Association of changes in the left ventricular ejection fraction with physical function characteristics and survival in patients with heart failure

doi:10.21203/rs.3.rs-4846304/v1

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Association of changes in the left ventricular ejection fraction with physical function characteristics and survival in patients with heart failure

https://doi.org/10.21203/rs.3.rs-4846304/v1

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Background: The relationship between the degree of change (Δ) in the left ventricular ejection fraction (ΔLVEF) and physical function and survival remains unclear. Therefore, we assessed the associations among physical characteristics, the ΔLVEF, and physical function and survival in response to heart failure (HF) treatment.

Methods: In this retrospective cohort analysis, patients with HF aged ≥65 years who underwent cardiopulmonary exercise testing (CPX) were classified into three groups based on the LVEF (recovered [HFrecEF], worsened [HFworEF], and unchanged [HFuncEF]). CPX measured the peak oxygen uptake (VO₂) and peak minute ventilation (VE).

Results: Overall, 191 patients were included. Age, height, and weight did not differ significantly between the groups. The HFworEF group showed significant deterioration in blood urea nitrogen, creatinine, brain natriuretic hormone, and estimated glomerular filtration levels. Oral administration of beta-blockers was significantly higher in the HFrecEF group than in the other groups. Based on the Kruskal–Wallis test, the three groups differed significantly in terms of the peak VO₂ (HFrecEF, median 806.5; HFworEF, 600.0; and HFuncEF, 749.0; P<.05), heart rate (HFrecEF, 121.0; HFworEF, 100.0; and HFuncEF, 107.0; P<.05), and VE (HFrecEF, 35.3; HFworEF, 25.8; and HFuncEF, 34.0; P<.01). Furthermore, the peak VO₂ (ρ: 0.25) and peak VE (ρ: 0.18) were not correlated with the ΔLVEF (all P<.01). The HFrecEF group had a significantly lower mortality rate at 60 months compared with the HFuncEF group (log-rank test, P<.05).

Conclusions: The HFworEF group had poor heart and kidney function and low physical function. The HFrecEF category had a relatively favourable long-term mortality rate at 60 months. ΔLVEF was not correlated with physical function.

peak minute ventilation

peak oxygen uptake

recovered left ventricular ejection fraction

unchanged left ventricular ejection fraction

worsened left ventricular ejection fraction

Heart failure (HF) affects an estimated 26 million people worldwide leading to > 1 million hospitalisations each year in both the United States and Europe [1]. HF is a complex clinical syndrome characterised by signs and symptoms resulting from structural or functional ventricular impairment [2]. Advances in the pharmacological treatment of HF have led to the development of varying strategies that can be used depending on the left ventricular ejection fraction (LVEF). Standard HF treatment (guideline-directed medical therapy [GDMT]) aligns with clinical guidelines. It includes angiotensin-converting enzyme/angiotensin receptor blocker inhibitors, beta-blockers, and mineralocorticoid receptor antagonists and can improve the ejection fraction (EF) in patients with a reduced LVEF, commonly referred to as HF with reduced EF (HFrEF) [3].

However, many patients whose EF returns to normal through GDMT may experience a reduction in EF after discontinuation [3], emphasising the necessity of continuing treatment. Treatment decisions should be based on HF with a mildly reduced EF (HFmrEF) and individual pathophysiology. HF with a preserved EF (HFpEF) is addressed primarily for congestion and comorbidities, often involving diuretic treatment [4]. Sodium-glucose co-transporter 2 inhibitors have been added as new recommendations for HFpEF [2]. However, changes in LVEF and its pathophysiology in response to treatment vary from case to case.

Cardiac rehabilitation is crucial in any pathology. Recent research has categorised changes in LVEF in response to treatment into three distinct categories: improvement, worsening, and maintenance. Among these, patients with newly defined HF with a recovered EF (HFrecEF) experience EF improvement throughout treatment. Contrastingly, patients with HF with a worsened LVEF (HF with a worsened EF [HFworEF]) experience deteriorating LVEF despite treatment progress. Furthermore, patients with HF with an unchanged LVEF (HF with an unchanged EF [HFuncEF]) maintain their EF status [4].

