Figure 1:
Figure 2:
Figure 3:
Figure 4:
Stepwise multivariable Cox analysis for all-cause long-term mortality
| Independent predictors for all-cause long-term mortality | |||||
|---|---|---|---|---|---|
| Men | Women | ||||
| HR* (95%CI) | p value | HR** (95%CI) | p value | ||
| Hemoglobin (per 1g/dl) | 0.88 (0.78 – 0.98) | 0.021 | Age (per 1 year) | 1.05 (1.02 – 1.09) | 0.003 |
| LnNT-proBNP (per 1 unit) | 1.28 (1.03 – 1.59) | 0.025 | LnNT-proBNP (per 1 unit) | 1.22 (1.01 – 1.47) | 0.035 |
| hs-TnT > 19.04 pg/mL | 1.91 (1.07 – 3.41) | 0.029 | hs-TnT > 15.83 pg/mL | 3.54 (2.07 – 6.07) | < 0.001 |
Baseline characteristics for outcome sex-specific hs-TnT cut-off groups in men and women_
| A. Categorical variables | ||||||||
|---|---|---|---|---|---|---|---|---|
| Men | Women | |||||||
| Variable | hs-TnT <19.02 pg/mL n (%) | hs-TnT ≥19.02 pg/mL n (%) | OR (95% CI) | p | hs-TnT <15.83 pg/mL n (%) | hs-TnT ≥15.83 pg/mL n (%) | OR (95% CI) | p |
| Heart failure characteristics | ||||||||
| NYHA III and IV | 38 (39.20 %) | 55 (64.00 %) | 2.75 (1.51–5.03) | 0.001 | 66 (48.18 %) | 60 (71.43 %) | 2.69 (1.51 –4.80) | 0.001 |
| Clinical congestion | 25 (25.80 %) | 48 (55.80 %) | 3.64 (1.95–6.78) | <0.0 01 | 39 (28.47 %) | 45 (53.57 %) | 2.90 (1.64 –5.11) | <0.0 01 |
| Hospitalization outcome | ||||||||
| Extended stay (>7 days) | 16 (16.50 %) | 36 (41.90 %) | 3.65 (1.84–7.24) | <0.0 01 | 12 (8.76 %) | 33 (40.24 %) | 7.02 (3.35 –14.68) | <0.0 01 |
| Comorbidities and risk factors | ||||||||
| Hypertension | 76 (78.40 %) | 65 (75.60 %) | 0.86 (0.43–1.70) | 0.657 | 117 (85.40 %) | 67 (79.76 %) | 0.67 (0.33 –1.37) | 0.276 |
| COPD | 9 (9.30 %) | 7 (8.10 %) | 0.87 (0.31–2.44) | 0.785 | 0 (0.00 %) | 3 (3.57%) | Not estimable | 0.054* |
| Prior stroke | 7 (7.20 %) | 13 (15.10 %) | 2.29 (0.87–6.04) | 0.087 | 15 (10.95 %) | 14 (16.67 %) | 1.63 (0.74 –3.57) | 0.222 |
| Atrial fibrillation | 45 (46.40 %) | 42 (48.80 %) | 1.10 (0.62–1.97) | 0.741 | 59 (43.07 %) | 45 (53.57 %) | 1.53 (0.88 –2.63) | 0.129 |
| Ischemic heart disease | 51 (52.60 %) | 40 (46.50 %) | 0.78 (0.44–1.40) | 0.413 | 53 (38.69 %) | 32 (38.10 %) | 0.98 (0.56 –1.71) | 0.930 |
| Prior myocardial infarction | 36 (37.10 %) | 32 (37.20 %) | 1.00 (0.55–1.83) | 0.989 | 22 (16.06 %) | 16 (19.05 %) | 1.23 (0.60 –2.50) | 0.568 |
| Type 2 diabetes | 30 (30.90 %) | 30 (34.90 %) | 1.20 (0.65–2.22) | 0.569 | 39 (28.47 %) | 32 (38.10 %) | 1.55 (0.87 –2.75) | 0.137 |
| Obesity | 42 (43.30 %) | 32 (37.20 %) | 0.78 (0.43–1.40) | 0.402 | 69 (50.36 %) | 34 (40.48 %) | 0.67 (0.39 –1.16) | 0.15 3 |
| Peripheral artery disease | 11 (11.30 %) | 10 (11.60 %) | 1.03 (0.41–2.56) | 0.951 | 7 (5.11 %) | 5 (5.95%) | 1.18 (0.36 –3.83) | 0.769* |
| Chronic kidney disease | 41 (42.30 %) | 58 (67.40 %) | 2.83 (1.55–5.18) | 0.001 | 64 (46.72 %) | 66 (78.57%) | 4.18 (2.25 –7.77) | <0.0 01 |
| Echocardiographic characteristics | ||||||||
| Severe aortic stenosis | 1 (1.00%) | 1 (1.20%) | 1.13 (0.07–18.34) | 1.000* | 0 (0.00%) | 4 (4.76%) | Not estimable | 0.020* |
