Obesity in the United States is an epidemic that affects approximately five million people. Obesity is a known risk factor in development of cardiovascular disease, stroke, incidence of cancer, and diabetes.1 It has also been identified as a risk factor for adverse postoperative morbidities, such as infections and renal disease, and ultimately poor survival in the patients who get heart transplantation.2,3 The most recent The International Society for Heart & Lung Transplantation guideline recommended a body mass index (BMI) of less than 35 kg/m2 as ideal for transplant candidacy because higher BMI (≥35 kg/m2) is associated with worse outcomes after heart transplantation.4 Obesity may also be associated with adverse events after left ventricular assist device (LVAD) implantation5,6; however, the impact of obesity on outcomes in patients with LVAD remains controversial.7,8
There are several studies investigating the relationship between BMI and outcomes in patients with LVAD. In a large number of patients enrolled in the HeartMate II bridge to transplantation and destination therapy trials, extremely obese patients had higher rates of device-related infection and rehospitalization, and underweight patients experienced more bleeding events, yet, survival was compatible among different BMI groups.7 Other investigators reported no relationship between BMI and risk of infection.9 There are other studies which demonstrated worse survival in patients with lower BMI.10–12 Hence it is clear that there is an overall lack of consensus regarding the association between BMI and outcomes. Notably, these studies investigated different BMI groups, thus compared obese patients with nonobese patients. Although the influence of BMI and obesity has been previously described, the impact of changes in BMI post-LVAD implantation particularly in the obese patient population has not been described. The purpose of this study is to determine the impact of change in BMI on outcomes in obese patients who received LVAD.
Materials and Methods
This is a single institutional retrospective review of all continuous-flow LVADs implanted between January 1, 2010, and June 30, 2015, approved by the institutional review board at The Ohio State University Wexner Medical Center. The need for informed consent was excused because of the retrospective nature of the study.
Inclusion criteria were as follows: the patients who underwent LVAD implantation for the first time during time above, with BMI ≥30 kg/m2 at the time of implantation, and were followed for more than 6 months on device. All patients met with nutritionists and received advice before and after LVAD implantation. If rehabilitation was recommended by physical therapist/occupational therapist, the patients either continued cardiac rehabilitation at an inpatient facility or outpatient center. The patients were divided into two groups based on whether they experienced decrease in their BMI after 6 months of device support when compared with the time of implantation (decrease; group D: 38, increase; group I: 21) and were compared.
Baseline Assessment and Outcomes
Baseline assessments included demographic characteristics, health history, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles, hemodynamics, inotrope dose, blood chemistry, and hematological data. Outcomes after LVAD implantation included characteristics after LVAD surgery as well as BMI, laboratory data, and heart failure medications at 6 months after LVAD implantation, adverse events, and survival at 2 years. Adverse events were captured by using standardized INTERMACS definitions and were followed up to 2 years.
Statistical analysis was performed using SPSS, version 2 for Windows (SPSS Inc, Chicago, IL). Continuous variables were expressed as mean and standard deviations and were analyzed using Student’s unpaired t test. Categorial variables were expressed as frequencies and percentage and were analyzed using either χ2 or Fisher’s exact tests. Kaplan-Meier analysis with log-rank test was used for survival analysis between group D and group I. For all tests, p value <0.05 was considered statistically significant.
There were 62 patients identified with a BMI ≥30 kg/m2 during this time period. After excluding three patients who could not be supported by devices for more than 6 months (1) or could not be measured BMI at 6 months (2), 59 patients were retrospectively analyzed.
Table 1 summarizes the baseline demographic and clinical characteristics for group D and group I. Baseline characteristics were overall similar between the groups with the exception of weight and BMI, which were significantly higher in the patients in group D compared with group I (D, 111.6 ± 14.5 vs. I, 101.9 ± 13.2 kg; p = 0.013 and D, 35.9 ± 4.0 vs. I, 33.4 ± 3.5 kg/m2; p = 0.018, respectively). The percentage of the patients who were implanted with LVAD for destination therapy was comparable between the groups (D, 68 vs. I, 57%; p = 0.386). INTERMACS profiles tended to be worse in group D (profiles 1 and 2; D, 45 vs. I, 29%; p = 0.223), but, again, it was not statistically significant
Characteristics After LVAD Surgery
Patients’ characteristics just after LVAD implantation are shown in Table 2. No significant differences were found between the groups. The length of hospital stay trended toward longer in group D, but this did not reach statistical significance (D, 22.7 ± 14.3 vs. I, 17.6 ± 6.3 days; p = 0.124).
