ARTICLE IN PRESS doi:10.1510/icvts.2009.203729 Editorial
www.icvts.org
Institutional report - Cardiopulmonary bypass
Department of Cardiovascular Surgery, Akita University School of Medicine, Hondo 1-1-1, Akita, 010-8543 Japan b Department of Cardiovascular Surgery, National Cardiovascular Center, Japan
a
Abstract
Pressure overload was induced in four-week-old male rats by abdominal aortic constriction (AC). Under pentobarbital anesthesia (60 mgykg body weight), the abdominal aorta was isolated just below the diaphragm and constricted to an outside diameter of 0.45 mm with a 6-0 silk suture. The diameter of the constriction was regulated by using a blunted 26 G needle (0.45 mm OD) as a template. Control (C) animals underwent full sham operations without constriction of the aorta.
The heart was excised under pentobarbital anesthesia (60 mgykg body weight) and then mounted on an aortic cannula (2.0 mm OD) on a perfusion apparatus. The Lan-
Brief Case Report Communication
2.3. In vitro perfusion of isolated hearts
Historical Pages
䊚 2009 Published by European Association for Cardio-Thoracic Surgery
2.2. Induction of hemodynamic overload
Nomenclature
*Corresponding author. Tel.: q81-18-884-6135; fax: q81-18-836-2625. E-mail address:
[email protected] (H. Yamamoto).
Male Wistar rats were used in all studies. The animals received humane care in compliance with the ‘Principles of Laboratory Care’ formulated by the National Society for Medical Research and the ‘Guide for the Care and Use of Laboratory Animals’ published by the National Institutes of Health (NIH publication No. 85-23, revised 1996).
Best Evidence Topic
2.1. Animals
State-of-the-art
Pressure overload-induced myocardial hypertrophy has been shown to result in a reduced tolerance to ischemia in terms of cardiac function w1–4x and coronary vasodilator reserve w5, 6x. In hypertensive patients without coronary artery stenosis, altered coronary vasodilator reserve is associated with left ventricular (LV) diastolic dysfunction w7x. Hypertrophied hearts exhibit a greater LV diastolic dysfunction after ischemia than does the non-hypertrophied heart, the cause of which has been speculated to be abnormalities in myocardial perfusion w3x, recruitment of anaerobic glycolysis w2, 4x, and coronary vascular turgor effect w8x. It has been demonstrated that the use of a high perfusion pressure resulted in improved post-ischemic recovery w9x, because relative under perfusion during reperfusion is thought to be responsible for the reduced tolerance to ischemia of the hypertrophied myocardium. On the other hand, coronary perfusion pressure is a determinant of myocardial distensibility, and a high perfusion pressure is known to increase myocardial stiffness w10–12x, which may cause post-ischemic diastolic dysfunction in hypertrophied hearts. The present study was designed to investigate the effect of coronary perfusion pressure during reperfusion on LV function in the post-ischemic hypertrophied heart.
Follow-up Paper
2. Materials and methods
Negative Results
1. Introduction
Proposal for Bailout Procedure
Keywords: Coronary turgor effect; Ischemia; Reperfusion; Myocardial stiffness; Pressure-overload hypertrophy
ESCVS Article
We investigated the effect of coronary perfusion pressure on post-ischemic left ventricular (LV) diastolic function in the hypertrophied heart. LV pressure overload was induced in four-week-old rats by abdominal aortic constriction (AC), with controls (C) undergoing sham operations. At six weeks of age, isolated Langendorff-perfused hearts (perfusion pressures: 75 and 110 mmHg in C and AC hearts, respectively) were subjected to hypothermic global ischemia (15 8C, 210 min) followed by 65 min of reperfusion (group I: C hearts subjected to aerobic perfusion alone, group II: C hearts subjected