| Severe aortic regurgitation | 0 (0.00%) | 2 (2.30%) | Not estimable | 0.219* | 0 (0.00%) | 3 (3.57%) | Not estimable | 0.054* |
| Severe mitral regurgitation (grade 3–4) | 8 (8.20%) | 17 (19.80 %) | 2.74 (1.12–6.72) | 0.024 | 10 (7.30%) | 22 (26.19%) | 4.51 (2.01–10.10) | <0.001 |
| Severe tricuspid regurgitation | 9 (9.30%) | 13 (15.10 %) | 1.74 (0.70–4.30) | 0.226 | 13 (9.49%) | 22 (26.19%) | 3.38 (1.60 –7.17) | 0.001 |
| Pulmonary hypertension | 36 (37.10 %) | 49 (57.00 %) | 2.24 (1.24–4.06) | 0.007 | 58 (42.34 %) | 52 (61.90%) | 2.21 (1.27 –3.86) | 0.005 |
| Pericardial effusion | 5 (5.20%) | 4 (4.70%) | 0.90 (0.23–3.46) | 1.000* | 8 (5.84%) | 10 (11.90%) | 2.18 (0.82–5.76) | 0.110 |
| Biological characteristics | ||||||||
| eGFR <60 mL/min/1.73 m2 | 15 (15.50 %) | 37 (43.00 %) | 4.13 (2.06–8.28) | <0.001 | 34 (24.82 %) | 47 (55.95%) | 3.85 (2.16–6.87) | <0.001 |
Independent parameters associated with increased hs-TnT - Multivariable analysis
| Men hs-TnT > 19.02 pg/mL | Women hs-TnT > 15.83 pg/mL | ||||
|---|---|---|---|---|---|
| HR* (95%CI) | p value | HR** (95%CI) | p value | ||
| Clinical congestion | 2.24 (1.16 – 5.07) | 0.019 | Age | 1.08 (1.02 – 1.14) | 0.005 |
| LnNT-proBNP | 3.30 (1.42 – 7.67) | 0.005 | LnNT-proBNP | 4.22 (2.02 – 8.81) | < 0.001 |
| eGFR | 0.97 (0.95 – 0.99) | 0.001 | eGFR | 0.98 (0.96 – 0.99) | 0.016 |
| LVEF | 0.96 (0.93 – 0.99) | 0.027 | |||
General characteristics for male and female patients
| Demographics and risk factors | Entire group (n=404) | Female (n=221) | Male (n=183) | p value* |
|---|---|---|---|---|
| General characteristics | ||||
| Age (years) | 71.87 (±10.06) | 74.24 (±8.93) | 69.00 (±10.61) | <0.001 |
| Systolic BP (mmHg) | 144.77 (±29.14) | 147.29 (±30.53) | 141.80 (±27.21) | 0.077 |
| Dyastolic BP (mmHg) | 81.39 (±13.62) | 82.44 (±13.59) | 80.15 (±13.60) | 0.115 |
| Heart rate (bpm) | 85.01 (±25.63) | 85.60 (±26.32) | 84.28 (±24.79) | 0.624 |
| Heart failure characteristics | ||||
| HFrEF | 129 (31.9%) | 50 (22.6%) | 79 (43.2%) | <0.001 |
| HFmrEF | 121 (30.0%) | 69 (31.2%) | 52 (28.4%) | |
| HFpEF | 152 (37.6%) | 102 (46.2%) | 50 (27.3%) | |
| NYHA class III | 243 (60.1%) | 134 (60.6%) | 109 (59.6%) | 0.827 |
| NYHA class IV | 58 (14.5%) | 32 (14.5%) | 26 (14.5%) | 0.995 |
| Hospitalization outcome | ||||
| Length of stay (days) | 6.00 [5.00–8.00] | 6.00 [4.00–8.00] | 6.00 [5.00–9.75] | 0.498 |
| Extended stay | 97 (24.1%) | 45 (20.5%) | 52 (28.4%) | 0.066 |
| All cause mortality | 149 (36.9%) | 78 (35.3%) | 71 (38.8%) | 0.467 |
| Comorbidities and risk factors | ||||
| Arterial Hypertension | 325 (80.4%) | 184 (83.3%) | 141 (77.0%) | 0.117 |
| COPD | 19 (4.7%) | 3 (1.4%) | 16 (8.7%) | <0.001 |
| History of stroke | 49 (12.1%) | 29 (13.1%) | 20 (10.9%) | 0.501 |
| Atrial fibrillation | 191 (47.3%) | 104 (47.1%) | 87 (47.5%) | 0.923 |
| Ischemic heart disease | 176 (43.6%) | 85 (38.5%) | 91 (49.7%) | 0.023 |
| Prior myocardial infarction | 106 (26.2%) | 38 (17.2%) | 68 (37.2%) | <0.001 |
