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Introduction

Mitral valve replacement surgery is one of the main surgical methods in the treatment of rheumatic valvular disease (1). During the operation, deep hypothermia is required, and the cardiopulmonary bypass is used to carry out respiratory and circulatory support (2). Extracorporeal circulation as a non-physiological circulation mode can cause the pathological and physiological changes of pulmonary vessels and pulmonary parenchyma after operation in patients who received mitral valve replacement surgery (3). Postoperative acute lung injury is relatively common and is capable of inducing serious respiratory distress syndrome, seriously affecting the patient's quality of life during peri-operation (4). Previous studies on rats have shown that, lung ischemic preconditioning treatment can significantly improve the postoperative PaO2 level, and significantly reduce pulmonary arterial pressure, lung wet/dry weight ratio and the level of malondialdehyde (MDA) (4), indicating that ischemic preconditioning treatment can reduce lung ischemia/reperfusion injury in these animal models (5). Although the underlying mechanisms of lung ischemia/reperfusion injury are not fully elucidated, it is thought to involve the activation of TRPC6 channels (6).

Previous findings indicated that the process of pulmonary ischemia/reperfusion injury can be effectively improved after the use of ACEI before cardiopulmonary bypass surgery in patients with valve disease (7). However, after use of captopril, the metabolism of bradykinin (BK) decreased and accumulated in the blood, resulting in lung activation (8). Patients experience varying degrees of complications, while other patients exhibit respiratory symptoms such as bleeding (9), which is not conducive to postoperative wound healing. Telmisartan is a new type of antihypertensive drug that acts as a specific angiotensin II (AngII) type 1 receptor (AT1) antagonist (10). Telmisartan antagonizes the binding of angiotensin II receptor to the AT1 receptor subtype. In the absence of an agonist effect, telmisartan can be selectively combined with the AT1 receptor with a lasting effect. Compared with ACEI, ARB can significantly reduce respiratory secretions (12).

In the present study, 180 cases of patients with rheumatic heart disease were selected to undergo mitral valve replacement. Prior to extracorporeal circulation, the patients were administered telmisartan, captopril and placebo pretreatment to observe the condition of postoperative ischemia reperfusion injury, and the clinical efficacy of telmisartan and captopril was subsequently examined.

Subjects and methods

Subjects and groups

Between March October, 2013 to March, 2015, 180 patients were diagnosed via clinical symptoms, signs and echocardiogram as having rheumatic heart disease. The patients included 132 cases of single valve replacement, and 48 cases of double valve replacement. The patients were randomly assigned to the placebo (n=60), captopril preconditioning (n=60) and telmisartan preconditioning (n=60) groups. Detailed information of the enrolled patients is shown in Table I.

Table I. Patient information.

Table I.

Patient information.

Groups	No. of males	No. of females	Age (years)
Telmisartan	27	33	52.4±12.3
Captopril	25	35	55.6±7.2
Placebo	32	28	58.3±12.8

The present study was approved by the ethics committee of The People's Hospital of Guizhou (Guizhou, China).

Inclusion and exclusion criteria

The inclusion criteria for the study were: i) NYHA: grades II–III; ii) diagnosis of rheumatic heart disease via clinical symptoms, signs and echocardiography. The exclusion criteria for the study were: 3 months prior to operation, a history of activity of rheumatic disease, infection, heart failure, and history of unconsciousness; iii) within 2 weeks of surgery, the patients were administered ACEIs or ARBs. The perioperative administration of nitrates included: iv) patients and family members cannot cooperate with the inspection, and v) mental illness or consciousness disorder.

Pretreatments

Captopril (1 mg/kg/day) was administered 96–48 h before surgery. The blood pressure, heart rate, heart rate and subjective discomfort were observed prior to and after patients were administered the drug.

Telmisartan (1 mg/kg/day) was administered 96–48 h before surgery. The parameters investigated were identical to those of the captopril group.

A placebo with similar size, color and shape was administered as indicated above.

Pulmonary vascular resistance (PVR) was calculated using the equation: [mean arteriral pressure (MAP) - pulmonary cap wedge pressure (PCWP)] × 79.92 cardiac output (CO). The alveolar-arterial oxygen gradient was calculated as:

A-aDO2 = FiO2 (Patm - 47 mmHg) - PaCO2 - PaO2

The correction value was measured as: Hb (before CPB)/Hb (the specimen) × measured value.

