Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients’ Characteristics
2.2. Determination of HFimpEF
2.3. Medical Information Collection
2.4. Examination of Hemodynamics
2.5. Glomerular Filtration Rate Calculation
2.6. Blood Sampling
2.7. Biomarker Evaluation
2.8. Cell-Free DNA Extraction
2.9. Measurement of Cell-Free DNA in Plasma Samples
2.10. Statistical Analysis
3. Results
3.1. General Clinical Characteristics of the Patients
3.2. The Dynamics of Circulating Biomarker Levels
3.3. The Reliability of Circulating Levels of cf-nDNA: The Results of the ROC Curve Analysis
3.4. The Predictors of HFimpEF: The Univariate and Multivariate Logistic Regressions
3.5. Comparison of the Models for HFimpEF
4. Discussion
5. Study Limitations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variables | Entire Patient Cohort (n = 452) | Patients with HFimpEF (n = 177) | Patients with Persistent HFrEF (n = 275) | p-Value |
---|---|---|---|---|
Demographic and anthropomorphic parameters | ||||
Age, year | 59 (50–68) | 59 (52–65) | 60 (49–72) | 0.48 |
Male/female n (%) | 266 (58.9)/186 (41.2) | 102 (57.6)/75 (42.3) | 164 (59.6)/111 (40.4) | 0.36 |
BMI, kg/m2 | 25.8 ± 3.5 | 25.1 ± 2.9 | 26.1 ± 2.7 | 0.44 |
Comorbidities and CV risk factors | ||||
Dyslipidemia, n (%) | 286 (63.2) | 115 (64.5) | 171 (62.2) | 0.77 |
Hypertension, n (%) | 71 (15.7) | 28 (15.8) | 43 (15.6) | 0.88 |
Ischemia-induced cardiomyopathy, n (%) | 141 (31.2) | 44 (24.9) | 97 (35.3) | 0.04 |
Dilated cardiomyopathy, n (%) | 68 (15.0) | 21 (11.9) | 47 (17.1) | 0.52 |
AF, n (%) | 137 (30.3) | 47 (26.6) | 90 (32.7) | 0.28 |
Smoking, n (%) | 168 (37.2) | 65 (36.7) | 103 (37.5) | 0.88 |
Abdominal obesity, n (%) | 112 (24.8) | 46 (26.0) | 66 (24.0) | 0.87 |
T2DM, n (%) | 146 (32.3) | 54 (30.5) | 92 (33.5) | 0.26 |
LVH, n (%) | 316 (69.9) | 120 (67.8) | 196 (71.3) | 0.44 |
CKD 1–3 grades, n (%) | 132 (29.2) | 45 (25.4) | 87 (31.6) | 0.42 |
Complete LBBB/RBBB on ECG, n (%) | 98 (21.7) | 35 (19.8) | 63 (22.9) | 0.18 |
CRT, n (%) | 13 (2.9%) | 5 (2.8%) | 8 (2.9%) | 0.94 |
NYHA functional classification | ||||
I/II HF NYHA classes, n (%) | 144 (31.9) | 71 (40.1) | 73 (26.6) | 0.001 |
III HF NYHA class, n (%) | 230 (50.8) p * = 0.022 | 85 (48.0) p * = 0.48 | 145 (52.7) p * = 0.018 | 0.06 |
IV HF NYHA class, n (%) | 78 (17.3) p * = 0.01; p ** = 0.024 | 21 (11.9) p * = 0.001; p ** = 0.001 | 57 (20.7) p * = 0.012; p ** = 0.46 | 0.036 |
Hemodynamic performances | ||||
SBP, mm Hg | 128 ± 11 | 129 ± 9 | 125 ± 10 | 0.22 |
DBP, mm Hg | 78 ± 10 | 77 ± 8 | 74 ± 9 | 0.64 |
