Vol 30, No 5 (2023)
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The prognostic role of galectin-3 and endothelial function in patients with heart failure

Vasiliki Tsigkou12, Gerasimos Siasos123, Evangelos Oikonomou12, Marina Zaromitidou1, Konstantinos Mourouzis1, Stathis Dimitropoulos1, Evanthia Bletsa12, Nikolaos Gouliopoulos1, Panagiota K. Stampouloglou12, Maria-Evi Panoilia12, Georgios Marinos1, Konstantinos Tsioufis1, Manolis Vavuranakis12, Dimitris Tousoulis1
Pubmed: 35975796
Cardiol J 2023;30(5):725-733.

Abstract

Background: Heart failure (HF) is nowadays classified as HF with reduced ejection fraction (HFrEF),
HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF). Endothelial dysfunction
(assessed by flow-mediated dilatation [FMD]), increased arterial stiffness (assessed by carotid-femoral
pulse-wave velocity [PWV]), and galectin-3, a biomarker of myocardial fibrosis, have been linked to
major adverse cardiovascular events (MACE) in patients with ischemic HF.
Methods: In this study we prospectively enrolled 340 patients with stable ischemic HF. We assessed
the brachial artery FMD, carotid-femoral PWV, and galectin-3 levels, and patients were followed up for
MACE according to HF group.
Results: Interestingly, the FMD values exhibited a stepwise improvement according to left ventricular
ejection fraction (LVEF) (HFrEF: 4.74 ± 2.35% vs. HFmrEF: 4.97 ± 2.81% vs. HFpEF: 5.94 ±
± 3.46%, p = 0.01), which remained significant after the evaluation of possible confounders including
age, sex, cardiovascular risk factors, and number of significantly stenosed epicardial coronary arteries
(b coefficient: 0.990, 95% confidence interval: 0.166–1.814, p = 0.019). Single-vessel coronary artery
disease was more frequent in the group of HFpEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%,
p = 0.049). PWV did not display any association with LVEF. Patients who presented MACE exhibited
worse FMD values (4.51 ± 2.35% vs. 5.32 ± 2.67%, p = 0.02), and the highest tertile of galectin-3 was
linked to more MACEs (36% vs. 5.9%, p = 0.01).
Conclusions: Flow-mediated dilatation displayed a linear improvement with LVEF in patients with
ischemic HF. Deteriorated values are associated with MACE. Higher levels of galectin-3 might be used
for risk stratification of patients with ischemic HF

clinicAL CARDIOLOGY

original article

Cardiology Journal

2023, Vol. 30, No. 5, 725–733

DOI: 10.5603/CJ.a2022.0074

Copyright © 2023 Via Medica

ISSN 1897–5593

eISSN 1898–018X

The prognostic role of galectin-3 and endothelial function in patients with heart failure

Vasiliki Tsigkou*12Gerasimos Siasos*123Evangelos Oikonomou12Marina Zaromitidou1Konstantinos Mourouzis1Stathis Dimitropoulos1Evanthia Bletsa12Nikolaos Gouliopoulos1Panagiota K. Stampouloglou12Maria-Evi Panoilia12Georgios Marinos1Konstantinos Tsioufis1Manolis Vavuranakis12Dimitris Tousoulis1
1Department of Cardiology, ‘Hippokration’ General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
2Department of Cardiology, ‘Sotiria’ General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
3Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Address for correspondence: Dr. Evangelos Oikonomou, MD, MSc, PhD, 3rd Department of Cardiology, Athens Chest
Hospital “Sotiria”, National and Kapodistrian University of Athens, Medical School, Athens, Greece; Athens Chest
Hospital “Sotiria”, Mesogeion 152, Athens 11527, Greece, e-mail: boikono@gmail.com

Received: 1.02.2022 Accepted: 6.05.2022 Early publication date: 11.08.2022

*Vasiliki Tsigkou and Gerasimos Siasos contributed equally to the study.

