Total and regional aortic regurgitation
Herman L. Falsetti, Robyn J. Carroll James A. Cramer With Iowa
the technical city, Iowa
myocardial
blood
in
M.D.
assistance
of Rick
A. Lenth
The mechanism of angina pectoris in patients with aortic valve diseaseand aortic regurgitation, in particular, is a subject of great interest. It is suspected that these patients may have inadequate coronary flow in the presence of normal coronary arteries. Studies on the femoral, brachial, and subclavian arteries of patients with aortic regurgitation have shown considerable retrograde 00w.‘-~ These studies have been conflrmed in d0gs.j Experimental studies in dogs with mechanically-induced aortic regurgitation6, 7 have demonstrated reverse diastolic coronary flow. This has also been documented in patients using coronary electromagnetic ilow probes at surgery.” Coronary angiographic studies have demonstrated abnormal phasic coronary tlow in patients with aortic valve disease.sAlthough it is known”-” that phasic coronary blood flow in the epicardial arteries shifts from diastole to systole in the presence of acute aortic regurgitation, controversy still exists whether there are compensatory regional coronary flow changes which maintain adequate blood flow to the myocardium. The purpose of this study was to investigate total and regional myocardial blood flow and see if they were related to the degree of induced aortic regurgitation in acute, open-chest dogs. From the Cardiovascular Center, Cardiovascular ment of Internal Medicine, University of Iowa, tration Hospitals, Iowa City, Iowa 52242.
Division, and Veterans
Supported in part by grants from the Iowa Heart Association, Administration, and the National Institutes of Health 0143438 and HL 20829. Received
for publication
Apr.
Accepted
for publication
June
DepartAdminisVeterans Grants HL
7, 1978. 14, 1978.
Reprint requests: Herman L. Falsetti, Laboratory, Dept. of Internal Medicine, Iowa City, Iowa 52242.
OOOZ-8703/79/040485
flow
+ 09$00.90/O
M.D., Director, Hemodynamics University of Iowa Hospitals,
0 1979
The
C. V. Mosby
Co.
Methods
Studies were made on 12 dogs weighing 24.1 kilograms + 3.01 SD. They were anesthetized with sodium pentobarbital, 34 mg./Kg. intravenously. The tracheas were intubated, and the dogs were ventilated with room air and oxygen using a Harvard respiratory pump. Arterial blood samples were monitored to maintain pH between 7.3 and 7.4, pC0, between 35 and 40 mm. Hg, and p0, greater than 90 mm. Hg. The right femoral artery and vein, as well as the right brachial artery, were isolated and catheterized. A midsternal thoracotomy was performed, and the heart was suspended by a pericardial cradle. A cannula was placed in the left atria1 appendage, and a 6.5 mm. high fidelity transducer (Konigsberg) was placed into the left ventricle via the left atria1 incision. Left ventricular pressure and Vmax’O were determined from the high fidelity left ventricular pressure tracings. Aortic pressure was also measured with a high fidelity transducer. An electromagnetic flow probe (2 to 3 mm.) was placed on the proximal portion of the left anterior descending artery. A 14 to 18 mm. electromagnetic flow probe was placed on the ascending aorta approximately 4 cm. above the aortic valve. A Statham Model SP2201 Autoranging Blood Flowmeter with non-occlusive zero function was used to obtain simultaneous aortic and coronary flow measurements. Electrocardiogram and pressure signals were recorded on a Brush-Gould Multi-Channel Recorder, as well as a HewlettPackard 3960 FM tape system for later playback and analysis. Pressure analysis was done by hand calculation as well as on a PDP 11/35 computer. The subclavian artery was exposed just above
American
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Fig. 1. Catheter device for production of temporary aortic regurgitation. The inner stylet is connected to the outer catheter at the tip. Positioning the plunger of the syringe which is attached to the inner stylet will collapse or expand the umbrella tip of the outer catheter. The calibration on the syringe allows recording of catheter manipulation.
the aortic arch, and a special catheter device for introducing aortic insufficiency was advanced into the left ventricle. The device used to produce acute temporary aortic regurgitation is shown in Fig. 1. This type of valve-spreading catheter was originally described by Spring and Rowe.” The catheter used in the present study is similar to a later modification used by Folts and Rowe,6 in that it is made entirely of plastic and contains no metal, since metal interferes with the electromagnetic flow field. The device is different in that it has an inner stylet and syringe arrangement, which allows gradation of the aortic regurgitation. This is illustrated in Fig. 1. Control observations were made of mean and phasic aortic and anterior descending coronary artery blood flows, left ventricular and aortic pressures, and the electrocardiogram. With the catheter in the left ventricle, a baseline myocardial perfusion was measured. Then acute aortic regurgitation was induced at three different degrees: mild, moderate, and severe (5 to 25 per cent, 25 to 50 per cent, and 50 to 80 per cent) regurgitation as determined from the aortic electromagnetic flow recording. Animals were allowed to return to baseline conditions between each level of aortic regurgitation. After five minutes, all the above variables were recorded again, and differently-labeled microspheres were injected into the left atrium after each degree of aortic regurgitation. Myocardial perfusion was measured as previously reported from this laboratory.” The area enclosed between the positive, systolic
486
portion in the aortic flow meter tracing and zero flow represents the forward flow ejected from the left ventricle. This was measured electronically with a standard integrator circuit channel for ten cycles. The regurgitant aortic flow was similarly measured as the area below the zero flow line. The ratio of aortic regurgitation was determined as the ratio of regurgitant aortic flow to forward flow, as described by Malooly and associates.‘” This value was represented as per cent regurgitation. Both the full-scale range (non-linearity + 1 per cent full-scale) and the zero reference ( t 2 per cent preset full-scale) were checked with built-in electronic functions just before each flow recording. A 15-second occlusion with subsequent reactive hyperemia was performed before the control recording to check the electronic zero function and also to make sure the coronary probe was not stenosing the artery. If a reactive hyperemia of greater than three times baseline flow was not obtained, the coronary artery probe was replaced with a larger one. The calibration of the flowmeter and probe was also determined for each dog as follows: Before each dog was killed, the coronary flow probe was placed around either the femoral or brachial artery. Blood was collected from a cannula just distal to the probe. By adjusting the stopcock on the cannula, flow was varied while it was measured with a stopwatch and graduated cylinder. These data were plotted, and a correction factor was obtained for each dog. Systolic and diastolic coronary flows were
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Aoftic PmsmJre
mmiig
LV Pmmure
mmHg
2. Tracing showing aortic blood flow and coronary blood flow during control conditions and after induction of aortic regurgitation. The amount of aortic regurgitation (58 per cent) is quantitated by planimetrizing the areas above and below the zero flow line as indicated in the text. There is a marked increase in systolic coronary blood flow and diastolic blood flow remains the same (D/S = 0.76).
