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Heart failure and cardiomyopathies
Original research article
Malnutrition, congestion and mortality in ambulatory patients with heart failure
  1. Shirley Sze1,
  2. Pierpaolo Pellicori1,
  3. Jufen Zhang1,2,
  4. Andrew L Clark1
  1. 1 Department of Cardiology, Castle Hill Hospital, Hull York Medical School (at University of Hull), York, UK
  2. 2 Faculty of Medical Science, Anglia Ruskin University, Cambridge, UK
  1. Correspondence to Dr Shirley Sze, Department of Cardiology, Castle Hill Hospital, Hull York Medical School (at University of Hull), Hull HU16 5JQ, UK; hy9ks1{at}hyms.ac.uk

Abstract

Background In patients with chronic heart failure (CHF), malnutrition might be related to right heart dysfunction and venous congestion, which predispose to bowel oedema and malabsorption, thereby leading to malnutrition. We explored the relation between congestion, malnutrition and mortality in a large cohort of ambulatory patients with CHF.

Methods We assessed malnutrition using the Geriatric Nutritional Risk Index (GNRI). Congestion was defined by echocardiography (raised right atrial pressure (RAP)=dilated inferior vena cava≥21 mm/raised pulmonary artery systolic pressure (PAsP)=transtricuspid gradient of ≥36 mm Hg/right ventricular systolic dysfunction (RVSD)=tricuspid annular plane systolic excursion <17 mm).

Results Of the 1058 patients enrolled, CHF was confirmed in 952 (69% males, median age 75 (IQR: 67–81) years, median N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) 1141 (IQR: 465–2562) ng/L). 39% had HF with -reduced ejection fraction (left ventricular ejection fraction, LVEF <40%) and 61% had HF with normal (HeFNEF, LVEF ≥40% and NT-pro-BNP >125 ng/L) ejection fraction. Overall, 14% of patients were malnourished (GNRI ≤98). 35% had raised RAP, 23% had raised PAsP and 38% had RVSD. Congestion was associated with malnutrition. During a median follow-up of 1683 days (IQR: 1096–2230 days), 461 (44%) patients died. Malnutrition was an independent predictor of mortality. Patients who were malnourished with both RVSD and increased RAP had much worse outcome compared with non-malnourished patients without RVSD who had normal RAP.

Conclusion Malnutrition and congestion are modestly correlated and each is independently associated with increased mortality in patients with CHF. Patients with HF with both malnutrition and congestion as evidenced by right heart dysfunction should be managed with additional vigilance.

  • heart failure
  • echocardiography

https://doi.org/10.1136/heartjnl-2018-313312

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    Introduction

    Malnutrition is common among patients with chronic heart failure (CHF). It has been implicated in the origin of cachexia,1 2 and is associated with worse prognosis.3–5 However, its pathophysiology is not fully understood.

    CHF is characterised by congestion and high systemic venous pressures. Previous work has suggested that cachexia in CHF is associated with both high right atrial pressure (RAP) and tricuspid regurgitation.6–8 There is an association between right ventricular (RV) dysfunction and intestinal and liver congestion9 10 and abnormal body composition11 in cachectic patients with CHF. However, the relation between malnutrition, RV dysfunction and systemic venous congestion in patients with CHF has not been studied.

    We hypothesised that patients with CHF who have significant clinical congestion, high right heart pressures and RV dysfunction might be at risk of developing congestive enteropathy, malabsorption and anorexia, thereby leading to clinical malnutrition and worse outcome. We studied the relation between congestion (assessed clinically and with echocardiography) and malnutrition, and the relation between these features and outcome in a large cohort of well-characterised ambulatory patients with CHF.

    Methods

    Study population

    From 2000, patients referred by either primary or secondary care physicians to a community CHF clinic serving a local population of about 500 000 people were enrolled in a longitudinal observational study of patients with CHF (The Hull LifeLab). Some patients had no prior diagnosis of CHF and were treatment naive, therefore requiring initiation of guideline-recommended therapy; many others had a pre-existing diagnosis of CHF and had already been initiated on treatment that might, however, require optimisation. We have previously reported the prevalence of moderate to severe malnutrition among patients with CHF is 7%–10%, depending on the screening tool and definition used.12 In patients hospitalised for HF, up to 46% were malnourished.13 In the present paper, we focused on a subset of patients from the Hull LifeLab who were enrolled between 2008 and 2012 for whom we have detailed echocardiographic images, and studied the relation between congestion and malnutrition.

