Perioperative Hypoalbuminemia Affects Improvement in Exercise Tolerance After Left Ventricular Assist Device Implantation

Abstract

Background: Although survival rates have improved for patients receiving implantable continuous flow left ventricular assist devices (I-CF LVAD), postoperative exercise tolerance levels are not necessarily satisfactory.

Methods and Results: We enrolled 51 patients who had received an I-CF LVAD and underwent follow-up between 2006 and 2014; all patients underwent cardiopulmonary exercise testing 3 months following surgery: 26 (51%) patients achieved peak oxygen consumption (PV̇O₂) ≥14 ml·kg⁻¹·min⁻¹ and had significantly lower readmission rates for cardiovascular events than those with PV̇O₂ <14 ml·kg⁻¹·min⁻¹ during 2 years of LVAD treatment (17 vs. 43%, P=0.033). Uni- and multivariate logistic regression analyses showed that the preoperative serum albumin (S-ALB) level was an independent predictor for PV̇O₂ ≥14 ml·kg⁻¹·min⁻¹ at 3 months (P=0.023, odds ratio 6.132). Patients with persistently normal S-ALB levels during the perioperative period had the lowest preoperative serum C-reactive protein level (S-CRP, 0.7±0.9 mg/dl), and the majority (77%) showed improved exercise tolerance. Conversely, patients with persistently low S-ALB levels during this period had the highest preoperative S-CRP level (2.8±1.2 mg/dl) and did not achieve the test endpoint.

Conclusions: Both pre- and postoperative low S-ALB impedes recovery of exercise tolerance after I-CF LVAD surgery, and this may be attributable to inflammatory responses caused by heart failure.

Survival rates for patients receiving a left ventricular assist device (LVAD) have improved owing to the development of implantable continuous flow (I-CF) LVADs and the introduction of sophisticated perioperative management protocols.^1–4 However, exercise tolerance does not always improve following LVAD therapy^5,6 and impaired exercise capacity is problematic, especially when long-term LVAD treatment is considered. Therefore, the next challenge is to improve post-LVAD exercise capacity to better the quality of life for patients.

Hypoalbuminemia is often associated with advanced heart failure (HF),⁷ and the preoperative serum albumin (S-ALB) level is a well-known predictor of survival in patients receiving LVAD therapy.^8,9 Low S-ALB level is associated with skeletal muscle abnormalities and results in exercise intolerance.¹⁰ Therefore, in the present study, we analyzed the prognostic effect of S-ALB level in relation to post-LVAD exercise tolerance.

Methods

Patient Selection

Between 2008 and 2015, 51 patients received an I-CF LVAD (21 EVAHEART; 12 DuraHeart; 12 HeartMate II; 6 Jarvik 2000) and underwent follow-up. All participants were assigned to INTERMACS profile 2–4 regardless of guideline-directed medical treatment,¹ and did not present any contraindications for heart transplant at the time of LVAD implantation. None of the patients had received extracorporeal membrane oxygenation, and those receiving prophylactic intra-aortic balloon pump support were assigned to profile 2.⁸ Patients with hemodynamic decline alongside worsening of end-organ function were also assigned to profile 2. None of the patients suffered from significant infection before LVAD implantation. Written informed consent was given by all patients before surgery. The study protocol was approved by the Ethics Committee of the Graduate School of Medicine, University of Tokyo (Japan). Following surgery, the rotation speed was adjusted after consideration of hemodynamics and the results of routine echocardiography.¹¹

Evaluated Outcomes

Preoperative characteristics, including demographics and laboratory variables, were obtained 24 h before surgery. Hemodynamic and echocardiographic variables were obtained 1 week prior to surgery.

