Periodontitis and bone metabolism in patients with advanced heart failure and after heart transplantation.

AIMS: Heart failure (HF) is a multi-organ, pro-inflammatory syndrome that impairs bone metabolism. Pro-inflammatory cytokines and bone catabolism enhance periodontal disease, a local inflammatory, bacteria-induced disease that causes bone loss and periodontal soft tissue destruction. METHODS AND RESULTS: Medical and dental examinations were performed on patients with HF (n = 39), following heart transplantation (post-HTx, n = 38) and controls (n = 32). Blood, saliva, and gingival crevicular fluid were analysed for bone metabolism and inflammation markers. HF average New York Heart Association classification was III. Average time since HTx was 1414 days. Pro-inflammatory tumour necrosis factor-alpha was higher in HF and HTx as compared with controls (P < 0.05). Both HF and HTx participants had higher levels of bone resorption marker C-terminal telopeptide and parathyroid hormone with subjects in the HF group having the highest serum levels of all groups (P ≤ 0.05). In contrast, 25-hydroxyvitamin D was lowest in HF. HF patients had greater clinical attachment loss, cumulative pockets depth (greater than 3 mm) and probing depth (P < 0.05) as compared with controls. Cumulative pockets depth correlated significantly with measures of the inflammatory burden, ß-glucuronidase in saliva (r = 0.4863, P < 0.01), interleukin-1b in saliva (r = 0.5149, P < 0.01), and gingival crevicular fluid (r = 0.6056, P < 0.001) in HF. However, adjustment of periodontal results for measures of oral hygiene (plaque, bleeding on probing), systemic 25-hydroxyvitamin D, and race attenuated significant differences between groups. CONCLUSIONS: Patients with HF exhibit more severe periodontal disease associated with increased bone turnover markers when compared with control patients. However, local and systemic factors may account for this association and should be evaluated in future studies.

Factors associated with postoperative requirement of renal replacement therapy following off-pump coronary bypass surgery.

Cardiopulmonary bypass usage provokes a systemic inflammatory response resulting in deterioration of renal function. However, risk factors for requiring renal replacement therapy (RRT) following off-pump coronary artery bypass graft surgery (CABG) have not yet been fully elucidated. We reviewed 718 consecutive patients undergoing elective off-pump CABG at our institution, excluding patients on chronic hemodialysis preoperatively. Sub-analysis of patients with preserved renal function, defined as a creatinine level below a cut-off value of 1.12 mg/dL (obtained by receiver operating characteristic curve), was also performed. Of the 718 patients, 41 (5.7 %) required RRT. There were 556 patients (77.4 %) with preserved renal function preoperatively, and 13 (2.4 %) of these required postoperative RRT. Multivariate analysis revealed that age (years) and preoperative serum creatinine (mg/dL) and brain natriuretic peptide (BNP) levels (pg/dL) were associated with RRT [odds ratios (OR) 1.052, 95 % confidence interval (CI) 9.064 and 1.001, respectively, all p < 0.05] in the total population, whereas low albumin concentration was the only independent predictor for RRT in patients with preserved renal function (OR 0.062, p < 0.0001). When creatinine levels were below 1.5 mg/dL, the predictive power of hypoalbuminemia for RRT requirement overwhelmed that of creatinine or BNP levels. Older age, preoperative elevated creatinine and BNP levels were associated with a requirement for RRT following off-pump CABG. In patients with preserved renal function, hypoalbuminemia was most significantly related to the RRT requirement.

The impact of surgical left atrial appendage amputation/ligation on stroke prevention in patients undergoing off-pump coronary artery bypass grafting.

Stroke is a major adverse event in patients developing atrial fibrillation (AF) after cardiac surgery. Surgical left atrial appendage amputation/ligation (LAA-A/L) during off-pump coronary artery bypass grafting (OPCAB) is routinely performed in our institution. We analyzed 578 consecutive patients (mean age 69 years, male 82%) undergoing OPCAB with or without concomitant LAA-A/L from 2011 to 2014 at our institution in a prospective observational manner. The safety and efficacy of the concomitant LAA-A/L on preventing early (<30 days) and overall postoperative stroke were examined. A total of 193 patients (33.4%) underwent LAA-A/L, consisting of amputation in 154 and ligation in 39 patients (80 and 20% of the cases, respectively). Preoperative characteristics, operative time, requirement of blood transfusion, and 30-day mortality were not significantly different between those with and without LAA-A/L. The incidences of postoperative AF and early and overall stroke were not significantly different between the groups in the analysis based on a total cohort. In a subanalysis of patients without LAA-A/L, early and overall stroke occurred more frequently in those developing postoperative AF than those without AF (2.8 vs. 0%; p = 0.005, 6.2 vs. 1.5%; p = 0.017, respectively), while in patients receiving LAA-A/L, stroke incidences did not differ between those with and without AF. Multivariate logistic regression showed postoperative AF without LAA-A/L as the only independent positive predictor of overall stroke (OR 3.69, p = 0.03). Concomitant LAA-A/L with OPCAB can safely prevent postoperative stroke occurrence in case patients develop AF, the most common arrhythmia associated with stroke.

