Obesity is a complex and multifactorial condition characterized by an excess of body fat that can present with or without reduction of the total body lean mass. The World Health Organization (WHO) defines overweight as a body mass index (BMI) of 25 kg/m² or greater and obesity as a BMI ≥30 kg/m². The prevalence of obesity worldwide has markedly increased over the last few decades, reaching epidemic proportions. In 2008, more than 1.4 billion adults worldwide were overweight. In the U.S., 69% of adults are overweight, and 33% are obese.¹ Importantly, obesity commonly complicates heart failure populations and their management.

Several studies have demonstrated that obesity has numerous adverse effects on health, quality of life, and life expectancy. A high BMI has been shown to have an independent and direct negative effect on cardiac structure, as well as left ventricular (LV) systolic and, especially, diastolic function.² Metabolic syndrome further increases cardiovascular risk over and above simple obesity and is likely related to the clustering of potent cardiovascular risk factors in addition to obesity. In a study of 2,902 patients, obese people with metabolic syndrome had a two-fold increased risk for cardiovascular disease (CVD). Normal weight people meeting criteria for metabolic syndrome had a three-fold increased risk for CVD.³

The management of obese patients with advanced refractory heart failure is particularly challenging since many benefits of advanced heart failure therapies may be attenuated or absent by the impact of obesity on these outcomes. However, information regarding outcomes following left ventricular assist device (LVAD) implantation and/or heart transplantation in these patients is limited, and expectations must commonly be extrapolated from other experiences. Moreover, reports and trials of advanced heart failure therapies have generally excluded obese patients with BMIs >35 (Table 1).^4,5 Major LVAD trials (e.g., HeartMate II Bridge to Transplant [BTT] and Destination Therpay [DT]) have excluded subjects with BMI ≥40 kg/m² and, therefore, LVAD outcomes in these specific patients is uncertain.²

Table 1: Adverse Outcomes Associated With Obesity in the Setting of LVAD, Heart Transplantation and Other Major Cardiothoracic Operations

Adverse outcomes	LVAD	Heart Transplant	CT Surgery
Infection	X	X	X
Thrombosis	X	X	X
Longer Mechanical Ventilator Support & ICU Stay			X
Premature Device Failure	X
Cardiac Arrhythmias			X
Early Postoperative Mortality	X	X
Late Mortality			X

Most studies defined obesity as BMI >30 kg/ m². However, the studies that investigated the outcomes when BMI >35 kg/ m² revealed significantly higher adverse outcomes.

In general, cardiac surgery outcomes are compromised by obesity. In a prospective study of 10,268 patients undergoing coronary artery bypass graft, multivariate Cox regression analyses revealed morbid obesity (BMI ≥35 kg/ m²) as an independent predictor of late mortality (hazard ratio 1.67, CI 1.15-2.43, p = 0.007).⁶ Higher BMI also increases the risk of early postoperative complications and is associated with prolonged mechanical ventilator support, longer intensive care unit stays, increased surgical wound infection and dehiscence, more mediastinitis, and reoperation.^7,8,9 Obesity is also associated with postoperative hyperglycemia in non-diabetic patients after cardiac surgery,¹⁰ which increases the risk of infection, sepsis, and cardiac arrhythmias as well as prolonging convalescence.

In one of the few LVAD reports that included a >35 kg/m² cohort, severe obesity carried a significant risk. In that study of 590 consecutive patients stratified by their BMI (<20, 20-24, 25-29, 30-35; >35) a BMI >35 kg/m² was associated with an almost six-fold risk of the combined endpoint of postoperative mortality and failure of procedural success (OR 5.8; 95% CI, 1.8-18.8, p = 0.003).¹¹

Several mechanisms lead to inferior outcomes in obese patients. One factor related to poor outcomes in very obese patients is the susceptibility to infection and, in particular, LVAD-related infections. In the pivotal ADVANCE BTT trial and Continued Access Protocol (CAP), drive-line associated infections and sepsis were more common in patients with higher BMIs (p = 0.015).¹²

