*Article* **High Plasma Docosahexaenoic Acid Associated to Better Prognoses of Patients with Acute Decompensated Heart Failure with Preserved Ejection Fraction**

**Naoaki Matsuo 1, Toru Miyoshi 1,\*, Atsushi Takaishi 2, Takao Kishinoue 2, Kentaro Yasuhara 2, Masafumi Tanimoto 2, Yukari Nakano 3, Nobuhiko Onishi 2, Masayuki Ueeda <sup>4</sup> and Hiroshi Ito <sup>1</sup>**


**Citation:** Matsuo, N.; Miyoshi, T.; Takaishi, A.; Kishinoue, T.; Yasuhara, K.; Tanimoto, M.; Nakano, Y.; Onishi, N.; Ueeda, M.; Ito, H. High Plasma Docosahexaenoic Acid Associated to Better Prognoses of Patients with Acute Decompensated Heart Failure with Preserved Ejection Fraction. *Nutrients* **2021**, *13*, 371. https://doi.org/ 10.3390/nu13020371

Academic Editor: Yoshihiro Fukumoto Received: 11 December 2020 Accepted: 22 January 2021 Published: 26 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Abstract:** The clinical relevance of polyunsaturated fatty acids (PUFAs) in heart failure remains unclear. The aim of this study was to investigate the association between PUFA levels and the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). This retrospective study included 140 hospitalized patients with acute decompensated HFpEF (median age 84.0 years, 42.9% men). The patients' nutritional status was assessed, using the geriatric nutritional risk index (GNRI), and their plasma levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) were measured before discharge. The primary outcome was all-cause mortality. During a median follow-up of 23.3 months, the primary outcome occurred in 37 patients (26.4%). A Kaplan–Meier analysis showed that lower DHA and DGLA levels, but not EPA or AA levels, were significantly associated with an increase in all-cause death (log-rank; *p* < 0.001 and *p* = 0.040, respectively). A multivariate Cox regression analysis also revealed that DHA levels were significantly associated with the incidence of all-cause death (HR: 0.16, 95% CI: 0.06–0.44, *p* = 0.001), independent of the GNRI. Our results suggest that low plasma DHA levels may be a useful predictor of all-cause mortality and potential therapeutic target in patients with acute decompensated HFpEF.

**Keywords:** heart failure with preserved ejection fraction; docosahexaenoic acid; geriatric nutritional risk index

#### **1. Introduction**

Heart failure (HF) is a common and growing public health problem with an estimated prevalence of over 37.7 million cases worldwide [1]. Despite recent developments of HF treatments, including pharmacological and device therapy, HF still results in high mortality and re-hospitalization rates [2]. HF clinically manifests in two modes, which are defined by ventricular function: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) [3]. Unfortunately, standard pharmacological therapies for HFrEF such as angiotensin-converting enzyme inhibitors and β-blockers show a lack of efficacy in the treatment of HFpEF [4]. Patients with HFpEF are more likely to be older, female, and have hypertension, renal disease, atrial fibrillation, and malnutrition [5]. Malnutrition, in particular, is a common problem in elderly patients with HFpEF and is a known risk factor for a poor prognosis [6].

Polyunsaturated fatty acids (PUFAs) play structural and functional roles as membrane components and precursors of physiologically active substances involved in inflammation [7]. Fish oils, sunflower, safflower, and corn oils are rich in omega-3 PUFAs, while meat from farm animals are rich in omega-6 PUFAs [8]. Omega-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and oemga-6 PUFAs, such as arachidonic acid (AA) and dihomo-gamma-linolenic acid (DGLA), have been shown to have opposite effect [9]. It has been reported that AA-derived metabolites are pro-inflammatory, while EPA- and DHA-derived metabolites are pro-resolution/anti-inflammatory [10–12]. Some metabolites have been reported to play a critical role in the development of cardiac hypertrophy and heart failure by regulating inflammatory reactions [12–14]. However, omega-7 and omega-9 monounsaturated fatty acids, such as palmitoleic acid and oleic acid, are components of complex lipids, such as sphingosines and phospholipids, and could interfere with cellular injury [15–17].

Several clinical trials and meta-analysis have demonstrated that omega-3 PUFAs are beneficial for patients with cardiovascular events [18–20]. Regarding the association between omega-3 PUFAs and heart failure, a meta-analysis of seven prospective studies with 176,441 subjects and 5480 cases of HF found a lower risk of HF in patients that took high amounts of marine omega-3 PUFAs [21]. Another study including 6562 patients, in over 13 years, found that plasma EPA levels were significantly lower in HF patients, compared to HF-free patients [22]. Small-scale clinical trials have indicated that omega-3 PUFAs may improve the outcomes of patients with HF [23–26]. However, recent large-scale randomized controlled studies investigating cardiovascular benefit of omega-3 supplementation showed conflicting findings [27,28].

The aim of this study was to investigate the role of PUFAs in the prognosis of patients with acute decompensated HFpEF. In addition, the impact of the patients' nutritional status on the association between PUFAs and their prognosis was evaluated.

#### **2. Materials and Methods**

#### *2.1. Study Design and Participants*

This study was a retrospective single-center cohort study. The study protocol was approved by the Institutional Review Board of Mitoyo General Hospital (19CR01-122) and conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived because of the low-risk nature of the study and inability to obtain consent directly from all the study subjects. Instead, we announced this study protocol extensively at Mitoyo General Hospital and on the hospital website (http://mitoyo-hosp.jp) and provided patients with the opportunity to withdraw from the study. We initially enrolled 301 consecutive patients with acute decompensated HFpEF that were not receiving hemodialysis and who were admitted to Mitoyo General Hospital between August 2015 and January 2019. Acute decompensated HF was diagnosed based on the Framingham's criteria. [29]. A diagnosis of HF was made if a patient had at least two major criteria or one major criterion and two minor criteria. The major criteria are acute pulmonary edema, cardiomegaly, hepatojugular reflex, distended neck veins, paroxysmal nocturnal dyspnea, pulmonary rales, and third heart sound. The minor criteria are ankle edema, dyspnea on exertion, hepatomegaly, nocturnal cough, pleural effusion, and tachycardia [29]. HFpEF was defined as HF with a left ventricular ejection fraction ≥50%. Patients with HFrEF and those receiving omega-3 PUFA therapy were excluded. Figure 1 shows the flow diagram of this study. Follow-ups were performed by referring to patient electronic medical records, direct contact with the patients' physicians in the outpatient clinic, and telephone interviews with patients or family members. A total of 140 patients were ultimately included in the final analysis.

**Figure 1.** Flowchart of study population. Heart failure (HF) was defined based on the Framingham criteria. Heart failure with reduced ejection fraction (HFrEF); Heart failure with preserved ejection fraction (HFpEF) was defined as HF with a left ventricular ejection fraction ≥50%. PUFAs, polyunsaturated fatty acids.

#### *2.2. Blood Sampling and Equations*

Whole blood samples were collected within 24 h of admission. Approximately 20 mL of blood was collected by venipuncture and separated into tubes containing clot activator, gel serum separator, ethylenediaminetetraacetic acid dipotassium, and heparin sodium. Plasma levels of EPA, DHA, AA, and DGLA were measured by using gas chromatography (SRL Inc., Tokyo, Japan) [30]. Routine laboratory tests were performed, using an automated analyzer, at Mitoyo General Hospital. The estimated glomerular filtration rate (eGFR) was calculated based on the Japanese equation that uses serum creatinine level, age, and sex as follows: eGFR (mL/min/1.73 m2) = 194 × serum creatinine−1.094 × age−0.287 (for females = ×0.739) [31]. The geriatric nutritional risk index (GNRI) was calculated as follows, using the serum albumin level, body weight, and height obtained on admission: GNRI = 14.89 × serum albumin (g/dL) + 41.7 × (actual body weight/ideal body weight). GNRI is a nutrition-related risk index that makes it possible to classify patients according to a risk of morbidity and mortality, and the GNRI ≥98 means no nutritional-related risk [32]. The ideal body weight in the present study was calculated by using a body mass index of 22 kg/m2.

#### *2.3. Assessment of Additional Risk Factors*

Hypertension was defined as having a seated blood pressure >140/90 mmHg or undergoing current treatment with antihypertensive medications. Diabetes mellitus was defined as having a previous diagnosis of diabetes mellitus in the medical records, a hemoglobin A1C (national glycohemoglobin standardization program calculation) level ≥6.5%, or receiving treatment with oral antidiabetic agents or insulin. Dyslipidemia was defined as one or more of the following characteristics: ≥150 mg/dL serum triglyceride, <40 mg/dL highdensity lipoprotein cholesterol (HDL-cholesterol), ≥140 mg/dL low-density lipoprotein cholesterol (LDL-cholesterol), or current treatment with a lipid-lowering drug. Smoking status was defined as "currently smoking".

#### *2.4. Study Outcomes*

The primary endpoint was all-cause mortality. Furthermore, as an ad hoc analysis, patients were divided into four groups, based on the median DHA level and median GNRI, so that the association between the primary endpoint and each group could be evaluated. The secondary endpoints were cardiac death and re-hospitalization for HF.

#### *2.5. Statistical Analyses*

The results are presented as the mean ± standard deviation when they are normally distributed, and as the median and interquartile range (IQR) when they are non-normally distributed. The normality of distribution was determined by the Kolmogorov–Smirnov test. Differences between the groups were analyzed by using the unpaired Student's t-test or Mann–Whitney U test for continuous variables, and the chi-squared test or Fisher's exact test for dichotomous variables, as appropriate. For the survival analyses, Kaplan– Meier survival plots were constructed by dividing the patients' PUFA levels on admission into two groups, according to the median values, and log-rank testing was performed to study the influence of PUFA levels on primary and secondary endpoints. To evaluate the influence of PUFA levels on the primary endpoint, Cox proportional-hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI). To avoid overfitting, variables that were included in the principal multivariate models were adjusted for age, sex, hypertension, dyslipidemia, diabetes mellitus, and GNRI. All the tests were two-tailed, and a value of *p* < 0.05 was considered statistically significant. All the analyses were performed by using IBM SPSS statistics version 24.0 (IBM Corp., Armonk, NY, USA).

#### **3. Results**

#### *3.1. Baseline Characteristics*

Table 1 shows the baseline characteristics of the patients in this study and a comparison of those characteristics between the patients with and without primary endpoints. The median age of all the patients was 84.0 years, 42.9% were male, and 56.4% had atrial fibrillation. The prevalence of hypertension and diabetes mellitus within the group of patients was 90.0% and 22.9%, respectively.

