1. Study population

We prospectively enrolled 48 patients with severe mitral valvular disease scheduled for MV surgery (repair or replacement). Patients with combined significant valvular heart disease, ischemic heart disease, cardiomyopathies, right ventricular (RV) dysfunction, previous MV surgery, diabetes, cirrhosis or active hepatitis, thyroid disease, chronic inflammatory or infectious diseases, and active malignancy (i.e. diseases that could affect metabolism, nutritional status and body composition), known pregnancy, use of steroid, antidepressant, and other appetite stimulants were excluded.

This study was approved by the Ethics Committee and Institutional Review Board of Yonsei University College of Medicine, and written informed consent was obtained from all patients prior to enrolment.

2. Short nutrition assessment questionnaire (SNAQ)

Appetite was measured using the Simplified Nutritional Appetite Questionnaire (SNAQ) [7]. The SNAQ includes four questions based on following numerical scale: A = 1, B = 2, C = 3, D = 4, E = 5.

1. My appetite is (A. very poor/ B. poor/ C. average/ D. good/ E. very good)
2. When I eat (A. I feel full after eating only a few mouthfuls/ B. I feel full after eating about a third of a meal/ C. I feel full after eating over half of meal/ D. I feel full after eating most of the meal/ E. I hardly ever feel full)
3. Food tastes (A. Very bad/ B. Bad/ C. Average/ D. Good/ E. very good)
4. Normally I eat (A. Less than one meal a day/ B. One meal a day/ C.Two meals a day/ D.Three meals a day/ E. More than 3 meals a day).

The total SNAQ score range from four to 20. Those with SNAQ scores <14 has been reported to be at significant risk for weight loss >5% within 6 months, with a sensitivity of 81.3%, and a specificity of 76.4% [7].

3. Echocardiography

Echocardiography was performed using a GE Vingmed System 7 ultrasound system (Horten, Norway) with a 2.5-MHz transducer for image acquisition. Standard two-dimensional measurements were obtained with the patient in the left lateral position. Left ventricular ejection fraction (LVEF) was measured using the modified Simpson method. Left ventricular (LV) outflow tract diameter (LVOTd) was measured in the parasternal long axis view in early systole immediately adjacent to the point of aortic cusp insertion. LVOT velocity–time integral (VTI_LVOT) measured using pulsed wave Doppler was recorded from the apical five chamber view in the LVOT, by placing the sample volume approximately five mm apically from the aortic valve and aligning it parallel with blood flow. LV stroke volume (SV) was obtained by multiplying the LVOT area by VTI_LVOT using the formula SV (ml) = LVOT area (cm²) x VTI_LVOT (cm). Left atrial (LA) volumes were calculated by biplane Simpson method using apical four and two chamber views. The LA volume index (LAVI) was calculated as LA volume/body surface area (mL/m²). Right ventricular systolic pressure (RVSP) was estimated from the maximal tricuspid regurgitant jet velocity by using the modified Bernoulli equation (4V²) and the addition of estimated right atrial pressure on the basis of inferior vena cava diameter and collapsibility as previously described [8].

Echocardiographic severity of valvular stenosis or regurgitation was assessed according to EAE/ASE recommendations for clinical practice [9–10].

4. Dual-energy X-ray absorptiometry (DXA)

Body compositions were measured by a standardized method, using DXA and assessed using whole body composition software (BHR-140-P Discovery A, Hologic Inc., Bedford, MA, USA). All scans were acquired and analyzed according to each manufacturer's standard scanning and positioning protocols. DXA scanned the weight (g) of total mass, fat mass, lean body mass, and the percentage of fat (fat mass divided by total mass) was calculated. Bone mineral content was expressed in g, and bone mineral density (BMD) in g/cm². The coefficient of variation for both spine and whole body calibration phantoms was less than 1%.

