Abstract
Background
Acute decompensated heart failure (ADHF) causes multi-organ damage associated with congestion, hypoperfusion, or both. However, its impact on pancreatic exocrine function (PEF), which can be associated with impaired digestion and absorption and contribute to malnutrition, remains unclear. Thus, in this proof-of-concept study, we investigated whether hospitalized patients with ADHF have impaired PEF.
Methods and Results
Patients admitted to the cardiac intensive care unit were enrolled. Following initial stabilization, the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test, which is the only clinically available PEF test in Japan, was performed. Data from 51 patients (age 73.3±9.8 years; 80.4% men; body mass index 23.9±5.0 kg/m2) were assessed. Patients hospitalized for ADHF (n=33) exhibited significantly lower levels of urinary PABA excretion rate (i.e., pancreatic function diagnostic [PFD] value) than in those hospitalized for other cardiovascular conditions (52.4±20.1% vs. 66.4±17.3%; P=0.022). Simple regression analyses revealed that decreased PFD values were associated with advanced age, increased hemoglobin A1c level, impaired kidney function, low urinary volume in the BT-PABA test, and ADHF-related hospitalization. Multiple regression analysis revealed that only reduced estimated glomerular filtration rate (coefficient 0.319; P=0.031) and ADHF-related hospitalization (coefficient −0.326; P=0.027) were associated with poor PFD values.
Conclusions
PEF was impaired in hospitalized patients with ADHF. Our findings could inform further hypotheses regarding how improved PEF in hospitalized patients with ADHF affects their nutritional status.
Key Words: Congestion, Multi-organ damage, N-benzoyl-L-tyrosyl-p-aminobenzoic acid test, Pancreatic function diagnostic
Central Figure.
Despite recent advances in understanding the pathophysiology and treatment options for heart failure (HF), clinical outcomes remain poor.1–3 Major pathophysiological issues of HF, such as congestion and hypoperfusion, result in multi-organ dysfunction, leading to increased morbidity and mortality.4 Regarding multi-organ damage in HF, dysfunction of the kidneys,5 lungs,6 respiratory system,7,8 and liver9 are well documented. However, the interaction between HF and pancreatic function, particularly pancreatic exocrine function (PEF), remains unclear.
Several studies suggest that HF-related hypoperfusion might induce pancreatic damage.10–15 Conversely, passive congestion in association with acute decompensated HF (ADHF) may lead to pancreatic acinar cell atrophy and disappearance of prezymogen granules in atrophied pancreatic acinar cells,10,16 potentially reducing the production or release of pancreatic exocrine enzymes. Thus, the association between PEF and ADHF is of clinical interest. We previously demonstrated that serum levels of pancreatic enzymes, such as amylase and lipase, which are suggestive of PEF,17 were lower in patients with ADHF than in those without HF. A decrease in serum levels of these enzymes, especially lipase, was associated with congestion parameters. Moreover, changes in the serum levels of exocrine pancreatic enzymes corresponded to changes in volume overload status during hospitalization.18 These findings suggest that ADHF may impair PEF through congestion-associated decreased production of exocrine enzymes, at least transiently. Furthermore, in our previous study,18 we found that low serum levels of these enzymes were associated with nutritional status parameters. This finding suggests that PEF impairment and the resulting digestive dysfunction may contribute to malnutrition, which is common and generally associated with poor clinical outcomes in patients with ADHF.19–24 Notably, in patients hospitalized for ADHF, low serum levels of pancreatic enzymes, particularly lipase, on admission are a predictor of poor clinical outcomes.25 This relationship is independent of baseline nutritional status, suggesting that alterations in nutritional status during hospitalization, alongside PEF impairment, may also independently affect clinical outcomes in patients with ADHF. Thus, assessing PEF in hospitalized patients with ADHF is essential.
As serum amylase and lipase levels are only suggestive but not definitive markers of PEF, a direct assessment of pancreatic function is required to confirm PEF. In Japanese clinical settings, the pancreatic function diagnostic (PFD) test (i.e., the N-benzoyl-L-tyrosyl-p-aminobenzoic acid [BT-PABA] test) is the only clinically available test for PEF. Therefore, with this proof-of-concept study, we aimed to assess PEF in patients hospitalized for acute cardiovascular conditions (including ADHF) using the BT-PABA test and determine whether PEF is impaired in patients with ADHF.