Although some reports suggest that the prognosis remains unaffected by LVEF [5], others indicate that patients in the HFrecEF category have a relatively favourable short-term mortality rate at 24 months [6]. Other studies highlight the potential to improve HF prognosis through exercise therapy, emphasising the need for enhanced exercise function [3]. Nevertheless, the relationship between the degree of change in LVEF (ΔLVEF) and physical function and survival remains unclear. Therefore, this study aimed to assess the association between physical characteristics and ΔLVEF, as well as between physical function and survival rates, in three distinct categories: HFrecEF, HFworEF, and HFuncEF.

Study design

The Institutional Review Board of Asahi University Hospital approved the study protocol (approval no. : 2022-11-01), and the study adhered to the principles of the 1975 Declaration of Helsinki. As this study involved a retrospective analysis of medical records, we employed an opt-out method for informed consent. Patients who did not wish to participate were informed that they could withdraw from the study by contacting the hospital.

Measurements

This was a retrospective cohort analysis of older patients aged ≥ 65 years with HF who underwent cardiopulmonary exercise testing (CPX) between April 2016 and December 2022. Patients who did not undergo echocardiography or who died were excluded. Baseline patient data, including physical characteristics, blood test results, and medication status, were retrieved from electronic medical records.

Echocardiographic ultrasound system

A Philips iE33 electronic sector probe (S5; Amsterdam, the Netherlands) was used as the ultrasound device. The left ventricular (LV) end-diastolic diameter, LV end-systolic diameter, ventricular septal thickness, and LV posterior base thickness were measured using the M-mode method or tomographic measurements as echocardiographic indices. The left atrial volume (LAV), calculated from the apex biluminal and tetraluminal sections (biplane Simpson method), was corrected for the body surface area, and the LAV index (LAVI) and other parameters were measured. Additionally, the LVEF (%) was measured using the modified Simpson method, which is recommended by the American Society of Echocardiography and is based on the sum of 20 discs perpendicular to the LV longitudinal axis taken from two cross-sections of the apical two-lumen and four-lumen sections. The sum of the two discs perpendicular to the LV longitudinal axis was considered the LV volume.

Classification of HF by change in the LVEF over time

The study participants were classified into the following three groups based on the LVEF, according to the Japanese Circulation Society/Japan Heart Failure Society (JCS/JHFS) 2021 guidelines: HFrecEF, in which the LVEF improved during the treatment course and the condition transitioned from HFrEF to HFmrEF or HFpEF, or from HFmrEF to HFpEF; HFworEF, in which the LVEF decreased during treatment and the condition transitioned from HFpEF to HFmrEF or HFrEF, or from HFmrEF to HFrEF; and HFuncEF, in which no major change was observed in the LVEF throughout the treatment course [4].

CPX

CPX was performed using a cycle ergometer (STB-3400; NIHON KOHDEN, Tokyo, Japan). Heart rate (HR) was continuously monitored using a stress system, STS2100 (NIHON KOHDEN). CPX was performed using a ramp stress test to determine the stress system. CPX measured the peak oxygen uptake (VO₂) and peak minute ventilation (VE). Peak VO₂ was calculated as follows: peak HR × peak VO₂/HR. Peak VE was calculated as follows: peak tidal volume (Vt) × peak respiratory rate (RR).

Statistical analyses and sample size

The characteristics of the study participants at enrolment were summarised using standard descriptive statistics. The data distribution was assessed using the Shapiro–Wilk test. Non-normally distributed variables are reported as median (interquartile range), and normally distributed variables are expressed as mean (standard deviation). Delta values for outcome measures are expressed as percentage changes after treatment. Furthermore, the χ-square test was used to analyse internal medications. The Kruskal–Wallis test was used to compare the three groups, and statistical significance was set at P < .05. Additionally, the three characteristic comparisons that were significant in the Kruskal–Wallis test were compared using the Dunn–Bonferroni test, which uses a pre-set significance level (significance level of P < .05 to the third power). The correlation between ΔLVEF and physical function was analysed using Spearman’s rank correlation coefficient. The survival curve for mortality at 60 months after hospital admission was estimated using the Kaplan–Meier method and compared using the log-rank test. Statistical significance was set at P < .05. All statistical analyses were performed using IBM SPSS Statistics version 28 (IBM Corp., Armonk, NY, USA).

