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Left ventricular mass and wall thickness in hypertension
Left Ventricular Mass and Wall Thickness in Hypertension Comparison of M Mode and Two Dimensional Echocardiography in Two Experimental Models
ERNEST0 E. SALCEDO, MD, FACC KRZYSZTOF GOCKOWSKI, MD ROBERT C. TARAZI, MD, FACC Cleveland, Ohio
From the Department of Cardiology and the Research Division, Cleveland Clinic Foundation, Cleveland, Ohio. These studies were supported in part by grants from the American Heart Association (Northeast Ohio Chapter), Cleveland, Ohio, Merck, Sharp 8 Dohme, West Point, Pennsylvania, and the Research Project Committee Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript received July 31, 1979, accepted August 3, 1979. Address for reprints: Ernest0 E. Salcedo, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
936
October 22, 1979
The performance of noninvasive echocardiography, both M mode and two dimensional, was achieved in conscious dogs, allowing the study of direct anatomic-echocardiographic correlations of ventricular wall thickness and mass. Forty-three dogs, 33 with normotension and 10 with experimental hypertension, were studied. Good correlation between measurements of wall thickness was found between M mode echocardiography and corresponding anatomic sites in the interventricular septum (r = 0.62, P
Relatively little is known about the patterns of left ventricular hypertrophy in response to hypertension. Its rate of development, symmetry and type can vary widely among individual patients and different types of hypertensive disease.1-4 Progress in these areas has been hampered by the lack of an experimental model for critically evaluating these structural changes in different types of hypertension. Echocardiography appeared useful in this respect. Information from M mode tracings correlated fairly well with hemodynamic angiographic measurements5m7 However, many of these calculations, angiographic as well as echocardiographic, were based on a series of assumptions, most notably the prolate ellipsoid hypothesis. s In addition, the M mode technique imposed the approximation, among others, that the left ventricular long axis was twice as large as any of the short axes9 and the assumption that left ventricular wall thickness was uniform throughout the chamber. Moreover, very few studies have correlated direct anatomic determinations with echocardiographic measurements of wall thickness and mass; in man, these studies have necessarily been limited to terminally ill patientslO or patients undergoing open heart surgery.ll Trials in experimental animals have involved, for the most part, direct cardiac application of transducers in anesthetized open chest dogs.i* Only the study of Mashino et a1.i3used surface echocardiography in the dog; calculations of stroke volume were correlated with indicator-dilution measurements, but the accuracy of left ventricular mass determinations was not assessed in relation to postmortem findings.
The American Journal of CARDIOLOGY
Volume 44
LEFT VENTRICULAR
Therefore, this study was undertaken, first, to define the reliability of echocardiographic determinations of left ventricular wall thickness and mass by making comparisons with direct measurements in dogs killed immediately after the noninvasive procedure. Furthermore, the accuracy of M mode echocardiography was determined by comparing the results with those obtained with two dimensional echocardiography. Introduction of the latter technique represented a significant advance in that it allowed unwarranted assumptions about ventricular diameter and wall thickness to be replaced by their actual determinations. The value of these assumptions could be tested in different conditions. The study was therefore not limited to normotensive dogs because left ventricular hypertrophy can alter geometry and invalidate conclusions based on the normal heart alone. Two experimental models of hypertension (deoxycorticosterone [DOC] injection and. renal arterial stenosis) were also investigated in the same manner as the normotensive animals, The results confirmed the need to evaluate echocardiographic measurements in different models of disease. The cube formula14 was accurate in many normotensive dogs, but it fell far from the mark in dogs with experimental hypertension and irregular thickening of left ventricular walls. Methods Experimental animals: A total of 43 dogs were studied, 33 with normal blood pressure and 10 with hypertension induced by deoxycorticosterone injections15 or renal arterial narrowing. l6 All dogs had noninvasive M mode echocardiographic records; in addition, 10 normotensive and 9 hypertensive dogs also had two dimensional echocardiograms. Blood pressure in the hypertensive animals was recorded by direct measurements through a chronically inserted right iliac catheter.17 Deoxycorticostefone hypertension was induced in four dogs by intramuscular injection of 25 mg Percorten@ pivalate every 3 weeks. Excessive hypokalemia was avoided by maintaining
PHONO
ir
I,
‘!
MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL.
