Carbon Monoxide Diffusing Capacity Predicts Cardiac Readmission in Patients Undergoing Left Ventricular Assist Device Implantation in Japan.

Carbon monoxide diffusion capacity (DLCO) is impaired in heart failure patients; however, its clinical impact has not been well investigated in the left ventricular assist device (LVAD) population. We explored the predictive value of preoperative DLCO in the survival and cardiac readmission rates after LVAD implantation. Seventy-six patients who received continuous-flow LVAD as bridge-to-transplant therapy from November 2007 to September 2018 and underwent pulmonary function test before LVAD implantation were included. The primary study endpoints were death and readmission for heart failure or arrhythmia (cardiac readmission). Patients were stratified into two groups according to the percent of predicted DLCO (%DLCO). Pulmonary vascular resistance (PVR) was equivocal between the groups preoperatively, whereas the low DLCO group (%DLCO < 80%) showed significantly high PVR postoperatively. The mortality rate was not different between the groups. The 2 year cardiac readmission rate was 33.5% in the low DLCO group and 8.7% in the high DLCO group (%DLCO ≥ 80%) (P = 0.028). The %DLCO was associated with cardiac readmission in univariate and multivariate analyses (hazard ratio: 4.32; 95% CI: 1.50-15.9; P = 0.005). Low %DLCO was associated with high PVR postoperatively and was a risk factor for cardiac readmission after LVAD implantation.

Differences in the prognoses of patients referred to an advanced heart failure center from hospitals with different bed volumes.

Few reports have discussed appropriate strategies for patient referrals to advanced heart failure (HF) centers with available left ventricular assist devices (LVADs). We examined the association between the characteristics and prognoses of referred patients with advanced HF and the bed volume of the referring hospitals. This retrospective analysis evaluated 186 patients with advanced HF referred to our center for consultation about the indication of LVAD between January 1, 2015, and August 31, 2018. We divided the patients into two groups according to the bed volume of their referring hospital (high bed volume hospitals (HBHs): ≥ 500 beds in the hospital; low bed volume hospitals (LBHs): < 500 beds). We compared the primary outcome measure, a composite of LVAD implantation and all-cause death, between the patients referred from HBHs and patients referred from LBHs. The 186 patients with advanced HF referred to our hospital, who were referred from 130 hospitals (87 from LBHs and 99 from HBHs), had a mean age of 43.0 ± 12.6 years and a median left ventricular ejection fraction of 22% [15-33%]. The median follow-up duration of the patients was 583 days (119-965 days), and the primary outcome occurred during follow-up in 42 patients (43%) in the HBH group and 20 patients (23%) in the LBH group. Patients referred from HBHs tended to require catecholamine infusion on transfer more often than those referred from LBLs (36.5% (HBH), 20.2% (LBL), P = 0.021). Kaplan-Meier analysis indicates that the occurrence of the primary outcome was significantly higher in the HBH patients than in the LBH patients (log-rank P = 0.0022). Multivariate Cox proportional hazards analysis revealed that catecholamine support on transfer and long disease duration were statistically significant predictors of the primary outcome. Patients from HBHs had a greater risk of the primary outcome. However, the multivariate analysis did not indicate an association between referral from an HBH and the primary outcome. In contrast, catecholamine support on transfer, long duration of disease, and low blood pressure were independent predictors of the primary outcome. Therefore, these should be considered when determining the timing of a referral to an advanced HF center, irrespective of the bed volume of the referring hospital.

Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

AIMS: Nephrotoxicity of calcineurin inhibitors (CNIs) is associated with adverse events in patients undergoing heart transplant (HTx), although studies directly comparing tacrolimus (TAC) versus cyclosporin A (CsA), especially in combination with everolimus and low-dose CNIs approach, are limited. Thus, we sought to investigate the associations of TAC and CsA with clinical outcomes in HTx recipients, with specific focus on renal function. METHODS AND RESULTS: From August 2007 to February 2017, 72 consecutive patients (39 treated with TAC vs. 33 with CsA) receiving de novo HTx in a single transplant centre were retrospectively evaluated. We used the instrumental variable method to account for unmeasured confounding. The study outcomes were percentage change in estimated glomerular filtration rates (eGFR) (safety endpoint) and biopsy-proven acute rejection (efficacy endpoint) within the first year after HTx. The enrolled patients (median age 40 years) were predominantly men (68%). There were no significant differences in baseline characteristics, including eGFR (64.8 [45.7-96.4] mL/min/1.73 m2 in TAC vs. 65.6 [57.9-83.0] mL/min/1.73 m2 for CsA; P = 0.48), other than sex (male, 49% for TAC vs. 91% for CsA; P < 0.001) between the two groups. Within the first year after HTx, 23 (59%) in the TAC group switched mycophenolate mofetil to everolimus, whereas 16 (48%) in the CsA group (P = 0.52). At 12 months, the rates of mortality and end-stage renal disease requiring renal replacement therapies were both 0%. In the instrumental variable analysis, no differences in renal function as well as graft rejection for 1 year after HTx existed between the TAC and CsA groups. These results were similar when taking into account of everolimus use. CONCLUSIONS: Irrespective of everolimus use with low-dose CNIs, our analysis using the instrumental variable method showed no differences in renal function as well as graft rejection during the first year after HTx between HTx recipients who received TAC or CsA.

Controlling Nutritional Status Score As a Predictive Marker for Patients With Implantable Left Ventricular Assist Device.

Although a correlation between the nutritional status and the prognosis of patients with heart failure has been suggested, a correlation between the nutritional status and outcomes after the left ventricular assist device (LVAD) implantation remains unclear. We aimed to investigate the efficacy of the Controlling Nutritional Status (CONUT) score (range 0-12, including serum albumin, total cholesterol, and lymphocytes) as a nutritional index in speculating the prognosis of patients undergoing LVAD implantation. We examined 63 consecutive patients who underwent the continuous-flow LVAD implantation. Using the preoperative CONUT score, patients were categorized into two groups: lower CONUT score (0-4: normal to mild malnutrition) and higher CONUT score (5-12: moderate to severe malnutrition). We compared for the backgrounds and the clinical events after LVAD implantation. The higher CONUT group exhibited a significantly higher mean right atrial pressure (10.9 ± 4.7 vs. 7.3 ± 4.1 mmHg; p = 0.0019). In that group, the mortality rate was significantly higher (25% vs. 2.6%; p = 0.0059) and the Kaplan-Meier analysis showed lower survival rate. Furthermore, more bleeding events significantly occurred in the higher CONUT group. The preoperative CONUT score may reflect systemic venous congestion and offer a useful prognostic index of clinical courses after LVAD implantation.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Abdominal skeletal muscle mass as a predictor of mortality in Japanese patients undergoing left ventricular assist device implantation.

AIMS: We assessed preoperative muscle wasting in patients undergoing left ventricular assist device (LVAD) implantations using abdominal skeletal muscle images on computed tomography (CT) and explored the associations between the preoperative muscle wasting and clinical outcomes after LVAD implantation. METHODS AND RESULTS: We retrospectively examined the records of 111 patients who underwent continuous-flow LVAD implantations as bridge-to-transplant therapy from January 2010 to December 2016 at our institution. After 33 patients were excluded, the study cohort consisted of 78 individuals. CT images used to calculate the skeletal muscle index (SMI) at the third lumbar vertebra level were obtained before the LVAD implantation procedures. Patients were classified as having muscle wasting if their SMI fell into the lowest gender-based tertile. The median SMI for the study patients was 37.6 cm2 /m2 . The SMI cut-off values for the lowest tertiles were 36.7 cm2 /m2 for men and 28.2 cm2 /m2 for women, resulting in 26 patients (33.3%) with muscle wasting in this study. During the mean follow-up of 738 ± 379 days, there were 10 deaths (12.8% mortality). Seven of the 26 patients with muscle wasting (26.9%) died, and 3 of the 52 patients without muscle wasting (5.8%) died. The times to all-cause mortality were significantly different between patients with and without muscle wasting (P = 0.0094). Muscle wasting was found to be associated with mortality in univariate and multivariate Cox analyses (hazard ratio: 4.32; 95% CI: 1.19-20.2). CONCLUSIONS: Preoperative muscle wasting was associated with a higher mortality in patients with LVAD. Assessment of the abdominal skeletal muscle area on CT prior to LVAD implantation can help predict mortality.

