Long‐term changes in body weight and serum cholesterol in heart transplant recipients

Abstract

Introduction

Long‐term changes in weight and blood lipids beyond 12 months after heart transplantation are largely unknown. We quantified changes in weight, body mass index (BMI), blood cholesterol, and triglycerides in heart transplant recipients (HTRs) during the 36 months after transplantation, and we assessed the influence of statin therapy on these outcomes.

Methods

Retrospective cohort study of adult HTRs, transplanted 1990–2017, in Queensland, Australia. From each patient's medical charts, we extracted weight, total cholesterol, triglycerides, and statin therapy at four time‐points: time of transplant (baseline), and 12‐, 24‐, 36‐month post‐transplant. Changes in weight and blood lipids were assessed according to baseline BMI.

Results

Among 316 HTRs, 236 (median age 52 years, 83% males) with available information were included. During the 36 months post‐transplant, all patients gained weight (83.5–90.5 kg; p < .001), especially those with baseline BMI < 25.0 km/m² (67.9–76.2 kg; p < .001). Mean blood cholesterol (4.60–4.90 mmol/L; p = .004) and mean blood triglycerides (1.79–2.18 mmol/L; p = .006) also increased significantly in all patients, particularly in those with baseline BMI ≥ 25.0 km/m² but the differences were not significant (total cholesterol 4.42–5.13 mmol/L; triglycerides 1.76–2.47 mmol/L). Total cholesterol was highest in patients not taking statins, and levels differed significantly (p = .010) according to statin dosing changes during the 36 months post‐transplant.

Conclusion

Patients demonstrate significant rises in weight and blood lipids in the 36 months after heart transplantation.

1. INTRODUCTION

Heart transplantation is a life‐saving measure for end‐stage heart failure, and long‐term survival after transplantation has increased substantially during the last decades. However, cardiovascular disease‐related complications, especially cardiac allograft vasculopathy (CAV), progressively increase with elapsed time after transplant, ¹ causing transplant rejection and mortality. ² Weight gain contributes to CAV development, ¹ and many patients gain weight in the short‐term after transplantation ³ due to side‐effects of medications ⁴ , ⁵ and altered energy metabolism. ⁶ The extent of short‐term weight gain after transplantation differs by country of residence, ⁷ ranging from 3 kg in European heart transplant recipients (HTRs) to around 10 kg in HTRs in the United States in the first year. ³ , ⁸ However, little is known about the extent and severity of weight gain in contemporary HTRs after the first year, despite this knowledge being crucial for long‐term monitoring of transplant outcomes. ⁹

Hyperlipidaemia also contributes to the development of CAV. ⁴ At 5‐year post‐transplantation, 88% of HTRs experience post‐operative dyslipidaemia despite standard statin treatment. ¹ , ¹⁰ However, blood lipid levels can vary according to body mass index (BMI). Linear correlations between weight and serum cholesterol and triglycerides have been reported among Australian HTRs in the short term ¹¹ while longer term increases in Brazilian HTRs’ serum cholesterol and triglycerides were even higher in those with BMI ≥ 25 kg/m². ¹² Only two known studies have examined blood lipids and weight/BMI for longer than 12 months post‐transplantation. ¹² , ¹³

We aimed to quantify longer‐term changes in weight and BMI, up to 36 months post‐transplantation, along with related changes in blood lipid levels in Australian HTRs, accounting for post‐transplant corticosteroid therapy. Since immunosuppressive agents can influence blood lipid levels, ¹⁴ , ¹⁵ we also investigated tacrolimus and cyclosporine, as well as statin and corticosteroid therapy, in relation to blood lipids.

2. MATERIALS AND METHODS

This was a retrospective cohort study of HTRs who received care at The Prince Charles Hospital, Queensland's Cardiac Transplantation Centre 1990–2017. We reviewed medical charts and collected information for all eligible patients, namely those aged ≥18 years at the time of transplantation and alive 36 months post‐transplantation. Informed consent from patients was waived as identifiable data were removed and unable to contact patients. Study protocols were approved by institutional human research ethics committees (HREC/17/QPCH/471).

