European Journal of Cardiovascular Medicine

Chronic obstructive pulmonary disease (COPD) remains a significant global health challenge, ranking as the fourth leading cause of death worldwide. In 2021 alone, COPD was responsible for 3.5 million deaths, accounting for approximately 5% of all global fatalities. The burden of COPD disproportionately affects low- and middle-income countries (LMIC), where nearly 90% of deaths in individuals under 70 years occur, underscoring significant disparities in healthcare access and prevention strategies.

NT-proBNP, a peptide biomarker synthesized and secreted by cardiomyocytes in response to cardiac load, has gained attention in recent years for its potential role in respiratory diseases. Chronic Obstructive Pulmonary Disease (COPD), a chronic and progressive inflammatory condition affecting the respiratory system, is frequently associated with comorbidities involving the cardiovascular system ^[1].

Adding to the complexity, structural and functional changes in the heart that occur secondary to COPD can obscure the presence of underlying cardiac dysfunction. Chronic hypoxia, a common feature of advanced COPD, induces pulmonary hypertension, which can lead to right ventricular hypertrophy and eventual right-sided heart failure. These changes may present with clinical and echocardiographic findings that resemble primary cardiac conditions, such as cor pulmonale or even biventricular dysfunction in severe cases ^[2].

For these challenges, the availability of accurate, non-invasive diagnostic tools is paramount for the early identification of cardiac complications in COPD patients. Biomarkers like NT-proBNP offer valuable insights into cardiac stress and function, while advanced imaging modalities, such as echocardiography, provide a detailed assessment of cardiac structure and performance. When used together, these can help differentiate between respiratory and cardiac contributions to symptoms, enabling timely interventions. Moreover, combining these diagnostic approaches into routine clinical practice can improve outcomes by facilitating early detection and tailored management of cardiac dysfunction in COPD^[3].

High prevalence of a 10-year cardiovascular risk by more than 20% was found in COPD patients aged 55–74 than the general population^[4] Reduced left ventricular filling in patients with COPD and hyperinflation is a treatable trait, as lung deflation with either pharmacological or bronchoscopic lung volume reduction improves cardiac function indicated by an increase in the left ventricle (LV) size^[5]. NT-proBNP is associated with systolic as well as diastolic left ventricular (LV) dysfunction, and low levels in such patients can rule out LV failure^[6].

A cross-sectional observational study was conducted at Dr. D. Y. Patil Medical College Hospital and Research Institute in Kolhapur, Maharashtra, a Tertiary care center. Over a two-year period from January 2023 to January 2025. study subjects were selected according to inclusion and exclusion criteria. Inclusion criteria: Clinically and Spirometrically Diagnosed COPD cases, Age > 18 years.

exclusion criteria:Not willing to give consent, patients with previous Myocardial infarction, valve replacement, rheumatic heart disease, congenital heart disease, cardiomyopathy, patients having known history of pre-existing renal disease (chronic kidney disease), patients having known history of additional lung pathology such as ILD, cystic fibrosis.

METHODOLOGY

The methodology involved an assessment of each patient’s COPD status, confirmed through spirometry, which included the FEV₁/FVC ratio <0.7 and predicted FEV₁. Patients were classified according to the GOLD 2023 criteria, which categorized severity into GOLD 1, GOLD 2, GOLD 3, GOLD 4, depending on the FEV₁/FVC ratio <0.7 and predicted FEV₁ values.

NT-proBNP levels were assessed with cutoffs set at 125 pg/mL for individuals younger than 75 years and 450 pg/mL for those who were older than 75 years to evaluate cardiac dysfunction. The above cut-off values were uniform for both sexes.

Echocardiographic Assessment

All patients underwent transthoracic echocardiography using a standard echocardiography machine Fujifilm Sonosite M-turbo Q5WP35

The following parameters were assessed: Right Ventricular systolic dysfunction using Tricuspid Annular Plane Systolic Excursion (TAPSE) in M- mode, values <16 mm indicating RV systolic dysfunction. Right Ventricular systolic dysfunction was characterized by an ejection fraction of less than 50%. Left Ventricular Systolic dysfunction: Left Ventricular Ejection Fraction (LVEF%) calculated using Simpson's biplane method. Left ventricular systolic dysfunction was characterized by an ejection fraction of less than 50%.

