Left ventricular sickle cell crisis
performance
during
and
after
J. Val-Mejias, M.D. W. K. Lee, M.D. A. B. Weisse, M.D. T. J. Regan, M.D. Newark, N. J.
Although it is generally recognized that chronic anemia produces a high output state associated with cardiac hypertrophy, the influence on the myocardium may be affected by the specific form of anemia. Cor pulmonale secondary to pulmonary hypertension is well recognized in sickle cell anemia. In addition, left heart failure is known to occur in subjects in the third and fourth decades without the usual cardiac risk factors or valvular disease.” ” Defective hemoglobin synthesis in patients with sickle cell (SS) hemoglobin is not known to be paralleled by an analogous abnormality of cardiac contractile protein as a. basis for heart failure. Microvascular occlusion by sickled red cells in the myocardium has been postulated to produce ischemic necrosis, which on a chronic basis may be the cause of cardiac decompensation.g As an alternative hypothesis there has been indication that the many years of chronic hemolysis” in SS patients may result in deposition of iron in body tissues.” This process is evidently less severe than in secondary hemochromatosis where a large iron load from multiple blood transfusions may lead to heart failure in the first or second decades6 To examine whether a milder form of left ventricular dysfunction may exist in patients From the Department of New Jersey-New
of Medicine, Jersey Medical
College of Medicine School, Newark,
This investigation was supported in part by Research 09914 and Postgraduate Training Grant No. HL National Heart, Lung and Blood Institute. Received
for publication
Apr.
Accepted
for publication
June
Reprint Medical
requests: Timothy School, 100 Bergen
0002-8703/79/050585
and Dentistry N. J. Grant No. 05510 from
HL the
27, 1978. 2, 1978. J. Regan, St., Newark,
+ 07$00.70/O
M.D., CMDNJ-New N. J. 07103.
0 1979
The
Jersey
C. V. Mosby
Co.
with SS hemoglobin without the conditions for secondary hemochromatosis, subjects were studied noninvasively by the systolic time interval method supplemented by echocardiographic measurements. The question of ischemic injury was considered by serial testing of patients during and after an acute crisis as well as analysis of serum enzymes known to reflect cardiac injury. A timedependent effect of the chronic hemolytic process as a potential basis for myocardial abnormalities was evaluated in different age groups. Materials
and methods
Eleven black patients admitted in sickle cell crisis were studied serially; four were restudied during a subsequent crisis. All subjects had hemoglobin SS by electrophoresis. For studies after crisis or at intercrisis intervals, additional subjects without recent illness were included at 1 to 5 months after their last episode. Patients were excluded if they were hypertensive, diabetic, obese, uremic, had known pulmonary disease, or were heavy smokers or addicts. Excessive use of ethanol or habitual drug usage was excluded by history and generally confirmed by a relative or close friend. Subjects with prior blood transfusions or oral iron medication were not included. Diagnosis was based upon a presentation with pain in joints or skeleton that was usually similar to the symptomatology of prior crises, and was mild and moderate in degree. Most had a Grade 2 to 3 systolic murmur at the apex or left sternal border. Body temperatures per rectum during the first day were elevated by 0.6 to 1.7” F. and usually returned to normal by day six. Serum electrolytes, glucose, and BUN were in the
American
Heart
Journal
585
Val-Mejias
Table
et al.
I. Clinical data in sickle cell patients during
Table
II. Left ventricular
systolic time intervals
crisis
II I. L. c. K. c. D. P. G. R. I. R.
w. L. P. M. w. W. M. D. C. s. B. Mean SE.
13 17 20 21 22 22 23 24 26 31 --38
F F F M M F F M M M F
Cardiothoracic ratio
26 24 26 25 20 31 27 25 31 26 23
120/80 118/78 125/75 140/80 128/74 130/90 140/90 120/70 126/80 130/76 130/82
4 11 5 15 17 17 15 14 20 20 -30
0.46 0.54 0.48 0.53 0.49 0.47 0.54 0.55 0.50 0.53 0.55
25 1.3
128/80 2.2 1.7
15 2.2
0.51 0.01
normal range. Hematocrit, blood pressure, and heart rate are indicated in Tables I and II. Twelve-lead ECG’s and chest roentgenograms were obtained at the time of admission and were repeated within three days. Serum samples were analyzed for SGOT,’ (upper limit 40 units) and CPK8 (upper limit 145). Serum samples in some of the patients were kept at 0’ C. and analyzed for identification of the isoenzymes of CPK.” Systolic time intervals were measured within 24 hours of admission to the hospital, generally before medications were administered. This set of studies was repeated after 3 to 5 days and again after 7 to 10 days when the crisis had subsided and medication had been discontinued. The systolic time intervals were measured as described by Weissler and associates1ofrom simultaneous ECG, phonocardiogram, and carotid pulse tracings. Recordings were done on an oscillographic recorder (Electronics for Medicine, White Plains, N. Y.) at a paper speed of 150 mm./sec. and time lines at 0.02 sec. intervals. Ten to 12 complexes were analyzed and averaged. Preejection period (PEP), left ventricular ejection time (LVET), and electromechanical systole (QS’) were calculated and then corrected for heart rate, using Weissler’s regression equation. Twenty-two volunteers without heart disease or anemia with a mean age of 34 + 1.9 years, served as a control group. All studies were done between 8:00 A.M. and 12:00 noon, in the postabsorptive phase and supine position. In addition, six anemic subjects without sickle cell disease
586
> I. L. c. K. c. D. P. G. R. I. R.
w. L. P. M. w. W. M. D. C. s. B. Mean f Normals (N = 22) rt P vs normals
*None of values differed
106 92 83 99 100 64 104 107 76 77 - 97
.332 ,367 ,361 ,262 ,303 .325 ,502 ,488 .321 ,433 i----299
77 96 90 84 78 114 99 81 69 77 - 106
,474 ,383 ,312 ,293 ,357 ,360 ,490 ,414 ,454 ,535 L 405
91 4.3
,363 ,024
88 4.2
,407 ,023
67 1.6
.313 ,006 < 0.0001
< 0.006
< 0.0001 < 0.05 significantly
from post-crisis.
