Search

Thermal therapy for heart failure is recognized to improve clinical symptoms. We describe our experience with appendicular thermal therapy applied to a patient fitted with an extracorporeal left ventricular assist device (LVAD) who was wait-listed for a heart transplant. A 21-year-old male with end-stage heart failure due to dilated cardiomyopathy was fitted with a LVAD. His general condition stabilized after LVAD placement and the status of his heart failure has remained at NYHA class II for the past 13 months. However, his cardiac function did not sufficiently recover to discontinue LVAD support. We conducted appendicular thermal therapy using a steam foot bath and heated gloves for 2 weeks. Immediately after thermal therapy, his average sublingual temperature increased from 36.3 to 37.0°C and the grade of mitral regurgitation, as well as LV ejection fraction and endothelial function improved. Furthermore, levels of oxidative and anti-oxidative stress markers decreased and increased, respectively, after 2 weeks of therapy. No complications developed. We conclude that appendicular thermal therapy was safe in this patient waiting for a heart transplant and who had an extracorporeal LVAD, and that the procedure might be beneficial for others with end-stage heart failure.

Objectives We performed dobutamine stress testing for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy (DCM). Background Catecholamine sensitivity is reduced in failing hearts as a result of myocardial abnormalities in the beta-adrenergic receptor signaling pathway. However, little is known about adrenergic myocardial contractile reserve in asymptomatic or mildly symptomatic patients with DCM. Methods The maximal first derivative of left ventricular pressure (LV dP/dtmax) was determined during infusion of dobutamine (10 μg kg−1 min−1) in 46 asymptomatic or mildly symptomatic (New York Heart Association functional class I or II) patients with DCM. The expression of messenger ribonucleic acid (mRNA) for contractile regulatory proteins in endomyocardial biopsy specimens was quantified by reverse transcription and real-time polymerase chain reaction analysis. Plasma norepinephrine levels were measured in all patients and [123I]metaiodobenzylguanidine (MIBG) scintigraphy performed. Results Patients were classified into 3 groups based on the percentage increase in LV dP/dtmax induced by dobutamine (ΔLV dP/dtmax) and on LV ejection fraction (LVEF) at baseline: group I (n = 18): ΔLV dP/dtmax >100% and LVEF >25%; group IIa (n = 17): ΔLV dP/dtmax ≤100% and LVEF > 25%; and group IIb (n = 11): ΔLV dP/dtmax ≤100% and LVEF ≤25%. The amounts of beta1-adrenergic receptor, sarcoplasmic reticulum Ca2+-adenosine triphosphatase, and phospholamban mRNA were significantly smaller in groups IIa and IIb than in group I. The plasma norepinephrine level was increased and the delayed heart/mediastinum count ratio in MIBG scintigraphy was decreased in both groups IIa and IIb. Conclusions Dobutamine stress testing is a useful diagnostic tool for identifying reduced adrenergic myocardial contractile reserve related to altered myocardial expression of beta1-adrenergic receptor, sarcoplasmic reticulum Ca2+-adenosine triphosphatase, and phospholamban genes even in asymptomatic or mildly symptomatic patients with DCM.

Background The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC). Methods and Results Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC0-12 h) was evaluated. The MPA AUC0-12 h h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 μg · h/ml and from 39.19 to 93.18 μg · h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC0-12 h based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC0-12 h in the CsA group was a 3-time-point model that included C0 h, C1 h and C2 h (r2, 0.96; mean prediction error, 0.15±7.85%); a 2-time-point model that included C0 h, and C2 h (r2, 0.94; mean prediction error, 0.495±10.35%) was also reliable. In the FK group, a 3-time-point model that included C1 h, C2 h and C4h (r2, 0.73; mean prediction error, 2.73±17.09%) was the best model for predicting the full MPA AUC0-12 h, but it was not reliable in clinical practice. Conclusion A 3-(C0 h, C1 h and C2 h) and a 2-time-point model (C0 h and C2 h) are useful for predicting the full MPA AUC0-12 h in Japanese heart transplant recipients treated with CsA but not with FK. (Circ J 2007; 71: 1022 - 1028)

Background The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after their 50s and may contribute to the high prevalence of diastolic heart failure in elderly women. A decrease in estrogen levels after menopause is postulated to be one of the mechanisms responsible for this phenomenon. However, there is a paucity of data on the relationship between the timing of menopause and the progression of LVDD in the clinical setting; thus, we investigated this relationship in healthy postmenopausal women. Methods We enrolled 115 women and divided them into two groups according to median menopause age: 61 who experienced menopause at ≤50 years (early menopause group), and 54 who experienced menopause at >50 years (late menopause group). We compared the echocardiographic and clinical characteristics between the two groups. Results There were no significant differences in LV diastolic parameters (mitral E/A, p = 0.561; e’, p = 0.052; E/e’, p = 0.081; DCT, p = 0.082; prevalence of LVDD class, p = 0.801), as well as other echocardiographic parameters and clinical characteristics between the two groups. Multivariate linear regression analysis showed that the independent determinants of LVDD were age and body mass index, but not the timing of menopause. Conclusions Early menopause did not influence the progression of LVDD in postmenopausal women. The sharp progression of LVDD in elderly women is complex and probably influenced by multiple factors.