Characteristics at 6 Months of LVAD Support
At 6 months post-LVAD implantation, BMI of the patients in group I was significantly higher compared with that in group D (D, 33.2 ± 4.0 vs. I, 35.6 ± 3.6 kg/m2; p = 0.03). Patients in group I had a significant increase in their BMI when compared with the patients in group D (change in BMI; D, −2.7 ± 2.3 vs. I, 2.2 ± 1.4 kg/m2; p < 0.01). Laboratory data were comparable between the groups (Table 3). Table 4 shows the heart failure medication regimen on the patients at 6 months after LVAD implantation. Overall, there were no statistically significant differences between the groups.
Adverse events occurred within 2 years after LVAD implantation are summarized in Table 5. The patients in group I had a significantly higher incident event rate for infection, local nondevice-related infection (events per patient-years: D, 0.18 vs. I, 0.35; p = 0.01), device-related infection (D, 0.1 vs. I, 0.32; p < 0.01), and sepsis (D, 0.1 vs. I, 0.32; p < 0.01). A similar statistical significance was noted for the incidence of heart failure exacerbation in group I (D, 0.1 vs. I, 0.25; p < 0.01) and heart failure requiring LVAD speed change, inotrope use or intravenous diuretic use in group I compared with group D (D, 0.05 vs. I, 0.18; p < 0.01). A significantly higher percentage of patients in group I had chronic renal failure compared with those in group D (D, 0.03 vs. I, 0.14; p < 0.01). The incidence of arrhythmias was trending toward higher in group I (D, 0.22 vs. I, 0.35; p = 0.06); however, it did not reach to statistical significance. The patients in group D showed a nonsignificant trend to developing more bleeding complications than those in group I (bleeding requiring red blood cell: D, 0.25 vs. I, 0.14; p = 0.07). In terms of cerebrovascular events, pump events, and rehospitalization, they were all comparable between group D and group I.
Figure 1 demonstrates Kaplan-Meier survival curves for the two groups. The 2-year actual survival rate was significantly lower in group I compared with group D (D, 84.8 vs. I, 57.1%; p = 0.024). The causes of death during LVAD support were as follows: heart failure due to pump thrombus (2), cerebrovascular events (1), and unknown (1) in group D; and sepsis (2), cerebrovascular events (3), multisystem organ failure (1), and heart failure due to pump thrombus (1) in group I. During the follow-up period, seven patients in group D and four patients in group I underwent heart transplantation with mean waiting duration of 377 ± 157 days (D, 18 vs. I, 19%; p = 0606).
In this study, we found that further increase of BMI in obese patients during LVAD support was related to worse survival with a significant increase in infection, heart failure, and renal failure. Obesity is a relative contraindication to heart transplantation because of higher incidence of adverse events with poor survival after transplantation.2,3 It could also be associated with worse outcomes after LVAD implantation; however, there is no definite consensus regarding this topic to date. Furthermore, few studies reported the relationship between further weight gain and prognosis in obese patients on LVAD.
The association between BMI and outcomes in patients supported by LVAD has remained under discussion. Previous studies suggest that lower BMI patients undergoing LVAD implantation had a higher mortality.10–12,14 On the other hand, it was reported that BMI had no impact on survival, although higher BMI patients experienced device-related infection more frequently.5–7 Raymond et al.5 demonstrated that the patients who developed driveline exit site infections had a significantly higher BMI at the time of LVAD implantation and continued to gain weight on device. Brewer et al.7 also reported that extremely obese patients, BMI ≥35 kg/m2 at the time of LVAD implantation, had higher rate of device-related infection as well as sepsis. These findings are very similar to our results. We showed that obese patients, who increased BMI after LVAD compared with before and whose BMI was 35.6 ± 3.6 kg/m2 at 6 months, thus severely obese, had more both local nondevice-related and device-related infection as well as sepsis.