within the age range of the SS group were studied to determine the effects of comparable degrees of chronic anemia without sickle disease on the systolic time intervals. These subjects had chronic intermittent blood loss 3 to 17 months in duration and had no cardiac risk factors. To further evaluate left ventricular function, SS subjects had echocardiograms at intercrisis intervals and were compared with normals of similar age range. The echocardiograms were obtained with a Hoffrel Model 101 Ultrasonoscope interfaced to an Electronics for Medicine DR-12 amplifier recorder system, for measurement of several left ventricular parameters I1 Results
During the period of crisis, precordial chest pain was not present and there were no significant abnormalities of the ST segment or pathologic Q waves. The patients studied during crisis represented a relatively broad range in terms of age and number of past crises. Hematocrits were moderately reduced to a mean of 25 * 3 and the cardiothoracic ratio as judged from a chest roentgenogram was enhanced in virtually all (Table I). The values for systolic time intervals measured on the first day of crisis are indicated in Table II. Although heart rate was higher than in the normal group, there were no significant changes
May.
1979,
Vol.
97. No.
5
LV performance
Table
Table
III. Serum enzymes
and sickle
cell crisis
IV. Age and intercrisis systolic time inter-
vals Name
fh I. w.
30t
14*
L. L. c. K. E. D. P. G. R. I. R.
P. M. W. W. M. D. C. s. B.
25 47 31 25 30 15 37 35 -
54 31 25 24 27 10 32 35 -
Mean +
28.8 3.5
29.8 3.9
98* 73 110
301 68 33
1.8
3.9
39
27
2.7
1.4
31 78
34 51
2.9 3.1
2.1 2.2
26 - 45
27 - 42
0.3 --2.4
0.7 1.9
62.5 11.2
*Blood samples obtained on admission tions. iSamples obtained on day 3 or 4.
39.0 5.0 to hospital
.4
1.0
1.94 .44 before
1.88 .40 any
injee-
in the individual time intervals when corrected for heart rate (LVETI, PEPI, Q&I). The ratio of PEP/LVET was significantly higher than normal in the initial study. In the 3 to 7 day period, the PEP/LVET ratio was higher than normal but not significantly different from the initial study at 0.385 t 0.03. In the post-crisis period when the patients were afebrile: both PEP1 and Q&I were significantly abnormal. The systolic time interval ratio was further elevated above normal to 0.407 + 0.02, although not significantly different from values of the initial day. Four individuals were restudied during an additional crisis. Both the initial and post-crisis studies were significantly abnormal and did not differ significantly from each other. In these four subjects, the post-crisis ratio of PEP/LVET was 0.412 +- 0.24 compared to 0.390 & 0.02 on the repeat study, Serum enzymes were determined on the day of admission to determine if acute myocardial necrosis was present. SGOT was found to be within normal limits in the nine patients assayed and there was no significant change in the repeat analyses. Total CPK activity was slightly elevated on the day of admission and was substantially reduced by days 2 or 3. To determine the nature of the CPK elevation, isoenzyme activity was assessedin seven patients. In none was there a significant elevation of the MB
American
Heart
Journal
Group A * I. w.t A. T. Wa. W. L. L.t W. B. c. P.t S. J. K. M.t
Age/ sex
13 13 14 17 18 20 21 22
F M F F M F M M
Hct
25 32 27 24 25 26 24 -21
Crises
16 1
4 15 2 3 4 -22
Mean S.E. k Group B C. J. P. M. G. B. G. D.t s. w. R. C.t I. s.t Wi. W. R. B.t J. T.
17.3 1.28
25.5
23 23 23 24 24 26 31 34 38 42
24 26 18 21 17 31 28 30 19 -28
42 27 15 49 2 31 24 37 60 - 16
Mean S.E.S PS
28.8 2.23 .009
24.20 1.63 NS
30.3 5.48 ,005
M F F M F M M M F M
1.13
8.4 2.84
Heart rate
PEP/ LVET
77 62 76 107 75 90 56 84
,474 ,299 .351 .408 ,274 .312 ,253 -L,293
.46 .45 .46 .54 .55 .48
78.4 5.63
,335 .023
.50 .02
71 90 75
,377 ,490 ,375
81
,414
75 69 77 100 106 - 70
,325 ,455 ,539 ,489 ,405 -,379
.51 .53 .50 .55 .51 .50 .53
81.4 4.1 NS
0.425 0.021 .02
C/T
53
.55 251 0.521 0.006 NS
*Group A patients were less than 23 years of age; Group B patients were at least 23 years old. tData were obtained no sooner than seven days after crisis. All others studied only at intercrisis. Each patient was normotensive. SGroup A vs B in unpaired t test with equal variances.
isoenzyme; the MM fraction was elevated in several individuals and declined by days 3 and 4. Thus, no evidence of enzyme leakage from cardiac tissue was observed during the sickle cell crisis. To determine whether a cumulative effect of the hemolytic process as judged by age may have been a determinant of the abnormal systolic time intervals, subjects studied after crisis and four additional individuals seen during an intercrisis period were assessed.Those in Group A were less than 23 years and those in Group B were at this age or older. As indicated in Table IV, PEP/ LVET ratio in the younger group was not significantly different from normal controls. However, in Group B the ratio was significantly increased at 0.413 + 0.03. The hematocrit, heart rate, and cardiothoracic ratio were at similar levels to those found in Group A but the cumulative number of crises were greater in Group B. The effect of age
587
Val-Mejias
et al.
V. Chronic anemia without sickle cell disease
Table
J. C. R. B. M.
N. M. W. w. M.
Sex
Age
Hct
M F F F M
19 25 26 34 -38
27 24 33 26 20
*Unpaired t test vs Normals (Table vs Group A (Table vs Group B (Table
Table
Hr
B
110
120/85
75 59 61 - 75
115/75 110/70 115/76 120/80
P
Q&Ix
PEPIx
561 548 548 531
132 132 140 125
429 416 408 407
-115
-417
PEP/ LVET
L VE TIx
,364 ,345 ,369 ,324
II) N.S. IV) N.S. IV) P < .03.