Statistical analysis

Continuous variables are represented as mean (± standard deviation) or median (inter-quartile range) if non-normally distributed. Categorical variables are presented as counts and proportions. Comparisons between before and after MV surgery were performed with paired t-test or Wilcoxon signed rank test for paired continuous data. Man-Whitney U test was used for non-parametric comparisons of continuous data between groups. Correlations of pre-operative SNAQ and ΔSNAQ with other variables were performed using Pearson’s coefficient (r) or Spearman correlation. The significance level was set at p <0.05. Statistical analyses were performed using SPSS version 23.0 (IBM, Armonk, NY, USA).

Body alterations after MV surgery

The alteration of body composition in wasting process consists of a reduction in fat mass, fat-free mass and bone mass [4–5]. Palmieri V. et al. suggested that more severe valvular insufficiency is associated with lower body mass index (BMI) and lower body fat mass, measured with bioimpedance [11]. Studies in dogs with mitral stenosis showed that cachectic changes became more pronounced and they lose fat and lean body mass over time [12].

For the reversibility of wasting process, patients with heart failure who underwent heart transplantation, showed an improved cardiac function leading to the cessation of wasting process with subsequent weight gain[13]. However, weight gain following the transplantation is also associated with the use of steroid and immune suppressants that cause increase in fat mass [14].

To our knowledge, this is the first study to demonstrate the reversibility of wasting process with the changes in body composition after corrective surgery for valvular heart disease. Majority of our patients with severe MV disease, who were scheduled for MV surgery, showed normal range of BMI with non-cachectic appearance preoperatively. As healthcare accessibility and HF management including cardiovascular medications improve, patients with typical cachectic appearance are hardly seen in recent practice of cardiology.

Nonetheless, our population showed evidences of significant malnourishment, as indicated by anemia, low albumin level, as well as poor DXA profile (low body fat percentage and BMD).

After MV surgery, the body profile alterations in our population could be contributed to a certain extent by the significant increase in their appetite after surgery. Similarly, Buchanan N. et al. reported that 11 patients with severe MV disease had experienced a marked increase in appetite after MV surgery [6].Though the precise mechanism is unclear, neurohormonal activation involved in poor appetite in HF might be alleviated by the corrective MV surgery, which improves the cardiac function. In laboratory findings, NT-proBNP, a surrogate of high LV filling pressure that stimulates lipolysis in adipose tissue [15], significantly declined and serum albumin increased after surgery. It identifies a nutritional improvement in patients recovering from heart failure after corrective MV surgery.

Furthermore, body compositionof this population showed alteration as an increase in body fat percentage and BMD, despite no significant difference in the BMI before and after MV surgery. As wasting process progressed in HF, fat loss precedes the loss of lean body mass, and alterations in lean body mass may be either inconclusive or decreased [16]. Melenovsky V. et al. had identified the decrease in fat mass and relative preservation of lean body mass in cachectic patients with advanced HF by using DXA [17]. In these patients with MR, although the depleted body fat and BMD were replenished over one year, lean body mass was significantly decreased after surgery. Considering that lean body mass detected by DXA is heterogeneous and consists of cell mass and total body water distributed in intracellular and extracellular spaces, the significant decrease of lean body mass In this study may reflect the loss of edema (body water) rather than the loss of cell mass with an improvement of heart failure after corrective surgery.

When we dichotomized the patients according to the primary valve lesion, both groups showed an improvement in appetite, echocardiographic and laboratory parameter in the same manner. Notably, even patients with MS were undersized, they had higher percentage of body fat than patients with MR, preoperatively. After surgery, only patients with MR showed a significant increase in BMD and body fat and the patients with MS did not. It suggests that body wasting in pre-operative patients with MS might be less advanced and surgical correction had less impact on body composition in patients with MS. However, it should also be taken into account low statistical power by small sample size of patients with MS.