the animals on a normal salt diet. Mean arterial pressure increased over 3 weeks from an average of 88 to 120 mm Hg; the dogs were followed up an average of 13 weeks (range 8 to 24). Renovascular hypertension in five dogs was induced using externally adjustable renal clamps.16Js Blood pressure increased more rapidly than with deoxycorticosterone and attained higher levels, averaging 150 mm Hg (range 120 to 180). The animals were killed after 4 weeks of sustained hypertension. Echocardiography: M mode echocardiograms were obtained with a Picker 80-C ultrasonoscope and a 6 mm diameter, 3.5 megahertz nonfocused transducer. The two dimensional studies were performed with a Toshiba SSH-IOA phasedearray ultrasonic sector scanner; they were recorded, reviewed and analyzed on a 0.5 inch (1.27 cm) cassette video tape system. All echocardiographic studies were performed in conscious animals trained to lie still; excellent tracings can also be obtained, if needed, under light anesthesia with morphine and thiopenthal sodium. The tracings were obtained with the dog on its left side with the upper limbs extended; the transducer was placed over a shaved area at the second or third intercostal space at the right sternal border. An echocardiographic scan from the aorta to the left ventricle could be obtained by angulating the transducer from a superior and leftward position to an inferior and rightward position. This scan results in a picture resembling that obtained from the left sternal border in man and gives excellent delineation of the interventricular septum, posterior left ventricular wall, mitral valve, aorta, aortic valve and left atrium (Fig. 1). A similar technique was used for the two dimensional echocardiograms. With the transducer placed in the second or third intercostal space at the right sternal border, the sector scan image plane was first. oriented to the long axis of the left ventricle. The transducer was then rotated 90° clockwise to obtain a short axis view of the left ventricle. A short axis sweep was then performed by slowly angling the image plane from the aorta to the apex (Fig. 2).
LONG AXIS
m
CROSS SECTION
AORTA
LEFT ATRIUM
FIGURE 1. Echocardiographic scan from the aorta to the left ventricle (LV) obtained noninvasively from the right sternal border in the dog. EKG = electrocardiogram: phono = phonocardiogram; RV = right ventricle. Arrow points to anterior mitral leaflet.
I ,MITRAL VALVE LEVEL II PAPILARY MUSCLE LEVEL FIGURE 2. Long axis and short axis two dimensional echocardiograms obtained noninvasively from the right sternal border in the dog. Upper figure, measurements of the long axis were obtained. Lower figures, the anterioposterior and transverse diameters were measured as was the wall thickness.
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
937
LEFT VENTRICULAR MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL
I I
I
I
I
I
FIGURE 3. Left ventricular echocardiogram showing the tip of a needle (open arrow) penetrating the septum(S), the left ventricular cavity (LV) into the posterior wall (PW) of the left ventricle. RV = right ventricle. A chorda tendinea is seen parallel and proximal to the endocardial surface of the posterior wall.
Anatomic studies: Two separate studies were performed, one to evaluate the accuracy of echocardiographic determinations of wall thickness and the second to correlate calculated “left ventricular mass” with actual left ventricular weight. The first study involved 24 dogs, 23 with normotension and 1 with renal hypertension. After the initial tracing, the animals were anesthetized and a second M mode echocardiogram was obtained. The exact site of origin of the echocardiographic images in the interventricular septum and posterior left ventricular wall was marked with 0.1 cc of methyl blue injected through a pericardiocentesis needle (No. 18) introduced parallel to the transducer (Fig. 3). Wall thickness was measured at the level of these methyl blue markers. The second study involved all 43 dogs; all were killed after receiving thiopenthal sodium anesthesia, with a saturated potassium chloride solution (15 ml intravenously). The hearts were immediately removed and washed thoroughly; both atria and the right ventricle were dissected away and the great vessels cut at the level of the semilunar valves. The left ventricle was dried with blotting paper and weighed on a precision balance.lg In dogs that had two dimensional echocardiograms, two cross-sectional cuts of the left ventricle were obtained, one at the tip of the mitral valve and the other through the mid papillary muscle level; wall thickness was measured in five locations at these levels (Fig. 4). Data analysis: A. Echocardiographic measurements: The two dimensional and M mode echocardiograms were interpreted without knowledge of the anatomic studies. All M mode measurements were taken according to the recommendations of the American Society of Echocardiography. The specific variables examined by M mode echocardiography included thickness of the septum and posterior left ventricular wall as well as the end-diastolic and end-systolic diameter. The specific variables examined in the two dimensional echocardiograms included the long axis of the left ventricle as well as its short anteroposterior and short lateral axes plus the wall thickness of the interventricular septum and the posterior, lateral and anterior walls (Fig. 4). These measurements were obtained at the level of both the mitral valve and the mid papillary muscle. B. Calculations of left ventricular mass: Left ventricular mass was calculated in different ways. For M mode tracings, the D3 method’4 was used with and without the correction factor of Teichholz et a1.21Calculation of left ventricular mass from the two dimensional echocardiograms was based on different variants of the following formula’?:
936
October 22, 1979
The American Journal of CARDIOLOGY
MITRAL VALVE LEVEL
II
PAPILLARY LEVEL
MUSCLE
FIGURE 4. Schematic representation of the different measurements performed in the two dimensional echocardiograms. The dotted arrow represents the long axis of the left ventricle. Arrows 1 and 2 correspond to the minor axes; arrow 3 = septum; arrow 4 = posterior wall; arrow 5 = posterior septum; arrow 6 = lateral wall; arrow 7 = anterior wall.