VI. Intercrisis echocardiography
Vcf Patient Group I. w. c. P. S. J. c. w. K. M.
Age/Sex
LVID*
% F.S.*
Circ./sec.
E.F.*
P. W.D.*
13 21 21 22 22
5.0 4.8 5.0 5.9 -5.3
33.0 33.3 36.9 37.3 39.6
1.217 1.648 1.221 1.519 1.357
.83 .70 .78 .75 - .78
0.8 0.7 0.8 0.9
5.2 0.2
36.0 1.3
1.392
0.085
0.77 0.021
0.86 0.08
5.9 6.2 5.3 4.9 4.2 6.3 5.0 -6.0
27.9 27.0 40.6 28.5 33.3 34.0 34.0 -26.8
1.157 ,869 1.175 1.398 1.265 1.133 1.514 0.869
.64 .61 .77 .63 .69 .63 .71 A60
0.7 0.8 0.9
0.9
28.6 2.4
5.5 0.26
31.5 1.7
1.173 0.080
.66 0.021
0.93 0.08
31 2.7 A) B)
4.64 .I3 < 0.03 < 0.01 NS
34.4
1.24 .06 NS NS < 0.09
.77 .02 NS < 0.08 < 0.005
.98 .03 NS NS NS
A
Mean S.E. +Group B P. M. c. J. s. w. G. D. R. C. I. s. Wi. Wa. J. T.
19.8
1.7 23 23 24 25 26 32 34 42
Mean S.E. f Normals Mean (N = 8) S.E. + P (normal vs Group P (normal vs Group Group A vs B ‘Abbreviations: wall thickness
F F F M M
F F F M M M M M
LVID = left ventricular (in mm.).
end-diastolic
1.9
< 0.05 NS < 0.08 internal
diameter
may be largely dependent on the severity of the hemolytic process or on the number of crises, as suggested by the fact that the two subjects in Group A with PEP/LVET above .40 had at least 15 crises. Since anemia per se is known to affect the cardiovascular system, five individuals were selected who had no known cardiac risk factors
588
(in cm.);
F.S. = fiber
shortening;
E.F.
= ejection
- 1.1
1.1
0.8 1.3
fraction;
P.W.D.
= posterior
but who had evidence of chronic blood loss. Hematocrit levels had stabilized by the time of the study. The levels of heart rate and arterial pressure were comparable to the sickle cell patients. However, the ratio of PEP/LVET was not significantly different from normal but was significantly less than in the Group B subjects (Table V).
May.
1979,
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5
LVperformance
Echocardiographic studies in some of the intercrisis subjects of Groups A and B as well as additional sickle cell patients between crises also revealed a difference in left ventricular performance (Table VI). Group A parameters were similar to normals, except for a larger left ventricular end-diastolic internal diameter and greater per cent fiber shortening, presumably due to the chronic anemia. Group B, despite a larger ventricular end-diastolic diameter, had significantly reduced ejection fraction and a nonsignificant reduction of fiber shortening compared to normals. Ejection fraction was also diminished when compared with Group B. Discussion
As a measure of left ventricular performance the systolic time interval method has been found to be sensitive and reliable,” as well as reproducible in normals.” In this study of sickle cell patients determinations during two different crises indicated a reasonable degree of reproducibility. Systolic time intervals were sequentially determined during sickle cell crisis to assess whether there was evidence of abnormal myocardial function consistent with an acute ischemic process. The latter has been postulated to exist due to microthrombi formed by the aggregates of sickle blood cells.” The observed patterns of the systolic time intervals during and following crisis contrasts with that occurring during myocardial infarction.‘:; Both situations are usually characterized by acute phase reactions for several days, which may in that period alter venous return, afterload, and neurohumoral regulation so as to affect the time intervals. During uncomplicated acute infarction, the abnormal ratio present on the first day appears to persist at about the same level through the first week.‘,’ By contrast, during crisis the ratio on the initial day was less abnormal than after the crisis, suggesting that myocardial ischemic injury was not present. Supporting this view was the absence of cardiac symptoms and ECG changes consistent with acute ischemia. In additon, the acute event was not associated with elevation of serum SGOT or CPK-MB isoenzyme, although transient increments of MM, presumably from skeletal muscle, were observed. Since it is not yet known whether necrosis of a small quantity of myocardium can occur without release of detectable levels of CPK-MB into the serum, these findings only
American
Heart
Journal
and sickle
cell crisis
exclude ischemic injury of sizeable portions of heart muscle. The observation that systolic time intervals were normal in anemic subjects without sickle cell disease is consistent with a prior study in which patients at this level of hematocrit reduction had time intervals within the normal range.” While it would appear that markedly reduced red cell mass can be associated with either substantially shortened or prolonged time intervals and heart failure,‘” this degree of anemia was not present in our patients. Abnormal left ventricular performance observed after crises or at intercrisis intervals was not observed in a prior study of sickle cell patients in which the temporal relation to acute crises or their relative number were not indicated.‘” Individuals less than 23 years of age had normal ventricular function by two noninvasive techniques, in agreement with our study. Older individuals consisted of seven females and four males. The mean PEP/LVET in the females was 0.32. While the seriesof males was too small to analyze statistically, two were clearly abnormal at 0.42 and one was borderline at 0.35. In comparing the individuals over 23 years by sex in our own series, the males had a ratio of .446 f .035 and females a ratio of .368 * .023. Thus, the negative conclusion of the previous report may have been due to the relatively few males in the older group.li An additional factor may relate to the number of crises in each patient. Even in the young patients forming Group A, those with the more abnormal systolic time intervals had at least 15 crises, while those in Group B with only several such episodes tended to have normal time intervals. The general relationship of diminished ventricular function to age was supported by our echocardiographic studies, which indicated that only Group B subjects had a reduced ejection fraction, despite an enhanced left ventricular end-diastolic diameter. Support for the view that the cumulative effect of chronic hemolysis and multiple crises over the years affect cardiac function is provided by reports on the occurrence of heart failure in patients with sickle cell anemia.‘- Iii In the earlier study the two subjects who died of congestive heart failure with pulmonary edema were males, 30 and 32 years old. In the latter study,“’ congestive heart failure that was presumably left- and right-sided occurred in three individuals between
589
Val-Mejias
et al.