The average sample size from three previous studies using the same three LVEF groups was approximately 100 cases [7–9]. Clinical studies have shown variations in the LVEF [10], and the JCS/JHFS 2021 guidelines state that HFuncEF ranges from 30–90%; HFworEF, from 2–30%; and HFrecEF, from 10–40% [4]. Considering these factors, we included > 100 patients with HF.

Clinical characteristics and cardiac function

Overall, 231 patients aged ≥ 65 years with HF were included. Forty patients who did not undergo follow-up echocardiography were excluded, and 191 patients were enrolled. Patients were assigned to three categories based on change (Δ) in the LVEF. The characteristics of each study group are shown in Table 1. Age, height, and weight did not differ significantly between the three groups. Blood samples showed significant differences in blood urea nitrogen (BUN), creatinine (Cr), brain natriuretic hormone (BNP), and estimated glomerular filtration rate (eGFR) levels. Additionally, oral beta-blocker administration was significantly higher in the HFrecEF group than in the other groups.

Table 1

Characteristics of each study group
	HFrecEF (n = 24)	HFworEF (n = 21)	HFuncEF (n = 146)
	Median (IQR)	Median (IQR)	Median (IQR)	P-value
Age (years)	71.5 (66.0–78.5)	78.0 (72.5–81.5)	75.0 (67.0–79.0)	.10
Male/female (n)	17/7	2/19	96/50	.45
Height (cm)	163.5 (156.0–168.7)	160.0 (154.0–163.5)	160 (153.7–166.2)	.55
Weight (kg)	59.6 (50.6–72.7)	59.3 (52.6–68.3)	58.0 (48.9–67.0)	.58
Δ EF (%)	13.0 (8.0–16.2)	-9.0 (-16 – -3)	-2.0 (0.0–3.0)	< .01
Echo period (pre-post)	8.0 (2.0–11.5)	11.0 (6.0–12.0)	11.0 (5.0–16.0)	.25
Before echo
Before EF (%)	39.5 (35.2–45.7)	53.3 (43.0–59.0)	51.0 (31.0–61.8)	.17
Before SV (2D) (mL)	40.0 (33.5–68.0)	55.0 (45.7–79.9)	52.1 (41.0–67.3)	.09
Before AOD (2D) (mm)	35.0 (31.0–38.0)	34.0 (28.0–36.5)	30.0 (23.0–35.0)	< .05
Before LVDd (2D) (mm)	50.5 (42.7–53.5)	54.0 (50.0–60.5)	52.0 (45.0–61.0)	.06
Before LVDs (2D) (mm)	38.0 (31.7–44.0)	41.0 (37.0–50.0)	38.5 (29.0–51.0)	.24
Before EDV (2D) (mL)	113.0 (79.5–130.0)	124.0 (107.0–180.0)	118.5 (83.7–169.2)	.1
Before ESV (2D) (mL)	59.0 (47.1–84.0)	70.0 (52.9–118.0)	58.1 (32.1–114.0)	.19
Before IVCi (mm)	9.6 (7.0–15.9)	11.0 (7.8–15.0)	9.8 (7.2–14.3)	.72
Before IVCe (mm)	16.2 (12.3–20.1)	15.0 (13.3–19.2)	15.1 (13.1–20.0)	.94
Before LAVI (mL/m²)	42.1 (27.2–44.3)	39.7 (32.0–64.6)	39.1 (30.4–54.9)	.79
Before mPAP (mmHg)	20.0 (17.0–28.0)	17.0 (16.0–19.5)	17.0 (14.7–20.0)	.05
After echo
After EF (%)	53.1 (50.2–58.0)	41.0 (37.5–47.0)	51.0 (33.0–62.0)	< .05