During the median follow-up of 23.3 months, 37 (26.4%) of the patients exhibited the primary endpoint. Patients experiencing the primary endpoint were older; had lower BMI and GNRI values; had a lower prevalence of hypertension and dyslipidemia; had lower statin use; and had lower hemoglobin, albumin, HDL-cholesterol, and LDL-cholesterol levels than those who did not experience the primary endpoint. No significant differences in the prevalence of atrial fibrillation, prior hospitalization for HF, or medication use, except for statins, were observed between the two groups. The median levels of EPA, DHA, DGLA, and AA, as well as the ratio of EPA to AA (EPA/AA), DHA to AA (DHA/AA), and AA + DGLA to EPA + DHA (AA + DGLA/EPA + DHA), on admission were 46.6 μg/mL, 116.1 μg/mL, 23.6 μg/mL, 159.8 μg/mL, 0.26, 0.74, and 1.15, respectively. The levels of DHA, DGLA, and AA for the patients with adverse events were significantly lower than for those patients without adverse events. The levels of EPA, EPA/AA, DHA/AA, and AA+DGLA/EPA+DHA did not differ between the two groups.

#### *3.2. Cumulative Event Rates Based on PUFA Levels*

The Kaplan–Meier analyses showed that lower levels of DHA and DGLA on admission were significantly associated with the incidence of adverse events (log-rank; *p* < 0.001 and *p* = 0.040, respectively) (Figure 2B,D). However, the EPA and AA levels and the EPA/AA, DHA/AA, and AA + DGLA/ EPA + DHA were not associated (log-rank; *p* = 0.051, *p* = 0.154, *p* = 0.649, *p* = 0.887, *p* = 0.712, respectively) (Figure 2A,C,E–G).

#### *3.3. Univariate and Multivariate Analyses of Parameters Contributing to the Primary and Secondary Endpoints*

The univariate Cox regression analyses showed that age, body mass index, statin use, hemoglobin, albumin, LDL-cholesterol, GNRI, DGLA level, and DHA level were associated with the incidence of the primary endpoint (Table 2). The multivariate Cox regression analyses revealed that patients with high DHA levels was significantly associated with a low incidence of the primary endpoint after an adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, and GNRI (HR: 0.16, 95% CI: 0.06–0.44, *p* = 0.001). However, the DGLA level was not significantly associated with the primary endpoint after an adjustment for confounding variables.


**Table 1.** Baseline characteristics according to the presence or absence of the primary endpoint.

Categorical variables are presented as number of patients (%). Continuous variables are presented as the mean ± standard deviation or median (interquartile range). PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; ACEs, angiotensinconverting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium channel blockers; MRAs, mineralocorticoid receptor antagonists; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein; BNP, brain natriuretic peptide; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DGLA, dihomo-gamma-linolenic acid; AA, arachidonic acid; DHA/AA, ratio of DHA to AA; AA+DGLA/EPA+DHA, ratio of AA+DGLA to EPA+DHA; GNRI, geriatric nutritional risk index.

**Figure 2.** *Cont*.

**Figure 2.** The associations between the primary outcomes and PUFA levels. The cumulative incidences of the primary endpoint (all-cause death) were estimated by using the Kaplan–Meier method. The patients were divided into two groups, based on the median levels of (**A**) EPA, (**B**) DHA, (**C**) AA, (**D**) DGLA, (**E**) EPA/AA, (**F**) DHA/AA, and (**G**) AA + DGLA/ EPA + DHA. Log-rank testing was performed to study the influence of PUFA levels on primary endpoint. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DGLA, dihomo-gamma-linolenic acid; AA, arachidonic acid; EPA/AA, ratio of EPA to AA; DHA/AA, ratio of DHA to AA; AA + DGLA/EPA + DHA; ratio of AA + DGLA to EPA + DHA.


**Table 2.** The association between PUFAs and the primary endpoint analyzed with Cox proportional hazards models.

The multivariate model-1 and model-2 were adjusted for age, sex, hypertension, dyslipidemia, diabetes mellitus, and GNRI. HR, hazard ratio; CI, confidence interval; GNRI, geriatric nutritional risk index; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DGLA, dihomogamma-linolenic acid; AA, arachidonic acid. EPA/AA, ratio of EPA to AA; DHA/AA, ratio of DHA to AA; AA + DGLA/EPA + DHA; ratio of AA + DGLA to EPA + DHA.

As an ad hoc analysis, the patients were divided into four groups, based on the median DHA and GNRI values. As shown in Figure 3, the low-GNRI and low-DHA groups showed the greatest incidence of the primary endpoint, compared to the other groups (log-rank; *p* < 0.001). In the multivariate Cox regression analyses, the low-GNRI and low-DHA groups had a significantly higher risk of the primary endpoint, compared with the high-GNRI and high-DHA groups, after an adjustment of age and sex (HR: 8.48, 95% CI: 2.47–29.07, *p* = 0.001) (Table 3).

The secondary endpoints occurred in 63 patients (cardiac death (*n* = 15) and rehospitalization for HF (*n* = 480)). As shown in Figure 4, none of the PUFA levels was associated with the secondary endpoints.

**Figure 3.** The associations between the primary outcomes and the DHA and GNRI values. The cumulative incidences of the primary endpoint (all-cause death) were estimated by using the Kaplan– Meier method. Log-rank testing was performed to study the influence of PUFA levels on primary endpoint. The patients were divided into four groups, based on the median DHA and GNRI values. DHA, docosahexaenoic acid; GNRI, geriatric nutritional risk index.

**Table 3.** The association between the DHA and GNRI values and primary endpoints analyzed with Cox proportional hazards models.


Multivariate analysis was adjusted by age, sex, hemoglobin, and GNRI. HR, hazard ratio; CI, confidence interval; DHA, docosahexaenoic acid; GNRI, geriatric nutritional risk index.

**Figure 4.** *Cont*.

**Figure 4.** The associations between the secondary outcomes and PUFA levels. The cumulative incidences of the secondary endpoints (cardiac death and re-hospitalization for heart failure) were estimated by using the Kaplan–Meier method. Log-rank testing was performed to study the influence of PUFA levels on primary endpoint. The patients were divided into two groups, based on the median levels of (**A**) EPA, (**B**) DHA, (**C**) AA, (**D**) DGLA, and (**E**) EPA/AA, (**F**) DHA/AA, and (**G**) AA + DGLA/EPA + DHA. PUFA, polyunsaturated fatty acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; AA, arachidonic acid; DGLA, dihomo-gamma-linolenic acid; EPA/AA, ratio of EPA to AA; DHA/AA, ratio of DHA to AA; AA + DGLA/EPA + DHA; ratio of AA + DGLA to EPA + DHA.

#### **4. Discussion**

The data from the present study showed that the acute decompensated HFpEF patients with lower plasma DHA levels had a significantly higher incidence of all-cause death, independent of GNRI. These findings suggest that plasma DHA levels are an important factor associated with prognosis, regardless of the nutritional status of patients with acute decompensated HFpEF. This suggests that measuring plasma DHA levels may be useful for the detection of high-risk patients hospitalized with HFpEF.

Several studies have shown the association between circulating concentrations of PUFAs and the incidence of HF. A previous cohort study, which included 2735 adults in the Cardiovascular Health Study from 1992 to 2006, reported that the total concentrations of omega-3 fatty acid were associated with the incidence of primary congestive HF [19]. A recent report from the Multi-Ethnic Study of Atherosclerosis (MESA) trial indicated that higher plasma EPA levels were significantly associated with a reduced risk of HF (for both reduced and preserved EF) [22]. In addition, regarding the association between PUFAs and the prognosis of patients with acute decompensated HF, a study showed that decreased plasma levels of DHA, DGLA, and AA were independently associated with long-term mortality in patients with acute decompensated HF [33]. Other studies have shown that lower omega-6 PUFAs levels were related to worse clinical outcomes in patients with acute decompensated HF [34,35]. However, most of the patients included in these studies had HFrEF. Thus, to the best of our knowledge, this is the first study to evaluate the correlation between PUFA levels and the prognosis of patients with HFpEF.

This study showed that lower DHA levels, but not EPA levels, were independently associated with all-cause mortality in patients with acute decompensated HFpEF. PUFAs play an important role in cellular membrane function [36]. While DHA is abundant in the cell membranes of cardiomyocytes [25], EPA is scarce. This difference may contribute to the distinct effects that DHA and EPA have on cardiac health. It should be noted, however, that while DHA can be obtained from the diet, it can also be synthesized from EPA [37]. In fact, the data from MESA suggested that EPA was more important than DHA for HF [19]. Therefore, any interpretation of the differences between the effects of DHA and EPA on the prognosis of HFpEF patients should be made with caution.

Although the present study showed a relationship between lower plasma DHA levels and a higher incidence of all-cause death, there was no significant association between DHA levels and composite events of cardiac death and re-hospitalization for HF. According to a Japanese cohort study called the Chronic Heart Failure Analysis and Registry in the Tohoku (CHART), the temporal trend in the mode of death in symptomatic HF has changed. As the prevalence of HFpEF in symptomatic HF increased from CHART-1 (2000–2005) to CHART-2 (2006–2010), the proportion of non-cardiac deaths increased from 23% in CHART-1 to 40% in CHART-2 [5]. In this study [5], those factors that were significantly associated with all-cause death were reported to be advanced age, low BMI, high systolic blood pressure, and absence of dyslipidemia. This is in line with our data shown in Table 1. Patients with HFpEF had more comorbidities than HFrEF patients, and noncardiac deaths occurred more frequently in HFpEF patients than in HFrEF patients [38].

Thus, the characteristics inherent to HFpEF patients specifically may be involved in the significant impact that DHA levels have on all-cause death, as opposed to cardiac death or re-hospitalization for HF.

Malnutrition is frequently observed and an important risk factor for poor outcomes in patients with HF. The GNRI is a simple and objective nutritional index, and a GNRI < 92 is generally used to evaluate the increased risk of morbidity and mortality in hospitalized elderly patients [21]. In our study, patients with the primary endpoint had an average GNRI of 90.8, suggesting a poor nutritional status. Although the patients with the primary endpoint also showed lower omega-3 PUFA levels, which were affected by oral intake, the Cox regression analyses revealed that the impact of the DHA levels on the patients' prognoses was independent of the GNRI. Even in the patients with a poor nutritional status, lower DHA levels were shown to be an independent predictor of all-cause mortality in HFpEF patients.

Inflammation is a normal process that is part of the body's defense and tissue-healing mechanism. However, excessive or unresolved inflammation can lead to uncontrolled tissue injury, and disease. Omega-6-derived metabolites, such as prostaglandins and leukotrienes, have pro-inflammatory effects, while omega-3-derived metabolites, such as resolvins and protectins, have anti-inflammatory and pro-resolving effects [10,11]. In this context, several clinical studies showed that the ratio of omega-3 to omega-6 PUFAs is a powerful predictor of heart disease [39–41]. Therefore, active screening of PUFAs would be beneficial in identifying patients at high risk of cardiovascular disease.

The GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure) trial was a large-scale, placebo-controlled, randomized study that showed that 1 g daily of omega-3 fatty acid administration reduced the risk of all-cause death by 9% and the risk of hospitalization due to cardiovascular reasons by 8% in patients with chronic heart failure [42]. Other clinical trials have indicated that omega-3 fatty acids might improve outcomes in patients with HF [23–26]. In addition, animal studies have shown that omega-3 fatty acids, including EPA and DHA, at supraphysiological levels, preserve left ventricular function and prevent interstitial fibrosis in a mouse model of pressure overload-induced HF [39,43,44]. Despite these potential benefits, the use of omega-3 fatty acids in patients with HF remains controversial. Future large-scale randomized clinical trials to investigate the benefit of high dosages of omega-3 fatty acids, on top of the guideline-directed medical therapy for patients with documented overt HF, will be needed.

This study had several limitations. First, the study was conducted in a single center, the sample size was small, and the follow-up period was short. Therefore, it may be difficult to generalize these results. Second, the PUFAs were not measured in the cell membrane. PUFAs in the cell membrane have been reported to be direct precursors of pro- and antiinflammatory eicosanoids. However, it has also been reported that cell-membrane PUFAs are significantly correlated with serum PUFAs in the Japanese population [30]. Third, food intake is associated with blood levels of PUFAs; however, measurement of dietary intake by using a frequency food questionnaire was not performed in this study. Moreover, the multivariate cox regression model included a limited number of variates to avoid statistical

overfitting, because of the small number of the primary outcome. Therefore, large-scale studies will be needed to confirm our findings. Finally, the study was an observational study, so the causal relationship between DHA levels and prognosis is uncertain.

#### **5. Conclusions**

Lower levels of DHA are significantly associated with an increase in all-cause death in patients with acute decompensated HFpEF, independent of nutritional status. Measurement of plasma DHA levels may be useful in identifying high-risk patients with HFpEF, and supplementation with DHA may be a potential therapeutic target in these patients.

**Author Contributions:** Conceptualization, A.T.; formal analysis, N.M. and T.M.; data curation, N.M.; T.K., K.Y., M.T., Y.N., N.O., and M.U.; investigation, N.M.; A.T.; T.K., K.Y., M.T., Y.N., N.O., and M.U.; writing—original draft preparation, N.M.; writing—Review and Editing, T.M.; A.T.; T.K., K.Y., M.T., Y.N., N.O., and M.U.; project administration, H.I. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study protocol was approved by the Institutional Review Board of Mitoyo General Hospital (19CR01-122).

**Informed Consent Statement:** Patient consent was waived because of the low-risk nature of the study and inability to obtain consent directly from all the study subjects.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Article* **Impact of Inadequate Calorie Intake on Mortality and Hospitalization in Stable Patients with Chronic Heart Failure**

**Yoshikuni Obata 1, Naoya Kakutani 1, Shintaro Kinugawa 1,2,\*, Arata Fukushima 1, Takashi Yokota 1,3, Shingo Takada 1, Taisuke Ono 4, Takeshi Sota 5, Yoshiharu Kinugasa 6, Masashige Takahashi 7, Hisashi Matsuo 8, Ryuichi Matsukawa 9, Ichiro Yoshida 10, Isao Yokota 11, Kazuhiro Yamamoto <sup>6</sup> and Miyuki Tsuchihashi-Makaya <sup>12</sup>**


**Abstract:** Malnutrition is highly prevalent in patients with heart failure (HF), but the precise impact of dietary energy deficiency on HF patients' clinical outcomes is not known. We investigated the associations between inadequate calorie intake and adverse clinical events in 145 stable outpatients with chronic HF who had a history of hospitalization due to worsening HF. To assess the patients' dietary pattern, we used a brief self-administered diet-history questionnaire (BDHQ). Inadequate calorie intake was defined as <60% of the estimated energy requirement. In the total chronic HF cohort, the median calorie intake was 1628 kcal/day. Forty-four patients (30%) were identified as having an inadequate calorie intake. A Kaplan–Meier analysis revealed that the patients with inadequate calorie intake had significantly worse clinical outcomes including all-cause death and HF-related hospitalization during the 1-year follow-up period versus those with adequate calorie intake (20% vs. 5%, *p* < 0.01). A multivariate logistic regression analysis showed that inadequate calorie intake was an independent predictor of adverse clinical events after adjustment for various factors that may influence patients' calorie intake. Among patients with chronic HF, inadequate calorie intake was associated with an increased risk of all-cause mortality and rehospitalization due to worsening HF. However, our results are preliminary and larger studies with direct measurements of dietary calorie intake and total energy expenditure are needed to clarify the intrinsic nature of this relationship.

**Keywords:** calorie intake; heart failure; hospitalization; malnutrition; mortality

**Citation:** Obata, Y.; Kakutani, N.; Kinugawa, S.; Fukushima, A.; Yokota, T.; Takada, S.; Ono, T.; Sota, T.; Kinugasa, Y.; Takahashi, M.; et al. Impact of Inadequate Calorie Intake on Mortality and Hospitalization in Stable Patients with Chronic Heart Failure. *Nutrients* **2021**, *13*, 874. https://doi.org/10.3390/nu13030874

Academic Editor: Yoshihiro Fukumoto

Received: 26 January 2021 Accepted: 4 March 2021 Published: 8 March 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Heart failure (HF) is common in adults and is associated with increased morbidity and mortality. Its prevalence is increasing due to the aging of the population in many countries [1]. Despite recent advances in pharmacological and non-pharmacological treatments for HF, the prognosis of individuals with chronic HF remains poor, and diet and exercise interventions are thus recognized as essential treatments for the prevention of HF progression.

Although obesity is a risk of incident HF, a low body mass index (BMI) is more closely associated with poor clinical outcomes in chronic HF patients, in a phenomenon known as the obesity paradox [2,3]. As one of the possible mechanisms of this paradox, malnutrition is a recent focus of attention among healthcare providers who are engaged in HF management. Malnutrition is highly prevalent in patients with chronic HF, and it increases their risk of death and hospitalization [4]. Patients with chronic HF have been demonstrated to have an increased energy expenditure compared to healthy sedentary subjects, but HF patients' dietary energy intake is often insufficient to meet their energy requirements for daily activities, even in a stable condition [5]. The negative energy balance leads to a catabolic state and causes protein–energy malnutrition, which results in muscle wasting and sarcopenia [6,7]. In addition, dietary guidance for HF patients has traditionally focused on reducing their salt and fluid intake; the patients' intake of dietary nutrients has tended to be less of a concern [8]. Restrictive diets for HF patients may cause a reduced intake of macronutrients and micronutrients, leading to increased morbidity and mortality [8].

We conducted the present study to determine whether calorie intake that is inadequate for the energy needed for daily activities is associated with adverse clinical events including all-cause death and HF-related hospitalization in stable patients with chronic HF. The patients' daily calorie intake was calculated by a brief self-administered diet-history questionnaire (BDHQ), which is a well-validated questionnaire for determining a patient's dietary pattern.

#### **2. Materials and Methods**

#### *2.1. Study Design*

This study was part of a multicenter, prospective observational investigation of the effects of dietary patterns on clinical outcomes in patients with chronic HF, and thus some of the data used herein were obtained from the same patients whose data were published previously but in a different context [9]. The study was approved by the ethics committees of Hokkaido University Hospital (approval no. 012-0224) and the other nine participating research institutes—Hakodate National Hospital, Hikone Municipal Hospital, Kitami Red Cross Hospital, Keiwakai Ebetsu Hospital, Kushiro City General Hospital, Obihiro Kyokai Hospital, Otaru Kyokai Hospital, Saiseikai Fukuoka General Hospital, and Tottori University Hospital. The study was conducted in accordance with the ethical principles described in the Declaration of Helsinki. Written informed consent was obtained from each patient before his or her participation in the study.

#### *2.2. Patients*

A total of 145 stable patients with chronic HF who were regularly visiting an outpatient ward for >1 month were enrolled between December 2012 and September 2014. These patients had a history of hospitalization due to worsening HF at least once within the 5 years before enrollment. The exclusion criteria included nephrotic syndrome, liver cirrhosis, cancer, a history of gastrointestinal surgery within the prior 3 months, or poorly controlled diabetes, i.e., glycosylated hemoglobin (HbA1c) >7.0%. We also excluded patients who were taking steroids or antidepressants, which could influence their appetite.

#### *2.3. Study Protocol*

At baseline, the patients underwent clinical and anthropometric measurements, blood testing, echocardiography, a 6-min walk test to assess exercise capacity, and the evaluation of their dietary pattern and calorie intake. The patients were then followed up for 1 year to evaluate adverse clinical events including all-cause death and hospitalization due to worsening HF.

#### *2.4. Anthropometric Measurements*

To assess the patients' muscle mass, we measured the circumferences of the upper arm and the thigh at the level of the muscle belly.

#### *2.5. Laboratory Measurements*

After blood collection, the patients' hemoglobin, serum albumin, HbA1c, and plasma levels of B-type natriuretic peptide (BNP) were determined by routine in-house analyses. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine values and the patient's age with the use of the Japanese equation [10]: eGFR = 194 × (serum creatinine, mg/dL)−1.094 × (age, years)−0.287 × (0.739 if female).

#### *2.6. Assessment of Dietary Calorie Intake*

Each patient's dietary pattern was evaluated using a BDHQ adjusted to typical Japanese diets. The BDHQ is a four-page fixed-portion questionnaire that calculates the frequency of the consumption of selected foods to estimate the intake of 58 food and beverage items during the preceding month, as described [11,12]. The BDHQ consists of five sections—(1) the intake frequency of food and nonalcoholic beverage items, (2) the daily intake of rice and miso soup, (3) the frequency of alcoholic beverage consumption and the amount per drink, (4) usual cooking methods, and (5) general dietary behavior. The dietary calorie intake was calculated as the sum of each energy conversion factor from the fats, proteins, and carbohydrates whose amount is estimated using the BDHQ, as described previously [13,14]. Dietary salt intake was estimated according to the diet history method using the quantitative information. In this estimation, intakes of table salt and salt-containing seasoning at the table, calculated using the qualitative information of general dietary behavior, were also considered, as described [12].