Left Ventricular Diastolic dysfunction:

Mitral inflow velocities (E wave and A wave) using pulsed-wave Doppler. E/A ratio < 1 indicates diastolic dysfunction. Tissue Doppler imaging (TDI) of the mitral annulus (e' velocity). Septal e′ < 7 cm/s or Lateral e′ < 10 cm/s indicates impaired LV relaxation. E/e' ratio. Ratio <8 indicates normal LV filling pressure and Ratio more than ≥ 15 indicates increased LV filling pressure (diastolic dysfunction)

Table 1: Demographic characteristics and Echocardiographic Right ventricular systolic and left ventricular systolic diastolic function with COPD Grades according to NT-proBNP Levels.

The study included 71 COPD patients, of which 60 had elevated NT-proBNP levels and 11 had normal levels. The mean age and gender distribution were similar between the groups, though a statistically significant difference was noted in gender proportions (p<0.001), possibly due to the small normal NT-proBNP subgroup.

Echocardiographic parameters such as RVEF%, TAPSE, showed significant differences in Higher NT-proBNP LEVEL Patients suggestive of Right Ventricular Systolic dysfunction in Higher COPD Grades.

Significantly lower LVEF% observed in higher NT-proBNP group suggestive of Left Ventricular dysfunction in higher grades of COPD.

Significantly lower E/A ratio and lower early diastolic mitral annular velocity (e') was observed in patients with High NT-proBNP levels, suggesting left ventricular diastolic dysfunction.

Figure 1: Bar diagram showing Distribution of Gender across NT-proBNP Levels

The bar chart depicts the gender distribution across NT-proBNP levels, showing that among patients with normal NT-proBNP levels, 15.80% were male and 15.2% were female, while in the High NT-proBNP group, 84.2% were male and 84.4% were female.

Figure 2: Bar diagram showing Distribution of Right Ventricular Systolic Function across NT-proBNP Levels.

RVEF% remains significantly different between the groups (60.91% in normal vs. 51.73% in High NT-proBNP Group), indicating significant reduction in right ventricular systolic function in High NT-proBNP Groups suggestive of Right ventricular systolic dysfunction in High NT-proBNP levels.

Figure 3: Bar diagram showing Distribution of Right Ventricular Systolic Function across NT-proBNP Levels.

The bar chart illustrates the distribution of key echocardiographic parameters across NT-proBNP levels. It shows difference in TAPSE values between groups (2.03 in Normal NT-proBNP VS 1.72 in Higher NT-proBNP ) suggestive of significant reduction TAPSE in High NT-proBNP levels i.e. more severe RV Systolic Dysfunction in High NT-proBNP group.

Figure 4: Bar diagram showing Distribution of Left Ventricular Systolic Function across NT-proBNP Levels.

LVEF% is significantly lower in the High NT-proBNP group (57.03%) compared to the normal group (63.73%), suggesting a reduction in left ventricular systolic function in individuals with elevated NT-proBNP levels.

Figure 5: Bar diagram showing Distribution of Left Ventricular Diastolic Function across NT-proBNP Levels.

E/A ratio in the High NT-proBNP group is 0.92 vs 1.36 in normal NT-proBNP suggestive of impaired relaxation in Higher NT-proBNP group and more diastolic dysfunction in Higher NT-proBNP group.

E/e' ratio, an indicator of left ventricular filling pressure, is slightly elevated in the High NT-proBNP group (12.13 vs. 9.38), indicating possibly left ventricular diastolic dysfunction in High NT-proBNP Group.

The e' velocity, reflecting diastolic relaxation, is lower in the High NT-proBNP group (7.7 vs. 9.23), supporting impaired myocardial relaxation. Overall, the pattern suggests that elevated NT-proBNP is associated with worsening diastolic function.