    All patients had a full medical history, physical examination, blood tests (including full blood count, urea and electrolytes and N-terminal pro-B-type natriuretic peptide, NT-pro-BNP), an ECG and an echocardiogram. Weight was measured with the patients wearing their casual clothes but without shoes. Body mass index (BMI) was calculated using the formula: BMI=weight in kilograms/(height in metres) squared.

    CHF was defined as the presence of symptoms or signs of CHF and evidence of cardiac dysfunction, with either: left ventricular (LV) systolic dysfunction (LV ejection fraction (LVEF) <40%; heart failure with reduced ejection fraction, HeFREF) or normal LV systolic function (LVEF ≥ 40%) and raised NT-pro-BNP of >125 ng/L (heart failure with normal ejection fraction, HeFNEF).14 Patients whose LVEF was -≥40% and who had NT-pro-BNP ≤125 ng/L were considered not to have CHF.

    A congestion score was constructed, based on lung auscultation (normal, presence of basal, mid-zone or diffuse crackles), jugular venous pressure (JVP) (not visible, raised 1–4 cm, raised to earlobe), peripheral oedema (none, ankles, below or above knees) and liver examination (not palpable, palpable) with one point attributed for each degree of severity and a total possible score of 9. Patients with a score of 3 or more were defined as severely congested.15

    Echocardiograms were performed by an experienced sonographer using a Vivid 5 or 7 scanner (GE, Fairfield, Connecticut) with a 2.5 MHz phased array transducer. LV systolic function was measured by calculating LVEF using Simpson’s method. RV systolic function was measured by tricuspid annular plane systolic excursion (TAPSE). Patients with TAPSE <17 mm were defined as having RV systolic dysfunction (RVSD).16 RV systolic pressure and RAP were estimated from the maximal tricuspid regurgitation velocity and inferior vena cava (IVC) diameter, respectively. Patients with IVC diameter of <21 mm were considered to have normal RAP, whereas those with IVC diameter of ≥21 mm were considered to have an increased RAP.16 Patients with transtricuspid gradient of ≥36 mm Hg were considered to have raised pulmonary arterial systolic pressure (PAsP).16 Mitral and tricuspid regurgitation were assessed semiquantitatively and expressed in four grades (absent, mild, moderate or severe).

    Ischaemic heart disease was defined as any medical history of acute coronary syndrome (ACS), percutaneous coronary intervention or coronary artery bypass surgery, or a diagnosis of myocardial ischaemia based on invasive or non-invasive diagnostic tests. Cerebrovascular disease was defined as any history of stroke or transient ischaemic attack. Peripheral vascular disease was defined as a clinical history of the diagnosis.

    Malnutrition screening

    Patients were screened for malnutrition using the Geriatric Nutritional Risk Index (GNRI),17 which we have previously shown12 to have the greatest prognostic value compared with two other commonly used malnutrition screening tools: the Controlling Nutritional Status score18 and the Prognostic Nutritional Index.19

    The GNRI was calculated using the formula: 1.489xserum albumin (g/L)+41.7x (body weight in kilograms/ideal body weight).16 Ideal body weight was calculated using the formula: 22xsquare of height in metres.20 Patients with GNRI >98 have normal nutritional status, those with GNRI 92–98, 82–91, <82 have mild, moderate and severe malnutrition, respectively.

    Endpoints and follow-up

    Patients were followed up until 1 May 2016. The primary endpoint was all-cause mortality. Our hospital is the only one in the region offering acute medical services. With previous consent from patients, we could access all their primary and secondary care records. Outcome was censored at the point of last medical contact in primary or secondary care. Data regarding hospitalisations and deaths were collected from the hospital’s electronic systems and were entered into a dedicated database, stored on a secure NHS server.

    Statistical analysis

    Continuous data are expressed as a median with IQR (25–75th centiles) and categorical data are expressed as N (%). Independent t-tests and Mann-Whitney U tests were used to compare two continuous variables for normally and non-normally distributed data. The χ2 test was used to compare proportions between groups. Pearson’s correlation or Spearman’s correlation coefficients were used to assess the relationships between two variables. Log-transformation was applied when the data were very skewed. Logistic regression analysis was used to estimate associations between other variables and malnutrition.

    The impact of variables on survival was investigated using the Cox proportional hazards model. Additionally, we created a base model for predicting mortality after adjusting for the following variables which are commonly available in clinical practice and are significantly associated with outcome: age, systolic blood pressure, New York Heart Association (NYHA) class, urea and NT-pro-BNP. We added the malnutrition score (GNRI), markers of congestion (clinical and echocardiographic) and combinations of malnutrition and markers of congestion in turn to the base model and used C-index (the area under receiver operating characteristic curves) and Net Reclassification Index (NRI) to evaluate model discrimination in logistic regression analysis. The C-index is defined as the probability that predictions and outcomes are the same. A C-index of 0.5 means that the relationship is no better than chance.