#### *2.7. Estimation of the Dietary Calorie Requirement*

The dietary calorie requirement was estimated using the Japanese Dietary Reference Intakes published by the Ministry of Health, Labour and Welfare (Japan) in 2015, as described previously [15,16]. Briefly, each patient's estimated dietary calorie requirement was determined in consideration of his or her age, gender, and physical activity level (low, moderate, or high). Since most of the patients were in a stable condition with New York Heart Association (NYHA) functional class I or II (normal or mild HF) and all the patients were ambulant and regularly visited an outpatient ward, the daily calorie requirement was estimated with the assumption that all of the patients were engaged in moderate physical activity (categorized as level II). This level requires the ability to do self-care activities (e.g., washing and dressing) and walk outside without any support. We then calculated the dietary energy adequacy (%) as the ratio of the individual patient's daily calorie intake to the estimated daily calorie requirement.

#### *2.8. Assessment of Nutritional Status*

Each patient's nutritional status was assessed by determining his or her controlling nutritional status (CONUT) score [17] and score on a geriatric nutritional risk index (GNRI) [18]. Briefly, the CONUT score was calculated based on the serum albumin level, total peripheral lymphocyte count, and total cholesterol level, and the scores are classified into normal (0–1 points), mild risk (2–4), moderate risk (5–8), and severe risk (9–12) of malnutrition. The GNRI was calculated from the patient's BMI and albumin concentration according

to the modified version—GNRI = 14.89 × serum albumin (g/dL) + 41.7 × BMI/22. The GNRI values are classified into four grades of malnutrition-related risk—major risk (GNRI < 82), moderate risk (GNRI 82–91), low risk (GNRI 92–98), and no risk (GNRI > 98).

#### *2.9. Statistical Analyses*

Continuous variables are expressed as medians (interquartile range), and categorical variables are expressed as numbers (percentages). We divided the 145 patients into two groups based on their dietary calorie intake adequacy—the adequate calorie intake group (dietary calorie intake adequacy ≥60%; *N* = 101) and the inadequate calorie intake group (dietary calorie intake adequacy <60%; *N* = 44). The cut-off value of dietary calorie intake adequacy rate (60%) was predetermined by the results of the multivariate analysis. Continuous variables were compared between these groups with a Mann–Whitney U-test, and the χ2-test was used for group comparisons of categorical variables. We performed a multivariate analysis to identify the decrease in dietary calorie intake adequacy that independently predicts adverse clinical events in chronic HF patients with other confounding factors that may influence dietary calorie intake, including age, BMI, NYHA functional class III, diabetes, left ventricular ejection fraction (LVEF), serum albumin, eGFR, and log BNP. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each variable from the logistic regression model. A Kaplan–Meier analysis with log-rank test was performed to assess the rates of all-cause death and rehospitalization due to worsening HF for 1 year. All analyses were performed using JMP Pro 13.1.0 software (SAS Institute, Cary, NC, USA). Probability (*p*)-values < 0.05 were considered significant.

#### **3. Results**

#### *3.1. Characteristics of the Total Chronic HF Cohort*

The characteristics of the total chronic HF cohort (*N* = 145) are summarized in Table 1. The median age of the patients with chronic HF was 67 years, and the median BMI was 22.9 kg/m2. We recruited stable outpatients with chronic HF, and 90% of the patients had an NYHA functional class I or II. The median LVEF was 45%, and both HF patients with a reduced LVEF and those with a preserved LVEF were included in this cohort. The majority of the chronic HF patients were being treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and a β-blocker. For the total chronic HF cohort, the median value of dietary calorie intake was 1628 kcal/day and the dietary calorie intake adequacy rate was 75%. The distribution of the dietary calorie intake adequacy rates of the patients is shown in Figure 1.

**Figure 1.** Distribution of dietary calorie intake adequacy rate of the female and male patients with chronic HF.


**Table 1.** Characteristics of total chronic heart failure (HF) cohort (*N* = 145).

Data are median (1st–3rd quartile) or *n* (%). ACE: angiotensin-converting enzyme; ARB: angiotensin II receptor blocker; BMI: body mass index; BNP: B-type natriuretic peptide; CONUT: controlling nutritional status; eGFR: estimated glomerular filtration rate; GNRI: geriatric nutritional risk index; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonist; NYHA: New York Heart Association.

#### *3.2. Characteristics of the Chronic HF Patients with and without Adequate Calorie Intake*

We divided the total chronic HF cohort into two groups—the adequate calorie intake group (*N* = 101) and the inadequate calorie intake group (*N* = 44). Inadequate calorie intake was defined as <60% of the estimated calorie requirement according to the results of the multivariate analysis. The baseline data of each group are summarized in Table 2. The median age of the chronic HF patients with inadequate calorie intake was younger than that of the patients with adequate calorie intake, but there was no significant difference in BMI or muscle mass (i.e., upper arm and thigh circumferences) between the groups. The percentage of diabetes was greater in the inadequate calorie intake group compared to the adequate calorie intake group. The LVEF, a parameter of LV systolic function, was significantly lower in the chronic HF patients with inadequate calorie intake. Renal function (i.e., eGFR) was more often impaired in the patients with inadequate calorie intake.


**Table 2.** Characteristics of chronic HF patients with adequate calorie intake and those with inadequate calorie intake.

Data are median (1st–3rd quartile) or n (%). Inadequate calorie intake was defined as <60% of estimated calorie requirement. ACE: angiotensin-converting enzyme; ARB: angiotensin II receptor blocker; BMI: body mass index; BNP: B-type natriuretic peptide; CONUT: controlling nutritional status; eGFR: estimated glomerular filtration rate; GNRI: geriatric nutritional risk index; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonist; NYHA: New York Heart Association.

> The nutritional parameters including the CONUT score and GNRI value were similar between the two groups. As expected, the chronic HF patients with inadequate calorie intake had a reduced daily calorie intake compared to those with an adequate calorie intake. In addition, most of foods and nutrients were less frequently consumed by the patient with inadequate calorie intake (Supplementary Tables S1 and S2). The daily salt intake was significantly reduced in the inadequate calorie intake group compared to the adequate calorie intake group (median (1st–3rd quartile range) 6.6 (5.4–8.3) vs. 10.2 (8.8–13.3) g/day, *p*<0.01) (Supplementary Table S2).

#### *3.3. Adverse Clinical Events*

During the 1-year follow-up period, the combined clinical events of all-cause death and HF-related hospitalization occurred in 14 patients (10%) (four deaths and 10 hospitalizations). The Kaplan–Meier analysis revealed that the patients with an inadequate calorie intake had a significantly higher risk of adverse clinical events than those with an adequate calorie intake (20% vs. 5%, respectively; *p <* 0.01) (Figure 2).

**Figure 2.** Kaplan–Meier curves for the cumulative event (all-cause death and HF-related hospitalization)-free ratio in the chronic HF patients with an adequate calorie intake (dietary calorie intake adequacy ≥60%) and those with an inadequate calorie intake (dietary calorie intake adequacy <60%).

#### *3.4. Predictors of Adverse Clinical Events in Patients with Chronic HF*

The results of the multivariate analysis revealed that after the adjustment for age, BMI, NYHA functional class III, LVEF, serum albumin, eGFR, and log BNP, inadequate calorie intake defined as <60% of the estimated calorie requirement was a significantly independent predictor of adverse clinical events including all-cause death and HF-related hospitalization over 1 year in the patients with chronic HF (Table 3).

**Table 3.** Multivariate analysis of predictors of adverse clinical events including all-cause death and HF-related hospitalization in patients with chronic HF.


As confounding factors that may influence patient's dietary calorie intake, age, BMI, NYHA functional class III, diabetes, LVEF, serum albumin, eGFR, and log BNP were included in each analysis. OR: odds ratio; CI: confidence interval.

#### **4. Discussion**

In the present cohort of 145 patients with chronic HF, the inadequate calorie intake group had a significantly higher risk of adverse clinical events including all-cause death and hospitalization due to worsening HF for the 1-year follow-up period compared to the adequate calorie intake group, when we defined inadequate calorie intake as <60% of estimated calorie requirement. The multivariate logistic regression analysis showed that dietary calorie intake adequacy <60% was an independent predictor of worse clinical outcomes after adjustment for age, BMI, NYHA functional class III, diabetes, LVEF, serum albumin, eGFR, and log BNP in chronic HF patients. To the best of our knowledge, this is the first study that revealed the impact of dietary energy deficiency on mortality and hospitalization in stable outpatients with chronic HF.

Although several nutritional assessment tools such as the CONUT score and the GNRI are used in clinical practice, we here focused on a questionnaire-based assessment of the daily calorie intake in patients with chronic HF. All of the patients were in stable condition at baseline, and most of them were categorized as having no risk or only a mild risk of malnutrition when they were evaluated using the CONUT score or the GNRI. The malnutrition risk scores calculated by these nutritional assessment tools did not differ between the patients with inadequate calorie intake and those with adequate calorie intake. Accordingly, our present finding that the lowered dietary calorie intake adequacy was associated with increased risks of death and hospitalization in chronic HF patients indicates that the dietary calorie intake can be a useful nutritional assessment tool to detect the early stage of malnutrition in stable patients with chronic HF.

Cardiac cachexia, characterized by weight loss, is a major contributor to a poor prognosis in chronic HF patients [19]. The negative energy balance caused by an inadequate dietary calorie intake that does not support energy needs may lead to protein breakdown, which results in muscle wasting and sarcopenia [6,7]. Although in the present investigation, the BMI and muscle mass measured at baseline were not reduced in the patients with inadequate calorie intake, a sustained dietary energy deficiency may contribute to the future onset of cardiac cachexia and sarcopenia.

Our analyses revealed that the daily intakes of macronutrients and micronutrients were significantly decreased in the chronic HF patients with inadequate calorie intake, and this pattern might lead to worse clinical outcomes. Deficiencies of micronutrients such as minerals and vitamins have been reported to potentially impair cardiac and systemic functional capacity, which results in reduced quality of life and poor prognosis [20,21]. Oxidative stress also plays a crucial role in the progression of HF [22–25], and in the present cohort, the patients with inadequate calorie intakes had lowered consumptions of antioxidative nutrients such as vitamin C, vitamin E, and carotenoids, which might also affect the increased rate of adverse clinical events.

Although we could not quantify the patient's appetite, intestinal congestion may cause appetite loss, which results in inadequate calorie intake in chronic HF patients. It is reported that cachectic patients with chronic HF had a larger bowel wall thickness (i.e., intestinal congestion) in the entire colon [26]. In addition, decreased hunger sensation and HF-related symptoms (such as fatigue, nausea, and anxiety) may be related to reduced calorie intake in chronic HF patients [27]. Taken together, digestive disturbance and HF-related symptoms may affect inadequate calorie intake in these patients.

Dietary salt restriction is widely recommended to HF patients as a dietary intervention. Unexpectedly, we observed that the daily salt intake was significantly lower in the patients with an inadequate calorie intake, who had a higher risk of adverse clinical events. It has been reported that strict adherence to salt restriction may lead to appetite loss and reduced calorie intake, which results in a dietary nutritional deficiency in chronic HF patients [28]. Accordingly, more comprehensive dietary interventions in consideration of dietary calorie intake adequacy and nutritional balance as well as salt restriction are necessary for the prevention of HF progression.

