Heart failure (HF) is a major public health problem in industrialized nations and the United States is responsible for approximately one million cases and 50,000 hospital deaths annually.1

Heart failure has cost in the USA over 8 million dollars a year and 5% of all admissions in the UK (United Kingdom) are diagnosed with heart failure.2 The prevalence of heart failure is increasing in many parts of the world and prognosis is poor, especially if the symptoms are due to left ventricular systolic dysfunction (LVSD). If patients are treated with Renin-Angiotensin blockers system, Aldosterone blockers, and B-blockers properly, prognosis could be better. Thus, the main importance is to identify LVSD fast in patients to start appropriate treatment with the confidence. Repeatedly shown that the diagnosis of heart failure in suspected patients are not reliable; patients with suspected heart failure should be sent for echocardiography commonly, but in many countries, echocardiography is hardly possible due to limited services in primary care. Records obtained more than 10 years ago shows that natriuretic peptides are markers of left ventricular wall stress, especially brain natriuretic peptide (BNP) or N-terminal product derived (NT-pro BNP) peptide progenitor, that possible resolve this problem.

Many studies have investigated the effect of natriuretic as a diagnostic factor of left ventricular dysfunction in patients.3 BNP is secreted by myocardial cells in response to increased volume and pressure. This precursor molecule is divided into active BNP and inactive N-Terminal fragment Pro-BNP (NT-Pro-BNP). Comparison of BNP and NT-Pro-BNP has shown that both molecules effective in diagnosing left ventricular dysfunction in acute care and rapid decision. All studies have shown NT-Pro-BNP levels as predictors of future cardiovascular changes and mortality following acute coronary syndromes.4 In an article published in 2005 it has reported that the in patients have been sent for echocardiography with suspected heart failure in primary care, NT-Pro-BNP levels are effective in refuse of left ventricular failure.3 Most studies are using Pro-BNP in diagnosis of heart failure but use of these tests in determining prognosis and classification of severity of heart failure is controversy. So, in this study we tried to determine the severity of heart failure according to Pro-BNP measurement that offer lower cost and faster method for assess the patients in emergency and classification of heart failure and thus reduce follow up costs and unnecessary admissions.

Aim: To analyze the relationship between NT-pro BNP levels and HF severity.

Study Design and Population

This was a prospective observational study conducted on 140 patients with clinically diagnosed chronic heart failure. Patients were recruited from the cardiology outpatient and inpatient services over a 12‑month period.

Natriuretic Peptide Measurements

Blood was collected at the screening visit. Plasma was isolated and immediately frozen at −20°C. On the same day, samples were shipped on dry ice to the closest of 6 designated regional laboratories affiliated with the central laboratory run by Quintiles Durham, NC (now IQVIA). The same assay kits were used to measure each peptide at each site. Specifically, NT-proBNP was measured using the Roche Elecys proBNP assay (Roche Diagnostics, Indianapolis, IN) and BNP using the Advia Centaur assay (Siemens Healthcare Diagnostics, Tarrytown, NY) as described previously

Inclusion criteria: Adults aged ≥18 years, with symptoms and signs of heart failure confirmed by echocardiography.

Exclusion criteria: Patients with acute decompensated heart failure, advanced valvular disease requiring surgery, severe renal failure (eGFR <30 mL/min/1.73 m²), or terminal non‑cardiac illness.

Clinical Assessment

Each patient underwent a detailed clinical evaluation including:

Demographics (age, sex, BMI).

Medical history (hypertension, diabetes, ischemic heart disease).

Functional status graded according to the New York Heart Association (NYHA) classification.

Laboratory Investigations

Venous blood samples were collected after overnight fasting. Serum NT‑proBNP levels were measured using a standardized electrochemiluminescence immunoassay. All samples were processed in the same laboratory to minimize variability.

Echocardiographic Evaluation

Two‑dimensional transthoracic echocardiography was performed for all patients. Parameters recorded included:

Left ventricular ejection fraction (LVEF).

Left atrial diameter.

Left ventricular end‑diastolic diameter (LVEDD).

Diastolic function indices (E/A ratio, E/e’).

Statistical Analysis

Continuous variables were expressed as mean ± standard deviation.