After SV (2D) (mL)	47.1 (40.0–75.1)	52.1 (43.8–81.3)	52.0 (43.7–65.0)	.87
After AOD (2D) (mm)	34.0 (29.2–37.0)	36.0 (27.5–37.0)	30.5 (23.0–36.0)	.09
After LVDd (2D) (mm)	49.0 (44.2–54.0)	56.0 (50.0–65.0)	52.0 (46.0–62.0)	< .05
After LVDs (2D) (mm)	35.5 (32.2–39.0)	45.0 (40.5–52.0)	38.0 (29.0–52.2)	< .01
After EDV (2D) (mL)	94.1 (75.5–141.0)	124.0 (110.0–206.0)	113.5 (92.1–173.0)	< .01
After ESV (2D) (mL)	47.2 (31.7–62.0)	78.6 (62.5–116.1)	58.1 (32.2–114.5)	< .01
After IVCi (mm)	8.9 (5.7–12.1)	11.6 (6.4–16.4)	8.5 (6.0–10.4)	.57
After IVCe (mm)	15.7 (12.0–17.0)	16.0 (13.1–20.7)	14.0 (11.9–17.7)	.24
After LAVI (mL/m²)	35.3 (25.7–49.3)	49.2 (38.7–68.5)	41.0 (31.0–52.0)	< .05
After mPAP (mmHg)	15.0 (14.0–16.0)	21.5 (16.5–32.0)	16.0 (14.0–19.0)	< .01
Blood test results
RBC (10⁴/µL)	403.0 (373.0–456.0)	389.0 (337.0–431.0)	411.0 (373.0–454.5)	.17
WBC (10²/µL)	5,650.0 (4,600–7,900)	5,400 (3,920–7,380)	5,900 (4,775–6,900)	.57
BUN (mg/dL)	17.2 (13.6–21.8)	24.0 (20.3–41.8)	20.1 (14.9–26.1)	< .01
Cr (mg/dL)	0.83 (0.69–1.03)	1.48 (1.06–2.68)	0.9 (0.79–1.18)	< .01
Albumin (g/dL)	3.9 (3.5–4.4)	3.7 (3.5–3.9)	3.9 (3.6–4.2)	.18
BNP (pg/mL)	82.8 (57.3–235.8)	685.5 (131.4–1123.2)	195.4 (81.7–355.8)	< .01
CPK (IU/L)	66.0 (45.5–82.0)	42.5 (29.0–114.0)	72.5 (46.0–109.5)	.32
Na (mEq/L)	140.0 (139.0–142.0)	140.0 (138.0–143.0)	140.0 (139.0–142.0)	.97
K (mEq/L)	4.5 (4.0–4.8)	4.3 (3.9–4.6)	4.3 (4.0–4.6)	.37
Blood sugar (mg/dL)	111.5 (96.7–227.5)	124.5 (98.2–148.0)	108.0 (95.0–141.0)	.53
eGFR (mL/min/_1.732)	63.9 (46.2–76.9)	35.7 (18.6–54.5)	56.4 (41.3–68.0)	< .01
Drugs
Beta blocker, n (%)	23 (95)	17 (80)	113 (78)	< .05
ACE, ARB n (%)	5(20)	6(28.6)	47(32.2)	.52
Tolvaptan, n (%)	2 (8)	6 (28)	22 (15)	.17
MRA, loop diuretic, n (%)	15 (62)	15 (71)	101 (70)	.89
CCB, n (%)	6 (25)	4 (19)	32 (22)	.89
CPX
Rest VO₂/w (mL/min/kg)	3.6 (3.1–3.9)	3.5 (3.1–3.6)	3.7 (3.3–4.1)	.05
Peak VO₂/w (mL/min/kg)	13.6 (11.9–15.4)	10.1 (7.8–11.8)	12.6 (9.4–15.1)	< .01
Rest VO₂ (mL/min)	216.0 (184.2–265.2)	200.0 (171.5–236.0)	208.5 (179.7–246.25)	.44
Reserve VO₂ (mL/min)	588.0 (425.7–926.7)	435.0 (227.0–488.5)	529.5 (296.5–707.5)	< .05
Peak VO₂ (mL/min)	806.5 (644.2–1189.5)	600.0 (430.5–698.5)	749.0 (479.5–952.0)	< .05
Rest HR (beats/min)	75.5 (65.5–86.5)	67.0 (59.0–84.0)	74.0 (65.7–84.0)	.14
Reserve HR (beats/min)	41 (28.2–53.5)	26.0 (19.0–33.0)	30.5 (19.7–30.5)	< .05
Peak HR (beats/min)	121.0 (108.0–131.7)	100.0 (79.5–115.0)	107.0 (95.5–125.0)	< .05
Rest VO₂/HR	3.0 (2.3–3.5)	3.0 (2.75–3.25)	2.8 (2.4–3.4)	.72
Reserve VO₂/HR	4.0 (2.9–6.1)	3.1 (1.9–4.8)	3.7 (2.5–4.9)	.16
