Role of NT-proBNP and lung ultrasound in diagnosing and classifying heart failure in a hospitalized oldest-old population: a cross-sectional study

doi:10.21203/rs.3.rs-3143107/v1

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Research Article

Role of NT-proBNP and lung ultrasound in diagnosing and classifying heart failure in a hospitalized oldest-old population: a cross-sectional study

https://doi.org/10.21203/rs.3.rs-3143107/v1

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published 20 Apr, 2024

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Aim: Diagnosing and classifying heart failure (HF) in the oldest-old patients has technical and interpretation issues, especially in the acute setting. We assessed the usefulness of the N-terminal pro-brain natriuretic peptide (NT-proBNP) and lung ultrasound (LUS) for confirming HF diagnosis and discriminating patients with reduced ejection fraction (HFrEF) in the acute setting.

Methods: We performed a cross-sectional study on 148 consecutive patients aged ≥ 80 admitted with manifestations compatible with HF according to the Framingham HF criteria and NT-proBNP at least ≥125 pg/mL at our Internal Medicine and Geriatrics Unit (IRCCS INRCA Institute, Ancona, Italy). We collected clinical, pharmacological and laboratory data at admission. We dosed serum NT-proBNP and performed LUS and transthoracic echocardiography (TTE) before diuretic therapy. We divided our cohort into HFrEF and non-HFrEF according to left ventricular ejection fraction (EF) ≤ 40% and ≥ 40%, respectively.

Results: Mean age was 88 ± 5 years. Male prevalence was 42%. NT-proBNP and the total number of B lines correlated with positive Framingham HF criteria. 19% had an EF < 40%. There were no differences between the two groups regarding clinical features, LUS findings, and laboratory, except for the NT-proBNP levels, which were higher in the HFrEF group. Overall, NT-proBNP showed an inverse correlation with EF (r = - 0.22, p = 0.007) and a direct correlation with age, total pulmonary B-lines, and intercostal spaces of pleural effusion. According to the ROCs, NT-proBNP levels, pulmonary B-lines and pleuric effusion extension were poorly predictive for HFrEF. The best-performing cut-offs were 9531 pg/mL (SP 0.70, SE 0.50) for NT-proBNP, 13 for total B-lines (SP 0.69, SE 0.85) and one intercostal space for pleural effusion (SP 0.55, SE 0.89). Patients with admission NT-proBNP ≥9531 pg/mL had a 2-fold higher risk for HFrEF (OR 2.7, 95% CI 1.2-6.2), while we did not find any association for total B-lines ≥ 13 or pleural effusion ≥ 1 intercostal space and HFrEF. A significant association with HFrEF emerged for the combination of NT-proBNP ≥9531 pg/mL, total B-lines ≥13 and intercostal spaces of pleural effusion ≥1 (OR 5.3, 95% CI 1.7-17), even after adjustment for age, sex and eGFR (adjusted OR 5.4, 95% CI 1.6-16).

Conclusions: Our study suggests that in older patients and acute settings, NT-proBNP levels, especially if combined with LUS, could be considered for confirming the HF diagnosis and identifying those at risk of HFrEF.

lung ultrasound

heart failure

NT-proBNP

older adults

Heart failure (HF) is a leading cause of hospitalization and death among older adults worldwide (1). In this population, classical clinical presentation features and standard radiologic imaging, well captured by the major and minor Framingham HF criteria (2), often lack accuracy, limiting early HF diagnosis and adequate treatment (3). Cognitive impairment, prolonged bed rest, low collaboration, and comorbidities are significant confounders in this setting. Considering these issues, serum biomarkers of cardiac overload, such as N-terminal pro-brain natriuretic peptide (NT-proBNP), have helped because of their high predictive diagnostic and prognostic value in HF patients of all ages (4-6). On the other side, lung ultrasound (LUS) has emerged as an effective and simple tool for distinguishing between causes of acute and chronic dyspnea (7). Unfortunately, objectifying and classifying a cardiac dysfunction, especially in the acute setting, remains a prerogative of trans-thoracic echocardiography (TTE), which is not always available or easy to perform, especially in older patients. TTE provides information on the pericardium, cardiac chambers volumes and geometry, valve morphology and function and ventricular performance, allowing the current clinical classification of reduced, mildly-reduced and preserved ejection fraction (HFrEF, HFmrEF and HFpEF, respectively) (8). Recognizing HFrEF is pivotal because its therapeutic approach is broader and based on more significant evidence (9). Specific devices and procedures, such as intracardiac defibrillator (ICD) or cardiac resynchronization therapy (CRT), and particular molecules, such as sacubitril/valsartan, are exclusive treatments for HFrEF (10).