There are some study limitations to consider. First, the number of patients with inadequate calorie intake was small (*N* = 44). Second, the dietary calorie and nutritional intake were evaluated on the basis of the patient's self-reported information about dietary patterns, and we thus could not directly measure their dietary calorie intake. In addition, each patient's calorie requirement was estimated using the Japanese Dietary Reference Intakes for the general population. Because HF patients' energy expenditure is likely to be higher than that of healthy subjects, we cannot completely exclude the possibility that our patients' calorie requirement might be underestimated. Direct measurements of calorie intake and energy expenditure considering the patients' daily physical activity level might increase the accuracy of the estimations of dietary calorie intake adequacy. Finally, we did not evaluate the social, economic, or environmental conditions of patients, although these factors may also affect dietary calorie intake.

#### **5. Conclusions**

In stable patients with chronic HF, inadequate dietary calorie intake was independently associated with an increased risk of adverse clinical events including all-cause death and hospitalization due to worsening HF.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/2072-664 3/13/3/874/s1. Table S1: Daily intakes of foods and beverages estimated using a BDHQ, Table S2: Daily intakes of nutrients estimated using a BDHQ.

**Author Contributions:** S.K. and M.T.-M. designed the study. S.K., A.F., T.Y., T.O., T.S., Y.K., M.T., H.M., R.M., I.Y. (Ichiro Yoshida), and K.Y. collected the data and contributed to the discussion. Y.O., N.K., S.K., A.F., T.Y., S.T., and I.Y. (Isao Yokota) contributed to the data analysis. Y.O., N.K., and T.Y. wrote the manuscript. S.K., A.F., S.T., I.Y. (Isao Yokota), and M.T.-M. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was partly supported by a Grant-in-Aid for Scientific Research from KAKENHI (no. JP24614001 to M.T.-M. and no. 18K08022 to T.Y.) and the Center of Innovation Program from the Japan Science and Technology Agency (no. JPMJCE1301 to T.Y.).

**Institutional Review Board Statement:** The study was approved by the ethics committees of Hokkaido University Hospital (approval no. 012-0224) and the other nine participating research institutes—Hakodate National Hospital, Hikone Municipal Hospital, Kitami Red Cross Hospital, Keiwakai Ebetsu Hospital, Kushiro City General Hospital, Obihiro Kyokai Hospital, Otaru Kyokai Hospital, Saiseikai Fukuoka General Hospital, and Tottori University Hospital.

**Informed Consent Statement:** The study was conducted in accordance with the ethical principles described in the Declaration of Helsinki. Written informed consent was obtained from each patient before his or her participation in the study.

**Data Availability Statement:** Data supporting the findings of this work are available from the corresponding author upon reasonable request. All the data are obtained from subjects and are not publicly available due to ethical reasons.

**Acknowledgments:** We thank Yoshihiro Himura (Hikone Municipal Hospital), Shigeo Kakinoki (Otaru Kyokai Hospital), Kazuya Yonezawa (National Hospital Organization Hakodate National Hospital), and Yoko Ikeda and Ayako Muramoto (Hokkaido University Hospital) for their kind support of this study. We also thank all of the participating patients, cardiologists, nurses, and dieticians who contributed to this study.

**Conflicts of Interest:** I.Y. received a speaking fee from Japan Tobacco, Inc. (Pharmaceutical Division). The other authors declare no conflict of interest relevant to this article.

#### **References**


### *Article* **Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals**

**Kenya Kusunose 1,\*, Yuichiro Okushi 1, Yoshihiro Okayama 2, Robert Zheng 1, Miho Abe 1, Michikazu Nakai 3, Yoko Sumita 3, Takayuki Ise 1, Takeshi Tobiume 1, Koji Yamaguchi 1, Shusuke Yagi 1, Daiju Fukuda 1, Hirotsugu Yamada 4, Takeshi Soeki 1, Tetsuzo Wakatsuki <sup>1</sup> and Masataka Sata <sup>1</sup>**


**Abstract:** A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, *p* < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both *p* < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.

**Keywords:** heart failure; vitamin D; mortality; big data

#### **1. Introduction**

The main treatment medications for heart failure (HF) remains to be β-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists in the guidelines [1]. Although it is well known that these medications can reduce the incidence of adverse cardiac events and improve cardiac function, HF is still a main cause of death worldwide [2]. Thus, supplementary treatment methods continue to be explored for improving the outcome of HF.

**Citation:** Kusunose, K.; Okushi, Y.; Okayama, Y.; Zheng, R.; Abe, M.; Nakai, M.; Sumita, Y.; Ise, T.; Tobiume, T.; Yamaguchi, K.; et al. Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals. *Nutrients* **2021**, *13*, 335. https://doi.org/10.3390/nu13020335

Academic Editor: Karl Michaëlsson Received: 22 December 2020 Accepted: 20 January 2021 Published: 23 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Vitamin D is a steroid hormone belonging to a group of lipid-soluble vitamins. Recently, many papers showed that a broad range of chronic conditions have been associated with vitamin D deficiency [3–5]. Around 90% of chronic HF patients have insufficient vitamin D levels, even in sunny climates [6,7]. Vitamin D has pleiotropic effects in the pathology of chronic HF [8]. Despite current evidence regarding the association of vitamin D with HF, there are many controversial results in previous clinical trials [9–11]. In these trials, lack of a large sample size and the small number of high-risk patients are major limitations. Our hypothesis was that vitamin D supplementation was associated with a decreased risk of in-hospital death in HF patients with specific clinical characteristics. Therefore, we sought to evaluate the outcomes of patients with vitamin D supplementation compared with a matched cohort using real-world big data based on HF hospitalizations.

#### **2. Materials and Methods**

#### *2.1. Study Population*

The study population was composed of hospitalized patients between April 2012 and March 2017 in The Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination (JROAD-DPC) database. JROAD-DPC is a nationwide registry, a medical database with information of admission and discharge for cardiovascular diseases, clinical examinations and treatment status, patient status and hospital overview. JROAD-DPC database integrates the information composed by JROAD-DPC data, with analysis data sets covering 5.1 million cases in 1022 hospitals between April 2012 and March 2017. The identification of HF (I50.0, I50.1, I50.9) hospitalization was based on the International Classification of Diseases (ICD)-10 diagnosis codes. Data regarding patient age and sex, main diagnosis, comorbidity at admission, length of hospitalization and treatment content were extracted from the database. We recruited 654,737 patients hospitalized with HF. Diagnosis of HF was defined as the main diagnosis, admission-precipitating diagnosis or most resource-consuming diagnosis. We excluded patients of unknown age (*n* = 1073), readmission cases (*n* = 172,805), age < 20 years (*n* = 1477), death in 24 h after admission (*n* = 10,298), planned hospitalization (*n* = 54,713), and incomplete data (*n* = 320,679). As a result, total 93,692 (88,205 patients without vitamin D and 5487 patients with vitamin D) were recruited to assess hospital mortality (Figure 1). For vitamin D supplementation, oral 25(OH)D 3 (Calcifediol, Dedrogyl®) was prescribed at a daily dose of 0.5–1.0 μg/day based on the attending physician's discretion.

**Figure 1.** Flowchart of this study. HF, heart failure; Vit D, vitamin D supplementation.

#### *2.2. Clinical Outcomes*

The main outcome was in-hospital mortality (total number of deaths during hospitalization). Death ≤ 7 and 30 days after admission was assessed as secondary outcomes.

#### *2.3. Sample Matching*

Propensity score (PS) matching was used to reduce confounding effects related to differences in patient background. PS was estimated with a logistic regression model, with vitamin D supplementation as the dependent variable and the following clinically relevant covariates; age, sex, body mass index (BMI), smoking, New York Heart Association functional classification (NYHA), comorbidities (hypertension: HT, diabetes: DM, dyslipidemia: DL, osteoporosis, atrial fibrillation/atrial flutter: Af/AFL, stroke, myocardial infarction: MI, peripheral vascular disease: PVD, renal disease, liver failure, chronic obstructive pulmonary disease: COPD, rheumatoid arthritis: RA, dementia, cancer), treatment (catecholamine, intra-aortic balloon pumping: IABP, percutaneous cardiopulmonary support: PCPS, ventilation, hemodialysis: HD, percutaneous coronary intervention: PCI). These covariates were chosen for their potential association with reference to risk factor of heart failure and in-hospital mortality [12–14]. Matching was performed with greedymatching algorithm (ratio = 1:1 without replacement), with a caliper of width 0.2 standard deviations of the logistic of the estimated propensity score. After matching, vitamin D and non-vitamin D groups of 5487 patients each were included in the final analysis. The area under the curve was 0.785 and the consistency of PS densities was matched after matching (Supplemental Figure S1). The balance of each covariate before and after matching between the 2 groups was evaluated by standardized differences. Absolute value of standardized differences less than 10% was considered to be a relatively small imbalance. Because the propensity score included cases in which vitamin D was used under the insurance of Japan (renal disease, osteoporosis, and dialysis), we believed the propensity score accounted for the factors that influence the prescription of vitamin D by general physicians in this analysis.

#### *2.4. Statistical Analysis*

Continuous variables are expressed as mean ± SD for parameters with normal distribution, as median (interquartile range; IQR) for parameters with skewed distribution, and categorical variables as proportion (%). We checked characteristics between groups with and without vitamin D supplementation using standardized difference. After matching, we estimated the OR for in-hospital mortality (total, within 7 days, 30 days) using mixed-effects logistic regression model with each institute as a random effect. We also analyzed subgroups in the PS-matched cohort. In-hospital mortality was assessed using Kaplan–Meier curves and log-rank test to compare the two groups. To clarify the beneficial group of vitamin D supplementation, odds ratios (ORs) and their 95% confidence interval (CI) for in-hospital mortality were calculated using multivariate models of multinomial logistic regression analysis in vitamin D (+) and vitamin D (−) groups. All statistical tests were 2-sided and *p* values less than 0.05 were considered statistically significant. Statistical analysis was performed using SAS version 9.4 and JMP version 14.0.

#### **3. Results**

#### *3.1. Patient Characteristics*

A total of 52.2% of patients in this study were male. Mean age was 79 ± 12 years, and half of all patients had hypertension (52.9%). Over 60% of the patients were NYHA class III or IV. Patients with vitamin D supplementation were more likely to have a history of chronic kidney disease, osteoporosis, hypoparathyroidism, or hemodialysis. There are differences for age, gender, BMI, smoking, hypertrophic cardiomyopathy, atrial fibrillation/atrial flutter, and rheumatoid arthritis between two groups. Around 19.7% took angiotensin converting enzyme inhibitors (ACE-I) or angiotensin-receptor blocker (ARB) and 9.1% took beta-blockers. About 19.4% of the patients took loop diuretic and 10.1% took K-sparing diuretics.

