Introduction
Methods
Study design
Search strategy
Eligibility criteria
Criteria for inclusion of published animal studies
| |
(a) Peer reviewed original article (b) In vivo animal study (c) Conducted on suitable animal species with characterised levels of collateralisation of the coronary circulation (rodents, rabbits, pig, cats, and dogs) (d) Documented period of ischemia (e) Documented period of reperfusion (f) Intervention group in which animals were administered a documented NO treatment (regardless of route of administration) within the latter stages of the ischaemic phase or in the early reperfusion phase (g) Clearly defined contemporary control group where animals received defined control treatment (h) Infarct size measured as endpoint by clearly documented method | |
Criteria for inclusion of published human studies
| |
(a) Peer reviewed original article (b) Documented period of myocardial ischemia (time from onset of chest pain) (c) Documented method of reperfusion (d) Intervention group in which patients were administered documented NO treatment (regardless of route of administration) prior to, or during PCI/thrombolysis (e) Completed randomised control trial with infarct size estimation as clearly defined endpoint |
(a) Details about study population including numbers in each treatment group and baseline characteristics (b) Details regarding intervention and control arms of the study (c) Specific endpoints being reported and how they were assessed (d) Whether randomisation of study participants took place (e) Timing of administration of the intervention being investigated (f) Reporting of study protocols such as methods and timings of ischemia and reperfusion (g) Assessment of sample size and power of study (h) Whether inclusion/exclusion criteria for study or its participants were stated (i) Whether methods of data analysis used were appropriate for data types being reported (j) Whether reporting of results was accurate and conclusion of study reflected results reported (k) Whether limitations of study or conflicts of interest were acknowledged by authors |
Article selection and data extraction
Reasoning | No. articles |
---|---|
Excluded during relevance screening (title plus abstract) level | 11,539 |
Total no. of articles appraised at full text level | 93 |
Excluded during full manuscript review | |
Inappropriate timing of NO donor administration | 24 |
Inadequate/lack of suitable control arm | 1 |
No clear period of ischaemia and/or reperfusion stated | 12 |
NO donation not primary mechanism of action being investigated | 8 |
Ex vivo/in vitro study | 4 |
Inappropriate outcomes measured | 11 |
Not myocardial I/R injury | 3 |
Abstract or preliminary results | 4 |
Review article | 1 |
Foreign language article | 1 |
No. of studies excluded at full text level | 69 |
No. of studies included after full text evaluation | 24 |
Meta-analysis
Results
Study inclusion/exclusion
Characteristics of experimental animal studies
Author, year | Animal species | Exp. protocol/primary endpoint determination | NO donor | Timing of NO administration |
n (Tx):n (control) | Effect of NO donor on outcome vs control |
---|---|---|---|---|---|---|
Lefer et al. (1993) | Adult male cats | LAD occlusion 90 min Reperfusion 270 min Endpoint: IS − TTC | Tx: novel sydnonimine NO donor C87-3754 (1 mg/kg/h) Control: non-NO donating analogue C88-3934 IV infusion | 10 min before reperfusion until end of experiment | 6:6 | ↓ % IS/AAR compared to control (12 vs 33 %) |
Hataishi et al. (2006) | 2–4 month old wild type mice | LCA occlusion (a) 30 min, (b) 60 min, (c) 120 min Reperfusion 24 h Endpoint: IS − TTC | Tx: iNO 80 ppm Control: inhalation of O2 (0 ppm N2) Mechanical ventilator | 20 min before reperfusion until end of experiment | (a) 13:14 (b) 6:7 (c) 9:11 | iNO 80 ppm ↓ IS/AAR % after 30, 60 and 120 min ischaemia iNO dose–response 40/80 ppm = ↓IS/AAR % but not 20 ppm iNO |
Duranksi et al. (2005) | Mice 8–10 week old | LCA occlusion 30 min Reperfusion 24 h Endpoint: IS − TTC | Tx: (a) NaNO2 48 nmol (b) NaNO2: 2.4, 4.8, 960 and 1,920 nmol Control: 48 nmol NaNO3