One possible explanation for our results, involving the higher risk of device-related infection in obese patients, is the influence of excess abdominal adipose tissue which receives less blood flow and contributes to less stability and poor healing, therefore increasing susceptibility to infection.4 It is also reported that subcutaneous tissue oxygenation is reduced in obese patients, and this may predispose to wound infection.15,16 This group is also prone to trauma at the driveline site due to retraction that leads to infection.15,16 Furthermore, it is reported that obesity is related to leptin deficiency. Leptin activates polymorphonuclear neutrophils, exerts proliferative and antiapoptotic activities on T lymphocytes, affects cytokine production, and regulates the activation of monocytes/macrophages.15,17 Leptin induction seems to be a protective component of the immune response, and genetic leptin deficiency in human beings has been associated with increased mortality due to infection.18 Thus, lack of leptin may contribute to increased susceptibility to infection and sepsis in obese patients.15
We also found a significantly higher incidence of late right ventricular (RV) failure (RVF) in patients who showed increased BMI after LVAD. This is consistent with previous studies which demonstrated higher incidence of RVF in obese patients during LVAD support.7,9 RVF is one of the most serious complications with increasing mortality during LVAD support.19 The factors which may induce acute or early RVF have been well investigated; however, little information exists regarding the predictors for late RVF to date.9,19 Takeda et al.20 reported that higher BMI was a significant predictor for late RVF. They speculated that infection, which occurs at a higher rate in obese patients, may deteriorate RV function. Obesity can also cause left as well as RV dysfunction, called obesity cardiomyopathy.21 Cardiac morphological abnormalities, such as increased heart weight and wall thickness, are noted in obese patients.22 These changes increase oxygen consumption and deteriorate cardiac function. Recently, myocardial lipotoxicity and lipoapoptosis have received considerable attention as a possible cause of cardiac dysfunction. In obese patients, excess free fatty acids and triglycerides accumulate in parenchymal space, which cause cellular dysfunction and death leading to myocardial dysfunction.21,22 It is notable that hypoxemia related to sleep apnea is very common in obese patients, which increases pulmonary vascular resistance, thus afterload against RV, and may contribute to RV dysfunction.22 Unfortunately, we did not have the data regarding sleep apnea in our patients, so we were not able to investigate the relation between sleep apnea and RV failure in this study. The incidence of chronic renal failure was also higher in the patients with increased BMI on LVAD, possibly related to worse RV function. We could also speculate that higher BMI might be related to increased water weight/content for these patients, although it is very tough to detect which are the chicken and the eggs. We suspect that relatively higher incidence of late RVF as well as chronic renal failure can contribute to worse survival in the patients with increased BMI on LVAD in addition to significantly higher rate of infection.
Our study is novel because the majority of previous studies classified the patients as obese or extremely obese based on BMI at the time of LVAD implantation contrary to our current study, which focused on BMI change at 6 months of device support. We selected this time point because we believe that the majority of patients can almost completely recover from the LVAD surgery at 6 months. Also, we previously reported that obese patients lose some weight at 6 months after LVAD implantation and their weight reached a minimum during LVAD support at this time point.23 Interestingly, patients in group I were obese at the time of implantation (BMI: 33.4 ± 3.5 kg/m2), but they were recognized as severely obese at 6 months (BMI: 35.6 ± 3.6 kg/m2). On the other hand, the patients in group D were severely obese at the time of implantation (BMI: 35.9 ± 4.0 kg/m2) but declined to the obese category at 6 months (BMI: 33.2 ± 4.0 kg/m2). This may suggest that higher BMI after LVAD implantation and continuing weight gain during LVAD support have more impact on outcomes. Most importantly, our study demonstrated an unfavorable impact of further weight gain after LVAD on obese patient survival.
There were several limitations to our study. First, because this study was based on a single-center experience, selection bias may have been present. Second, it was a retrospective study and is subject to all limitations inherent in such studies. Third, sample size was small, which may limit the power to detect differences. Finally, as we evaluated patients based on BMI at 6 months after LVAD implantation, we were not able to evaluate the impact of change of BMI before as well as after that time frame. Thus, we could not consider decrease in BMI before increase. However, 6 months after LVAD implantation seemed to be a reasonable point for most patients to stabilize the condition with body weight after surgery.
In conclusion, obese patients who gained further weight during the first 6 months of LVAD support had a significantly higher incidence of infection, late RVF, and chronic renal failure with worse survival at 2 years. Weight reduction in obese patients on LVAD could be associated with improved outcomes and may be one means of reducing adverse events.
The authors thank Sherri Wissman, RN, BSN, CCTC, our outstanding ventricular assist device coordinator, for her great assistance with this study.
1. Pi-Sunyer FX. Medical hazards of obesity
. Ann Intern Med 1993.119(7 pt 2): 655–660.