ages 33 and 44 years. In both studies, increased interstitial fibrous tissue and edema were observed, with vacuolization of myocardial fibers in the left ventricle. Microscopic fibrosis has also been described in a prior report.” The mechanism of the abnormal left ventricular performance in the older age group is not known. It is possible that the cumulative effects of anemia or arterial hypoxia on the process of hypertrophy may alter cardiac function in the long-term process of sickle cell disease, as compared to the lesser chronicity of the individuals with blood loss anemia. However, the role of chronic hypoxia would appear unlikely in view of the reported normal left ventricular status in life-long residents at high altitude.‘” Although classic hemochromatosis of the secondary type was not a factor in these patients, many years of chronic hemolysis are known to exist in patients with SS hemoglobin.’ Since serum ferritin concentrations are substantially elevated, significant deposition of iron in tissue may occur.’ in acquired iron storage disease of children who are recipients of many blood transfusions, left heart failure frequently appears by 20 years of age,” in contrast to at least a decade later in sickle cell anemia. Although a definitive morphologic study of myocardium is not available, the findings that interstitial fibrosis and ultimate loss of myocardial fibers that occurs in hemochromatosis, presumably as a reactive response to iron loading,” may also be seen in patients with SS hemoglobin’, I6 suggests that some patients who survive well into adulthood may incur some degree of left ventricular dysfunction on such a basis.
appeared unlikely. Four patients on subsequent admission exhibited systolic time interval values similar to the earlier crisis. To determine if there were chronic changes in cardiac function, subjects with sickle cell hemoglobin were studied between crises. Those under 23 years of age were not dissimilar from a group of normals and a group of patients with chronic blood loss anemia A significant abnormality of the PEP/LVET ratio was observed in subjects over 23 years of age. Similar observations were made on echocardiographv, with subjects over the age of 23 demonstr,:r*ing an abnormal ejection fraction compared to ihe younger group, despite enhanced end-diastolic diameter. Thus, it is suggested that the chronic hemolytic process in subjects with sickle cell anemia may effect cumulative myocardial alterations, resulting in chronic cardiac malfunction in the apparent absence of acute ischemia during crises. REFERENCES
1.
6.
7.
Summary
Although microvascular occlusion has been considered a basis for pathophysiology of the myocarditim during the crisis of sickle cell anemia, the status of the left ventricle in uncertain. To determine if left ventricular performance is affected by crisis, 11 patients were evaluated noninvasively by the systolic time interval method on the first day of crisis and serially until recovery. There were no significant differences in the time intervals over this period. In addition, since the serum CPK-MB isoenzyme was not elevated during crisis and evidence of acute injury was not present on ECG, myocardial necrosis
590
8.
9.
10.
11. 12.
13.
Winsor. T., and Burch, G. E.: The electrocardiogram and cardiac state in active sickle-cell anemia, AM. HEART J. 29:685, 1945. Klinefelter, H. F.: The heart in sickle cell anemia, Am. J. Med. Sci. 203:34, 1942. Margolies, M. P.: Sickle cell anemia. A composite study and survey, Medicine 30:357, 1951. Bensinger. T. A., and Gillette, P. N.: Hemolysis in sickle cell disease, Arch. Intern. Med. 133:624, 1974. Peterson. C. M.. Graziano. J. H.. de Ciutiis, A., Grady, R. W., Cerami, A:, Worwood, Ml, and Jacobs, A.: Iron metabolism, sickle cell disease, and response to cyanate, Blood 46:583, 1975. Engle, M. A., Erlandson, M., and Smith, C. H.: Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis, Circulation 30:698, 1964. Kessler, G., Rush, R. L., Leon, L., DeLea, A., and Cupiola, R.: Automated 340 nm measurement of SGOT, SGPT and LDH, in: Advances in automated analysis, Barton, E. C., et al., eds., Miami, Fla., 1971, Thruman Associates, vol. 1, pp. 67-74. Rosalki, S. B.: An improved procedure for serum creatine phosphokinase determination, J. Lab. Clin. Med. 69:696, 1967. Varat, M. A., and Mercer, D. W.: Cardiac specific creatine nhosphokinase isoenzyme in the diagnosis of acute myicar&al infarction, Circulation 5 1:855, 1975. W&&r. A. M.. Harris. W. S., and Schoenfeld, C. D.: Bedside technics for the evaluation of ventricular function in man, Am. J. Cardiol. 23:577, 1969. Feigenbaum, H.: Echocardiography, 2nd edit.. Philadelphia, 1976, Lea & Febiger, pp. 309-322. Lewis, R. P.. Leighton, R. F., Forester, W. F., and Weissler, A. M.: Systolic time intervals, in: Noninvasive cardiology, Weissler, A. M., ed, New York, 1974, Grune & Stratton, Inc., pp. 301-368. Naqvi, S. Z., Chisholm, A. W., and Shane, S. J.: Left
May,
1979,
Vol.
97. No.
5
LVperformance
14.
15.
ventricular function in ischemic heart disease: Assessment by noninvasive techniques, AM. HEART J. 90:312, 1975. Abdullah, A. K., Siddiqui, M. A., and Tajuddin M: Systolic time intervals in chronic anemia. AM. HEART J. 94:287-291, 1977. Gerry, J. L., Baird, M. G., and Fortuin, N. J.: Evaluation of left ventricular function in patients with sickle cell anemia, Am. J. Med. 60:96&S, 1976.
Information
16. 17.
18.
and sickle cell crisis
Uzsoy, N. K.: Cardiovascular findings in patients with sickle cell anemia, Am. J. Cardiol. 13:320, 1964. Baroldi, G.: High resistance of the human myocardium to shock and red blood cell aggregation (sludge), Cardiologia 54:271, 1969. Hecht, H. H.: A sea level view of altitude problems, Am. J. Med. 50:703, 1971.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1,1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: “The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors.” Authors will be consulted, when possible, regarding republication of their material.