Peak VO₂/HR	6.8 (5.4–9.6)	5.8 (4.9–8.1)	6.7 (5.0–8.0)	.29
Rest VE (mL/min)	9.8 (8.0–10.5)	9.3 (7.8–11.4)	10.0 (8.3–11.7)	.42
Reserve VE (mL/min)	25.8 (19.0–34.3)	18.5 (10.1–22.2)	23.8 (13.8–33.1)	< .05
Peak VE (mL/min)	35.3 (27.2–47.4)	25.8 (20.9–32.3)	34.0 (23.2–43.6)	< .05
Rest Vt (mL)	595.0 (517.2–709.2)	583.0 (515.0–691.5)	596.5 (475.7–711.2)	.98
Reserve Vt (mL)	683.0 (425.2–873.7)	443.0 (258.5–648.0)	578.0 (261.7–765.7)	< .05
Peak Vt (mL)	1355.5 (882.7–1564.2)	998.0 (846.5–1300.0)	1171.0 (802.0–1462.0)	.16
Rest RR (breaths/min)	17.3 (14.8–19.4)	17.9 (15.0–19.0)	17.6 (14.1–20.8)	.59
Reserve RR (breaths/min)	12.8 (8.6–15.2)	10.1 (7.4–12.4)	11.9 (7.9–15.6)	.21
Peak RR (breaths/min)	28.3 (25.5–30.8)	26.9 (24.2–30.2)	28.9 (25.8–33.9)	.12
Peak ETO₂ (%)	15.6 (15.2–16.2)	16.1 (15.8–16.3)	16.1 (15.6–16.5)	< .05
Peak ETCO₂ (%)	5.36 (5.02–5.96)	4.7 (4.5–5.2)	4.9 (4.5–5.3)	< .01
Peak VE/VCO₂ (mL/mL)	36.2 (30.3–39.8)	42.0 (36.3–45.8)	40.0 (36.2–45.8)	< .05
Minimum VE/VCO₂ (mL/mL)	34.2 (29.2–39.4)	40.7 (34.2–44.7)	38.1 (34.1–43.7)	< .05
Rest VD/Vt	0.38 (0.35–0.43)	0.41 (0.39–0.43)	0.41 (0.38–0.44)	.19
Peak VD/Vt	0.36 (0.33–0.41)	0.36 (0.34–0.43)	0.40 (0.35–0.44)	< .05
Peak Ti/Ttot	0.43 (0.34–0.45)	0.43 (0.41–0.45)	0.41 (0.32–0.45)	.08
ACE: angiotensin-converting-enzyme, AOD: aortic dimension, ARB: angiotensin receptor blocker, BNP: brain natriuretic hormone, BUN: blood urea nitrogen, CCB: calcium channel blocker, CPK: creatine phosphokinase, CPX: cardiopulmonary exercise testing, Cr: creatinine, eGFR: estimated glomerular filtration rate, EDV: end-diastolic volume, EF: ejection fraction, ESV: end-systolic volume, ETCO₂: end-tidal carbon dioxide, ETO₂: end-tidal oxygen tension, HFrecEF: HF with recovered EF, HFuncEF: HF with unchanged EF, HFworEF: HF with worsened EF, HR: heart rate, IQR: interquartile range, IVCe: inferior vena cava diameter during quiet expiration, IVCi: inferior vena cava diameter during quiet inspiration, LAVI: left atrial volume index, LVDd: left ventricular end-diastolic dimension, LVDs: left ventricular internal dimension in systole, mPAP: mean pulmonary artery pressure, MRA: mineralocorticoid receptor antagonist, RBC: red blood cell, RR: respiratory rate, SV: stroke volume, Ti: mean inspiratory time, Ttot: duration of the respiratory cycle, VD/VT: dead-space gas volume to tidal volume ratio, VE: minute ventilation, VE/VCO₂: minute ventilation/carbon dioxide output, VCO₂: carbon dioxide production, VO₂: oxygen uptake, VO₂/w: oxygen uptake/watt, Vt: tidal volume, WBC: white blood cell