The effect of tolvaptan on renal excretion of electrolytes and urea nitrogen in patients undergoing coronary artery bypass surgery.

BACKGROUND: Adequate fluid management is an important component of patient care following cardiac surgery. Our aim in this study was to determine the benefits of tolvaptan, an oral selective vasopressin-2 receptor antagonist that causes electrolyte-free water diuresis, in postoperative fluid management. We prospectively examined the effect of tolvaptan on renal excretion of electrolytes and urea nitrogen in cardiac surgery patients. METHODS: Patients undergoing coronary artery bypass surgery were randomized to receive conventional loop diuretics (Group C, n = 30) or conventional loop diuretic therapy plus tolvaptan (Group T, n = 27). Fractional excretions of sodium (FENA), potassium (FEK) and urea nitrogen (FEUN) were measured in both groups during post-surgical hospitalization. RESULTS: Urine output was greater with tolvaptan (Group T) than without it (Group C), and some patients in Group C required intravenous as well as oral loop diuretics. Serum sodium concentrations decreased after surgery in Group C, but were unchanged in Group T (postoperative day [POD] 3, 139.8 ± 3.5 vs. 142.3 ± 2.6 mEq/L, p = 0.006). However, postoperative FENA values in Group C did not decrease, and the values were similar in both groups. Serum potassium levels remained lower and FEK values remained higher than the preoperative values, but only in Group C (all p < 0.05). BUN increased postoperatively in both groups, but it remained higher than its preoperative value only in Group C (all p < 0.01). Group T showed an initial increase in BUN, which peaked and then returned to its preoperative value within a week. The FEUN increased postoperatively in both groups, but the change was more pronounced in Group T (POD7, 52.7 ± 9.3 vs. 58.2 ± 6.5 %, p = 0.025). CONCLUSIONS: Renal excretion of sodium and potassium reflects the changes in serum concentration in patients treated with tolvaptan. Patients treated only with loop diuretics showed a continuous excretion of sodium and potassium that led to electrolyte imbalance, whereas the combination of loop diuretics and tolvaptan increased renal urea nitrogen elimination. Tolvaptan therefore appears to be an effective diuretic that minimally affects serum electrolytes while adequately promoting the elimination of urea nitrogen from the kidneys in patients undergoing coronary artery bypass surgery. TRIAL REGISTRATION: The present study is registered with the UMIN Clinical Trials Registry (ID: UMIN000011039 ).

Factors influencing left atrial volume in a population with preserved ejection fraction: Left ventricular diastolic dysfunction or clinical factors?

BACKGROUND: Increased left atrial volume (LAV) predicts a higher incidence of cardiovascular events and is widely recognized as a major surrogate marker of left ventricular (LV) diastolic dysfunction (DD). Although the pathophysiology of LA enlargement is probably multifactorial, few studies have examined comprehensively the clinical factors that lead to LA enlargement in the absence of valvular disease or LV systolic dysfunction. Therefore, we investigated associations between LAV and several clinical and echocardiographic parameters including DD. METHODS: We enrolled 557 subjects without significant valve disease or LV systolic dysfunction from the health check-up clinic retrospectively. We performed univariable and multivariable linear regression using lnLAV index as the dependent variable and the following independent variables: gender, age, smoking status, drinking habit, hypertension, diabetes, body mass index (BMI), LV ejection fraction, DD, LV mass index, hemoglobin, serum creatinine, serum total cholesterol, serum uric acid, serum sodium, and serum iron. RESULTS: In multivariable analysis, LAV index was independently associated with BMI, lower hemoglobin, and moderate and severe DD compared with normal diastolic function (p<0.001), but not with mild DD (p=0.70). CONCLUSIONS: LA enlargement was independently associated with moderate and severe DD, but not with mild DD. Furthermore, obesity and lower hemoglobin were associated with LAV independently of DD.