Approximately 1 month after LVAD implantation, the S-ALB and serum C-reactive protein (S-CRP) levels were measured again. None of the patients showed significant bacterial infection, as assessed by procalcitonin levels, at the time of measurement of S-ALB or S-CRP. All patients underwent a hemodynamic study 3 months after surgery, and symptom-limited cardiopulmonary exercise testing 3 months after surgery. The test endpoint was peak oxygen consumption (PV̇O₂) ≥14 ml·kg⁻¹·min⁻¹.

Statistical Analysis

Statistical analyses were carried out using SPSS Statistics 22 (SPSS Inc, Chicago, IL, USA). The statistical tests used were 2-tailed, and P<0.05 was considered statistically significant. All data are expressed as mean±SD. Continuous variables were compared using unpaired t-tests or Mann-Whitney U tests, and categorical variables were compared using Chi-square tests or Fischer’s exact tests. A Kaplan-Meier analysis was performed to assess the readmission rate for cardiovascular events (including worsening of HF and cerebral thromboembolism). Receiver-operating characteristics analyses were performed to find the cutoff values of S-ALB and the area under curve (AUC) for the exercise test endpoint. Uni- and multivariate logistic regression analyses were performed to determine predictors of the exercise test endpoint among the preoperative variables. Multicollinearity was assessed using variance inflation factors (VIF). Pearson’s correlation coefficient was determined between S-ALB and other preoperative variables. The S-CRP levels among 4 groups stratified by pre- and postoperative S-ALB levels were compared with Tukey’s test when analyses of variances showed statistical significance. S-CRP levels before and after LVAD implantation were compared using paired t-tests.

Results

Prognosis During 2-Year LVAD Treatment

Patients with PV̇O₂ ≥14 ml·kg⁻¹·min⁻¹ had significantly lower readmission rates related to cardiovascular events (Figure 1) than those with PV̇O₂ <14 ml·kg⁻¹·min⁻¹ during the 2-year LVAD treatment.

Figure 1.

Readmission-free rates during 2-year left ventricular assist device treatment stratified by peak oxygen consumption (PV̇O₂) values. *P<0.05 with the log-rank test.

Preoperative Baseline Characteristics

Among the patients with an I-CF LVAD (41±13 years; 42 men), 26 (51%) reached PV̇O₂ ≥14 ml·kg⁻¹·min⁻¹ in the exercise test performed 3 months following surgery. Patients with improved exercise capacity were younger, had fewer comorbidities as characterized by their INTERMACS profile, and had higher S-ALB levels preoperatively (Table 1, P<0.05 for all comparisons).

Table 1. Preoperative Baseline Variables in Patients Stratified by Postoperative Exercise Tolerance

Preoperative variables	Total (n=51)	PV̇O2 ≥14 ml·kg−1·min−1 (n=26)	PV̇O2 <14 ml·kg−1·min−1 (n=25)	P value
Demographics
Age, years	41±13	37±14	43±10	0.030*
Male, n (%)	42 (82)	21 (81)	21 (84)	0.762
BMI	20.6±2.9	19.8±2.8	21.3±2.8	0.087
Etiology of ischemia, n (%)	2 (4)	1 (4)	1 (4)	0.977
HF duration, ×102 days	24.3±18.0	21.0±19.1	27.9±16.4	0.218
INTERMACS profile				0.009†
Profile 2, n (%)	22 (43)	7 (27)	15 (60)	–
Profile 3, n (%)	27 (53)	19 (73)	8 (32)	–
Profile 4, n (%)	2 (4)	0 (0)	2 (8)	–
Device type				0.346
Centrifugal, n (%)	33 (65)	18 (69)	15 (60)	–
Axial, n (%)	18 (35)	8 (31)	10 (40)	–
Laboratory data
Hemoglobin, g/dl	11.9±2.0	12.0±2.1	11.8±2.1	0.680
S-ALB, g/dl	3.7±0.5	3.9±0.4	3.5±0.5	0.005*
Serum total bilirubin, mg/dl	1.5±1.0	1.5±1.1	1.4±0.8	0.650
Serum creatinine, mg/dl	1.1±0.5	1.0±0.3	1.2±0.5	0.102
Plasma BNP, pg/ml	808±540	719±388	900±658	0.236
S-CRP, mg/dl	1.3±2.3	1.3±2.9	1.4±1.5	0.731
Echocardiography
LVDd, mm	75±14	73±12	77±16	0.408
LVEF, %	19±9	18±8	20±10	0.419
Hemodynamics
sBP, mmHg	87±14	88±13	85±15	0.445
HR, beats/min	83±15	83±15	83±16	0.985
mRAP, mmHg	9±4	8±4	9±5	0.213
PCWP, mmHg	22±8	23±9	22±7	0.502
Cardiac index, L·min−1·m−2	2.0±0.4	1.9±0.4	2.1±0.5	0.141
RVSWI, g/m	7.3±3.6	7.1±3.0	7.6±4.2	0.634