American
Heart
Journal
591
performance
during
and
after
J. Val-Mejias, M.D. W. K. Lee, M.D. A. B. Weisse, M.D. T. J. Regan, M.D. Newark, N. J.
Although it is generally recognized that chronic anemia produces a high output state associated with cardiac hypertrophy, the influence on the myocardium may be affected by the specific form of anemia. Cor pulmonale secondary to pulmonary hypertension is well recognized in sickle cell anemia. In addition, left heart failure is known to occur in subjects in the third and fourth decades without the usual cardiac risk factors or valvular disease.” ” Defective hemoglobin synthesis in patients with sickle cell (SS) hemoglobin is not known to be paralleled by an analogous abnormality of cardiac contractile protein as a. basis for heart failure. Microvascular occlusion by sickled red cells in the myocardium has been postulated to produce ischemic necrosis, which on a chronic basis may be the cause of cardiac decompensation.g As an alternative hypothesis there has been indication that the many years of chronic hemolysis” in SS patients may result in deposition of iron in body tissues.” This process is evidently less severe than in secondary hemochromatosis where a large iron load from multiple blood transfusions may lead to heart failure in the first or second decades6 To examine whether a milder form of left ventricular dysfunction may exist in patients From the Department of New Jersey-New
of Medicine, Jersey Medical
College of Medicine School, Newark,
This investigation was supported in part by Research 09914 and Postgraduate Training Grant No. HL National Heart, Lung and Blood Institute. Received
for publication
Apr.
Accepted
for publication
June
Reprint Medical
requests: Timothy School, 100 Bergen
0002-8703/79/050585
and Dentistry N. J. Grant No. 05510 from
HL the
27, 1978. 2, 1978. J. Regan, St., Newark,
+ 07$00.70/O
M.D., CMDNJ-New N. J. 07103.
0 1979
The
Jersey
C. V. Mosby
Co.
with SS hemoglobin without the conditions for secondary hemochromatosis, subjects were studied noninvasively by the systolic time interval method supplemented by echocardiographic measurements. The question of ischemic injury was considered by serial testing of patients during and after an acute crisis as well as analysis of serum enzymes known to reflect cardiac injury. A timedependent effect of the chronic hemolytic process as a potential basis for myocardial abnormalities was evaluated in different age groups. Materials
and methods
Eleven black patients admitted in sickle cell crisis were studied serially; four were restudied during a subsequent crisis. All subjects had hemoglobin SS by electrophoresis. For studies after crisis or at intercrisis intervals, additional subjects without recent illness were included at 1 to 5 months after their last episode. Patients were excluded if they were hypertensive, diabetic, obese, uremic, had known pulmonary disease, or were heavy smokers or addicts. Excessive use of ethanol or habitual drug usage was excluded by history and generally confirmed by a relative or close friend. Subjects with prior blood transfusions or oral iron medication were not included. Diagnosis was based upon a presentation with pain in joints or skeleton that was usually similar to the symptomatology of prior crises, and was mild and moderate in degree. Most had a Grade 2 to 3 systolic murmur at the apex or left sternal border. Body temperatures per rectum during the first day were elevated by 0.6 to 1.7” F. and usually returned to normal by day six. Serum electrolytes, glucose, and BUN were in the
American
Heart
Journal
585
Val-Mejias
Table
et al.
I. Clinical data in sickle cell patients during
Table
II. Left ventricular
systolic time intervals
crisis
II I. L. c. K. c. D. P. G. R. I. R.
w. L. P. M. w. W. M. D. C. s. B. Mean SE.
13 17 20 21 22 22 23 24 26 31 --38
F F F M M F F M M M F
Cardiothoracic ratio
26 24 26 25 20 31 27 25 31 26 23
120/80 118/78 125/75 140/80 128/74 130/90 140/90 120/70 126/80 130/76 130/82
4 11 5 15 17 17 15 14 20 20 -30
0.46 0.54 0.48 0.53 0.49 0.47 0.54 0.55 0.50 0.53 0.55
25 1.3
128/80 2.2 1.7
15 2.2
0.51 0.01
normal range. Hematocrit, blood pressure, and heart rate are indicated in Tables I and II. Twelve-lead ECG’s and chest roentgenograms were obtained at the time of admission and were repeated within three days. Serum samples were analyzed for SGOT,’ (upper limit 40 units) and CPK8 (upper limit 145). Serum samples in some of the patients were kept at 0’ C. and analyzed for identification of the isoenzymes of CPK.” Systolic time intervals were measured within 24 hours of admission to the hospital, generally before medications were administered. This set of studies was repeated after 3 to 5 days and again after 7 to 10 days when the crisis had subsided and medication had been discontinued. The systolic time intervals were measured as described by Weissler and associates1ofrom simultaneous ECG, phonocardiogram, and carotid pulse tracings. Recordings were done on an oscillographic recorder (Electronics for Medicine, White Plains, N. Y.) at a paper speed of 150 mm./sec. and time lines at 0.02 sec. intervals. Ten to 12 complexes were analyzed and averaged. Preejection period (PEP), left ventricular ejection time (LVET), and electromechanical systole (QS’) were calculated and then corrected for heart rate, using Weissler’s regression equation. Twenty-two volunteers without heart disease or anemia with a mean age of 34 + 1.9 years, served as a control group. All studies were done between 8:00 A.M. and 12:00 noon, in the postabsorptive phase and supine position. In addition, six anemic subjects without sickle cell disease
586
> I. L. c. K. c. D. P. G. R. I. R.
w. L. P. M. w. W. M. D. C. s. B. Mean f Normals (N = 22) rt P vs normals
*None of values differed
106 92 83 99 100 64 104 107 76 77 - 97
.332 ,367 ,361 ,262 ,303 .325 ,502 ,488 .321 ,433 i----299
77 96 90 84 78 114 99 81 69 77 - 106
,474 ,383 ,312 ,293 ,357 ,360 ,490 ,414 ,454 ,535 L 405
91 4.3
,363 ,024
88 4.2
,407 ,023
67 1.6
.313 ,006 < 0.0001
< 0.006
< 0.0001 < 0.05 significantly
from post-crisis.
