increased ventricular fibrillation threshold with severe myocardial ischemia

Increased ventricular fibrillation threshold with severe myocardial ischemia

The ventricular fibrillation threshold (VFT) is a measure of myocardial electrical vulnerability to exogenous electrical stimulation. Previous studies have shown that the VFT is inversely related to ischemia. We studied the relation of the VFT to myocardial blood flow (MBF) during ischemia produced by interruption of blood flow to the left anterior descending coronary artery, and severe ischemia produced by retrograde bleeding an ischemic segment of myocardium. The VFT with severe ischemia (8.8 k 1.3 mA; MBF 0.024 k 0.01 ml/min/gm tissue), although lower than nonischemic control values (14.2 i 2.0 mA; 0.76 i 0.05; both p < 0.05), was higher than that obtained with made&e ischemia (4.6 I? 0.9 mA; 0.15 + 0.02 ml/min/gm; both, p < 0.05). Thus the relationship between the VFT and MBF is nonlinear. Interventions which cause the VFT to rise may do so by worsening rather than improving regional MBF. (AM HEART J 103:966, 1982,)

Jeffrey Fisher, M.D., Edmund H. Sonnenblick, M.D., and Edward S. Kirk, Ph.D. Bronx, N. Y.

The ventricular fibrillation threshold (VFT) is a measure of myocardial electrical vulnerability to exogenous current. Prior studies have shown that the VFT decreases for some time following acute occlusion of the coronary arteries.le5 This increased vulnerability to fibrillation has been directly related to ischemia, with linear relationships demonstrated in dogs between VFT and antegrade coronary artery Aow,~ subsequent infarct size,7 myocardial blood flow (MBF),s and coronary collateral circulation.g

Despite the abundant evidence relating myocardial electrical vulnerability to ischemia, other mechanisms must exist to explain, for example, the ventricular arrhythmias that occur with reperfusion of an occluded coronary artery.‘O-‘” In addition, the greatest dispersion in refractory periods occurs in areas of myocardium with intermediate degrees of ischemia.13 Since dispersion of refractoriness has been related to electrical vulnerability, this suggests the possibility that the relationship between ischemia and VFT may be nonlinear. Moreover, it has been noted that after coronary artery occlusion, spontaneous ventricular arrhythmias decreased with more severe ischemia produced by retrograde bleed-

From the Cardiovascular Research Laboratories, Division of Cardiology, Albert Einstein College of Medicine.

This study was supported in part by Grant No. 5 R01 HL23171 from the National Institutes of Health, Bethesda, Md.

Received for publication Nov. 12. 1981; revision received Jan. 26, 19%: accepted Feh. 12, 1982.

Reprint requests: Jeffrey Fisher, M.D., Division uf Cardiology, The New York Hospital-Cornell Medical Center, 525 E. 68th St., New York, NY 100’1.

966

ing of the cannulated distal artery, thus depriving the myocardium of collateral flow.14 In this study, we investigated the relationship between MBF and VFT. Specifically, we sought to find whether severe ischemia (as produced by retrograde bleeding) con- ferred a protective effect on myocardial vulnerability to VF.

METHODS

General preparation. Ten mongrel dogs weighing from 18 to 30 kg were anesthetized with 2 mg/kg of urethane- chloralose (4 gm chloralose and 40 gm urethane dissolved in polyethylene glycol to total volume 100 ml) and respi- rated through a tracheostomy with 100% oxygen delivered via Harvard pump. After midsternal thoracotomy, the heart was suspended in a pericardial cradle and the midleft anterior descending coronary artery (LAD) was isolated.