*P<0.05 by unpaired t-test, ^†P<0.05 by Chi-square test. BMI, body mass index; BNP, B-type natriuretic peptide; HR, heart rate; LVDd, left ventricular diastolic diameter; LVEF, left ventricular ejection fraction; mRAP, mean right atrial pressure; PCWP, pulmonary capillary wedge pressure; RVSWI, right ventricular stroke work index; sBP, systolic blood pressure; S-ALB, serum albumin; S-CRP, serum C-reactive protein.

Predictors of Improvement of Post-LVAD Exercise Tolerance

Among the preoperative variables, S-ALB was an independent predictor of improved post-LVAD exercise capacity in the multivariate logistic regression analysis (Table 2; P=0.023, odds ratio 6.132). The cutoff value for reaching the exercise test endpoint was 3.5 g/dl (AUC 0.722, sensitivity 0.846, and specificity, 0.560).

Table 2. Logistic Regression Analyses for Improvement of Post-LVAD Exercise Tolerance Among Preoperative Variables

Preoperative variables	Univariate		Multivariate		VIF
	P value	OR (95% CI)	P value	OR (95% CI)
Age, years	0.021*	0.945 (0.900–0.991)	0.078	0.950 (0.901–1.010)	1.085
INTERMACS Profile	0.048*	2.274 (1.423–6.362)	0.398	1.619 (0.530–4.951)	1.079
S-ALB, g/dl	0.010*	6.450 (1.576–26.40)	0.023*	6.132 (1.290–29.14)	1.082

*P<0.05 by logistic regression analyses. CI, confidence interval; OR, odds ratio; LVAD, left ventricular assist device; VIF, variance inflation factors. Other abbreviations as in Table 1.

Correlation Between S-ALB and Other Preoperative Variables

Among the preoperative variables, S-CRP was significantly negatively associated with S-ALB (Table 3; P<0.001, r=−0.605). There were no other significant associations between the preoperative variables and S-ALB.

Table 3. Correlation Between S-ALB Level and Other Preoperative Variables in Patients With LVAD

	P value	R
Demographic variables
Age, years	0.119	–
BMI	0.672	–
HF duration, ×102 days	0.677	–
Laboratory variables
Hemoglobin, g/dl	0.087	–
Serum total bilirubin, mg/dl	0.932	–
Serum creatinine, mg/dl	0.839	–
Plasma BNP, pg/ml	0.428	–
S-CRP, mg/dl	<0.001*	−0.605
Echocardiographic variables
LVDd, mm	0.214	–
LVEF, %	0.151	–
Hemodynamic variables
sBP, mmHg	0.324	–
HR, beats/min	0.123	–
mRAP, mmHg	0.094	–
PCWP, mmHg	0.154	–
Cardiac index, L·min−1·m−2	0.603	–

*P<0.05 by Pearson’s correlation coefficient. Abbreviations as in Tables 1,2.