Quality of life of family caregivers of patients with a left ventricular assist device in Japan.

BACKGROUND: The role of caregivers is important for the successful support of left ventricular assist device (LVAD) patients. We aimed to (1) evaluate quality of life (QoL) of caregivers pre-and post-LVAD implant and (2) identify factors associated with caregivers' QoL. METHODS: The caregivers' QoL was assessed with the Short Form-8 before implant, at 3 and 6 months after LVAD implantation. The physical and mental component summary (PCS and MCS) scores were calculated. Caregiver burden was evaluated using the 8-item Zarit Caregiver Burden Interview. RESULTS: Data were collected from LVAD patients as bridge-to-transplant and their family caregivers in Japan. No significant changes were found in caregivers' PCS scores during the follow-up (before 52.7±7.1; at 3 months 49.7±6.5, and at 6 months 50.7±6.4, n=20). Compared with the scores before implant (38.9±9.3), the caregivers' MCS scores improved after LVAD implantation at 3 months (44.2±7.7; p=0.03) and at 6 months (46.2±7.4, p=0.003), but they were still lower than those of the Japanese general population (p<0.01). In multiple regression analysis at 3 months (n=40), caregivers' lower PCS scores were associated with older patient age [standard partial regression coefficients (sß)=-0.36, p=0.02] and caregiver unemployment (sß=0.30, p=0.04), whereas being female (sß=-0.26, p=0.03), being the patient's spouse (sß=-0.23, p=0.03), and having a mild to moderate caregiving burden (sß=-0.63, p<0.001) were associated with lower MCS scores among caregivers. CONCLUSIONS: LVAD implantation improves caregivers' mental QoL. Since caregivers' MCS scores are lower than the general population, it is important to identify family caregivers at risk for low QoL and reduce their caregiving burden.

Readmissions after continuous flow left ventricular assist device implantation.

Continuous flow left ventricular assist device (CF-LVAD) therapy has improved the survival of patients with advanced heart failure. However, the readmission rate of CF-LVAD patients is still relatively high. A total of 90 patients who received CF-LVADs between April 2011 and March 2016 at our institute and were discharged home were analyzed retrospectively. They were followed up through March 2017. Clinical data, including frequency, length and etiology of readmission, were obtained from medical records. The mean observation period after initial discharge was 713 ± 322 days. In total, 73 patients (81%) had 236 readmissions, 214 unplanned and 22 planned. The overall and unplanned readmission rates were 1.34 and 1.22 per patient-year, respectively. The rate of freedom from unplanned first readmission at 1 year after initial discharge was 39%. The median interval between the previous hospital discharge and first and second readmissions was 311 and 213 days, respectively (log-rank test, p = 0.117). The rate of readmission after more than three readmissions was significantly higher than that of first or second readmission (log-rank test, p < 0.001). The most common etiology of readmission was driveline infection (DLI) (36%), followed by stroke (9%). The median length of hospital stay due to DLI was 23 days. The patients with repeated unplanned readmissions had significantly lower EuroQol 5 dimensions questionnaire utility score than those with no or just one readmission. Readmission was common in CF-LVAD patients, and the most common etiology of readmissions was DLI. The interval to the next readmission seemed shorter for patients with repeated readmissions.

Quality of Life and Influential Factors in Patients Implanted With a Left Ventricular Assist Device.

