effect of coronary stenosis on myocardial function, ultrastructure and aortocoronary bypass graft...

Effect of Coronary Stenosis on Myocardial Function,

Ultrastructure and Aottocoronary Bypass Graft Hemodynamics

FRANZ SCHWARZ, MD’ WILLEM FLAMENG, MD KLAUS-ULRICH THIEDEMANN, PhD WOLFGANG SCHAPER, MD, PhD MARTIN SCHLEPPER, MD

Bad Nauheim and Giessen West Germany

The relation between different degrees of stenosis of the left anterior descending coronary artery and total and regional left ventricular fr!nction, myocardial ultrastructure, fibrotic content of the myocardium and hemodynamics of graft flow was studied in 70 patients with coronary artery disease. Patients with arteriographically visible collateral supply to the obstructed vessel were excluded. The degree of stenosis (quantitative measurement of luminal obstructton) and total and regional teft ventrtcular function were measured angiographically. Regional contractile reserve was determined from postextrasystolic angiograms. Ultrastructure and fibrotic content of the myocardium (morphometry) were determined from btopsy material taken at the time of bypass surgery from the area perfused by the left anterior descending artery. Graft flow to this artery was measured under basal conditions and after release of a 30 second graft oc- cluslon (hyperemic response). Five groups were formed: I, no stenosis; II, stenosis of 50 to 79 percent; III, of 80 to 89 percent; IV, of 90 to 99 percent; and V, 100 percent occlusion. Patients in group II had normal values for ejection fraction, regional functton and reserve, normal ultrastructure, a small degree of fibrosis and no hyperemic response after release of graft occlusion. Patients in group III had stmtlar findings except for a significant hyperemic response. Patients in group IV had moderate depression of ejection fraction, regional function and reserve, moderate ultrastructural alterations, increased myocardial fibrosis and a high hyperemic response. Patients in group V had a severely impaired ejection fraction, absent regional function and reserve, severe cell alterations and extensive scar formation.

Thus, a clear sequence of events occurs with progression of coronary stenosis: until 79 percent steno& no significant reduction of mechanical function and myocardial structure occurs. With 80 to 89 percent stenosis, poststenotic vasodilatlon fully compensates for the stenosis as documented by normal mechanical function and normal myocardial structure. At 90 to 99 percent stenosis, vasodilatory compensation is inadequate: Regional function decreases, degenerative ultrastructural alterations appear and the fibrotic content of the myocardium increases. With complete occlusion, compensation is ineffective, and severe loss of function and extensive scars develop.

From the Kerckhoff-Klinik, Kerckhoff-lnstitut, Max-Planck Gesellschaft. D-6350 Bad Nauheim and the Department of Cardiovascular Surgery,

‘~* Present address: Medizinische Poliklinik

Justus Liebig UniversitM, D-6300 Giessen. Man- uscript received November 15, 1977; revised manuscript received March 6. 1976, accepted Aoril 12. 1976.

with the extent of vessel disease.’ Cohn et aL2 in a consecutive series of

Regional myocardial dysfunction is a well known consequence of obstructive coronary artery disease. In general, the frequency of ventricular asynergy of contraction is thought to increase with the severity of vascular disease, but hemodynamic abnormalities do not always correlate

Giessen, Justus Liebig Universitit, Rodthohl 6, D-6300 Giessen, West GerrrMY.

Address for reprints: Wolfgang Schaper, MD, PhD, Kerckhoff-lnstitut, Sprudelhof, 6350 Bad Nauheim, West Germany.