2. Russo MJ, Hong KN, Davies RR, et al. The effect of body mass index
on survival following heart transplantation: Do outcomes support consensus guidelines? Ann Surg 2010.251: 144–152.
3. Grady KL, White-Williams C, Naftel D, et al. Are preoperative obesity
and cachexia risk factors for post heart transplant morbidity and mortality: A multi-institutional study of preoperative weight-height indices. Cardiac Transplant Research Database (CTRD) Group. J Heart Lung Transplant 1999.18: 750–763.
4. Mehra MR, Canter CE, Hannan MM, et al.; International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases Council; International Society for Heart Lung Transplantation (ISHLT) Pediatric Transplantation Council; International Society for Heart Lung Transplantation (ISHLT) Heart Failure and Transplantation Council: The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016.35: 1–23.
5. Raymond AL, Kfoury AG, Bishop CJ, et al. Obesity
and left ventricular assist device
driveline exit site infection. ASAIO J 2010.56: 57–60.
6. Zahr F, Genovese E, Mathier M, et al. Obese patients and mechanical circulatory support: weight loss, adverse events, and outcomes. Ann Thorac Surg 2011.92: 1420–1426.
7. Brewer RJ, Lanfear DE, Sai-Sudhakar CB, et al. Extremes of body mass index
do not impact mid-term survival after continuous-flow left ventricular assist device
implantation. J Heart Lung Transplant 2012.31: 167–172.
8. Go PH, Nemeh HW, Borgi J, Paone G, Morgan JA. Effect of body mass index
on outcomes in left ventricular assist device
recipients. J Card Surg 2016.31: 242–247.
9. Mohamedali B, Yost G, Bhat G. Obesity
as a risk factor for consideration for left ventricular assist devices. J Card Fail 2015.21: 800–805.
10. Mano A, Fujita K, Uenomachi K, et al. Body mass index
is a useful predictor of prognosis after left ventricular assist system implantation. J Heart Lung Transplant 2009.28: 428–433.
11. Mano A, Teuteberg JJ, Bermudez CA, et al. The relation of body size and outcome in patients using continuous flow left ventricular assist devices. J Heart Lung Transplant 2012.31: S258–S259.
12. Butler J, Howser R, Portner PM, Pierson RN III. Body mass index
and outcomes after left ventricular assist device
placement. Ann Thorac Surg 2005.79: 66–73.
13. Gaies MG, Jeffries HE, Niebler RA, et al. Vasoactive-inotropic score is associated with outcome after infant cardiac surgery: An analysis from the Pediatric Cardiac Critical Care Consortium and Virtual PICU System Registries. Pediatr Crit Care Med 2014.15: 529–537.
14. Clark AL, Loebe M, Potapov EV, et al. Ventricular assist device in severe heart failure: Effects on cytokines, complement and body weight. Eur Heart J 2001.22: 2275–2283.
15. Falagas ME, Kompoti M. Obesity
and infection. Lancet Infect Dis 2006.6: 438–446.
16. Cantürk Z, Cantürk NZ, Cetinarslan B, Utkan NZ, Tarkun I. Nosocomial infections and obesity
in surgical patients. Obes Res 2003.11: 769–775.
17. Zarkesh-Esfahani H, Pockley AG, Wu Z, Hellewell PG, Weetman AP, Ross RJ. Leptin indirectly activates human neutrophils via induction of TNF-alpha. J Immunol 2004.172: 1809–1814.
18. Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999.84: 3686–3695.
19. Kormos RL, Teuteberg JJ, Pagani FD, et al.; HeartMate II Clinical Investigators: Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device
: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010.139: 1316–1324.
20. Takeda K, Takayama H, Colombo PC, et al. Incidence and clinical significance of late right heart failure during continuous-flow left ventricular assist device
support. J Heart Lung Transplant 2015.34: 1024–1032.
21. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity
and the obesity
paradox on prevalence and prognosis in heart failure. JACC Heart Fail 2013.1: 93–102.
22. Alpert MA, Agrawal H, Aggarwal K, Kumar SA, Kumar A. Heart failure and obesity
in adults: Pathophysiology, clinical manifestations and management. Curr Heart Fail Rep 2014.11: 156–165.
23. Emani S, Brewer RJ, John R, et al. Patients with low compared with high body mass index
gain more weight after implantation of a continuous-flow left ventricular assist device
. J Heart Lung Transplant 2013.32: 31–35.