Pacing. Bipolar copper hook pacing electrodes (S,) (0.07 mm thickness) were sewn onto the epicardial surface of the right ventricle (RV) 1 cm below the conus of the pulmonary artery 2 mm apart (Fig. 1). Ligatures were placed around the isolated LAD artery and a test occlusion of the LAD artery was performed for 1 minute. The bipolar copper hook stimulating electrodes (S,) were sewn 2 mm apart onto the left ventricular (LV) epicardial surface at the interface of visible cyanosis between ischemic and normally perfused tissue in all dogs. One subgroup of five dogs had a second bipolar copper hook stimulating electrode placed in the nonischemic zone of the LV and a second subgroup (n = 5) had the second electrode placed in the center of visible cyanosis. The cervical thoracic sympathetic chain was dissected and interrupted bilaterally by surgical incision at the level of the stellate ganglia. The sinus node was crushed with

0002.8703/82/060966 + 07$00.70/O 11’ 1982 The C. 6'. Mosby Co.

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Number 6 Increased VFT with lowered MBF in ischemic LV 967

Fig. 1. The mid-LAD coronary artery is cannulated with a “Y” tube. Arm “A” perfuses the LAD from the carotid artery, while arm “B” measures peripheral coronary pressure during baseline VFT determinations. During ischemic trials, arm A is clamped, and for severe ischemia, A is clamped while retrograde flow is measured volumetrically. The pacing electrode (S,) is located 1 cm below the pulmonary artery (PA) conus, and the stimulating electrode is placed at the border of visual ischemic cyanosis and within the area of visible cyanosis or in the nonischemic zone of the left ventricle. Ao = aorta.

external clamps. The heart was then paced at a rate of 120 bpm, at 10 to 30 V, each impulse being of 10 msec duration, delivered to the RV pacing electrode from a Grass S-88 stimulator in series with a Grass stimulus isolation unit (Fig. 2). A lead II ECG signal was monitored on a Xetex electronics Model OS2000 storage oscilloscope which also displayed the stimuli. Calibrations for each experiment were performed using a current probe amplifi- er. Visual assessment of VFT was checked periodically by photography.

Ventricular fibrillation threshold. Twelve paced beats were followed by a compensatory pause of 100 msec timed from the last R wave. A train of 350 monophasic pulses, each of 1 msec duration, was delivered to one of the stimulating electrodes on the LV surface. Beginning with the zero current, three trials were given per current in increments of 1 to 2 mA until VF occurred. To avoid spurious decreases in VFT due to repetitive ventricular response, 1 to 2 minutes were allowed to elapse before increasing the VFT after premature ventricular contrac- tions (PVCs) were elicited. Defibrillation at lowest energy possible (10 to 100 wsec) was immediately performed with paddles applied to the pericardium in efforts to avoid myocardial injury and spurious elevation of the VFT. The stimulating electrodes were shielded from the pericardium by a 4 X 4 cm flap of Parafilm M (American Can Compa- ny) to avoid current dispersion. After defibrillation, the animals were allowed 10 to 15 minutes to recover. The VFT was recorded as being zero when spontaneous VF occurred.

Blood flow. One arm of a “Y”-shaped polyethylene catheter directed blood flow from the cannulated left carotid artery to the cannulated LAD (second arm). The third arm of the “Y” recorded peripheral coronary artery perfusion pressure upon a Clevite Brush Mark 260 recorder, and was used to retrogradely bleed the animals (Fig. 1). The VFT was studied in three blood flow conditions: (1) baseline, with the cannulated LAD artery being perfused from the carotid artery; (2) &hernia, with the antegrade perfusion from the carotid clamped but with the blood flow from any existing coronary collateral vessels main- tained; and (3) severe ischemia, produced by retrograde bleeding of the coronary collateral circulation (both pre- vention of antegrade blood flow and runoff of retrograde blood flow into a graduated cylinder). Each condition lasted 10 minutes at which time the VFT was ascer- tained.