2.1. Data collection

We extracted the following information: date of birth, sex, height (cm), date of transplant, and underlying heart disease. Weight (kg), serum cholesterol (total, low‐density lipoprotein) (LDL), high‐density lipoprotein (HDL)), and triglycerides (mmol/L) were collected from hospital records following post‐transplant discharge (baseline), and at 12‐, 24‐, and 36‐month post‐transplant. We also collected immunosuppressant and lipid‐lowering medication data at baseline, and annually thereafter to 36 months post‐transplant.

2.2. Statistical analysis

We included all HTRs who had information on weight at baseline and on at least one other occasion up to 36 months post‐transplant. Calculated BMI (kg/m²) was categorized as <25.0 kg/m² (underweight/normal weight), 25.0–29.9 kg/m² (overweight), and ≥30.0 kg/m² (obese). ¹⁶

We used linear mixed‐effects models to estimate weight, BMI, blood lipids over 36 months according to baseline BMI. ¹⁷ We examined changes in blood lipid levels over 36 months in relation to statin therapy [none; decreased/ceased; unchanged; increased/commenced] in the 12 months post‐transplant. Baseline BMI, statin therapy, and follow‐up time were included as fixed effects, and study participants, a random effect. Least square means [standard error (SE)] of outcomes by baseline BMI and statin therapy were calculated. Weight/ BMI outcomes were adjusted for prednisolone dose (mg/kg/day), and blood lipids for statin therapy. Median lipid levels were examined in relation to glucose levels and immunosuppressive agents using Mann–Whitney U or Kruskal–Wallis tests as appropriate. We used SAS version 9.4 (SAS Institute Inc., Cary, North Caroline, USA) for all statistical analyses. P < .05 was considered statistically significant (two‐tailed).

3. RESULTS

Among 316 HTRs eligible for inclusion, 236 (median age 52 years; 83% male) had information on weight at baseline and at least another occasion (Table 1). Underlying heart diseases were mostly coronary artery disease (81, 34%) and dilated cardiomyopathy (80, 34%). All HTRs received prednisolone 1 mg/kg/day at transplantation, and the most common immunosuppressive regimen was triple therapy with the combination of cyclosporine, mycophenolate, and prednisolone (93, 45%) (Table 1). Of the 236 study HTRs, 150 (64%) had blood cholesterol information at baseline and at least one other occasion, 86 (57%) of whom were taking statins at baseline. Those with missing information (n = 80) were the same median age, but comprised more females (26%; p = .06), fewer with dilated cardiomyopathy (18% vs 34%; p = .011) and more transplanted before 2004 (81% vs. 48%, p < .001).

TABLE 1.

Baseline characteristics of participants

	All (N = 236)
Age at transplant (years) a	52 (18, 69)
Sex
Males	197 (83)
Females	39 (17)
Etiology of heart disease requiring heart transplantation
Coronary artery disease	81 (34)
Dilated cardiomyopathy	80 (34)
Other b	75 (32)
Year transplanted
1990–2004	113 (48)
2005–2017	123 (52)
Immunosuppressive medication combinations
Cyclosporine/Mycophenolate/Prednisolone	93 (45)
Tacrolimus/Mycophenolate/Prednisolone	43 (18)
Others	61 (26)
Unclear/missing	39 (17)
Statin therapy (n = 150)
Yes	86 (57)
No	64 (43)

^aMedian (minimum, maximum).

^bOthers include: hypertrophic cardiomyopathy, familial dilated cardiomyopathy, valvular heart disease, restrictive myopathy.