Perioperative Changes in S-ALB and S-CRP

At 5 weeks after LVAD implantation, pulmonary capillary wedge pressure decreased significantly (down to 8 mmHg, P<0.001 compared with preoperative values), and the cardiac index increased significantly (up to 2.5 L·min⁻¹·m⁻², P<0.001 compared with preoperative values). Postoperative S-ALB at 1 month was also a significant predictor of improved exercise tolerance in logistic regression analysis (P<0.001, odds ratio 80.19). The cutoff value of postoperative S-ALB was 3.2 g/dl (AUC 0.846, sensitivity 0.846, and specificity 0.760). Scattered plots of pre/postoperative S-ALB are shown in Figure 2A.

Figure 2.

Scatter plots of pre- and postoperative serum albumin (S-ALB) levels (A) and stratification analysis by S-ALB (B). In (A), red circles represent patients with PV̇O₂ ≥14 ml·kg⁻¹·min⁻¹ at 3 months. *P<0.05 (Pearson’s correlation coefficient). (B) Percentage of patients with PV̇O₂ ≥14 ml·kg⁻¹·min⁻¹ is shown in each of 4 groups stratified by cutoff values of pre- and postoperative S-ALB.

Patients were stratified into 4 groups according to the cutoff values of pre- and postoperative S-ALB (Figure 2B): L-L group, persistently low S-ALB; L-N group, low S-ALB preoperative and normal S-ALB postoperative; N-N group, persistently normal S-ALB; and N-L group, preoperative normal S-ALB and low S-ALB postoperative. Of the patients in the L-N group, 43% experienced improved exercise capacity, whereas none of the patients in the L-L group achieved the exercise test endpoint.

Pre/postoperative levels of S-CRP in the 4 groups are shown in Table 4. Patients in the L-L group showed the highest S-CRP, whereas patients in the N-N group showed the lowest S-CRP. S-CRP did not change following LVAD implantation in all 4 groups, although there was a trend towards increasing levels in the N-L group (P=0.108).

Table 4. Comparison of Perioperative S-CRP Among Patients With LVAD

	Groups according to cutoff values of pre- and postoperative S-ALB
	L-L group (n=6)	L-N group (n=7)	P vs. L-L	N-L group (n=12)	P vs. L-L	N-N group (n=26)	P vs. L-L
Pre-op S-CRP, mg/dl	2.8±1.2	1.4±1.0	0.038*	1.3±1.2	0.024*	0.7±0.9	0.001*
Post-op S-CRP, mg/dl	2.3±1.4	0.9±1.0	0.014*	1.6±1.2	0.214	0.5±0.8	0.001*
P vs. Pre-op S-CRP	0.324	0.187		0.108		0.543

*P<0.05 by Dunnet’s test when analysis of variance approved significance. Abbreviations as in Tables 1,2.

Discussion

Our study showed that the preoperative S-ALB level was an independent predictor of better exercise performance at 3 months following LVAD implantation. Preservation or restoration of S-ALB levels was important in improving exercise tolerance after LVAD implantation. A lower S-ALB level was accompanied by elevated S-CRP level in most patients during the perioperative period.

Endpoint of the Present Study

PV̇O₂ <14 ml·kg⁻¹·min⁻¹ is a well-known prognostic predictor in patients with HF.¹² Consistently, patients in the present study with PV̇O₂ <14 ml·kg⁻¹·min⁻¹ during LVAD treatment experienced higher readmission rates for cardiovascular events, including worsening of HF or cerebral thromboembolism. Exercise intolerance after LVAD implantation is usually associated with LVAD-specific complications, such as chronic right ventricular failure (RVF) and aortic insufficiency.^11,13 Increased left or right ventricular pressure and enhanced thrombus formation around the aortic valve because of such complications may lead to cardiovascular events.

We assessed exercise capacity at 3 months, because such a short-term endpoint should not have been affected by various postoperative factors, such as postoperative cardiac rehabilitation or LVAD-related complications.