| Chronic kidney disease | 229 (56.7%) | 130 (58.8%) | 99 (54.1%) | 0.340 |
| Type 2 Diabetes Mellitus | 131(32.4%) | 71 (32.1%) | 60 (32.8%) | 0.888 |
| Obesity | 177 (43.8%) | 103 (46.6%) | 74 (40.4%) | 0.213 |
| Thyroid dysfunction | 36 (8.9%) | 30 (13.6%) | 6 (3.3%) | 0.003 |
| Echocardiographic characteristics | ||||
| LVEF | 42.06 (±12.48) | 44.59 (±11.54) | 39.12 (±12.91) | <0.001 |
| Severe aortic stenosis | 6 (1.5%) | 4 (1.8%) | 2 (1.1%) | 0.553 |
| Severe aortic regurgitation | 5 (1.2%) | 3 (1.4%) | 2 (1.1%) | 0.811 |
| Severe mitral regurgitation | 57 (14.1%) | 32 (14.5%) | 25 (13.7%) | 0.814 |
| Pulmonary hypertension | 195 (48.3%) | 110 (49.8%) | 85 (46.4%) | 0.505 |
| Pericardial effusion | 27 (6.7%) | 18 (8.1%) | 9 (4.9%) | 0.196 |
| Aortic atheromatosis | 151 (37.4%) | 95 (43.0%) | 56 (30.6%) | 0.036 |
| Biological characteristics | ||||
| Haemoglobin (g/dl) | 13.13 (±1.91) | 12.61 (±1.70) | 13.77 (±1.98) | <0.001 |
| ESR (mm/h) | 19.00 [8.75–34.00] | 20.50 [10.00–33.25] | 17.50 [7.00–34.00] | 0.020 |
| Serum Na (mmol/L) | 139.65 (±7.94) | 140.05 (±4.56) | 139.15 (±10.75) | 0.262 |
| Serum K (mmol/L) | 4.36 (±0.50) | 4.34 (±0.55) | 4.38 (±0.43) | 0.469 |
| eGFR (ml/min/1.73 m2) | 71.92 [55.06–88.75] | 66.16 [49.09–84.39] | 78.29 [57.35–89.37] | 0.026 |
| Glycemia (mg/dL) | 107.50 [94.00–134.50] | 111.50 [98.00–139.25] | 105.00 [88.75–126.75] | 0.401 |
| Total cholesterol (mg/dL) | 163.80 [137.00–207.25] | 172.75 [140.75–223.15] | 155.00 [127.35–190.75] | 0.010 |
| AST (UI/L) | 21.50 [17.47–28.57] | 21.00 [17.07–28.22] | 21.60 [17.62–28.72] | 0.264 |
| ALT (UI/L) | 18.10 [14.00–26.15] | 17.50 [13.45–24.85] | 19.90 [14.12–31.55] | 0.030 |
| NT-proBNP (ng/L) | 1687.50 [622.20–4319.75] | 1607.50 [504.62–3860.75] | 1777.50 [766.77–4859.00] | 0.595 |
| hs-TnT (pg/mL) | 17.06 [10.43–29.42] | 14.18 [9.21–25.25] | 22.44 [12.77–33.53] | <0.001 |
Troponin cut-off for all-cause mortality stratified by sex and LVEF
| Men | Women | |||||
|---|---|---|---|---|---|---|
| AUC 95%CI | Cut-off Se, Sp | p value | AUC 95%CI | Cut-off Se, Sp | p value | |
| LVEF < 50% | 0.644, 0.557–0.726 | > 23.25 64.29%, 63.64% | 0.004 | 0.742 0.654–0.818 | > 16.50 75.00%, 73.13% | <0.001 |
| LVEF ≥ 50% | 0.690 0.543–0.813 | >10.96 86.67%, 48.57% | 0.015 | 0.772 0.678–0.849 | > 15.05 61.54%, 82.89% | <0.001 |
Univariate Cox regression for all-cause mortality-comparison across groups
| Predictor | Men | Women | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| General characteristics | ||||||
| Age (per 1 year) | 1.03 | 1.01–1.05 | 0.013 | 1.08 | 1.05–1.11 | <0.001 |
| Heart failure characteristics | ||||||
| NYHA III and IV | 1.82 | 1.13–2.94 | 0.014 | 2.14 | 1.32–3.49 | 0.002 |
| Clinical congestion | 1.74 | 1.09–2.77 | 0.020 | 1.87 | 1.20–2.92 | 0.006 |
| Cardiovascular risk factors and comorbidities | ||||||
| HTN | 0.76 | 0.45–1.28 | 0.298 | 0.63 | 0.37–1.09 | 0.097 |
| Atrial fibrillation | 1.32 | 0.83–2.11 | 0.240 | 1.96 | 1.24–3.08 | 0.004 |