LVEDV, mL | 171 (149–192) | 168 (136–188) | 181 (150–202) | 0.04 |
LVESV, mL | 115 (89–127) | 109 (87–124) | 126 (90–131) | 0.01 |
LVEF, % | 32 (29–39) | 35 (31–39) | 30 (27–34) | 0.02 |
LVMMI, g/m2 | 226 ± 15 | 218 ± 15 | 234 ± 13 | 0.46 |
LAVI, mL/m2 | 46 (39–52) | 44 (35–51) | 47 (39–54) | 0.12 |
E/e`, unit | 17.3 ± 5.4 | 16.6 ± 4.1 | 19.1 ± 3.3 | 0.56 |
Biochemistry parameters | ||||
eGFR, mL/min/1.73 m2 | 72 ± 11 | 80 ± 9 | 65 ± 7 | 0.04 |
Fasting glucose, mmol/L | 5.11 ± 0.77 | 5.06 ± 0.60 | 5.19 ± 1.1 | 0.66 |
Creatinine, µmol/L | 99.6 ± 12.8 | 78.9 ± 9.1 | 115.2 ± 8.2 | 0.04 |
TC, mmol/L | 5.88 ± 0.90 | 5.61 ± 0.52 | 5.92 ± 0.70 | 0.62 |
HDL-C, mmol/L | 0.97 ± 0.14 | 0.97 ± 0.15 | 0.98 ± 0.18 | 0.68 |
LDL-C, mmol/L | 3.93 ± 0.18 | 3.80 ± 0.17 | 4.00 ± 0.12 | 0.02 |
TGs, mmol/L | 1.98 ± 0.17 | 1.90 ± 0.12 | 2.03 ± 0.15 | 0.64 |
hs-CRP, mg/L | 9.68 (4.31–13.70) | 9.25 (3.45–12.70) | 10.70 (5.80–17.50) | 0.22 |
TNF-alpha, pg/mL | 3.24 (2.70–3.98) | 3.11 (2.62–3.69) | 3.43 (2.95–4.12) | 0.04 |
NT-proBNP, pmol/mL | 3228 (1910–5215) | 3015 (1780–5220) | 3290 (1820–5470) | 0.44 |
cf-nDNA, μmol/L | 11.6 (7.68–15.7) | 9.8 (7.2–12.2) | 14.1 (11.8–16.5) | 0.02 |
Concomitant medications | ||||
ACEI, n (%) | 198 (43.8) | 79 (44.6) | 119 (43.3) | 0.88 |
ARNI, n (%) | 134 (29.6) | 53 (29.9) | 81 (29.5) | 0.90 |
ARB, n (%) | 86 (19.0) | 35 (19.7) | 51 (18.5) | 0.82 |
Ivabradine, n (%) | 78 (17.3) | 28 (15.8) | 50 (18.2) | 0.56 |
Beta-blockers, n (%) | 426 (94.2) | 165 (93.2) | 261 (94.9) | 0.90 |
Calcium channel blocker, n (%) | 67 (14.8) | 23 (13.0) | 44 (16.0) | 0.44 |
MRA, n (%) | 405 (89.6) | 161 (91.0) | 244 (88.7) | 0.86 |
Digoxin, n (%) | 51 (11.3) | 14 (7.9) | 37 (13.5) | 0.010 |
Loop diuretic, n (%) | 412 (91.2) | 159 (89.8) | 253 (92.0) | 0.46 |
Antiplatelet, n (%) | 141 (31.2) | 54 (30.5) | 87 (31.6) | 0.84 |
Anticoagulants, n (%) | 139 (30.8) | 55 (31.1) | 84 (30.5) | 0.82 |
Metformin, n (%) | 138 (30.5) | 54 (30.5) | 84 (31.0) | 0.86 |
SGLT2 inhibitors, n (%) | 434 (96.0) | 175 (98.9) | 259 (94.2) | 0.86 |
Statins, n (%) | 350 (77.4) | 139 (78.5) | 211 (76.7) | 0.88 |
Dependent Variable: HFimpEF | ||||
---|---|---|---|---|
Variables | Univariate Logistic Regression | Multivariate Logistic Regression | ||
OR (95% CI) | p-Value | OR (95% CI) | p-Value | |
Ischemia-induced cardiomyopathy (presence vs. absent) | 0.75 (0.62–0.88) | 0.044 | 0.77 (0.60–0.90) | 0.042 |
IV HF NYHA class | 0.71 (0.57–0.92) | 0.001 | 0.76 (0.63–0.87) | 0.001 |
T2DM (presence vs. absent) | 0.77 (0.71–0.82) | 0.040 | 0.84 (0.62–0.92) | 0.042 |