Methods
Study Participants
Consecutive patients admitted to the cardiac intensive care unit of Juntendo University Hospital (Tokyo, Japan) with acute cardiac conditions between April 2017 and March 2018 were included in this study. ADHF was defined based on modified Framingham criteria.26 The exclusion criteria encompassed patients with ST-segment elevation myocardial infarction, shock, inability to tolerate oral intake, gastrointestinal diseases (including diarrhea, defined as watery or soft stool ≥3 times per day), hepatobiliary diseases, oliguria or anuria, dialysis dependence, neoplasms, or a known history of pancreatic disease. Patients were also excluded if they had serum amylase and lipase levels 3 times greater than the upper limit of normal (diagnostic for acute pancreatitis27), a history of diabetes or related medications, thiazide diuretic use, anti-inflammatory drug use within the previous 3 days, or pregnancy or breastfeeding. The Institutional Review Board of the Juntendo University Hospital approved the study protocol (#16-200; trial registration UMIN000025838), which complied with the Declaration of Helsinki. Informed consent was obtained from all patients involved in the study.
Study Protocol
This cross-sectional study assessed PEF in hospitalized patients with acute cardiovascular conditions. After initial stabilization of the acute conditions, eligible patients underwent the BT-PABA test. Participants were orally administered 500 mg of PFD (Eizai Pharmaceutical, Tokyo, Japan) containing BT-PABA during the early morning fasting period. Urine samples were collected for up to 6 h after administration. Urinary PABA levels were measured using diazo coupling (Smith-modified Bratton–Marschal method) and subjected to colorimetry at 550 nm using a photometer. The urinary PABA elimination rate (PFD value) was calculated.28
Other Data Collection
Additional data were prospectively collected during the BT-PABA tests. Blood tests were performed on the day of the BT-PABA test. x Medical histories were obtained through direct interviews and clinical chart reviews. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation with a Japanese coefficient from baseline serum creatinine levels.29 Complete 2-dimensional echocardiography was performed for each patient, and the left ventricular ejection fraction was calculated using the modified Simpson method.
Statistical Analysis
Continuous variables were expressed as the mean±standard deviation, or median and interquartile range, while categorical variables were reported as number and percentage. Comparisons of PFD values between patients hospitalized for ADHF and those with other cardiovascular conditions were performed using the t-test.
Simple linear regression analyses, including the PFD value as a dependent variable, were performed to assess the relationships between the PFD values and other variables. Because the distributions of triglycerides, N-terminal pro B-type natriuretic peptide, and urinary volume in the BT-PABA test were skewed, their natural logarithm-transformed values were used in the regression analyses. Variables with P<0.10 in the simple regression analyses were incorporated into the multiple regression analysis. As the duration from admission to the BT-PABA test may affect the association between hospitalization due to the ADHF and PFD values, their interactions were assessed.
Statistical significance was set at P<0.05. All statistical analyses were performed using SPSS 23.0 (IBM Corp., Armonk, NY, USA).
Results
A total of 63 patients, including 41 hospitalized for ADHF, were enrolled in this study. Among them, 6 were excluded because of errors in the PFD test procedure: 5 owing to insufficient urine volume in the BT-PABA test (≤200 mL, probably due to missed urine collection), and 1 because of missed urine sampling. Thus, data from 51 patients, including 33 hospitalized for ADHF, were analyzed. The patient characteristics are summarized in Table 1. Among the patients hospitalized for other cardiovascular conditions, 12 had acute coronary syndrome, 4 had fatal arrhythmias, 1 had aortic dissection (Stanford B, DeBakey IIIa), and 1 had venous thromboembolism. All patients underwent the BT-PABA test during hospitalization following initial stabilization (duration from admission 4.0 [3.0] days). In the BT-PABA test, the PFD value and urinary volume were 57.3±20.1% and 350.0 (250.0) mL, respectively.
Table 1.