| Prior stroke | 1.47 | 0.75–2.88 | 0.258 | 1.09 | 0.58–2.06 | 0.797 |
| IHD | 1.14 | 0.72–1.82 | 0.580 | 0.77 | 0.48–1.23 | 0.270 |
| Prior MI | 1.36 | 0.85–2.18 | 0.203 | 0.91 | 0.50–1.65 | 0.759 |
| Type 2 diabetes | 0.82 | 0.49–1.37 | 0.444 | 1.24 | 0.78–1.97 | 0.358 |
| CKD | 1.78 | 1.09–2.89 | 0.021 | 2.31 | 1.40–3.81 | 0.001 |
| Obesity | 0.46 | 0.27–0.77 | 0.003 | 0.54 | 0.34–0.86 | 0.009 |
| Echocardiographic characteristics | ||||||
| LVEF (per 1%) | 0.97 | 0.95–0.99 | <0.001 | 0.96 | 0.95–0.98 | <0.001 |
| ePASP (per 1mmHg) | 1.03 | 1.01 – 1.05 | 0.002 | 1.03 | 1.01 – 1.05 | 0.004 |
| Severe MR | 2.08 | 1.16 – 3.73 | 0.015 | 2.34 | 1.39 – 3.93 | 0.001 |
| Severe TR | 1.71 | 0.89 – 3.26 | 0.10 | 2.61 | 1.58 – 4.32 | <0.001 |
| Severe AS | 1.59 | 0.22 – 11.47 | 0.65 | 2.21 | 0.69 – 7.02 | 0.18 |
| Biological characteristics | ||||||
| hs-TnT sex-specific cut-off | 2.66 | 1.62–4.34 | <0.001 | 5.50 | 3.38–8.94 | <0.001 |
| hs-TnT ≥14 pg/ml | 2.11 | 1.26–3.56 | 0.005 | 5.66 | 3.36–9.53 | <0.001 |
| lnNTproBNP (per 1 unit) | 1.57 | 1.31–1.88 | <0.001 | 1.58 | 1.34–1.87 | <0.001 |
| eGFR (per 1 mL/min/1.73m2) | 0.99 | 0.98–1.00 | 0.033 | 0.98 | 0.97–0.99 | 0.001 |
| Hemoglobin (per 1 g/dL) | 0.80 | 0.72–0.89 | <0.001 | 0.89 | 0.78–1.00 | 0.056 |
| Serum Na (per 1mmol/L) | 0.99 | 0.98 – 1.02 | 0.91 | 0.96 | 0.91 – 1.00 | 0.053 |
| Serum K (per 1 mmol/mL) | 0.89 | 0.51 – 1.55 | 0.67 | 1.42 | 0.94 – 2.14 | 0.092 |
STROBE checklist
| Item | STROBE recommendation (cohort) | Where addressed in this manuscript |
|---|---|---|
| 1 | Indicate study design in the title or abstract; provide an informative, balanced summary. | Abstract (Methods). |
| 2 | Explain scientific background and rationale. | Introduction (background and gap). |
| 3 | State specific objectives, including prespecified hypotheses. | Introduction-final paragraph. |
| 4 | Present key elements of study design early in the paper. | Materials and Methods-Study design, setting, and data source. |
| 5 | Describe setting, locations, and relevant dates (recruitment, exposure, follow-up). | Materials and Methods-Study design/setting; Outcome and follow-up. |
| 6a | Give eligibility criteria and methods of selection; describe follow-up methods. | Materials and Methods-Study population; Outcome and follow-up; Flow diagram showing derivation from HI-HF parent cohort. |
| 6b | For matched studies, give matching criteria and number of exposed/unexposed. | Not applicable (no matching). |
| 7 | Clearly define outcomes, exposures, predictors, confounders, effect modifiers; diagnostic criteria. | Materials and Methods-Definitions; Biomarker classification; Statistical analysis (covariate set). |
| 8 | For each variable, give data sources and details of assessment; comparability between groups. | Materials and Methods-Clinical variables; Echocardiography; Biomarker assays. |
| 9 | Describe efforts to address potential sources of bias. | Materials and Methods-Bias and confounding paragraph. |
