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Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid.

Zuurbier CJ, Heinen A, Koeman A, Stuifbergen R, Hakvoort TB, Weber NC, Hollmann MW - J Transl Med (2014)

Bottom Line: Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats.FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats.Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl.

ABSTRACT

Background: Acute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R.

Methods: Dependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R.

Results: 50 μM FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS(-/-) hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals.

Conclusions: The protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many "lost-in-translation" drugs and unnecessary clinical studies.

No MeSH data available.


Related in: MedlinePlus

Increased protection against 25 min I and 45 min R with increasing doses of FA in isolated perfused mouse hearts. (A) Cumulative lactate dehydrogenase (LDH) release during 45 min R (index of cell death) in groups treated with different FA doses; (B) End-diastolic pressure (EDP) at end R for the different groups of FA treatment; (C) % Rate-pressure product (RPP) determined at end R and normalized to baseline, pre-ischaemic, values for the different groups. (n = 3 hearts for all groups). Mean ± SEM, * P < 0.05 vs. FA = 0 group.
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Fig1: Increased protection against 25 min I and 45 min R with increasing doses of FA in isolated perfused mouse hearts. (A) Cumulative lactate dehydrogenase (LDH) release during 45 min R (index of cell death) in groups treated with different FA doses; (B) End-diastolic pressure (EDP) at end R for the different groups of FA treatment; (C) % Rate-pressure product (RPP) determined at end R and normalized to baseline, pre-ischaemic, values for the different groups. (n = 3 hearts for all groups). Mean ± SEM, * P < 0.05 vs. FA = 0 group.

Mentions: Baseline cardiac physiological parameters of the isolated WT hearts (Flow = 11.3 ± 0.4 ml/min/g; EDP = 6.1 ± 0.4 mmHg, Psys = 109 ± 3 mmHg, HR = 367 ± 8 beats/min, and RPP = 37.5 ± 1.3 103 mmHg/min) were similar between groups (Table 1). We first set out to examine to what extent various concentrations of FA were able to protect against a relatively short period of total, global ischaemia (25 min) in the isolated mouse heart (Figure 1). Increasing the FA concentration in the perfusate was associated with a continuous decreases in LDH release (Figure 1A). At the highest FA dose of 50 μM, LDH release was decreased by almost 95%, indicating very effective cardioprotection by FA in this specific model. These FA-induced reductions in cell death were mimicked by improvements of cardiac function: I/R-induced elevation of EDP was reduced by 73%, whereas %RPP recovery increased by 81% with 50 μM FA (Figure 1B and C). Subsequently, FA protective effects were studied employing an extended period of ischaemia (35 min). No protection against I/R-induced LDH release was observed with the various doses of FA (Figure 2A). Increasing FA concentration from 50 μM to 100 μM was even associated with a non-significant increase in LDH release. FA did not improve cardiac function after 35 min I, with a trend towards poorer recovery of the mechanical parameters when FA was increased from 50 μM to 100 μM (Figure 2B and C). Thus, the effect of FA on cardiac I/R injury is critically dependent on FA concentration and duration of the ischaemic insult.Table 1


Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid.

Zuurbier CJ, Heinen A, Koeman A, Stuifbergen R, Hakvoort TB, Weber NC, Hollmann MW - J Transl Med (2014)

Increased protection against 25 min I and 45 min R with increasing doses of FA in isolated perfused mouse hearts. (A) Cumulative lactate dehydrogenase (LDH) release during 45 min R (index of cell death) in groups treated with different FA doses; (B) End-diastolic pressure (EDP) at end R for the different groups of FA treatment; (C) % Rate-pressure product (RPP) determined at end R and normalized to baseline, pre-ischaemic, values for the different groups. (n = 3 hearts for all groups). Mean ± SEM, * P < 0.05 vs. FA = 0 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4265322&req=5

Fig1: Increased protection against 25 min I and 45 min R with increasing doses of FA in isolated perfused mouse hearts. (A) Cumulative lactate dehydrogenase (LDH) release during 45 min R (index of cell death) in groups treated with different FA doses; (B) End-diastolic pressure (EDP) at end R for the different groups of FA treatment; (C) % Rate-pressure product (RPP) determined at end R and normalized to baseline, pre-ischaemic, values for the different groups. (n = 3 hearts for all groups). Mean ± SEM, * P < 0.05 vs. FA = 0 group.
Mentions: Baseline cardiac physiological parameters of the isolated WT hearts (Flow = 11.3 ± 0.4 ml/min/g; EDP = 6.1 ± 0.4 mmHg, Psys = 109 ± 3 mmHg, HR = 367 ± 8 beats/min, and RPP = 37.5 ± 1.3 103 mmHg/min) were similar between groups (Table 1). We first set out to examine to what extent various concentrations of FA were able to protect against a relatively short period of total, global ischaemia (25 min) in the isolated mouse heart (Figure 1). Increasing the FA concentration in the perfusate was associated with a continuous decreases in LDH release (Figure 1A). At the highest FA dose of 50 μM, LDH release was decreased by almost 95%, indicating very effective cardioprotection by FA in this specific model. These FA-induced reductions in cell death were mimicked by improvements of cardiac function: I/R-induced elevation of EDP was reduced by 73%, whereas %RPP recovery increased by 81% with 50 μM FA (Figure 1B and C). Subsequently, FA protective effects were studied employing an extended period of ischaemia (35 min). No protection against I/R-induced LDH release was observed with the various doses of FA (Figure 2A). Increasing FA concentration from 50 μM to 100 μM was even associated with a non-significant increase in LDH release. FA did not improve cardiac function after 35 min I, with a trend towards poorer recovery of the mechanical parameters when FA was increased from 50 μM to 100 μM (Figure 2B and C). Thus, the effect of FA on cardiac I/R injury is critically dependent on FA concentration and duration of the ischaemic insult.Table 1

Bottom Line: Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats.FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats.Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Anaesthesiology, Department of Anaesthesiology, Academic Medical Centre, Amsterdam, The Netherlands. c.j.zuurbier@amc.uva.nl.

ABSTRACT

Background: Acute, high-dose folic acid (FA) administration has recently been shown to possess unprecedented effective cardioprotection against ischaemia/reperfusion (I/R) injury. Here we explore the translation potential of FA as treatment modality for cardiac I/R.

Methods: Dependency of FA protection on dose, ischaemia duration, and eNOS was examined in an isolated mouse heart I/R model, whereas dependency on animal health status and anaesthesia was examined in an in vivo rat model of regional cardiac I/R.

Results: 50 μM FA provided maximal reduction (by 95%) of I/R-induced cell death following 25 min ischaemia in isolated wild-type hearts, with protection associated with increased coupled eNOS protein. No protection was observed with 35 min I or in eNOS(-/-) hearts. Acute intravenous administration of FA during a 25 min ischaemic period reduced infarct size by 45% in in vivo pentobarbital-anaesthetised young, healthy rats. FA did not reduce infarct size in aged or pre-diabetic rats, although it did preserve hemodynamics in the pre-diabetic rats. Finally, using a clinically-relevant anaesthetic regimen of fentanyl-propofol anaesthesia, FA treatment was ineffective in young, aged and pre-diabetic animals.

Conclusions: The protective potential of an initially promising cardioprotective treatment of high dose FA against cardiac I/R infarction, is critically dependent on experimental conditions with relevance to the clinical condition. Our data indicates the necessity of expanded pre-clinical testing of cardioprotective interventions before embarking on clinical testing, in order to prevent too many "lost-in-translation" drugs and unnecessary clinical studies.

No MeSH data available.


Related in: MedlinePlus