RV impairment and body wasting

On correlation analysis, pre-operative SNAQ and ΔSNAQ were significantly associated with the respective values of eRVSP, and these results are limited to the patients with MR. Also, patients with Δfat ≥2% showed higher pre-operative eRVSP and ΔeRVSP levels than the patients with Δ fat <2% in patients with MR. This demonstrated that both ΔSNAQ and Δfat % have inverse relationships with ΔeRVSP and that RV pressure overload is involved in the occurrence and recovery of wasting process in severe MV disease, especially in MR. However, these results do not apply to the patients with MS despite the similar eRVSP values with those with MR. Among left-sided valvular heart disease, pathophysiological adaptation in MS begins with chronic pressure overload of LA and chronic pressure and volume overload in MR. By non-compliant LA, pulmonary venous pressure is elevated and lead to irreversible changes as deposition of type II collagen, which passively increases pulmonary arterial pressure (PAP). The difference in the two diseases is that PAP in MS is rapidly decreased after relief of the stenosis, whereas more time could be required in MR of which pulmonary hypertension is linked to volume overload [18]. These different responses of PAP after MV surgery might be involved in the different results of the two diseases in this study, although the precise mechanism remains unclear. However, as mentioned above, we should also consider the sample size and less advanced body wasting of patients with MS than those with MR. Further studies with more patients with valvular heart disease and serial follow-up are needed to confirm our results.

In this study, we found no significant relationship between the changes in LV systolic function and body composition, which is line with the previous reports that LV EF was similar in both cachectic and non-cachectic patients [4,19].

Although there are few data about the relation between RV function and wasting process, growing evidence suggests the importance of RV function and the associated parameters as principal factors of wasting process in HF [17, 20–22]. It has been reported that increased right atrial pressure and tricuspid regurgitation (TR) were significant predictors of malnutrition and were associated with the loss of fat mass in HF [20–22]. Melenovsky V. et al. identified that patients with RV dysfunction had lower BMI and less body fat mass than those with preserved RV function, whereas lean body mass was similar in both groups [17].

For the pathogenesis of wasting process, RV impairment leads to splanchnic venous congestion, liver stasis, and gastrointestinal edema, and it might be associated with anorexia, protein, and fat malabsorption. The catabolic effect of inflammatory cytokines and neurohormone might also play an important role in weight loss [23]. However, the underlying pathogenesis beginning with RV impairment until wasting is not fully elucidated.

The reversing of wasting process with improvement of RV dysfunction has been reported earlier, albeit small studies. Serum protein level in a patient with severe TR complicated by severe hypoproteinemia became normalized after tricuspid valve replacement [24], and patients with atrial septal defect (ASD) and massive TR showed a significant weight gain after successful ASD device closure [25]. Patients with HF and severe pulmonary hypertension, who underwent phosphodiesterase 5 inhibitor therapy, showed a significant decrease in pulmonary arterial pressure and maintained a steady body weight when compared with controls who experienced significant weight loss [26].

In this study, the patients with severe TR and RV dysfunction were excluded to assess the isolated effect of severe MV disease on body composition. Nonetheless, we found that RV pressure overload in itself could affect the body composition in severe MV disease and these results support the previous studies suggesting the crucial role of RV in the wasting process of HF.

Limitation

There are several limitations in this study. First, the study population was relatively small; a larger sample size and serial follow-up would provide more conclusive results. Although the noninvasive estimation of RVSP using echocardiography has been validated with invasively measured pressures in numerous studies, right heart catheterization would be the definitive modality for assessment of right heart pressures and function. To assess isolated effect of severe MV disease on body composition, we excluded the patients with low LV systolic function and other cardiomyopathies who would be expected to gain greater changes to the wasting process. Also, patients with RV dysfunction and severe TR were excluded and these results are restricted to the patients of MV disease without overt RV dysfunction. Since the corrective surgery in isolated TR and RV dysfunction cases are limited, it is hard to determine the role of RV dysfunction on wasting process. Most of patients had taken cardiovascular medications as statin, beta blocker and/or calcium channel blocker, which could also affect on the metabolism. Since it is difficult to consider all of these aspects, we exclude only patients taking medications which directly influence on the appetite as steroid, anti-depressant, and other appetite stimulants.