This study assesses the usefulness of the N-terminal pro-brain natriuretic peptide (NT-proBNP) and lung ultrasound (LUS) for identifying the oldest-old patients with HF and those at higher risk of HFrEF in acute settings.

1.1 Study Population and Protocol

From January 2022 to March 2023, we conducted a cross-sectional study on patients consecutively admitted at the Internal Medicine and Geriatrics Unit, IRCCS INRCA of Ancona, Italy, for acute medical conditions and concomitant suspected heart failure (HF). We considered the following inclusion criteria: i) patients aged ≥ 80 years and referred to the Emergency Department (ED) with symptoms compatible with HF according to the Framingham HF criteria, ii) NT-proBNP at least ≥125 pg/mL. We excluded patients with acute coronary syndrome, end-stage renal disease (ESRD) or dialysis, decompensated cirrhosis, active cancer, established interstitial lung disease (interstitial pneumonia, fibrosis), and patients having conditions with a life expectancy of less than one year. All patients included in the study provided informed consent, and the local ethical committee approved the investigation, according to the declaration of Helsinki. At admission, we collected clinical history, anthropometrics and laboratory parameters, basic activity of daily living (BADL) score, and pharmacological treatments. Before starting or increasing diuretic therapy or modifying/introducing other therapies for HF, we dosed NT-proBNP levels. Then we performed a complete LUS and transthoracic cardiac ultrasound (TTE) examination, according to the best clinical practice. In the analyses, we divided our population into HFrEF and non-HFrEF groups. HFrEF was determined by EF ≤40% at the TTE (8).

1.2 NT-proBNP assay

After blood sampling, NT-proBNP was measured using Elecsys proBNPII electrochemiluminescence immunoassay in a Cobas e601 immunoassay Roche analyzer. This assay contains two monoclonal antibodies that recognize epitopes located in the N-terminal part (1–76) of proBNP (1–108) (11).

1.3 Transthoracic Echocardiography

According to the American Society of Echocardiography (12), a trained sonographer performed the TTE at rest using a Vivid-7 (General Electric, Norway) ultrasound machine. Left ventricular (LV) volume, geometry, and mass (LVM) were assessed from the parasternal long-axis projection and adjusted for the body surface area (BSA). The modified biplane Simpson's method calculated the EF. Diastolic function was determined from the pattern of mitral inflow (early E wave and atrial a wave) acquired by pulsed Doppler and the average E/e' ratio after measuring septal and lateral mitral annular velocity (septal and lateral e') by tissue Doppler imaging (TDI). The right ventricle (RV) structure and function assessment was performed through the measure of tricuspid annular plane systolic excursion (TAPSE) and TD-derived tricuspid lateral annular systolic velocity (S'). Estimated systolic pulmonary artery pressure (PAPs) was derived from the tricuspid regurgitant jet together with an estimate of the right atrial pressure (RAP) based on inferior vena cava (IVC) size and breathing-related collapse.

1.4 Lung Ultrasound

LUS indirectly evaluated pulmonary interstitial involvement by detecting pulmonary B-lines (vertical hyperechoic laser-like artefacts arising from the pleura). Eight chest sites were scanned bilaterally, and the total bilateral B-lines (or Comet Score) were recorded. The interstitial syndrome was defined as three or more B-lines per intercostal space in at least two fields per side (13). Also, basolateral lung scanning was performed to assess the presence of pleural effusion. If present, we measured the extension of the pleural effusion in terms of the cranial-caudal total number of intercostal spaces involved.