LVM =
(L + 2WT) (D1 + 2WT) (Da + 2WT) 2 -~ LD1D2 2
1. x105
where LVM is the left ventricular mass, L the end-diastolic long axis, D, the anteroposterior minor axis, D2 the short transverse diameter, WT the wall thickness and 1.05 is the specific gravity of ventricular muscle. A first. approach (LD2) used the LD12 and thickness of the posterior left ventricular wall only. The second variant (LD1 D2) used the long axis,
both short diameters, but again only the posterior wall thickness. The third formula (LDID2 WT) used all three axes as well as the average of the wall thickness measured in five places at. the level of the mitral valve (Fig. 4). The various calculations were tried to evaluate the relative importance of the many assumptions involved in the simple cube for-
mula.14
Results Correlation between M mode echocardiography
and anatomic findings: (1) Thickness of septal and posterior walls: In 24 dogs direct anatomic-echocardiographic correlations of wall thickness were obtained by the methyl blue marker technique (Table I). The echocardiographic value for wall thickness was about 15 percent smaller than the anatomic measurement possibly because of changes in wall dimensions with death. However, there was a significant correlation between anatomic and echocardiographic wall thickness (r = 0.62 for the left ventricular septum and 0.75 for the posterior wall, P
Volume 44
The Teichholz
correctionzl
reduced
the dif-
LEFT
TABLE
VENTRICULAR
MASS
BY
ECHOCARDIOGRAPHY-SALCEDO
ET
AL
I
M Mode Echocardiography: Correlation With Anatomic Findings in 24 Dogs M Mode
Index Septal thickness (mm) Posterior wall thickness (mm) Left ventricular mass (9)
A%
Autopsy
I’
10.3 f
1.5
12.3 f
1.7
-16
10.3 f
1.6
11.9 f
1.5
-13
f 24
$71
162
f56’
95
-z
160
f
140
.” 0) B
120
3
100
LD2
CUBE
/
60
* Based on “cube” formula.” Values are average f standard deviation; A% represents deviation of echocardiographic measurements from anatomic determinations; P = probability.
60
I-
/
Lo Etil’
100
’ I I ’ ’
I20
140
CALCULATED
ference between calculated mass and weight to 23 percent but did not improve the correlation coefficient (r = 0.646, r2 = 42 percent). Two dimensional echocardiography: Two dimensional tracings were obtained in 19 dogs, 10 normotensive animals, 4 with deoxycorticosterone-induced hypertension and 5 with renovascular hypertension. Correlations with anatomic findings revealed an increasingly higher significance level, and the slope of the regression line approached the line of identity as assumptions implied in the D3 formula were replaced by actual determinations of the long axis and the left ventricular wall thickness in different areas (Table II) (Fig. 5).
160
160
200
MASS (gm)
CUBE(03+2Pwtl
r=a595
pco.01
LD2
I zo.730
p=QOOl
r=0.900
p= 0.0001
(LD2*2Pwt)
LDDO (L4Qf2wt)
FIGURE 5. Relative accuracy of calculating left ventricular (LV) mass from M mode and two dimensional echocardiograms. There is a significant improvement of the corretation coefficient and a closer approximation to the line of identity (dotted line) as the cube formula is substituted by formulas that include long axis measurements (L), both minor axes (D, 0s) and the average wail thickness (W). p = probability; r = correlation coefficient.
tied. In,all dogs in which the posterior left ventricular wall was marked with methyl blue in vivo, the needle followed the same path through the right ventricle, the mid portion of the interventricular septum and the posterobasal wall between the papillary muscles. Thus, measurements of the short anteroposterior ventricular diameter and wall thickness were obtained in a reproducible way in limited areas with this technique. However, calculation of left ventricular mass from M mode tracings was not precise, which is not surprising in view of the limited information these tracings afforded regarding complex three dimensional ventricular geometry. Besides, in evaluating hypertrophied hearts, M mode echocardiography is limited not only because of its restriction to a single ventricular diameter but also because measurement of the thickness of the septal and posterior walls, which are the only areas that can be visualized with this method, may not demonstrate changes occurring in other areas. Left ventricular hypertrophy in hypertension was not necessarily con-
Discussion
This study demonstrates that excellent quality noninvasive M mode as well as two dimensional echocardiograms can be obtained in conscious dogs. Our results support the value of M mode echocardiography in determining wall thickness of the left ventricle but underline the serious limitations of this technique in calculating left ventricular mass. In contrast, an excellent approximation of left ventricular weight can be obtained with two dimensional echocardiography (Table II) (Fig. 5). Limitations of M mode echocardiography: The good correlation between anatomic and echocardiographic wall thickness found in this study agrees with the data of others.lOJ1 The consistent underestimation of wall thickness by echocardiography is possibly related to postmortem alterations as the left ventricle is emp-
TABLE II Correlation Matrix of Lefl Ventricular Welght With Calculation of Left Ventricular Mass by Various Formulas Statistical Index Correlation coefficient (r) Probability (p) value Determination index I % 1 Standard deviation of rebression
M Mode Tracings D3
0.595
Teichholz*’ 0.573 =O.Ol 32.8 28.4
Two Dimensional Tracings LD,s
LDIDP
0.736 =O.OOl 54.2 26.0
0.775 =O.OOl 60.0 23.0
LD,D*WT 0.900 <0.0001 81 14.1
Left ventricular mass calculations are based on Troy’s formula. l4 For LDlD2 WT. the mean wall thickness (e) was the average from five different sites (Fig. 4). In all the others, the only thickness used was that of the posterior wall. The transverse short axis (D2) was used in the last two formulas. The actual long axis (L) of the left ventricle was used in all the two dimensional calculations. For the M mode calculations, the long axis was assumed to be twice as large as the anteroposterior diameter (D).