106 patients, found no significant difference in ejection fraction or asynergy among patients with one, two and three vessel disease, although hemodynamic abnormalities were more frequent in the patients with more extensive vascular lesions. They concluded that abnormal dynamic

August 1978 The American Journal of CARDIOLOGY Volume 42 193

CORONARY STENOSIS AND MYOCARDIAL UL~AS~~TURE-SCHWARZ ET AL.

morphology and hemodynamics may bear no direct relation to the extent of vessel involvement. Several other studies3-5 also failed to establish a clear-cut relation between the severity of coronary lesions and the hemodynamic and ventriculographic abnormalities, thus suggesting that the relation between coronary and myocardial lesions may not be simple. When regional dysfunction is severe, overt depression of overall cardiac function with recognizable clinical manifestations occurs. If regional dysfunction is less extensive, the clinical and mechanical abnormalities are more subtle. How- ever, these changes are important because they may represent a stage in which aortocoronary bypass surgery can considerably improve regional myocardial function.eg7 Furthermore, these subtle changes may precede the more severe stage of coronary artery disease that causes extensive loss of myocardium by infarction.s

Methods

Recently, a method of quantitative coronary arteriography was introduced that allows one to measure the vascular lesion with great accuracy.g This study was undertaken to reevaluate the effect of coronary stenosis, as assessed with quantitative coronary arteriography, on regional wall motion and myocardial structure. In addition, hemodynamic data on the aortocoronary bypass graft were obtained during open heart surgery to estimate the hemodynamic effect of vessel stenosis on the poststenotic vascular bed in the same patient group. Because the effect of coronary collateral vessels on function and structure of the myocardium in severe obstructive coronary artery disease remains un- clear,10-12 we excluded all patients with arteriographi- tally visible collateral supply to the poststenotic vessel segment.

Patients: Initially we studied 92 consecutive surgical patients with obstructive coronary artery disease who underwent aortocoronary bypass surgery or aneurysmectomy. The patients (6 women, 86 men) were 35 to 64 years old. From this group we excluded 22 patients who had one or more of the following: significant (more than 50 percent luminal narrowing) obstruction of the circumflex branch of the left coronary artery (18 patients), significant obstruction of the left main stem (2 patients), peripheral obstruction of the anterior descending branch of the left coronary artery (1 patient) or collateral supply to the anterior descending branch (17 patients). Criteria for the presence of coronary collateral vessels, either intracoronary or in~rcoronary anastomosis, required arteriographic visualization of the left anterior descending branch distal to the coronary obstruction. These criteria are similar to those of Hamby et a1.12 The remaining 70 patients had significant proximal obstructive disease of the left anterior descending branch, and 37 of them had additional disease of the right coronary artery. Twenty-nine patients had a typical history and el~tr~di~aphic changes (abnormal Q waves) suggestive of old myocardial infarction (anterior in 23, inferior in 6). All patients had ventriculographic and coronary arteriographic studies within 6 weeks before surgery because of chronic angina or previous myocardial infarction with symptoms of congestive heart failure or rhythm disturbances. No patient studied had an acute event between cardiac catheterization and aortocoronary bypass operation. Twenty-two patients who had no signs of coronary, myocardial or valvular heart disease served as controls for angiographic measurements.

Catheterization study: All patients were studied during normal sinus rhythm. No patient had chest pain during cardiac catheterization. No premeditation was used. Adminis- tration of nitrates and beta receptor blocking drugs was dis- continued at least 3 days before the study. Left heart catheterization was performed with the retrograde technique. After measurement of left ventricular pressure, biplane left ventricular ~giography was performed in the 30” right anterior oblique projection after injection of 50 ml Urografin-76a. Thereafter, coronary arteriography was carried out with the Judkins technique’s using 35 mm film taken at 48 frames/set utilizing the Philips dual field 9 and 5 inch (22.9 and 12.7 cm) image intensifier system. Selective coronary injections were made in multiple projections by manual injection of 6 to 8 cc of Urografin-76. From the cineangiographic frames, silhouettes of the left ventricular cavity were drawn at end- diastole and end-systole. Ectopic cycles were eliminated.