Fig.
determined by planimetry of the phasic coronary flow record for five cardiac cycles. A ratio of diastolic coronary blood flow to systolic coronary blood flow was determined as described by Folts and Rowe.” Simultaneous pressure recordings from the left ventricle and aorta were used to estimate the ratio of subendocardial coronary blood flow to the left ventricular oxygen requirements, as previously reported by Vincent and co-workers.‘1 According to this method, potential subendocardial perfusion is estimated by using a diastolic pressure time index (DPTI) obtained by planimetry of the area between the superimposed aortic and left ventricular pressure curves in diastole. Myocardial oxygen requirements are estimated from a modified tension-time index, obtained by planimetry of the area beneath the left ventricular pressure curve from the onset of ventricular systole to closure of the aortic valve, represented by the dicrotic notch on the aortic pressure
American
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tracing. If the dicrotic notch was not apparent, we then chose the point at which aortic flow fell below zero as the time of aortic valve closure. Since this is a pressure measurement rather than a tension measurement, it is termed the systolic pressure-time index (SPTI). The ratio DPTI: SPTI is used as an estimate of the inadequacy of left ventricular subendocardial blood flow. Myocardial perfusion was measured with 7 to 9p microspheres labeled with 8Sr, ‘We %c and 9”Nb. This technique has been described by this laboratory in detail elsewhereI and is only briefly summarized below. For each flow measurement, between 1.76 X lo6 to 4.67 x 10’ microspheres were suspended in 0.1 to 1.9 ml. of 10 per cent dextran and injected into the left atrium. Prior to injection, the vial containing the microspheres and Tween-80 was vigorously agitated mechanically for at least three minutes. Microscopic examination of each new bottle of microspheres dispersed in the manner described above showed
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I. Hemodynamic variables of 12 dogs with aortic regurgitation: mean raw change from baseline during aortic regurgitation
Table
Mean control values and Aortic
Mild (5-25s)
Control Heart rate (beatsimin) LV SYS (mm. Hg) LV DIAS (mm. Hg) Aortic SYS (mm. Hg) Aortic DIAS (mm. Hg) DPTI/SPTI Vmax (28.8 x length/set.) Aortic flow (L./min.) LAD flow (ml./min.) DIAS/SYS ratio DIAS LAD flow (ml./min.) SYS LAD flow (ml./min.) MYO. flow (ml.1100 g./min.) Endocardium (ml./100 g./min.) Epicardium (ml./100 g./min.) ENDO/EPI ratio *Denotes significant change from baseline Abbreviations: LV SYS = left ventricular zero load; DPTUSPTI = diastolic pressure epicardial coronary blood flow; DIAWSYS
163.42 126.58 4.80 126.67 101.00 1.18 68.93 1.80 30.34 4.23 23.92 6.41 99.90 97.27 100.15 0.99
f 2 i 2 + + f -c f f 2 2 f * +f
20.09 21.99 2.39 22.17 21.66 0.17 12.92 0.70 14.18 2.02 11.35 3.45 34.22 30.73 37.25 0.11
+ t * k f -c f f lr k i+k ++ f
Moderate (25-50%) 9.99 11.27 1.70 12.44 11.65 0.11 6.45 0.30 6.60 2.33 4.83 2.91 20.30 20.95 20.63 0.07
-4.83* 2.50 0.00 -2.64 -19.64* -0.24* 18.89* -0.20 4.43 -1.64* 1.17 3.26* 11.18 10.26 7.88 0.01
F k +k k t t +-+ t k t t t k t
Severe (50-80%) 5.65 11.39 2.26 11.98 14.84 0.12 12.26 0.42 5.62 1.62 4.06 2.48 36.45 38.71 33.28 0.05
-8.56 6.44 1.67 -3.78 -49.33* -0.56* 26.62* -0.23 10.20’ -3.31* -2.15 12.36* 21.63 7.39 21.58 -0.11
k 9.00 i 12.30 t 2.00 k 10.54 t 20.40 + 0.22 -t 13.47 k 0.55 t 8.65 z!z 2.31 + 6.04 i- 6.97 + 23.28 i 25.57 f 23.09 k 0.18
state (p = 0.05). systolic pressure; LV DIAS = left ventricular diastolic pressure; Vmax = contractile element velocity at time index divided by systolic time index; ENDO/EPI ratio = ratio of endocardial coronary blood flow to ratio = ratio of diastolic coronary blood flow to systolic coronary blood flow.
that in excess of 98 per cent of the spheres were completely dispersed. Occasionally, small groups of three to five spheres were observed. Starting 30 seconds before injection and continuing until three minutes after injection, blood was withdrawn simultaneously from the right brachial and right femoral arteries at 2.06 ml. per minute with a Harvard pump. Following this study, the animals were killed with an injection of potassium chloride. The heart was excised and the free walls of the right atrium, right ventricle, left atrium, great vessels, valves, surface vessels, and epicardial fat were removed. Utilizing the posterior descending coronary artery as a starting point, the left ventricle was divided into four equal slices of eight segments each, and each segment was divided into three layers: endocardium, mid-wall, and epicardium of approximately equal thickness. Thus, the left ventricle was divided into 96 segments, and the relative geometric position of each segment was constant from animal to animal. Subsequently, the myocardial segments were weighed (to the nearest mg.), placed in glass tubes, and counted for five minutes each in three inch, well-type sodium iodide gamma counter. The average weight of the segments was 1.02 5 SD 0.18 gms.
488
-5.00 0.40 0.00 -2.10 -8.80 -0.12* 7.82* 0.07 3.91 -0.28 2.76 1.17 -5.63 -5.28 -7.38 0.01
regurgitation
The reference blood samples were divided into aliquots, making their counting geometry similar to that of the myocardial samples. Energy windows utilized were A6Sc700 to 1500 keV, Y!?r 400 to 600 keV, ““Nb 650 to 800 keV, and ‘We 126 to 175 keV. Isotope separation was performed utilizing standard techniques. The myocardial blood flow was calculated using the following formula: MBF = Cm x 100 x RBF + CR, where MBF = myocardial blood flow in c.c./lOO gm. per minute, Cm = counts per gram of myocardium, RBF = reference blood flow (rate of withdrawal from reference arteries), and CR = total counts in the reference blood. The counts in the femoral and brachial blood samples were averaged. The number of spheres present in the brachial and femoral reference samples was rarely identical.” The average difference between simultaneous paired reference samples was 3.74 -+ 3.42 per cent (mean -+ SD). Thus, of the 12 animals studied and 47 flows measured, one flow had a greater than 17 per cent difference between any pair of reference samples and was deleted. The counts per minute, sample weight, and geometric reference number of each segment were punched on computer paper tape. Subsequent
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II. Mean perfusion of major subgroups during baseline, mild (525%), moderate (25~50%), and severe (50-80%) aortic regurgitation
Table
Levels
A
Base Mild Mod sev
104.34 106.41 106.93 106.12
Layers
B + k k t
5.54 6.45 5.44 3.40
EPI
Base Mild Mod Sev
99.44 97.44 97.37 101.36
k + + ?I
Base Mild Mod Sev
98.39 100.85 98.65 100.89
i k + t
f f k k
4.00 4.55 5.07 2.38
MID 5.87 4.83 6.19 5.15
POST
Walls
96.14 95.14 96.30 97.37
C
102.00 104.07 105.09 109.97
100.04 98.78 98.08 97.04
* t 2 *
3.40 2.59 4.06 2.90
106.75 107.80 103.11 102.34
f c f k
6.93 13.4 8.38 3.92
END0 + * f f
3.03 3.39 4.23 5.49*
SEPT 3.37 4.45 3.65 4.36
95.24 93.83 94.67 95.00
D
i f rt t
98.27 98.42 97.37 85.95
+ 5.30 k 4.73 + 7.02 2 11.8*
ANT 3.64 2.92 3.05 2.42*
101.54 99.95 101.18 101.45
f f f i
LAT 3.63 4.01 3.34 4.70
100.01 f 100.55 f 102.00 It: 100.73 2
3.82 3.44 4.54 3.16
The left ventricle was divided into four levels (A to D) from base to apex. Each level was divided into eight subsections (two each from anterior, lateral, septal and posterior walls). Each subsection was divided into three layers (epicardium, mid-wall, and endocardium). Each individual segment was assigned a geometric reference number (1.. to 96) so that similar segments could be compared from study to study. Normalized flow to the major subgroups in per cent are obtained by dividing the absolute flow to that subgroup by the mean flow of all 96 segments. Abbreviations: Epi = epicardium; Mid = mid-wall; Endo = endocardium; Post = posterior; Sept = septum; Ant = anterior; Lat = lateral. *Indicates that a significant change from the baseline state occurred (P = 0.05).