Background The aim of our study was to examine and compare the predictive value of operative mortality of the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, the Society of Thoracic surgeons (STS) score, the Ambler score, and the Japan score in patients undergoing aortic valve replacement (AVR) for aortic stenosis (AS). Methods A total of 406 patients undergoing AVR with or without coronary artery bypass grafting (CABG, n = 139) at our institution from August 2002 to December 2013 were enrolled in this cohort study. Accuracy of calibration and discrimination performance of four risk scores was assessed in the overall patient population and quartiles of each risk score. Results Operative mortality was 3.4% ( n = 14). The mean EuroSCORE II, STS score, Ambler score, and the Japan score were 3.1%, 4.9%, 5.7%, and 3.2%, respectively, giving observed-to-expected (O/E) ratio of 1.09, 0.69, 0.59, and 1.06. The C -statistics for operative mortality were 0.704 (EuroSCORE II), 0.781 (STS score), 0.709 (Ambler score), and 0.771 (Japan score). In the last quartile, the EuroSCORE II demonstrated excellent calibration (O/E ratio = 0.97) and discrimination ( C -statistic = 0.904), and the STS score (O/E ratio = 0.86, C -statistic = 0.779) and the Japan score (O/E ratio = 1.14, C -statistic = 0.80) showed reasonable correlation. However, the risk calibration by the Ambler score in the last quartile was unacceptable (O/E ratio = 0.60). Conclusions The EuroSCORE II and the Japan score showed superior ability of calibration, but the STS score and the Ambler score overestimated the risk. However, the discrimination power was similar among the four risk scores. In the last quartile of risk, the EuroSCORE II gave an excellent predictive performance.

Epicardial adipose tissue is a source of pro-inflammatory cytokines and has been linked to the development of coronary artery disease. No study has systematically assessed the relationship between local epicardial fat volume (EFV) and myocardial perfusion defects. We analyzed EFV in patients undergoing SPECT myocardial perfusion imaging combined with computed tomography (CT) for attenuation correction. Low-dose CT without contrast was performed in 396 consecutive patients undergoing SPECT imaging for evaluation of coronary artery disease. Regional thickness, cross-sectional areas, and total EFV were assessed. 295 patients had normal myocardial perfusion scans and 101 had abnormal perfusion scans. Mean EFVs in normal, ischemic, and infarcted hearts were 99.8 ± 82.3 cm(3), 156.4 ± 121.9 cm(3), and 96.3 ± 102.1 cm(3), respectively (P 0.001). Reversible perfusion defects were associated with increased local EFV compared to normal perfusion in the distribution of the right (69.2 ± 51.5 vs 46.6 ± 32.0 cm(3); P = 0.03) and left anterior descending coronary artery (87.1 ± 76.4 vs 46.7 ± 40.6 cm(3); P = 0.005). Our results demonstrate increased regional epicardial fat in patients with active myocardial ischemia compared to patients with myocardial scar or normal perfusion on nuclear perfusion scans. Our results suggest a potential role for cardiac CT to improve risk stratification in patients with suspected coronary artery disease.

Background— The differentiation of hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) on the basis of morphological information obtained by conventional echocardiography is occasionally problematic. We investigated whether strain rate (SR) imaging derived from tissue Doppler imaging (TDI) is able to discriminate HCM from H-LVH. Methods and Results— Conventional echocardiography and TDI were performed with 34 patients with LVH and 16 reference subjects. Mean values of systolic strain (ε sys ), peak systolic SR, and early diastolic SR obtained from 8 left ventricular (LV) segments were calculated. LV pressures were recorded simultaneously in the patients. Patients were diagnosed with HCM (n=20) or H-LVH (n=14) on the basis of conventional echocardiography and endomyocardial biopsy findings. Multivariate analysis revealed that septum/posterior wall thickness ratio ( P =0.00013) and ε sys ( P sys cutoff value of −10.6% discriminated between HCM and H-LVH with a sensitivity of 85.0%, specificity of 100.0%, and predictive accuracy of 91.2%. The combination of the septum/posterior wall thickness ratio and ε sys discriminated HCM from H-LVH with a predictive accuracy of 96.1%. The ε sys parameter was significantly correlated with pulmonary arterial wedge pressure, LV end-diastolic pressure, the peak positive first derivative of LV pressure, and the time constant of LV pressure decay. Conclusions— SR imaging is able to discriminate HCM from H-LVH, with ε sys reflecting myocardial contractile and lusitropic properties.

Background and Purpose— Stroke is a major adverse event after left ventricular assist device (LVAD) surgery. The purpose of this study was to describe differences in hemispheric distribution of stroke in LVAD patients. Methods— We reviewed 317 consecutive patients who underwent LVAD surgery between November 2000 and July 2011. Stroke during LVAD support was analyzed. Results— In total, 46 strokes occurred at 76.0±96.8 days postoperatively. Among the 46 strokes, 27 events (58.7%) occurred in right hemisphere, 13 events (28.2%) in the left hemisphere, 3 events (8.7%) occurred bilaterally, and 2 events (4.3%) were vertebrobasilar lesions. The right hemispheric stroke was significantly more common in patients with postoperative infection compared with left hemispheric events. Conclusions— Stroke after LVAD implantation has a right hemispheric predominance. This finding suggests LVAD-related thrombus in the setting of infection and/or the anatomic configuration of LVAD outflow cannula-ascending aorta anastomosis to be highly associated with stroke after LVAD surgery.

Peripheral vascular disease (PVD) portends increased morbidity and mortality in patients with heart failure. In those with advanced heart failure, heart transplantation (HT) is the only causative therapy to increase survival. However, little is known about the impact of symptomatic PVD on survival of HT recipients in large multicenter cohorts. The aim of this study was to investigate an association between recipient symptomatic PVD and survival after HT. We analyzed 20,297 patients from the United Network of Organ Sharing data set. Survival analysis using a control cohort established by propensity matching was performed. There was an increased prevalence of traditional cardiovascular risk factors in 711 patients with symptomatic PVD compared with 19,586 patients without PVD. Patients with pre-transplant symptomatic PVD had increased post-transplant mortality compared with those without PVD (1-, 5- and 10-year survival rate 91.5% vs 94.9%, 74.8% vs 82.6%, 48.6% vs 54.7%, respectively, log-rank p