Microspheres. Radioactive microspheres, 15 pm in diameter, labeled with the nuclides 141-Ce, 85-S, and 51-Cr (3M Company) were used to measure MBF and cardiac output (CO) with techniques identical to those previously described by this laboratory.‘5,‘” In each case lo6 microspheres suspended in 10 ml of 63% sucrose solution were injected into the left atrium. We used a technique developed in this laboratory,15.‘” in which microspheres were excluded from the LAD region to quantitate the overlap of normally perfused tissue in the ischemic samples. In this procedure the LAD was cannulated and perfused at normal aortic pressures from a two-chambered reservoir which trapped the microspheres

968 Fisher, Sonnenblick, and Kirk June, 1982

American Heart Journal

P=2Hz, 10 MSEC

S--350 MSEC TRAIN 100 Hz, 1 MSEC

PACING ELECTRODE STIMULATING ELECTRODE

+ PULSES

1 1 I I I

-0,5 0 O*l 0,45 1.05SEC

Fig. 2. Schematic representation of equipment and specifics for pacing and producing ventricular fibrillation. See text for details.

destined for the LAD. Later normal perfusion could be restored and ischemic and retrograde bleeding could be interposed as desired. A second set of microspheres was injected during one of the periods of LAD occlusion (ischemia), and a third set was injected during one of the periods of LAD occlusion combined with retrograde bleeding (severe ischemia). At the time of microsphere injec- tions, an arterial sample was withdrawn from the femoral artery for CO computation. After termination of the experiments the hearts were removed and the tissue supplied by the cannulated LAD was visualized by injection of Evan’s blue into the cannula. The hearts were stripped of epicardial fat, and representative 1.5 X 1.5 cm sections of ischemic and nonischemic LV walls were removed. In addition to these samples, all of the tissue stained with blue (which included all of the ischemic tissue as well as some inadvertently included normal tissue) was analyzed in a Searle Analytic Model 1085 gamma scintillation counter with a 3-inch crystal. Punched paper tape from the counter was analyzed by a Wang 2200 S computer which corrected for background and crossover and provided tissue flows in ml/min/gm. CO was calculated from the count data from the blood samples.

MBF technique. As has been shown previously, tissue obtained near the border of the LAD region contained significant numbers of microspheres from the injection made during reservoir perfusion of the LAD.15.16 This shows that tissues supplied by the LAD interdigitates to various degrees with adjacent normally perfused tissue

and cannot easily be separated. Even the samples used for our measurements of flow in the LAD region which were not deliberately near the border of the region showed some amount of overlap with normally perfused tissue. This overlap averaged 4.8 + 1.8% in this experiment. In our view only the tissue supplied by the LAD is made ischemic by LAD occlusion and flow in the interdigitating normal tissue must be subtracted from the measured flows to evaluate the flow in the ischemic tissue.‘” Corrected flows are reported here and are representative of tissue normally supplied exclusively by the LAD. Because of the near zero flows obtained with retrograde bleeding of the LAD, the corrections significantly influenced the absolute levels of flows reported, but it should be emphasized that the conclusions are not altered significantly by omitting this correction.

Data acquisition and analysis. Aortic and peripheral coronary pressures were monitored with Stathem P23Db transducers and recorded on a Clevite Model 260 recorder. Each of the three experimental conditions (control, ischemia, and severe ischemia) were repeated several times in each animal (n = 3.1 i 0.4). Trials of ischemia and severe ischemia were randomly alternated between control runs. In two animals microsphere measurements were not made during ischemia because of spontaneous VF (this did not occur under conditions of severe ischemia in these animals; see below). Ischemic MBFs for these two experiments were calculated by dividing the measured retrograde flows (milliliters per minute) by the mass of ischemic tissue (grams). The blue-stained tissue that was

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Number 6

Table I. Hemodynamic data and VFT ~- -

Severe Control lschemia ischemia

-

Cardiac output (mUmin) 1931 1484 1987 (n = 8) zk 281 + 142 k 250

Mean aortic pressure (mm Hg) 87.3 73.4 76.7 (n = 10) t 3.2 t 3.8* k 2.5’