[insert Table 1 here]

Comparison of physical characteristics among the three groups

The Kruskal–Wallis test was used to compare the groups. Peak VO₂ was significantly different among the groups (HFrecEF 806 [95% confidence interval {CI}: 644.2–1,189.5] vs. HFworEF 600.0 [95% CI: 430.5–698.5] vs. HFuncEF 749.0 [95% CI: 479.5–952.0]; P < .05). Peak HR was also significantly different, with lower values in the HFworEF group than in the other groups (HFrecEF 121.0 [95% CI: 108.0–131.7] vs. HFworEF 100.0 [95% CI: 79.5–115.0] vs. HFuncEF 107.0 [95% CI: 95.5–125.0]; P < .05). Additionally, peak VE volume was significantly different among the groups (HFrecEF 35.3 [95% CI: 27.2–47.4] vs. HFworEF 25.8 [95% CI: 20.9–32.3] vs. HFuncEF 34.0 [95% CI: 23.2–43.6]; P < .01).

The three characteristics that were statistically significant according to the Kruskal–Wallis test were compared using the Dunn–Bonferroni test. Peak VO₂, HR, and VE were found to be significantly different between the HFrecEF and HFworEF groups (all P < .05) (Fig. 1).

Relationship between ΔLVEF and physical function

The relationship between the ΔLVEF and physical function was analysed using Spearman’s rank correlation coefficient. The ΔLVEF was not correlated with the peak VO₂ (ρ = 0.252, P < .01), VO₂/HR (ρ = 0.190, P < .01), peak carbon dioxide production (VCO₂) (ρ = 0.251, P < .01), end VE (ρ = 0.184, P < .01), end-tidal carbon dioxide output (ETCO₂) (ρ = 0.251, P < .01), VE/VO₂ (ρ=-0.273, P < .01), VE/VCO₂ (ρ=-0.273, P < .01), or dead-space gas volume to Vt ratio (ρ=-0.13, P = .138) (Fig. 2).

Survival curves for the 60-month period

The Kaplan–Meier analysis was used to analyse changes in the LVEF (HFrecEF, HFworEF, and HFuncEF) and peak VO₂. The HFrecEF group had a significantly lower mortality rate at 60 months than the HFuncEF group (log-rank test, P < .05; Fig. 3). Further, a peak VO₂ less than 12 mL/min/kg significantly decreased mortality (log-rank test, P < .01; Fig. 3).

This study evaluated the physical characteristics of patients in the HFrecEF, HFworEF, and HFuncEF categories, as well as the relationships among the ΔLVEF, physical function, and echocardiographic features. The results showed no significant differences in height, weight, and age among the three groups (HFrecEF, HFworEF, and HFuncEF). Blood sample results showed that BUN, Cr, BNP, and eGFR were all poorer in the HFworEF group than in the other groups. Additionally, the peak VO₂, HR, and VE were significantly lower in the HFworEF group than in the other groups. However, the relationship between ΔLVEF and peak VO₂ showed no correlation. In addition, at 60 months, the mortality rate was significantly lower in the HFrecEF group than in the HFuncEF group. To the best of our knowledge, this is the first report that has simultaneously assessed long-term mortality rates in patients with HFrecEF, HFworEF, and HFuncEF.