Progressive renal dysfunction develops in patients with advanced HF. We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C compared with established markers of renal function in patients with heart failure (HF) because they might improve prognostic assessment of patients with HF.Serum samples were collected from 40 patients with stable HF (age: 58 ± 8 years, body mass index [BMI]: 28.4 ± 6.4 kg/m(2)), 40 HF patients undergoing ventricular assist device (VAD) implantation (age: 53 ± 11 years, BMI: 26.8 ± 5.5 kg/m(2)), 40 patients undergoing VAD removal at cardiac transplantation, and 24 controls (age: 48 ± 7 years, BMI: 29.4 ± 4.2 kg/m(2)). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease formula.Patients with stable HF showed elevated NGAL and cystatin C levels compared with controls (NGAL: 114.9 ± 48.3 ng/mL vs 72.0 ± 36.6 ng/mL, p0.0001; cystatin C: 1490.4 ± 576.1 ng/mL vs 954.7 ± 414.2 ng/mL, p = 0.0026). Unlike cystatin C, NGAL increased in advanced HF patients requiring VAD implantation (158.7 ± 74.8 ng/mL, p0.001). On VAD support, NGAL levels decreased (127.1 ± 80.4 ng/mL, p = 0.034). NGAL was higher in patients who developed right ventricular failure (187.8 ± 66.0 vs 130.9 ± 67.0 ng/mL, p = 0.03) and irreversible renal dysfunction (190.0 ± 73.8 ng/mL vs 133.8 ± 54.2 ng/mL, p0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = -0.2188, p = 0.01).NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.

Thrombus formation inside of the pump is a major cause for device malfunction following the left ventricular assist device (LVAD) implantation. We recently established a novel ramp test protocol facilitating continuous bedside echo monitoring to optimize LVAD function and diagnosing device malfunctions. We describe a case of 29-year-old woman undergoing HeartMate II LVAD implantation, in whom serial ramp studies were used to diagnose intra-device thrombus after device implantation. The 1st ramp study at postoperative day (POD) 26 revealed adequate reduction in ventricular size according to the increase in LVAD speed (left ventricular end-diastolic diameter [LVEDD] at minimum and maximum speeds, 68 and 37 mm, respectively). The patient was discharged home and received routine anticoagulation maintenance therapy. However, a 2nd ramp test was performed on POD 56 due to increased lactase dehydrogenase and brain natriuretic peptide levels and showed marked increase in left ventricle (LV) chamber size without adequate response to the LVAD speed changes (LVEDD at minimum and maximum speeds, 88 and 76 mm, respectively). Given the suspicion for partial pump thrombosis, the patient was immediately hospitalized and received intravenous heparin infusion. After the optimization of the intensive anticoagulation therapy, the patient underwent a 3rd ramp study, which showed a remarkable improvement of the adequate response to LVAD speed changes. The patients eventually underwent cardiac transplant successfully, and the partial clot was found inside of the pump. This case demonstrates the usefulness of serial ramp studies in patients who are suspected to have device thrombosis.

A noninvasive detection of allograft rejection is one of the major objectives in the management of heart transplant recipients. Endomyocardial biopsy still remains the gold standard for diagnosing rejection; however, it is invasive, expensive, and subject to sampling error and interobserver variability. Advances in echocardiographic techniques provide an important role for the reliable detection of rejection. This article reviews recently developed echocardiographic modalities and their clinical utility for rejection monitoring in transplant recipients.Conventional two-dimentional (2D)-echocardiographic and Doppler echocardiographic parameters can be useful to detect an increase in left ventricular (LV) mass and diastolic and/or systolic dysfunction associated with acute rejection; however, these parameters are not sufficiently reliable to guide the treatment strategy of asymptomatic, clinically stable patients. Tissue-Doppler Imaging (TDI), which is now widely used, has been reported to detect rejection more accurately than conventional parameters. More recently, 2D speckle-tracking echocardiography (2D-STE)-derived LV torsion and strain parameters, which are calculated by off-line using conventional 2D images, are expected to detect subclinical rejection.Considering the advantages of TDI and 2D-STE over conventional echocardiograms, including pre-load and after-load independency, angle-independency and simple-offline calculation, such newly developed echocardiographic modalities will emerge as useful follow-up tools for monitoring rejection in transplant recipients.

Background Noninvasive detection of rejection is a major objective in the management of heart transplant recipients. Methods and Results To investigate the utility of 2-dimensional speckle-tracking echocardiography (2D-STE), we retrospectively evaluated 160 sets of endomyocardial biopsies and echocardiograms from 59 asymptomatic heart transplant recipients. Conventional International Society for Heart and Lung Transplantation grade 1B or higher rejection was considered as treatment-requiring rejection (group R), whereas International Society for Heart and Lung Transplantation grade 0 or 1A was classified as group Non-R. Left ventricular global longitudinal strain (GLS), global circumferential strain, and global radial strain were assessed by 2D-STE. Twenty-five specimens were classified into group R. GLS was significantly associated with treatment-requiring rejection, whereas neither global radial strain nor global circumferential strain were. Lower GLS remained significantly associated with an increased risk of treatment-requiring rejection (odds ratio, 1.15 [95% CI, 1.01-1.30]; P=0.03) even in multivariate analysis. GLS with the absolute value of less than 14.8% showed sensitivity and specificity of 64% and 63%, respectively, for detection of treatment-requiring rejection. Conclusion The 2D-STE–derived left ventricular GLS was associated with treatment-requiring rejection. Two-dimensional STE might be useful as a noninvasive supplemental tool for monitoring heart transplant recipients for possible treatment-requiring rejection.