3.1. Baseline BMI associations

Among the 236 study participants, four (2%) were underweight, 90 (38%) normal, 99 (42%) overweight, and 43 (18%) obese at baseline. In the next 36 months, mean weight clearly increased (p < .001), particularly in the first 12 months (Figure 1A and Table S1). Mean weights within each category of baseline BMI rose significantly (p < .001) at each time‐point. Trends in mean weight over 36 months were similar across BMI groups (time‐by‐baseline BMI interaction p = .32). Overall, mean BMI increased over 36 months (p < .001) (Figure 1B and Table S1), with mean BMI significantly different (p < .001) at each time‐point in relation to baseline BMI. However, estimated mean BMI within categories did not differ over time (time‐by‐baseline BMI interaction p = .24).

FIGURE 1.

Estimated mean (A) body weight and (B) BMI overtime by baseline BMI category (N = 236). Underweight/normal weight = BMI < 25.0 kg/m²; overweight = BMI 25.0–29.9 kg/m²; obese = BMI ≥ 30 kg/m². Underweight/normal weight (n = 94, 40%); overweight (n = 99, 42%); obese (n = 43, 18%). (A) weight p‐values for time: <.001; baseline BMI: <.001; time‐by‐baseline BMI interaction: .32; 12 months prednisolone dose: .23; 24 months prednisolone dose: .68; 36 months prednisolone dose: .65. (B) BMI p‐values for time <.001; baseline BMI < .001; time‐by‐baseline BMI interaction .25; 12 months prednisolone dose: .15; 24 months prednisolone dose: .73; 36 months prednisolone dose: .42. BMI, body mass index

3.2. Serum lipid changes and baseline BMI

At baseline, mean cholesterol levels in all groups were within normal range (Figure S1A and Table S2). Mean total cholesterol increased significantly over 36 months (p = ..004) in all HTRs, particularly in the first 12 months (p  <.0001), with levels thereafter stable or decreasing. Mean total cholesterol within BMI categories was similar at each time‐point. No interaction between patterns of change in total cholesterol across baseline categories (BMI‐by‐time interaction p = .6). Triglyceride levels also increased over 36 months (p = .006). While mean triglyceride levels at each time‐point within BMI categories did not differ, trajectories significantly differed by BMI category (baseline BMI‐by‐time interaction p = .021) (Figure S1B and Table S2). In contrast, neither mean LDL nor HDL changed significantly over time (Table S3). While underweight/normal‐weight groups tended to have lower LDL levels, there were no differences by BMI, nor interactions between BMI categories and changes in LDL and HDL over time.

3.3. Lipid levels and statins

Those with not taking statins during the first 12 months experienced the greatest increase in total cholesterol and levels tended to be stable or declined slightly from 12 to 36 months post‐transplantation in all therapy categories (Figure S2 and Table S4). Mean total cholesterol levels at each time‐point differed significantly according to statin dose alteration (p = .012), as did patterns over time (statin therapy‐by‐time interaction p = .005). There were no significant differences in mean triglyceride levels by statin therapy or changes over time by statin therapy (Figure S2 and Table S4).

3.4. Prednisolone, glycemia, and lipids

Patients not taking prednisolone at 12 months gained significant weight and BMI compared with those taking prednisolone (p < .05) (Table S5), but HTRs taking low levels of prednisolone (>0 to <.11 mg/kg/day) showed higher median lipid levels (apart from L ²¹ DL) (Table S6). Glycemia was controlled in the majority of HTRs (median blood glucose levels 5.9 mmol/L (range 2.1–15.0) at 12 months; 5.6 mmol/L (range 3.9–13.2) at 36 months), and showed no association with blood lipids.

3.5. Tacrolimus versus cyclosporine

Patients taking tacrolimus or cyclosporine decreased over time. At 12 months, we observed significantly lower median total cholesterol in those taking tacrolimus (4.4 mmol/L) compared with those taking cyclosporine (4.9 mmol/L, p = .040) and similarly lower LDL levels (tacrolimus 2.3 mmol/L, cyclosporine 2.7 mmol/L, p = .023), but significantly higher HDL levels (Table S7). By 36 months post‐transplantation, there were no significant differences in any lipid levels.