    All statistical analyses were performed using SPSS V.22 (SPSS) and the Stata (V.14, StataCorp) statistical computer package. A two-tailed p value of <0.05 was considered significant in all analyses.

    Results

    Patient characteristics

    Baseline characteristics (clinical data and measures of congestion) of the overall cohort are shown in table 1 (online supplementary appendix 1a,b). Baseline characteristics by GNRI (malnourished vs not malnourished), by RVSD and clinical congestion are shown in table 2A–C (online supplementary appendix 2). Of the patients with CHF, 10% had mild malnutrition and 4% had moderate to severe malnutrition. (table 1 and online supplementary appendix 2). Malnutrition was more common in patients with HeFREF than HeFNEF (17% vs 12%, p=0.01) (online supplementary appendix 1a).

    Supplementary file 1

    Supplementary file 3

    View this table:
    Table 1

    Baseline characteristics of the entire cohort

    View this table:
    Table 2A

    Baseline characteristics of patients with HF (malnourished vs not malnourished)

    View this table:
    Table 2B

    Baseline characteristics of patients with HF (RVSD vs no RVSD)

    View this table:
    Table 2C

    Baseline characteristics of patients with HF (clinical congestion vs no clinical congestion)

    Prevalence of clinical signs of congestion

    Although a small proportion of patients without CHF had signs of congestion on clinical examination, patients with CHF were much more likely to have these signs (table 1). Patients with HeFREF were as likely to have clinical signs of congestion as patients with HeFNEF (online supplementary appendix 1a).

    Prevalence of RV dysfunction and increased PAsP and RAP

    Compared with patients without CHF, those with CHF were more likely to have RVSD, raised PAsP and raised RAP. RVSD and increased RAP were more common in patients with HeFREF than in those with HeFNEF (online supplementary appendix 1b).

    Supplementary file 2

    Clinical associations of malnutrition

    Compared with patients with normal nutritional status, patients with malnutrition were older, had lower BMI, worse renal function and HF symptoms, and higher NT-pro-BNP levels (table 2A, online supplementary appendix 2).

    Malnutrition and clinical signs of congestion

    Patients with CHF and malnutrition were more likely to have signs of congestion on clinical examination than those without malnutrition. Malnourished patients with HeFREF or HeFNEF were equally likely to have signs of congestion (online supplementary appendix 2). Of the four clinical signs of congestion, peripheral oedema and raised JVP were the two most common.

    Malnutrition and echocardiographic findings

    Patients with malnutrition were more likely to have RVSD and increased PAsP and RAP compared with those with normal nutrition (table 2A). The simultaneous presence of RVSD and increased RAP was much more common in malnourished patients than in non-malnourished patients (33% vs 17%, p<0.001). The prevalence of LV systolic dysfunction and LA dilation was not related to malnutrition (table 2A). Box plot figures comparing the key echocardiographic measures in malnourished versus non-malnourished patients with HeFREF versus HeFNEF were shown in online supplementary appendix 3a–e.

    Correlations between malnutrition and echocardiographic findings

    Worsening malnutrition correlated with increasing NT-pro-BNP levels, increasing age and worsening RV dysfunction by ultrasound: decreasing TAPSE, increasing RAP and PAsP (online supplementary appendix 4). Malnutrition was more strongly linked to elevated right-sided pressures than to either or LV dysfunction (online supplementary appendix 4).

    Supplementary file 9

    If we used an NT-pro-BNP cut-off of >400 ng/L to diagnose HeFNEF, in accordance to National Institute for Health and Care Excellence guidelines,21 the prevalence of congestion and malnutrition would have been slightly higher among patients with HeFNEF (congestion: from 15% to 18%; RVSD: from 30% to 34%, malnutrition from 12% to 15%). However, the change of cut-off does not alter the modest relationship between congestion, RVSD and malnutrition (worsening malnutrition correlated with decreasing TAPSE (correlation coefficient from 0.21 to 0.17 (both p<0.001) and increasing congestion score (correlation coefficient remains the same: 0.05, p=0.15 and p=0.16, respectively).

    Logistic regression analysis of clinical and echocardiographic variables associated with malnutrition is shown in table 3. NT-pro-BNP (OR 5.7, 95% CI 3.2 to 10.1, p<0.001) had the strongest association with malnutrition, followed by transtricuspid gradient (OR 1.11, 95% CI 1.0 to 1.2, p=0.03) (table 3).

