the peak VO2 improved significantly, and the increases in the RCR group did not exhibit any significant differences compared to those in the historical controls. During follow-up, the proportion of patients whose exercise capacity increased by 10% or more was also evaluated; this finding did not indicate a statistically significant distinction between the groups. Conclusions: RCR during the recovery phase of cardiovascular diseases proved equally efficient and safe as center-based CR.

Clinical and Prognostic Values of ALBI Score in Patients With Acute Heart Failure.

BACKGROUND: Although liver dysfunction is one of the common complications in patients with acute heart failure (AHF), no integrated marker has been defined. The albumin-bilirubin (ALBI) score has recently been proposed as a novel, clinically-applicable scoring system for liver dysfunction. We investigated the utility of the ALBI score in patients with AHF compared to that for a preexisting liver dysfunction score, the Model of End-Stage Liver Disease Excluding prothrombin time (MELD XI) score. METHODS: We evaluated ALBI and MELD XI scores in 1,190 AHF patients enrolled in the prospective, multicentre Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure study. The associations between the two scores and the clinical profile and prognostic predictive ability for 1-year mortality were evaluated. RESULTS: The mean MELD XI and ALBI scores were 13.4±4.8 and -2.25±0.48, respectively. A higher ALBI score, but not higher MELD XI score, was associated with findings of fluid overload. After adjusting for pre-existing prognostic factors, the ALBI score (HR 2.11, 95% CI: 1.60-2.79, p<0.001), but not the MELD XI score (HR 1.02, 95% CI: 0.99-1.06, p=0.242), was associated with 1-year mortality. Likewise, area under the receiver-operator-characteristic curves for 1-year mortality significantly increased when the ALBI score (0.71 vs. 0.74, p=0.020), but not the MELD XI score (0.71 vs. 0.72, p=0.448), was added to the pre-existing risk factors. CONCLUSIONS: The ALBI score is potentially a suitable liver dysfunction marker that incorporates information on fluid overload and prognosis in patients with AHF. These results provide new insights into heart-liver interactions in AHF patients.

Specialty-Related Differences in the Acute-Phase Treatment and Prognosis in Patients With Acute Heart Failure　- Insights From REALITY-AHF.

BACKGROUND: The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. Methods and Results: We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58-2.14). CONCLUSIONS: Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF.

Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure.

BACKGROUND: Acute heart failure (AHF) is a life-threatening disease requiring urgent treatment, including a recommendation for immediate initiation of loop diuretics. OBJECTIVES: The authors prospectively evaluated the association between time-to-diuretic treatment and clinical outcome. METHODS: REALITY-AHF (Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure) was a prospective, multicenter, observational cohort study that primarily aimed to assess the association between time to loop diuretic treatment and clinical outcome in patients with AHF admitted through the emergency department (ED). Door-to-furosemide (D2F) time was defined as the time from patient arrival at the ED to the first intravenous furosemide injection. Patients with a D2F time <60 min were pre-defined as the early treatment group. Primary outcome was all-cause in-hospital mortality. RESULTS: Among 1,291 AHF patients treated with intravenous furosemide within 24 h of ED arrival, the median D2F time was 90 min (IQR: 36 to 186 min), and 481 patients (37.3%) were categorized as the early treatment group. These patients were more likely to arrive by ambulance and had more signs of congestion compared with the nonearly treatment group. In-hospital mortality was significantly lower in the early treatment group (2.3% vs. 6.0% in the nonearly treatment group; p = 0.002). In multivariate analysis, earlier treatment remained significantly associated with lower in-hospital mortality (odds ratio: 0.39; 95% confidence interval: 0.20 to 0.76; p = 0.006). CONCLUSIONS: In this prospective multicenter, observational cohort study of patients presenting at the ED for AHF, early treatment with intravenous loop diuretics was associated with lower in-hospital mortality. (Registry focused on very early presentation and treatment in emergency department of acute heart failure syndrome; UMIN000014105).

Accuracy of nonstenotic coronary atherosclerosis assessment by multi-detector computed tomography.