Myocardial blood flow (mllminigm) 0.76 0.15 u.024 (n = 10) It 0.05 + 0 lp* - . - * 0.01’1

VFT (mA) 14.2 4.6 8.6 (n = 10) t 2.0 ? 0.9* -+ 1.3*t

- *p < 0.05 (to cuntrol). tp < 0.05 (to ischemia).

separated from the heart overestimates the mass of ischemic tissue as a result of inadvertent inclusions of normal tissue. Fortunately, the microspheres injected during reservoir perfusion of the LAD permitted correction for this overlap and the calculated ischemic mass was used in the blood flow calculation. This calculation of ischemic MHF has been shown to yield values which correspond closely to values obtained via microspheres.17 Significance of paired and unpaired data was analyzed using two-tailed t tests, and significance between groups of data were tested with a one-way analysis of variance using the Scheffe procedure. Results are presented as mean k standard error.

RESULTS

Hemodynamics. CO and mean aortic pressure (MAP) in the three experimental conditions are shown in Table I. CO during ischemia (LAD cannula occlusion) was not obtained in two dogs because of spontaneous VF (not occurring with severe ischemia produced by LAD occlusion and retrograde bleeding). The differences in CO in the three groups did not achieve significance. However, MAP was decreased with ischemia and severe ischemia compared with control.

Retrograde blood flow. Retrograde blood flow ranged from 1.0 to 12.0 ml/min (mean = 2.9 +- .l.2 ml/min).

Myocardial blood flow. Transmural MBF under baseline physiologic conditions (no ischemia) was taken as the MBF in the circumflex artery (CX) region (0.51 to 0.98, mean 0.76 f 0.05 ml/min/gm tissue at the time when the balloon apparatus prevented microspheres from entering the LAD region). MBF in the LAD distribution during the two experimental ischemic conditions and at rest in the CX distribution are shown in Table I. With ischemia produced by occlusion of the LAD cannula,

Increased VFT with lowered MBF in ischemic LV 969

-

40 t

01

30 - a10 04

20- 0?

5 2&AA0 lo-

L : 30 11 12

9

0 I I I NORMAL LAD LAD

LAD OCCLUSION OCCLUSION FLOW +

RETROGRADE BLEEDING

I I I 0891 O-23 0.06

MYOCARDIAL BLOOD FLOW IN LAD REGION (ml/min 9-l)

Fig. 3. Results of a representative experiment. 0 = control myocardial flow; l = ischemia; A = severe &hernia. Numbers accompanying symbols refer to order in which trials were performed, and indicate the reproducibility of the VFT. With severe ischemia the VFT rises though it is still lower than control.

MBF was reduced to less than 20% of that occurring during rest (mean = 0.15 * 0.02 ml/min/gm tissue). Severe ischemia produced by simultaneous LAD occlusion and retrograde bleeding reduced regional LAD flow to less than 3% of normal control MBF (mean = 0.024 it 0.01 ml/min/gm tissue).

Arrhythmias. VPCs were noted with LAD occlusion and with LAD occlusion and retrograde bleeding. Spontaneous VF occurred in three dogs during LAD occlusion but did not occur with LAD occlusion and simultaneous retrograde bleeding (this includes one animal which had three episodes of spontaneous VF with LAD cannula occlusion alone).

VFT to MBF relationships. The relationship between VFT in milliamperes and MBF for a representative experiment is shown graphically in Fig. 3. Four trials were performed in each condition. This indicates the reproducibility of the VFT technique with each condition. As has been shown previously, the VFT decreases with LAD occlusion. However, with more severe ischemia produced by simultaneous LAD cannula occlusion and retrograde bleeding, the VFT increases, resulting in a nonlinear relationship between VFT and MBF.