FIGURE 1. E~i~tolic (dashed line) and end-systolic (dotted Me) ventriculographic silhouettes of the left vantricle. The tong axis (mid aortic root to apex) for en&dIk=istole (solld Hne) and end-eystole (dashed line) is depicted. The open circles represent the “mid point” of each silhouette. The percent shortening of each hemiaxis (R, to Rs and L) is calculated as end-diastolic minus end-systolic hemiaxis, divided by end-diitolic hemiaxis times 100 percent. The ante&x wall is marked by the shaded area. The area perfused by the anterior descending branch of the left coronary artery was taken as the average of fl2 + R3 + L.

Ventricular volumes and ejection fraction were calculated using the biplane area-length method.r4 Correction factors for magni~cation and pincushion effect were obtained from a grid filmed in the plane occupied by the left ventricle. The regression equation of Kasser and Kennedy15 was used. In 15 patients without heart disease we found no significant difference between angiographically assessed stroke volume and stroke volume determined from manually checked cardiac output determinations obtained with the therm~ilution technique (no. 7F Swan-Ganz therm~ilution catheter cou- pled to a cardiac output computer [Fa. Diefenbach, Ffm.] and to a Kipp B-12 direct-writing system). Stroke vohune assessed with thermodilution was 45.4 f 10.8 ml/m2 (mean f standard deviation); the angiographic value was 44.8 f 10.2 ml/m2. These values are in close agreement with the normal data re- ported by others.‘6

Wall motion was measured from the frontal end-diastolic and end-systolic outlines of the left ventricle (Fig. 1). The iong

$94 Au%uef 1978 The Amerkan Journal of CARDIOLOGY Volume 42

CORONARY STENOSIS AND MYOCARDIAL ULTRASTRUCTURE-SCHWARZ ET AL.

axis was divided into four equal parts, and three perpendicular lines were constructed. Each hemiaxis (from the long axis to the endocardial surface) was measured, and percent shortening was determined as end-diastolic minus end-systolic hemiaxis divided by end-diastolic hemiaxis times 100 percent.17-lg The individual values for three hemiaxes, Rz, Rs and L,wereaveragedtogetarepresentativemeasurementofre- gional motion of those areas of myocardial territory distal to obstruction of the anterior descending branch of the left coronary artery. Regional wall motion was also analyzed in postextrasystolic beats that followed a coupling interval of less than 400 msec.20.21 The degree of coronary stenosis of the left anterior descending branch was measured using the technique of quantitative coronary arteriography, as suggested by Brown et a1.g

Coronary arterial lesions were traced from two projected perpendicular 35 mm cineangiographic views. Magnification and distortion were corrected using the coronary catheter. The technique assumes an elliptical lumen of the vessel and calculates the percent reduction in luminal area in the stenosis. Diameters of the vessel were measured from diastolic frames. The normal lumen is calculated as the average of the normal vascular lumen proximal and distal to the stenosis. Two assessments of 14 stenoses by the same trained observer showed an average difference of 1.8 f 2.0 (mean value f standard deviation) percent stenosis. The single assessments by two trained observers of 18 stenoses showed an average difference of 2.8 f 1.6 percent stenosis.

Coronary bypass surgery: All patients were operated on with use of total cardiopulmonary bypass and a disposable bubble-type oxygenator. A transmural needle biopsy specimen measuring 1.5 mm in diameter (Tru-Cut biopsy needle, Tra- venol Laboratories) was obtained from the center of the area perfused by the diseased anterior descending branch. The biopsy specimens were taken from the beating heart before cross-clamping of the aorta. Immediately after biopsy, the tissues were divided into a subepicardial, intramural and subendocardial sample (of about equal size) and were fixed in cacodylate-buffered 6 percent glutaraldehyde. After im-

TABLE I

mersion fixation for 24 hours at 4’ C the samples were rinsed in 0.1 molar cacodylate buffer with 7.5 percent sucrose during 12 hours at 4’ C. After postfixation for 1 hour in 2 percent osmium tetroxide in Verona1 acetate buffer at pH 7.4 with 4 percent sucrose at 4’ C, the tissues were dehydrated in graded series of ethanol, treated with propylene oxide and embedded in Epon-812. After polymerization, semithin sections of 1 to 2 Km thickness were prepared and stained with alkaline to- luidine blue for light microscopy. Each block measured from 1 to 4 mm2 in area.