Characteristics of Patients
| Variable | n=51 |
|---|---|
| Age (years) | 73.3±9.8 |
| Men | 41 (80.4) |
| BMI (kg/m2) | 23.9±5.0 |
| Systolic blood pressure (mmHg) | 117.1±16.2 |
| Diastolic blood pressure (mmHg) | 64.6±8.5 |
| Heart rate (beats/min) | 70.5±12.8 |
| Hospitalization due to ADHF | 33 (64.7) |
| Left ventricular ejection fraction (%) | 46.9±14.8 |
| Ischemic heart disease | 23 (45.1) |
| Atrial fibrillation | 20 (39.2) |
| Hemoglobin (g/dL) | 12.7±2.2 |
| Albumin (g/dL) | 3.4±0.4 |
| LDL-cholesterol (mg/dL) | 94.6±29.8 |
| HDL-cholesterol (mg/dL) | 43.8±13.7 |
| Triglycerides (mg/dL) | 78 [54.0] |
| Glucose (mg/dL) | 111.5±38.2 |
| HbA1c (%) | 6.3±0.8 |
| Sodium (mmol/L) | 140.0±4.0 |
| Potassium (mmol/L) | 4.0±0.5 |
| BUN (mg/dL) | 19.5±9.5 |
| Creatinine (mg/dL) | 1.0±0.3 |
| eGFR (mL/min/1.73 m2) | 63.7±22.0 |
| NT-proBNP (pg/mL) | 2,393.5 [4,759.8] |
| Use of β-blockers | 41 (80.4) |
| Use of ACE-Is/ARBs | 42 (82.4) |
| Use of aldosterone blockers | 28 (54.9) |
| Use of loop diuretics | 31 (60.8) |
Data are presented as n (%), median [IQR] or mean±SD. ACE-I, angiotensin-converting enzyme inhibitors; ADHF, acute decompensated heart failure; ARBs, angiotensin II receptor blockers; BMI, body mass index; BT-PABA, N-benzoyl-L-tyrosyl-p-aminobenzoic acid; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro B-type natriuretic peptide.
A comparison of the PFD values between patients hospitalized for ADHF and those with other cardiovascular conditions revealed significantly lower PFD values in patients hospitalized for ADHF than in those hospitalized for other cardiovascular conditions (52.4±20.1% vs. 66.4±17.3%; P=0.022; Figure).
Figure.
Comparison of pancreatic function diagnostic (PFD) values between patients hospitalized for acute decompensated heart failure (ADHF) and other patients. Patients hospitalized for ADHF showed significantly lower PFD values than other patients (52.4±20.1% vs. 66.4±17.3%; P=0.022).
Table 2 summarizes the results of the simple regression analyses. Increased age tended to be inversely associated with the PFD values, while elevated serum creatinine levels were inversely associated with the PFD values, resulting in a significant direct association between the eGFR and PFD values. Additionally, increased HbA1c levels and urinary volume in the BT-PABA test were associated with better PFD values, whereas hospitalization for ADHF correlated with worse PFD values. Multiple collinearities were observed between age, creatinine levels, and eGFR. As age and creatinine are components of the eGFR formula, only the eGFR was included in the multiple regression analysis. The results of the multiple regression analysis, wherein the PFD value was considered as a dependent variable, while the HbA1c level, eGFR, urinary volume in the PT-PABA test, and hospitalization for ADHF were considered as independent variables, are presented in Table 3. Only reduced eGFR and hospitalization for ADHF were associated with poor PFD values. No interaction was observed between the duration from admission to the BT-PABA test and the association between hospitalization for ADHF and the PFD values (P=0.397).
Table 2.