Intraventricular | Admin into LV cavity 5 min prior to reperfusion |
a = 8
b = 6 per dose Control = 11 | All NO2
− doses (except 1,920 nmol) = significant ↓ IS/AAR % compared with control 48 nmol nitrite significantly (P < 0.001) reduced IS compared to control |
Hendgen-Cotta et al. (2008) | Mice 14 ± 3 week old | LCA occlusion 30 min Reperfusion 24 h Endpoint: IS − TTC | Tx: NaNO2 48 nmol Control: 48 nmol NaNO3
Intraventricular | Admin into LV cavity 5 min prior to reperfusion | 7:7 | 48 nmol nitrite significantly (P < 0.01) reduced IS compared to control |
Johnson et al. (1990a) | Adult male cats | LAD occlusion 1.5 h Reperfusion 4.5 h Endpoint: IS − TTC | Tx = acidified NaNO2 in 0.12 M HCl at pH 2.0 (a) 50 mmol/kg/h (b) 25 mmol/kg/h (c) 12.5 mmol/kg/h Control: acid vehicle IV infusion | 30 min after induction of ischaemia until end of reperfusion | Sham:7 Control = 6
a = 7
b = 6
c = 6 |
a = maximal cardioprotection Inf. rates of <12.5 mmol/kg/h provide NS protection IS/AAR significantly ↓ in NaNO2 (a + b + c) compared to vehicle treated groups |
Baker et al. (2007) | Male rats 8 weeks old | LCA occlusion 30 min Reperfusion 2 h Endpoint: IS − TTC | Tx: NaNO2 4 mg/kg IV at time of admin until end of reperfusion phase Control: saline IV infusion | (a) NO2
− 15 min after ischaemia (b) NO2
− 10 secs after reperfusion | 6:6:6 | NaNO2 admin in (a) produced significant ↓ IS/AAR compared to control NaNO2 admin in (b) shows no significant ↓ in IS |
Johnson et al. (1990) | Adult male cats | LAD occlusion 1.5 h Reperfusion 4.5 h Endpoint: IS − TTC, serum CK levels | Tx: acidified NaNO2 (pH 2.0), 12.5 mmol/kg/h Control: acid vehicle IV infusion | 30 min post-occlusion until end of reperfusion | 6:6 | Significant ↓ IS in Tx group compared to control |
Lefer et al. (1993b) | Dogs (M/F) | LAD occlusion 60 min Reperfusion 270 min Endpoint: IS − TTC | Tx: novel cysteine containing mononitrate NO donor (SPM-5185) Control: NO deficient analogue (SPM-5267) IV infusion | After 60 min of ischaemia, IV infusion to achieve plasma conc of 500 nM | 6:5 | Highly significant ↓ IS/AAR % in Tx group (14.5 %) compared to control (47.5 %) |
Tripathi et al. (1997) | Adult male mongrel dogs | LAD occlusion 90 min Reperfusion 4 h Endpoint: IS − TTC, VF − ECG | Control: saline reperfused Tx: acidified NaNO2 infusion 0.30 Mol/L HCl pH 2 IV infusion | Saline or NaNO2 infused at time of reperfusion for 4 h | 10:10 | NS diff in NaNO2 vs saline Tx groups in % IS/AAR or LV |
Liu et al. (2007) | Juvenile pigs (M/F) | Balloon-mounted stent for 50 min Reperfusion 240 min Endpoint: IS − TTC | Tx: iNO: 80 ppm Tx: IV-NTG: 2 µg/kg/min Control: IV saline IV infusion | 10 min before reperfusion until end of experiment | Saline = 14 iNO = 12 IV-NTG = 11 | IV-NTG did not significantly ↓ IS/AAR compared to control iNO ↓ IS by 47 % compared to control |
Lefer et al. (1993a) | Canines (M/F) | LAD occlusion 60 min Reperfusion 270 min Endpoint: IS − TTC | Tx: novel cysteine containing mononitrate NO donor (SPM-5185) Control: saline IV infusion | 60 min of ischaemia throughout reperfusion | 10:7 | ↓ IS in Tx group (SPM5185 = 3.1 %, control = 13.6 %) |
Nossuli et al. (1997) | Adult male cats | LAD occlusion 90 min Reperfusion 4.5 h Endpoint: IS − TTC | ONOO− 1 µmol/L in pH 8.4 saline as Tx group Control = pH 8.4 saline Intra-ventricular or IV infusion | 10 min prior to reperfusion until end of experiment | 6:6 | Significant ↓ in IS/AAR (P < 0.001) and necrosis/LV (P < 0.02) in Tx group compared to control |
Shinbo et al. (2013) | 10 week old male mice | LCA occlusion 60 min Reperfusion 24 h Endpoint: IS − TTC | Tx: iNO 80 ppm gas Control:FiO2 0.3 Inhaled via mechanical ventilator | 5 min prior to reperfusion until end of experiment | 5:5 | IS/AAR significantly ↓ in iNO mice compared to control |
Nagasaka et al. (2008) | Male mice | LCA occlusion 60 min Reperfusion 24 h Endpoint: IS − TTC | Tx; iNO 80 ppm Control: mice breathing O2