Morphometry was carried out with the light microscope using a special grid with vertical and horizontal lines providing 121 intersections (points). According to the basic principles of morphometry,22 counting of the number of points overlying a certain structure results in a quantitative determination of the volume of the structure under investigation in relation to the volume of the entire tissue under the square grid. The total number of points was regarded as 100 percent, and the points counted in the fibrotic area were expressed as the percent of the entire tissue within the limits of the grid. The axis of the square grid was then rotated about 45O and determination of the points was repeated.

Paired analysis of the first (x) and second (y) determinations after rotation within the same area showed no significant difference (P >0.05). Regression analysis revealed the following relation of both measurements: y = 0.54 + 0.98 x, cor- relation coefficient (r) = 0.986. After a random sampling procedure, a different area of the same section was chosen and the points overlying fibrotic tissue were counted with the grid in control position and after rotation of about 45”. Paired comparison of the first determination in the control position (x) and the second determination in the control position of a different area (y) showed no significant difference (P >0.05). Regression analysis showed the following equation: y = 3.87 + 0.93 x, r = 0.922. In this way two different areas of each section were counted twice.

Only longitudinal sections at a magnification of X250 were evaluated, and blood vessels and perivascular interstitial cells were excluded from the fibrotic area. For each patient three

Relation of Degree of Coronary Stenosis to Functional and Morphologic Characteristics (mean values f standard error of the mean)

Maximal

Ejection LAD wall motion Patients Reactive

Fibrosis Patients LAD Fraction, Normal PES

Wii Myo- of LAD fibrillar

Hyperemia

PatiEr;ts Stenosis With

Normal of LAD

beat Beat Groups . W) Beat (%) (%) (%)

Region Lysis (“/) (“/)

Cell Atrophy Graft (%) (%)

I

II

P

Ill

P’

IV

P

V

22 0 65.2 f 1.9 (no. = 22)

6 50-79 64.8 f 1.8 (no. = 5)

. . . . . NS

24 80-89 62.4 f 2.1 (no. =a)

. . . . . . NS

34 90-99 54.9 f 2.5 (no. = 25)

. . . . . co.05

6 100 40.0 f 2.1 (no. = 6)

39.4 f 2.1 47.8 f 1.9 (no. = 22) (no. = 22)

35.8 f 2.2 45.2 f 2.7 (no. = 6) (no. = 5)

NS NS

34.0 f 1.6 43.0 f 2.2 (no. =23) (no. = 11)

NS NS

22.8 f 2.2 26.9 f 2.7 (no. = 32) (no. = 19)

<O.OOl <O.OOl

4.0 f 1.5 6.4 f 1.7 (no. = 6) (no. = 5)

. .

29.5 f 0.7 (no. = 5)

. . 27.8 f 1.9

(no. = 15)

NS

41.5 f 3.8 (no. = 16)

<O.Ol

79.0 f 2.5 (no. = 5)

. .

0 (no. = 5)

. .

40 (no. = 15)

38 (no. = 16)

0 (no. = 5)

. . .

0 102.3 f 1.8 (no. = 5) (no. = 6)

. 0 125.1 f 4-8

(no. = 15 (no. = 22)

<O.OOl

31 159.5 f 11.4 (no. = 16) (no. = 27)

. <O.Ol

100 (no. = 5)

P’ . . . . . . <O.OOl <0.001 <O.OOl <O.OOl . . . . p’= probability value, comparison with preceding group. LAD = anterior descending branch of the left coronary artery; NS = not significant; PES = postextrasystolic.

.