4. DISCUSSION

We have shown in a large cohort of Australian HTRs, that substantial weight gain occurs in the 36 months after heart transplantation, especially during the first 12 months. Although the extent of weight gain was small, it continued from 12 to 36 months post‐transplantation including those who were obese at baseline. Mean total cholesterol and triglyceride levels also increased substantially over the 36 months in all HTRs.

Significant weight gain occurred in the first 12 months, consistent with earlier studies ⁸ , ¹² , ¹³ , ¹⁸ that also show the amount gained varies with geographic location. ⁷ For example, weight gain in North American HTRs was about 10 kg (BMI +3.25 kg/m²) compared with about 6 kg in Australia (based on 22 HTRs) ¹¹ and about 3 kg (BMI + .78 kg/m²) in European countries. ⁷ Our contemporary study HTRs had heavier mean BMI throughout than Australian HTRs two decades previously, but weight increase was smaller. ¹³

Weight gain in HTRs may be due partly to increased lean mass due to increased physical activity after transplantation; we could not distinguish an increase in fat from lean mass. A study of 59 Norwegian HTRs observed a relatively stable total lean mass with a small total fat mass increase (26%–28%), ¹⁹ consistent with the majority of HTRs living a sedentary lifestyle, ¹⁹ , ²⁰ and weight gain more likely due to increased fat. ¹⁹ , ²¹ , ²² , ²³

Our findings regarding serum total cholesterol are consistent with previous observations that the highest increases also occur in the first 12 months, ¹² , ¹³ though others have observed a further increase in cholesterol levels after 12 months, and a Brazilian study of 82 HTRs reported significantly higher blood lipids in patients with BMI ≥25 kg/m² compared with <25 kg/m² at 5 years. ¹² We showed that cholesterol levels were generally well‐controlled, particularly among HTRs on statin therapy at 12 months post‐transplantation as recommended. ²⁴ Statins are beneficial in reducing serum cholesterol in HTRs and in improving other health outcomes such as survival. ²⁵ As expected, statin therapy did not affect triglyceride levels in our study.

While the primary approach to treating dyslipidaemia in HTRs is through medications, dietary approaches favorably combat lipid and weight increases. ²¹ In a UK feasibility study, 41 thoracic transplant recipients were randomly allocated to either a Mediterranean or low‐fat diet for 12 months, and showed weight reduction in the former (−1.8 kg), negligible weight gain in the latter (.2 kg), but 2‐kg gain in those who did not participate. ²⁶ Cholesterol and triglyceride levels decreased with both diets. ²⁶ Likewise, among 42 Italian HTRs followed‐up for 48 months, those who adhered to dietary advice reduced weight and lipids, while those who did not increase weight and lipids at 12 and 48 months. ²¹ Similar beneficial effects on weight and blood lipids were observed after a 6‐month lifestyle intervention. ²⁷ Thus long‐term lifestyle interventions in HTRs can help prevent excessive weight gain, and optimize weight and lipid profiles.

The clinical significance of our findings of progressive weight gain and increasing blood cholesterol levels in the years immediately after transplantation lies in the resulting CAV and other cardiovascular events such as stroke and peripheral artery disease, ² , ²⁸ as well as increased risks of infection and graft loss. ⁹ , ²⁹ , ³⁰ Therefore, clinical advice and treatment to prevent predictable excess weight gain and control blood cholesterol, especially in the first year, are critical to enhance graft and patient survival.