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Abstract
Background: Heart failure (HF) is nowadays classified as HF with reduced ejection fraction (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF). Endothelial dysfunction (assessed by flow-mediated dilatation [FMD]), increased arterial stiffness (assessed by carotid-femoral pulse-wave velocity [PWV]), and galectin-3, a biomarker of myocardial fibrosis, have been linked to major adverse cardiovascular events (MACE) in patients with ischemic HF.
Methods: In this study we prospectively enrolled 340 patients with stable ischemic HF. We assessed the brachial artery FMD, carotid-femoral PWV, and galectin-3 levels, and patients were followed up for MACE according to HF group.
Results: Interestingly, the FMD values exhibited a stepwise improvement according to left ventricular ejection fraction (LVEF) (HFrEF: 4.74 ± 2.35% vs. HFmrEF: 4.97 ± 2.81% vs. HFpEF: 5.94 ± 3.46%, p = 0.01), which remained significant after the evaluation of possible confounders including age, sex, cardiovascular risk factors, and number of significantly stenosed epicardial coronary arteries (b coefficient: 0.990, 95% confidence interval: 0.166–1.814, p = 0.019). Single-vessel coronary artery disease was more frequent in the group of HFpEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%, p = 0.049). PWV did not display any association with LVEF. Patients who presented MACE exhibited worse FMD values (4.51 ± 2.35% vs. 5.32 ± 2.67%, p = 0.02), and the highest tertile of galectin-3 was linked to more MACEs (36% vs. 5.9%, p = 0.01).
Conclusions: Flow-mediated dilatation displayed a linear improvement with LVEF in patients with ischemic HF. Deteriorated values are associated with MACE. Higher levels of galectin-3 might be used for risk stratification of patients with ischemic HF. (Cardiol J 2023; 30, 5: 725–733)
Key words: heart failure, galectin-3, endothelial function, prognosis, ejection fraction

Introduction

Heart failure (HF) is a complex clinical syndrome that is the result of numerous structural and functional alterations of the heart [1]. The prevalence of HF is about 1–2% in adults, although it might be much higher due to underdiagnosis, and it increases with age and the presence of comorbidities [2]. Ischemic HF is attributed to coronary artery disease (CAD) and is one of the most common etiologies of HF, especially in western countries [3]. Understanding the specific cause of HF and its pathophysiologic background may facilitate treatment of the patients [1]. HF is currently classified into three categories: HF with reduced ejection fraction (EF) (HFrEF, when EF ≤ 40%, which depicts an important deterioration of left ventricular [LV] systolic function), HF with mildly reduced EF (HFmrEF, when 40% < EF ≤ 49%), and HF with preserved EF (HFpEF, when EF ≥ 50% along with the presence of structural or functional dysfunction and/or elevated natriuretic peptides) [1, 4].

Endothelial dysfunction has been associated with the initiation and development of cardiovascular disease [5]. Endothelial function is impaired in patients with ischemic HF contrary to patients without ischemic HF [6]. Flow-mediated dilatation (FMD) of the brachial artery is a non-invasive method for the assessment of endothelial function, which evaluates the endothelium-dependent vasomotor properties of the vascular wall due to nitric oxide (NO) production [7]. Arterial stiffness and markers of wave reflection, such as pulse wave velocity (PWV), have been associated with poorer cardiovascular prognosis, especially when measured together with classic risk factors [8]. Moreover, biomarkers of fibrosis and cardiovascular remodeling have demonstrated a prognostic capability in patients with HF along with natriuretic peptides [9]. Indeed, galectin-3, a well-known biomarker of fibrosis and myocardial remodeling, has exhibited a correlation with clinical status in patients with chronic HF [10].

The aim of this prospective follow-up study was to investigate the association of endothelial dysfunction, arterial stiffness, and galectin-3 with left ventricular ejection fraction (LVEF) categorization in ischemic HF and their prognostic value.

Methods

Study design

In this single-center, prospective cohort study we enrolled 340 patients (age 62 ± 11 years) with ischemic heart disease and HF according to European Society of Cardiology (ESC) guidelines of HF (2016) [11]. All patients were recruited from the HF outpatient clinic of Hippokration University Hospital, Athens, were in stable clinical condition for at least 6 months and under optimal medical treatment, and were classified as HFrEF, HFmrEF, or HFpEF [11].

Coronary artery disease was defined by history of myocardial infarction (MI) or stenosis of at least one epicardial vessel with ≥ 50% narrowing of the artery lumen based on invasive coronary angiography and evidence of myocardial ischemia [12, 13]. All patients underwent coronary angiography according to indications (i.e., positive stress test, angina, post-acute coronary syndrome [ACS]); coronary angiography was assessed by at least two experienced cardiologists, and the degree of vessel stenosis was evaluated with the quantitative coronary angiography system.

We excluded patients with significant valvular or congenital heart disease, uncontrollable hypertension, persistent or permanent atrial fibrillation, severely impaired functional capacity (New York Heart Association [NYHA] class IV), advanced renal disease (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), advanced liver disease, chronic lung disease, severe systematic or inflammatory disease and active malignancy, morbid obesity, thyroid disease, and transplantation.

Informed consent form was obtained from each of the subjects before enrollment in the study.

Several demographic and clinical parameters were recorded such as age, sex, body mass index (BMI), the presence of arterial hypertension, diabetes mellitus, dyslipidemia, and smoking. Smokers of at least one cigarette per day or those who quitted smoking less than a year before enrollment in the study were defined as current smokers; patients who smoked before this time were classified as ex-smokers; and patients who had never smoked were classified as never-smokers.