Low Preoperative S-ALB and “Cardiac Cachexia”

Hypoalbuminemia is often associated with advanced HF.⁷ Low preoperative S-ALB may indicate malnutrition, which facilitates dissimilation of skeletal muscle with a consequent reduction of exercise tolerance.¹⁴ LVAD candidates often suffer from long-term HF before surgery, with restricted daily activity and decreased peripheral perfusion, which also enhances atrophy of skeletal muscle from disuse syndrome.¹⁵ Atrophic skeletal muscle increases consumption of S-ALB, which results in a decrease in the S-ALB level.^16,17 Under such circumstances, PV̇O₂ is significantly reduced by skeletal muscle dysfunction.¹⁸ Chronic inflammation, which is often present in patients with decompensated HF, can be another cause of low S-ALB, because it represses hepatic synthesis of ALB.¹⁹ In our study, we observed that higher S-CRP was significantly associated with lower S-ALB prior to LVAD implantation. Overall, preoperative hypoalbuminemia may be consistent with the syndrome of cardiac cachexia. In fact, a preoperative lower S-ALB was significantly associated with lower PV̇O₂ obtained in the 19 patients who could perform the cardiopulmonary exercise test prior to the surgery for LVAD implantation (P=0.010, r=0.576).

Perioperative Changes in S-ALB and Chronic Inflammation

Hypoalbuminemia occasionally persists for several months following LVAD implantation, irrespective of hemodynamic stabilization.²⁰ Caruso et al have shown that inflammatory activation, together with oxidative stress, does not necessarily resolve in the early phase of hemodynamic recovery and LV unloading after LVAD implantation.²¹ Highly active inflammation, indicated by elevated preoperative S-CRP levels, may have been prolonged after LVAD implantation in the L-L group, and continue to repress the recovery of hypoalbuminemia. However, Vega et al reported that hypoalbuminemia can be normalized after LVAD implantation because of improvement in hemodynamics.²² We observed a significant recovery of S-ALB in approximately half of the patients who had low preoperative S-ALB (L-N group). In the L-N group, the preoperative S-CRP levels were relatively low compared with the patients in the L-L group, which may suggest they had less severe inflammation. Hepatic synthesis of S-ALB can be recovered by amelioration of congestion and successful suppression of inflammatory responses. Therefore, the exercise capacity was likely to improve after LVAD implantation in those patients (3/7=43%). The post-LVAD PV̇O₂ in the L-N group was consistently higher compared with the L-L group (15.2 vs. 11.4 L·min⁻¹·kg⁻¹, P=0.035).

The S-ALB level decreased in a considerable number of patients with normal preoperative S-ALB (N-L group). Patients in this group were less likely to achieve successful recovery of exercise tolerance (3/12=25%). Furthermore, patients in this group showed a trend towards increasing S-CRP levels even after LVAD implantation. Postoperative RVF, which is sometimes observed after LVAD implantation, may activate inflammatory responses that in turn decrease S-ALB, accompanied by decreased exercise tolerance.¹⁹ We previously defined postoperative RVF after LVAD implantation, which was observed in 38% of patients in the previous study, as an RV stroke work index <4.0 g/m², at any rotation speed, at 5 weeks.¹¹ Overall, in the present study, 17 patients (33%) with postoperative RVF had higher postoperative S-CRP compared with the 34 without RVF (1.6±1.4 mg/dl vs. 0.7±0.6 mg/dl, P=0.032); and 7 in 12 patients (58%) in the N-L group suffered RVF. Congestion indicated by higher right atrial pressure was consistently associated with hypoalbuminemia (P=0.003, r=−0.405). Patients with postoperative RVF had decreased PV̇O₂ compared with those without RVF (11.6 vs. 14.9 L·min⁻¹·kg⁻¹, P=0.001).