to ischemiayreperfusion, group III: AC hearts subjected to aerobic perfusion alone, group IV: AC hearts subjected to ischemiayreperfusion; ns6ygroup). LV end-diastolic pressure (LVEDP) at a constant balloon volume was assessed under perfusion pressures of 110, 75, and 0 mmHg during aerobic perfusion alone (groups I and III) or postischemic perfusion (groups II and IV). The LVEDP differences between perfusion pressures of 75 and 110 mmHg were 6.2"3.2, 3.2"2.7, 3.2"1.5, and 12.8"4.2* mmHg in groups I, II, III, and IV, respectively (*P-0.05 vs. group III). Pressure overload-induced hypertrophied hearts exhibit post-ischemic diastolic dysfunction, which may be caused partly by the enhanced coronary vascular turgor effect on myocardial stiffness. 䊚 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
Institutional Report
Received 26 January 2009; received in revised form 22 June 2009; accepted 23 June 2009
Protocol
Hiroshi Yamamotoa,*, Fumio Yamamotoa, Hajime Ichikawab
Work in Progress Report
Enhanced coronary vascular turgor effect on post-ischemic diastolic function in hypertrophied hearts
New Ideas
Interactive CardioVascular and Thoracic Surgery 9 (2009) 605–608
ARTICLE IN PRESS 606
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gendorff technique was employed at perfusion pressures of 75 mmHg (100 cmH2O) and 110 mmHg (150 cmH2 O) in the C and AC hearts, respectively. These perfusion pressures were chosen to provide similar basal coronary flowyunit heart weight in the C and AC hearts. The perfusion medium was a modified bicarbonate buffer of the following composition (in mmolyl): NaCl 118.5, NaHCO3 25.0, KCl 4.8, MgSO4 1.2, KH2PO4 1.2, CaCl2 1.4, and glucose 11.0. The buffer was continuously gassed with 95% oxygen and 5% carbon dioxide (pH 7.4 at 37 8C). After cannulation, an ultra-thin balloon w13x was inserted into the LV through the mitral valve, and two silver wires were attached to the left atrium and the aortic cannula, following excision of the right atrium, to enable atrial pacing. 2.4. Experimental protocols The experimental protocols are shown in Fig. 1. Isolated hearts from rats of six weeks of age were divided into four groups: C hearts subjected to aerobic perfusion alone (group I, ns6), C hearts subjected to ischemia and reperfusion (group II, ns6), AC hearts subjected to aerobic perfusion alone (group III, ns6), and AC hearts subjected to ischemia and reperfusion (group IV, ns6). At the end of a 15-min-stabilization period, the intraventricular balloon was inflated to give an LV end-diastolic pressure (LVEDP) of 12 mmHg during atrial pacing at 300 beatsymin, and LV systolic pressure (LVSP) and coronary flow were measured 20 min later. In groups I and III, to assess the effect of a change in coronary vascular turgor on cardiac function in non-ischemic hearts, the perfusion pressure was changed (from 75 to 110 mmHg in group I and from 110 to 75 mmHg in group III), and 1 min later, LVEDP, LVSP, and coronary flow were measured. Subsequently, to eliminate the coronary vascular turgor effect (i.e. to assess myocardial stiffness without coronary perfusion) in groups I and III, the perfusion pressure was changed to 0 mmHg (total coronary occlusion), and 1 min later, LVEDP was measured. In groups II and IV, the balloon volume was measured and then adjusted to obtain an LVEDP of 4 mmHg, pacing was
Fig. 1. Experimental protocols after a stabilization period. The perfusion pressure (in mmHg) is shown as a value in each column. Group I, shamoperated control hearts subjected to aerobic perfusion alone; group II, shamoperated control hearts subjected to ischemia and reperfusion; group III, aortic constriction hearts subjected to aerobic perfusion alone; group IV, aortic constriction hearts subjected to ischemia and reperfusion; ns6ygroup.