In addition, a strong association between obesity and thrombosis has been reported in several observational studies. Chronic inflammation, impaired fibrinolysis, dysregulated expression and secretion of adipokines (e.g., leptin) appear to be major effector mechanisms of thrombosis in obesity.¹³ Morbid obesity (BMI ≥35 kg/m²) has also been associated with a prothrombotic state after cardiac surgery, with shortening of clotting time, partial thromboplastin time and an increase in platelet count and fibrinogen.¹⁴ A retrospective study of 956 LVAD patients noted that a higher BMI (29.1+/- 5.6 vs. 27+/-5.8 kg/m²) was an independent risk factor for pump thrombosis (HR: 1.71; 1.5-2.77; p = 0.031).¹⁵ A report from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) that included 6,910 adult patients reported a similar effect of obesity on the risk of pump thrombosis.¹⁶

Many heart transplant programs impose weight limits (i.e., BMI ≤35 kg/m²) on their candidates and require patients over the weight limit to lose weight in order to qualify for heart transplantation. Many programs will place an LVAD in these patients using a "bridge to weight loss" strategy. Unfortunately, the vast majority of obese, LVAD-supported patients are unable to lose a sufficient amount of weight to qualify for heart transplantation.¹⁷ In fact, many of these patients gain weight and subsequently experience post-LVAD complications related to the progressive obesity. A retrospective study of 52 patients who underwent LVAD implantation at Johns Hopkins University between 2004 and 2009 reported that 52% of such subjects gained weight after LVAD therapy, with a mean weight gain of 6.5 kg. Among patients with BMI >35 kg/m² before LVAD implantation, there was a mean weight gain of 0.7 kg after device therapy. Thirty percent of the patients who gained weight after LVAD implantation developed drive-line infections.¹⁸

Obesity also negatively impacts heart transplantation outcomes. Lietz et al. reported that obese patients had a higher five-year mortality compared with normal weight or overweight heart transplantation recipients.¹⁹ In a multicenter study of 4,515 heart transplantation patients out of the Cardiac Transplant Research Database (CTRD), preoperative percent ideal body weight (PIBW) >140% was associated with increased risk of infection. In men, a higher PIBW was a significant risk factor for death within the first six postoperative months (p = 0.0003). There was a similar trend for women (p = 0.07).²⁰

Obesity Paradox

In contrast to the poor outcomes with LVAD and transplant in obese patients with heart failure, several observational studies have suggested that the natural history of heart failure in obese patients may be better than underweight or even normal weight subjects. This phenomenon has been referred to as the "obesity paradox." This prognostic paradox appears to extend to advanced heart failure patients as well. Horwich et al. studied 1,203 patients with advanced heart failure and after adjusting for multiple confounders (hypertension, diabetes mellitus, peak VO₂, age, gender, medications), obesity (BMI >31 kg/m²) was associated with a significant survival benefit at one and two years.²¹ Clark et al. studied 3,187 advanced heart failure patients (81% New York Heart Association [NYHA] III/IV) with a mean ejection fraction of 22.9%, mean left ventricular end-diastolic dimensions of 68.3 mm, mean peak VO₂ 13.5, for the primary outcomes of death, urgent heart transplantation or need for VAD placement. In men, two-year, event-free survival was better for high (BMI ≥25 kg/m²) versus normal BMI (63.2% vs. 53.5%, p <0.001) and for high (≥88 cm in women, ≥102 cm in men) versus normal WC (78.8% vs. 63.1%, p = 0.01). In women, two-year event-free survival was better for an elevated BMI (67.1% vs. 56.6%, P = 0.01).²² These observations should be taken into consideration when advanced therapies are being considered in any obese patient.

Ultimately, deciding which patients will benefit from advanced cardiac therapies and the ideal time for these interventions is still an "art and a science."²³ In the obese patient, the available evidence clearly demonstrates poor outcomes with LVAD and transplantation. For the morbidly obese patients, these risks are exaggerated and should be prohibitive. Considering these observations and the obesity paradox, even at advanced stages of HF (Figure 1), the authors of this Expert Analysis article argue that clinicians should use a high threshold when considering LVAD support in obese patients and that a BMI ≥35 kg/ m² should be considered a contraindication for this therapy.