Patients were followed-up for major adverse cardiovascular events (MACE) including cardiovascular death, MI, coronary revascularization, stroke, and hospitalization due to HF. Deterioration of HF clinical status was defined as a secondary endpoint.

Assessment of endothelial function

Flow-mediated dilatation measured at the right brachial artery was used as a marker of endothelial dysfunction [7]. All patients were in a fasting state for at least 12 h before their participation in the study and withdrew any vasoactive medications for that period. The measurement took place in a quiet and temperature-controlled room after a 10-min rest period. Then, the examiner assessed the right brachial artery in a longitudinal section using a Vivid e-ultrasound system (General Electric, Milwaukee, Wisconsin, USA) equipped with a 5.0–13.0-MHz (harmonics) linear array ultrasound transducer positioned 5 cm above the antecubital fossa. A pneumatic cuff was placed on the forearm distally to the ultrasound probe and was inflated to suprasystolic pressure for 5 min to induce reactive hyperemia. After the release of the cuff, the brachial artery diameter was assessed manually with electronic calipers (as the average value of several measurements of the arterial diameter at the border of the media adventitia). Measurements were repeated every 15 s for a period of 2 min. FMD was defined as the percentage change of the brachial artery diameter from the baseline measurement to the maximum artery diameter post cuff release. All the measurements were performed by the same examiner throughout the study, whereas another blinded observer evaluated the FMD values to avoid systemic bias [14].

Assessment of arterial stiffness

Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) [15]. The pulse transit time and the distance traveled between the 2 recording sites was recorded to calculate the carotid-femoral PWV (PWV = distance in meters divided by the transit time in seconds). All measurements were performed by a well-validated non-invasive device (SphygmoCor; AtCor Medical). Pulse waves were recorded with the transducer at the base of the neck for the common carotid and over the right femoral artery. Distance was defined as the distance from the suprasternal notch to the femoral artery minus the distance from the carotid artery to the suprasternal notch.

Echocardiographic evaluation

All patients underwent echocardiographic assessment with a vivid e-cardiovascular ultrasound system (General Electric, Milwaukee, WI, USA) equipped with a 2.0–3.6 MHz (harmonics) phased array transducer. According to the guidelines of the European Association of Cardiovascular Imaging and American Society of Echocardiography, LVEF was evaluated according to the Simpson biplane method [16].

Biochemical measurements

Blood samples were collected with venipuncture after a fasting of 12 h and were centrifuged at 3000 rpm. Serum/plasma samples were stored at –80°C until their analysis. Galectin-3 levels were assessed by the biochemistry laboratory of the 1st Cardiology Clinic, Hippokration University Hospital, Athens, Greece with commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions (R&D Systems Inc., Minneapolis, MN, USA).

Bioethics

All participants were informed for the purposes and the aims of the research, and a written consent form was obtained before the initiation of the study. The study was performed according to the Declaration of Helsinki (1989) and was accepted by the Scientific Institute for Research of Hippokration University Hospital.

Statistical analysis

All variables were tested for normal distribution with the use of P-P plots. Variables with normal distribution were expressed as means ± standard deviation, and otherwise as median with interquartile range. Categorical variables were expressed as valid percentages of the specific subpopulation. The t-test was applied to test for intergroup differences between two categories of normally distributed variables. One-way analysis of variance (ANOVA) or Kruskal-Wallis test was applied to test for intergroup differences of continuous variables according to LVEF classification. Bonferroni correction for multiple comparisons was applied to test for intergroup differences among the three studied groups. The χ2 test was performed to evaluate differences between categorical variables. To examine the interrelationship of FMD with LVEF independently of confounders known to affect FMD, we applied a linear regression analysis. To examine the prognostic significance of variables for MACE, we performed a receiver operating characteristics (ROC) analysis. All the reported p-values corresponded to two-sided tests. P-values were considered statistically significant at the level of < 0.05. Data were analyzed using SPSS version 26.0 (IBM, SPSS Statistics, Version 25.0. Armonk, NY, USA).

Results

Baseline characteristics of the study population

The basic demographic and clinical characteristics of the study population are demonstrated in Table 1. The mean age of the patients was 62 ± 11 years, and 63% were males. The mean value of BMI was 28.11 ± 3.95 kg/m2 (24% had normal weight, 50% were obese, and 26% were overweight). 73% of the patients had hypertension, 28% were diabetic, and 76% had dyslipidemia. Current smokers comprised 25% of the study population, whereas ex-smokers and never-smokers were 57% and 18%, respectively. Additionally, 60% of the patients had single vessel disease. Furthermore, the mean eGFR was 96 ± 32 mL/min/1.73 m2. According to LVEF, 26% of the patients were diagnosed with HFrEF, 28% with HFmrEF, and 46% with HFpEF. Also, the mean FMD was 5.05 ± 2.78%, and the mean PWV was 8.91 ± 2.49 m/s.