BACKGROUND: The ability to evaluate coronary stenosis using multi-detector computed tomography (MDCT) has been well discussed. In contrast, several studies demonstrated that the plaque burden measured by intravascular ultrasound (IVUS) has a relationship to the risk of cardiovascular events. the accuracy of MDCT was studied to determine plaque and vessel size compared with IVUS. METHODS AND RESULTS: Fifty-six proximal lesions (American College of Cardiology/American Heart Association classification: segment 1, 5, 6) from 33 patients were assessed using MDCT and IVUS. The plaque and vessel area were measured from the cross-sectional image using both MDCT and IVUS. Eight coronary artery lesions with motion artifacts and heavily calcified plaques were excluded from the analysis. The vessel and lumen size evaluated using MDCT were closely correlated with those evaluated by IVUS (R(2)=0.614, 0.750 respectively). Furthermore, there was a strong correlation between percentage plaque area assessed by MDCT and IVUS (R(2)=0.824). CONCLUSION: MDCT can noninvasively quantify coronary atherosclerotic plaque with good correlation compared with IVUS in patients with atherosclerosis.

HLA mismatches and PRA in kidney retransplants.

1. For kidney transplants, overall graft survival with 1st transplants was better than with multiple transplants. 2. One-year graft survival rates have become similar with 1st and 2nd transplants, but some differences persisted for 5-year survival. 3. HLA mismatches have decreased with both 1st and 2nd DDTs, but with 1st and 2nd LDTs HLA mismatches remained at almost the same level. 4. PRA levels increased with the number of transplants. 5. The percent of 1st transplant patients with 0% PRA has increased year by year. However, with 2nd transplants the percent with higher PRA levels also increased year by year. 6. The trend in number of HLA mismatches was similar with both 1st and 2nd DDTs and LDTs even when higher HLA mismatch levels increased over the years. 7. The graft survival of all PRA levels improved. The differences in 1-year graft survival between each PRA group became smaller, and pretransplant PRA diminished with 1-year graft survival. However, pretransplant PRA still affected 5-year graft survival.

Association of kidney transplant failure and antibodies against MICA.

Despite the progress in renal transplantation, acute rejection and graft failure still occur and chronic rejection continues to be the main problem in long-term allograft survival. Although kidney transplant rejection has been linked to anti-HLA antibodies, not all patients with failed kidney transplants have anti-HLA antibodies, indicating that other loci may be involved. Sera of 63 patients who experienced kidney rejection were compared against sera of 82 patients with functioning transplants. Sera were examined for IgG and IgM anti-HLA Class I and II antibodies. They were also tested by cytotoxicity against panels of 26 endothelial cell lines, 8 MHC class I chain-related gene A (MICA) recombinant cell lines, and 28 B lymphoblast cell lines. Among patients whose transplants failed, 65% had anti-HLA antibodies compared with 45% of those with functioning kidneys (p < 0.05). Similarly, among those whose transplants failed, 41% had anti-endothelial cell antibodies in contrast to 22% in functioning patients (p < 0.05). Among patients whose grafts failed, 52% had anti-MICA antibodies versus 21% of those with functioning grafts (p < 0.001). Eleven patients with failed grafts and 32 with functioning grafts were negative for all of the above. However, 6 of the former and 7 of the latter showed positive cytotoxicity against B lymphoblasts (p < 0.05). Taking all antibodies together, 92% of patients with graft failure had antibodies as opposed to 70% of patients with functioning grafts (p < 0.001). We postulate that antibodies against HLA, MICA, endothelial cells, and B lymphoblasts could be independently involved in the slow process of chronic graft failure.

Frequency of MIC antibody in rejected renal transplant patients without HLA antibody.

Antibodies to MICA and MICB antigens were sought in the sera of 139 kidney transplant recipients. MICA*001, *002, *007, *008, and MICB*002 antigens were produced in Escherichia coli and then tested using enzyme-linked immunosorbent assay plates. Among 35 normal sera, 6% had MIC antibodies, and among 14 sera from pregnant women, 21% had MIC antibodies. Among 34 patients with functioning transplants with human leukocyte antigen (HLA) antibodies, 24% had MIC antibodies, and 19% of 32 patients without HLA antibodies had MIC antibodies. Among 46 patients who lost grafts with HLA antibodies, 26% had MIC antibodies, and among 27 failed patients without HLA antibodies, 37% had MIC antibodies. We conclude that antibodies to MIC are produced in the course of immunization by pregnancies and kidney transplants. They also occurred more frequently in rejected patients (30%) than in those with functioning grafts (21%).

Detection of HLA and MICA antibodies before kidney graft failure.

390 serum samples taken from a series of 28 patients who lost their grafts were retrospectively investigated for antibodies by single antigen HLA Class I&II and MICA Luminex beads. In 20 patients with immunological failure, 10 patients had DSA, 16 had epitope-related NDSA, and 16 had NDSA or MICA antibodies. In 16 which increased antibodies leading up to the graft failure, DSA were found in 7 patients. However, in 9 patients who similarly rejected their grafts, 6 were epitope-related DSA and 3 were NDSA. We were unable to establish why NDSA might be associated with the failure, but this was clearly the case in these patients. Of the 25 patients whose grafts were rejected, 23 (92%) produced antibody prior to failure. Our results strongly suggest that antibody monitoring is important as a means of detecting chronic rejection before a rise in SCr. Early detection of antibody would allow for appropriate and timely interventions to save a graft.