Results of Simple Regression Analyses to the PFD Value
| Variable | Coefficient | P value |
|---|---|---|
| Age | −0.240 | 0.090 |
| Men | −0.030 | 0.833 |
| BMI | 0.033 | 0.816 |
| Systolic blood pressure | −0.193 | 0.174 |
| Diastolic blood pressure | −0.083 | 0.560 |
| Heart rate | −0.063 | 0.660 |
| Left ventricular ejection fraction | 0.100 | 0.490 |
| Ischemic heart disease | 0.102 | 0.478 |
| Atrial fibrillation | −0.150 | 0.294 |
| Hemoglobin | 0.119 | 0.405 |
| Albumin | 0.056 | 0.702 |
| LDL-cholesterol | −0.112 | 0.435 |
| HDL-cholesterol | 0.183 | 0.198 |
| Triglycerides | 0.183 | 0.111 |
| Glucose | 0.126 | 0.384 |
| HbA1c | 0.302 | 0.035 |
| Sodium | −0.091 | 0.527 |
| Potassium | −0.199 | 0.161 |
| BUN | −0.157 | 0.271 |
| Creatinine | −0.399 | 0.004 |
| eGFR | 0.384 | 0.005 |
| NT-proBNP | −0.040 | 0.789 |
| Use of β-blockers | 0.056 | 0.699 |
| Use of ACE-Is/ARBs | −0.114 | 0.425 |
| Use of aldosterone blockers | −0.104 | 0.469 |
| Use of loop diuretics | −0.180 | 0.207 |
| Urinary volume in BT-PABA test | 0.375 | 0.007 |
| Hospitalization due to ADHF | −0.337 | 0.016 |
PFD, pancreatic function diagnostic. Other abbreviations as in Table 1.
Table 3.
Result of a Multiple Regression Analysis of the PFD Values
| Variable | Partial correlation coefficient | P value |
|---|---|---|
| HbA1c | 0.173 | 0.250 |
| eGFR | 0.319 | 0.031 |
| Urinary volume in BT-PABA test | 0.105 | 0.486 |
| ADHF | −0.326 | 0.027 |
Abbreviations as in Tables 1,2.
Discussion
This proof-of-concept study demonstrated that patients hospitalized for ADHF exhibited greater PEF impairment than those hospitalized for other acute cardiovascular conditions, as assessed using the BT-PABA test. In the multivariable analysis, hospitalization for ADHF was significantly and independently associated with impaired PEF, as assessed by examining PFD values and the extent of kidney dysfunction. Our findings provide novel insights into the relationship between HF and organ damage, as only a few studies, including ours, have investigated the relationship between HF and pancreatic damage. Given that impaired PEF may contribute to malnutrition, a significant comorbidity of ADHF and a predictor of poor clinical outcomes, the findings of this study may contribute to identifying potential therapeutic targets for HF, such as PEF, in hospitalized patients with ADHF.
Passive congestion due to ADHF may cause atrophic changes in pancreatic acinar cells and the possible production or release of pancreatic exocrine enzymes,10,16,17 leading to PEF impairments. The serum levels of pancreatic enzymes are lower in patients with ADHF than in those without HF, with levels proportional to congestion.18 Furthermore, changes in the serum levels of exocrine pancreatic enzymes correspond to changes in volume overload status,18 suggesting that ADHF transiently impairs PEF. In patients with ADHF, the association between low serum levels of pancreatic exocrine enzymes and nutritional status parameters18 indicates that ADHF-related PEF impairment prevents digestion and absorption, possibly causing malnutrition and poor clinical outcomes.19–22 Our recent study demonstrated that low serum lipase levels on admission were a predictor of poor clinical outcomes in patients hospitalized for ADHF, independent of baseline nutritional status.25 This finding suggests that even transient PEF impairment and its associated malnutrition during initial hospitalization affect subsequent clinical outcomes. As the serum levels of pancreatic exocrine enzymes are not definitive PEF markers, the functional assessment of PEF is essential. Thus, in this study, PEF impairments were assessed using the BT-PABA test. Given that recovery of the serum levels of pancreatic exocrine enzymes was accompanied by improved congestion, patients hospitalized for ADHF experience at least transient PEF impairment.18 However, because the serum lipase levels are associated with poor long-term clinical outcomes,25 the possible effects of transient PEF impairment on nutritional status require further investigation. Moreover, whether PEF impairment directly causes malnutrition remains speculative, as longitudinal data are lacking. Thus, large-scale prospective observational studies are required to investigate the association between improved PEF and nutritional status. Establishing this causality would strengthen the rationale for designing future interventional trials involving pancreatic enzyme supplementation.
The present study focuses on impaired PEF as a possible contributor to malnutrition in patients with HF; however, increased catabolism plays a crucial role in nutritional decline in HF.30 In addition, other factors such as systemic inflammation, disease severity, or decreased organ perfusion may contribute to impaired PEF and malnutrition. Although we did not identify relationships between body mass index and PFD values in the present study, patients with HF and obesity may exhibit improved clinical outcomes if a direct relationship between PEF and nutritional status exists. In other words, this mechanism may provide another explanation for the obesity paradox. As clinical outcome data were not available and the sample size was too small to assess relationships between PEF and clinical outcomes while considering the obesity paradox in this study, further large-scale outcome studies will be warranted to explore this possibility.