Background— Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation, and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pretransplant serum albumin concentration on post-transplant outcome in heart transplant recipients. Methods and Results— Preoperative laboratory variables, including albumin concentration and donor-related information, were obtained from 822 consecutive patients undergoing heart transplant at Columbia University Medical Center between 1999 and 2010. The association between pretransplant albumin concentration and post-transplant 1-year survival was analyzed. Available data from the United Network for Organ Sharing (n=13 671) were also analyzed to evaluate the impact of preoperative albumin levels on post-transplant outcome. In our cohort, multivariable analysis revealed that preoperative albumin (mg/dL; hazard ratio, 0.46; P P =0.0002) were associated with post-transplant 1-year mortality. This implied that for every 1 mg/dL increase in albumin concentration, the post-transplant 1-year mortality rate decreased by 54%. The Kaplan–Meier analysis based on our patients cohort and the United Network for Organ Sharing dataset showed lower survival rate at 1-year post-transplant in patients with albumin levels ≤3.5 mg/dL compared with those with >3.5 mg/dL (our patients, 91.3 versus 72.4%; P P Conclusions— Pretransplant serum albumin concentration is a strong prognostic marker for post-transplant survival in heart transplant recipients.

We thank Bandera et al for their insightful comments on our recent publication demonstrating synergistic effects of exercise parameters and cardiac biomarkers, such as brain natriuretic peptide, for risk prediction in ambulatory and euvolemic patients with advanced heart failure.1 We agree with the assumption that levels of brain natriuretic peptide in this cohort might reflect different degrees of myocardial load and associated wall stress …

We thank Haufe et al for their insightful comments on our study of adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure (HF) and the impact of mechanical unloading.1 We appreciate the observation that incorrect homeostasis model of insulin resistance (HOMA-IR) values were listed in Table 3. Upon recalculation using the HOMA-IR formula, the correct values were found to be 1.0±0.6 for controls, 7.6±7.7 in advanced HF ( P =0.02 versus controls) and 4.5±3.6 after left ventricular assist device (LVAD) support ( P =0.01 versus HF). This supports the conclusion …

Aims Abnormal bone metabolism and progressive demineralization have been described in patients with heart failure (HF). We hypothesized that mechanical unloading through implantation of a ventricular assist device (VAD) with subsequent haemodynamic improvement would correct abnormal bone metabolism in patients with advanced HF. Methods and results Serum was collected from 14 controls, 20 patients with moderate HF, 34 patients with advanced HF undergoing VAD implantation, and 34 patients at the time of VAD explantation (mean duration: 169 ± 125 days). Bone metabolism markers were measured using enzyme-linked immunosorption assay (ELISA) or chemiluminescence immunoassay (CLIA). Compared with controls, HF patients showed increased parathyroid hormone (PTH: 42 ± 19 vs. 117 ± 117 pg/mL in HF; P < 0.02) with decreased 25-hydroxyvitamin D [25(OH)D: 29 ± 14 vs. 21 ± 11 ng/mL in HF; P = 0.05]. While procollagen-1 N-terminal peptide (P1NP) and osteocalcin were similar, cross-linked C- and N-telopeptides of type I collagen (CTX and NTX) were both higher in HF (NTX: 14 ± 6 vs. 20 ± 11 ng/mL; P < 0.05; CTX: 0.35 ± 0.13 vs. 1.05 ± 0.78 ng/mL; P < 0.01 for controls and HF, respectively). P1NP increased markedly after VAD implantation (49 ± 37 vs. 121 ± 62 ng/mL; P < 0.0001), with a mild decrease in CTX and NTX levels indicating a shift towards anabolic bone formation. Serum PTH correlated with estimated glomerular filtration rate (r = –0.245, P < 0.05). Conclusion Patients with advanced HF are characterized by increased levels of biochemical markers of bone resorption potentially as a result of secondary hyperparathyroidism and uncoupling of bone remodelling. Haemodynamic improvement and mechanical unloading after VAD implantation lead to correction of bone metabolism and increased levels of anabolic bone formation markers.

BACKGROUND Chronic heart failure is associated with higher risk for developing diabetes mellitus. Secretory products from adipocytes may contribute to the deterioration in glycemic control and increased insulin resistance (IR). Retinol binding protein 4 (RBP4) is an adipose tissue-derived protein with pro-diabetogenic effects. The aim of the present study was to investigate the relationship of RBP4 in patients with heart failure. METHODS AND RESULTS Serum levels of RBP4, insulin, and fasting glucose were assessed in 58 patients with severe heart failure at the time of left ventricular assist device (LVAD) implantation and in 44 patients at the time of explantation, as well as in 10 normal control subjects. Serum RBP4 levels were measured by specific enzyme-linked immunosorbent assay, and IR was assessed using the homeostatic model of IR (HOMA-IR). Fasting glucose, insulin and HOMA-IR were significantly higher in patients at the time of LVAD implantation compared to controls (all P

This study sought to develop a novel approach to optimizing continuous-flow left ventricular assist device (CF-LVAD) function and diagnosing device malfunctions.In CF-LVAD patients, the dynamic interaction of device speed, left and right ventricular decompression, and valve function can be assessed during an echocardiography-monitored speed ramp test.We devised a unique ramp test protocol to be routinely used at the time of discharge for speed optimization and/or if device malfunction was suspected. The patient's left ventricular end-diastolic dimension, frequency of aortic valve opening, valvular insufficiency, blood pressure, and CF-LVAD parameters were recorded in increments of 400 rpm from 8,000 rpm to 12,000 rpm. The results of the speed designations were plotted, and linear function slopes for left ventricular end-diastolic dimension, pulsatility index, and power were calculated.Fifty-two ramp tests for 39 patients were prospectively collected and analyzed. Twenty-eight ramp tests were performed for speed optimization, and speed was changed in 17 (61%) with a mean absolute value adjustment of 424 ± 211 rpm. Seventeen patients had ramp tests performed for suspected device thrombosis, and 10 tests were suspicious for device thrombosis; these patients were then treated with intensified anticoagulation and/or device exchange/emergent transplantation. Device thrombosis was confirmed in 8 of 10 cases at the time of emergent device exchange or transplantation. All patients with device thrombosis, but none of the remaining patients had a left ventricular end-diastolic dimension slope-0.16.Ramp tests facilitate optimal speed changes and device malfunction detection and may be used to monitor the effects of therapeutic interventions and need for surgical intervention in CF-LVAD patients.