After propensity score matching, 10,974 patients were included in the survival analysis. In the matched cohort, there were no significant differences between groups for age, gender, comorbidities, and treatments (Table 1).


**Table 1.** Baseline characteristics before and after propensity score matching.

Data are presented as percentage of patients or median (interquartile range). A standardized difference of < 10% suggests adequate balance. Abbreviations: Vit.D, vitamin D supplementation; std.diff, standardization difference; BMI, body mass index; NYHA, New York heart association functional class; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy; Af, atrial fibrillation; AFL, atrial flatter; AT, atrial tachycardia, MI, myocardial infarction; PVD, peripheral vascular disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; RA, rheumatoid arthritis, IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary system; PCI, percutaneous coronary intervention; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

#### *3.2. Outcomes*

In-hospital mortality, mortality within 7 days and within 30 days of hospitalization are summarized in Table 2. Even after matching, patients with vitamin D supplementation had significantly lower in-hospital mortality (6.5 vs. 9.4%, *p* < 0.001; OR, 0.67, 95% CI: 0.58–0.77), mortality within 7 days of hospitalization (0.9 vs. 2.5%, *p* < 0.001; OR, 0.34, 95% CI: 0.25–0.48), and mortality within 30 days of hospitalization (3.8 vs. 6.5%, *p* < 0.001; OR, 0.56, 95% CI: 0.47–0.67).


**Table 2.** In-hospital mortality before and after propensity score matching.

Data given as proportion. Abbreviations: OR, odds ratio.

Kaplan–Meier curves of in-hospital mortality were shown in Figure 2. Vitamin D supplementation was strongly associated with survival rate (*p* < 0.001).

**Figure 2.** Kaplan Meier curves of in-hospital mortality and hospitalization days. Comparison between with and without vitamin D (Vit.D) supplementation.

Multivariate analysis was performed with covariates that were significant in the univariate analysis to assess the association with in-hospital mortality for all patients. Major contributors were age, BMI, NYHA, hypertension, peripheral vascular disease, chronic kidney disease, artificial ventilation, PCI, catecholamine, and atrial fibrillation/flutter in this cohort. After adjustment of clinical backgrounds, vitamin D supplementation was associated with low in-hospital mortality (OR, 0.63, 95% CI: 0.49–0.81, *p* < 0.001) (Table 3A).


**Table 3.** Multivariate analysis of covariates for in-hospital mortality.


**Table 3.** *Cont.*

In multivariate analysis, there were many same risks (Table 3B,C: age, hypertension, artificial ventilator, PCI, catecholamine) for in-hospital mortality in vitamin D (+) and vitamin D (−). We have checked the difference of ORs between two groups for the risk distribution. Osteoporosis patients seemed to be protected in vitamin D (+) group, however, to be at increased risk in vitamin D (−) group. Based on this result, especially osteoporosis patients may have benefits from vitamin D supplementation during heart failure admissions. For hemodialysis and chronic kidney disease, there seemed to be small benefit in using vitamin D from ORs. BMI was associated with death in patients taking vitamin D (OR, 0.91, 95% CI: 0.87–0.95, *p* < 0.001), however, BMI was not associated with mortality in patients with vitamin D supplementation (OR, 0.97, 95% CI: 0.92–1.02, *p* = 0.22). The BMI may be an extra risk beyond the selection of patients with kidney disease or osteoporosis.

Predictive values using ROC analysis for in-hospital morality were good (Supplemental Figure S2: C-statistics: 0.85 for vitamin D (+) and 0.84 for vitamin D (−)) compared with the previous prediction models [15]. Thus, we thought that risk prediction performance was not different in both populations.

#### *3.3. Subgroup-Analysis*

Mortality in each sub-group, forest plots of OR are shown in Figure 3. Regardless of gender, BMI, NYHA, hypertension, and chronic kidney disease, patients with vitamin D supplementation had significantly lower in-hospital mortality than matched patients. Mortalities in patients with age < 75 (OR, 0.84, 95% CI: 0.59–1.24, *p* = 0.54), diabetes (OR, 0.75, 95% CI: 0.56–1.02, *p* =0.06), dyslipidemia (OR, 0.67, 95% CI: 0.42–1.07, *p* = 0.09), Af/AFL (OR, 0.79, 95% CI: 0.58–1.07, *p* = 0.13), cancer (OR, 0.71, 95% CI: 0.47–1.07, *p* = 0.10), ACEi/ARB medication (OR, 0.72, 95% CI: 0.47–1.10, *p* = 0.13), and β-blocker usage (OR, 0.80, 95% CI: 0.41–1.57, *p* = 0.51) were not affected by vitamin D supplementation. Thus,

this analysis suggested that there were specific clinical characteristics in patients benefitting from vitamin D supplementation.

**Figure 3.** Odds ratio of in-hospital mortality. Patients with vitamin D compared with matched patients without vitamin D. Dots and lines mean OR and 95% CI, respectively.

#### **4. Discussion**

The main findings of the present study were (1) HF patients with vitamin D supplementation had significantly lower in-hospital mortality and mortality within 7 and 30 days of hospitalization in the propensity matched cohort; (2) mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker medication, and β-blocker were not affected by vitamin D supplementation; (3) by multivariate analysis we identified that it was mainly osteoporosis patients that benefit from being treated with vitamin D supplementation when they were admitted for HF. Mortality was consistently low in patients with vitamin D supplementation at 7 days, 30 days, and during hospitalization. On the other hand, there are specific clinical characteristics in HF patients who do not benefit much from vitamin D. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful in determining targets of future studies.

#### *4.1. Impact of Vitamin D on HF Mortality*

Although there is much evidence showing that a lack of vitamin D could result in poor prognosis among patients with HF, different studies have reported controversial results about the benefit of vitamin D supplementation in patients with HF. In recent years, there were some randomized control trials for the effects of vitamin D on patients with HF. For example, the Vitamin D treating patients with chronic heart failure (VINDICATE) study showed that vitamin D supplementation has beneficial effect on left ventricular (LV) structure and function [11]. An individual participant data meta-analysis observed an association between low vitamin D level and increased risk of all-cause mortality [16]. On the other hand, another meta-analysis reported that vitamin D supplementation did not improve LV ejection fraction and 6-min walk distance in the treatment of chronic HF [17]. A recent updated meta-analysis also reported that vitamin D supplementation was not significantly associated with reduced major adverse cardiovascular events [18].

While randomized clinical trials (RCT) provide a foundation for clinical evidence, trials are often performed in highly controlled environments with narrow inclusion and exclusion criteria, which reduces their generalizability and external validity. Highly protocolled care in an RCT may differ substantially from interventions in routine settings [19]. The Mendelian Randomization study is a new concept of analysis, however, the genetic variants are unclear in the vitamin D3 levels [20]. A notably limitation of these trials is that none were focused on vitamin D supplementation in patients with high-risk cohort including NYHA 3 and 4. From our subgroup analysis, patients, the effect of vitamin D on in-hospital mortality was seemed to be greater in NYHA III-IV patients compared with NYHA I-II (NYHA III-IV: OR: 0.63, *p* < 0.001 and NYHA I-II: OR: 0.72, *p* = 0.014). We believe that the key to proving the worth of vitamin D supplementation is to create clinical studies that also involve a significant number of decompensated HF patients.

#### *4.2. Mechanisms of Vitamin D for HF*

There are some theories for the association between vitamin D and HF prognosis. In HF, cardiac contraction and relaxation are affected due to overload of Ca2+ ions in myocardial cells. Lack of vitamin D may intervene with the functions of Ca2+ in myocardial cells, resulting in cardiomyocyte hypertrophy, intra-organisational inflammatory reaction and fibrosis [21,22]. Low vitamin D levels may activate the renin–angiotensin system [23], give rise to inflammatory reactions [24] and result in endothelial dysfunction [25]. Interestingly, our subgroup analysis suggested that patients without ACEi/ARB had received more beneficial effects from vitamin D in regards to in-hospital mortality. The effect of vitamin D was more pronounced in patients without ACEi/ARB usage, hence suggesting an activated renin–angiotensin system in these patients.

The effects of vitamin D on the cardiovascular system are additionally mediated through elevated parathyroid hormone levels [26]. An age-related increase in parathyroid hormone levels has been demonstrated in several studies [27]. In our cohort, elderly patients (with suspected elevation of parathyroid hormone) with vitamin D supplementation were associated with lower in-hospital mortality (age < 75: OR: 0.84, *p* = 0.40 and age ≥ 75: OR: 0.66, *p* < 0.001). This result may suggest a link between vitamin D and elevated parathyroid hormone levels in the cardiovascular system. Based on the basic knowledge of these mechanisms, the link between vitamin D and prognosis in HF may be explained.

#### *4.3. Clinical Implication*

Even with the current wealth of guidelines and recommendations about HF and development of many new treatment methods, HF is associated with a high in-hospital mortality [1]. For patients with HF, vitamin D supplementation is a low-cost low-risk choice, and certain patients may benefit greatly from this therapy. According to our data from the large high-risk HF cohort, patients with vitamin D supplementation had lower mortality, and specific clinical characteristics were linked to better in-hospital mortality. The identified specific clinical characteristics that might be useful for future RCT studies.

#### *4.4. Limitations*

The study based on ICD codes has several limitations. First, we analyzed only patients with HF hospitalized in facilities contributing to the database, which may lead to selection bias. Second, the database has no information on echocardiography or laboratory data to assess the prognosis of HF. Third, the database lacked information on the specific doses of vitamin D supplementation in each patient. Dose dependency was unable to be examined. Forth, propensity score-matching reports the potential differences between groups, with only a certain degree of accuracy. Despite the application of propensity matching to the comparator group of patients, this non-randomized observational study could still be subject to hidden biases related to patient selection, because of unknown unadjusted differences. To overcome this issue, we used treatment devices and catecholamine medication as markers of HF severity. All-cause mortality was used as the primary end point in our patient population. The most likely cause of death in our patient population is HF, given the known high-risk nature of our patient population. The patients in this study are mostly Japanese. Results may differ due to racial or cultural differences in other countries. The JROAD-DPC dataset extracts only a record which contains all types of cardiovascular diseases in any categories of diagnosis based on the DPC dataset in Ministry of Health, Labor and Welfare in Japan. The DPC dataset has already been validated in past studies [28]. However, we were unable to check the undefined diseases by the coding system in our final dataset. This registry data does not include laboratory data. However, there would be no difference in background between the two groups as we corrected for many confounding factors. Finally, the results cannot be applied to all heart failure admissions. The results can be applied to the group of patients who should receive vitamin D supplementation but did not get it. The reason is that there were many osteoporosis and hemodialysis patients in both groups. Thus, the vitamin D group was suspected to have higher serum 25(OH)D compared with the non-vitamin D group. Considering these limitations, the present study should be considered as a hypothesis generating study for future RCT studies.