Does MICA influence acute rejection in kidney transplantation?

MHC class 1-related chain A (MICA) has been reported to be recognized by specific antibodies in the sera of transplanted patients, and it may be a target molecule in allograft rejection. MICA was originally pointed out to be an HLA-related polymorphic gene, the product of which may be recognized by a subpopulation of intestinal gamma delta T-cells and may play a role in the activation of a subpopulation of natural killer cells. Although their association with chronic rejection has been demonstrated before, there are few reports of any relation with acute rejection. We encountered a possible case of MICA-related acute early rejection. The recipient was a 25-year-old female; the original disease was IgA nephropathy, and the hemodialysis period was 12 months. She underwent ABO-compatible living-related renal transplantation from her mother. The HLA type was A24, A31, B7, B52, DR1, and DR15 in the donor and A31, A33, B7, B44, DR1, and DR12 in the recipient. A pre-operative direct cross-match was negative by a conventional cytotoxic test, and HLA class 1 and 2 antibodies were negative by LABScreen single antigen testing. Induction immunosuppressive therapy was started with TAC, MMF, MP, and BXM. The graft functioned at once, and SCr was 2.4 mg/dl on post-transplant day 1. SCr increased from post-transplant day 2, and oliguria progressed. Hemodialysis was restarted on post-transplant day 6. A biopsy revealed Banff 2b vascular rejection. The graft was finally rescued by steroid pulse and plasma exchange therapy. SCr went down to 1.07 mg/dl, and a re-biopsy showed improvement on post-transplant day 42. HLA class 1 and 2 antibodies were negative during this period, and MICA019 antibody was higher before transplantation retrospectively. Additionally, this antibody titer was decreased at the time of discharge. These data show that MICA may induce rejection in the early phase of renal transplantation. Further study is needed to evaluate this phenomenon.

Simultaneous antibody-mediated rejection of multiple allografts in modified multivisceral transplantation.

The patient was an 8-year-old-female with a history of intestinal pseudo-obstruction who underwent a modified multivisceral transplant (stomach, duodenum, pancreas, and small intestine). Following transplantation, she developed HLA antibody (donor-specific and non-donor-specific). Donor-specific HLA antibodies decreased 2 weeks after transplantation, but non-donor-specific HLA antibodies remained high throughout the posttransplant course. The patient experienced repeated acute rejection episodes throughout the post-transplant course, ultimately resulting in the replacement of all allografts 250 days after the initial transplantation. The explanted allografts all revealed acute vascular rejection, but at varying degrees. There was also concurrent chronic rejection, with the intestinal allograft being affected most severely. This case suggests that HLA antibodies played a critical role in antibody-mediated acute rejection and chronic rejection and that there is varying susceptibility to this form of rejection among multiple allografts.

Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure.

The role of HLA antibodies in chronic allograft rejection was examined utilizing a unique resource of sera collected annually and stored over a 12-year period from patients with rejected or retained grafts. In patients selected for not having preformed HLA antibodies, 679 postoperative serial serum samples from 39 patients who rejected their grafts and 26 with functioning grafts were tested for HLA Class I and Class II antibodies by flow cytometry and for MICA antibodies by cytotoxicity on recombinant cell lines. HLA antibodies were found in 72% of patients who rejected grafts, compared to 46% with functioning transplants (p<0.05). In addition, the incidence of IgG HLA plus MICA antibodies was higher (77%) among those with failed transplants than those with functioning transplants (42%) (p<0.01). Finally, if patients with IgM anti-HLA antibodies were included, 95% of the 39 patients who rejected their grafts had HLA or MICA antibodies, compared to 58% with functioning grafts (p<0.01). Patients who rejected transplants had HLA and MICA antibodies more frequently than those with functioning grafts. These antibodies found in the peripheral circulation, were not necessarily donor-specific, but their association with failure is consistent with a causality hypothesis.

Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation.