analysis was performed with a PDP 11/35 computer. Individual sample counts greater than 3.5 standard deviations above the mean were deleted to eliminate clumping. This resulted in lessthan one segment per animal being discarded. Standard statistical techniques (paired t test which gives mean, standard deviations, Student t distribution and one-way Anova) were utilized to analyze the data. All results are expressed as the mean k 1 standard deviation. Results
Fig. 2 shows aortic blood flow, left anterior descending coronary blood flow, aortic pressure, and left ventricular pressure under control conditions. The coronary flow tracing demonstrates the phasic nature of coronary flow and, in particular, that the majority of flow occurs during diastole. In contrast, forward aortic flow occurs almost exclusively during systole. Fig. 2 also demonstrates aortic and coronary blood flow after the induction of aortic regurgitation. In this case there is approximately 58 per cent aortic regurgitation, as determined from the aortic electromagnetic flow tracing. With the induction of aortic regurgitation, there is a change in the
American
Heart
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phasic flow in the proximal LAD artery. Systolic flow increases and diastolic flow decreases. There were no significant changes in total coronary flow, in contrast to large changes in the DPTI/ SPTI ratio and phasic coronary flow ratio. Table I is a summary of the mean control values and mean raw changes of measured variables during the induction of aortic regurgitation. The data in this table was analyzed with a standard statistical paired t test. There are no significant changes in heart rate or left ventricular systolic pressure under mild, moderate, and severe aortic regurgitation. Contractile state, as measured by Vmax, increases significantly with regurgitation. As expected, the aortic diastolic pressure decreases significantly with the induction of severe aortic regurgitation. Total coronary flow, as measured by the radioisotope technique, shows no significant change from control to severe aortic regurgitation. There is a decrease in the endocardial/epicardial ratio which is not statistically significant. For moderate and severe regurgitation, there are significant changes in the diastolic/systolic ratios and in the DPTI/SPTI ratios. Table II shows the distribution of flow during
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et al.
the ENDO/EPI ratio. As published by other authors,‘“. 1dit is assumed that DPTI/SPTI ratio of less than 0.7 is associated with an abnormal ENDO/EPI ratio. As can be seen with increasing abnormalities of the DPTISPTI ratio, there is only a weak correlation (r = .36) between the two ratios. Discussion
. . 1
.
t
. l
.
nl
. 0
10
20 30 % Aortic
40 50 60 Regurgitation
70
80
Fig. 3. Plot of coronary diastolic/systolic blood flow ratio versus per cent aortic regurgitation. There is a variation in the diastolic/systolic coronary flow ratio in the baseline condition for the 12 animals studied (11 with zero regurgitation and one with 4 per cent aortic regurgitation). As the ratio decreases (less than one) the majority of flow occurs during systole.
baseline, mild, moderate, and severe aortic regurgitation. As can be seen, there are only small changes in the major subgroups. The largest change is a decrease in the per cent of normalized f-low to the endocardium during severe aortic regurgitation. This results in an insignificant change in the ENDO/EPI ratio (see Table I). Fig. 3 is a plot of the diastolic/systolic coronary blood flow ratio versus the per cent of aortic regurgitation. As can be seen, as the per cent of aortic regurgitation increases, the ratio decreases (r = -0.60). There is a significant increase of systolic blood flow with diastolic flow remaining unchanged (see Table I). Fig. 4 is a plot of the ENDO/EPI ratio versus the per cent of aortic regurgitation. As the degree of aortic regurgitation increases, there is little change. Statistical analysis shows no direct linear correlation (r = -0.28). Fig. 5 is a plot of phasic coronary blood flow versus ENDO/EPI ratios. There is no direct correlation (r = .37). Fig. 6 is a plot of the DPTI/SPTI ratio versus
490
Although previous reports’” failed to demonstrate a significant alteration in coronary blood flow in the presence of aortic regurgitation, more recent studie@ ‘. I6 have demonstrated consistent changes in coronary artery flow with the production of acute aortic regurgitation. The present investigation, which is an acute study in openchest dogs, demonstrates the same findings seen in chronic preparations,” that systolic coronary blood flow increases and diastolic coronary tlow remains the same as aortic regurgitation is increased. The purpose of the present study was to evaluate the phasic flow relationship and regional myocardial perfusion in aortic regurgitation. In a study of a somewhat similar condition, acute arteriovenous fistula, Buckberg and colleagues’; reported a decrease in total coronary blood flow with a redistribution of flow, in particular an underperfusion of the subendocardial muscle. In both conditions, aortic diastolic pressure falls, but there is no backflow across the aortic valve with an A-V fistula. Also, diastolic myocardial stresses may be quite different in the two situations. In the current study, there is a marked change in phasic flow from diastole to systole with aortic regurgitation (see Table I). This is noted in Table I and is statistically significant with moderate and severe degrees of aortic regurgitation. Another interesting feature shown in Table I is that, with increasing amounts of aortic regurgitation, total coronary flow remained essentially unchanged. This implies a compensatory mechanism such that, although phasic flow changes from diastole to systole, average flow or bulk flow remains fairly constant. This has previously been shown by Griggs and Chen.‘” An important question is whether there is a change in spatial distribution of flow while total flow remains approximately the same. The spatial distribution of flow with various degrees of aortic regurgitation is shown in Table II. There are no significant changes to major subgroups. However, there is a
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1979, Vol. 97, No. 4
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0.0
’
0
10
20
I
I
I
I
30
40
50
60
70
myocardial
flow
60
% Aortic Regurgitation Fig. 4. Plot of coronary ENDO/EPI ratio versus becomes greater than 50 per cent there is a decrease
significant decrease in flow to the endocardial layer. The flows to the endocardial and epicardial layers do not cause a statistically significant change in the endocardial/epicardial ratio. As seen in Tables I, II and Fig. 4, there is no linear relationship between distribution of coronary flow and degree of aortic regurgitation. Myocardial metabolic studies done by Griggs and Chen’” note biochemical signs of anaerobic metabolism of the inner wall of the myocardium only during severe aortic regurgitation. The current study also indicates that, with aortic regurgitation, there are changes in phasic flow in the epicardial vessels,but adaptive mechanisms come into play which tend to preserve the spatial distribution of flow in mild and moderate aortic regurgitation. These mechanisms are inadequate when there is severe aortic regurgitation. The mechanism by which there is a reduction in diastolic flow and an increase in systolic flow in aortic insufficiency is not clear. Coronary blood flow is related to the driving force, or pressures at the coronary ostialR and the resistance of the arterial bed. These resistances consist of: (1) large vessel resistance, (2) intramyocardial stress, and (3) local or terminal resistance. In the present study there is a large change in phasic flow. Because this is a phasic phenomenon, we do not believe it is secondary to small vessel resistance which is thought to be controlled by local metabolic regulators. The three factors which then remain are: large vessel coronary resistance, the
American
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aortic regurgitation. As the in the endo/epi ratio.
degree
of aortic
regurgitation
. . .
