Table 1.

Characteristics of the included studies.

Study, Year [Ref.]	Study Design	N° of Patients	Population	Control Group	MMP	Other Factos	Outcomes	Main Findings
Bradham, 2002 [10]	Prospective observational NRCT	51	Patient with HOCM submitted to alcohol septal ablation (51 pts)	-	MMP-2, MMP-8, MMP-9, MMP-13, TIMP-1	CK CK-MB1	To analyse the temporal profile of MMPs plasma levels after alcohol-induced MI; To evaluate the relationship between alcohol-induced MI and MMPs plasma levels.	MMP-2 increased at 4 h post alcohol injection. MMP-8 increased by 6 h post injection and remained elevated for up to 60 h post injection. MMP-9 increased at 6 h and remained elevated for up to 50 h post injection. MMP-13 decreased at 24 h post injection. TIMP-1 increased at late time points post alcohol injection but without statistical significance. MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios increased post alcohol septal ablation.
Lombardi, 2003 [11]	Prospective observational NRCT	50	Patient with HOCM (36 pts)	Healthy subjects (14 pts)	MMP-1, MMP-2, MMP-9, TIMP-1	ICTP, PICP, PINP	To evaluate myocardial collagen turnover; To assess myocardial collagen turnover on diastolic function.	HOCM patients had higher MMPs plasma levels than the control group. No correlation between biomarkers of collagen turnover and severity of left ventricular hypertrophy.
Fassbach, 2004 [12]	Prospective observational NRCT	64	Patient with HOCM (26 pts)	Healthy subjects (38 pts)	MMP-1, TIMP-1	ICTP, PICP	To evaluate myocardial collagen turnover; To assess myocardial collagen turnover on diastolic function.	TIMP-1 was elevated in HOCM patients. MMP-1 was higher in HOCM patients. MMP-1/TIMP-1 ratio was lower in HOCM patients.
Noji, 2004 [13]	Prospective observational NRCT	78	Patient with HOCM (28 pts)	Healthy subjects (50 pts)	MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2	-	To test if MMPs are altered in patients with HOCM and are associated with LV remodelling.	MMP-2 and TIMP-2 were higher in HOCM patients with EF < 25% than those with EF ≥ 25% and the control group. TIMP-1 was higher in the HOCM patients than the control group. MMP-3 and MMP-9 were similar among groups.
Stroud, 2005 [14]	Prospective observational NRCT	34	Patient with HOCM submitted to alcohol septal ablation (18 pts)	Healthy subjects (16 pts)	TIMP-4	-	To assess if variation in plasma TIMP-4 levels occurs after alcohol-induced myocardial infarction.	TIMP-4 increased in HOCM patients. TIMP-4 increased at 10 h post alcohol injection and decreased after 30 h.
Roldàn, 2008 [15]	Prospective observational NRCT	125	Patient with HOCM (67 pts)	Healthy subjects (58 pts)	MMP-1, MMP-2, MMP-9, TIMP-1	NT-proBNP	To evaluate the correlation between MMPs and myocardial collagen turnover, fibrosis, functional status, and prognosis.	MMP-2 and MMP-9 were higher in HOCM patients. MMP-2 was associated with dyspnoea and correlated with MMP-9 and NT-proBNP. MMP-9 was associated with fibrosis.
Saura, 2009 [16]	Prospective observational NRCT	73	Patient with HOCM (73 pts)	-	MMP-2, TIMP-1	NT-pro-BNP, C-reactive protein	To assess the influence of left atrial volume on exercise performance to MMP2 and TIMP-1.	Enlarged left atrial volume is associated with MMP-2. Left atrial volume is significantly associated with TIMP-1.
Kitaoka, 2010 [17]	Retrospective observational NRCT	41	Patient with HOCM (41 pts)	-	MMP-2, MMP-9, TIMP-1	BNP	To evaluate the role of MMPs levels in the LV remodelling process; To assess the MMPs as a predictor of heart failure in HOCM patients.	MMP-2 levels were higher in HOCM patients with severe symptoms; MMP-2 and TIMP-1 levels were positively associated with LV end-systolic and left atrial dimensions, and inversely related to LV EF. MMP-2 levels were positively related to BNP levels; MMP-9 were not related to echocardiographic parameters and plasma BNP levels.
Kitaoka, 2011 [18]	Prospective observational NRCT	16 *	Patient with HOCM (16 pts)	-	MMP-2, MMP-9, TIMP-1	BNP	To evaluate whether MMPs plasma levels were related to LV remodelling; To observe whether MMPs levels were related to the deterioration in left ventricular systolic function in HOCM patients with preserved LV EF.	MMP-2 levels were inversely related to LV EF; MMP-9 levels were inversely related to LV end-diastolic dimension and positively related to the maximum LV wall thickness.