60

EF 4o

?b

20

0

* pc.05 vs preceding stenosis

I f SEM

k ,

0 20 40 60 80 100

% LAD STENOSIS

FlQlJRE 2. Reduction of ejection fraction (EF) with increasing severity of stenosis of the left anterior descending coronary artery (LAD) in isolated disease of this artery without any collateral supply. When stenosis exceeds 80 percent of luminal diameter, ejection fraction decreases sharply. p = probability: SEM = standard error of the mean.

tissue samples and from each sample two sections were counted. For electron microscopic examination thin sections were cut with an LKB Ultratome III ultramicrotome, mounted on uncoated copper grids, stained with saturated aqueous uranyl acetate and lead citrate and examined with an electron microscope (Philips 300).

Distal coronary arterial-venous anastomoses were performed using cardioplegic arrest. Measurements of aortocoronary bypass flow (Statham E.M. flowmeter, Fa. Hellige direct-writing system) were obtained after the patients had been taken off cardiopulmonary bypass and the cannulas re- moved and when heart rate and arterial pressure had stabi- lized, as measured using brachial arterial cannulation and Statham pressure transducer. After basal graft flow was measured, the graft was cross-clamped with a rubber-tipped forceps for 30 seconds and thereafter the hyperemic response was recorded. The maximal hyperemic response was expressed as maximal hyperemic flow divided by basal flow times 100 percent.

Results

The data for biplane ejection fraction, regional wall motion, myocardial fibrosis, myocardial ultrastructure and graft flow were grouped according to the degree of stenosis of the left anterior descending coronary artery (Table I). Group I comprised normal patients without vessel stenosis (0 percent stenosis); group II, patients with 50 to 79 percent stenosis; group III, patients with 80 to 89 percent stenosis; group IV, patients with 90 to 99 percent stenosis; and group V, patients with 100 percent obstruction (complete occlusion). Evidence of previous anterior infarction was found in none of the 6 patients in group II, in 4 of the 24 patients (17 percent) in group III, in 13 of the 34 patients (38 percent) in group IV and in 6 of the 6 patients (100 percent) in group V.

Hemodynamic data: Figure 2 shows the effect of different degrees of isolated stenosis of the left anterior descending coronary artery on ejection fraction of the left ventricle. A nonlinear relation was found: Ejection

hj L

100 L 20 . 1 , 0 20

I , 40 60 80 lb0

‘10 LAD STENOSIS

FIGURE 3. Reduction of wall motion of the area perfused by the left anterior descending coronary artery (LAD) with increasing severity of stenosis (upper panel). With stenosis exceeding 80 percent, a sharp decrease in wall motion develops during normal (opee circles) and postextrasystollc (PES, desed ok&s) beats. lhe lower panel shows the reactive hyperemic response of the bypass graft to the left anterior descending artery after 30 seconds of occlusion of the graft. Abbre- viations as in Figure 2.

fraction remained normal until stenosis reached 80 percent. Then a steep decline occurred, reaching a mean value of 40 percent when this artery was completely occluded. There was also a nonlinear relation between degree of stenosis and the regional wall motion of the area perfused by the left anterior descending artery (Fig. 3). When stenosis reached 80 percent, there was a sharp decrease in wall motion with normal and potentiated beats. At complete occlusion, akinesia developed.

Myocardial fibrosis: The extent of interstitial myocardial fibrosis varied among patients; typical ex- amples are shown in Figure 4, a and b. Figure 4a shows a small amount of connective tissue, whereas Figure 4b illustrates severe fibrosis and loss of myocardial muscle tissue. The degree of fibrosis was generally greater in the subendocardial tissue samples than in the subepicardial samples (46 versus 7 percent, P <O.Ol). The relation between the degree of stenosis of the left anterior descending artery and the fibrotic content of the transmural biopsy specimen is shown in Figure 3 (lower panel, open circles). The degree of fibrosis remained unchanged between stenosis of 50 to 79 percent and 80

196 Augusl1978 The American Journal of CARDIDLDDY Volume 42


to 89 percent but showed a sharp and significant increase when stenosis exceeded 90 percent. When the artery was completely occluded, the level of fibrous tissue reached 80 percent.