0. l e . l
0.5
0.6
0.7
0.8
0.9
Endo/Epi Fig. 5. Plot of coronary versus ENDO/EPI ratios.
1.0
1.1
.
1.2
1.3
Ratio
diastolic/systolic
blood
flow
ratio
driving force at the coronary ostium, and intramyocardial stress. Large vessel coronary resistance is related to the epicardial vessels’ ability to store flow during one part of the cardiac cycle and maintain intramyocardial tlow during the rest of the cardiac cycle. This shift of flow pattern from mainly diastole in the epicardial
491
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1.4 -
1.2 -
1.0 0
z d 0.8 i= Q v)
l
2 0.6 Q Q l
0.0
1
I
L
0.5
0.6
0.7
Fig.
6. Plot
L
0.6
of DPTI/SPTI
vessels to systole in the capillaries has been documented.19 In regard to driving force at the coronary ostia, Bellhouse and associates?‘,22 have studied the importance of aortic valve in maintaining a blood vortex in the aortic sinus which positions the aortic cusps such that coronary blood flow can occur. These aortic sinus vortices produce the pressure gradient at the coronary orifice. The gradient at the coronary orifice plus the aortic pressure are the driving force for coronary flow. The aortic diastolic pressure is decreased in aortic regurgitation. The pressure gradient at the coronary orifice has not been studied. In studies on valves with aortic stenosiqzo, *I a turbulent jet during ejection has been noted which prevented the normal vortex formation in the aortic sinus and produced an abnormal coronary ostial pressure gradient. It is conceivable that aortic regurgitation can produce faulty movement of the aortic cusps, and there could be a change in the pressure gradient across the coronary ostium secondary to the vortex as well as the decrease in diastolic aortic pressure. The intramyocardial stress during diastole is directly proportional to the pressure in the ventricle as well as to the shape of the ventricle. With aortic regurgitation, left ventricular diastolic
492
a
0.9 EndolEpi
1.0
1.1
1.2
1.3
Ratio
versus
ENDO/EPI
ratios.
pressure increases, and there is an increase in end-diastolic volumezz so that the intramyocardial stressesare probably increased, thus causing increased resistance to flow during diastole. The relationship of intramyocardial stresses to coronary flow is not known. However, recent studies’:{ have documented that there is a transmural gradient of myocardial blood flow when coronary inflow was limited to systole. This resulted in subendocardial underperfusion with subepicardial layers normally perfused. Summary
Total, phasic, and regional flow were studied in 12 open-chest dogs with aortic regurgitation. An adjustable catheter device was used to produce aortic regurgitation. Four differently labeled 7 to 9p microspheres were injected into the left atrium during control, mild (5 to 25 per cent), moderate (25 to 50 per cent), and severe (50 to 80 per cent) regurgitation. Aortic regurgitation (AR) and the ratio of diastolic coronary blood flow to systolic coronary blood flow (DIASSYS RATIO) were measured from the electromagnetic flow tracings. The simultaneous left ventricular and aortic pressures were used to calculate DPTI/SPTI (diastolic pressure time index to systolic time index). Myocardial flow, flow to major subgroups, and
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1979, Vol. 97, No. 4
Regional
endocardial/epicardial ratios were from radioisotope analysis of the left Mean absolute control values changes of key variables from control Table
determined ventricle. and mean were:
III
5.
6.
Mild AR
Mod AR
Severe AR
-5.00
-4.a3*
-8.56
1.18
-0.12*
4.23
-0.56* -3.31*
99.90
-0.28 -5.63
-0.24* -1.64*
97.27 100.15
Control
Heart rate (beats/ min.) DPTUSPTI Dias/Sys ratio Myo. flow (ml./100 g./min.) Endocardidm (ml./ 100 g./min.) Epicardium (ml./ 100 g./min.) ENDO/EPI ratio *Denotes
4.
significant
163.42
11.18
21163
-5.28
10.26
7.39
-7.38
7.88
21.58
7.
8.
9.
10.
0.99 change
from
0.01 control
0.01 state
-0.11
(P = 0.05).
12.
The phasic coronary blood flow results in this study are similar to those reported in chronic, intact anesthetized dogs; when the degree of aortic regurgitation increased, there was a significant decrease in diastolic coronary blood flow with an increase in systolic coronary blood flow. Not previously reported are the changes in the distribution of myocardial perfusion. Total myocardial flow increased slightly. There were minimal changes in blood flow to the endocardium which resulted in a slight decrease in the ENDO/ EPI ratio and a decrease in the per cent of flow to the endocardium. These results indicate that, although acute aortic regurgitation produces significant changes in phasic coronary Ilow, there are much smaller effects on total ‘and regional myocardial blood flow. The catheter spreading device by Jim Rogers of Jim’s Instrument Oak Lake Rd., Iowa City, Iowa.
used in this study Manufacturing,
was made Inc., 1699
13.
14.
15.
16.
17.
18.
19.
20. REFERENCES
Rittenhouse, E. A., and Strandness, D. E.: Oscillatory flow patterns in patients with aortic valve disease, Am. J. Cardiol. 28:568, 1971. Tunstall-Pedoe, D. S.: Blood velocity measurements in aortic regurgitation using heated thin film and ultrasonic techniques, Br. Heart J. 33:611, 1971. Rowe, G. G., Afonso, S., Castillo, C. A., McKenna, D. H.: The mechanism of the production of Duroziez’s murmur, N. Engl. J. Med. 272:1207, 1965.
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21. 22.
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Folta, J. D., Young, W. P., and Rowe, G. G.: A study of Duroziez’s murmur of aortic insufficiency in man utilizing an electromagnetic flowmeter, Circulation 38:426, 1968. Schenk, W. G., Menno, A. D., and Martin, J. W.: Hemodynamics of chronic experimental aortic insufficiency, Ann. Surg. 154:295, 1961. Folts, J. D., and Rowe, G. G.: Coronary and hemodynamic effects of temporary acute aortic insufficiency in intact anesthetized dogs, Circ. Res. 35:238, 1974. Karp, R. B., and Roe, B. B.: Effect of aortic insufficiency on phasic flow patterns in the coronary artery, Ann. Surg. 164:959, 1966. Folts, J. D., Rowe, G. G., Kahn, D. R., Kroncke, G. M., and Young, W. P.: Phasic change in human coronary blood flow with aortic insufficiency (Abstr.), Physiologist 19:193, 1976. Carroll, R. J., and Falsetti, H. L.: Retrograde coronary artery flow in aortic valve disease, Circulation 54:494, 1976. Falsetti, H. L., Mates, R. E., Greene, D. G., and Bunnell, as an index of contractile state, Circulation I. L.: v,,, 43:467,
11.
myocardial
1971.