Background— Heart failure (HF) is characterized by inflammation, insulin resistance, and progressive catabolism. We hypothesized that patients with advanced HF also develop adipose tissue inflammation associated with impaired adipokine signaling and that hemodynamic correction through implantation of ventricular assist devices (VADs) would reverse adipocyte activation and correct adipokine signaling in advanced HF. Methods and Results— Circulating insulin, adiponectin, leptin, and resistin levels were measured in 36 patients with advanced HF before and after VAD implantation and 10 healthy control subjects. Serum adiponectin was higher in HF patients before VAD implantation compared with control subjects (13.3±4.9 versus 6.4±2.1 μg/mL, P =0.02). VAD implantation (mean, 129±99 days) reduced serum adiponectin (7.4±3.4 μg/mL, P P P 2 versus 5583±142 μm 2 in control subjects; P P Conclusions— Adipose tissue inflammation and adiponectin resistance develop in advanced HF. Mechanical unloading of the failing myocardium reverses adipose tissue macrophage infiltration, inflammation, and adiponectin resistance in patients with advanced HF.

Abdominal tumors involving both roots of the celiac and superior mesenteric artery are deemed unresectable by conventional surgical methods. We performed three cases of multivisceral ex vivo surgery involving temporary removal of the entire abdominal viscera followed by vascular reconstruction, ex vivo tumor resection and autotransplantation of excised organs. We achieved a complete tumor resection with negative margins in all cases. All patients have survived with no tumor recurrence to date at 17-, 27- and 38-month follow-up. Postoperative complications included diarrhea, sphincter of Oddi dysfunction and arterial stenosis; all responded to directed treatments. Multivisceral ex vivo surgery applying techniques of deceased donor multivisceral transplantation is feasible in achieving local control of otherwise unresectable abdominal tumors. This surgery is best suitable for locally invasive tumors unresectable because of location and vascular involvement.

Heart transplantation provides considerable survival benefits for patients with end-stage heart failure, but it is available for only a small fraction of these patients due to donor shortage. Especially in Japan, domestic legal issues had severely limited the number of heart transplantation until the Revised Organ Transplant Law was launched in 2010. The mean waiting period of Japanese heart transplant candidates after left ventricular assist device (LVAD) surgery had exceeded 2 years and occasionally reached 4 years until recently (Sasaoka T et al., 2010). The long-term LVAD support can result in serious complications such as cerebrovascular accident (CVA), the most common cause of death following LVAD surgery (Rose EA et al., 2001; Holman WL, 2009; Saito S, et al. 2010). CVA is the leading cause of death and the primary reason for elimination from transplant eligibility. In addition, transplant recipients with a history of CVA face tremendous difficulties in being reintegrated into society, often for years after transplant (Nakajima I et al., 2011). Therefore, we investigated factors associated with CVA after LVAD surgery in Japanese patients, as well as we reviewed our treatment strategies for CVA and the outcome of these patients after developing CVA.

Background Neurologic complications (NCs) are the major adverse events after left ventricular assist device (LVAD) surgery. Pre-operative and post-operative factors associated with NCs in patients with LVADs were investigated. Methods We reviewed 307 consecutive patients undergoing LVAD surgery (167 HeartMate I and 140 HeartMate II devices) at Columbia University Medical Center between November 2000 and December 2010. Clinical characteristics and hemodynamic and laboratory indexes were analyzed. NC was defined according to the Interagency Registry for Mechanically Assisted Circulatory Support definition of neurologic dysfunction, including transient ischemic attack (TIA) and ischemic or hemorrhagic cerebrovascular accident (CVA). Results NCs developed in 43 patients (14.0%) at 91.8 ± 116.3 days post-operatively. The frequency of NC development was similar in HeartMate I and II patients. Patients with NC showed a higher frequency of pre-LVAD CVA history (27.9% vs 15.5%, p = 0.046), lower pre-operative sodium (129.0 ± 7.0 vs 132.1 ± 8.1 mg/dl, p = 0.018) and albumin concentrations (3.5 ± 0.7 vs 3.7 ± 0.6 mg/dl, p = 0.049), lower post-operative hematocrit (34.9% ± 5.1% vs 37.8% ± 6.1%, p = 0.0034), sodium (131.6 ± 7.7 vs 134.4 ± 6.4 mg/dl, p = 0.010) and albumin concentrations (3.7 ± 0.5 vs 3.9 ± 0.5 mg/dl, p = 0.0016), and higher frequency of post-operative infection (39.5% vs 19.3%, p = 0.003) than those without NC. Multiple regression analysis revealed that CVA history (odds ratio, 2.37, 95% confidence interval, 1.24–5.29; p = 0.011) and post-operative infection (odds ratio, 2.99, 95% confidence interval, 1.16–10.49; p = 0.011) were highly associated with NC development. The combination of CVA history, pre-operative and post-operative sodium and albumin, and post-operative hematocrit and infection could discriminate patients developing NCs with a probability of 76.6%. Conclusions Previous stroke, persistent malnutrition and inflammation, severity of heart failure, and post-LVAD infections are key factors associated with development of NCs after LVAD implantation.