Figure 6: Bar diagram showing Distribution of COPD Severity across NT-proBNP Levels

The bar chart displays the distribution of COPD severity (as per GOLD staging) across Normal and High NT-proBNP levels.

COPD GOLD class 1 have all normal NT-proBNP And COPD GOLD Class 2 11.1% have Normal NT-proBNP Levels and 88.9% have Higher NT-proBNP levels. COPD GOLD Class 3 and Class 4 have 100% High NT-proBNP levels.

This suggests that higher NT-proBNP levels are associated with more severe COPD, reflecting increased cardiopulmonary strain as COPD severity advances.

Figure 7: Bar diagram showing Distribution of Risk Factor across NT-proBNP Levels

The bar chart shows the distribution of smoking status as a risk factor across NT-proBNP levels. In the Normal NT-proBNP group 17.9% was Non Smoker and 12.5% was Smoker.

In the High NT-proBNP group 82.1% was Non Smoker and 87.5% was Smoker

This suggests that smoking status percentage was slightly higher in High NT-proBNP Groups.

The statistical analysis revealed no significant difference in age between patients with normal and High NT-proBNP levels.When evaluating echocardiography findings, patients with High NT-proBNP levels demonstrated significantly reduced RVEF%, TAPSE, LVEF%, E/A ratio, and (all p<0.05), suggesting impaired cardiac function. The E/e' ratio, although higher in the High NT-proBNP group, did not show a statistically significant difference (p=0.184).

In terms of COPD severity, Higher NT-proBNP levels were significantly associated with more advanced GOLD stages. Notably, all patients in GOLD stages 3 and 4 had High NT-proBNP , with a significant trend observed across severity levels (p<0.05).

Table 2: Echocardiography Findings (Right ventricular systolic function and Left ventricular systolic and diastolic function) according to COPD Severity:

*Indicates significance (p value<0.05), here significance is tested for Gold 2 and Gold 3 only.

This table presents echocardiographic Right ventricular systolic function and Left ventricular systolic and diastolic function findings categorized by COPD severity according to GOLD staging.

Right Ventricular Systolic Function : As COPD severity increased from GOLD 1 to GOLD 4, a progressive decline was observed in right ventricular ejection fraction (RVEF%), with significant differences across groups (p=0.001), indicating worsening right ventricular function.

Similarly, tricuspid annular plane systolic excursion (TAPSE) significantly declined with increasing severity (p=0.001), further reflecting compromised right ventricular systolic performance.

Left Ventricular Systolic Function : Left ventricular ejection fraction (LVEF%) also decreased significantly in GOLD 4 class (p<0.001), suggesting biventricular involvement in advanced COPD.

Left Ventricular Diastolic Function : E/e' Ratio increases in advanced COPD grades and E/A ratio showed a significant downward trend (p=0.022), implying progressive diastolic dysfunction. The early diastolic mitral annular velocity (e) also trended lower with increasing severity with statistical significance (p=0.001).

Figure 8

Figure 8, 9: Line graph showing Distribution of COPD Severity wise RV SYSTOLIC FUNCTION. (RVEF%, TAPSE)

The line graph compares right ventricular systolic function between GOLD 1 to GOLD 4 COPD severity groups. It shows that patients with GOLD 4 severity exhibit worse cardiac function parameters:

RVEF% in COPD Class 4 was significantly lower than class 1 (41% vs 65.2%)

TAPSE IN COPD Class 4 was significantly lower than class 1 (1.03 vs 2.32)

suggestive of Right ventricular systolic function worsens as severity of COPD increases.

Figure 10: Line graph showing Distribution of COPD Severity wise LV SYSTOLIC FUNCTION.

LVEF% IN COPD Class 4 was significantly lower than class 1 (44.5% vs 66%) suggestive of Left ventricular systolic function worsens as severity of COPD increases.

Figure 11

Figure 12

Figure 13

Figure 11, 12 and 13: Line graph showing Distribution of COPD Severity wise LV DIASTOLIC FUNCTION.

Higher E/e' ratio In COPD GOLD Class 4 than Class 1 (23.32 vs. 11.77), suggesting elevated left ventricular filling pressure in GOLD class 4 than GOLD class 1.