Spring, D. A., and Rowe, G. G.: Device for production of aortic insufficiency in intact experimental animals, J. Appl. Physiol. 29:538, 1970. Falsetti, H. L., Carroll, R. J., and Marcus, M. L.: Temporal heterogeneity of myocardial blood flow in anesthetized dogs, Circulation 52:848, 1975. Malooly, D. A., Donald, D. E., Marshall, H. W., and Wood, E. H.: Assessment of an indicator-dilution technique for quantitating aortic regurgitation by electromagnetic flowmeter, Circ. Res. 12:487, 1963. Vincent, W. R., Buckberg, G. D., and Hoffman, J. I. E.: Left ventricular subendocardial &hernia in severe valvar and supravalvar aortic stenosis: A common mechanism, Circulation 49:326, 1974. Nolan, S. P., and Muller, W. H.: Instantaneous coronary artery blood flow in aortic insufficiency, Surg Forum 14:251, 1963. Griggs, D. M., Jr., and Chen, C. C.: Coronary hemodynamics and regional myocardial metabolism in experimental aortic insufficiency, J. Clin. Invest. 53:1599, 1974. Buckberg, G. D., Fixler, D. E., Archie, J. P., and Hoffman, J. I. E.: Total and regional coronary blood flow after acute arteriovenous fistula, Surg. Forum 21:171, 1970. Buckberg, G. D., Fixler, D. E., Archie, J. P., and Hoffman, J. I. E.: Experimental subendocardial ischemia in dogs with normal coronary arteries, Circ. Res. 30:67, 1972. Tillmanns, H., Ikeda, S., Hansen, H., Sarma, J. S. M., Fauvel, J. M., and Bing, R. J.: Micro-circulation in the ventricle of the dog and turtle, Circ. Res. 34:561, 1974. Bellhouse, B. J., and Bellhouse, F. H.: Fluid mechanics of model normal and stenosed aortic valves, Circ. Res. 25:693, 1969. Bellhouse, B. J., and Talbot, L.: The fluid mechanics of the aortic valve, J. Fluid Mech. 35:731, 1969. Le.&in, S. J., Horwitz, L. D., and Mitchell, J. H.: Dimensional analysis of the left ventricle: Effects of acute aortic regurgitation, Am. J. Physiol. 228:536, 1975. Hess, D. S., and Bathe, R. J.: Transmural distribution of myocardial blood flow during systole in the awake dog, Circ. Res. 38:5, 1976.
493
Herman L. Falsetti, Robyn J. Carroll James A. Cramer With Iowa
the technical city, Iowa
myocardial
blood
in
M.D.
assistance
of Rick
A. Lenth
The mechanism of angina pectoris in patients with aortic valve diseaseand aortic regurgitation, in particular, is a subject of great interest. It is suspected that these patients may have inadequate coronary flow in the presence of normal coronary arteries. Studies on the femoral, brachial, and subclavian arteries of patients with aortic regurgitation have shown considerable retrograde 00w.‘-~ These studies have been conflrmed in d0gs.j Experimental studies in dogs with mechanically-induced aortic regurgitation6, 7 have demonstrated reverse diastolic coronary flow. This has also been documented in patients using coronary electromagnetic ilow probes at surgery.” Coronary angiographic studies have demonstrated abnormal phasic coronary tlow in patients with aortic valve disease.sAlthough it is known”-” that phasic coronary blood flow in the epicardial arteries shifts from diastole to systole in the presence of acute aortic regurgitation, controversy still exists whether there are compensatory regional coronary flow changes which maintain adequate blood flow to the myocardium. The purpose of this study was to investigate total and regional myocardial blood flow and see if they were related to the degree of induced aortic regurgitation in acute, open-chest dogs. From the Cardiovascular Center, Cardiovascular ment of Internal Medicine, University of Iowa, tration Hospitals, Iowa City, Iowa 52242.
Division, and Veterans
Supported in part by grants from the Iowa Heart Association, Administration, and the National Institutes of Health 0143438 and HL 20829. Received
for publication
Apr.
Accepted
for publication
June
DepartAdminisVeterans Grants HL
7, 1978. 14, 1978.
Reprint requests: Herman L. Falsetti, Laboratory, Dept. of Internal Medicine, Iowa City, Iowa 52242.
OOOZ-8703/79/040485
flow
+ 09$00.90/O
M.D., Director, Hemodynamics University of Iowa Hospitals,
0 1979
The
C. V. Mosby
Co.
Methods
Studies were made on 12 dogs weighing 24.1 kilograms + 3.01 SD. They were anesthetized with sodium pentobarbital, 34 mg./Kg. intravenously. The tracheas were intubated, and the dogs were ventilated with room air and oxygen using a Harvard respiratory pump. Arterial blood samples were monitored to maintain pH between 7.3 and 7.4, pC0, between 35 and 40 mm. Hg, and p0, greater than 90 mm. Hg. The right femoral artery and vein, as well as the right brachial artery, were isolated and catheterized. A midsternal thoracotomy was performed, and the heart was suspended by a pericardial cradle. A cannula was placed in the left atria1 appendage, and a 6.5 mm. high fidelity transducer (Konigsberg) was placed into the left ventricle via the left atria1 incision. Left ventricular pressure and Vmax’O were determined from the high fidelity left ventricular pressure tracings. Aortic pressure was also measured with a high fidelity transducer. An electromagnetic flow probe (2 to 3 mm.) was placed on the proximal portion of the left anterior descending artery. A 14 to 18 mm. electromagnetic flow probe was placed on the ascending aorta approximately 4 cm. above the aortic valve. A Statham Model SP2201 Autoranging Blood Flowmeter with non-occlusive zero function was used to obtain simultaneous aortic and coronary flow measurements. Electrocardiogram and pressure signals were recorded on a Brush-Gould Multi-Channel Recorder, as well as a HewlettPackard 3960 FM tape system for later playback and analysis. Pressure analysis was done by hand calculation as well as on a PDP 11/35 computer. The subclavian artery was exposed just above
American
Heart
Journal
485
Falsetti
et al.
Fig. 1. Catheter device for production of temporary aortic regurgitation. The inner stylet is connected to the outer catheter at the tip. Positioning the plunger of the syringe which is attached to the inner stylet will collapse or expand the umbrella tip of the outer catheter. The calibration on the syringe allows recording of catheter manipulation.
the aortic arch, and a special catheter device for introducing aortic insufficiency was advanced into the left ventricle. The device used to produce acute temporary aortic regurgitation is shown in Fig. 1. This type of valve-spreading catheter was originally described by Spring and Rowe.” The catheter used in the present study is similar to a later modification used by Folts and Rowe,6 in that it is made entirely of plastic and contains no metal, since metal interferes with the electromagnetic flow field. The device is different in that it has an inner stylet and syringe arrangement, which allows gradation of the aortic regurgitation. This is illustrated in Fig. 1. Control observations were made of mean and phasic aortic and anterior descending coronary artery blood flows, left ventricular and aortic pressures, and the electrocardiogram. With the catheter in the left ventricle, a baseline myocardial perfusion was measured. Then acute aortic regurgitation was induced at three different degrees: mild, moderate, and severe (5 to 25 per cent, 25 to 50 per cent, and 50 to 80 per cent) regurgitation as determined from the aortic electromagnetic flow recording. Animals were allowed to return to baseline conditions between each level of aortic regurgitation. After five minutes, all the above variables were recorded again, and differently-labeled microspheres were injected into the left atrium after each degree of aortic regurgitation. Myocardial perfusion was measured as previously reported from this laboratory.” The area enclosed between the positive, systolic
486
portion in the aortic flow meter tracing and zero flow represents the forward flow ejected from the left ventricle. This was measured electronically with a standard integrator circuit channel for ten cycles. The regurgitant aortic flow was similarly measured as the area below the zero flow line. The ratio of aortic regurgitation was determined as the ratio of regurgitant aortic flow to forward flow, as described by Malooly and associates.‘” This value was represented as per cent regurgitation. Both the full-scale range (non-linearity + 1 per cent full-scale) and the zero reference ( t 2 per cent preset full-scale) were checked with built-in electronic functions just before each flow recording. A 15-second occlusion with subsequent reactive hyperemia was performed before the control recording to check the electronic zero function and also to make sure the coronary probe was not stenosing the artery. If a reactive hyperemia of greater than three times baseline flow was not obtained, the coronary artery probe was replaced with a larger one. The calibration of the flowmeter and probe was also determined for each dog as follows: Before each dog was killed, the coronary flow probe was placed around either the femoral or brachial artery. Blood was collected from a cannula just distal to the probe. By adjusting the stopcock on the cannula, flow was varied while it was measured with a stopwatch and graduated cylinder. These data were plotted, and a correction factor was obtained for each dog. Systolic and diastolic coronary flows were
April,
1979,
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4
Regional
myocardial
flow
Aoftic PmsmJre
mmiig
LV Pmmure
mmHg
2. Tracing showing aortic blood flow and coronary blood flow during control conditions and after induction of aortic regurgitation. The amount of aortic regurgitation (58 per cent) is quantitated by planimetrizing the areas above and below the zero flow line as indicated in the text. There is a marked increase in systolic coronary blood flow and diastolic blood flow remains the same (D/S = 0.76).