within the age range of the SS group were studied to determine the effects of comparable degrees of chronic anemia without sickle disease on the systolic time intervals. These subjects had chronic intermittent blood loss 3 to 17 months in duration and had no cardiac risk factors. To further evaluate left ventricular function, SS subjects had echocardiograms at intercrisis intervals and were compared with normals of similar age range. The echocardiograms were obtained with a Hoffrel Model 101 Ultrasonoscope interfaced to an Electronics for Medicine DR-12 amplifier recorder system, for measurement of several left ventricular parameters I1 Results
During the period of crisis, precordial chest pain was not present and there were no significant abnormalities of the ST segment or pathologic Q waves. The patients studied during crisis represented a relatively broad range in terms of age and number of past crises. Hematocrits were moderately reduced to a mean of 25 * 3 and the cardiothoracic ratio as judged from a chest roentgenogram was enhanced in virtually all (Table I). The values for systolic time intervals measured on the first day of crisis are indicated in Table II. Although heart rate was higher than in the normal group, there were no significant changes
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1979,
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LV performance
Table
Table
III. Serum enzymes
and sickle
cell crisis
IV. Age and intercrisis systolic time inter-
vals Name
fh I. w.
30t
14*
L. L. c. K. E. D. P. G. R. I. R.
P. M. W. W. M. D. C. s. B.
25 47 31 25 30 15 37 35 -
54 31 25 24 27 10 32 35 -
Mean +
28.8 3.5
29.8 3.9
98* 73 110
301 68 33
1.8
3.9
39
27
2.7
1.4
31 78
34 51
2.9 3.1
2.1 2.2
26 - 45
27 - 42
0.3 --2.4
0.7 1.9
62.5 11.2
*Blood samples obtained on admission tions. iSamples obtained on day 3 or 4.
39.0 5.0 to hospital
.4
1.0
1.94 .44 before
1.88 .40 any
injee-
in the individual time intervals when corrected for heart rate (LVETI, PEPI, Q&I). The ratio of PEP/LVET was significantly higher than normal in the initial study. In the 3 to 7 day period, the PEP/LVET ratio was higher than normal but not significantly different from the initial study at 0.385 t 0.03. In the post-crisis period when the patients were afebrile: both PEP1 and Q&I were significantly abnormal. The systolic time interval ratio was further elevated above normal to 0.407 + 0.02, although not significantly different from values of the initial day. Four individuals were restudied during an additional crisis. Both the initial and post-crisis studies were significantly abnormal and did not differ significantly from each other. In these four subjects, the post-crisis ratio of PEP/LVET was 0.412 +- 0.24 compared to 0.390 & 0.02 on the repeat study, Serum enzymes were determined on the day of admission to determine if acute myocardial necrosis was present. SGOT was found to be within normal limits in the nine patients assayed and there was no significant change in the repeat analyses. Total CPK activity was slightly elevated on the day of admission and was substantially reduced by days 2 or 3. To determine the nature of the CPK elevation, isoenzyme activity was assessedin seven patients. In none was there a significant elevation of the MB
American
Heart
Journal
Group A * I. w.t A. T. Wa. W. L. L.t W. B. c. P.t S. J. K. M.t
Age/ sex
13 13 14 17 18 20 21 22
F M F F M F M M
Hct
25 32 27 24 25 26 24 -21
Crises
16 1
4 15 2 3 4 -22
Mean S.E. k Group B C. J. P. M. G. B. G. D.t s. w. R. C.t I. s.t Wi. W. R. B.t J. T.
17.3 1.28
25.5
23 23 23 24 24 26 31 34 38 42
24 26 18 21 17 31 28 30 19 -28
42 27 15 49 2 31 24 37 60 - 16
Mean S.E.S PS
28.8 2.23 .009
24.20 1.63 NS
30.3 5.48 ,005
M F F M F M M M F M
1.13
8.4 2.84
Heart rate
PEP/ LVET
77 62 76 107 75 90 56 84
,474 ,299 .351 .408 ,274 .312 ,253 -L,293
.46 .45 .46 .54 .55 .48
78.4 5.63
,335 .023
.50 .02
71 90 75
,377 ,490 ,375
81
,414
75 69 77 100 106 - 70
,325 ,455 ,539 ,489 ,405 -,379
.51 .53 .50 .55 .51 .50 .53
81.4 4.1 NS
0.425 0.021 .02
C/T
53
.55 251 0.521 0.006 NS
*Group A patients were less than 23 years of age; Group B patients were at least 23 years old. tData were obtained no sooner than seven days after crisis. All others studied only at intercrisis. Each patient was normotensive. SGroup A vs B in unpaired t test with equal variances.
isoenzyme; the MM fraction was elevated in several individuals and declined by days 3 and 4. Thus, no evidence of enzyme leakage from cardiac tissue was observed during the sickle cell crisis. To determine whether a cumulative effect of the hemolytic process as judged by age may have been a determinant of the abnormal systolic time intervals, subjects studied after crisis and four additional individuals seen during an intercrisis period were assessed.Those in Group A were less than 23 years and those in Group B were at this age or older. As indicated in Table IV, PEP/ LVET ratio in the younger group was not significantly different from normal controls. However, in Group B the ratio was significantly increased at 0.413 + 0.03. The hematocrit, heart rate, and cardiothoracic ratio were at similar levels to those found in Group A but the cumulative number of crises were greater in Group B. The effect of age
587
Val-Mejias
et al.
V. Chronic anemia without sickle cell disease
Table
J. C. R. B. M.
N. M. W. w. M.
Sex
Age
Hct
M F F F M
19 25 26 34 -38
27 24 33 26 20
*Unpaired t test vs Normals (Table vs Group A (Table vs Group B (Table
Table
Hr
B
110
120/85
75 59 61 - 75
115/75 110/70 115/76 120/80
P
Q&Ix
PEPIx
561 548 548 531
132 132 140 125
429 416 408 407
-115
-417
PEP/ LVET
L VE TIx
,364 ,345 ,369 ,324
II) N.S. IV) N.S. IV) P < .03.