stopped, and the heart was arrested with a 2-min infusion, via a roller pump, of St Thomas’ Hospital cardioplegic solution (in mmolyl; NaCl 110.0, KCl 16.0, MgCl2 16.0, CaCl2 1.2, and NaHCO3 10.0; pH adjusted to 7.8) at 15 8C. This was followed by 210 min of hypothermic (15 8C) global ischemia. C hearts (group II) and AC hearts (group IV) were normothermically (37 8C) reperfused at perfusion pressures of 75 and 110 mmHg, respectively, for 65 min (initial 45 min: unpaced, balloon deflated; subsequent 20 min: paced at 300 beatsymin, balloon inflated to the volume giving an LVEDP of 12 mmHg pre-ischemia). After measurements of LVEDP, LVSP and coronary flow during atrial pacing at 300 beatsymin, to assess the effect of a change in coronary vascular turgor on cardiac function in post-ischemic hearts, the perfusion pressure was then changed (from 75 to 110 mmHg in group II and from 110 to 75 mmHg in group IV), and 1 min later, LVEDP, LVSP, and coronary flow were measured. Finally, to eliminate the coronary vascular turgor effect in groups II and IV, the perfusion pressure was changed to 0 mmHg (total coronary occlusion), and 1 min later, LVEDP was measured. 2.5. Statistical analysis Data are reported as means"S.D. of the means. Multiple comparisons between groups were performed by using oneway analysis of variance with post-hoc analysis by means of the BonferroniyDunn procedure. Comparisons between the two groups were performed using Student’s t-test. A probability of -5% (P-0.05) that a difference between groups occurred by chance was accepted as being statistically significant. 3. Results 3.1. Basal characteristics At six weeks of age, LV wet weight was significantly greater in the AC hearts than in the C hearts (926"127 and 641"44 mg, respectively). Body weight of the AC rats was significantly less than that of the C rats (167"22 and 212"22 g, respectively). LV dry weightybody weight ratio was significantly greater in the AC hearts than in the C hearts (5.57"0.34 and 3.08"0.20 mgyg, respectively). There were no differences in the balloon volume giving an LVEDP of 12 mmHg between the groups (259"78, 167"49, 159"64, and 158"54 ml in groups I, II, III, and IV, respectively). In the hearts subjected to ischemia and reperfusion, there was no difference between groups II and IV in pre-ischemic coronary flowyunit heart weight (15.8"1.7 and 13.9"2.9 mlyminyg wet weight, respectively). The infusion volume of St Thomas’ Hospital cardioplegic solution was adjusted so as to administer a similar total volumey unit heart weight to group II and group IV (20.1"2.2 and 21.5"2.0 mlyg wet weight, respectively). 3.2. Effects of changes in perfusion pressure on LVEDP and LVSP In group I, when the perfusion pressure was increased from 75 to 110 mmHg, LVEDP and LVSP increased (LVEDP: see Table 1, LVSP: 122"10 and 136"12 mmHg, respec-
ARTICLE IN PRESS H. Yamamoto et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 605–608
3.4. Effects of ischemia and reperfusion on the coronary vascular turgor effect
LVEDP at PP110
LVEDP at PP75
LVEDP at PP110
12 12
18.2"3.2 NM
NM 15.2"5.9
NM 18.3"3.2
LVEDP at PP110
LVEDP at PP75
LVEDP at PP110
LVEDP at PP75
12 12
8.8"1.5 NM
NM 42.0"14.2
NM 29.2"10.5
LVEDP difference
C I (mmHg) II (mmHg)
AC III (mmHg) IV (mmHg)
6.2"3.2 3.2"2.7
The LVEDP differences between the perfusion pressures of 75 and 110 mmHg are shown in Table 1. There was no difference in the LVEDP difference between groups I and II (Ps0.0963). The LVEDP difference in group IV was significantly greater than those in group III (P-0.0001). 3.5. Effects of ischemia and reperfusion on myocardial stiffness without coronary perfusion
3.2"1.5 12.8"4.2*
The results from the present study demonstrated i) LV diastolic dysfunction after cardioplegic arrest and hypothermic ischemia in hypertrophied hearts produced by a 2-week pressure overload in four-week-old rats, and ii) a greater coronary vascular turgor effect on the post-ischemic diastolic function in hypertrophied hearts than in nonhypertrophied hearts.
C
LVEDP at PP0 (mmHg)
AC
I
II
III
IV
5.3"1.0
6.2"2.2
4.0"1.5
7.3"2.0
Groups
AC II
III
IV
– 0.4126 0.1956 0.0583
0.4126 – 0.0417 0.2551
0.1956 0.0417 – 0.0032
0.0583 0.2551 0.0032 –
P-value, probability value; LVEDP, left ventricular end-diastolic pressure; C, sham-operated control; AC, aortic constriction; Group I, C hearts subjected to aerobic perfusion alone; Group II, C hearts subjected to ischemia and reperfusion; Group III, AC hearts subjected to aerobic perfusion alone; Group IV, AC hearts subjected to ischemia and reperfusion (ns6ygroup).
Brief Case Report Communication
I
Historical Pages
I II III IV
C
Nomenclature
Table 3 Results (P-values) of post-hoc analysis for LVEDP at a perfusion pressure of 0 mmHg
Best Evidence Topic
Values are expressed as means"S.D. of means. PP0, perfusion pressure of 0 mmHg; LVEDP, left ventricular end-diastolic pressure; C, sham-operated control; AC, aortic constriction; Group I, C hearts subjected to aerobic perfusion alone; Group II, C hearts subjected to ischemia and reperfusion; Group III, AC hearts subjected to aerobic perfusion alone; Group IV, AC hearts subjected to ischemia and reperfusion (ns6y group).