Fig.
determined by planimetry of the phasic coronary flow record for five cardiac cycles. A ratio of diastolic coronary blood flow to systolic coronary blood flow was determined as described by Folts and Rowe.” Simultaneous pressure recordings from the left ventricle and aorta were used to estimate the ratio of subendocardial coronary blood flow to the left ventricular oxygen requirements, as previously reported by Vincent and co-workers.‘1 According to this method, potential subendocardial perfusion is estimated by using a diastolic pressure time index (DPTI) obtained by planimetry of the area between the superimposed aortic and left ventricular pressure curves in diastole. Myocardial oxygen requirements are estimated from a modified tension-time index, obtained by planimetry of the area beneath the left ventricular pressure curve from the onset of ventricular systole to closure of the aortic valve, represented by the dicrotic notch on the aortic pressure
American
Heart
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tracing. If the dicrotic notch was not apparent, we then chose the point at which aortic flow fell below zero as the time of aortic valve closure. Since this is a pressure measurement rather than a tension measurement, it is termed the systolic pressure-time index (SPTI). The ratio DPTI: SPTI is used as an estimate of the inadequacy of left ventricular subendocardial blood flow. Myocardial perfusion was measured with 7 to 9p microspheres labeled with 8Sr, ‘We %c and 9”Nb. This technique has been described by this laboratory in detail elsewhereI and is only briefly summarized below. For each flow measurement, between 1.76 X lo6 to 4.67 x 10’ microspheres were suspended in 0.1 to 1.9 ml. of 10 per cent dextran and injected into the left atrium. Prior to injection, the vial containing the microspheres and Tween-80 was vigorously agitated mechanically for at least three minutes. Microscopic examination of each new bottle of microspheres dispersed in the manner described above showed
487
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I. Hemodynamic variables of 12 dogs with aortic regurgitation: mean raw change from baseline during aortic regurgitation
Table
Mean control values and Aortic
Mild (5-25s)
Control Heart rate (beatsimin) LV SYS (mm. Hg) LV DIAS (mm. Hg) Aortic SYS (mm. Hg) Aortic DIAS (mm. Hg) DPTI/SPTI Vmax (28.8 x length/set.) Aortic flow (L./min.) LAD flow (ml./min.) DIAS/SYS ratio DIAS LAD flow (ml./min.) SYS LAD flow (ml./min.) MYO. flow (ml.1100 g./min.) Endocardium (ml./100 g./min.) Epicardium (ml./100 g./min.) ENDO/EPI ratio *Denotes significant change from baseline Abbreviations: LV SYS = left ventricular zero load; DPTUSPTI = diastolic pressure epicardial coronary blood flow; DIAWSYS
163.42 126.58 4.80 126.67 101.00 1.18 68.93 1.80 30.34 4.23 23.92 6.41 99.90 97.27 100.15 0.99
f 2 i 2 + + f -c f f 2 2 f * +f
20.09 21.99 2.39 22.17 21.66 0.17 12.92 0.70 14.18 2.02 11.35 3.45 34.22 30.73 37.25 0.11
+ t * k f -c f f lr k i+k ++ f
Moderate (25-50%) 9.99 11.27 1.70 12.44 11.65 0.11 6.45 0.30 6.60 2.33 4.83 2.91 20.30 20.95 20.63 0.07
-4.83* 2.50 0.00 -2.64 -19.64* -0.24* 18.89* -0.20 4.43 -1.64* 1.17 3.26* 11.18 10.26 7.88 0.01
F k +k k t t +-+ t k t t t k t
Severe (50-80%) 5.65 11.39 2.26 11.98 14.84 0.12 12.26 0.42 5.62 1.62 4.06 2.48 36.45 38.71 33.28 0.05
-8.56 6.44 1.67 -3.78 -49.33* -0.56* 26.62* -0.23 10.20’ -3.31* -2.15 12.36* 21.63 7.39 21.58 -0.11
k 9.00 i 12.30 t 2.00 k 10.54 t 20.40 + 0.22 -t 13.47 k 0.55 t 8.65 z!z 2.31 + 6.04 i- 6.97 + 23.28 i 25.57 f 23.09 k 0.18
state (p = 0.05). systolic pressure; LV DIAS = left ventricular diastolic pressure; Vmax = contractile element velocity at time index divided by systolic time index; ENDO/EPI ratio = ratio of endocardial coronary blood flow to ratio = ratio of diastolic coronary blood flow to systolic coronary blood flow.
that in excess of 98 per cent of the spheres were completely dispersed. Occasionally, small groups of three to five spheres were observed. Starting 30 seconds before injection and continuing until three minutes after injection, blood was withdrawn simultaneously from the right brachial and right femoral arteries at 2.06 ml. per minute with a Harvard pump. Following this study, the animals were killed with an injection of potassium chloride. The heart was excised and the free walls of the right atrium, right ventricle, left atrium, great vessels, valves, surface vessels, and epicardial fat were removed. Utilizing the posterior descending coronary artery as a starting point, the left ventricle was divided into four equal slices of eight segments each, and each segment was divided into three layers: endocardium, mid-wall, and epicardium of approximately equal thickness. Thus, the left ventricle was divided into 96 segments, and the relative geometric position of each segment was constant from animal to animal. Subsequently, the myocardial segments were weighed (to the nearest mg.), placed in glass tubes, and counted for five minutes each in three inch, well-type sodium iodide gamma counter. The average weight of the segments was 1.02 5 SD 0.18 gms.