NT‑proBNP levels were compared across NYHA classes using ANOVA (or Kruskal–Wallis test for non‑normal data).

Correlation between NT‑proBNP and echocardiographic parameters was assessed using Pearson correlation coefficients.

A p‑value <0.05 was considered statistically significant.

Statistical analysis was performed using SPSS version 25.0.

The study included 140 patients with chronic heart failure. The mean age was 60.7 years, and males comprised 58.6% of the cohort. Hypertension (52.9%), diabetes mellitus (44.3%), and ischemic heart disease (34.3%) were the most common comorbidities (Table 1).

Serum NT‑proBNP levels increased progressively with worsening NYHA functional class. Patients in NYHA class I had mean levels of 410 pg/mL, while those in class IV had markedly elevated levels averaging 7,650 pg/mL (Table 2). This demonstrates a strong association between NT‑proBNP concentration and clinical severity of heart failure.

Echocardiographic analysis revealed a negative correlation between NT‑proBNP and left ventricular ejection fraction (r = –0.58, p <0.001), and positive correlations with left ventricular end‑diastolic diameter (r = +0.61, p <0.001), left atrial diameter (r = +0.55, p <0.001), and diastolic indices (E/e’ ratio, r = +0.49, p <0.01) (Table 3). These findings confirm that higher NT‑proBNP levels reflect worsening systolic and diastolic dysfunction.

Patients with diabetes mellitus and ischemic heart disease had significantly higher NT‑proBNP levels compared to those without these comorbidities (p = 0.04 and p = 0.01 respectively), while hypertension showed no significant difference (Table 4). When stratified by NT‑proBNP quartiles, patients in the highest quartile (>6,000 pg/mL) experienced the greatest burden of hospitalizations, averaging 3.4 admissions per year, compared to only 0.6 admissions in the lowest quartile (<1,000 pg/mL) (Table 5). This highlights the prognostic value of NT‑proBNP in predicting adverse outcomes.

Table 1. Baseline Characteristics of Study Population (n=140)

Table 2. Serum NT‑pro BNP Levels Across NYHA Classes

Table 3. NT‑pro BNP vs. Echocardiographic Parameters

Table 4. Mean NT‑pro BNP Levels in Patients With vs. Without Comorbidities

Table 5. NT‑pro BNP Levels and Hospitalization Frequency

Summary

• The mean age was ~61 years, with a male predominance.
• NT‑proBNP levels rose progressively with worsening NYHA class.
• Strong negative correlation with LVEF and positive correlation with LV dimensions and diastolic indices.
• Patients with diabetes and ischemic heart disease had significantly higher NT‑proBNP levels.
• Higher NT‑proBNP quartiles were associated with increased hospitalization frequency, indicating prognostic relevance.

The study aimed to evaluate the relationship between NT-pro BNP levels and left ventricular diastolic dysfunction in patients with COVID-19. Our study showed that plasma NT-proBNP levels in patients with increased diastolic dysfunction were related to the severity of the disease so that with increasing severity of diastolic dysfunction, NT-proBNP levels also increase. It was also found that the cut-off point of NT-pro BNP = 799 pg/ml could be used as a predictor of diastolic dysfunction grades 2 and 3. A person with COVID-19 who has high-grade diastolic dysfunction is 100% likely to have a serum NT-pro BNP level above 799 pg/ml. In this study, patients with a serum NT-pro BNP level above 799 had a 37 times higher chance of having diastolic dysfunction than those with a serum NT-pro BNP level below this amount. There are studies that, similar to our study, found significantly higher NT-pro BNP levels in patients with advanced diastolic dysfunction.

In one study, this level was 286 ± 31 pg/ml [13], in another study, the NT-pro BNP level was 46 to 48 pg/ml above normal [14] and in another study, it was 14 ± 13 pmol/l [15]. Although these late peptides have been shown to be associated with severe diastolic dysfunction, their role in the diagnosis of mild diastolic heart dysfunction is uncertain [16]. In a study on 396 patients that showed a strong association between plasma NT-pro BNP levels and the risk of death in patients with COVID-19, the best median NT-pro BNP for predicting mortality at 53 days of follow-up was 847.5 pg/ml. According to this study, NT-pro BNP was associated with mortality both in the entire study population and after the exclusion of patients with heart failure. NT-pro BNP above this level was associated with a higher risk of mortality in these patients due to cardiac complications raised by complex interactions between previous conditions, ischemia, systemic inflammation, and direct pathogen damage to the cardiovascular system [17]. This amount was lower than the cut-off of our study which predicted grades 2 and 3 diastolic dysfunctions as a poor outcome.