Lower E/A ratio (1.90 vs. 0.51), indicating impaired LV filling in GOLD class 4 than GOLD class 1. Indicated impaired diastolic function in GOLD Class 4 than GOLD Class 1.

Reduced e' velocity (4.54 vs. 10.47), reflecting poor myocardial relaxation and more diastolic dysfunction in GOLD 4 than GOLD 1 Class.

Overall analysis of echocardiography parameters across COPD severity levels showed a significant deterioration in cardiac function with increasing disease severity. RVEF%, TAPSE, LVEF%, E/A ratio, and e' velocity progressively declined from GOLD 1 to GOLD 4, while the E/e' ratio increased significantly (all p<0.001), indicating worsening cardiac function with disease progression. Overall, it suggests as severity of copd increases from gold 1 to gold 4 left ventricle diastolic function worsens.

Table 3: Correlation between NT-proBNP and RV systolic, LV systolic and diastolic function:

 *Indicates significance (p value<0.05)

Figure 14: Correlation analysis supported these findings, showing strong negative correlations between NT-proBNP levels and RVEF% (r = -0.745), TAPSE, LVEF%, E/A, and e', and a positive correlation with the E/e' ratio (r = 0.408), all statistically significant at p<0.001. These results suggest that elevated NT-proBNP levels are closely linked with impaired biventricular function in COPD patients and may serve as a useful marker for disease severity and cardiac involvement.

In our study, a significant correlation with reduced right ventricular ejection fraction (RVEF%) was observed (p < 0.001) in the higher NT-proBNP group. Echocardiographic parameters such as RVEF% (p < 0.001) and TAPSE (p = 0.016) showed significant differences in patients with higher NT-proBNP levels, indicating right ventricular dysfunction in higher grades of COPD. Significantly lower LVEF% (p = 0.034) was observed in the higher NT-proBNP group, suggestive of left ventricular dysfunction in advanced COPD.

A significantly lower E/A ratio (p = 0.036), a higher E/e′ ratio (p = 0.184), and a lower early diastolic mitral annular velocity (e′) (p < 0.001) were observed in patients with high NT-proBNP levels, suggesting left ventricular diastolic dysfunction.

RV DYSFUNCTION:

Su XJ, Lei T, Yu HC, Zhang L et al., Conducted Studies investigating NT- proBNP and pulmonary hypertension (a common cause of RV strain in COPD) demonstrated stronger associations, with SMD values of 0.82 (95% CI: 0.69– 0.96; p < 0.0001) ^[1].

LV DYSFUNCTION: Chen et al. (2017) involving 209 patients hospitalized with acute exacerbation of chronic bronchitis (AECB), the diagnostic utility of NT-proBNP in detecting left ventricular systolic dysfunction (LVSD) was evaluated.

Patients with LVSD had significantly higher NT-proBNP levels (mean 3,303 pg/mL) compared to those without LVSD (1,092 pg/mL), with a highly significant p-value (p = 0.0001). Using a cutoff value of 1,505 pg/mL, the test achieved 76.6% sensitivity and 83.3% specificity ^[7]

Echocardiography and COPD Severity (GOLD Stages)

In our study, a progressive and statistically significant decline in right ventricular systolic and left ventricular systolic diastolic function was observed with increasing severity of Chronic Obstructive Pulmonary Disease (COPD)

Sulaiman et al. (2023) conducted study on patients (GOLD I–IV) suggestive of E/A ratio declined from Stage I to IV (1.04 → 0.72, p = 0.024) LV diastolic dysfunction and mild RV dilation found in advanced stages. ^[8]

NT-proBNP Changes Across COPD Severity (GOLD Stages)

In our study COPD GOLD class 1 have all normal NT-proBNP levels and COPD GOLD Class 2 11.1% have Normal NT-proBNP Levels and 88.9% have Higher NT-proBNP levels.

COPD GOLD Class 3 and Class 4 have 100% High NT-proBNP levels.

This suggests that higher NT-proBNP levels are associated with more severe COPD, reflecting increased cardiopulmonary strain as COPD severity advances.