The involvement of immunologic and nonimmunologic events in long-term kidney allograft failure is difficult to assess. The development of HLA antibodies after transplantation is the witness of ongoing reactivity against the transplant, and several studies have suggested that the presence of HLA antibodies correlates with poor graft survival. However, they have not discriminated between donor-specific (DS) and non-specific (NDS) antibodies. A total of 1229 recipients of a kidney graft, transplanted between 1972 and 2002, who had over a 5-yr period a prospective annual screening for HLA antibodies with a combination of ELISA, complement-dependent cytotoxicity, and flow cytometry tests were investigated; in 543 of them, the screening was complete from transplantation to the fifth year postgrafting. Correlations were established between the presence and the specificity of the antibodies and clinical parameters. A total of 5.5% of the patients had DS, 11.3% had NDS, and 83% had no HLA antibodies after transplantation. NDS antibodies appeared earlier (1 to 5 yr posttransplantation) than DS antibodies (5 to 10 yr). In multivariate analysis, HLA-DR matching, pretransplantation immunization, and acute rejection were significantly associated with the development of both DS and NDS antibodies and also of DS versus NDS antibodies. The presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria. Screening of HLA antibodies posttransplantation could be a good tool for the follow-up of patients who receive a kidney transplant and allow immunosuppression to be tailored.

Trends in serum creatinine levels and transplant year.

The serum creatinine (SCr) level has a strong predictive value for kidney graft survival. On average, the SCr levels of recipients whose grafts continued to function were lower (< 1.5 mg/dl) than those for recipients who died with a functioning graft during the following year (-2.0 mg/dl) and were much lower than those for recipients whose graft failed within a year due to chronic rejection (-3.0 mg/dl). The average one-year SCr levels have fallen steadily since 1995 among recipients of living and deceased donor kidney transplants, suggesting that immunosuppression and clinical management have improved graft function. These improvements have come despite increasing transplantation of older donor kidneys and heavier recipients, both of which are factors predisposing to higher SCr levels. Even though the average one-year SCr levels have dropped over the past 10 years, there has not been a substantial improvement in long-term graft survival.

Serum creatinine as a predictor of transplant survival and death.

Taking ALL patients transplanted in a given calendar year, we have shown that serum creatinine values have gradually decreased over the past 15 years. Donor age was a major factor influencing serum creatinine. This was followed by the recipient sex. Of lesser importance was the different immunosuppressive drugs employed, and whether the donor was deceased or living. The strong predictive value of serum creatinine was shown at various times after transplantation. Also, one year prior to failure, the creatinine values were very significantly elevated. A similar finding was noted one year prior to the death of patients with a functioning graft.

Serum creatinine levels in 10-year survivors of cadaveric kidney transplants.

A yearly history of serum creatinine levels was made in a selected cohort of cadaver donor transplant patients who survived 10 years. 1. A stepwise increase in serum creatinine levels was noted with increasing age of the donor. 2. A similar increase was found with increasing recipient weight. 3. In all analyses of kidney size in relation to recipient weight, such as sex of the donor and races, a corresponding relationship to the serum creatinine was noted. That is, whenever the kidney was smaller, or the recipient was larger, an increased level of serum creatinine was found. 4. Rejection at discharge and cold ischemia time had a small long-term effect on serum creatinine levels. Kidneys from donors who had a stroke had higher serum creatinine levels than those who died of anoxia or head trauma. 5. In general, patients with polycystic kidney disease had the lowest serum creatinine levels, whereas those with SLE and GN had higher serum creatinine levels. 6. Patients with 0-A,B,DR mismatched kidneys had the lowest serum creatinine levels every year from the first year on through the tenth year. 7. The rates at which serum creatinine increases with time was established for patients with various original diseases, as well as in the total population. The increase in serum creatinine levels in those who failed after 5 years was similar to those who failed in 10 years.

Cardiac myocytes are recruited by bone marrow-derived cells in intact murine heart.

It is generally believed that the cardiac myocytes withdraw from the cell cycle shortly after birth and thereafter any loss of myocardial tissue cannot be repaired. However, recent reports indicate that cardiac myocytes can be regenerated by stem cells derived from bone marrow in the damaged hearts. In this study, we investigated whether bone marrow-derived cells can differentiate into cardiac myocytes in the intact hearts. We performed bone marrow transplantation from syngenic male mice to female c57/B6 mice. In female mice's hearts, the presence of cells from male mice was examined by FISH method that detects Y chromosome. Using the same samples, we also performed immunohistochemical staining with muscle specific antibodies. In the heart sections of female mice, there were some cells that were considered as differentiated myocytes derived from male bone marrow (0.01~0.09% of total myocytes) and the proportion of the cells increased as the period after bone marrow transplantation became longer (3 months after vs. 8 months after). These results suggest that, not only in the damaged heart but also in the intact heart, a portion of cardiac myocytes is recruited by bone marrow-derived cells.