Table 1. Basic demographic and clinical characteristics of the study population.

Characteristics of the study population

Data

Age [years]

62 ± 11

Male sex

63%

Body mass index [kg/m2]

28.11 ± 3.95

Hypertension

73%

Diabetes mellitus

28%

Dyslipidemia

76%

Smoking:

Current smokers

25%

Ex-smokers

57%

Never-smokers

18%

eGFR [mL/min/1.73 m2]

96 ± 32

Heart failure category:

HFpEF (EF ≥ 50%)

46%

HFmrEF (EF: 41–49%)

28%

HFrEF (EF ≤ 40%)

26%

Single vessel disease

60%

Flow mediated dilatation [%]

5.05 ± 2.78

Pulse wave velocity [m/s]

8.91 ± 2.49

Galectin-3 [ng/mL]

9.58 (8.32, 15.88)

Population study characteristics according to LVEF category

There were no significant differences among the study groups regarding age (HFrEF: 62 ± 11 vs. HFmrEF: 61 ± 11 vs. HFpEF: 61 ± 11, p = 0.64), eGFR (HFrEF: 93 ± 32 vs. HFmrEF: 94 ± 32 vs. HFpEF: 94 ± 33, p = 0.97), and male sex (HFrEF: 61% vs. HFmrEF: 63% vs. HFpEF: 64%, p = 0.10). Interestingly, single-vessel CAD was more frequent in subjects with HFpEF compared to subjects with HFmrEF and HFrEF (HFrEF: 56% vs. HFmrEF: 64% vs. HFpEF: 73%, p = 0.049; Table 2). FMD displayed an improvement in patients with HFmrEF and HFpEF, contrary to patients with HFrEF (HFrEF: 4.74 ± 2.35 vs. HFmrEF: 4.97 ± 2.81 vs. HFpEF: 5.94 ± 3.46, p = 0.01; Table 2).

Table 2. Characteristics of the study population according to heart failure category

Variable

HFrEF

HFmrEF

HFpEF

P

Age [years]

62 ± 11

61 ± 11

61 ± 11

0.64

Male sex

61%

63%

64%

0.10

Body mass index [kg/m2]

27.75 ± 4.33

27.93 ± 3.47

28.18 ± 3.86

0.75

Hypertension

68%

78%

78%

0.09

Diabetes mellitus

27%

31%

24%

0.50

Dyslipidemia

76%

69%

84%

0.07

Smoking:

0.40

Current smokers

29%

28%

25%

Ex-smokers

57%

56%

48%

Never-smokers

14%

16%

27%

eGFR [mL/min/1.73 m2]

93 ± 32

94 ± 32

94 ± 33

0.97

Single vessel disease

56%

64%

73%

0.049

Stable clinical condition [months]

16 (10, 29)

16 (11, 26)

15 (10, 23)

0.23

Flow mediated dilatation [%]

4.74 ± 2.35

4.97 ± 2.81

5.94 ± 3.46

0.01

Pulse wave velocity [m/s]

8.97 ± 2.51

8.83 ± 2.50

8.89 ± 2.50

0.91

Galectin-3 [ng/mL]

9.50 (8.26, 16.39)

10.02 (8.74, 14.58)

9.66 (5.78, 53.00)

0.61

Evaluation of arterial function according to LVEF classification: Factors affecting arterial function

Our results revealed a stepwise impairment of FMD according to HF classification (HFpEF: 5.94 ± 3.46% vs. HFmrEF: 4.97 ± 2.80% vs. HFrEF: 4.74 ± ٢.٣٥٪, p = 0.01; Fig. 1A). PWV values did not differ among the study groups (HFpEF: 8.89 ± 2.50 m/s vs. HFmrEF: 8.83 ± 2.50 m/s vs. HFrEF: 8.87 ± ٢.٥١, p = 0.91; Fig. 1B). Also, galectin-3 levels were similar between the study groups (HFrEF: 9.50 [8.26, 16.39] vs. HFmrEF: 10.02 [8.74, 14.58] vs. HFpEF: 9.66 [5.78, 53.00], p = 0.61; Table 2). In order to examine whether any demographic or clinical parameters affected FMD, we performed a multiple linear regression analysis, in which we included all variables possibly affecting FMD (i.e., age, sex, BMI, hypertension, diabetes mellitus, dyslipidemia, smoking, number of vessel disease and HF group) (Table 3). FMD was reduced in patients with HFrEF compared to HFpEF by approximately 1.0% (b coefficient: 0.990, 95% confidence interval [CI]: 0.166–1.814, p = 0.019) independently of the aforementioned confounders (Table 3). Regression analysis revealed that FMD was inversely associated with age and BMI (Table 3).