October 22,197Q
The American Journal of CARDIOLOGY
Volume 44
939
LEFT VENTRICULAR MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL
centric or symmetric. 22 Hence, although M mode echocardiography accurately measures the limited areas that it can visualize, it is of limited value in the overall evaluation of the left ventricle. The greater the number of assumptions implicit in a formula meant for calculating left ventricular mass, the greater the possibility of error; this applied particularly to diseased hearts in which hypertrophy may be asymmetric. Accuracy of two dimensional echocardiography in the diagnosis of left ventricular hypertrophy: In contrast with M mode tracings, an excellent approximation of left ventricular weight was obtained with two dimensional echocardiography not only in normotensive but also in hypertensive dogs. In addition to determination of the minor anteroposterior diameter and both septal and posterior wall thicknesses, this technique allows the left ventricular transverse minor diameter, long axis and anterolateral wall thickness to be determined. In calculations of volume from M mode echocardiography, the long axis is assumed to be twice as large as the short axis; the two dimensional studies proved that this is not always the case. Calculation of ventricular weight based on the “LD” formula increased the correlation coefficient from 0.595 to 0.736 and reduced the standard error of regression by 52 percent (Table II). A greater improvement in estimating ventricular weight was introduced by determining left ventricular wall thickness at different sites (Fig. 4). The correlation coefficient was increased from 0.736 to 0.900 when wall thickness was measured from these areas instead of calculated from the posterior wall alone.
In this regard, two dimensional echocardiography is particularly important in studying the different patterns of left ventricular hypertrophy in hypertension. Thus, early septal hypertrophy has been described in borderline hypertension, which contrasts with the more uniform hypertrophy in patients with long-standing hypertension.22 However, a steep angle between the interventricular septum and the aorta can lead to oblique transection of the former by the echocardiographic beam, giving an erroneous impression of asymmetric septal hypertrophy.2” This potential problem is avoided with two dimensional echocardiography. Contrariwise, two dimensional echocardiography led to a more precise diagnosis of early hypertrophy in dogs with sustained significant hypertension at a stage when M mode echocardiography showed an apparently normal left ventricle. In these dogs, hypertrophy was mainly seen in the anterolateral left ventricular wall. Furthermore, two dimensional echocardiography revealed an increase in papillary muscle size, quite evident qualitatively but difficult to quantify precisely. Implications: Our results suggest that evaluation of left ventricular changes in hypertension cannot depend on M mode echocardiography alone; a two dimensional view will avoid unwarranted and sometimes misleading assumptions. Cardiac involvement in hypertension can assume many forms. ls4 Our model may help determine its multiple aspects, the rate of development of hypertrophy and particularly the possibility and consequences of its reversal by specific therapy.
References 1. Tarazi, RC, ferrario CM, Dustan HP: The heart in hypertension. In, Hypertension: Physiopathology and treatment (Genest J, Koiw E, Kuchel 0, ed). New York, McGraw-Hill, 1977, p 738-754 2. Cohn JN, Limas CJ, Guiha NH: Hypertension and the heart. Arch Intern Med 133:969-979, 1974 3. Sen S, Tarazi RC, Khairallah PA, Bumpus FM: Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 35:775-781, 1974 4. Guazzi M, Fiorentini C, Olivari MT, Polese A: Cardiac load and function in hypertension. Am J Cardiol 44:1007-1012, 1979 5. Salcedo EE. Pichard A, Siegel W: Evaluation of left ventricular function by cardiac catheterization, echocardiography and systolic time intervals. Cleve Clin Quart 43:151-162, 1976 6. Pombo J, Troy BL, Russel RO Jr: Left ventricular volumes and ejection fraction by echocardiography. Circulation 43:480-490, 1971 7. Fortuin NJ, Hood WP Jr, Sherman E, Cralge E: Determinations of left ventricular volumes by ultrasound. Circulation 44575584, 1971 8. Dodge HT, Sandler H, Balleu DW, Lord JR: Use of biplane angiocardiography for the measurement of left ventricular volume in man. Am Heart J 60:762-776, 1960 9. Popp RL, Harrison DC: Ultrasonic cardiac echocardiography for determining stroke volume and valvular regurgitation. Circulation 61:493-502, 1970 10. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Circulation 55:613-618, 1977 11. Feigenbaum H, Popp RL, Chip JN, Haine C: Left ventricular wall thickness measured by ultrasound. Arch Intern Med 121:391-395, 1968 12. Kerber RE, Marcus ML, Ehrhard J, Wilson R, Abboud FM: Correlation between echocardiographically demonstrated segmental dyskinesis and regional myocardial perfusion. Circulation 52: 1097-l 104, 1975
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October 22, 1979
The American Journal of CARDIOLOGY