CKD (presence vs. absent) | 0.89 (0.84–0.96) | 0.048 | 0.88 (0.80–0.10) | 0.050 |
AF (presence vs. absent) | 0.94 (0.80–1.09) | 0.064 | - | |
LVEDV | 0.93 (0.90–1.01) | 0.052 | - | |
LAVI | 0.95 (0.92–0.98) | 0.042 | 0.96 (0.90–1.00) | 0.050 |
E/e` | 0.92 (0.89–0.97) | 0.080 | - | |
NT-proBNP (≤1940 pmol/mL vs. >1940 pmol/mL) | 1.42 (1.19–1.98) | 0.001 | 1.35 (1.12–1.76) | 0.001 |
Relative decrease in NT-proBNP levels (>35% vs. ≤35%) from baseline | 1.67 (1.51–1.82) | 0.001 | 1.70 (1.61–1.83) | 0.001 |
TNF-alpha (≤2.88 pg/mL vs. >2.88 pg/mL) | 1.06 (1.00–1.12) | 0.48 | - | |
hs-CRP (≤7.02 mg/L vs. >7.02 mg/L) | 1.08 (1.00–1.17) | 0.60 | - | |
cf-nDNA (≤7.5 μmol/L vs. >7.5 μmol/L) | 1.56 (1.07–2.94) | 0.001 | 1.64 (1.10–2.07) | 0.001 |
Digoxin (presence vs. absent) | 0.85 (0.72–0.97) | 0.042 | 0.93 (0.86–1.00) | 0.052 |
Predictive Models | AUC | NRI | IDI | |||
---|---|---|---|---|---|---|
M (95% CI) | p-Value | M (95% CI) | p-Value | M (95% CI) | p-Value | |
Model 1 (ischemia-induced CMP) | 0.766 (0.712–0.836) | - | Reference | - | Reference | - |
Model 2 (IV NYHA class) | 0.771 (0.720–0.811) | 0.260 | 0.12 (0.10–0.15) | 0.360 | 0.11 (0.09–0.13) | 0.520 |
Model 3 (NT-proBNP ≤ 1940 pmol/mL) | 0.783 (0.700–0.840) | 0.144 | 0.18 (0.12–0.23) | 0.196 | 0.17 (0.12–0.23) | 0.280 |
Model 3 (relative decrease in NT-proBNP levels ≤ 35% from baseline) | 0.795 (0.745–0.861) | 0.06 | 0.23 (0.17–0.30) | 0.170 | 0.21 (0.18–0.25) | 0.240 |
Model 4 (cf-nDNA ≤ 7.5 μmol/L) | 0.875 (0.795–0.950) | 0.001 | 0.54 (0.43–0.67) | 0.001 | 0.51 (0.45–0.58) | 0.001 |
Model 5 (NT-proBNP levels ≤ 1940 pmol/mL + cf-nDNA) | 0.872 (0.820–0.941) | 0.001 | 0.48 (0.42–0.55) | 0.001 | 0.49 (0.41–0.56) | 0.001 |
Model 6 (relative decrease in NT-proBNP levels ≤ 35% from baseline + cf-nDNA) | 0.893 (0.844–0.962) | 0.001 | 0.58 (0.45–0.72) | 0.001 | 0.55 (0.49–0.62) | 0.001 |
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Berezina, T.; Berezin, O.O.; Lichtenauer, M.; Berezin, A.E. Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction. Cardiogenetics 2024, 14, 183-197. https://doi.org/10.3390/cardiogenetics14040014
Berezina T, Berezin OO, Lichtenauer M, Berezin AE. Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction. Cardiogenetics. 2024; 14(4):183-197. https://doi.org/10.3390/cardiogenetics14040014
Chicago/Turabian StyleBerezina, Tetiana, Oleksandr O. Berezin, Michael Lichtenauer, and Alexander E. Berezin. 2024. "Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction" Cardiogenetics 14, no. 4: 183-197. https://doi.org/10.3390/cardiogenetics14040014