Preoperative hepatic dysfunction could predict postoperative mortality and morbidity in patients undergoing cardiac surgery: Utilization of the MELD scoring system.

BACKGROUND: According to recent advances in operative techniques, an increasing number of patients with liver dysfunction have been subjected to cardiac surgery. Model of End-Stage Liver Disease (MELD and MELD-XI) scores allow risk stratification of patients undergoing cardiac and non-cardiac surgeries. METHODS: We retrospectively analyzed 1856 consecutive patients (69.3% male, mean 66.8 ± 12.2 years) undergoing cardiac surgery between 2008 and 2013 at our institution. RESULTS: The mean values of MELD/MELD-XI scores obtained from the total cohort were 9.7 ± 4.6/11.9 ± 4.8. Patients with high MELD/MELD-XI scores (>12) were older, more anemic, and had lower left ventricular ejection fraction than those with low scores (all p<0.0001). High scores were associated with longer hospitalization (36.8 ± 33.0 vs. 23.6 ± 21.5 days for MELD, 36.7 ± 34.0 vs. 23.5 ± 21.0 days for MELD-XI, both p<0.0001) and higher in-hospital all-cause mortality (6.6% vs. 1.0% for MELD, 7.7% vs. 0.7% for MELD-XI). Atrial fibrillation occurred more frequently in the high MELD group, but this difference was not found for MELD-XI. MELD/MELD-XI could predict mortality with a sensitivity of 64.3%/60.0% and specificity of 79.1%/85.3%. Comparison of AUC values among MELD scores, individual MELD components, and Child-Turcotte-Pugh (CTP) classification showed that the predictive strength of MELD scores for mortality was stronger than individual parameters or CTP classification (AUC: 0.7702 for MELD, 0.7655 for MELD-XI, 0.5799 for CTP classification with pairwise p<0.0001 and p=0.0002 vs. MELD and MELD-XI, respectively). CONCLUSIONS: Assessment of liver dysfunction using the MELD scores can be useful for predicting postoperative morbidity and mortality, which may allow additional risk stratification in patients undergoing cardiac surgery.

Early Postoperative Outcome of Off-Pump Coronary Artery Bypass Grafting: A Report from the Highest-Volume Center in Japan.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCAB) has evolved into a standard technique in coronary artery bypass grafting. However, a detailed investigation in Japanese population undergoing OPCAB has not yet been fully elucidated. METHODS: A total of 1109 consecutive patients undergoing isolated OPCAB between 2006 and 2013 at Juntendo University were reviewed. The data was evaluated in the light of previously published OPCAB-associated reports. RESULTS: There were 904 male (81.5%) and a mean was 67.5 ± 9.8 years. Eight patients (0.5%) died within 30 days postoperatively or before discharge, which was equivalent to or rather better than the previously reported mortality rates, including the European System for Cardiac Operation Risk Evaluation II (2.1 ± 2.1) data. A morbidity analysis revealed that prolonged intubation (>24 h) occurred in 43 patients (3.6%), surgical site infections in 18 (1.9%), neurological complications in 13 (1.3%). A reduced preoperative left ventricular ejection fraction (less than 40%) was found to be a risk factor for early postoperative death (odds ratio 10.58, respectively, p <0.05) in our cohort. CONCLUSIONS: Early postoperative mortality and morbidity rates in Japanese population after OPCAB were rather satisfactory and similar to those reported by other countries.

Comparison of modern risk scores in predicting operative mortality for patients undergoing aortic valve replacement for aortic stenosis.

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.

Early introduction of tolvaptan after cardiac surgery: a renal sparing strategy in the light of the renal resistive index measured by ultrasound.