13. Mashino I, Nelson RR, Cohn JN, Franciosa JA: Ventricular dimensions measured non-invasively by echocardiography in the awake dog. J Appl Physiol41:953-959, 1976 14. Troy BL, Pombo J, Rackley CE: Measurements of left ventricular wall thickness and mass by echocardiography. Circulation 45: 602-611, 1972 15 Conway J, Hatton R: Development of deoxycciticosterone acetate hypertension in the dog. Circ Res 43:Suppl 1:1-82-l-86, 1978 16. Ferrario C, Page I: Current views concerning cardiac output in the genesis of experimental hypertension. Circ Res 43:821-831, 1978 17. Ferrario CM: Contribution of cardiac output and peripheral resistance to experimental renal hypertension, Am J Physiol 226: 711-717.1974 18. Ferrario CM, Blume C, Nadzam GR, McCubbin JW: An externally adjustable renal artery clamp. J Appl Physiol 31:635-637, 1971 19 Geiser EA, Bove KE: Calculation of left ventricular mass and relative wall thickness. Arch Pathol 97:13-21, 1974 20. Sahn DJ, DeMaria A, Kisslo J, Weyman A: The Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978 21. Teichholr LE, Kreulen T, Herman AV, Gorlin R: Problems in echocardiographic volume determinations: echocardiographicangiographic correlations in the presence or absence of asynergy. Am J Cardiol 37:7-l 1, 1976 22 Safar ME, Lehner JP, Vincent MI, Plafnfosse MT, Simon AC: Echocardiographic dimensions in borderline and sustained hypertension. Am J Cardiol 44:932-937, 1979 23. Fowles RE, Martin RP, Popp RL: Erroneous diagnosis of asymmetric septal hypertrophy due to angled interventricular septum (abstr). Am J Cardiol 43:348, 1979
Volume 44
ERNEST0 E. SALCEDO, MD, FACC KRZYSZTOF GOCKOWSKI, MD ROBERT C. TARAZI, MD, FACC Cleveland, Ohio
From the Department of Cardiology and the Research Division, Cleveland Clinic Foundation, Cleveland, Ohio. These studies were supported in part by grants from the American Heart Association (Northeast Ohio Chapter), Cleveland, Ohio, Merck, Sharp 8 Dohme, West Point, Pennsylvania, and the Research Project Committee Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript received July 31, 1979, accepted August 3, 1979. Address for reprints: Ernest0 E. Salcedo, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
936
October 22, 1979
The performance of noninvasive echocardiography, both M mode and two dimensional, was achieved in conscious dogs, allowing the study of direct anatomic-echocardiographic correlations of ventricular wall thickness and mass. Forty-three dogs, 33 with normotension and 10 with experimental hypertension, were studied. Good correlation between measurements of wall thickness was found between M mode echocardiography and corresponding anatomic sites in the interventricular septum (r = 0.62, P
Relatively little is known about the patterns of left ventricular hypertrophy in response to hypertension. Its rate of development, symmetry and type can vary widely among individual patients and different types of hypertensive disease.1-4 Progress in these areas has been hampered by the lack of an experimental model for critically evaluating these structural changes in different types of hypertension. Echocardiography appeared useful in this respect. Information from M mode tracings correlated fairly well with hemodynamic angiographic measurements5m7 However, many of these calculations, angiographic as well as echocardiographic, were based on a series of assumptions, most notably the prolate ellipsoid hypothesis. s In addition, the M mode technique imposed the approximation, among others, that the left ventricular long axis was twice as large as any of the short axes9 and the assumption that left ventricular wall thickness was uniform throughout the chamber. Moreover, very few studies have correlated direct anatomic determinations with echocardiographic measurements of wall thickness and mass; in man, these studies have necessarily been limited to terminally ill patientslO or patients undergoing open heart surgery.ll Trials in experimental animals have involved, for the most part, direct cardiac application of transducers in anesthetized open chest dogs.i* Only the study of Mashino et a1.i3used surface echocardiography in the dog; calculations of stroke volume were correlated with indicator-dilution measurements, but the accuracy of left ventricular mass determinations was not assessed in relation to postmortem findings.
The American Journal of CARDIOLOGY
Volume 44
LEFT VENTRICULAR
Therefore, this study was undertaken, first, to define the reliability of echocardiographic determinations of left ventricular wall thickness and mass by making comparisons with direct measurements in dogs killed immediately after the noninvasive procedure. Furthermore, the accuracy of M mode echocardiography was determined by comparing the results with those obtained with two dimensional echocardiography. Introduction of the latter technique represented a significant advance in that it allowed unwarranted assumptions about ventricular diameter and wall thickness to be replaced by their actual determinations. The value of these assumptions could be tested in different conditions. The study was therefore not limited to normotensive dogs because left ventricular hypertrophy can alter geometry and invalidate conclusions based on the normal heart alone. Two experimental models of hypertension (deoxycorticosterone [DOC] injection and. renal arterial stenosis) were also investigated in the same manner as the normotensive animals, The results confirmed the need to evaluate echocardiographic measurements in different models of disease. The cube formula14 was accurate in many normotensive dogs, but it fell far from the mark in dogs with experimental hypertension and irregular thickening of left ventricular walls. Methods Experimental animals: A total of 43 dogs were studied, 33 with normal blood pressure and 10 with hypertension induced by deoxycorticosterone injections15 or renal arterial narrowing. l6 All dogs had noninvasive M mode echocardiographic records; in addition, 10 normotensive and 9 hypertensive dogs also had two dimensional echocardiograms. Blood pressure in the hypertensive animals was recorded by direct measurements through a chronically inserted right iliac catheter.17 Deoxycorticostefone hypertension was induced in four dogs by intramuscular injection of 25 mg Percorten@ pivalate every 3 weeks. Excessive hypokalemia was avoided by maintaining
PHONO
ir
I,
‘!
MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL.
the animals on a normal salt diet. Mean arterial pressure increased over 3 weeks from an average of 88 to 120 mm Hg; the dogs were followed up an average of 13 weeks (range 8 to 24). Renovascular hypertension in five dogs was induced using externally adjustable renal clamps.16Js Blood pressure increased more rapidly than with deoxycorticosterone and attained higher levels, averaging 150 mm Hg (range 120 to 180). The animals were killed after 4 weeks of sustained hypertension. Echocardiography: M mode echocardiograms were obtained with a Picker 80-C ultrasonoscope and a 6 mm diameter, 3.5 megahertz nonfocused transducer. The two dimensional studies were performed with a Toshiba SSH-IOA phasedearray ultrasonic sector scanner; they were recorded, reviewed and analyzed on a 0.5 inch (1.27 cm) cassette video tape system. All echocardiographic studies were performed in conscious animals trained to lie still; excellent tracings can also be obtained, if needed, under light anesthesia with morphine and thiopenthal sodium. The tracings were obtained with the dog on its left side with the upper limbs extended; the transducer was placed over a shaved area at the second or third intercostal space at the right sternal border. An echocardiographic scan from the aorta to the left ventricle could be obtained by angulating the transducer from a superior and leftward position to an inferior and rightward position. This scan results in a picture resembling that obtained from the left sternal border in man and gives excellent delineation of the interventricular septum, posterior left ventricular wall, mitral valve, aorta, aortic valve and left atrium (Fig. 1). A similar technique was used for the two dimensional echocardiograms. With the transducer placed in the second or third intercostal space at the right sternal border, the sector scan image plane was first. oriented to the long axis of the left ventricle. The transducer was then rotated 90° clockwise to obtain a short axis view of the left ventricle. A short axis sweep was then performed by slowly angling the image plane from the aorta to the apex (Fig. 2).
LONG AXIS
m
CROSS SECTION
AORTA
LEFT ATRIUM
FIGURE 1. Echocardiographic scan from the aorta to the left ventricle (LV) obtained noninvasively from the right sternal border in the dog. EKG = electrocardiogram: phono = phonocardiogram; RV = right ventricle. Arrow points to anterior mitral leaflet.
I ,MITRAL VALVE LEVEL II PAPILARY MUSCLE LEVEL FIGURE 2. Long axis and short axis two dimensional echocardiograms obtained noninvasively from the right sternal border in the dog. Upper figure, measurements of the long axis were obtained. Lower figures, the anterioposterior and transverse diameters were measured as was the wall thickness.
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
937
LEFT VENTRICULAR MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL
I I
I
I
I
I
FIGURE 3. Left ventricular echocardiogram showing the tip of a needle (open arrow) penetrating the septum(S), the left ventricular cavity (LV) into the posterior wall (PW) of the left ventricle. RV = right ventricle. A chorda tendinea is seen parallel and proximal to the endocardial surface of the posterior wall.
Anatomic studies: Two separate studies were performed, one to evaluate the accuracy of echocardiographic determinations of wall thickness and the second to correlate calculated “left ventricular mass” with actual left ventricular weight. The first study involved 24 dogs, 23 with normotension and 1 with renal hypertension. After the initial tracing, the animals were anesthetized and a second M mode echocardiogram was obtained. The exact site of origin of the echocardiographic images in the interventricular septum and posterior left ventricular wall was marked with 0.1 cc of methyl blue injected through a pericardiocentesis needle (No. 18) introduced parallel to the transducer (Fig. 3). Wall thickness was measured at the level of these methyl blue markers. The second study involved all 43 dogs; all were killed after receiving thiopenthal sodium anesthesia, with a saturated potassium chloride solution (15 ml intravenously). The hearts were immediately removed and washed thoroughly; both atria and the right ventricle were dissected away and the great vessels cut at the level of the semilunar valves. The left ventricle was dried with blotting paper and weighed on a precision balance.lg In dogs that had two dimensional echocardiograms, two cross-sectional cuts of the left ventricle were obtained, one at the tip of the mitral valve and the other through the mid papillary muscle level; wall thickness was measured in five locations at these levels (Fig. 4). Data analysis: A. Echocardiographic measurements: The two dimensional and M mode echocardiograms were interpreted without knowledge of the anatomic studies. All M mode measurements were taken according to the recommendations of the American Society of Echocardiography. The specific variables examined by M mode echocardiography included thickness of the septum and posterior left ventricular wall as well as the end-diastolic and end-systolic diameter. The specific variables examined in the two dimensional echocardiograms included the long axis of the left ventricle as well as its short anteroposterior and short lateral axes plus the wall thickness of the interventricular septum and the posterior, lateral and anterior walls (Fig. 4). These measurements were obtained at the level of both the mitral valve and the mid papillary muscle. B. Calculations of left ventricular mass: Left ventricular mass was calculated in different ways. For M mode tracings, the D3 method’4 was used with and without the correction factor of Teichholz et a1.21Calculation of left ventricular mass from the two dimensional echocardiograms was based on different variants of the following formula’?:
936
October 22, 1979
The American Journal of CARDIOLOGY
MITRAL VALVE LEVEL
II
PAPILLARY LEVEL
MUSCLE
FIGURE 4. Schematic representation of the different measurements performed in the two dimensional echocardiograms. The dotted arrow represents the long axis of the left ventricle. Arrows 1 and 2 correspond to the minor axes; arrow 3 = septum; arrow 4 = posterior wall; arrow 5 = posterior septum; arrow 6 = lateral wall; arrow 7 = anterior wall.