970 Fisher, Sonnenblick, and Kirk June, 1982


A LAD occlusion t retrograde bleeding

,001 ,002 001 .02 a05 0.1 0.2 0.5 1.0 MYOCARDIAL BLOOD FLOW IN LAD REGION (ml / min.9-l)

Fig. 4. VFT (expressed as percent control) and regional blood flow (on logarithmic scale) in the 10 experiments. The VFT is lowest at flows between 0.015 and 0.3 ml/min l g-l tissue, and increases at flow less than 0.015 ml/min l gm-’

The group data are shown in Table I. The VFT decreased significantly from control in both ischemic conditions. Although the VFT with severe ischemia was reduced from control, it was higher than the VFT obtained with LAD occlusion alone (p < 0.03). Retrograde bleeding with LAD occlusion resulted in MBF that was less than 0.02 ml/min/gm tissue (severe ischemia) in nine dogs. In eight of these animals the VFT increased with retrograde bleeding from the value during the milder ischemia caused by LAD occlusion alone. This is shown in Fig. 4 where VFT is expressed as percent control and is plotted against MBF. A logarithmic scale for flow was used to provide greater separation of the points at low flow. When VFT was compared with MBF without reference to the ischemic condition, a clear bimodal distribution was seen. In nine trials with MBF equal to or less than 0.15 ml/min/gm tissue,

, the VFT was nearly twice that of 10 trials where ,MBF ranged between 0.015 and 0.3 ml/min/gm kissue (Fig. 5). The relationship between VFT and MBF was nonlinear-with severe ischemia and extremely depressed MBF the VFT rose.

VFT and stimulating electrode site. As seen in Fig. 6, the site of the stimulating electrode did not significantly alter the values obtained for the VFT in the three MBF conditions. Independent of the stimulating site, the VFT fell with ischemia and rose with retrograde bleeding and worsening of regional MBF.

DISCUSSION

Reproducibility of present VFT technique. The VFT technique has been used to assess myocardial vulnerability to VF with experimental ischemia and

myocardial infarction, and has been employed in the assessment of antiarrhythmicl’ and anti-ischemiclg drugs. Unfortunately, because of the variations in the techniques employed (general preparation, anes- thetics, sympathectomy,20 single pulse vs trains,” type and location of pacing and stimulating elec- trode9, l8 some findings have appeared discordant. Using the present technique we were able to attain reproducible values in the three MBF conditions. In contrast with others,5 we did not find variations in the VFT due to stimulating electrode position, perhaps because of production of only transient ischemia in our model.

Nonlinear relation of VFT to MBF in the ischemic LV. Previous studies have demonstrated a direct relationship between VFT in an ischemic area and the MBF measured directly and indirectly by subsequent infarct size and coronary collateral circulation.‘-” However, prior studies have not investigated the effects of reversible severe ischemia on VFT. We have found that worsened ischemia produced by transient retrograde bleeding of an occluded coronary artery segment produces an increase in VFT compared to coronary occlusion alone. The reason for the increased myocardial electrical stability with more severe ischemia is uncertain. Our data suggest that the severity of ischemia, rather than the mechanism of its production (retrograde bleeding), accounts for the nonlinearity found between VFT and MBF.

Mechanisms of increased VFT with worsened LV ischemia. That the VFT should increase with worsening ischemia is supported by the finding of Bats- ford et al.*“; dispersion of refractory periods was greatest with intermediate levels of ischemia and

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Number 6 Increased VFT with lowered MBF in ischemic LV 971

MYOCARDIAL BLOOD FLOW IN LAD REGION (ml/min -9-l)

Fig. 5. Data from Fig. 4 replotted to show that with severe ischemia (flow < 0.015 ml/min l gm-‘) the VFT is nearly twice that obtained with flows between 0.015 and 0.3 ml/min l gm-’ tissue.