BACKGROUND: Improving quality of life (QOL) has become an important goal in left ventricular assist device (LVAD) therapy. We aimed (1) to assess the effect of an implantable LVAD on patients' QOL, (2) to compare LVAD patients' QOL to that of patients in different stages of heart failure (HF), and (3) to identify factors associated with patients' QOL. METHODS AND RESULTS: The QOL of 33 Japanese implantable LVAD patients was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short-form 8 (SF-8), before and at 3 and 6 months afterwards. After LVAD implantation, QOL significantly improved [MLHFQ, SF-8 physical component score (PCS), SF-8 mental component score (MCS), all P<0.05]. Implanted LVAD patients had a better QOL than extracorporeal LVAD patients (n=33, 32.1±21.9 vs. n=17, 47.6±18.2), and Stage D HF patients (n=32, 51.1±17.3), but the score was comparable to that of patients who had undergone a heart transplant (n=13). In multiple regression analyses, postoperative lower albumin concentration and right ventricular failure were independently associated with poorer PCS. Female sex and postoperative anxiety were 2 of the independent factors for poorer MCS (all P<0.05). CONCLUSIONS: Having an implantable LVAD improves patients' QOL, which is better than that of patients with an extracorporeal LVAD. Both clinical and psychological factors are influence QOL after LVAD implantation.

Midterm outcome of implantable left ventricular assist devices as a bridge to transplantation: Single-center experience in Japan.

BACKGROUND: Two implantable continuous-flow left ventricular assist devices (LVADs), DuraHeart (Terumo Heart, Ann Arbor, MI, USA) and EVAHEART (Sun Medical, Nagano, Japan), were approved in Japan in April 2011. We analyzed the midterm outcome of patients implanted with these implantable LVADs at the University of Tokyo Hospital. METHODS AND RESULTS: A total of 31 patients who underwent implantation of LVADs (10 DuraHeart, 21 EVAHEART) as a bridge to transplantation at our institution between April 2011 and August 2013 were retrospectively reviewed. All patients were followed up through December 2013. Seven patients underwent conversions from NIPRO paracorporeal LVAD (Nipro, Osaka, Japan) to an implantable LVAD. The mean observation period was 483±239 days (41.0 patient years). Eight patients were transplanted and one patient showed functional recovery with subsequent LVAD explantation. Four patients died due to cerebrovascular accident, empyema, or device malfunction due to pump thrombosis after cerebral bleeding. Kaplan-Meier analysis revealed 6-, 12-, and 24-month survival rates of 93%, 86%, and 86%, respectively. The rates of freedom from cerebrovascular accidents and device-related infections at 1 year after LVAD implantation were 65% and 36%, respectively. Twenty-nine patients were discharged home after LVAD implantation. During the period of this study, there were 59 readmissions (53 urgent, 6 elective) among 22 patients (76%). The overall and urgent readmission rates were 1.66 and 1.49 per patient year, respectively. The common reason for readmission was device-related infection (31%), followed by cerebrovascular accidents (17%). The total out-of-hospital time after the primary discharge was 90%. CONCLUSIONS: Our midterm survival rate after LVAD implantation is satisfactory. However, patients undergoing LVAD support were often readmitted with adverse events.

Cardiac allograft vasculopathy can be distinguished from donor-transmitted coronary atherosclerosis by optical coherence tomography imaging in a heart transplantation recipient: double layered intimal thickness.

Although survival after heart transplantation (HTx) has improved in recent years, cardiac allograft vasculopathy (CAV) is still the leading cause of remote morbidity and mortality in HTx recipients, partly because of difficulty with its diagnosis. In general, routine surveillance for CAV is advocated with coronary angiography accompanied by intravascular ultrasound (IVUS) if necessary. However, these modalities have limitations with respect to low spatial resolution, and sufficient qualitative/quantitative assessment of coronary intima has not been accomplished. Recently, optical coherence tomography (OCT) has emerged as a novel intracoronary imaging technique using an optical analogue of ultrasound with a spatial resolution of 10-20 µm, which is 10 times greater than IVUS. We here experienced a 49-year-old male who received a HTx 3 years ago, and OCT was executed during low molecular weight dextran injection. OCT demonstrated distinct double intimal layers probably consisting of a donor-transmitted atherosclerotic layer and an inner intimal proliferation due to CAV, which was indistinguishable by IVUS and virtual histological analyses. We believe that OCT imaging is not only a new loadstar during treatment of CAV but also a new generation modality for screening for early CAV in HTx recipients.

Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery.

To date, there have been few reports demonstrating preoperative predictors for left ventricular reverse remodeling (LVRR) after LV assist device (LVAD) implantation, especially among patients with dilated cardiomyopathy (DCM). We retrospectively analyzed 60 patients with stage D heart failure due to DCM who had received LVAD treatment [pulsatile flow (PF) type, 26; continuous flow type, 34]. Data were evaluated at 6 months or just before explantation of the LVAD. We defined "LV reverse remodeling" (LVRR) by the achievement of an LV ejection fraction (LVEF) of ≥ 35 % after 6 months of LVAD support or explantation of LVAD within 6 months. LVRR occurred in 16 of our patients (26.7 %). Uni/multivariate logistic regression analyses for LVRR demonstrated that of the preoperative variables evaluated, PF LVAD usage and insufficient preoperative ß-blocker treatment were independent predictors for LVRR. Patients who accomplished LVRR had a better clinical course, including lower levels of aortic valve insufficiency and lower levels of plasma B-type natriuretic peptide. Of the six patients (10.0 %) in whom LVADs were eventually explanted, all had an LVEF of ≥ 35 % before explantation or at 6 months. Based on these results, we conclude that DCM patients with insufficient preoperative ß-blocker treatment have a chance to achieve LVRR under LVAD support as a bridge to recovery.

Successful treatment of hemodynamic compromise caused by antibody-mediated and cellular rejection in a recipient 12 years after heart transplantation.

Heart transplantation (HTx) is an established therapy for stage D heart failure due to recent advances in immunosuppressive regimens. However, antibody-mediated rejection remains an unsolved problem because of its refractoriness to standard immunosuppressive therapy with high mortality and graft loss. We experienced a 16-year old patient with hemodynamic compromise caused by both cellular and antibody-mediated rejection 12 years after HTx. The rejection was refractory to repeated steroid pulse treatment, intravenous immunoglobulin administration, and intensifying immunosuppression including addition of everolimus. Eventually, she was successfully treated with repeated plasma exchange accompanied by a single administration of the anti-CD20 monoclonal antibody rituximab.

Everolimus-incorporated immunosuppressant strategy improves renal dysfunction while maintaining low rejection rates after heart transplantation in Japanese patients.

The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CNI dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CNI dosage in a dose-dependent manner (P < 0.001, r = -0.807). Neutrophil count increased significantly (P < 0.05) with a reduction in the dosage of MMF (P = 0.009, r = -0.671). Cytomegalovirus antigenemia remained negative after EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.

[Mid-long term result of implantable ventricular assist device treatment for end-stage heart failure in the University of Tokyo Hospital].

Two implantable left ventricular assist devices(I-LVADs)were approved in Japan in 2011. I-LVADs were used for end-stage heart failure of 20 patients in our institute until March 2012. We examine the clinical course of these 20 patients who were treated with I-LVADs. End points are transplantation, death, or weaning from I-LVADs. Mean hospital days after I-LVAD implantation were 58.1 days, and all 20 patients could discharge from hospital alive. Until September 2012, mean follow up interval was 515 days. Five patients reached heart transplantation, 2 died, weaning from an I-LVAD could be done in 1 patient, and 12 continued to wait for heart transplantation. Survival rate was 100% at 1 month, 95% at 3 months, and 89% at 1 year, respectively. Mean follow up duration after discharge were 457 days, and 16 patients(80%)needed a total of 41 times of readmission in this period. Freedom from readmission was 75% at 1 month, 60% at 3 months, and 25% at 1 year, respectively. In conclusion, prognosis of I-LVAD treatment was good, but many patients needed readmission after I-LVAD implantation and follow up system for I-LVAD treatment should be improved immediately.