BACKGROUND: Renal failure is a serious complication after cardiac surgery, which can be caused by long-term intravenous (IV) loop diuretic use. Tolvaptan is an oral selective vasopressin-2 receptor antagonist used in patients irresponsive to loop diuretics. We investigated their renal perfusion changes using the resistive index (RI) postoperatively. METHODS: Serial renal RI, echocardiography, and laboratory examinations from 14 patients requiring continuous postoperative IV loop diuretics were reviewed. Eight patients received tolvaptan (Group T) and six received oral loop diuretics before the discontinuation of IV loop diuretics (Group L). The 1(st) data were obtained between postoperative day 0 and 2, the 2(nd) when patients were still under IV loop diuretic treatment, the 3(rd) after the initiation of tolvaptan or oral loop diuretic, and the 4(th) after the discontinuation of IV diuretics. RESULTS: The 2(nd) RI value was higher in Group T than Group L (0.77 ± 0.09 vs. 0.69 ± 0.01, p = 0.049) but significantly decreased after tolvaptan administration [0.77 ± 0.09 to 0.65 ± 0.05 (2(nd) to 3(rd)), to 0.62 ± 0.04 (to 4(th)), both p = 0.006], while no such changes were seen in Group L. The serum sodium and albumin levels, and echo-derived tricuspid annular plane systolic excursion increased only in Group T (134.1 ± 1.5 to 138.8 ± 3.2 mEq/L, 3.3 ± 0.3 to 3.7 ± 0.5 g/dL, 16.4 ± 3.6 to 19.7 ± 4.2 mm, all p <0.05). The duration of IV loop diuretics tended to be shorter in Group T than Group L (5.6 ± 1.6 vs. 8.7 ± 3.6 days, p = 0.051). CONCLUSIONS: Administration of tolvaptan in patients undergoing cardiac surgery may improve their renal perfusion, as reflected by the renal RI measured using renal Doppler ultrasound.

Left Atrial Appendage Closure Reduces the Incidence of Postoperative Cerebrovascular Accident in Patients Undergoing Cardiac Surgery.

BACKGROUND: Cerebrovascular accidents (CVA) are a major adverse event following cardiac surgery, for which atrial fibrillation (AF) is considered as a risk factor. We have recently performed left atrial appendage (LAA) surgical closure or amputation (LAAC/A), which is the main source of emboli, during open-heart surgery. METHODS AND RESULTS: A prospective observational study of 1,831 consecutive patients (69.2% male, aged 66.8±12.2 years) undergoing cardiac surgery between 2009 and 2013 was performed. The incidence of postoperative CVA within 6 months in patients with and without LAAC/A was compared. We further stratified patients according to their risk of CVA using CHA2DS2-VASc score; dichotomizing low-risk (score <2) and high-risk groups (≥2). A total of 369 patients (20.2%) underwent LAAC/A. Although these patients had larger left atrial diameter preoperatively and developed postoperative AF more frequently than those without LAAC/A (45.4 vs. 41.1 mm, 49.3 vs. 39.1%, respectively, both P<0.001), the CVA incidence was not different between the groups (3.5 vs. 3.0%, P=0.612). Multivariate analysis revealed no association between LAAC/A and CVA in patients with CHA2DS2-VASc score ≥2, whereas in patients with CHA2DS2-VASc score <2, LAAC/A was the only and independent factor negatively associated with CVA development (odds ratio <10(-6); P=0.021). CONCLUSIONS: Additional LAA procedure at the time of cardiac surgery reduces the incidence of early postoperative CVA in patients with low CHA2DS2-VASc score.

Supplementation of l-Alanyl-l-Glutamine and Fish Oil Improves Body Composition and Quality of Life in Patients With Chronic Heart Failure.

BACKGROUND: Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of ω-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. METHODS AND RESULTS: In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either l-alanyl-l-glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak VO2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1α, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. CONCLUSIONS: The combined supplementation of l-alanyl-l-glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01534663.

Preoperative factors associated with postoperative requirements of renal replacement therapy following cardiac surgery.

Renal dysfunction is a major adverse event after cardiovascular surgery. Therefore, the preoperative prediction of which patients will require renal replacement therapy (RRT) after cardiac surgery is an important issue. In the present study, 1,822 consecutive patients who underwent cardiovascular surgery from 2008 and 2013 at a single institution were reviewed. Patients who were already receiving long-term hemodialysis before surgery (n = 134) were excluded. The remaining 1,688 patients were separated into 2 groups: those requiring postoperative RRT and those without RRT requirement. A total of 128 patients (7.6%) required RRT. Patients requiring RRT had greater perioperative blood loss, longer intubation time, and longer hospital stays (p <0.0001 for all). Multivariate analysis revealed that cardiopulmonary bypass use, preoperative body surface area, the left ventricular ejection fraction, serum albumin, and creatinine were independent risk factors for postoperative RRT (odds ratios 2.435, 0.204, 0.976, 0.556, and 5.394, 95% confidence intervals 1.471 to 4.140, 0.054 to 0.841, 0.962 to 1.025, 0.363 to 0.860, and 3.671 to 8.223, respectively, p <0.05 for all). A subgroup of patients with relatively preserved renal function before surgery (creatinine <1.12 mg/dl, a cut-off value for RRT requirement obtained from receiver-operating characteristic curve analysis [area under the curve 0.74748, sensitivity 60.2%, specificity 85.0%]) showed that preoperative serum albumin concentration was most significantly associated with postoperative RRT requirement (odds ratio 0.048, 95% confidence interval 0.023 to 0.095, p <0.0001). In conclusion, cardiopulmonary bypass use, preoperative renal impairment as reflected by elevated creatinine level, small body size, a low left ventricular ejection fraction, and hypoalbuminemia were associated with a requirement for postoperative RRT. In patients with preserved renal function, hypoalbuminemia was most significantly related to requirement for RRT.

Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction.

BACKGROUND: Functional and structural liver abnormalities may be found in patients with advanced heart failure (HF). The Model of End-Stage Liver Disease Excluding INR (MELD-XI) score allows functional risk stratification of HF patients on and off anti-coagulation awaiting heart transplantation (HTx), but these scores may improve or worsen depending on bridging therapies and during time on the waiting list. Liver biopsy is sometimes performed to assess for severity of fibrosis. Uncertainty remains whether biopsy in addition to MELD-XI improves prediction of adverse outcomes in patients evaluated for HTx. METHODS: Sixty-eight patients suspected of advanced liver disease underwent liver biopsy as part of their HTx evaluation. A liver risk score (fibrosis-on-biopsy + 1) × MELD-XI was generated for each patient. RESULTS: Fifty-two patients were listed, of whom 14 had mechanical circulatory support (MCS). Thirty-six patients underwent transplantation and 27 patients survived ≥1 year post-HTx (74%, as compared with 88% average 1-year survival in HTx patients without suspected liver disease; p < 0.01). Survivors had a lower liver risk score at evaluation for HTx (31.0 ± 20.4 vs 65.2 ± 28.6, p < 0.01). A cut-point of 45 for liver risk score was identified by receiver-operating-characteristic (ROC) analysis. In the analysis using Cox proportional hazards models, a liver risk score ≥45 at evaluation for HTx was associated with greater risk of death at 1 year post-HTx compared with a score of <45 in both univariable (HR 3.94, 95% CI 1.77-8.79, p < 0.001) and multivariable (HR 4.35, 95% CI 1.77-8.79, p < 0.001) analyses. Patients who died <1 year post-HTx had an increased frequency of acute graft dysfunction (44.4% vs 3.7%, p = 0.009), longer ventilation times (55.6% vs 11.1%, p = 0.013) and severe bleeding events (44.4% vs 11.1%, p = 0.049). The liver risk score at evaluation for HTx also predicted 1-year mortality after HTx listing (p < 0.001). CONCLUSIONS: Patients with HF and advanced liver dysfunction are high-risk HTx candidates. Liver biopsy in addition to MELD-XI improves risk stratification of patients with advanced HF and suspected irreversible liver dysfunction.

Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.

BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.

Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failure.

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 < 0.05; and IGFBP-3, 3,880 ± 934 versus 1,935 ± 862 ng/ml in HF, p = 0.05). The GH/IGF-1 ratio, a marker of GH resistance, was elevated in HF (0.002 ± 0.002 versus 0.048 ± 0.1 pre-VAD; p < 0.0039). After VAD support, skeletal muscle expression of IGF-1 and IGFBP-3 increased (10-fold and 5-fold, respectively; p < 0.05) accompanied by enhanced oxidative gene expression (CD36, CPT1, and PGC1α) and increased oxidation rates (+1.37-fold; p < 0.05). Further, VAD implantation increased the oxidative muscle fiber proportion (38 versus 54 %, p = 0.031), fiber cross-sectional area (CSA) (1,005 ± 668 versus 1,240 ± 670 µm(2), p < 0.001), and Akt phosphorylation state in skeletal muscle. Finally, hand grip strength increased 26.5 ± 27.5 % at 180 days on-VAD (p < 0.05 versus baseline). CONCLUSION: Our data demonstrate that VAD implantation corrects GH/IGF-1 signaling, improves muscle structure and function, and enhances oxidative muscle metabolism in patients with advanced HF.

Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, p < 0.0001; 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, p < 0.001). 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, p < 0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = -0.2188, p = 0.01). CONCLUSIONS: 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.