returned toward normal with more severe ischemia. The marked heterogeneity of blood flow found with coronary artery occlusiorP4 may account for the dispersion of refractoriness; worsened ischemia may lead to greater homogeneity of blood flow and decreased proclivity to VF. Harris and Matlockzl found nonlinearity of the VFT with graded degrees of anoxia; with worsened anoxia the VFT rose. Similarly, severe ischemia may lead to metabolic alterations resulting in an electrically inexcitable region of myocardium which may reduce the “criti- cal mass” needed to sustain VF.22

The VFT is also affected by alterations in myocardial diastolic excitability independent of myocardial inhomogeneity of refractoriness,23 and hence changes in regional MBF may be associated with changes in the VFT despite indetectable changes in refractoriness. In addition, retrograde bleeding may remove arrhythmogenic substances and increase myocardial electrical stability to exogenous current despite worsening ischemia, or may elicit cardiac or coronary reflexes with beneficial hemodynamic and electrophysiologic effects.24*25

Conclusions and clinical implications. We have shown that there is a nonlinear relationship between myocardial electrical stability as measured by the VFT and MBF in dogs; at extremely low levels of MBF the VFT increased. The implications of this study are twofold. First, it is possible that with markedly severe ischemia the ventricle is less apt to fibrillate than with less severe reduction in MBF. However, our experimental preparation is quite removed from the clinical setting. Nonetheless, these experimental findings may be viewed in paral-

Normal

0 Border

q lschemic

0 Non-lschemic

LAD occlusion

LAD occlusion +

retrograde bleeding

Fig. 6. A comparison of the percent control ventricular fibrillation threshold (VFT) in the three myocardial blood flow conditions obtained with the three different stimulating electrodes (placed in normal, ischemic, and “border” zones). The site of stimulation does not affect the relative VFT nor the finding that the threshold rises with more severe ischemia (*, t = p < 0.05).

lel with the findings of increased VF and sudden death in patients with nontransmural vs transmural myocardial infarctions after VF2’j and infarction27; both experimentally and clinically it may be safer to be “dead” than alive.2s Attempts to salvage ischemic myocardium via increases in MBF may paradoxical- ly be deleterious to myocardial vulnerability to ventricular arrhythmias. Secondly, this study adds another caveat in the use of the VFT technique: interventions which increase the VFT may do so despite worsening regional MBF.

REFERENCES

1. Wiggers CJ, Wkgria R, Pifiera B: The effects of myocardial ischemia on the fibrillation threshold-the mechanism of spontaneous ventricular fibrillation following coronary occlusion. Am J Physiol 131:309, 1940.

2. Harris AS: Terminal electrocardiographic patterns in experimental anoxia, coronary occlusion, and hemorrhagic shock. AM HEART J 35:895, 1948.

3. Han J: Ventricular vulnerability during acute coronary occlusion. Am J Cardiol 24:857, 1969.

4. Burgess MJ, Abildskov JA, Millar K, Geddes JS, Green LS: Time course of vulnerability to fibrillation after experimental coronary occlusion. Am J Cardiol 27:617, 1971.

5. Roland JM, Dashkoff N, Varghese PJ, Pitt B: Time course of ventricular fibrillation threshold in infarcted and non- infarcted myocardium after acute coronary ligation. AM HEART J 94:336, 1977.

6. Dixon ME, Trank JW, Dobell ARC: Ventricular fibrillation threshold: Variation with coronary flow and its value in assessing experimental myocardial revascularization. J Tho- rat Cardiovasc Surg 47:620, 1964.

7. Bloor CM, Ehsani A, White FC, Sobel BE: Ventricular

972 Fisher, Sonnenblick, and Kirk June. 1982


tibrillation threshold in acute mvocardial infarction and its relation to myorardial inf’arct s-ize. (‘ardiovasc Res 9:468.

1;. Kirk ES: blquivalence 01 retrograde t)I~~od III)\\ and collateral flow f’ollowin:: acute coronary clcclusion (ahstr). (‘irculation

197r,. 62:IIl-(ifi. 1980. Hi. (‘leman hl. Varghese t’<J, Pitt H: Myucardial blood tlow as R

determinant f’actor in the electrical stability 01’ the myocardium. .4~ H~:wI .J 99::)5. 1980.