State-of-the-art
Groups
Follow-up Paper
Table 2 LVEDP at a perfusion pressure of 0 mmHg (1 min after total coronary occlusion)
Negative Results
In group I, when the perfusion pressure was increased from 75 to 110 mmHg, coronary flow increased (14.9"3.4 and 20.0"4.7 mlyminyg wet weight, respectively). In group II, coronary flow decreased in the post-ischemic period at the same perfusion pressure as pre-ischemia (i.e. 75 mmHg). When the perfusion pressure was increased from 75 to 110 mmHg, post-ischemic coronary flow increased (10.7"2.0 and 14.1"2.2 mlyminyg wet weight, respectively). In group III, when the perfusion pressure was decreased from 110 to 75 mmHg, coronary flow decreased (9.5"2.0 and 6.0"1.7 mlyminyg wet weight, respectively). In group IV, coronary flow decreased in the postischemic period at the same perfusion pressure as pre-ischemia (i.e. 110 mmHg). When the perfusion pressure was decreased from 110 to 75 mmHg, post-ischemic coronary flow decreased (7.8"2.7 and 5.8"2.2 mlyminyg wet weight, respectively). At identical perfusion pressures (75 or 110 mmHg) in groups II and IV, the post-ischemic coronary flow in group II was significantly greater than that in group IV.
4. Discussion Proposal for Bailout Procedure
3.3. Effects of changes in the perfusion pressure on coronary flow
ESCVS Article
tively). In group II, LVEDP increased in the post-ischemic period at the same perfusion pressure as pre-ischemia (i.e. 75 mmHg). When the perfusion pressure was increased from 75 to 110 mmHg, post-ischemic LVEDP and LVSP increased (post-ischemic LVEDP: see Table 1, post-ischemic LVSP: 100"22 and 108"20 mmHg, respectively). In group III, when the perfusion pressure was decreased from 110 to 75 mmHg, LVEDP and LVSP decreased (LVEDP: see Table 1, LVSP: 135"20 and 92"22 mmHg, respectively). In group IV, LVEDP increased in the post-ischemic period at the same perfusion pressure as pre-ischemia (i.e. 110 mmHg). When the perfusion pressure was decreased from 110 to 75 mmHg, post-ischemic LVEDP and LVSP decreased (postischemic LVEDP: see Table 1, post-ischemic LVSP: 138"15 and 104"5 mmHg, respectively).
Institutional Report
Values are expressed as means"S.D. of means. *P-0.05 vs. Groups I, II, and III. PP75 , perfusion pressure of 75 mmHg; PP110, perfusion pressure of 110 mmHg; LVEDP, left ventricular end-diastolic pressure; C, sham-operated control; AC, aortic constriction; Group I, C hearts subjected to aerobic perfusion alone; Group II, C hearts subjected to ischemia and reperfusion; Group III, AC hearts subjected to aerobic perfusion alone; Group IV, AC hearts subjected to ischemia and reperfusion; NM, not measured (ns6ygroup).
In all hearts, within 1 min after total coronary occlusion, LVEDP decreased and became stable enough to be measured precisely. There was no difference in LVEDPs at the perfusion pressure of 0 mmHg between groups I and II or between groups I and III (Table 2). LVEDP at the perfusion pressure of 0 mmHg in group IV was significantly greater than those in groups I, II, and III (Table 2). The results of inter-group post-hoc analysis for LVEDP are shown in Table 3.