Ultrastructural findings: Electron microscopy showed ultrastructural cell abnormalities predomi- nantly in groups IV and V, they occurred only rarely in group III and not at all in group II (Table I). These abnormalities consisted of (1) disorganization and loss of contractile elements; (2) abnormalities of Z band material; (3) alterations of mitochondria, sarcoplasmic reticulum, lysosomes and ribosomes; and (4) cell atrophy. Normal ultrastructural appearance of myocardium was found in patients in group II. The sarcomeres were normally arranged and there was only a small degree of fibrosis. Myofibrillar lysis was found in patients in groups III and IV (Fig. 5). When myofibrillar lysis was severe, “empty cells” could be seen on light microscopy (Fig. 5a). These cells showed marginally arranged myofibrils of reduced thickness but regular arrange- ment, whereas the areas devoid of contractile material were filled with glycogen, increased masses of sarcoplasmic reticulum, cytoskeletal filaments and few mitochondria (Fig. 5b). The loss of myofibrils was ac- companied by abnormal formation of Z band material in streaming and clumping patterns (Fig. 5~). The destruction of contractile material more often involved thick than thin filaments. A more advanced stage of cell degeneration was found in patients in groups IV and V: Destruction of all cell organelles was often seen, re- sulting in entirely atrophic cells (Fig. 6).

Absolute objective quantification of ultrastructural changes in myocardial cells is not impossible with our technique, but some qualitative evaluation can be obtained. We accepted degenerative changes of the myocardium as significant when they were found in the

majority of tissue samples. No ultrastructural changes were evident in patients in group II. Myofibrillar lysis was found in 40 percent of patients in group III, but there were no atrophic cells in this group. Myofibrillar lysis occurred in 38 percent and cell atrophy in 31 percent of patients in group IV. Only 31 percent of patients in this group had normal ultrastructure. Atrophic cells were evident in all patients in group V.

Aortocoronary bypass hemodynamics: Original tracings of aortic pressure, the electrocardiogram and graft flow are shown in Figure 7. In the presence of 71 percent stenosis, no significant hyperemic response was found, whereas in patients with 94 percent stenosis a high hyperemic response occurred after release of graft occlusion. The mean values for all patients are shown in Figure 3, lower panel. In group II no hyperemic response was found. In group III a significant hyperemic response occurred, whereas wall motion and extent of fibrosis remained unchanged from findings in group II. In group IV a high hyperemic response existed, wall motion decreased and the extent of fibrosis began to increase. Because the patients with complete coronary occlusion (group V) underwent aneurysmectomy rather than bypass grafting, no graft flow data were obtained in this group. In group II, heart rate during graft flow measurements was 89 f 7 beats/min (mean f standard error of the mean) and mean systemic pressure was 100 f 8 mm Hg; in group III, heart rate was 88 f 4 beats/ min and mean systemic pressure 102 f 4 mm Hg, and in group IV the respective values were 89 f 3 beats/min and 100 f 4 mm Hg. No significant differences between groups were found (P >0.05). Basal flows in the graft to the left anterior descending coronary artery in groups II, III and IV were 79.7 f 7.7,79.4 f 9.1 and 65.4 f 7.1 ml/min, respectively, and were not different from each other (P >0.05).