Approximately 5 million Americans suffer from heart failure (HF), the burden of which will grow exponentially over the next 50 years. HF currently results in 3.5 million hospitalizations and 20% of all hospital admissions among individuals >65 years of age. Surgical interventions for HF include cardiac repair (coronary artery bypass grafting, valve repair or replacement), cardiac support (mechanical circulatory support devices) and cardiac replacement (heart transplantation). These modern interventions of cardiac surgery and critical care medicine dramatically improved outcomes. They are offered to patients with increasingly high-risk clinical profiles and a higher likelihood of complications. The development of vital-organ support therapies (respirator, dialysis, transfusion, etc) in the intensive care units (ICUs) increased the survival of critically ill patients. However, despite these organ-saving therapies, up to 15% of these patients have an unfavourable perioperative course. Frequently, more than one organ system becomes dysfunctional, leading to progressive multiorgan dysfunction (MOD) (Lietz et al., 2007). The hallmark of MOD is the development of progressive physiologic dysfunction in two or more organ systems after an acute threat to systemic homeostasis. MOD is the leading cause of morbidity and mortality in the ICUs and after mechanical circulatory support device (MCSD) implantation (Deng et al., 2005).

1. Mone T. One Legacy organ procurement network staff letter (personal communication), January 19, 2011. 2. Organ Procurement and Transplantation Network. National data. U.S. Department of Health and Human Services. Available at: http://optn. transplant.hrsa.gov/latestData/step2.asp. (accessed January 22, 2011). 3. U.S. vehicle median age increased in 2008, R.L. Polk & Co. Available at: http://usa.polk.com/News/LatestNews/2009_0303_vehicle_median_ age.htm. (accessed January 22, 2011).

Cerebrovascular accident (CVA) is a major adverse event following left ventricular assist device (LVAD) surgery. This study investigates pre- and post-operative factors associated with CVA in this population.A total of 118 consecutive patients who underwent LVAD surgery at our institution between April 1994 and April 2009 were retrospectively reviewed. Clinical characteristics, hemodynamic data, and laboratory indexes associated with CVA after LVAD surgery were analyzed. In total, 57 (48.3%) patients developed CVA 133.5 ± 184.7 days after surgery. The combination of baseline heart disease, type of LVAD surgery, mean right atrial pressure (mRA), serum total bilirubin and total protein concentration, and right ventricular end-diastolic dimension (RVEDd) was associated with CVA at any time after LVAD surgery, with a discriminant probability of 718%. With regard to CVA development later than 3 months after surgery, the combination of mRA and RVEDd before surgery [odds ratio (OR), 1.24, 1.20; 95% confidential interval (CI), 1.07-1.42, 1.06-1.34; P = 0.004, P = 0.006, respectively], positive blood culture, and C-reactive protein after surgery (OR, 7.66, 2.19; 95%CI, 1.50-39.0, 1.47-3.25; P = 0.015, P0.0001, respectively) was associated with CVA with a discriminant probability of 85.9%.Patients' general condition including malnutrition, in addition to device selection, contributed to overall CVA development after surgery. In the chronic phase after surgery, pre-LVAD right heart failure and post-LVAD systemic infection were highly associated with CVA development.

Hypoalbuminemia has been recognized as a marker of poor outcomes in patients with chronic diseases including those with advanced heart failure. We recently reported that pre-operative hypoalbuminemia is associated with poor prognosis following LVAD surgery, although post-operative normalization of albumin level would improve their survival [1]. We also reported that pre-transplant serum albumin concentration is a strong prognostic marker for 1-year post-transplant survival in heart transplant (HTx) recipients [2]. However, an association between pre-transplant serum albumin and long-term outcome in HTx recipients has not yet been fully elucidated. In the present investigation, we aimed to create a post-transplant survival probability equation based on a preoperative albumin level using parametric survival model to estimate survival reflecting multiple factors such as nutrition, inflammation, hepatic function and overall catabolic state. We reviewed a total of 822 consecutive patients undergoing HTx at Columbia University Medical Center between 1999 and 2010. Pre-transplant clinical data including serum albumin concentration were obtained. For patients with multiple laboratory measurements prior to the transplants, the results obtained at the closest date to the surgery were used for the analysis. A parametric model of survival using an arbitrary value of albumin was analyzed and a formula to estimate survival provability based on pre-transplant albumin value was created. We also analyzed an available data from the United Network of Organ Sharing (UNOS). Patients with available albumin levels before HTx were selected for the current study (n=13,671). In the same manner, a parametric survival estimation formula was created based on the UNOS data. Survival probability of S(t) and the moment mortality of λ were determined by a parametric analysis as follows; S(t)=exp(−λt); λ=exp(β0+Σβjxj) β0, constant number; βj, partial regression coefficient of covariable xj. Univariate parametric analysis for post-transplant mortality based on our institutional data revealed that an serum albumin value before transplant (mg/dL) was associated with a hazard ratio (HR) of 0.559 with 95% confidence interval (CI) ranged from 0.453 to 0.689. Multivariate analysis including pre-and peri-operative parameters revealed the strongest association between pre-operative albumin level and post-transplant mortality (HR 0.540, 95%CI 0.421–0.693, p

We thank Dr. Valentova and colleagues for their insightful comments on our recent study [(1)][1] of liver function abnormalities characterized by various MELD (Model of End Stage Liver Disease) scoring systems in patients evaluated for heart transplantation (HTx). On the basis of our analysis

The number of heart transplant (HTx) surgeries in Japan is expected to increase under the Revised Organ Transplant Law. To date, among 69 HTx surgeries performed in Japan, 27 operations (39.1%) were performed at our institution, the National Cardiovascular Center (NCVC), located in Osaka. We have reviewed the outcomes of HTx conducted at NCVC during a 10 year period (May 1999 to January 2009). Among 27 heart transplant recipients at NCVC, the clinical charts of 26 recipients whose post-HTx period exceeded 1 year were retrospectively reviewed and compared to data from the International Society for Heart and Lung Transplantation (ISHLT) Registry. The survival rate of our recipients was 96.2% at 10.8 years, which was excellent even compared to the ISHLT Registry. The immunosuppressive regimen at NCVC was equivalent to that of the ISHLT Registry, except for more frequent use of Muromonab-CD3 (26.9% versus 3.3%, P0.0001) and an initial CSA-based regimen (65.3% versus 34.4%, P0.001). The drug we use for induction therapy has been recently changed from Muromonab-CD3 to Basiliximab. The incidences of post-HTx hypertension, diabetes, hyperlipidemia, and renal insufficiency were significantly less in patients at NCVC compared to those in the ISHLT Registry, however, the incidence of transplant coronary artery disease (TxCAD) was almost identical. Clinical review of post-HTx outcome at NCVC can provide useful information for Japanese transplant cardiologists who will engage in HTx management.