Patients with less severe inflammation showed normal S-ALB levels before and after LVAD implantation (N-N group), and the majority (77%) showed improvement in exercise tolerance. Patients with these characteristics would be good candidates for LVAD therapy aimed at better exercise tolerance and prognosis. These patients were less sick and presented better hemodynamics before LVAD therapy (ie, mostly INTERMACS profile 3), and preventing end-organ dysfunction may be key to obtaining such a favorable result.

Taking into consideration our results, hypoalbuminemia may be a marker for severity of HF, especially in terms of inflammatory response. Early LVAD implantation, before progression of hypoalbuminemia, would be a good strategy to improve post-LVAD exercise tolerance and prognosis, even though postoperative RVF may predispose to sustained inflammation, hypoalbuminemia, and impaired exercise tolerance.

Study Limitations

First, the present study was retrospective with small patient numbers from a single center. Our data should be confirmed in a prospective larger-scale study. Particularly, a precise nutrition assessment and prophylactic aggressive intervention prior to LVAD implantation may improve postoperative exercise tolerance.¹⁵ Second, patients assigned to INTERMACS profile 1 were not enrolled in the present study because such a population is not allowed to receive an I-CF LVAD in Japan.²³ Similarly, those aged over 65 years were not enrolled,²³ and the conclusions may not be applicable in this population. Third, we assessed exercise tolerance at 3 months following surgery because we were focused on perioperative predictors. Exercise capacity during years of LVAD treatment may be affected by various postoperative events or interventions such as aggressive cardiac rehabilitation. Forth, we have used PV̇O₂ to assess the patients’ exercise tolerance. A more detailed assessment of exercise tolerance using questionnaires may be useful to understand patients’ daily activities in the “real world”. Fifth, we used S-CRP as a marker of systemic inflammatory responses. Measurement of other biomarkers, including interleukin-6 or tumor necrosis factor-α, may add further insights.

Conclusions

Early implantation of an I-CF LVAD before the development of hypoalbuminemia is a key factor in improving exercise tolerance post-LVAD surgery.

Disclosures

None.

