Study designs and response outcome definitions
| Study ID | Design | Participants recruited | HF/CRT participants | Inclusion criteria | Observation period | Assessments | ECM biomarkers | CRT responder definition | Response rate |
| Dong et al26 | Prospective observational | 65 (20 healthy controls) | 45 | LVEF≤35%, NYHA III–IV, QRS>120 ms, SR and OMT | 6 months | Baseline/3 months/6 months: NYHA, 6MWT, TTE, blood samples | PIIINP | ↓≥15% LVESVi and survived at 6 months | 22 (48.9%) |
| Tolosana et al24 | Prospective observational | 55 (13 excluded after recruitment) | 42 | LVEF≤35%, NYHA III–IV, QRS>120 ms and OMT or cardiac pacing indication (LVEF<35%) | 12 months | Baseline/6 months/12 months: NYHA, QoL (MLHFQ), 6MWT, TTE, ECG, blood samples | MMP-2, TIMP-1 | ↑>10% 6 MWT or if test not performed ↑>1 NYHA and survived/no heart transplant at 12 months | 25 (59.6%) |
| Truong et al25 | Prospective observational | 73 | 73 | LVEF<35%, NYHA II–IV, QRS≥120 ms, OMT, HF decompensation <12 months | 24 months (IQR 20.4–24.0) | Baseline: NYHA, ECG, TTE 1 month/3 months 6 months Clinical FU | Gal-3 | Improvement HF clinical composite score30 at 6 months | 40 (54.7%) |
| Umar et al10 | Prospective observational | 64 | 64 | LVEF<35%, NYHA III–IV, QRS>120ms | 6 months | Baseline/6 months: NYHA, TTE; QoL (MLHFQ), 6MWT, blood samples | PINP, PIIINP, ICTP, proMMP-1, TIMP-1 | ↓≥10% LVESV at 6 months | 46 (71.8%) |
| Garcia-Bolao et al 9 | Prospective observational | 61 | 59 | LVEF≤35%, NYHA III–IV, LBBB, QRS≥130 ms, OMT | 12 months | Baseline/12 months: NYHA, QoL (MLWHFQ), 6MWT, TTE, ECG, blood samples | PICP, CITP, MMP-1, MMP-2, MMP-9, TIMP-1 | ↑≥10% 6 MWT and survival from cardiac mortality at 12 months | 35 (59.3%) |
| Lopez-Andres et al8* | Substudy randomised control trial: CARE-HF | 260 (CARE-HF cohort available) | 132 (CRT-P only) | LVEF<35%, NYHA III–IV, QRS>150 ms or 120–149 ms with echocardiographic dyssynchrony, OMT | Substudy: 18 months; CARE-HF: 29.4 months (range, 18.0–44.7) | Substudy Baseline/3 months/18 months: TTE, blood samples | PINP, PIIINP, ICTP, MMP-1, Gal-3 | Survival and LVEF more than 35% at 18 months | CRT-p (n=108): 72 (66.6%); OMT (n=117): 103 (88.0%), p=0.0001 |
*Median (IQR).
CITP, carboxy-terminal telopeptide of collagen type-I; CRT, cardiac resynchronisation therapy; CRT-p, CRT-pacemaker; ECM, extracellular cardiac matrix; Gal-3, galectin-3; HF, heart failure; ICTP, carboxy-terminal telopeptide of type I collagen; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVESVi, left ventricular end-systolic volume indexed; 6MWT, six min walk test; MLHFQ, Minnesota living with heart failure questionnaire; MMP, metalloproteinases; NYHA, New York Heart Association; OMT, optimal medical therapy; PINP, N-terminal propeptides of type I procollagens; PIIINP, N-terminal propeptides of type III procollagens; QoL=quality of life; SR, sinus rhythm; TIMP, tissue inhibitors of MMPs; TTE, transthoracic echocardiogram.