According to an article published in the European Heart Association in 2016, a cut-off point of 125, along with other anatomical and functional signs, was used to diagnose diastolic heart dysfunction. In patients with COVID-19, pro-BNP levels cannot be satisfied with the previous standard figures due to the possibility of high levels of infection, inflammation and hypoxia. It seems that a different cut-off point should be considered. Based on the results of this study, NT-pro BNP levels above 799 pg/ml were obtained to diagnose high-grade diastolic dysfunction in patients with severe COVID-19 [18]. The sensitivity of NT-pro BNP for the diagnosis of diastolic dysfunction in our study was 100% and it was an accurate screening test that in Lu Bien’s study [13] had a sensitivity of 85% for the diagnosis of diastolic dysfunction in non-COVID patients, this value in another study was reported to be 69% and NT-pro BNP was not recommended for screening diastolic dysfunction. However, this study was performed on people over 45 living in the community years before the COVID pandemic who were randomly included in the study [19].

In this study, we compared NT-pro BNP for the diagnosis of diastolic dysfunction in hospitalized patients with COVID-19 with echocardiographic indices as a routine non-invasive procedure. However, the standard for assessing diastolic heart function is to measure the pressure–volume relationship with a catheter, which is an invasive procedure. In our study, there was a positive correlation between NT-pro BNP levels and some echocardiographic parameters including RA_size, LVED, LV_Ee, and LV_E, and this indicates that as NT-proBNP levels increase, these indices also increase. Significant negative correlation between NT-pro BNP level and one of the echocardiographic parameters including LVEF increases with decreasing LVEF serum NT-pro BNP level number. According to this study, NT-pro BNP above 556 pg/ml in severe patients with COVID-19 has a predictive value of 97.2% for the presence of RV_EA > 2 and also NT-pro BNP above 556 pg/ml in these patients has a predictive value of 63.9% for the presence of LV_Ee > 4 in echocardiography. These two echocardiographic parameters indicate an increase in right heart filling pressure/s and due to the relationship between right heart pressure and left heart filling pressure/s and its relationship with pulmonary pressure, hypoxia and lung pressures, it seems that diastolic dysfunction of the right side of the heart begins at lower levels of NT-pro BNP.

According to other results from this study, if a person has an NT-pro BNP above 1479 pg/ml, LV_E would be greater than 50 cm for 100% (E wave velocity above 50). Given that the E-wave velocity showed a compression gradient between the atrium and the ventricle and depended on the left ventricular complication and left ventricular pressure, it could be said that NT-pro BNP above 1479 pg/ml should avoid volumetric and compressive overload. In this study, for every unit increase in SPAP, the chance of diastolic dysfunction increases by 22%. SPAP levels are associated with inflammation and hypoxia of the lungs and are also associated with increased and limited left-filling pressures. The limitations of this study included if it was an observational, single-center study with the inherent limitations of this type of design. The number of samples and the possibility of performing echocardiography were limited due to policies focused on the prevention of SARS-CoV-2 transmission.

Serum NT-pro BNP levels correlate strongly with HF severity. Higher levels indicate advanced disease and worse prognosis. NT-pro BNP is a valuable biomarker for guiding therapy and monitoring progression.

BNP and NT-pro BNP levels have become important diagnostic tools in the diagnosis and management of heart failure. Although NT-pro BNP testing has high sensitivity and specificity in the diagnosis of heart failure, the levels can be affected by many confounding factors such as age, renal function, anaemia and body mass. In our study it is observed that the NT-pro BNP levels increased with advancing age, as shown by several studies. There was a negative correlation between NT-pro BNP levels and LVEF. LA enlargement and LV hypertrophy were present in a majority of the studied population. Low e-GFR and low haemoglobin levels also showed negative correlation with NT-pro BNP levels. When interpreting NT-pro BNP levels, these factors have to be taken into account while making clinical decision and initiation of appropriate therapy.

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