References

• 1.    Kinugawa  K. How to treat stage D heart failure?: When to implant left ventricular assist devices in the era of continuous flow pumps? Circ J 2011; 75: 2038–2045.
• 2.    Imamura  T,  Kinugawa  K,  Hatano  M,  Fujino  T,  Inaba  T,  Maki  H, et al. Low cardiac output stimulates vasopressin release in patients with stage D heart failure. Circ J 2014; 78: 2259–2267.
• 3.    Kirklin  JK,  Naftel  DC,  Pagani  FD,  Kormos  RL,  Stevenson  LW,  Blume  ED, et al. Sixth INTERMACS annual report: A 10,000-patient database. J Heart Lung Transplant 2014; 33: 555–564.
• 4.    Rose  EA,  Gelijns  AC,  Moskowitz  AJ,  Heitjan  DF,  Stevenson  LW,  Dembitsky  W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345: 1435–1443.
• 5.    Imamura  T,  Kinugawa  K,  Nitta  D,  Inaba  T,  Maki  H,  Hatano  M, et al. Novel scoring system using cardiopulmonary exercise testing predicts prognosis in heart failure patients receiving guideline-directed medical therapy. Circ J 2015; 79: 560–566.
• 6.    Dunlay  SM,  Allison  TG,  Pereira  NL. Changes in cardiopulmonary exercise testing parameters following continuous flow left ventricular assist device implantation and heart transplantation. J Card Fail 2014; 20: 548–554.
• 7.    Arques  S,  Ambrosi  P. Human serum albumin in the clinical syndrome of heart failure. J Card Fail 2011; 17: 451–458.
• 8.    Imamura  T,  Kinugawa  K,  Shiga  T,  Endo  M,  Kato  N,  Inaba  T, et al. Novel risk scoring system with preoperative objective parameters gives a good prediction of 1-year mortality in patients with a left ventricular assist device. Circ J 2012; 76: 1895–1903.
• 9.    Kato  TS,  Kitada  S,  Yang  J,  Wu  C,  Takayama  H,  Naka  Y, et al. Relation of preoperative serum albumin levels to survival in patients undergoing left ventricular assist device implantation. Am J Cardiol 2013; 112: 1484–1488.
• 10.    Kokkinos  PF,  Choucair  W,  Graves  P,  Papademetriou  V,  Ellahham  S. Chronic heart failure and exercise. Am Heart J 2000; 140: 21–28.
• 11.    Imamura  T,  Kinugawa  K,  Kato  N,  Muraoka  H,  Fujino  T,  Inaba  T, et al. Late-onset right ventricular failure in patients with preoperative small left ventricle after implantation of continuous flow left ventricular assist device. Circ J 2014; 78: 625–633.
• 12.    Mancini  DM,  Eisen  H,  Kussmaul  W,  Mull  R,  Edmunds  LH Jr,  Wilson  JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83: 778–786.
• 13.    Imamura  T,  Kinugawa  K,  Fujino  T,  Inaba  T,  Maki  H,  Hatano  M, et al. Aortic insufficiency in patients with sustained left ventricular systolic dysfunction after axial flow assist device implantation. Circ J 2014; 79: 104–111.
• 14.    Reddy  HK,  Weber  KT,  Janicki  JS,  McElroy  PA. Hemodynamic, ventilatory and metabolic effects of light isometric exercise in patients with chronic heart failure. J Am Coll Cardiol 1988; 12: 353–358.
• 15.    Holdy  K,  Dembitsky  W,  Eaton  LL,  Chillcott  S,  Stahovich  M,  Rasmusson  B, et al. Nutrition assessment and management of left ventricular assist device patients. J Heart Lung Transplant 2005; 24: 1690–1696.
• 16.    Anker  SD,  Sharma  R. The syndrome of cardiac cachexia. Int J Cardiol 2002; 85: 51–66.
• 17.    Rahman  A,  Jafry  S,  Jeejeebhoy  K,  Nagpal  AD,  Pisani  B,  Agarwala  R. Malnutrition and cachexia in heart failure. J Parenter Enteral Nutr 2015 January 29, doi:10.1177/0148607114566854.
• 18.    Harrington  D,  Anker  SD,  Chua  TP,  Webb-Peploe  KM,  Ponikowski  PP,  Poole-Wilson  PA, et al. Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol 1997; 30: 1758–1764.
• 19.    Bouras  G,  Giannopoulos  G,  Hatzis  G,  Alexopoulos  D,  Leventopoulos  G,  Deftereos  S. Inflammation and chronic heart failure: From biomarkers to novel anti-inflammatory therapeutic strategies. Med Chem 2014; 10: 682–699.
• 20.    Imamura  T,  Kinugawa  K,  Nitta  D,  Inaba  T,  Maki  H,  Hatano  M, et al. Readmission due to driveline infection can be predicted by new score by using serum albumin and body mass index during long-term left ventricular assist device support. J Artif Organs 2015 January 21, doi:10.1007/s10047-015-0816-2.
• 21.    Caruso  R,  Verde  A,  Campolo  J,  Milazzo  F,  Russo  C,  Boroni  C, et al. Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance. Cytokine 2012; 59: 138–144.
• 22.    Vega  JD,  Poindexter  SM,  Radovancevic  B,  Burnett  CM,  Lonquist  JL,  Birovljev  S, et al. Nutritional assessment of patients with extended left ventricular assist device support. ASAIO Trans 1990; 36: M555–M558.
• 23.    Saito  S,  Yamazaki  K,  Nishinaka  T,  Ichihara  Y,  Ono  M,  Kyo  S, et al. Post-approval study of a highly pulsed, low-shear-rate, continuous-flow, left ventricular assist device, EVAHEART: A Japanese multicenter study using J-MACS. J Heart Lung Transplant 2014; 33: 599–608.