Au~uet 1978 The American Journal of CARDIOLOGY Volume 42 197


Discussion

Possible limitations of study: This study attempted to correlate the degree of coronary stenosis with the consequences for the poststenotic myocardium as evaluated from angiographic and histologic studies and graft hemodynamic measurements. Luminal obstruc-

tion of coronary stenosis was determined using the technique introduced by Brown et aLg This technique assumes that the coronary artery and the stenosis have an elliptical vessel cross section and calculates the percent luminal obstruction from paired perpendicular angiographic views that are not filmed simultaneously. Frame pairs are selected from different coronary arterial

FDURE 5. Groups Ill and IV. a, light mlcrograph (X650, reduced by 25 percent) of rnyoc~Ilal cells showing myoflbrlllar lysls. The intemtltial fibrosis (F) is mild, but the cells show large areas free of myofibrils (arrowhaada). The sarcomeres are marglnally arranged; around the nuclei (N) palely staining areas are seen. b, electron mlcrograph (X2.400, reduced by 25 percent) of a myocyte with moderate loss of contractile material (myofibrillar lysis). Bundles of myofibrlls are arranged marginally. The center of the cell is devoid of conlmctile materlll and contains ml&hon&ii (M), the nucleus (N) and ground substance. Fragments of sarcomerlc units are seen (arrcwhaada). c, electron micrograph (X20.000, reduced by 25 percent) of a part of a myocardttl cell exhibiting myoflbrillar lysls. The bundles of myofibrils are thinned and irregularly arranged. The 2 bands show focal widening (arrow). Some thick flla- n-rents have lost their interconnections (arrow- heads).

198 August 1978 The American Journal of CARDIOLOGY Volume 42


FIGURE 8. Group V. Electron micrograph (X5,600, reduced by 25 percent) of two atrophic myocardial cells in an area of extensive fibrosis (F). lhe cells are almost completely devoid of normally arranged contractile material and contain only small numbers of irregularly shaped mitochondria (M). The cells are connected to each other by intercalated discs (ar- rowheads). Remaining 2 band mate&l is seen within the cells (arrows).

injections but from the same point in the cardiac cycle, that is, end-diastole. Three main factors can interfere with correct measurement: (1) poor image quality, (2) obscuring of a lesion by an overlapping vessel, and (3) end-on viewing.g However, with careful attention to filming technique, we have found that more than 95 percent of lesions of the left anterior descending coronary artery can be adequately measured. We have used this technique to measure percent luminal obstruction, but not the length, the atheromatous mass or the resistance of the stenosis, and we have found good agreement among measurements. For this study only three groups of stenoses were differentiated: 50 to 79 percent, 80 to 89 percent and 90 to 99 percent; thus, erroneous measurement probably had little influence

FIGURE 7. Original tracings of electrocardiogram (ECG), aortic pressure (AOP), phasic and mean graft flow to the left anterior descending coronary artery (LAD) in two patients. The left panel shows tracings from a patient with 71 percent stenosis (group II), the rfghl panel shows tracings of a patient wlth 94 percent stenosis (group IV). No hyperemlc response was seen in the former in contrast to the lat- ter. Mean resting flow was 73 ml/ min in the patient with 71 percent stenosis and 90 mllmin in the one with 94 percent stenosis.

71 qro

on our results. Currently used techniques using visual estimates may have considerably more error.23

Regional motion was assessed from normal and postextrasystolic beats. Postextrasystolic potentiation has been proposed to be useful in evaluating residual myocardial function in areas that are asynergic during normal beats.21 The anterior wall motion in postextrasystolic beats represents the maximal contractile power of this region.

The transmural biopsy technique used in our study was previously performed by Stinson et a1.24 in patients with coronary artery disease. They found the method accurate when the data were compared with electro- cardiographic and ventriculographic findings. We believe that the sampling error is small when biopsy is

LAD-stenosis

94 9b

graft flow 1Q) ml lmin ,I -:I --..



performed after localization of the perfusion area of the diseased area. We evaluated the anterior region of the left ventricle, rather than the anteroapical region evaluated by Stinson et aL2* We find the technique safe because it is performed under direct vision.