The results from our study are novel in that they quantify long‐term weight and blood lipid profile changes after heart transplantation beyond the first year after transplantation. However, our study was limited by its retrospective design, whereby important information was not always documented (especially diagnoses of diabetes) and records of weight and other clinical information before transplantation were often incomplete. Different types of statins may have different potencies, but we assumed that types of statins did not change during follow‐up. Also, given that CAV and graft failure progressively become leading causes of mortality with increasing time since transplantion, ² a further study limitation was our lack of longer‐term clinical data among HTRs; ideally, we would have related weight change to outcomes, particularly CAV, at 5–10 years post‐transplant. ²³ Finally, since this is a single center study and the representativeness is unknown, findings may not be generalizable.

In conclusion, we have demonstrated in a large cohort of Australian HTRs that significant weight gain occurs over the 36 months post‐transplantation, with most weight gain occurring during the first 12 months. Our patients had generally well‐managed blood lipids during the follow‐up period, and the changes in blood lipids tended to reflect fluctuations in weight. Early statin therapy was beneficial in controlling cholesterol during the 36 months post‐transplantation. Research into dietary and other lifestyle interventions is urgently needed to mitigate the risk of long‐term obesity and dyslipidaemia in HTRs.

AUTHOR CONTRIBUTIONS

Kyoko Miura conceptualized, design and conducted the study, managed and analyzed data, and wrote the manuscript. Regina Yu collected the data and assisted data interpretation. Timothy R. Entwistle assisted conceptualizing the study and data interpretation. Scott C. McKenzie helped data acquisition and assisted data interpretation. Adèle C. Green obtain the funding, conceptualized and design the study, and assisted data interpretation. All authors critically reviewed the manuscript and approved the final version submitted for publication.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Supporting information

Supplemental Figure 1: Estimated mean a) total cholesterol and b) triglycerides overtime by baseline BMI category (n = 150)

BMI: body mass index

Underweight/normal weight = BMI < 25.0 kg/m²; Overweight = BMI 25.0–29.9 kg/m²; Obese = BMI ≥30 kg/m²

Underweight/normal weight (n = 66, 44%); overweight (n = 56, 37%); obese (n = 28, 19%).

a) total cholesterol p‐values for time: .004; baseline BMI: .84; baseline BMI‐by‐time interaction: .66; statin therapy: .05.

b) triglycerides p‐values for time: .006; baseline BMI: .19; baseline BMI‐by‐time interaction: .021; statin therapy: .48.

Supplemental Figure 2: Estimated mean a) total cholesterol and b) triglycerides overtime by statin therapy at 12 months

(n = 150)

Not taking (n = 35, 23%); decreased/ceased (n = 28, 19%); therapy ongoing, unchanged (n = 40, 27%); increased/commenced (n = 47, 31%).

a) Total cholesterol: p‐values for time: .003; statin therapy: .010; statin therapy‐by‐time interaction: .005.

b) Triglycerides: p‐values for time: .043; statin therapy: .46; statin therapy‐by‐time interaction: .76.

Supplemental Table 1: Estimated mean body weight and BMI over time by baseline BMI

Supplemental Table 2: Estimated mean total cholesterol and triglycerides over time by baseline BMI

Supplemental Table 3: Estimated mean LDL and HDL cholesterol over time by baseline BMI

Supplemental Table 4: Estimated mean total cholesterol and triglycerides over time by statin therapy

Supplemental Table 5: Median changes in weight and BMI (minimum, maximum) by prednisolone doses at 12 months post‐transplantation

Supplemental Table 6: Median serum lipid levels (minimum, maximum) at 12 months by prednisolone doses at 12 months post‐transplantation

Supplemental Table 7: Comparison of median serum lipid levels between patients who were taking tacrolimus vs. cyclosporine overtime

Miura K, Yu R, Entwistle TR, McKenzie SC, Green AC. Long‐term changes in body weight and serum cholesterol in heart transplant recipients. Clin Transplant. 2022;36:e14819. 10.1111/ctr.14819

DATA AVAILABILITY STATEMENT

The datasets generated and/or analyzed during the current study are not publicly available due to confidentiality of clinical data belonging to the small numbers of hospital patients involved, but are available from the corresponding author upon reasonable request.