Figure 1. Box plots of arterial function parameters (arterial stiffness and endothelial function) according to left ventricular ejection fraction (EF) classification; A. Flow-mediated dilatation (FMD) values according to heart failure (HF) classification; B. Pulse wave velocity (PWV) values according to HF classification. Abbreviations — see Table 1.
Table 3. Multiple linear regression analysis for the association of flow-mediated dilatation (FMD) with heart failure (HF) group and multiple confounders.

Regression analysis for the association of FMD
(dependent variable) with HF group after adjustment
for multiple cardiovascular risk factors

b coefficient

95% CI

P

Age [years]

–0.04

(–0.07, –0.02)

0.003

Male sex

–0.70

(–1.58, 0.18)

0.118

Body mass index [kg/m2]

–0.12

(–0.19, –0.04)

0.003

Hypertension

0.11

(–0.63, 0.84)

0.772

Diabetes mellitus

–0.07

(–0.74, 0.60)

0.836

Dyslipidemia

0.09

(–0.64, 0.84)

0.792

Smoking

Never-smokers (reference category):

Ex-smokers

–0.07

(–0.93, 0.79)

0.882

Current smokers

0.30

(–0.68, 1.29)

0.544

Single vessel disease [%]

–0.13

(–0.75, 0.49)

0.692

HFrEF (reference category):

HFmrEF

0.14

(–0.54, 0.81)

0.692

HFpEF

0.99

(0.17, 1.81)

0.019

Cardiovascular events

The median follow-up period of the study population was 48 months (interquartile range: 36, 76 months). During follow-up 30 patients died, 14 patients suffered a stroke, 41 patients were hospitalized for HF deterioration, 69 patients underwent angiography, and 28 patients suffered a MI. In total 38.2% developed a MACE.

Left ventricular ejection fraction was not associated with MACE (HFrEF: 38.2% vs. HFmrEF: 41.2% vs. HFpEF: 34.0%, p = 0.24). FMD was impaired in subjects who presented a MACE, compared to those without a MACE (4.51 ± 2.35% vs. 5.32 ± 2.67%, p = 0.02). Interestingly, patients in the highest tertile of galectin-3 presented more MACEs compared to the subjects of the other tertiles (36% vs. 5.9%, p = 0.01) (Suppl. Fig. 1A–D). According to ROC analysis (Suppl. Fig. 2A–C), LVEF category and the highest tertile of galectin-3 did not display any prognostic capability for MACE (LVEF: area under the curve [AUC] = 0.526, 95% CI: 0.453–0.599, p = 0.49, highest tertile of galectin-3: AUC = 0.600, 95% CI: 0.486–0.713, p = 0.11, respectively). On the other hand, FMD had the greatest prognostic capability for MACE (FMD: AUC = 0.608, 95% CI: 0.532–0.685, p = 0.006). Last but not least (Suppl. Fig. 3A–C), ROC analysis for LVEF, FMD, and galectin-3 (highest tertile) displayed no prognostic value for the combined end-point of rehospitalization for HF and/or death (LVEF: AUC = 0.504, 95% CI: 0.394–0.614, p = 0.94; FMD: AUC = 0.591, 95% CI: 0.460–0.722, p = 0.15; highest tertile of galectin-3: AUC = 0.532, 95% CI: 0.393–0.671, p = 0.67).

Discussion

In this prospective cohort study we evaluated the effects of galectin-3, brachial artery FMD, and carotid-femoral PWV on cardiovascular prognosis in patients with ischemic HF according to LVEF [16]. Interestingly, FMD was significantly improved in patients with HFpEF in contrast to patients with reduced EF, independently of possible confounders. Arterial stiffness, assessed by PWV, was not associated with LVEF. Furthermore, FMD was impaired in patients who developed a MACE during follow-up, and patients in the highest tertile of galectin-3 exhibited more MACEs. Our results did not indicate an association between MACE and LVEF category. Lastly, single-vessel CAD was more frequent in patients with HFpEF.

Deteriorated endothelial function has been linked to the development and progression of ischemic HF [15]. Indeed, endothelial dysfunction is associated with decreased production of NO and reduced vascular relaxation [7]. Endothelial dysfunction favors the production of vasoconstrictors, and the proliferation of vascular smooth muscle cells and extracellular matrix, which is implicated in cardiac remodeling and decreased cardiac output in HF [17]. In our study, FMD demonstrated a stepwise improvement with the increase of EF, and specifically patients with HFpEF demonstrated higher levels of FMD, independently of possible confounders. Evidence from the literature shows that FMD has an inverse association with LVEF in patients with chronic HF, but this is statistically non-significant in regression analysis models [18].