SPSS 19.0 software (Chicago, IL, USA) was used for statistical analysis in the present study. Data were presented as (mean ± SD). Quantitative data were compared by analysis of variance. Qualitative data were compared by the Chi-square test. The Fisher's exact test method was used to calculate the exact probability. The correlation between postoperative lymphocyte changes and biliary tract infection were evaluated by the logistic model. The difference was statistically significant when P<0.05.

Results

General clinical situation of three groups of patients

Between October, 2013 to March, 2015, 180 patients were diagnosed via clinical symptoms, signs and echocardiogram as having rheumatic heart disease. The patients included 132 cases of single valve replacement, and 48 cases of double valve replacement. The patients were randomly assigned to the placebo (n=60), captopril preconditioning (n=60) and telmisartan preconditioning (n=60) groups. The patient's age, body weight, cardiac function classification, cardiopulmonary bypass time, and vena cava blocking time were recorded and analyzed (Table II).

Table II. Data and variables regarding the three groups of patients (mean ± SD).

Table II.

Data and variables regarding the three groups of patients (mean ± SD).

Group	Case no.	Age (years)	Body weight (kg)	NYHA (II/III)	CPB (min)	VC (min)
Telmisartan	60	0.52.4±12.3	68.3±21.9	29/31	72.3±12.6	51.2±12.7
Captopril	60	55.6±7.2	66.4±27.1	28/32	77.8±8.5	53.2±22.1
Placebo	60	58.3±12.8	63.4±19.8	34/26	74.8±19.7	52.6±13.9
F-value	–	0.27	0.62	0.33	0.48	0.99
P-value	–	0.37	0.44	0.68	0.55	0.17

[i] NYHA, New York Heart Association. VC, vena cava blocking time.

PVR in the three groups

Preoperative PVR was higher, and compared with PVR measured at 1, 3, 6 or 12 h prior to CPB treament, there was no significant difference in the groups (P>0.05). After valve replacement, the PVR of the captopril and telmisartan groups was significantly decreased (P<0.05) at each time-point. However, no significant difference was found between the captopril and telmisartan groups (P>0.05) (Table III).

Table III. PVR in the three groups.

Table III.

PVR in the three groups.

Group	Case no.	Before CPB	1 h after CPB	3 h after CPB	6 h	12 h	F-value	P-value
Telmisartan	60	331.6±25.7	231.7±45.3	182.7±42.8	92.3±29.6	122.4±23.6	31.5	0.002
Captopril	60	348.9±12.6	252.6±23.8a	184.5±33.6a	93.2±22.8	121.4±22.5	48.3	0.001
Placebo	60	349.3±12.8	261.6±19.4	212.6±48.6	134.8±26.9	129.4±12.9	39.1	0.001
F-value	–	0.33	0.41	2.57	14.7	21.2	–	–
P-value	–	0.37	0.33	0.02	0.01	0.01	–	–

a Compared with the other groups, P<0.05. PVR, pulmonary vascular resistance.

Measurement of the level of secondary variables SOD, MDA, AngII and NO in left atria blood before and 30 min after treatment with CPB

The left atrium blood SOD and NO value was significantly higher, whereas the MDA value was significantly lower in the telmisartan group than that in the placebo group 30 min after treatment with CPB. As for AngII, there was no difference between the captopril and telmisartan groups, compared with the placebo group 30 min after CPB (Table IV).

Table IV. Measurement of the level of secondary variables SOD, MDA, AngII and NO in left atria blood before and 30 min after treatment with CPB.

Table IV.

Measurement of the level of secondary variables SOD, MDA, AngII and NO in left atria blood before and 30 min after treatment with CPB.

	Groups	Case no.	Before CPB	1/2 h after CPB	F-value	P-value
SOD (IU/ml)	Telmisartan	60	131.6±15.7	171.7±49.3	21.5	0.002
	Captopril	60	138.9±12.8	172.6±22.8	58.3	0.001
	Placebo	60	134.9±14.8	141.6±16.4	19.1	0.010
F-value		–	0.33	0.41	–	–
P-value		–	0.37	0.33	–	–
MDA (nmol/ml)	Telmisartan	60	2.28±0.14	3.38±1.02	4.37	0.017
	Captopril	60	2.39±0.21	3.25±0.97	5.56	0.011
	Placebo	60	2.52±0.17	4.63±1.25	2.71	0.026
F-value		–	0.39	12.5	–	–
P-value		–	0.66	0.01	–	–
AngII (pg/ml)	Telmisartan	60	77.4±12.81	168.4±10.9	2.38	0.021
	Captopril	60	80.4±13.9	166.4±12.8	1.98	0.024
	Placebo	60	81.2±10.6	189.7±21.3	1.28	0.031
F-value		–	0.62	21.4	–	–
P-value		–	0.39	0.02	–	–
NO (µmol/l)	Telmisartan	60	38.4±11.3	78.2±22.4	10.29	0.018
	Captopril	60	35.7±14.8	74.4±23.5	11.33	0.014
	Placebo	60	36.8±10.9	43.8±18.7	9.82	0.016
PMN (×109/l)	Telmisartan	60	0.28±0.56	3.72±1.15	7.87	0.023
	Captopril	60	0.35±0.76	2.41±1.73	6.59	0.032
	Placebo	60	0.44±0.21	9.33±0.29	11.33	0.001
F value			0.38	9.94
P value			0.72	0.002