In our study, many patients had HFuncEF with no change in EF after HF treatment. However, the treatment of HF may alter cardiac function. Owing to the lack of a standard definition of HFrecEF with improved cardiac function and the lack of clinical data on patients with HFrecEF, there are no current guidelines on how these patients should be followed up and managed [11]. Also, predictors of an increased EF may include less severe HF, fewer complications, a shorter HF duration, and patients with more recently initiated treatment for HF, indicating less remodelling and, therefore, a greater chance of recovery [12].

In this study, the HFworEF group had deteriorating blood results, indicating deteriorating renal and cardiac function. Additionally, post-treatment echocardiographic results showed a reduction in LV diastolic and systolic diameters in the HFrecEF group. Moreover, the diastolic and systolic LV volumes showed a reduced volume load in the HFrecEF group. The most remarkable change was in the LAVI (i.e., the value of the LAV corrected for body surface area). The left atrium (LA) constitutes an elastic reservoir for pulmonary venous inflow during LV systole, a passive conduit for pulmonary venous flow during early ventricular diastole, and a booster pump to assist LV filling during late ventricular diastole. Conversely, the LV filling pressure is reciprocally transmitted back to LA pressure, is related to LA size, and is structurally and functionally correlated with LV function. Therefore, changes in the LV filling pressure may be associated with the LA size [13]. In this study, patients with HFrecEF showed a decrease in the LAVI, whereas those with HFworEF showed an increase in the LAVI. In other words, as LVEF changed, the LV filling pressure and volume load also changed, which we attribute to the reverse remodelling of the LA. This modelling is consistent with the results of a previous study [13].

Regarding echocardiography and physical function, CPX is a useful index for assessing physical function. However, its relationship with HFrecEF, HFworEF, and HFuncEF remains unknown. In the present study, patients with HFrecEF had a higher peak VO₂ than patients with HFworEF. VO₂/HR is also an index of stroke volume (SV) under load and is expressed as the product of SV and the arteriovenous oxygen content (c[A-V]O₂ difference). While the c(A-V)O₂ difference increased linearly with load, SV reached a plateau in the middle of the load. The resting HR did not differ significantly between the HFrecEF and HFworEF groups. However, the HR in the HFrecEF group showed a good HR response. This response was directly related to the peak VO₂ results. VO₂ is the product of the cardiac output, CO, and c(A-V)O₂ difference. In other words, VO₂ is strongly influenced by both the SV and HR. We believe that the difference in HR response is responsible for the higher HFrecEF values at peak VO₂. In contrast, in the HFworEF category, many patients had a reduced HR response (chronotropic competence). Notably, the pathophysiological mechanisms of reduced exercise tolerance due to HF include cardiac function, breathing, skeletal muscle, and the vascular endothelium [14].

Therefore, we also examined physical function: the lowest value of VE/VCO₂ found between the ventilatory work threshold (LT)1 and LT2 is the minimum VE/VCO₂, which is an indicator of the severity of HF. In other words, it can indicate a ventilatory blood flow imbalance distribution. Hansen et al. [15] found that the normal value for the minimum VE/VCO₂ in patients aged > 60 years was 29.4 ± 2.3. In our study, the patients in all three groups had values above normal. Patients with HF can have a ventilatory blood flow imbalance with or without an improvement in EF. However, the VE/VCO₂ was significantly higher in the HFworEF group than in the other groups, indicating that deteriorating HF can lead to ventilation blood flow imbalance. Furthermore, the mean pulmonary arterial pressure was significantly higher in the HFworEF group than in the other groups, suggesting that the right ventricular load was higher in HFworEF.

The peak VE was significantly lower in the HFworEF group than in the HFrecEF group. As a result, we examined whether this significant difference in VE was due to the Vt or RR. The change in the peak Vt was small; however, the changes in the peak Vt and peak RR were not significant when compared among all groups. In other words, patients with HFworEF had a lower peak VE during exercise than those with HFrecEF.