488
-5.00 0.40 0.00 -2.10 -8.80 -0.12* 7.82* 0.07 3.91 -0.28 2.76 1.17 -5.63 -5.28 -7.38 0.01
regurgitation
The reference blood samples were divided into aliquots, making their counting geometry similar to that of the myocardial samples. Energy windows utilized were A6Sc700 to 1500 keV, Y!?r 400 to 600 keV, ““Nb 650 to 800 keV, and ‘We 126 to 175 keV. Isotope separation was performed utilizing standard techniques. The myocardial blood flow was calculated using the following formula: MBF = Cm x 100 x RBF + CR, where MBF = myocardial blood flow in c.c./lOO gm. per minute, Cm = counts per gram of myocardium, RBF = reference blood flow (rate of withdrawal from reference arteries), and CR = total counts in the reference blood. The counts in the femoral and brachial blood samples were averaged. The number of spheres present in the brachial and femoral reference samples was rarely identical.” The average difference between simultaneous paired reference samples was 3.74 -+ 3.42 per cent (mean -+ SD). Thus, of the 12 animals studied and 47 flows measured, one flow had a greater than 17 per cent difference between any pair of reference samples and was deleted. The counts per minute, sample weight, and geometric reference number of each segment were punched on computer paper tape. Subsequent
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4
Regional
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flow
II. Mean perfusion of major subgroups during baseline, mild (525%), moderate (25~50%), and severe (50-80%) aortic regurgitation
Table
Levels
A
Base Mild Mod sev
104.34 106.41 106.93 106.12
Layers
B + k k t
5.54 6.45 5.44 3.40
EPI
Base Mild Mod Sev
99.44 97.44 97.37 101.36
k + + ?I
Base Mild Mod Sev
98.39 100.85 98.65 100.89
i k + t
f f k k
4.00 4.55 5.07 2.38
MID 5.87 4.83 6.19 5.15
POST
Walls
96.14 95.14 96.30 97.37
C
102.00 104.07 105.09 109.97
100.04 98.78 98.08 97.04
* t 2 *
3.40 2.59 4.06 2.90
106.75 107.80 103.11 102.34
f c f k
6.93 13.4 8.38 3.92
END0 + * f f
3.03 3.39 4.23 5.49*
SEPT 3.37 4.45 3.65 4.36
95.24 93.83 94.67 95.00
D
i f rt t
98.27 98.42 97.37 85.95
+ 5.30 k 4.73 + 7.02 2 11.8*
ANT 3.64 2.92 3.05 2.42*
101.54 99.95 101.18 101.45
f f f i
LAT 3.63 4.01 3.34 4.70
100.01 f 100.55 f 102.00 It: 100.73 2
3.82 3.44 4.54 3.16
The left ventricle was divided into four levels (A to D) from base to apex. Each level was divided into eight subsections (two each from anterior, lateral, septal and posterior walls). Each subsection was divided into three layers (epicardium, mid-wall, and endocardium). Each individual segment was assigned a geometric reference number (1.. to 96) so that similar segments could be compared from study to study. Normalized flow to the major subgroups in per cent are obtained by dividing the absolute flow to that subgroup by the mean flow of all 96 segments. Abbreviations: Epi = epicardium; Mid = mid-wall; Endo = endocardium; Post = posterior; Sept = septum; Ant = anterior; Lat = lateral. *Indicates that a significant change from the baseline state occurred (P = 0.05).
analysis was performed with a PDP 11/35 computer. Individual sample counts greater than 3.5 standard deviations above the mean were deleted to eliminate clumping. This resulted in lessthan one segment per animal being discarded. Standard statistical techniques (paired t test which gives mean, standard deviations, Student t distribution and one-way Anova) were utilized to analyze the data. All results are expressed as the mean k 1 standard deviation. Results
Fig. 2 shows aortic blood flow, left anterior descending coronary blood flow, aortic pressure, and left ventricular pressure under control conditions. The coronary flow tracing demonstrates the phasic nature of coronary flow and, in particular, that the majority of flow occurs during diastole. In contrast, forward aortic flow occurs almost exclusively during systole. Fig. 2 also demonstrates aortic and coronary blood flow after the induction of aortic regurgitation. In this case there is approximately 58 per cent aortic regurgitation, as determined from the aortic electromagnetic flow tracing. With the induction of aortic regurgitation, there is a change in the
American
Heart
Journal
phasic flow in the proximal LAD artery. Systolic flow increases and diastolic flow decreases. There were no significant changes in total coronary flow, in contrast to large changes in the DPTI/ SPTI ratio and phasic coronary flow ratio. Table I is a summary of the mean control values and mean raw changes of measured variables during the induction of aortic regurgitation. The data in this table was analyzed with a standard statistical paired t test. There are no significant changes in heart rate or left ventricular systolic pressure under mild, moderate, and severe aortic regurgitation. Contractile state, as measured by Vmax, increases significantly with regurgitation. As expected, the aortic diastolic pressure decreases significantly with the induction of severe aortic regurgitation. Total coronary flow, as measured by the radioisotope technique, shows no significant change from control to severe aortic regurgitation. There is a decrease in the endocardial/epicardial ratio which is not statistically significant. For moderate and severe regurgitation, there are significant changes in the diastolic/systolic ratios and in the DPTI/SPTI ratios. Table II shows the distribution of flow during
Falsetti
et al.
the ENDO/EPI ratio. As published by other authors,‘“. 1dit is assumed that DPTI/SPTI ratio of less than 0.7 is associated with an abnormal ENDO/EPI ratio. As can be seen with increasing abnormalities of the DPTISPTI ratio, there is only a weak correlation (r = .36) between the two ratios. Discussion
. . 1
.
t
. l
.
nl
. 0
10
20 30 % Aortic
40 50 60 Regurgitation
70
80
Fig. 3. Plot of coronary diastolic/systolic blood flow ratio versus per cent aortic regurgitation. There is a variation in the diastolic/systolic coronary flow ratio in the baseline condition for the 12 animals studied (11 with zero regurgitation and one with 4 per cent aortic regurgitation). As the ratio decreases (less than one) the majority of flow occurs during systole.
baseline, mild, moderate, and severe aortic regurgitation. As can be seen, there are only small changes in the major subgroups. The largest change is a decrease in the per cent of normalized f-low to the endocardium during severe aortic regurgitation. This results in an insignificant change in the ENDO/EPI ratio (see Table I). Fig. 3 is a plot of the diastolic/systolic coronary blood flow ratio versus the per cent of aortic regurgitation. As can be seen, as the per cent of aortic regurgitation increases, the ratio decreases (r = -0.60). There is a significant increase of systolic blood flow with diastolic flow remaining unchanged (see Table I). Fig. 4 is a plot of the ENDO/EPI ratio versus the per cent of aortic regurgitation. As the degree of aortic regurgitation increases, there is little change. Statistical analysis shows no direct linear correlation (r = -0.28). Fig. 5 is a plot of phasic coronary blood flow versus ENDO/EPI ratios. There is no direct correlation (r = .37). Fig. 6 is a plot of the DPTI/SPTI ratio versus
490
Although previous reports’” failed to demonstrate a significant alteration in coronary blood flow in the presence of aortic regurgitation, more recent studie@ ‘. I6 have demonstrated consistent changes in coronary artery flow with the production of acute aortic regurgitation. The present investigation, which is an acute study in openchest dogs, demonstrates the same findings seen in chronic preparations,” that systolic coronary blood flow increases and diastolic coronary tlow remains the same as aortic regurgitation is increased. The purpose of the present study was to evaluate the phasic flow relationship and regional myocardial perfusion in aortic regurgitation. In a study of a somewhat similar condition, acute arteriovenous fistula, Buckberg and colleagues’; reported a decrease in total coronary blood flow with a redistribution of flow, in particular an underperfusion of the subendocardial muscle. In both conditions, aortic diastolic pressure falls, but there is no backflow across the aortic valve with an A-V fistula. Also, diastolic myocardial stresses may be quite different in the two situations. In the current study, there is a marked change in phasic flow from diastole to systole with aortic regurgitation (see Table I). This is noted in Table I and is statistically significant with moderate and severe degrees of aortic regurgitation. Another interesting feature shown in Table I is that, with increasing amounts of aortic regurgitation, total coronary flow remained essentially unchanged. This implies a compensatory mechanism such that, although phasic flow changes from diastole to systole, average flow or bulk flow remains fairly constant. This has previously been shown by Griggs and Chen.‘” An important question is whether there is a change in spatial distribution of flow while total flow remains approximately the same. The spatial distribution of flow with various degrees of aortic regurgitation is shown in Table II. There are no significant changes to major subgroups. However, there is a
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1979, Vol. 97, No. 4
Regional
0.0
’
0
10
20
I
I
I
I
30
40
50
60
70
myocardial
flow
60
% Aortic Regurgitation Fig. 4. Plot of coronary ENDO/EPI ratio versus becomes greater than 50 per cent there is a decrease
significant decrease in flow to the endocardial layer. The flows to the endocardial and epicardial layers do not cause a statistically significant change in the endocardial/epicardial ratio. As seen in Tables I, II and Fig. 4, there is no linear relationship between distribution of coronary flow and degree of aortic regurgitation. Myocardial metabolic studies done by Griggs and Chen’” note biochemical signs of anaerobic metabolism of the inner wall of the myocardium only during severe aortic regurgitation. The current study also indicates that, with aortic regurgitation, there are changes in phasic flow in the epicardial vessels,but adaptive mechanisms come into play which tend to preserve the spatial distribution of flow in mild and moderate aortic regurgitation. These mechanisms are inadequate when there is severe aortic regurgitation. The mechanism by which there is a reduction in diastolic flow and an increase in systolic flow in aortic insufficiency is not clear. Coronary blood flow is related to the driving force, or pressures at the coronary ostialR and the resistance of the arterial bed. These resistances consist of: (1) large vessel resistance, (2) intramyocardial stress, and (3) local or terminal resistance. In the present study there is a large change in phasic flow. Because this is a phasic phenomenon, we do not believe it is secondary to small vessel resistance which is thought to be controlled by local metabolic regulators. The three factors which then remain are: large vessel coronary resistance, the
American
Heart
Journal
aortic regurgitation. As the in the endo/epi ratio.