1.5 Statistical analysis

Continuous variables were checked for normality and expressed as mean ± standard deviation or as the median and interquartile range (IQR) for markedly skewed variables. Categorical variables were expressed as numbers and percentages. Correlations between non-parametric variables were assessed by Spearman's 2-tailed method. Comparisons between variables were performed using the Student's t-test and the Mann Witney U-test. The diagnostic utility of NT-proBNP levels and LUS parameters in detecting HFrEF was determined using receiver-operating characteristic (ROC) curves. The best threshold was obtained by selecting the ROC curve point that maximized sensitivity and specificity (Youden index). Multivariable logistic regression was used to test the independent associations between covariates and the outcome of HFrEF diagnosis. A p-value < 0.05 was considered statistically significant. All statistical analyses were conducted with SPSS version 23 [SPSS Inc., Chicago, IL, USA], Microsoft Windows version.

A total of 148 patients were enrolled in the study; 62 (42%) were males, and mean age and BMI were 88 ± 5 years and 25 ± 4 Kg/m², respectively. The prevalent comorbidities were hypertension (90%), chronic kidney disease (CKD) (53%), chronic HF (49%), and atrial fibrillation (AF) (44%). Framingham HF criteria were positive in 75%. The average BADL score was 3 ± 2 points. The overall median NT-proBNP level was 7457 pg/mL (IQR 3261-15597). LUS detected pulmonary interstitial syndrome in 31% of patients, with an overall median of 9 total B-lines (IQR 6 - 15). Pleural effusion was detected in 68% of LUS examinations with a median extension of 3 intercostal spaces (IQR 1-4). According to the TTE findings, 28 patients (19%) were diagnosed with HFrEF. There were no meaningful differences between the HFrEF group and the non-HFrEF one regarding clinical features and the positivity of Framingham HF criteria, LUS and TTE findings, and laboratory, except for the NT-proBNP level, significantly higher in the HFrEF group (p = 0.039). Also, there was no difference in the mean eGFR calculated with the Cockroft-Gault equation (p = 0.050) and the prevalence of previous treatment with loop diuretics, beta-blockers (BBs), and renin-angiotensin-aldosterone inhibitors (RAASi) between the two groups. Clinical and laboratory parameters and ultrasound measurements are reported in Table 1.

2.1 Correlations between NT-proBNP, LUS and TTE parameters

NT-proBNP levels showed a direct correlation with age (r = 0.25, p = 0.002), the total number of pulmonary B-lines (r = 0.18, p = 0.025), pleural effusion extension (r = 0.26, p = 0.001), and with the positivity of the Framingham HF criteria (r = 0.14, p = 0.026). An inverse correlation was found between NT-proBNP, EF (r = - 0.22, p = 0.007) and eGFR (r = - 0.33, p < 0.001). The total number of B-lines and the extension of pleural effusion were inversely correlated with EF (r = - 0.25, p = 0.002 and r = - 0.22, p = 0.008, respectively) and directly related with age and the positivity of the Framingham HF criteria (r = 0.19, p = 0.027 and r = 0.21, p = 0.011, respectively).

2.2 ROCs

According to the ROCs, NT-proBNP levels (AUC 0.63, p = 0.039), pulmonary B-lines (AUC 0.77, p = 0.001) and the pleuric effusion extension (AUC 0.67, p = 0.005) all can predict HFrEF. The optimal cut-offs for HFrEF prediction were NT-proBNP 9531 pg/mL (SP 0.70, SE 0.50), n° 13 total B-lines (SP 0.69, SE 0.85) and n° 1 intercostal space of pleural effusion (SP 0.55, SE 0.89); Figure 1.

2.3 Associations between NT-proBNP, B-lines, the extension of pleural effusion with HFrEF diagnosis

The optimal cut-offs found in the ROCs were used to investigate the association with HFrEF diagnosis.