#### **5. Conclusions**

Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in this propensity matched cohort. The causality should be tested in the future RCTs in specific population based on our study.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/2072-664 3/13/2/335/s1, Figure S1a: Receiver operating characteristic curve and concordance index. Figure S1b: comparison of the consistency of propensity score densities before and after matching. Figure S2: Predictive values for in-hospital mortality.

**Author Contributions:** K.K. conceived the idea for this study. Y.O. (Yuichiro Okushi) and Y.O. (Yoshihiro Okayama) conducted the data analyses. The initial draft of the manuscript was produced by K.K. and Y.O. (Yuichiro Okushi). All authors (K.K., Y.O. (Yuichiro Okushi), Y.O. (Yoshihiro Okayama), R.Z., M.A., M.N., Y.S., T.I., T.T., K.Y., S.Y., D.F., H.Y., T.S., T.W., and M.S.) were involved in interpreting the results and writing the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was partially supported by Japan Society for the Promotion of Science Kakenhi Grants (Number 20K17084 to Y. Okushi, 19H03654 to M. Sata), the Takeda Science Foundation (to K. Kusunose), and Japan Agency for Medical Research and Development under Grant Number JP19lk1010035 (to K. Kusunose).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Tokushima University (protocol no. 3503).

**Informed Consent Statement:** Patient consent was waived because the analysis used anonymous clinical data.

**Data Availability Statement:** The datasets are available from the corresponding author on reasonable request.

**Conflicts of Interest:** The authors have no conflicts of interest to declare.

#### **References**


### *Article* **Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life**

**Tatsuhiro Shibata 1,2, Kazutoshi Mawatari 1, Naoko Nakashima 2,3, Koutatsu Shimozono 1, Kouko Ushijima 3, Yumiko Yamaji 3, Kumi Tetsuka 3, Miki Murakami 2,3, Kouta Okabe 1, Toshiyuki Yanai 1, Shoichiro Nohara 1, Jinya Takahashi 1, Hiroki Aoki 4, Hideo Yasukawa <sup>1</sup> and Yoshihiro Fukumoto 1,\***

	- <sup>2</sup> Kurume University Hospital Palliative Care Team, Kurume University, Kurume 830-0011, Japan; nakashima\_naoko@kurume-u.ac.jp (N.N.); yoshigai\_miki@kurume-u.ac.jp (M.M.)
	- <sup>3</sup> Department of Nursing, Kurume University Hospital, Kurume 830-0011, Japan; ushijima\_kouko@kurume-u.ac.jp (K.U.); yumi0802minami@yahoo.co.jp (Y.Y.); tetsuka\_kumi@kurume-u.ac.jp (K.T.)

**Abstract:** Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.

**Keywords:** heart failure; palliative care; end-of-life care discussion; advance care planning; food intake; artificial nutrition

#### **1. Introduction**

Recent developments in new drugs, monitoring systems, and device therapies have evolved heart failure (HF) therapy; however, these developments may stabilize HF but rarely cure it. Furthermore, these advances are often only available for a limited number of patients. During HF progression, patients experience a high symptom burden and poor quality of life similar to that reported by patients with cancer [1,2]. HF often follows an unpredictable illness trajectory, with stable periods interrupted by exacerbations and sometimes resulting in sudden cardiac death, leading to difficulties in estimating survival [3]. When focusing on end-of-life decision making, such prognostic uncertainty complicates the patients' plans concerning their end-of-life wishes and sometimes leads to an overestimation of survival [4]. Furthermore, traditionally in Japan, patients rarely participate in

**Citation:** Shibata, T.; Mawatari, K.; Nakashima, N.; Shimozono, K.; Ushijima, K.; Yamaji, Y.; Tetsuka, K.; Murakami, M.; Okabe, K.; Yanai, T.; et al. Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life. *Nutrients* **2021**, *13*, 2387. https:// doi.org/10.3390/nu13072387

Academic Editor: Bradley S. Ferguson

Received: 10 June 2021 Accepted: 10 July 2021 Published: 13 July 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

173

discussions about their own goals and preferences for end-of-life care (EOLC), because their families may hesitate to bring bad news. As patients tend to lose their decision-making ability toward the end of life [5], they sometimes have no opportunity to express their wishes and preferences regarding their EOLC. Until recently in Japan, these situations often led to providing life-prolonging treatment to critically ill patients, regardless of the medical futility [6]. In addition, at the end-stage of HF, associated symptoms such as anorexia, nausea, vomiting, and dyspnea are observed, and food intake decreases [7]. In patients with end-stage HF, the goal of nutritional care is to optimize quality of life and comfort. Even though patients eventually lose their appetite spontaneously, artificial nutrition has often been attempted in the past.

Palliative care comprises a multidisciplinary team approach for patients and their families facing serious illnesses that focuses on improving quality of life and death. Recently, palliative care has been recommended by the Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS) and American College of Cardiology (ACC)/American Heart Association (AHA) HF guidelines [8,9]. The core elements of a multidisciplinary palliative care team (PCT) include not only expert assessment of physical and psychosocial distress but also the establishment of care goals and support for advance care planning (ACP) and complex decision-making, including EOLC discussion. In Japan, a multidisciplinary PCT is available in most of the regional cancer centers; however, it is only available in 9% of JCS-authorized cardiology training hospitals [10]. One of the major reasons is that PCT intervention had not been reimbursed for patients with HF by April 2018. Given that these services are not yet widely available, there has been insufficient clinical data regarding PCTs in patients with HF in Japan. Moreover, even in Western countries, only limited evidence is available regarding the patient-centered EOLC discussions of inpatient PCTs with patients with HF [11,12].

Therefore, the main purpose of this study was to compare changes in HF therapies in terms of palliative care and EOLC discussions, with a focus on food intake at the end of life in HF, before and after the initiation of HF-specific PCT (HF-PCT) activities at our institute.

#### **2. Materials and Methods**

#### *2.1. Study Design and Population*

The study was performed at Kurume University Hospital, a 1000-bed tertiary medical center located in the southern part of Fukuoka Prefecture, Japan. We retrospectively analyzed the medical records of 215 consecutive patients who died at the Division of Cardiology of our hospital between May 2013 and July 2020. Among these, we excluded 163 cases of non-HF deaths, including acute myocardial infarction, and patients treated only in the intensive care unit. HF was diagnosed by at least two specialist cardiologists based on the Framingham criteria [13]. Thus, we conducted a final analysis of 52 patients with HF who died in our department. These patients were divided into two groups according to their time of death before (Era 1; May 2013 to May 2015) and after (Era 2; June 2015 to July 2020) the HF-PCT activity started in June 2015. In this study, a multidisciplinary palliative approach for patients and their families was provided by an HF-PCT, which consisted of cardiologists, palliative care physicians, nurses (inpatient, outpatient, and a certified palliative care nurse), pharmacists, a psychologist, a medical social worker, and a managerial dietitian. The HF-PCT was available for all HF patients and assisted the treatment of patients with HF through refractory symptom relief, the establishment of care goals, psychosocial support, support of ACP and EOLC discussions, and provision of nutritional support for EOLC.

The demographic and clinical information of each patient was extracted from the electronic medical records of Kurume University Hospital. We obtained data on the patients' background, etiology of HF, duration of HF, comorbidities, echocardiographic findings, HF treatments, sedative medications, laboratory data, location of death, invasive procedures undergone before death (cardiopulmonary resuscitation, intubation, direct current shocks, and mechanical circulatory support) and length of hospital stay. We also assessed differences in the palliative care intervention, such as the use of opioids and sedative medications for refractory symptoms, psychiatric support, and multidisciplinary support for EOLC discussions, between the patients who died in Era 1 and those who died in Era 2. To assess the nutritional status of patients with end-stage HF, we examined the method of receiving nutrition three days prior to death and nutritional interventions (discontinuation of salt reduction, allowing non-hospital meals, and use of oral nutritional supplements) for patients who were maintaining oral intake at the time. We also examined factors associated with the use of artificial nutrition (total parenteral nutrition and tube feeding) three days prior to death.

#### *2.2. Statistical Analysis*

Continuous variables are presented as mean ± standard deviation (SD) or median (interquartile range (IQR)), as appropriate; they were compared using Student's *t*-test. Categorical baseline variables are presented as numbers (percentage) and compared using the chi-square or Fisher's exact test. Univariate associations between baseline characteristics and multidisciplinary support for end-of-life discussions were performed using univariate logistic regression. Variables relevant to the model were selected based on a univariate threshold *p*-value (≤0.05) and included in a multivariate logistic model to predict the odds of receiving artificial nutrition in the final three days prior to death. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Statistical significance was set at *p* < 0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R Commander designed to add statistical functions that are frequently used in biostatistics.

#### **3. Results**

#### *3.1. Patient Characteristics*

Patient characteristics are shown in Table 1. Among the 52 patients, 22 (42%) were female, with an age of 70.0 ± 15.1 years. The median number of HF hospitalizations prior to death was 3 (IQR 1–5, and 42% of patients had non-ischemic cardiomyopathy (NICM) etiology. The median left ventricular ejection fraction was 35% (IQR 20–56%), and the median N-terminal B-type natriuretic peptide (NT-proBNP) was 12,683 pg/mL (IQR 5181–31,264 pg/mL). Nineteen patients who died during Era 1 and 33 patients who died during Era 2 were included in the analyses. There were no significant differences in demographics or clinical characteristics between the two groups, except for the etiology of "Others".




**Table 1.** *Cont.*

Data are presented as mean ± SD, median (IQR) and n (%); HF = heart failure; HFrEF = HF with reduced ejection fraction; NYHA = New York Heart Association functional classification; ACE-I = angiotensin-converting-enzyme inhibitor; ARB = angiotensin II receptor blocker; NT-proBNP = n-terminal b-type natriuretic peptide. \* *p* < 0.05.