LVM =
(L + 2WT) (D1 + 2WT) (Da + 2WT) 2 -~ LD1D2 2
1. x105
where LVM is the left ventricular mass, L the end-diastolic long axis, D, the anteroposterior minor axis, D2 the short transverse diameter, WT the wall thickness and 1.05 is the specific gravity of ventricular muscle. A first. approach (LD2) used the LD12 and thickness of the posterior left ventricular wall only. The second variant (LD1 D2) used the long axis,
both short diameters, but again only the posterior wall thickness. The third formula (LDID2 WT) used all three axes as well as the average of the wall thickness measured in five places at. the level of the mitral valve (Fig. 4). The various calculations were tried to evaluate the relative importance of the many assumptions involved in the simple cube for-
mula.14
Results Correlation between M mode echocardiography
and anatomic findings: (1) Thickness of septal and posterior walls: In 24 dogs direct anatomic-echocardiographic correlations of wall thickness were obtained by the methyl blue marker technique (Table I). The echocardiographic value for wall thickness was about 15 percent smaller than the anatomic measurement possibly because of changes in wall dimensions with death. However, there was a significant correlation between anatomic and echocardiographic wall thickness (r = 0.62 for the left ventricular septum and 0.75 for the posterior wall, P
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The Teichholz
correctionzl
reduced
the dif-
LEFT
TABLE
VENTRICULAR
MASS
BY
ECHOCARDIOGRAPHY-SALCEDO
ET
AL
I
M Mode Echocardiography: Correlation With Anatomic Findings in 24 Dogs M Mode
Index Septal thickness (mm) Posterior wall thickness (mm) Left ventricular mass (9)
A%
Autopsy
I’
10.3 f
1.5
12.3 f
1.7
-16
10.3 f
1.6
11.9 f
1.5
-13
f 24
$71
162
f56’
95
-z
160
f
140
.” 0) B
120
3
100
LD2
CUBE
/
60
* Based on “cube” formula.” Values are average f standard deviation; A% represents deviation of echocardiographic measurements from anatomic determinations; P = probability.
60
I-
/
Lo Etil’
100
’ I I ’ ’
I20
140
CALCULATED
ference between calculated mass and weight to 23 percent but did not improve the correlation coefficient (r = 0.646, r2 = 42 percent). Two dimensional echocardiography: Two dimensional tracings were obtained in 19 dogs, 10 normotensive animals, 4 with deoxycorticosterone-induced hypertension and 5 with renovascular hypertension. Correlations with anatomic findings revealed an increasingly higher significance level, and the slope of the regression line approached the line of identity as assumptions implied in the D3 formula were replaced by actual determinations of the long axis and the left ventricular wall thickness in different areas (Table II) (Fig. 5).
160
160
200
MASS (gm)
CUBE(03+2Pwtl
r=a595
pco.01
LD2
I zo.730
p=QOOl
r=0.900
p= 0.0001
(LD2*2Pwt)
LDDO (L4Qf2wt)
FIGURE 5. Relative accuracy of calculating left ventricular (LV) mass from M mode and two dimensional echocardiograms. There is a significant improvement of the corretation coefficient and a closer approximation to the line of identity (dotted line) as the cube formula is substituted by formulas that include long axis measurements (L), both minor axes (D, 0s) and the average wail thickness (W). p = probability; r = correlation coefficient.