    View this table:
    Table 3

    Logistic regression analysis of clinical and echocardiographic variables associated with malnutrition in all HF subjects (backward selection)

    Malnutrition, echocardiographic findings and hospitalisation in the year before recruitment

    -539 (57%) patients were admitted to hospital in the year before recruitment, of which 181 (34%) were HF admissions. Patients with previous hospitalisations for HF were more likely to be malnourished and have raised RAP/PAsP or RVSD compared with patients with previous cardiovascular but non-HF hospitalisations or no hospitalisations (online supplementary appendix 5).

    Supplementary file 10

    Malnutrition, RVSD and mortality

    During a median follow-up of 1683 days (IQR: 1096–2230 days), 461 (44%) patients died.

    Univariable and multivariable predictors of mortality for the overall population and for the different HF phenotypes are shown in table 4 and online supplementary appendix 6a–b. In univariable analysis, the presence of malnutrition, signs of congestion, increasing PASP, RAP and Left Atrial Volume Index (LAVI) and decreasing TAPSE and LVEF were associated with worse outcome.

    Supplementary file 11

    View this table:
    Table 4

    Univariable and multivariable analysis of factors predicting outcomes in patients with HF (overall population)

    In a multivariable model including all the patients, malnutrition was independently associated with an increased risk of all-cause mortality. Of the echocardiographic variables, only increasing RAP and LAVI were significant predictors of mortality (table 4, online supplementary appendix 7).

    Supplementary file 12

    The Kaplan-Meier curve for the relationship between malnutrition, RV dysfunction, increased RAP and outcome is shown in figure 1. Compared with patients who were not malnourished with normal RV function and RAP, those with malnutrition and normal RV function and RAP had a twofold increase in the risk of death for any cause. Those who were malnourished with RV dysfunction and raised RAP had the worst outcome (figure 1).

    Figure 1
    Figure 1

    Kaplan-Meier curve showing the relation among malnutrition (mal), RVSD and increased RAP and all-cause mortality. RAP, right atrial pressure; RVSD, right ventricular systolic dysfunction.

    A base model (including age, systolic blood pressure, NYHA class, urea and NT-pro-BNP) for predicting mortality achieved a C-index=0.79 (table 5). Moderate to severe malnutrition by GNRI and markers of congestion (both clinical and echocardiographic), when added individually, did not improve performance of the base model. The NRI produced similar results. Addition of moderate to severe malnutrition by GNRI and clinical congestion (congestion score ≥3) in combination and addition of moderate to severe malnutrition by GNRI and IVC diameter in combination improved performance of base model (C=0.80 and 0.81, respectively, p=0.02 for both).

    View this table:
    Table 5

    Effect of addition of clinical congestion and echocardiographic markers of right cardiac dysfunction to base model in predicting mortality

    Discussion

    Ours is one of the few studies9 10 22 23 to explore the relation between malnutrition and congestion in patients with CHF. Our study comprehensively investigated the associations between malnutrition, right heart dysfunction and venous congestion assessed clinically, biochemically and by echocardiography.

    We hypothesised that malnutrition might be caused by congestion, but only found a modest relation between malnutrition and measures of congestion. Although ours is a study of associations of malnutrition, and thus few conclusions can be drawn about causation, the weakness of the correlation between the two suggests that one does not directly cause the other. Congestion and malnutrition were independent predictors of mortality, again suggesting that they are measures of different aspects of the HF syndrome and may not be causally related.

    One explanation for our findings might be that it is historical congestion that causes malnutrition and that the malnutrition we measured at the time of the assessment would not be related to any congestion present at the time. We found that patients with previous admissions for HF were more likely to be malnourished or have raised RAP, PAsP or RVSD compared with patients with previous cardiovascular but non-HF hospitalisations or no hospitalisation, which might imply a closer link between malnutrition and previous congestion.

    Our findings are similar to those from Valentova et al, who studied the relationship between congestion and cardiac cachexia in 169 outpatients with HF due to LV systolic dysfunction.9 They found that cachexia was more common in patients with reduced RV function and elevated RAP than in patients with either reduced RV function but normal RAP or preserved RV function (67 vs 15 vs 7%). They also found that cachexia was associated with thicker bowel wall (OR 1.3; 95% CI 1.1 to 1.6; p=0.002).