SummaryBackgroundEvaluating donor heart as accurately as possible upon the organ procurement would help lead careful post-transplant heart management. Our institution (National Cerebral and Cardiovascular Center, Osaka, Japan) has sent a transplant cardiologist upon the organ procurement for evaluating a donor heart ever since our first case of heart transplantation.MethodsThirteen consecutive bedside echocardiograms obtained from donors upon the organ procurement and post-transplant echocardiograms obtained from their recipients were retrospectively reviewed. The impact of donor echocardiograms on their recipients’ post-transplant time course was analyzed and both the donor echocardiographic parameters and their recipients’ parameters within 1 week after the heart transplant were compared.ResultsBoth the left ventricular end-diastolic diameter and the ventricular wall thickness of donors correlated well with those parameters of their corresponding recipients (r2=0.740, p

Reduced left ventricular torsion (LV-tor) has been reported to be associated with acute rejection in heart transplant (HTx) recipients. We investigated the utility of LV-tor analysis derived from 2-dimensional speckle-tracking echocardiography (2D-STE) for detecting allograft rejection.A total of 301 endomyocardial biopsies (EMBs), right heart catheterizations and echocardiograms were performed in 32 HTx recipients. Echocardiography was done within 3 hours from EMB or simultaneously with the procedures. The LV-tor was defined as the difference between apical and basal end-systolic rotations. The LV-tor values with and without cellular rejection were compared. In addition, we investigated whether the change in LV-tor values predicts the change in rejection grade in each patient. The baseline LV-tor value in each patient was defined as a mean value of the first 3 LV-tor measurements obtained when the patient was free from rejection.According to the conventional International Society for Heart and Lung Transplantation criteria, 274 biopsies showed a rejection Grade of 0, 1a or 1b (Group AR(-)), whereas 27 biopsies were Grade 2 or higher (Group AR(+)). LV-tor decreased more in Group AR(+) than in Group AR(-) (9.3 ± 0.7 vs 12.2 ± 0.2 degrees, p0.0001). In the LV-tor measurement for each patient, the 25% reduction in LV-tor value from baseline predicted Grade 2 or higher rejection with a predictive accuracy of 92.9%.LV-tor derived from 2D-STE could be of clinical value for non-invasive monitoring of acute rejection in HTx recipients.

Reversible posterior leukoencephalopathy syndrome (RPLS) is one of the important adverse events following organ transplantation, associated with calcineurin inhibitors (CNIs). We describe a case of 54-year-old woman, who was diagnosed with RPLS within weeks after transplantation. Considering the risk of causing fatal rejection by discontinuation of CNIs, the immunosuppressive regimen of the patient was switched from a cyclosporine A-based regimen to a tacrolimus-based regimen. The patient recovered rapidly from RPLS following the switch to tacrolimus. This case demonstrated that not only discontinuation but also a substitution of CNIs would be a valid treatment option for RPLS in transplant recipients.

Mammalian target of rapamycin (mTOR) inhibitors display antiproliferative effects with less nephrotoxicity than calcineurin inhibitors. However, clinical use of mTOR inhibitors can be associated with a series of adverse events. We experienced cases of aphthous stomatitis associated with everolimus (EVL) in four Japanese heart transplant recipients treated at the target trough EVL blood level after a switch from mycophenolate mofetil between April and December 2007. All four patients developed aphthous stomatitis; three required reduction of the exposure and one, EVL discontinuation due to stomatitis as well as other side effects. All patients recovered from stomatitis after reduction or withdrawal of EVL. Thus, we considered that EVL-related stomatitis might occur commonly among the Japanese population. The proper dosage, effects, and frequency of the side effects of mTOR inhibitors may vary by ethnic population.

Objective: Differences in B-type natriuretic peptide (BNP) values before and after left ventricular assist device (LVAD) surgery were evaluated as a predictor of survival after the surgery. Background: The impact of reduction of pre-operative BNP values, following LVAD surgery, on post-operative survival in heart failure (HF) patients is not known. Methods: Among a total of 287 patients who underwent LVAD surgery at Columbia University Medical Center between 2000 and 2010, 72 patients who had plasma BNP measurements at both 1 week before and 1 month after surgery were enrolled. Patients were divided into 2 groups according to % change of BNP value through surgery (% BNP change): greater (group A) or less than (group B) the median % BNP change. Result: Neither pre-operative nor post-operative BNP values were significantly correlated with post-surgical survival. The % BNP change was significantly correlated with post-surgical survival. Clinical characteristics, laboratory examination, and hemodynamics before and after surgery were not different between the two groups. Group A patients showed significantly better survival at 100 and 200 post-surgical days compared to group B (86.1 % vs. 74.6 %, 80.6 % vs. 54.5%, p=0.0399, respectively). Conclusion: The % BNP change could predict survival after LVAD surgery.

SummaryBackground and purposeThe majority of heart transplant (HTx) candidates require left ventricular assist device (LVAD) support for more than 2 years before transplantation in Japan. However, the only currently available device is the extracorporeal pulsatile LVAD. The long-term management of extracorporeal LVAD support has improved remarkably over the years. To determine which post-operative management factors are related to the long-term survival of patients on such LVAD, we retrospectively compared the incidence of complications and their management strategies between the initial and recent eras of LVAD use, classified by the year of LVAD surgery.MethodsSixty-nine consecutive patients supported by extracorporeal pulsatile LVAD as a bridge to HTx between 1994 and 2007 were reviewed retrospectively. The patients were assigned according to the time of LVAD surgery to either group A (n=30; between 1994 and 2000) or group B (n=39; between 2001 and 2007).ResultsPatients in group B survived significantly longer on LVAD support than those in group A (674.6 vs. 369.3 days; p

Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement.