Association with the HFrEF diagnosis was found for an NT-proBNP value ≥ 9531 pg/mL (OR 2.7, 95% CI 1.2-6.2) but not for B-lines ≥ 13 (OR 1.6, 95% CI 0.7-4) and intercostal spaces of pleural effusion ≥ 1 (OR 1.7, 95% CI 0.6-4.2). Considering the concomitant presence of NT-proBNP and LUS variables above the cut-offs (25% in the HFrEF group vs 6% in the non-HFrEF), a significant increase in HFrEF risk emerged (OR 5.4, 95% CI 1.7-17). The multivariable analysis demonstrated that the association of the combination of the NT-proBNP and LUS parameters with HFrEF diagnosis remained valid even after adjustment for age, sex and eGFR (adj. OR 5.2, 95% CI 1.7-16), as reported in Table 2.

Diagnosing HF in very old patients represents a daily challenge for clinicians in the EDs and medical wards. Considering dyspnea as the most frequent symptom of HF presentation, comorbidities such as COPD, AF, CKD, and anemia complicate the diagnosis, severely limiting early and accurate HF recognition and adequate treatment. Distinguishing HFrEF from non-HFrEF, characterized by different pathophysiologic aspects, treatment and prognosis, superimposes a challenge within a challenge (14). Despite being the diagnostic gold standard, TTE is not widely available and needs adequate clinician training, time, and complete compliance of the patients, which is not easily obtained in the older population. In our analysis, 42% of the patients suffered from a cognitive decline, and the average BADL scale scored 3, indicating a moderate to severe reduction in personal autonomy. These conditions and comorbidities could compromise the feasibility and accuracy of the TTE. A retrospective study of 116 patients with a median age of 86 and an established diagnosis of HF reported that those who did not undergo TTE during the hospitalization were older (median age 89) and frailer compared with those who received the echocardiographic evaluation (3). Over the last decades, cardiac biomarkers have dramatically changed how HF patients are evaluated and treated. NPs, particularly B-type natriuretic peptide (BNP) and NT-proBNP, have emerged as robust markers for diagnosing, prognosis and managing patients with HF (15). Although most studies on plasma NT-proBNP concentrations only included individuals with a mean age of fewer than 70, most HF patients are older in daily practice. Several studies have demonstrated that age and cardio-renal and pulmonary comorbidities increase NT-proBNP levels, dramatically lowering the accuracy of HF diagnosis (16). Thus, in the setting of HF diagnosis in senior patients >75 years old a diagnostic cut-off of 1800 pg/mL was proposed (17). NPs levels have maintained their negative predictive value, which helps rule out cardiogenic dyspnea when values are below specific cut-offs (18, 19). Accordingly, the median NT-proBNP level in our older population was 7457 pg/mL, about four times higher. Also, authors have demonstrated that NT-proBNP correlated directly with LV end-diastolic dimension (LVEDD) and volumes and inversely with EF, along with significant differences between HFrEF patients and non-HFrEF ones (20). In one report including more than 2000 patients with a median age of 73, the median NT-proBNP in the HFrEF population was 4580 pg/mL (IQR 2065–9765 pg/mL) vs 2900 pg/mL (IQR 2065–9765 pg/mL) in the non-HFrEF one (p < 0.01) (21). Likewise, a solid linear and inverse correlation emerged in our analysis comparing NT-proBNP levels and EF (r = - 0.22, p = 0.007), confirming that even older patients with HFrEF have higher NT-proBNP levels reflecting significant myocardial stress and adverse remodeling (20). Accordingly, our best cut-off value for HFrEF is slightly above 9500 pg/mL. However, the ability of NT-proBNP to predict HFrEF is weak (AUC 0.63, p < 0.05), and the threshold lacked accuracy (70% specificity, 50% sensibility) to recognize HFrEF. Similarly, LUS seems to be as simple as an accurate method for assessing pulmonary congestion related to AHF in clinical practice. Still, it has not been validated in the old population. Indeed, previous studies have documented the presence of B-lines in normal lungs among healthy geriatric patients, mainly isolated and confined to the lateral-basal areas (22). Multiple bilateral B-lines and the detection of pleural effusion can increase the probability of a cardiogenic aetiology of dyspnea (23). Furthermore, the total number of B-lines has been associated with depressed EF [median B lines total number of 32 (IQR 27–38) in the HFrEF group vs 30 (IQR 25–36) in the non-HFrEF one; p = 0.05] in a prospective cohort of 250 patients with a median age of 80 years admitted with a diagnosis of HF (24). Thereby, data concerning the usefulness of LUS for detecting HF and HFrEF in this particular population are scarce. As well as for NT-proBNP, we found pulmonary B-pattern and pleural effusion poorly predictive for HFrEF, with cut-offs of n°13 total B-lines and n° 1 intercostal space, respectively, being far from clinically acceptable diagnostic accuracy. Despite the low diagnostic performance, the patients with NT-proBNP ≥ 9531 pg/mL had an almost three-fold risk of HFrEF. Moreover, considering the subgroup who contemporary had NT-proBNP ≥ 9500 pg/mL + B-lines ≥ 13 + intercostal spaces of pleural effusion ≥ 1, the multivariable analysis reported a further significant higher risk of HFrEF, almost up to five times, even after adjustment for age, sex and renal function. NT-proBNP and LUS signs reflect cardiovascular overload and pulmonary congestion, depending on volume status, diuretic therapy, and renal function. However, we did not find any difference between loop diuretic therapy prevalence and mean eGFR between groups.