Meta-analytic Evidence

A meta-analysis by Zhou et al., analyzing data from 29 studies and 8,534 patients, confirmed that NT-proBNP levels were significantly higher in patients with more severe airflow obstruction (FEV₁ < 50%). The standardized mean difference (SMD) was 0.17 (P = 0.0058). ^[9]

SPIROMICS cohort study (Wang et al., 2018) involving 1,051 GOLD stage 1– 4 COPD patients demonstrated that higher baseline NT-proBNP independently predicted exacerbations over one year, with an incident rate ratio (IRR) of 1.13 per standard deviation increase (95% CI: 1.06–1.19, P < 0.0001), even after adjusting for cardiac comorbidities. ^[10]

This study demonstrates that NT-proBNP is a sensitive and valuable biomarker for detecting cardiac dysfunction in COPD patients. It significantly correlates with GOLD COPD stages, and echocardiographic indices of Right ventricular Systolic function TAPSE and RVEF% And left ventricular systolic and diastolic function LVEF% and E/A Ratio,E/e' Ratio e' respectively. Echocardiographic changes across COPD severity reflect progressive cardiac involvement, validating the role of echocardiography. However, technical limitations due to lung hyperinflation must be acknowledged.

In conclusion, a dual-modality approach combining NT-proBNP and echocardiography enhances diagnostic precision, supports early identification of at- risk patients, and provides a framework for management in COPD patients with suspected cardiac dysfunction.

LIMITATION

1. Single-center study, limiting generalizability
2. Small sample size in the normal NT-proBNP group (n=11), limiting subgroup comparisons

1. Su XJ, Lei T, Yu HC, Zhang L, Feng ZZ, Shuai TK, et al. NT-proBNP in different patient groups of COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2023;18:811-25. doi:10.2147/COPD.S396663.
2. Zangiabadi A, De Pasquale CG, Sajkov D. Pulmonary hypertension and right heart dysfunction in chronic lung disease. Biomed Res Int. 2014;2014:739674. doi:10.1155/2014/739674.
3. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail. 2009;11(2):130-9. doi:10.1093/eurjhf/hfn013.
4. AboEl-Magd GH, Hassan T, Aly MH, Mabrouk MM. Echocardiography and N-terminal pro-brain natriuretic peptide in assessment of left ventricular diastolic dysfunction in stable COPD in relation to disease severity. Egypt J Chest Dis Tuberc. 2017;66(1):9-14. doi:10.1016/j.ejcdt.2016.08.010.
5. Abdo M, Watz H, Alter P, Kahnert K, Trudzinski F, Groth EE, et al.; COSYCONET Cohort. Characterization and mortality risk of impaired left ventricular filling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2023;207(10):1236-46. doi:10.1164/rccm.202208-1361OC.
6. Cavefors O, Einarsson F, Holmqvist J, Bech-Hanssen O, Ricksten SE, Redfors B, et al. Cardiac biomarkers for screening and prognostication of cardiac dysfunction in critically ill patients. ESC Heart Fail. 2024;11(6):4009-18. doi:10.1002/ehf2.14980.
7. Chen YC, Chen CR, Hsu WH, Chen CY, Chen CF, Hsu CW, et al. Utility of NT-proBNP for identifying LV failure in acute exacerbation of chronic bronchitis. Int J Chron Obstruct Pulmon Dis. 2017;12:471-8. doi:10.2147/COPD.S124180.
8. Sulaiman A, Singh S, Sahoo S, Sharma A. Assessing cardiac function in chronic obstructive pulmonary disease patients through echocardiography: a correlation with disease severity. Healthc Bull. 2023;5(3):147-52.
9. Zhou L, Liu X, Xu D, Xu H, Xu X, Zhang Y, et al. Prognostic value of NT-proBNP in chronic obstructive pulmonary disease: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2023;18:1345-56. doi:10.2147/COPD.S414799.
10. Wang X, Wells JM, Dransfield MT, Bhatt SP. Association between NT-proBNP and incident exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(7):980-3. doi:10.1164/rccm.201802-0247LE.