As for HFpEF, the literature reveals that coronary microvascular rarefaction, cardiac hypertrophy, and fibrosis induce LV diastolic dysfunction and impaired coronary flow reserve [19]. Microvascular rarefaction might be a significant contributor of diastolic dysfunction in older patients with HFpEF [20]. Similar associations have been demonstrated for obese patients, who display a worse profile of microvascular rarefaction, myocardial and pericardial fibrosis, and abnormal filling pressure of LV [21]. Our study did not find an association between PWV and LVEF. PWV is a marker of arterial stiffness, and higher levels of central PWV have been linked to the incidence of HF in the community [22]. PWV is also a marker of ageing, and higher values have been found in patients with HFrEF and HFpEF as well as in patients with HFmrEF [23–25]. Also, other published data indicate that HFpEF exhibits similar aortic stiffness with the group of HFrEF despite the presence of higher central blood pressures and wave reflections [26].

On the other hand, in our study FMD levels were deteriorated in patients who had more MACEs during follow-up. Persistently elevated levels of FMD have been correlated to worse cardiovascular prognosis in patients with chronic ischemic HF [27]. Moreover, there is evidence that FMD is associated with deteriorated prognosis among patients with advanced HF [28].

As for cardiovascular prognosis, our data showed that MACE was not linked to LVEF category. To date, patients with HFmrEF have a better prognosis than those with HFrEF [29]. Observational studies indicate that patients with HFpEF display better prognosis than those with HFrEF [30]. Indeed, in the MAGGIC meta-analysis, the group with HFpEF had decreased adjusted mortality risk compared to those with HFrEF [31]. Nevertheless, EF may vary with time in the same individual; therefore, patients who progress to HFrEF might have worse prognosis than patients who remain clinically stable or progress to a better clinical status [32, 33].

In our study, the presence of single-vessel CAD was more frequent in the group with HFpEF, to a less extent in patients with HFmrEF, and less frequently in HFrEF. Interestingly, HFmrEF is defined as HF with mildly-reduced EF (compared to HF with mid-range EF in the former guidelines of HF) because patients might benefit from the therapeutic approaches of the HFrEF category [1, 4]. Surprisingly, HFmrEF shares common characteristics with HFrEF, which might be attributed to the presence of underlying CAD, contrary to the group of HFpEF [4]. It is widely perceived that patients with multivessel CAD, compared to those with single-vessel or two-vessel disease, have decreased alteration in EF during dipyridamole stress echocardiography test, indicating the severity of the disease [34]. On the other hand, multivessel CAD has been linked to higher in-hospital incidence of HFpEF in patients who present with acute MI [35]. Consequently, HF is a more complex entity which is not solely explained by the evaluation of EF per se [36].

Lastly, patients with the highest levels of galectin-3 displayed more MACEs in our study. Indeed, higher levels of galectin-3 are linked to worse cardiovascular prognosis in patients with chronic ischemic HF due to the development of cardiac remodeling and associations with biomarkers of oxidative stress, inflammation, and renal dysfunction [37]. This seems reasonable because galectin-3 is a well-established marker of fibrosis participating in the processes of apoptosis, angiogenesis, and inflammation [38]. The clinical utility of galectin-3 is under investigation and has received a class IIb recommendation in the guidelines for HF as a possible risk factor, revealing the need for future studies to determine its possible role in HF diagnosis [39].

Limitations of the study

Our study had several limitations. To begin with, we did not display information about NYHA functional status of the patients and concurrent medications of the patients. Moreover, we did not perform an assessment of natriuretic peptides. EF may vary with time in the same individual, and this should be taken into account when interpreting cardiovascular prognosis. Also, the small size of our study population should be considered for the evaluation of the statistical significance of the results. The effects of other under-evaluated confounders might also affect the robustness of our results. Finally, our results cannot provide an etiologic explanation of the association of FMD and galectin-3 with cardiovascular prognosis.

Conclusions

Flow-mediated dilatation is significantly deteriorated in patients with HFrEF of ischemic etiology independently of confounders, and it displays a linear increase with the improvement of EF. Decreased FMD levels are associated with the incidence of MACE during follow-up in patients with ischemic HF, although LVEF per se does not affect survival. Also, higher levels of galectin-3 might serve as a risk factor of worse cardiovascular prognosis in patients with ischemic HF.