VI. Intercrisis echocardiography
Vcf Patient Group I. w. c. P. S. J. c. w. K. M.
Age/Sex
LVID*
% F.S.*
Circ./sec.
E.F.*
P. W.D.*
13 21 21 22 22
5.0 4.8 5.0 5.9 -5.3
33.0 33.3 36.9 37.3 39.6
1.217 1.648 1.221 1.519 1.357
.83 .70 .78 .75 - .78
0.8 0.7 0.8 0.9
5.2 0.2
36.0 1.3
1.392
0.085
0.77 0.021
0.86 0.08
5.9 6.2 5.3 4.9 4.2 6.3 5.0 -6.0
27.9 27.0 40.6 28.5 33.3 34.0 34.0 -26.8
1.157 ,869 1.175 1.398 1.265 1.133 1.514 0.869
.64 .61 .77 .63 .69 .63 .71 A60
0.7 0.8 0.9
0.9
28.6 2.4
5.5 0.26
31.5 1.7
1.173 0.080
.66 0.021
0.93 0.08
31 2.7 A) B)
4.64 .I3 < 0.03 < 0.01 NS
34.4
1.24 .06 NS NS < 0.09
.77 .02 NS < 0.08 < 0.005
.98 .03 NS NS NS
A
Mean S.E. +Group B P. M. c. J. s. w. G. D. R. C. I. s. Wi. Wa. J. T.
19.8
1.7 23 23 24 25 26 32 34 42
Mean S.E. f Normals Mean (N = 8) S.E. + P (normal vs Group P (normal vs Group Group A vs B ‘Abbreviations: wall thickness
F F F M M
F F F M M M M M
LVID = left ventricular (in mm.).
end-diastolic
1.9
< 0.05 NS < 0.08 internal
diameter
may be largely dependent on the severity of the hemolytic process or on the number of crises, as suggested by the fact that the two subjects in Group A with PEP/LVET above .40 had at least 15 crises. Since anemia per se is known to affect the cardiovascular system, five individuals were selected who had no known cardiac risk factors
588
(in cm.);
F.S. = fiber
shortening;
E.F.
= ejection
- 1.1
1.1
0.8 1.3
fraction;
P.W.D.
= posterior
but who had evidence of chronic blood loss. Hematocrit levels had stabilized by the time of the study. The levels of heart rate and arterial pressure were comparable to the sickle cell patients. However, the ratio of PEP/LVET was not significantly different from normal but was significantly less than in the Group B subjects (Table V).
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1979,
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Echocardiographic studies in some of the intercrisis subjects of Groups A and B as well as additional sickle cell patients between crises also revealed a difference in left ventricular performance (Table VI). Group A parameters were similar to normals, except for a larger left ventricular end-diastolic internal diameter and greater per cent fiber shortening, presumably due to the chronic anemia. Group B, despite a larger ventricular end-diastolic diameter, had significantly reduced ejection fraction and a nonsignificant reduction of fiber shortening compared to normals. Ejection fraction was also diminished when compared with Group B. Discussion
As a measure of left ventricular performance the systolic time interval method has been found to be sensitive and reliable,” as well as reproducible in normals.” In this study of sickle cell patients determinations during two different crises indicated a reasonable degree of reproducibility. Systolic time intervals were sequentially determined during sickle cell crisis to assess whether there was evidence of abnormal myocardial function consistent with an acute ischemic process. The latter has been postulated to exist due to microthrombi formed by the aggregates of sickle blood cells.” The observed patterns of the systolic time intervals during and following crisis contrasts with that occurring during myocardial infarction.‘:; Both situations are usually characterized by acute phase reactions for several days, which may in that period alter venous return, afterload, and neurohumoral regulation so as to affect the time intervals. During uncomplicated acute infarction, the abnormal ratio present on the first day appears to persist at about the same level through the first week.‘,’ By contrast, during crisis the ratio on the initial day was less abnormal than after the crisis, suggesting that myocardial ischemic injury was not present. Supporting this view was the absence of cardiac symptoms and ECG changes consistent with acute ischemia. In additon, the acute event was not associated with elevation of serum SGOT or CPK-MB isoenzyme, although transient increments of MM, presumably from skeletal muscle, were observed. Since it is not yet known whether necrosis of a small quantity of myocardium can occur without release of detectable levels of CPK-MB into the serum, these findings only
American
Heart
Journal
and sickle
cell crisis
exclude ischemic injury of sizeable portions of heart muscle. The observation that systolic time intervals were normal in anemic subjects without sickle cell disease is consistent with a prior study in which patients at this level of hematocrit reduction had time intervals within the normal range.” While it would appear that markedly reduced red cell mass can be associated with either substantially shortened or prolonged time intervals and heart failure,‘” this degree of anemia was not present in our patients. Abnormal left ventricular performance observed after crises or at intercrisis intervals was not observed in a prior study of sickle cell patients in which the temporal relation to acute crises or their relative number were not indicated.‘” Individuals less than 23 years of age had normal ventricular function by two noninvasive techniques, in agreement with our study. Older individuals consisted of seven females and four males. The mean PEP/LVET in the females was 0.32. While the seriesof males was too small to analyze statistically, two were clearly abnormal at 0.42 and one was borderline at 0.35. In comparing the individuals over 23 years by sex in our own series, the males had a ratio of .446 f .035 and females a ratio of .368 * .023. Thus, the negative conclusion of the previous report may have been due to the relatively few males in the older group.li An additional factor may relate to the number of crises in each patient. Even in the young patients forming Group A, those with the more abnormal systolic time intervals had at least 15 crises, while those in Group B with only several such episodes tended to have normal time intervals. The general relationship of diminished ventricular function to age was supported by our echocardiographic studies, which indicated that only Group B subjects had a reduced ejection fraction, despite an enhanced left ventricular end-diastolic diameter. Support for the view that the cumulative effect of chronic hemolysis and multiple crises over the years affect cardiac function is provided by reports on the occurrence of heart failure in patients with sickle cell anemia.‘- Iii In the earlier study the two subjects who died of congestive heart failure with pulmonary edema were males, 30 and 32 years old. In the latter study,“’ congestive heart failure that was presumably left- and right-sided occurred in three individuals between
589
Val-Mejias
et al.