[i] MDA, malondialdehyde.

Complications and hospital time

In the present study, we found that, 24 patients experienced varying degrees of cough in the captopril group, whereas no symptoms of cough were evident in the telmisartan group (P<0.05). Hospitalization time was compared for the three groups of patients and it was found to be significantly shorter in the telmisartan group compared to the captopril and placebo groups. The difference was statistically significant (P<0.05) (Table V).

Table V. Complications and hospital time.

Table V.

Complications and hospital time.

Groups	Case no.	Cough	Hospital time (days)
Telmisartan	60	0	7.87±1.3
Captopril	60	24	9.36±2.82
Placebo	60	2	10.6±1.44
P-value	–	0.01	0.01

Discussion

During CPB, a large number of oxygen-free radicals are generated in the lung following ischemia/reperfusion leading to the leukocyte aggregation and activation of the complement (1). This is an important mechanism leading to CPB after lung injury (2–4). Therefore, the protective effect of lung ischemia reperfusion injury following cardiopulmonary bypass has attracted considerable attention (5). PMN aggregation is important in the pathogenesis of acute lung injury after cardiopulmonary bypass (11). Neutrophil aggregation in the lung releases a variety of enzymes and generates a large number of oxygen-free radicals by degranulation. Additionally, neutrophil aggregation induces damage to endothelial cells and strong lipid peroxidation, resulting in lung injury (6,12). In the present study, the PMN levels in the three groups of patients after 30 min of CPB were significantly higher than those prior to treatment with CPB (P<0.05).

After CPB, the patient has a certain degree of PMN aggregation. Subsequent to pretreatment with captopril and telmisartan, the difference was decreased compared to the placebo group. This difference was statistically significant (P<0.05). The results indicated that preoperative preconditioning has a positive effect on reducing the aggregation of PMN in the lung after CPB.

Captopril, a compound that belongs to the angiotensin-converting enzyme inhibitors mainly affects the renin-angiotensin system (RAS) (9). Captopril inhibits the release of BK, which in turn, inhibits the increase of endogenous BK. At present, BK acts as a trigger of pretreatment. Additionally, BK acts on the endothelium of the BK-β2 receptor, which induces a rapid and transient translocation of protein kinase C, triggering the release of endogenous NO and PGI2 (8,13). NO is capable of inhibiting the adhesion of PMN and endothelial cells, promotes the relaxation of blood vessels and reduces vascular permeability. In the present study, following pretreatment with captopril and telmisartan, the NO in left atrial blood was significantly higher than that in the placebo group (P<0.05).

In the absence of NO releases, cGMP levels were increased, which decreased the adhesion and aggregation of neutrophils in the lung, thereby reducing lung injury. Telmisartan is an angiotensin receptor inhibitor that binds with the AngII receptor with AT I receptor subtype. Previous findings suggest that, telmisartan has no agonist effect on AT I receptor site (14,15). Therefore, telmisartan can be combined with AT receptor for a relatively long period of time. In addition to other receptors, such as AT2, telmisartan showed no affinity. Telmisartan does not inhibit renin, nor block ion channels, and does not exert an inhibitory effect on angiotensin-converting enzyme. In the present study, we found that in the captopril group, 24 patients experienced varying degrees of cough symptoms, whereas in the telmisartan group, no obvious cough symptoms were evident (P<0.05). Hospitalization time was compared in the three groups of patients and was significantly shorter in the telmisartan group compared to the captopril and placebo groups, with the difference being statistically significant (P<0.05).

In conclusion, the use of telmisartan as a pretreatment drug prior to treatment with CPB is recommended in the prevention of pulmonary ischemia and reperfusion injury. The effect of telmisartan and captopril in the prevention of pulmonary ischemia reperfusion injury was virtually identical. However, telmisartan significantly improved the cough symptoms and other adverse reactions of captopril in protecting lung ischemia reperfusion injury.

References