Protocol
Post-ischemia
LVEDP at PP75
Work in Progress Report
Pre-ischemia
New Ideas
Group
Editorial
Table 1 LVEDP at perfusion pressures of 75 and 110 mmHg
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4.1. Effects of ischemia and reperfusion on the coronary vascular turgor effect Apstein and colleagues w10–12x have demonstrated that the erectile effect of coronary perfusion (‘coronary vascular turgor’) is a significant component of wall stiffness. Vogel and colleagues w12x demonstrated in their study, dealing with the coronary vascular erectile effect on LV wall stiffness in non-hypertrophied hearts, that the decrease in LVEDP during transient coronary occlusion was greater in ischemia-induced damaged hearts than in nonischemic control hearts. It is, therefore, conceivable that changes of perfusion pressure in hypertrophied hearts might contribute to the post-ischemic diastolic dysfunction. The results from the present study suggest that after myocardial ischemia and reperfusion, the coronary vascular turgor effect on LV diastolic function is enhanced in the pressure overload-induced hypertrophied heart but not in the nonhypertrophied heart. The post-ischemic LVEDP was significantly greater in group IV than in group II, although coronary flowyunit heart weight was significantly less in group IV than in group II, suggesting that the post-ischemic diastolic dysfunction is not caused by greater coronary flow. These results contradict those of a study suggesting that coronary flow is a primary determinant of the erectile contribution to wall stiffness w12x. 4.2. Effects of ischemia and reperfusion on myocardial stiffness without coronary perfusion In the present study, there was no difference in LVEDP at the perfusion pressure of 0 mmHg between groups I and II or between groups I and III, whereas LVEDP at PP0 in group IV was significantly greater than those in groups III, suggesting that in the absence of a coronary vascular turgor effect, i) myocardial stiffness increases after ischemia and reperfusion in the pressure overload-induced hypertrophied heart, and ii) pressure overload-induced hypertrophy itself does not affect myocardial stiffness. 5. Conclusions Our results suggest that cardiac surgery in a heart with hypertension-induced hypertrophy is likely to be associated with a greater risk of post-ischemic diastolic dysfunction
compared to a non-hypertrophied heart, which is caused partly by the enhanced coronary vascular turgor effect on myocardial stiffness. References w1x Menasche P, Grousset C, Apstein CS, Marotte F, Mouas C, Piwnica A. Increased injury of hypertrophied myocardium with ischemic arrest: preservation with hypothermia and cardioplegia. Am Heart J 1985; 110:1204–1209. w2x Gaasch WH, Zile MR, Hoshino PK, Weinberg EO, Rhodes DR, Apstein CS. Tolerance of the hypertrophic heart to ischemia. Studies in compensated and failing dog hearts with pressure overload hypertrophy. Circulation 1990;81:1644–1653. w3x Buser PT, Wikman-Coffelt J, Wu ST, Derugin N, Parmley WW, Higgins CB. Post-ischemic recovery of mechanical performance and energy metabolism in the presence of left ventricular hypertrophy A 31P-MRS study. Circ Res 1990;66:735–746. w4x Anderson PG, Allard MF, Thomas GD, Bishop SP, Digerness SB. Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts. Circ Res 1990;67:948–959. w5x Wangler RD, Peters KG, Marcus ML, Tomanek RJ. Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator reserve. Circ Res 1982;51:10–18. w6x Marcus ML. Effects of cardiac hypertrophy on the coronary circulation. In: Marcus ML, editor. The coronary circulation in health and disease. New York: McGraw Hill Inc, 1990;285–306. w7x Galderisi M, Cicala S, Caso P, Simone LD, D’Errico A, Petrocelli A, de Divitiis O. Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertention. Am J Cardiol 2002;90:860–864. w8x Apstein CS, Menasche P, Lorell BH. Hypoxia, ischemia, and the hypertrophied myocardium: basic medical and surgical considerations. In: Swynghedauw B, editor. Cardiac hypertrophy and failure, 1st edition. Paris: INSEMyJohn Libbey Eurotext, 1990;65–87. w9x Snoeckx LHEH, van der Vusse GJ, Reneman RS. The effects of global ischemia and reperfusion on compensated hypertrophied rat hearts. J Mol Cell Cardiol 1990;22:1439–1452. w10x Vogel WM, Briggs LL, Apstein CS. Separation of inherent diastolic myocardial fiber tension and coronary vascular erectile contributions to wall stiffness of rabbit hearts damaged by ischemia, hypoxia, calcium paradox and reperfusion. J Mol Cell Cardiol 1985;17:57–70. w11x Apstein CS, Wexler LF, Vogel WM, Weinberg EO, Ingwall JS. Comparative effects of ischemia and hypoxia on ventricular relaxation in isolated perfused hearts. In: Grossman W, Lorell BH, editors. Diastolic relaxation of the heart, 1st edition. Boston: Martinus Nijhoff, 1988;169–184. w12x Vogel WM, Apstein CS, Briggs LL, Gaasch WH, Ahn J. Acute alterations in left ventricular diastolic chamber stiffness. Role of the ‘erectile’ effect of coronary arterial pressure and flow in normal and damaged hearts. Circ Res 1982;51:465–478. w13x Curtis MJ, MacLeod BA, Tabrizchi R, Walker MJA. An improved perfusion apparatus for small animal hearts. J Pharmacol Methods 1986;15:87– 94.