This article reports changes in tacrolimus (FK506) blood levels connected with carbamazepine (CBZ). A drug interaction between FK506 and CBZ was investigated in a woman, who was in her 40s, who underwent heart transplantation. Pharmacokinetic parameters were measured, including dose and trough blood levels (C(0)), area under the serum concentration-time curve from 0 to 12 hours (AUC(0-12h)), and apparent clearance of oral FK506 (CL/F) for FK506 alone (about 3 months before starting CBZ) and combined with CBZ (11 days and about 3 months after starting CBZ). FK506 C(0) levels were decreased within 7 days of CBZ treatment. FK506 dosing required a 1.3- to 1.4-fold increase to maintain adequate blood levels while taking 200 mg CBZ daily. The AUC(0-12h)/dose 11 days after CBZ treatment was about 50% of the value before CBZ, and was about 70% at 3 months after CBZ treatment. The CL/F at 11 days and about 3 months after starting CBZ treatment was about 2 times higher than before CBZ therapy. FK506 C(0) levels are decreased by CBZ treatment, and blood levels should be closely monitored.

To evaluate regional and global left ventricular (LV) function and LV wall thickness (LVWT) in patients with hypertrophic cardiomyopathy (HCM).Observational study at the National Cardiovascular Centre and Nagoya University Hospital in Japan.Thirty-six patients with HCM and 16 patients with hypertensive LV hypertrophy (LVH).Conventional echocardiography and strain rate (SR) imaging derived from tissue Doppler imaging were performed. Systolic strain (epsilon(sys)), peak systolic SR (SR(sys)), peak early diastolic SR (SR(dia)) and LVWT were obtained from eight LV segments. LV pressure was simultaneously recorded with a high-fidelity micromanometer.The regional epsilon(sys) and SR(sys) were correlated with LVWT in patients with HCM (r = 0.50, p0.001 and r = 0.63, p0.001, respectively) but not in patients with hypertensive LVH. The standard deviations of LVWT, epsilon(sys) and SR(sys) obtained from the eight LV segments of each subject were greater for patients with HCM than for patients with hypertensive LVH. The standard deviation of LVWT was correlated with those of epsilon(sys) and SR(sys) (r = 0.55, p0.001 and r = 0.56, p0.001, respectively). The standard deviations of LVWT, epsilon(sys) and SR(sys) were correlated with tau (r = 0.35, p0.05; r = 0.47, p0.001; and r = 0.39, p0.005, respectively).Heterogeneity of regional LV systolic function detected by SR imaging is in part attributable to heterogeneity of LVH and may be linked to impaired global LV relaxation in HCM.

Recent reports have demonstrated that use of a left ventricular assist system (LVAS) can initiate recovery of cardiac function, and subsequent weaning from the LVAS has attracted considerable interest. In this study we investigated reliable predictors of LVAS weaning.Eighty-two patients underwent LVAS implantation between April 1994 and July 2006 at our institution. Cardiac function was restored in 8 patients, who were weaned from LVAS after a mean of 5 months (Group R). Thirty-three patients remained on LVAS support for1 year (Group N) because natural heart function did not show adequate improvement. We retrospectively evaluated the differences between these two groups. Group R was younger, and had a shorter duration of heart failure than Group N (23.4 vs 36.7 years and 13.3 vs 56.1 months, p0.01, respectively). Pathologic findings showed that the interstitial fibrosis score was lower in Group R (p0.01). Three months after LVAS insertion, B-type natriuretic peptide (BNP) and fractional shortening (FS) were more favorable (66.6 +/- 46 vs 264.5 +/- 170 pg/ml, p0.01, and 23 +/- 17.1 vs 12 +/- 9.1%, p0.05, respectively) in Group R. Furthermore, Group R received a higher dose of beta-blocker (15.4 +/- 8.4 vs 5.8 +/- 3.9 mg, p0.05).Younger age, shorter history of heart failure, and less interstitial fibrosis were effective predictors of weaning from LVAS. Restoration of natural heart function was more rapid and more persistent in candidates for LVAS explantation, and presence of beta-blocker played a prominent role in improving cardiac function after LVAS implantation.

Purpose Galectin-3 (gal-3) is a novel biomarker implicated in cardiac fibrosis and is shown to correlate with the severity of heart failure (HF) and to independently predict mortality in HF. We investigated if hemodynamic improvement after left ventricular assist device (LVAD) implantation affects gal-3 levels. Methods and Materials Plasma samples were acquired from patients at time of LVAD implantation (HMII or Heartware, n=57), at 3 (n=17) and 6 months post-LVAD (n=14), and at explantation (n=23), as well as from healthy age and gender matched controls (n=30). Gal-3 was measured using a commercially available ELISA assay (BG Medicine, Waltham, MA). Data was analyzed with Prism 5. Events rates were calculated using the Kaplan-Meier method. Results At time of LVAD implantation, HF patients had significantly higher gal-3 levels compared to controls (29.2±14 ng/ml vs. 13±9 ng/ml; p figure 1 ] Conclusions Gal-3 levels are associated with HF state and predict survival on LVAD support. Distinct dynamics in gal-3 levels occur in patients following LVAD implantation with an initial decrease but subsequent increase. Gal-3 may serve as a new biomarker for risk assessment of patients before LVAD implantation.

Background Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF. Methods Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology. Results Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p

Heart failure (HF) patients have a high incidence of new-onset atrial fibrillation (AF). Because of the adverse prognostic influence of AF in HF, the identification of patients at high risk of developing AF, while they are still sinus rhythm, may be of great clinical value. The incidence of and