#### *3.2. Palliative and End-of-Life Care*

Table 2 presents an overview of the palliative care and EOLC provided prior to death. In patients who died during Era 2, the rates of attempted cardiopulmonary resuscitation, intubation, and direct current shock at the end of life were significantly lower than in those who died in Era 1 (53% vs. 6%; *p* < 0.001, 47% vs. 0%; *p* < 0.001, 37% vs. 6%; *p* = 0.005, respectively). Compared to Era 1, a greater proportion of patients who died in Era 2 received opioids (11% vs. 70%). All the patients who received opioids were non-intubated and the administration was indicated to relieve dyspnea resistant to hemodynamic interventions (afterload reduction, diuretics, and inotropes). Sedative medications were significantly more commonly used in intubated patients who died in Era 1 and non-intubated patients who died in Era 2 (*p* < 0.05). Sedative medications without intubation were used for refractory symptoms, such as dyspnea, malaise, and delirium. Patients who died in Era 2 received more psychiatric consultations, although the difference was not significant. In Era 2, 70% of patients received multidisciplinary EOLC discussion support, a significant increase from 5% in Era 1 (*p* < 0.001).

**Table 2.** Palliative and end-of-life care.


**Table 2.** *Cont.*


Data are presented as median (IQR) and n (%); EOLC = end-of-life care. \* *p* < 0.05.

#### *3.3. Nutrition in the Three Days Prior to Death*

Among the patients who died in Era 1 and Era 2, total parenteral nutrition was provided to 7 (37%) and 11 (33%), tube feeding to 1 (5%) and 5 (15%), and 9 (47%) and 12 (36%) patients fasted, respectively. There were no significant differences in nutrition administration methods between the two groups. Food intake three days before death was maintained in 9 out of 19 patients (47%) in Era 1 and 16 out of 33 patients (48%) in Era 2. The characteristics of the patients who maintained food intake three days prior to death are summarized in Table 3. Compared to the patients who died in Era 1 (n = 9), significantly more patients who died in Era 2 (n = 16) maintained food intake during opioid administration (11% vs. 63%, respectively, *p* = 0.013). In addition, food intake during sedation was not observed in Era 1 but was observed in 19% of patients who died in Era 2 (*p* = 0.166). Nutritional counseling was more frequently provided to patients who died in Era 2 than to those who died in Era 1 (33% vs. 81%, respectively, *p* = 0.017), and the change from a low-sodium diet to a regular-sodium diet was also significantly more frequent (59% vs. 22%, respectively, *p* = 0.025). Permission for non-hospital foods, such as bringing a patient's favorite meal cooked by their family, also tended to be more frequently granted to patients who died in Era 2 as compared to those who died in Era 1 (*p* = 0.053).



Data are presented as n (%). \* *p* < 0.05.

Logistic regression analysis of factors associated with the administration of artificial nutrition three days prior to death was performed (Table 4). In the univariate regression analysis, the number of previous hospitalizations for HF (OR 0.69; 95% CI 0.51–0.93; *p* = 0.014) and HF due to NICM (OR 3.30; 95% CI 1.03–10.60; *p* = 0.045) were significantly associated with the administration of artificial nutrition in the final three days of life. Multivariate analysis demonstrated that the number of previous HF hospitalizations (OR 0.63; 95% CI 0.44–0.91; *p* = 0.014), NICM-caused HF (OR 15.8; 95% CI 2.42–103.00; *p* = 0.004), and multidisciplinary support for EOLC discussions (OR 0.15; 95% CI 0.03–0.91; *p* = 0.039) were independent factors related to the administration of artificial nutrition three days prior to death.


**Table 4.** Results of univariate and multivariate analysis associated with the administration of artificial nutrition three days prior to death.

OR = odds ratio; CI = confidence interval; ICM = ischemic cardiomyopathy; NICM = non-ischemic cardio myopathy; VHD = valvular heart disease; HF = heart failure; EOLC = end-of-life care. \* *p* < 0.05.

#### **4. Discussion**

In this study, we compared the changes in HF therapies in terms of palliative care and EOLC discussions before and after the initiation of HF-PCT activities at our institute, with a focus on food intake at the end of life. The major findings were that after HF-PCT activities, (a) fewer invasive procedures were performed, (b) the use of opioids and nonintubated sedatives for symptom relief increased, (c) support from the multidisciplinary team in EOLC discussions increased, and (d) quality of meals was improved at the end of life in patients (from low-sodium diet to regular diet, adequate symptom relief with opioids, provision of non-hospital meals such as patients' favorite meals mainly by family members). Furthermore, the administration of artificial nutrition in the final three days prior to death was associated with NICM etiology, number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. To the best of our knowledge, this is the first report on changes in HF palliative care and end-of-life food intake after the initiation of HF-PCT activities.

#### *4.1. End-of-Life Discussion with Patients with HF*

Considering the plateau in diagnostic capacity and treatment efficacy for HF, new problems have arisen related to difficult EOLC decision-making under uncertain disease trajectories [14]. In addition, physicians often discuss EOLC with the families rather than the patients in Far East Asian countries such as China, South Korea, and Japan [15–17], where physicians and patients' families traditionally tend to avoid giving unfavorable information to patients. However, Matsushima et al. showed that 85% of English-speaking Japanese Americans desired to make treatment decisions on their own, as compared to only 36% of Japanese individuals living in Japan [18]. Another Japanese study had shown that only 4.7% of patients with end-stage HF participated in EOLC discussions [19]. In the present study, EOLC discussions were more frequent in patients who died in Era 2. Moreover, the number of patients who underwent invasive procedures prior to death was significantly lower among patients who died in Era 2. Our findings suggest that HF-PCT activities might facilitate EOLC discussions based on patient values and preferences and could avoid unnecessary invasive treatment prior to death.

The current study did not confirm the existence of the ACP process. However, EOLC discussions with patients are an extension of the ACP process. The latest survey, conducted by the Japanese Ministry of Health, Labour and Welfare in 2017, indicated that 64.9% of Japanese individuals approved ACP and that 66% of them agreed to make an advance directive [20]. Furthermore, the newly revised Japanese Guidelines on the Diagnosis and Treatment of Acute and Chronic Heart Failure consider ACP as a class I recommendation for the management of HF [9]. Reflecting such situations, ACP and patient-centered decision-making processes have become an increased focus in Japan.

#### *4.2. Symptom Management*

In this study, many patients who died in Era 2 received opioids for refractory dyspnea. Kuragaichi et al. reported in a nationwide survey that dyspnea is the most common symptom requiring palliative care in patients with HF [10]. Some small studies have shown that low-dose opioids, especially morphine, relieve breathlessness in these patients [21,22], although another study does not support this finding [23]. Further studies are required to investigate appropriate opioid use in patients with HF and refractory dyspnea. Furthermore, there has been little evidence for palliative sedation in non-cancer patients, including HF [24]; however, in this study, 36% of non-intubated patients with HF who died in Era 2 received palliative sedation. Palliative sedation is only performed to relieve intractable distress at the end of life, but not to hasten death [25]. Clinicians should discuss the indication of palliative sedation with a multidisciplinary team such as an HF-PCT in terms of the patients' benefits, goals, and risks, as well as the limited prognosis and presence of treatable factors. Psychological issues are also important problems in patients with HF. In particular, depression has an independent impact on morbidity and mortality in HF [26,27]. It is important to recognize psychological problems that may occur in the complex disease trajectory of HF. In this study, specialized psychiatric care was more often performed in patients with HF who died in Era 2; therefore, the HF-PCT may promote psychological support.

#### *4.3. Diet in Palliative Care of Patients with HF*

Food intake is extremely important in human life. Clinical evidence on the administration of artificial nutrition at the end of life is limited, even in oncology, and even more in HF. However, the goal of nutritional care at the end of life may be the same in both cancer and HF, in which it needs to change from maintaining nutritional status and function to ensure the patient's well-being and quality of life [7]. In addition, the enjoyment of food may increase when restrictions are lifted. In Era 2 of this study, patients with HF, who had maintained food intake until three days prior to death, were provided symptomatic relief using opioids and dietary modification—providing a normal diet, not a low-sodium diet. Extensive communication and psychosocial support between the healthcare team and patients and/or families are important to alleviate distress related to food intake and weight loss, eliminate false expectations about nutrition, and set goals for nutritional care [28]. In this study, discussing EOLC with multidisciplinary support was associated with a decrease in the use of artificial nutrition in the last three days of life. If HF-PCT activities provide more opportunities to discuss EOLC in the future, the administration of unnecessary artificial nutrition may be avoided, and patients may be able to enjoy their meals at the end of life.

#### *4.4. Limitations*

The present study has several limitations. First, the retrospective and single-center nature of this study, including the small number of study patients, might have resulted in a certain extent of bias. Second, patients who die at a university hospital may be a selected group, incorporating bias. Thus, future studies should include a larger population and more hospitals. Third, although palliative care should be provided at the early stage of a life-threatening illness, only patients with HF who died at our hospital were included in this study. Further research is required to confirm whether palliative care would benefit patients from an earlier stage of HF. Fourth, since this study focuses on correlations between eras, reverse causality and hidden causal relationships may exist. Fifth, Era 1 and Era 2 differ not only in the existence of HF-PCT but also in the time background of HF palliative care awareness. The time background may be responsible for the differences found between the two eras. Sixth, because of the retrospective nature of the study, we could not evaluate objective health-related quality of life indicators in determining the effectiveness of HF-PCT consultation. Seventh, we will examine a longer period before death in the next study in near future. Finally, further research is required to examine how to provide HF palliative care that is adapted to the healthcare system in Japan.

#### **5. Conclusions**

Despite increasing attention on palliative care in HF, providing optimal palliative care at the end of life presents many challenges and complexities. The present study indicated that HF-PCT activities provide an opportunity to discuss EOLC with patients, reduce the burden of physical and mental symptoms, and may shift the goals of end-of-life nutritional care to ensuring comfort and quality of life.

**Author Contributions:** Conceptualization, T.S., K.M., K.S. and N.N.; methodology, H.A. and Y.F.; formal analysis, T.S.; investigation, K.U., Y.Y., K.T., M.M., K.O. and T.Y.; data curation, T.S.; writing original draft preparation, T.S.; supervision, S.N., J.T. and H.Y.; project administration, Y.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Kurume University (No. 18066).

**Informed Consent Statement:** The release of research information in this study allowed us to collect and analyze data without obtaining written informed consent from each patient.

**Data Availability Statement:** Data supporting the results obtained in this study are available from the corresponding author upon reasonable request. All data were obtained from the subjects and are not available to the public for ethical reasons.

**Acknowledgments:** The authors thank the great contribution of the Heart Failure Support Team of Kurume University Hospital (Tomomi Sano, Toyoharu Oba, Takanobu Nagata, Naoki Horikawa, Hiroshi Eguchi, Koji Akasu, Kyoko Nuruki, Michiko Mukae, Moe Tokunaga, Mika Sumiyoshi, Masae Aoki, Yuki Umeno, Ryoko Fukumori, Tomoko Ishikawa, Miki Sakaguchi, Natsumi Maruyama, Yuki Kamori, Hideki Kojima, and Keiko Nishie) and all medical staff involved in this study.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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