Conflict of interest: None declared

References

  1. van Riet EES, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016; 18(3): 242–252, doi: 10.1002/ejhf.483, indexed in Pubmed: 26727047.
  2. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the american heart association. Circulation. 2020; 141(9): e139–e596, doi: 10.1161/CIR.0000000000000757, indexed in Pubmed: 31992061.
  3. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021; 23(3): 352–380, doi: 10.1002/ejhf.2115, indexed in Pubmed: 33605000.
  4. Chioncel O, Lainscak M, Seferovic PM, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017; 19(12): 1574–1585, doi: 10.1002/ejhf.813, indexed in Pubmed: 28386917.
  5. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39(2): 257–265, doi: 10.1016/s0735-1097(01)01746-6, indexed in Pubmed: 11788217.
  6. Patel AR, Kuvin JT, Pandian NG, et al. Heart failure etiology affects peripheral vascular endothelial function after cardiac transplantation. J Am Coll Cardiol. 2001; 37(1): 195–200, doi: 10.1016/s0735-1097(00)01057-3, indexed in Pubmed: 11153738.
  7. Klosinska M, Rudzinski T, Grzelak P, et al. Endothelium-dependent and -independent vasodilation is more attenuated in ischaemic than in non-ischaemic heart failure. Eur J Heart Fail. 2009; 11(8): 765–770, doi: 10.1093/eurjhf/hfp091, indexed in Pubmed: 19578078.
  8. Oeing CU, Tschöpe C, Pieske B. [The new ESC Guidelines for acute and chronic heart failure 2016]. Herz. 2016; 41(8): 655–663, doi: 10.1007/s00059-016-4496-3, indexed in Pubmed: 27858115.
  9. Wu AHB, Wians F, Jaffe A. Biological variation of galectin-3 and soluble ST2 for chronic heart failure: implication on interpretation of test results. Am Heart J. 2013; 165(6): 995–999, doi: 10.1016/j.ahj.2013.02.029, indexed in Pubmed: 23708172.
  10. Oikonomou E, Karlis D, Tsalamadris S, et al. Galectin-3 and arterial stiffness in patients with heart failure: a pilot study. Curr Vasc Pharmacol. 2019; 17(4): 396–400, doi: 10.2174/1570161116666180703094919, indexed in Pubmed: 29968538.
  11. Tousoulis D, Antoniades C, Stefanadis C. Evaluating endothelial function in humans: a guide to invasive and non-invasive techniques. Heart. 2005; 91(4): 553–558, doi: 10.1136/hrt.2003.032847, indexed in Pubmed: 15772232.
  12. Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Nucl Cardiol. 2017; 24(5): 1759–1792, doi: 10.1007/s12350-017-0917-9, indexed in Pubmed: 28608183.
  13. Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet. 2013; 381(9867): 639–650, doi: 10.1016/S0140-6736(13)60108-7, indexed in Pubmed: 23439103.
  14. Rajzer MW, Wojciechowska W, Klocek M, et al. Comparison of aortic pulse wave velocity measured by three techniques: Complior, SphygmoCor and Arteriograph. J Hypertens. 2008; 26(10): 2001–2007, doi: 10.1097/HJH.0b013e32830a4a25, indexed in Pubmed: 18806624.
  15. Tousoulis D, Oikonomou E, Siasos G, et al. Dose-dependent effects of short term atorvastatin treatment on arterial wall properties and on indices of left ventricular remodeling in ischemic heart failure. Atherosclerosis. 2013; 227(2): 367–372, doi: 10.1016/j.atherosclerosis.2013.01.015, indexed in Pubmed: 23433403.
  16. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015; 28(1): 1–39.e14, doi: 10.1016/j.echo.2014.10.003, indexed in Pubmed: 25559473.
  17. Remme WJ. Congestive heart failure: pathophysiology and medical treatment. J Cardiovasc Pharmacol. 1986; 8(Suppl. 1): S36–S52, doi: 10.1097/00005344-198600081-00009.
  18. Ciccone MM, Iacoviello M, Puzzovivo A, et al. Clinical correlates of endothelial function in chronic heart failure. Clin Res Cardiol. 2011; 100(6): 515–521, doi: 10.1007/s00392-010-0275-y, indexed in Pubmed: 21212968.
  19. Mohammed SF, Hussain S, Mirzoyev SA, et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015; 131(6): 550–559, doi: 10.1161/CIRCULATIONAHA.114.009625, indexed in Pubmed: 25552356.
  20. Xu Z, Gu HP, Gu Y, et al. Increased index of microcirculatory resistance in older patients with heart failure with preserved ejection fraction. J Geriatr Cardiol. 2018; 15(11): 687–694, doi: 10.11909/j.issn.1671-5411.2018.11.010, indexed in Pubmed: 30534143.
  21. Packer M, Kitzman DW. Obesity-Related heart failure with a preserved ejection fraction: the mechanistic rationale for combining inhibitors of aldosterone, neprilysin, and sodium-glucose cotransporter-2. JACC Heart Fail. 2018; 6(8): 633–639, doi: 10.1016/j.jchf.2018.01.009, indexed in Pubmed: 29525327.