Consequences of different degrees of coronary stenosis: We evaluated graft flow at rest and after 30 seconds of graft occlusion. Graft flows were measured when blood pressure and heart rate had reached normal levels. Several studies have used graft flow measurements to evaluate the potential of coronary bypass grafts to increase blood flow to the myocardium sup- plied by obstructed arteries.25p2s The significance of a hyperemic response is not fully understood. Kreulen et aL2s found that the hyperemic response was correlated with the pressure gradient of the stenosjs, that is, the severity of stenosis. However, it cannot be entirely ruled out that a positive hyperemic response represents ischemia to some extent. Reneman and Spencer27 have shown that stenosis of graft anastomosis will decrease the hyperemic response. Such a mechanism seems un- likely in the majority of cases, as demonstrated by the identical graft flow values in groups II, III and IV. Narrowing of the distal coronary artery could have produced a similar reaction, but we studied no patient with peripheral stenosis.

Poststenotic vasodilation was not found in patients with 50 to 79 percent stenosis (no hyperemic response). A significant hyperemic response could be shown in patients with 80 to 89 percent stenosis, and the com- pensating effect of vasodilation was documented by a normal wall motion and regional reserve by the small degree of fibrosis and a normal ultrastructure in most cases. In patients with 90 to 99 percent stenosis the poststenotic vasodilation was associated with a decrease in mechanical function and an increase of fibrosis and is therefore indicative of myocardial ischemia.

Regional function and reserve and overall ventricular function were related nonlinearly to the severity of vessel obstruction when cases with arteriographically visible collateral vessels were excluded. One difficulty in evaluating collateral vessels is that the resolving power of a&&graphic equipment limits identification to vessels with a diameter of 100 pm or more.12 It is therefore not entirely ruled out that in some cases collateral vessels of smaller diameter may have existed but

were not visualized arteriographically. Whether this type of collateral has any significance remains to be determined.

Our results show that regional contractile reserve decreased when myocardial fibrosis increased. We found greater amounts of connective tissue in the subendocardium than in the subepicardium, thus providing direct evidence that the subendocardium is more vulnerable than the subepicardium in patients with coronary artery disease. Our results are supported by careful postmortem studie&29 that established a close relation between wall motion abnbrmalities and myocardial fibrosis within discrete myocardial segments.

The most severe cell changes (atrophic cells) were found in group V; mild changes occurred in group IV. The cell changes were generally found when fibrotic content was moderately increased, but a significant number of patients had cell alterations without increased amount of fibrosis (group III). Obviously lysis of myofibrils precedes cell atrophy. Furthermore, when the cell structure is severely impaired, scar formation progresses. The lysis of myofibrils was associated with moderate contractile dysfunction (hypokinesia). We therefore suggest that the moderate cell alterations described (lysis of myofibrils) represent the morphologic correlate of hypokinesia. We believe that these alterations may be at least partially reversible when blood flow reduction is corrected by aortocoronary bypass grafting. This hypothesis is supported by the finding that the hypokinetic state often reverts to normal after restoration of blood flow.

In summary, our results established a nonlinear relation between the degree of coronary stenosis and poststenotic characteristics of the myocardium in human patients. With progression of stenosis up to 89 percent of luminal diameter, no significant reduction of mechanical function and myocardial structure was found. Above this level, an abrupt decrease in poststenotic motion and contractile reserve and a sharp increase in the fibrotic content of the myocardium occurred. Typical ultrastructural alterations preceded the stage of severe scar formation when coronary stenosis became more severe. These findings suggest that severe coronary lesions cause sequential changes in the morphologic features and function of the poststenotic myocardium and in themselves are an indication for operation.

1.

2.

3.

4.

5.

References

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209 Au9uet 1978 The Amerkan Journal ot CARDlOLDGY Volume 42

CORONARY STENOSIS AND MYOCARDIAL ULTFIASTRUCTURE-SCHWARZ ET AL.

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Auguef 1978 lhe Arnerkan Journal of CARBIGLGGY Votume 42 201

effect of coronary stenosis on myocardial function, ultrastructure and aortocoronary bypass graft...

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