| 10 | Explain how study size was arrived at. | Materials and Methods-Study population (cohort = all eligible patients meeting criteria). |
| 11 | Explain handling of quantitative variables; groupings and rationale. | Materials and Methods-Troponin categories; ln(NT-proBNP); landmark/time re-zeroing. |
| 12a | Describe all statistical methods, including confounding control. | Materials and Methods-Statistical analysis (Cox models; covariate adjustment). |
| 12b | Describe methods for subgroup analyses and interactions. | Materials and Methods-Statistical analysis (sex and troponin interaction). |
| 12c | Explain how missing data were addressed. | Materials and Methods-Statistical analysis (patients with missing data were excluded). |
| 12d | If applicable, explain how loss to follow-up was addressed. | Materials and Methods-Outcome and follow-up (registry-based ascertainment; censoring). |
| 12e | Describe sensitivity analyses. | Results (time-dependent covariates) |
| 13a | Report numbers at each stage (eligible, included, followed-up, analysed). | Results-Study population; PRISMA diagram with counts |
| 13b | Give reasons for non-participation at each stage. | PRISMA diagram provided; Materials and Methods-Study population. |
| 13c | Consider use of a flow diagram. | PRISMA diagram provided |
| 14a | Give characteristics of study participants and information on exposures/confounders. | Results-Baseline (Table 1; troponin category tables). |
| 14b | Indicate number of participants with missing data for each variable of interest. | Patients with missing data were excluded |
| 14c | Summarize follow-up time (e.g., average/total follow-up). | Results-Follow-up summary (median and IQR). |
| 15 | Report numbers of outcome events or summary measures over time. | Results-Deaths; Kaplan–Meier; Cox models. |
| 16a | Give unadjusted and adjusted estimates with precision; state confounders and why included. | Results-Univariable and multivariable Cox tables; covariate list in Materials and Methods-Statistical analysis. |
| 16b | Report category boundaries when continuous variables categorized. | Results-hs-TnT thresholds stated, outcome sex-specific cutoffs stated. |
| 16c | If relevant, translate relative risk into absolute risk for a meaningful time period. | Not required; optional. |
| 17 | Report other analyses (subgroups, interactions, time-dependent, sensitivity). | Results-LVEF subgroup analysis; sex-stratified models; interaction models; time-dependent and landmark analyses. |
| 18 | Summarize key results with reference to objectives. | Discussion-opening paragraph. |
| 19 | Discuss limitations and potential bias/imprecision (direction/magnitude). | Discussion-Limitations section. |
| 20 | Give cautious overall interpretation considering objectives, limitations, and other evidence. | Discussion-Interpretation and comparison with literature. |
| 21 | Discuss generalisability (external validity). | Discussion-final paragraph (Generalisability). |
| 22 | Give funding source and role of funders. | Funding: None |