  22. Tsao CW, Lyass A, Larson MG, et al. Relation of central arterial stiffness to incident heart failure in the community. J Am Heart Assoc. 2015; 4(11), doi: 10.1161/JAHA.115.002189, indexed in Pubmed: 26597152.
  23. Kawaguchi M, Hay I, Fetics B, et al. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107(5): 714–720, doi: 10.1161/01.cir.0000048123.22359.a0, indexed in Pubmed: 12578874.
  24. Wang KL, Cheng HM, Sung SH, et al. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study. Hypertension. 2010; 55(3): 799–805, doi: 10.1161/HYPERTENSIONAHA.109.139964, indexed in Pubmed: 20065155.
  25. Huang WM, Sung SH, Yu WC, et al. Perturbations of pulsatile hemodynamics and clinical outcomes in patients with acute heart failure and reduced, mid-range or preserved ejection fraction. PLoS One. 2019; 14(8): e0220183, doi: 10.1371/journal.pone.0220183, indexed in Pubmed: 31381586.
  26. Parragh S, Hametner B, Bachler M, et al. Determinants and covariates of central pressures and wave reflections in systolic heart failure. Int J Cardiol. 2015; 190: 308–314, doi: 10.1016/j.ijcard.2015.04.183, indexed in Pubmed: 25935618.
  27. Takishima I, Nakamura T, Hirano M, et al. Predictive value of serial assessment of endothelial function in chronic heart failure. Int J Cardiol. 2012; 158(3): 417–422, doi: 10.1016/j.ijcard.2011.01.059, indexed in Pubmed: 21371765.
  28. Shechter M, Matetzky S, Arad M, et al. Vascular endothelial function predicts mortality risk in patients with advanced ischaemic chronic heart failure. Eur J Heart Fail. 2009; 11(6): 588–593, doi: 10.1093/eurjhf/hfp053, indexed in Pubmed: 19406838.
  29. Tsao CW, Lyass A, Enserro D, et al. Temporal trends in the incidence of and Mortality associated with heart failure with preserved and reduced ejection fraction. JACC Heart Fail. 2018; 6(8): 678–685, doi: 10.1016/j.jchf.2018.03.006, indexed in Pubmed: 30007560.
  30. Pocock SJ, Ariti CA, McMurray JJV, et al. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J. 2013; 34(19): 1404–1413, doi: 10.1093/eurheartj/ehs337, indexed in Pubmed: 23095984.
  31. Dunlay SM, Roger VL, Weston SA, et al. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012; 5(6): 720–726, doi: 10.1161/CIRCHEARTFAILURE.111.966366, indexed in Pubmed: 22936826.
  32. Lawson CA, Zaccardi F, Squire I, et al. 20-year trends in cause-specific heart failure outcomes by sex, socioeconomic status, and place of diagnosis: a population-based study. Lancet Public Health. 2019; 4(8): e406–e420, doi: 10.1016/S2468-2667(19)30108-2, indexed in Pubmed: 31376859.
  33. Lupón J, Gavidia-Bovadilla G, Ferrer E, et al. Dynamic trajectories of left ventricular ejection fraction in heart failure. J Am Coll Cardiol. 2018; 72(6): 591–601, doi: 10.1016/j.jacc.2018.05.042, indexed in Pubmed: 30071987.
  34. Squeri A, Gaibazzi N, Reverberi C, et al. Ejection fraction change and coronary artery disease severity: a vasodilator contrast stress-echocardiography study. J Am Soc Echocardiogr. 2012; 25(4): 454–459, doi: 10.1016/j.echo.2011.12.009, indexed in Pubmed: 22243999.
  35. Xu M, Yan L, Xu J, et al. Predictors and prognosis for incident in-hospital heart failure in patients with preserved ejection fraction after first acute myocardial infarction: an observational study. Medicine (Baltimore). 2018; 97(24): e11093, doi: 10.1097/MD.0000000000011093, indexed in Pubmed: 29901624.
  36. Triposkiadis F, Butler J, Abboud FM, et al. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J. 2019; 40(26): 2155–2163, doi: 10.1093/eurheartj/ehz158, indexed in Pubmed: 30957868.
  37. Medvedeva EA, Berezin II, Surkova EA, et al. Galectin-3 in patients with chronic heart failure: association with oxidative stress, inflammation, renal dysfunction and prognosis. Minerva Cardioangiol. 2016; 64(6): 595–602, indexed in Pubmed: 27119370.
  38. Frunza O, Russo I, Saxena A, et al. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis. Am J Pathol. 2016; 186(5): 1114–1127, doi: 10.1016/j.ajpath.2015.12.017, indexed in Pubmed: 26948424.
  39. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017; 70(6): 776–803, doi: 10.1016/j.jacc.2017.04.025, indexed in Pubmed: 28461007.