Inhaled via mechanical ventilator | iNO administered during ischaemia for (before reperfusion): (a) 60 min (b) 5 min (c) 0.5 min | (a) 9:10 (b) 8:9 (c) 6:7 |
a = ↓ IS/AAR by 32 % compared to O2 mice (P < 0.05)
b = ↓ IS/AAR by 31 % compared to O2 mice (P < 0.05) |
Nagasaka et al. (2011) | WT mice 8-12 week old Mice with sGC
α1
−/−
deficiency | LCA occlusion 60 min Reperfusion 24 h Endpoint: IS − TTC | Tx: iNO 80 ppm Control: O2 inhalation Inhaled via mechanical ventilator | 60 min beginning 10 min after LCA occlusion until 10 min reperfusion | WT = 10:12 sGC
α1
−/−
= 10:10 | iNO Tx in WT mice caused 41 % ↓ in MI/AAR (P < 0.001), however did not alter MI/AAR in sGC
α1
−/−
mice |
Pabla et al. (1995) | Mongrel dogs (M/F) | LAD occlusion 90 min Reperfusion 270 min Endpoint: IS − TTC | Tx: long acting NO donor: CAS-1609 IV bolus 1.25 mg, followed by infusion of 1 mg/h Control: normal saline bolus and infusion IV infusion | Bolus 10 min before reperfusion followed by infusion for reperfusion period | 7:7 | IS/AAR in Tx group = 8 %, control = 29 % (P < 0.01) (70 % ↓ in necrosis) |
Salloum et al. (2007) | Male NZ white rabbits | LCA occlusion 30 min Reperfusion 3 h Endpoint: IS − TTC | Tx: NTG 2 µg/kg/min IV via continuous infusion Control: 0.9 % saline IV infusion | 5 min prior to reperfusion continuing for 65 min | 7:6 | NS diff in IS/AAR between NTG and saline groups (31.5 vs 33.8 % respectively) |
Nossuli et al. (1998) | Adult male cats | LAD occlusion 90 min Reperfusion 270 min Endpoint: IS − TTC | Tx : ONOO− infusion in pH8.4 saline at: (a) 0.2 µM (b) 2 µM (c) 20 µM Control = pH 8.4 saline Route: IV infusion | Intraventricular infusion admin 10 nmin prior to reperfusion and maintained throughout reperfusion | Control = 6
a = 6
b = 7
c = 6 | Only 2 µM dose of ONOO− significantly ↓ IS/AAR %, (14.4 % in Tx compared to 30.3 % control P < 0.01) |
Neye et al. (2012) | Male rats | LCA occlusion 120 min Reperfusion 3 h Endpoint: IS − TTC | Tx: iNO 50 ppm Control: room air Inhaled via mechanical ventilator | (a) iNO/control admin throughout 3 h reperfusion (b) iNO/control admin throughout 5 h period of I and R | 8:8 |
a = IS/LV ↓ in iNO compared to control however IS/AAR was NS
b = IS/LV was significantly ↓ compared to control and group a |
Siegfried et al. (1992) | Adult male mongrel cats | LAD occlusion 90 min Reperfusion 270 min Endpoint: IS − TTC |
a = NO donor: SIN-1
b = NO donor:C87-3754
c = inactive NO donor: C88-3934
d = control: 0.9 % saline Bolus 1 mg/kg followed by 1 mg/kg/h infusion IV | Administered into jugular vein 10 min prior to reperfusion until end of reperfusion period |
a = 8
b = 6
c = 6
d = 6 |
a = ↓ IS/AAR from 29 to 9 % (P < 0.001)
b = ↓ IS/AAR from 31 to 11 % (P < 0.001) |
Johnson et al. (1991) | Adult male cats | LAD occlusion 90 min Reperfusion 270 min Endpoints: IS − TTC |
a = NO in solution
b = vehicle 1.1 mL/kg/h IV | 30 min after LAD ligation until end of reperfusion period |
a = 6
b = 6 |
a = ↓ IS/AAR from 26 to 7 % (P < 0.01) |
Characteristics of human clinical studies
Author, year | NO donor (dose, route, duration) | Time from onset of chest pain to admission (h) | Reperfusion technique | Infarct size determination |
n (Tx):n (control) | Effect of NO donor on outcome vs control |
---|---|---|---|---|---|---|
Hildebrandt et al. (1992) | Isosorbide dinitrate 1.0–10.0 mg/mL Infusion for 48 h | ≤8 | Thrombolysis with streptokinase | CK-MB every 4 h for 72 h | 50:49 | No reduction in infarct size when reperfusion confirmed |
Morris et al. (1995) | Isosorbide dinitrate 1.0–6.0 mg/h Infusion for 24 h minimum | ≤24 | Thrombolysis | αHBDH blood samples every 12 h on days 1 and 2 and daily on days 3, 4, and 5 | 150:151 | No reduction in infarct size, ventricular remodelling or ST segment resolution at day 3 |
Siddiqi et al. (2014) | Sodium nitrite 70 μmol Infusion for 5 min | ≤12 | PPCI | CMR % LV mass 6–8 days post infarct | 118:111 | No reduction in infarct size or secondary endpoints including ejection fraction and troponin 1 |