Figure 1: LVADs for Obese Individuals: Rarely

References

1. World Health Organization (WHO). Obesity and Overweight (WHO website). 2014. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed 12/22/2014.
2. Lavie C, Alpert M, et al. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. JCHF 2013;1:93-102.
3. Meigs JB, Wilson PW, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 2006;91:2906-12.
4. Butler J, Howser R, et al. Body mass index and outcomes after left ventricular assist device placement. Ann Thorac Surg 2005;79:66-73.
5. Coyle L, Ising M, et al. Destination therapy: one-year outcomes in patients with a body mass index greater than 30. Artif Organs 2010;34:93-7.
6. Van Straten A, Bramer S, et al. Effect of body mass index on early and late mortality after coronary artery bypass grafting. Ann Thorac Surg 2010;89:30-7.
7. Yap Ch, Mohajeri M, et al. Obesity and early complications after cardiac surgery. Med J Aust 2007;186:350-4.
8. Rehman SM, Elzain O, et al. Risk factors for mediastinitis following cardiac surgery: the importance of managing obesity. J Hosp Infect 2014;88:96-102.
9. Ranucci M, Ballota A, et al. Post-operative hypoxia and length of intensive care unit stay after cardiac surgery: the underweight paradox? PLoS One 2014;9:e93992.
10. Kuznetzova LA, Iavorovskii AG, et al. Predictive value of body mass index for perioperative hyperglycemia occurrence in cardio-surgical patients without diabetes mellitus. Anesteziol Reanimatol 2014;1:11-3.
11. Musci M, Loforte A, et al. Body mass index and outcome after ventricular assist device placement. Ann Thorac Surg 2008;86:1236-42.
12. John R, Aaronson K, et al. Drive line infections and sepsis in patients receiving the HVAD system as a left ventricular assist device. J Heart Lung Transplant 2014;33:1066-73.
13. Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol 2013;20:437-44.
14. Kindo M, Minh T, et al. The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass. Thromb Res 2014;134:346-53.
15. Boyle A, Jorde U, et al. Pre-operative risk factors of bleeding and stroke during left ventricular assist device support. J Am Coll Cardiol 2014;63:880-8.
16. Kirklin J, Naftel D, et al. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HearMate II left ventricular assist device. J Heart Lung Transplant 2014;33:12-22.
17. Jones W, Garcia L, et al. LVAD support as a bridge to transplant in the morbidly obese needs a long-term weight loss strategy. J Cardiac Fail 2010;16:S47.
18. Dordunoo D, Beck T, Mudd J, Shah AS, Conte JV, Bubb T. Bridge to weight loss: myth or reality. J Cardiac Fail 2010;16:S47-8.
19. Lietz K, John R, et al. Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation. Transplantation 2001;72:277-83.
20. Grady K, White-Williams C, 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. J Heart Lung Transplant 1999;18:750-63.
21. Horwich T, Fonarow G, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38:789-95.
22. Clark A, Chyu J, et al. The obesity paradox in men versus women with systolic heart failure. Am J Cardiol 2012;110:77-82.
23. Fang JC. Rise of the machines – left ventricular assist devices as permanent therapy for advanced heart failure. N Engl J Med 2009;361:2282-5.

Keywords: Adipokines, Adipose Tissue, Arrhythmias, Cardiac, Body Mass Index, Body Weight, Cardiac Surgical Procedures, Cardiovascular Diseases, Convalescence, Coronary Artery Bypass, Diabetes Mellitus, Disease-Free Survival, Equipment Failure, Fibrinogen, Fibrinolysis, Heart Failure, Heart Transplantation, Heart-Assist Devices, Hyperglycemia, Hypertension, Ideal Body Weight, Inflammation, Intensive Care Units, Leptin, Life Expectancy, Mediastinitis, Metabolic Syndrome, Obesity, Morbid, Overweight, Partial Thromboplastin Time, Platelet Count, Prevalence, Prospective Studies, Quality of Life, Registries, Regression Analysis, Reoperation, Retrospective Studies, Risk Factors, Sepsis, Surgical Wound Infection, Thinness, Thrombosis, Weight Gain, Weight Loss

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