ages 33 and 44 years. In both studies, increased interstitial fibrous tissue and edema were observed, with vacuolization of myocardial fibers in the left ventricle. Microscopic fibrosis has also been described in a prior report.” The mechanism of the abnormal left ventricular performance in the older age group is not known. It is possible that the cumulative effects of anemia or arterial hypoxia on the process of hypertrophy may alter cardiac function in the long-term process of sickle cell disease, as compared to the lesser chronicity of the individuals with blood loss anemia. However, the role of chronic hypoxia would appear unlikely in view of the reported normal left ventricular status in life-long residents at high altitude.‘” Although classic hemochromatosis of the secondary type was not a factor in these patients, many years of chronic hemolysis are known to exist in patients with SS hemoglobin.’ Since serum ferritin concentrations are substantially elevated, significant deposition of iron in tissue may occur.’ in acquired iron storage disease of children who are recipients of many blood transfusions, left heart failure frequently appears by 20 years of age,” in contrast to at least a decade later in sickle cell anemia. Although a definitive morphologic study of myocardium is not available, the findings that interstitial fibrosis and ultimate loss of myocardial fibers that occurs in hemochromatosis, presumably as a reactive response to iron loading,” may also be seen in patients with SS hemoglobin’, I6 suggests that some patients who survive well into adulthood may incur some degree of left ventricular dysfunction on such a basis.
appeared unlikely. Four patients on subsequent admission exhibited systolic time interval values similar to the earlier crisis. To determine if there were chronic changes in cardiac function, subjects with sickle cell hemoglobin were studied between crises. Those under 23 years of age were not dissimilar from a group of normals and a group of patients with chronic blood loss anemia A significant abnormality of the PEP/LVET ratio was observed in subjects over 23 years of age. Similar observations were made on echocardiographv, with subjects over the age of 23 demonstr,:r*ing an abnormal ejection fraction compared to ihe younger group, despite enhanced end-diastolic diameter. Thus, it is suggested that the chronic hemolytic process in subjects with sickle cell anemia may effect cumulative myocardial alterations, resulting in chronic cardiac malfunction in the apparent absence of acute ischemia during crises. REFERENCES
1.
6.
7.
Summary
Although microvascular occlusion has been considered a basis for pathophysiology of the myocarditim during the crisis of sickle cell anemia, the status of the left ventricle in uncertain. To determine if left ventricular performance is affected by crisis, 11 patients were evaluated noninvasively by the systolic time interval method on the first day of crisis and serially until recovery. There were no significant differences in the time intervals over this period. In addition, since the serum CPK-MB isoenzyme was not elevated during crisis and evidence of acute injury was not present on ECG, myocardial necrosis
590
8.
9.
10.
11. 12.
13.
Winsor. T., and Burch, G. E.: The electrocardiogram and cardiac state in active sickle-cell anemia, AM. HEART J. 29:685, 1945. Klinefelter, H. F.: The heart in sickle cell anemia, Am. J. Med. Sci. 203:34, 1942. Margolies, M. P.: Sickle cell anemia. A composite study and survey, Medicine 30:357, 1951. Bensinger. T. A., and Gillette, P. N.: Hemolysis in sickle cell disease, Arch. Intern. Med. 133:624, 1974. Peterson. C. M.. Graziano. J. H.. de Ciutiis, A., Grady, R. W., Cerami, A:, Worwood, Ml, and Jacobs, A.: Iron metabolism, sickle cell disease, and response to cyanate, Blood 46:583, 1975. Engle, M. A., Erlandson, M., and Smith, C. H.: Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis, Circulation 30:698, 1964. Kessler, G., Rush, R. L., Leon, L., DeLea, A., and Cupiola, R.: Automated 340 nm measurement of SGOT, SGPT and LDH, in: Advances in automated analysis, Barton, E. C., et al., eds., Miami, Fla., 1971, Thruman Associates, vol. 1, pp. 67-74. Rosalki, S. B.: An improved procedure for serum creatine phosphokinase determination, J. Lab. Clin. Med. 69:696, 1967. Varat, M. A., and Mercer, D. W.: Cardiac specific creatine nhosphokinase isoenzyme in the diagnosis of acute myicar&al infarction, Circulation 5 1:855, 1975. W&&r. A. M.. Harris. W. S., and Schoenfeld, C. D.: Bedside technics for the evaluation of ventricular function in man, Am. J. Cardiol. 23:577, 1969. Feigenbaum, H.: Echocardiography, 2nd edit.. Philadelphia, 1976, Lea & Febiger, pp. 309-322. Lewis, R. P.. Leighton, R. F., Forester, W. F., and Weissler, A. M.: Systolic time intervals, in: Noninvasive cardiology, Weissler, A. M., ed, New York, 1974, Grune & Stratton, Inc., pp. 301-368. Naqvi, S. Z., Chisholm, A. W., and Shane, S. J.: Left
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ventricular function in ischemic heart disease: Assessment by noninvasive techniques, AM. HEART J. 90:312, 1975. Abdullah, A. K., Siddiqui, M. A., and Tajuddin M: Systolic time intervals in chronic anemia. AM. HEART J. 94:287-291, 1977. Gerry, J. L., Baird, M. G., and Fortuin, N. J.: Evaluation of left ventricular function in patients with sickle cell anemia, Am. J. Med. 60:96&S, 1976.
Information
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and sickle cell crisis
Uzsoy, N. K.: Cardiovascular findings in patients with sickle cell anemia, Am. J. Cardiol. 13:320, 1964. Baroldi, G.: High resistance of the human myocardium to shock and red blood cell aggregation (sludge), Cardiologia 54:271, 1969. Hecht, H. H.: A sea level view of altitude problems, Am. J. Med. 50:703, 1971.
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Heart
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