degree
of aortic
regurgitation
. . .
0. l e . l
0.5
0.6
0.7
0.8
0.9
Endo/Epi Fig. 5. Plot of coronary versus ENDO/EPI ratios.
1.0
1.1
.
1.2
1.3
Ratio
diastolic/systolic
blood
flow
ratio
driving force at the coronary ostium, and intramyocardial stress. Large vessel coronary resistance is related to the epicardial vessels’ ability to store flow during one part of the cardiac cycle and maintain intramyocardial tlow during the rest of the cardiac cycle. This shift of flow pattern from mainly diastole in the epicardial
491
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et al.
1.4 -
1.2 -
1.0 0
z d 0.8 i= Q v)
l
2 0.6 Q Q l
0.0
1
I
L
0.5
0.6
0.7
Fig.
6. Plot
L
0.6
of DPTI/SPTI
vessels to systole in the capillaries has been documented.19 In regard to driving force at the coronary ostia, Bellhouse and associates?‘,22 have studied the importance of aortic valve in maintaining a blood vortex in the aortic sinus which positions the aortic cusps such that coronary blood flow can occur. These aortic sinus vortices produce the pressure gradient at the coronary orifice. The gradient at the coronary orifice plus the aortic pressure are the driving force for coronary flow. The aortic diastolic pressure is decreased in aortic regurgitation. The pressure gradient at the coronary orifice has not been studied. In studies on valves with aortic stenosiqzo, *I a turbulent jet during ejection has been noted which prevented the normal vortex formation in the aortic sinus and produced an abnormal coronary ostial pressure gradient. It is conceivable that aortic regurgitation can produce faulty movement of the aortic cusps, and there could be a change in the pressure gradient across the coronary ostium secondary to the vortex as well as the decrease in diastolic aortic pressure. The intramyocardial stress during diastole is directly proportional to the pressure in the ventricle as well as to the shape of the ventricle. With aortic regurgitation, left ventricular diastolic
492
a
0.9 EndolEpi
1.0
1.1
1.2
1.3
Ratio
versus
ENDO/EPI
ratios.
pressure increases, and there is an increase in end-diastolic volumezz so that the intramyocardial stressesare probably increased, thus causing increased resistance to flow during diastole. The relationship of intramyocardial stresses to coronary flow is not known. However, recent studies’:{ have documented that there is a transmural gradient of myocardial blood flow when coronary inflow was limited to systole. This resulted in subendocardial underperfusion with subepicardial layers normally perfused. Summary
Total, phasic, and regional flow were studied in 12 open-chest dogs with aortic regurgitation. An adjustable catheter device was used to produce aortic regurgitation. Four differently labeled 7 to 9p microspheres were injected into the left atrium during control, mild (5 to 25 per cent), moderate (25 to 50 per cent), and severe (50 to 80 per cent) regurgitation. Aortic regurgitation (AR) and the ratio of diastolic coronary blood flow to systolic coronary blood flow (DIASSYS RATIO) were measured from the electromagnetic flow tracings. The simultaneous left ventricular and aortic pressures were used to calculate DPTI/SPTI (diastolic pressure time index to systolic time index). Myocardial flow, flow to major subgroups, and
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1979, Vol. 97, No. 4
Regional
endocardial/epicardial ratios were from radioisotope analysis of the left Mean absolute control values changes of key variables from control Table
determined ventricle. and mean were:
III
5.
6.
Mild AR
Mod AR
Severe AR
-5.00
-4.a3*
-8.56
1.18
-0.12*
4.23
-0.56* -3.31*
99.90
-0.28 -5.63
-0.24* -1.64*
97.27 100.15
Control
Heart rate (beats/ min.) DPTUSPTI Dias/Sys ratio Myo. flow (ml./100 g./min.) Endocardidm (ml./ 100 g./min.) Epicardium (ml./ 100 g./min.) ENDO/EPI ratio *Denotes
4.
significant
163.42
11.18
21163
-5.28
10.26
7.39
-7.38
7.88
21.58
7.
8.
9.
10.
0.99 change
from
0.01 control
0.01 state
-0.11
(P = 0.05).
12.
The phasic coronary blood flow results in this study are similar to those reported in chronic, intact anesthetized dogs; when the degree of aortic regurgitation increased, there was a significant decrease in diastolic coronary blood flow with an increase in systolic coronary blood flow. Not previously reported are the changes in the distribution of myocardial perfusion. Total myocardial flow increased slightly. There were minimal changes in blood flow to the endocardium which resulted in a slight decrease in the ENDO/ EPI ratio and a decrease in the per cent of flow to the endocardium. These results indicate that, although acute aortic regurgitation produces significant changes in phasic coronary Ilow, there are much smaller effects on total ‘and regional myocardial blood flow. The catheter spreading device by Jim Rogers of Jim’s Instrument Oak Lake Rd., Iowa City, Iowa.
used in this study Manufacturing,
was made Inc., 1699
13.
14.
15.
16.
17.
18.
19.
20. REFERENCES
Rittenhouse, E. A., and Strandness, D. E.: Oscillatory flow patterns in patients with aortic valve disease, Am. J. Cardiol. 28:568, 1971. Tunstall-Pedoe, D. S.: Blood velocity measurements in aortic regurgitation using heated thin film and ultrasonic techniques, Br. Heart J. 33:611, 1971. Rowe, G. G., Afonso, S., Castillo, C. A., McKenna, D. H.: The mechanism of the production of Duroziez’s murmur, N. Engl. J. Med. 272:1207, 1965.
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Heart
Journal
21. 22.
23.
flow
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