Otsuka et al. [16] found no relationship between the rate of increase in the peak VO₂ and LVEF. Furthermore, some studies have reported no correlation between LVEF and survival and that the mortality rate in HFpEF is comparable to that in HFmrEF and lower than that in HFrEF [17, 18]. In the present study, we evaluated the potential correlation between ΔLVEF and physical function but found no association. This may be due to the different pathological characteristics described above. ΔLVEF did not directly affect physical function; however, high BNP, deteriorating renal function, and age may have played a secondary role.

The results of this study were similar to those of previous reports of a lower peak VO₂ being associated with a poorer life expectancy [19]. However, the 60-month survival rate in the HFrecEF group was significantly higher than that in the HFuncEF group. Notably, the HFrecEF group in this study had a better prognosis at 60 months. In other words, improvement in the EF in response to treatment is directly related to life expectancy. Nonetheless, the HFworEF and HFuncEF groups followed a similar trajectory regarding life expectancy. This indicates that if the EF does not improve in response to treatment, the long-term prognosis may remain the same; in this case, the emphasis should be placed on low physical function.

This study has some limitations. First, its retrospective design may have biased the measurements in each group. Second, the study period was between April 2016 and December 2022; thus, it did not reflect the most recent medications, such as angiotensin receptor neprilysin inhibitors. Finally, there may be cases with a lower tendency of improvement among certain HF aetiologies (i.e., ischaemic, specific cardiomyopathies). As such, the difference in EF has specific limitations over time to assess prognosis and functional capacity.

The long-term prognosis in the HFrecEF group was favourable. The HFworEF group had poor heart and kidney function blood results and low physical function. No correlation between ΔLVEF and physical function was found. Thus, comprehensive treatment including cardiac rehabilitation is needed to improve physical function, rather than just cardiac function improvement.

A-V

arteriovenous

BNP

brain natriuretic hormone

BUN

blood urea nitrogen

confidence interval

CPX

cardiopulmonary exercise testing

creatinine

ejection fraction

eGFR

estimated glomerular filtration rate

ETCO₂

end-tidal carbon dioxide output

GDMT

guideline-directed medical therapy

heart failure

HFmrEF

HF with a mildly reduced EF

HFpEF

HF with a preserved EF

HFrecEF

heart failure with recovered ejection fraction

HFrEF

HF with reduced EF

HFuncEF

heart failure with unchanged ejection fraction

HFworEF

heart failure with worsened ejection fraction

heart rate

JCS

Japanese Circulation Society

JHFS

Japan Heart Failure Society

left atrium

LAV

left atrial volume

LAVI

left atrial volume index

left ventricular

LVEF

left ventricular ejection fraction

respiratory rate

stroke volume

VCO₂

carbon dioxide production

ventilation

VO₂

oxygen uptake

tidal volume

Ethics approval and consent to participate

The Institutional Review Board of Asahi University Hospital approved the study protocol (approval no.: 2022-11-01), and the study adhered to the principles of the 1975 Declaration of Helsinki. As this study involved a retrospective analysis of medical records, we employed an opt-out method for informed consent. Patients who did not wish to participate were informed that they could withdraw from the study upon contacting the hospital.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

YF: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. ST: Investigation, Validation, Writing – review & editing. TK: Investigation, Validation, Writing – review & editing. SA: Investigation, Validation, Writing – review & editing. SS: Investigation, Validation, Writing – review & editing. AY: Investigation, Validation. NT: Investigation, Validation, Writing – review & editing. TF: Methodology, Project, administration, Validation, Writing – review & editing. TS: Data curation, Validation, Writing – review & editing.

Acknowledgements

The authors thank all members of the Department of Cardiology, Asahi University Hospital, and Shinichi Arizono.

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No competing interests reported.

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Association of changes in the left ventricular ejection fraction with physical function characteristics and survival in patients with heart failure

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Abstract

Figures

BACKGROUND

METHODS

Study design

Measurements

Echocardiographic ultrasound system

Classification of HF by change in the LVEF over time

CPX

Statistical analyses and sample size

RESULTS

Clinical characteristics and cardiac function

Comparison of physical characteristics among the three groups

Relationship between ΔLVEF and physical function

Survival curves for the 60-month period

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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