Zachariah, 2012 [19]	Prospective observational NRCT	45	Patient with HOCM (45 pts)	-	MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TIMP-3, TIMP-4	-	To evaluate the association between ventricular arrythmia and MMPs.	Patients with ventricular arrythmia had significantly higher MMP-3 levels than patients without arrythmia. Ventricular arrythmia was independently associated with MMP-3.
Fucikova, 2016 [20]	Prospective observational NRCT	30	Patient with HOCM (17 pts)	Healthy subjects (17 pts)	MMP-2, MMP-9, TIMP-1, TIMP-2	BNP, fibronectin	To assess the abundance of proteins and plasma fibronectin in HOCM patients.	TIMP-2 levels were higher in HOCM patients; MMP2, MMP-9, and TIMP-1 were similar between groups.
Munch, 2016 [21]	Retrospective observational NRCT	54	Patient with HOCM (54 pts)	-	MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1	-	To evaluate if myocardial collagen turnover changes according to gender; To evaluate myocardial collagen turnover proteins and cardiac events.	MMP-9 was associated with fibrosis and cardiac events in females; Increased MMP-2 levels in females were associated with lower fibrosis; MMP-3 levels were positively associated with cardiac events; No association was detected for MMP-1 and TIMP-1.
Fernlund, 2017 [22]	Prospective observational NRCT	105	Patient with HOCM (39 pts)	Healthy subjects (66 pts)	MMP-9	-	To evaluate whether serum biomarkers reflect myocardial remodelling in the early stage of HOCM.	MMP-9 levels were increased in the HOCM patients and correlated to the LV mass index.
Yang, 2019 [23]	Prospective observational NRCT	52	Patient with HOCM submitted to surgical myectomy (52 pts)	-	MMP-2, MMP-9, TIMP-1	-	To assess the biomarkers of myocardial fibrosis in HOCM patients submitted to cardiac surgery.	TIMP-1 plasma levels were correlated to myocardial content; MMP-2 and MMP-9 were not significantly correlated with those of myocardial tissues; Plasma MMP-9 levels were found to be significantly related to TIMP-1 levels; Plasma MMP-2 levels were positively correlated with collagen volume fraction.
Qian, 2020 [24]	Prospective observational NRCT	30	Patient with HOCM submitted to percutaneous intramyocardial septal radiofrequency ablation (30 pts)	-	MMP-2	-	To assess myocardial fibrosis after percutaneous intramyocardial septal radiofrequency ablation in HOCM patients.	At 1-month follow-up, MMP-2 levels were lower than before the procedure.
Bi, 2021 [25]	Prospective observational NRCT	55	Patient with HOCM submitted to surgical myectomy (55 pts)	-	MMP-2, MMP-9, TIMP-1	-	To demonstrate the relationship among myocardial collagen turnover proteins, microvascular remodelling, and myocardial fibrosis in HOCM patients. To assess the prognostic value of collagen-related biomarkers in HOCM patients after cardiac surgery.	Plasma MMP-2 correlated with left atrium diameters; Septal thickness was associated with the plasma MMP-9/TIMP-1 ratio, MMP-2/TIMP-1 ratio, and TIMP-1 levels; LVOT pressure gradient was correlated with MMP-2/TIMP-1 ratio; Microvascular density was inversely correlated with MMP-2/TIMP-1 ratio; Microvascular density was higher in patients with lower MMP-2 levels; MMP-9 and MMP-9/TIMP-1 were not related to microvascular density; No significant correlations were found between myocardial MMPs and plasma MMPs.

* Among 16 patients, 11 patients were included in a previous study by the same group (Kitaoka 2010). Abbreviations: CK, creatine kinase; EF, ejection fraction; HOCM, hypertrophic obstructive cardiomyopathy; ICTP, collagen I carboxy-terminal telopeptide; LV, left ventricle; MI, myocardial infarction; MMP, metalloproteinase; NRCT, not randomized controlled trial; NT-proBNP, N-terminal pro B-type natriuretic peptide; PICP, procollagen type I carboxy-terminal propeptide; PINP, procollagen type I amino-terminal propeptide; RCT, randomized controlled trial; TIMP, tissue inhibitors of metalloproteinases.