9. t;arza I).~, White IT, Hall RE, Hluor C&l: E1fec.t oi’coronaq collateral devellqtment on \:entricular fi hrillation threshold. Basic Res Cardiol 69:X 1. 1X.1.

IO. Rattle WE, Naimi S, Avitall B. Hrilla AH, Hanas +JS. Hetr .JM, I,evine H.J: Distinctive time cuurse of ventricular vulnerahil- ity to fibrillation during and after release of coronary ligati~~n. Am -1 Cardiol 34:4% 1X4.

I I. Axelrod PJ, Verrier RI,. Lawn R: Vulnerability to ventric,ular fihrillatiun during acute coronary arterial occlusion and release. Am .I C’ardiol 36:K6, 1X5.

12. Giilker H, Krtimer H, Stephan K, Meesman W: (‘hanges in ventricular fibrillation t.hreshold during repeated short-term coronary occlusion and release. Basic Res Cardiol 72:54’Y, 1977.

21. Harris AS. Matlock It-f’: ‘l‘he etfects $11 ~n~J?tcmic, anosia on t~xc~ital)ilit?-. c,onduction and ref’raltorinehh 01 mammalian cardiac muscle. Am ,I Physiol 140:49:(, 194;.

22. (iarrey FVE: ‘I‘he nature (11’ fihrillatory contra<.titrn I)(’ the heart--~-itX relation to tissue mass and l’orm. Am .I I’h\-sic11 33:xX, 191.1.

Ti. (;aum WE:. Elharrar \‘. .Jirak ‘1’1,. Ziprs. l)P: Influenct, 111 excitabilitv on the ventricular fibrillation thresholds (ah&r). (‘lin Hes i4:.‘liiA, 1976.

1X. Hatsford 1VP. (‘annom 1%. Zaret BL: Kelaticms hetween ventricular rel’ractoriness and regional myocardial blood flow after acute coronary occlusion. Am J Cardiol 41:1083. 1978.

11. Hirata M, Kkuchi Ii, Hashimoto K: Disappearance uf ventricular arrhythmia caused hy coronary occlusion during retrograde hleeding through collaterals. .Jpn circ .J 34:X11. 19;o.

Z-1. hlallillni .I. Schwartz P-J, Zaochetti A: A Sympathetic reflex Plioted by experimental curonary occlusion. Am .J l’hysiol 217:Xl:i 1969.

5. Zucker IH. C’ornish li: Retiex cardictvascular and respirator) ett’etts of serottrnin in conscious and anesthetized dogs. Circ Re> 47:509, I’JXO.

1.5. Hirzel HO. Nelson GR, Sonnenblick EH, Kirk ES: Red&r- bution ot’ collateral blood flow t’rum necrotic to surviving myocardium f’ollowing coronary occlusion in the dog. Circ Res 39:“11, 1976.

16. Patterson HE. Kirk ES: Apparent improvement in canine collateral myocardial blood flow during vasodilation depends on criteria used to identify ischemic myocardium. Circ Res 47:10x. 1981).

%i. Schalf’er 1\.1. ( ‘~~t)h 1,:2: Recurrent ventricular hhrillation and modes (11 dual h in survivors OF out-oi’-hospital ventricular fibrillation. N Engl cI Med 293:359, 1975.

L’Y. C~~nnom IIS. I,evy W. Cohen 1,s: The shtrrt and long-term progn(& (11’ patients with transmural and nontransmural myocardial infarction. Am .J Med 61:46?, 19’;fi.

28. 1Varrttn *IV: I)i hi dolce morte. It may he safer to be dead than alive il%iitoriall. (‘irculation 5O:-t15. 197.1.

increased ventricular fibrillation threshold with severe myocardial ischemia

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