Although we excluded patients with factors influencing PFD values, potential confounding factors may persist in the relationship between ADHF and PEF, as assessed using the BT-PABA test. For instance, the duration between admission and the BT-PABA test and kidney function were considered. Regarding the duration between admission and the BT-PABA test, no interaction was found between this duration and the relationship between ADHF and PFD, indicating that variations in timing did not affect the relationship between ADHF and PEF. In the multiple regression analysis, kidney dysfunction was associated with the PFD value, as assessed by examining the eGFR; however, the effects of the eGFR were independent of those of ADHF. In Japanese clinical settings, the BT-PABA test is the only available test for PEF, although the gold standard for PEF assessment is the measurement of fecal elastase-1 (FE-1).31 The BT-PABA test cannot detect mild impairment of PEF and is no longer in clinical use in most Western countries.32 As the measurement of FE-1 is not clinically available in Japan, securing a research grant is necessary to enable its implementation. However, to support a grant application, preliminary data for impaired PEF in patients with ADHF are needed. This highlights the importance of reporting this study’s findings, despite the limitations of the methodology for evaluating PEF.
Study Limitations
Our study had some limitations. First, this was an observational cross-sectional study. Thus, a causal relationship between ADHF and impaired PEF assessed using the BT-PABA test has not been established. Second, a PFD value <70% is generally regarded as the cut-off value for pancreatic exocrine insufficiency.33 However, whether this cut-off value is applicable to pancreatic exocrine insufficiency in patients with ADHF is unclear. Moreover, the BT-PABA test only provides an indirect assessment of PEF and does not directly measure the degree of nutrient malabsorption. Additionally, we did not directly assess malabsorption in the present study. Thus, whether patients with ADHF truly exhibit pancreatic exocrine insufficiency remains to be elucidated. Third, other unknown confounding factors may be present; thus, the results of this study should be interpreted with caution. Fourth, as only patients from a Japanese institution were enrolled in the present study, the generalizability of the relationship between PEF and ADHF to other ethnicities remains unclear. Last, temporal changes in PFD values may affect malnutrition and long-term clinical outcomes in patients with ADHF, necessitating further investigation.
Conclusions
PEF was impaired in hospitalized patients with ADHF. This was confirmed by only 1 proof-of-concept study; thus, further mechanistic studies using FE-1 are required. Large-scale prospective observational studies are required to confirm the association between improved PEF and nutritional status. Subsequently, interventional trials involving pancreatic enzyme supplementation can be considered.
Disclosures
T. Kasai is affiliated with departments endowed by Philips, ResMed, Fukuda Denshi, and Paramount Bed. H.D. received manuscript fees, research funds, and scholarship funds from Kirin Co., Ltd; Kaken Pharmaceutical Co., Ltd; Abbott Japan Co., Ltd; Astellas Pharma Inc.; AstraZeneca K.K.; Bayer Yakuhin Ltd; Boston Scientific Japan K.K.; Bristol-Myers Squibb; Daiichi Sankyo Company; MSD K.K.; Pfizer Inc.; Philips Unk Onics; Sanofi K.K.; and Takeda Pharmaceutical Co., Ltd. The authors declare no conflicts of interest. The funding sources had no role in the design of the study, collection, analyses, or interpretation of data, writing of the manuscript, or the decision to publish the results. H.D. is a member of Circulation Reports’ Editorial Team.
IRB Information
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Juntendo University Hospital (#16-200).
Acknowledgments
This research was partly supported by JSPS KAKENHI (grant nos. 17K09527, 18K15904, JP21K08116, JP21K16034, and JP21K16035), a Grant-in-Aid for Scientific Research (grant nos. 20FC1027, and 23FC1031) from the Ministry of Health, Labor, and Welfare of Japan, and a research grant from the Japanese Center for Research on Women in Sport, Juntendo University.
Data Availability Statement
The datasets generated and analyzed in the present study are not publicly available, but can be provided by the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed in the present study are not publicly available, but can be provided by the corresponding author upon reasonable request.