Study limits

Several limitations apply to our research and should be addressed. Even though the same sonographer recorded all the ultrasound imaging (LUS and TTE), an inevitable intraobserver interpretation variability must be considered. The small sample size and the low number of events may have produced statistical biases despite the selected population with a very high mean age. Also, the small sample size negatively affected the adequate evaluation of the diagnostic performance of the combined variables.

Accurate diagnosis and classification of HF patients according to the EF still preserve a role in guiding the clinician to optimize the pharmacological and non-pharmacological therapy to reduce symptoms recurrence, hospitalization and mortality effectively. Our study on a very old cohort evidenced the correlation between NT-proBNP levels and the total number of B-lines with positive Framingham HF criteria. Also, we tested the predictive value of NT-proBNP and LUS for HFrEF. According to the results, in our oldest-old population, NT-proBNP measurement and LUS evaluation might help physicians to confirm the clinical suspicion of HF and to identify those at risk of HFrEF. However, the low diagnostic accuracy in this population does not allow us to avoid the systematic use of TTE altogether to distinguish HF phenotype. As we witness a definite trend for longer life expectancy and related health and socio-economic issues, alternative tools to select patients worthy of further cardiological insights (e.g. TTE) should be developed and investigated.

Ethics approval and consent to participate: All patients included in the study provided informed consent, and the local ethical committee (INRCA IRCCS of Ancona, Italy) approved the investigation. The study was performed according to the declaration of Helsinki.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

Conflict of Interests: The authors declare no conflict of interest.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author’s contributions: ML made the analyses, wrote the entire manuscript and elaborated the tables and figures; FS and RS supervised the entire process and revised the manuscript, and all other authors contributed equally to the data collection and preparation of the dataset.

Acknowledgements: Authors would like to express sincere gratitude to all the individuals and organizations contributing to this research paper.

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Table 1. Main clinical characteristics, laboratory and ultrasound measures