    Previous work has mainly focused on identifying mechanistically plausible explanations for the association between cachexia/malnutrition and congestion/cardiac dysfunction in patients with CHF. Congestion and cardiac dysfunction have been implicated as a cause of malnutrition. Systemic venous congestion in the hepatic and splanchnic beds cause intestinal congestion and dysmotility, anorexia, malabsorption and increased intestinal permeability with protein loss and endotoxin translocation.24 Neurohormonal activation exacerbates renal dysfunction, leading to more salt and water retention, contributing to bowel congestion and development of malnutrition.8 Chronic intestinal congestion might cause persistent lipopolysaccharide translocation which might induce systemic release of proinflammatory cytokines and worsen the underlying intestinal congestion.8 In addition, RV dysfunction and pulmonary hypertension cause the release of natriuretic peptides,25 which stimulates lipolysis of adipose tissue26 and indirectly stimulate secretion of adiponectin which promotes glucose and fatty acid utilisation,27 resulting in weight loss and increased mortality.

    Malnutrition might itself aggravate underlying left and right heart dysfunction, leading to a vicious spiral of deterioration. Metabolites and cytokines released secondary to malnourishment state might adversely affect cardiac performance. Cytokines, such as tumor necrosis factor alpha (TNF-α), raised in patients with cachexia, have potent negative inotropic effects and might subsequently impair RV and LV systolic function.28

    Although we found that malnutrition is associated with congestion, the association is modest, suggesting that they are two distinct entities. Other factors such as advanced age and severity of CHF might also have important roles to play in the pathogenesis of malnutrition. Patients with CHF often suffer from multiple comorbidities, such as osteoarthritis, airways disease, renal dysfunction, cognitive impairment, anxiety and depression, which might interact with and/or modify the course of CHF and have negative impact on medication adherence, self-care ability and food intake.29 Lack of social support and financial constraints negatively impact on activities of daily living, such as shopping and preparing meals, hence predisposing to malnutrition.

    Limitations

    This is a single-centre study conducted in the UK; external validation of our results from other countries with different healthcare and social systems is needed. Second, we have only studied one of the large numbers of tools available to screen for malnutrition. Third, this is an observational study, and thus causality cannot be addressed.

    Additionally, uptitration of anti-HF medications during follow-up for patients with HeFREF might have led to an improved congestive and nutritional status, and perhaps outcome, in some.

    Furthermore, this study is an explorative analysis using a comprehensive prospective data collection undertaken as part of the Hull LifeLab database between 2008 and 2012. The analysis plan was decided post hoc, and results might have changed overtime, particularly as newer treatments have become available.

    The GNRI is derived from serum albumin and the ratio of body weight to ideal body weight. Although it is questionable whether an ideal BMI of 22 kg/m2 as used in our formula to calculate ideal body weight applies to a UK population, as it might underestimate prevalence of malnutrition in our population, a recent report from UK Biobank enrolling more than 200 000 UK residents without cardiovascular risk factors supports these findings.30

    Lastly, we have included patients with HeFNEF, for which there is no universally agreed diagnostic definition and some might not accept our definition based only on the evidence of signs or symptoms supported by a natriuretic peptide level above the diagnostic level suggested by current ESC-HF guidelines (125 ng/L).

    Conclusion

    Malnutrition and congestion are both common but are only modestly associated with each other in patients with CHF. The concomitant presence of malnutrition and congestion is strongly associated with a high mortality in patients with CHF; these patients should thus be managed with additional vigilance.

    Key messages

    What is already known on this subject?

    • Malnutrition is common among patients with chronic heart failure (CHF) and is associated with worse prognosis, but its pathophysiology is not fully understood.

    • Weight loss in CHF is associated with right heart dysfunction and intestinal congestion.

    What might this study add?

    • We explored the relation between malnutrition and congestion (assessed clinically or by echocardiography) in a large cohort of well-characterised ambulatory patients with CHF and found that malnutrition and congestion are modestly associated with each other.

    • The concomitant presence of malnutrition and congestion is strongly associated with high mortality.

    How might this impact on clinical practice?

    • Patients with malnutrition and congestion are at high risk and should be managed with additional vigilance.

    • Studies are needed to see if treating malnutrition specifically is helpful.

    Supplementary file 4

    Supplementary file 5

    Supplementary file 6

    Supplementary file 7

    Supplementary file 8

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    Footnotes

    • Contributors SS, PP and ALC designed the study, interpreted the data and drafted the manuscript. SS and PP collected the data. SS, JZ and PP analysed the data. All authors critically revised and approved the final version of the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval The study conformed to the principles outlined in the Declaration of Helsinki and was approved by relevant ethical bodies.

    • Provenance and peer review Not commissioned; externally peer reviewed.