Clinical parameters	Total (n = 148)	HFrEF (n = 28)	non-HFrEF (n = 120)	p (HFrEF vs non HFrEF)
Age (years)	88 ± 5	88 ± 5	88 ± 5	0.927
Sex (males, %)	62 (42)	14 (50)	48 (40)	0.334
BMI (Kg/m²)	25 ± 4	25 ± 4	25 ± 5	0.879
Hypertension (%)	134 (90)	27 (96)	107 (90)	0.237
Atrial fibrillation (%)	64 (44)	11 (40)	54 (45)	0.583
Diabetes Mellitus (%)	31 (21)	5 (18)	26 (21)	0.656
Ischemic Heart Disease (%)	49 (33)	12 (43)	37 (31)	0.223
Chronic Heart Failure (%)	72 (48)	16 (57)	56 (47)	0.318
COPD (%)	47 (32)	7 (25)	40 (33)	0.394
Anemia (Hb < 12 g/dL) (%)	65 (44)	9 (32)	56 (46)	0.163
Non-end stage CKD (%)	78 (53)	18 (64)	60 (50)	0.173
Cognitive impairment (%)	61 (42)	10 (36)	51 (42)	0.511
Loop diuretic (%)	103 (70)	21 (75)	82 (68)	0.490
Beta-blockers (%)	86 (58)	17 (60)	69 (57)	0.855
RAASi (%)	77 (52)	15 (53)	62 (51)	0.949
Framingham HF + (%) Laboratory parameters	112 (76)	24 (86)	88 (73)	0.169
NT-proBNP (pg/mL)	7051 (2541-15249)	9983 (5314-15597)	5700 (2286-11083)	*0.039*
eGFR (ml/min)	46 ± 22	40 ± 20	48 ± 22	*0.050*
LUS parameters
B-lines (n)	12 (6-18)	16 (13-19)	12 (6-15)	*0.001*
IS of pleural effusion (n)	3 (1-4)	3 (2-4)	1 (0-3)	*0.004*
TTE parameters
LVEF (%)	50 ± 11	30 ± 7	55 ± 7	*0.001*
RWT	0.49 ± 0.14	0.48 ± 0.16	0.50 ± 0.13	0.067
LVMi (g/m²)	106 ± 29	120 ± 40	104 ± 26	*0.014*
LAVi (ml/m²)	44 ± 19	50 ± 27	43 ± 16	0.057
E/E’	13 ± 4	12 ± 5	14 ± 5	0.356
TRV (m/s)	2.8 ± 0.5	2.6 ± 0.5	2.8 ± 0.5	0.326
TAPSE (mm)	20 ± 5	17 ± 4	19 ± 5	*0.031*
IVC (mm)	20 ± 4	21 ± 5	19 ± 4	0.189
PAPs (mmHg)	40 ± 12	37 ± 11	40 ± 12	0.254
Non-collapsible IVC (%)	61 (41)	14 (50)	47 (40)	0.230

BMI = body mass index, COPD = chronic obstructive pulmonary disease, Hb = haemoglobin, BADL = basic activity of daily living, CKD = chronic kidney disease, RAASi = renin-angiotensin-aldosterone system inhibitors, NT-proBNP = amino-terminal pro-brain-natriuretic peptide, eGFR = estimated glomerular filtration rate, LUS = lung ultrasound, IS = intercostal spaces, LVEF = left ventricular ejection fraction, RWT = relative wall thickness, LVMi = left ventricular mass index, LAVi = left atrial volume index, TRV = tricuspid regurgitation velocity, TAPSE = tricuspid annular plane systolic excursion, IVC = inferior vena cava, PAPs = systolic pulmonary arterial pressure.

Table 2. Odds-ratios for the HFrEF diagnosis

	HFrEF + (%)	HFrEF – (%)	OR (95% CI)	OR¹ (95% CI)
Total	n = 28 (19)	n = 120 (81)	-	-
NT-proBNP < 9531 pg/mL	13	84	Ref.	Ref.
NT-proBNP ≥ 9531 pg/mL	15	36	2.7 (1.2-6.2)	-
B-lines < 13	16	83	Ref.	Ref.
B-lines ≥ 13	12	37	1.6 (0.7-4)	-
Intercostal spaces < 1	7	43	Ref.	Ref.
Intercostal spaces ≥ 1	21	77	1.7 (0.6-4.2)	-
Combination -	21	113	Ref.	Ref.
Combination +	7	7	5.3 (1.7-17)	5.4 (1.6-16)

OR¹ = adjusted for age, sex and eGFR
HFrEF = heart failure with reduced ejection fraction, NT-proBNP = amino-terminal pro-brain natriuretic peptide

No competing interests reported.

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Role of NT-proBNP and lung ultrasound in diagnosing and classifying heart failure in a hospitalized oldest-old population: a cross-sectional study

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Journal Publication

Version 1