tied. In,all dogs in which the posterior left ventricular wall was marked with methyl blue in vivo, the needle followed the same path through the right ventricle, the mid portion of the interventricular septum and the posterobasal wall between the papillary muscles. Thus, measurements of the short anteroposterior ventricular diameter and wall thickness were obtained in a reproducible way in limited areas with this technique. However, calculation of left ventricular mass from M mode tracings was not precise, which is not surprising in view of the limited information these tracings afforded regarding complex three dimensional ventricular geometry. Besides, in evaluating hypertrophied hearts, M mode echocardiography is limited not only because of its restriction to a single ventricular diameter but also because measurement of the thickness of the septal and posterior walls, which are the only areas that can be visualized with this method, may not demonstrate changes occurring in other areas. Left ventricular hypertrophy in hypertension was not necessarily con-
Discussion
This study demonstrates that excellent quality noninvasive M mode as well as two dimensional echocardiograms can be obtained in conscious dogs. Our results support the value of M mode echocardiography in determining wall thickness of the left ventricle but underline the serious limitations of this technique in calculating left ventricular mass. In contrast, an excellent approximation of left ventricular weight can be obtained with two dimensional echocardiography (Table II) (Fig. 5). Limitations of M mode echocardiography: The good correlation between anatomic and echocardiographic wall thickness found in this study agrees with the data of others.lOJ1 The consistent underestimation of wall thickness by echocardiography is possibly related to postmortem alterations as the left ventricle is emp-
TABLE II Correlation Matrix of Lefl Ventricular Welght With Calculation of Left Ventricular Mass by Various Formulas Statistical Index Correlation coefficient (r) Probability (p) value Determination index I % 1 Standard deviation of rebression
M Mode Tracings D3
0.595
Teichholz*’ 0.573 =O.Ol 32.8 28.4
Two Dimensional Tracings LD,s
LDIDP
0.736 =O.OOl 54.2 26.0
0.775 =O.OOl 60.0 23.0
LD,D*WT 0.900 <0.0001 81 14.1
Left ventricular mass calculations are based on Troy’s formula. l4 For LDlD2 WT. the mean wall thickness (e) was the average from five different sites (Fig. 4). In all the others, the only thickness used was that of the posterior wall. The transverse short axis (D2) was used in the last two formulas. The actual long axis (L) of the left ventricle was used in all the two dimensional calculations. For the M mode calculations, the long axis was assumed to be twice as large as the anteroposterior diameter (D).
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LEFT VENTRICULAR MASS BY ECHOCARDIOGRAPHY-SALCEDO
ET AL
centric or symmetric. 22 Hence, although M mode echocardiography accurately measures the limited areas that it can visualize, it is of limited value in the overall evaluation of the left ventricle. The greater the number of assumptions implicit in a formula meant for calculating left ventricular mass, the greater the possibility of error; this applied particularly to diseased hearts in which hypertrophy may be asymmetric. Accuracy of two dimensional echocardiography in the diagnosis of left ventricular hypertrophy: In contrast with M mode tracings, an excellent approximation of left ventricular weight was obtained with two dimensional echocardiography not only in normotensive but also in hypertensive dogs. In addition to determination of the minor anteroposterior diameter and both septal and posterior wall thicknesses, this technique allows the left ventricular transverse minor diameter, long axis and anterolateral wall thickness to be determined. In calculations of volume from M mode echocardiography, the long axis is assumed to be twice as large as the short axis; the two dimensional studies proved that this is not always the case. Calculation of ventricular weight based on the “LD” formula increased the correlation coefficient from 0.595 to 0.736 and reduced the standard error of regression by 52 percent (Table II). A greater improvement in estimating ventricular weight was introduced by determining left ventricular wall thickness at different sites (Fig. 4). The correlation coefficient was increased from 0.736 to 0.900 when wall thickness was measured from these areas instead of calculated from the posterior wall alone.
In this regard, two dimensional echocardiography is particularly important in studying the different patterns of left ventricular hypertrophy in hypertension. Thus, early septal hypertrophy has been described in borderline hypertension, which contrasts with the more uniform hypertrophy in patients with long-standing hypertension.22 However, a steep angle between the interventricular septum and the aorta can lead to oblique transection of the former by the echocardiographic beam, giving an erroneous impression of asymmetric septal hypertrophy.2” This potential problem is avoided with two dimensional echocardiography. Contrariwise, two dimensional echocardiography led to a more precise diagnosis of early hypertrophy in dogs with sustained significant hypertension at a stage when M mode echocardiography showed an apparently normal left ventricle. In these dogs, hypertrophy was mainly seen in the anterolateral left ventricular wall. Furthermore, two dimensional echocardiography revealed an increase in papillary muscle size, quite evident qualitatively but difficult to quantify precisely. Implications: Our results suggest that evaluation of left ventricular changes in hypertension cannot depend on M mode echocardiography alone; a two dimensional view will avoid unwarranted and sometimes misleading assumptions. Cardiac involvement in hypertension can assume many forms. ls4 Our model may help determine its multiple aspects, the rate of development of hypertrophy and particularly the possibility and consequences of its reversal by specific therapy.
References 1. Tarazi, RC, ferrario CM, Dustan HP: The heart in hypertension. In, Hypertension: Physiopathology and treatment (Genest J, Koiw E, Kuchel 0, ed). New York, McGraw-Hill, 1977, p 738-754 2. Cohn JN, Limas CJ, Guiha NH: Hypertension and the heart. Arch Intern Med 133:969-979, 1974 3. Sen S, Tarazi RC, Khairallah PA, Bumpus FM: Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 35:775-781, 1974 4. Guazzi M, Fiorentini C, Olivari MT, Polese A: Cardiac load and function in hypertension. Am J Cardiol 44:1007-1012, 1979 5. Salcedo EE. Pichard A, Siegel W: Evaluation of left ventricular function by cardiac catheterization, echocardiography and systolic time intervals. Cleve Clin Quart 43:151-162, 1976 6. Pombo J, Troy BL, Russel RO Jr: Left ventricular volumes and ejection fraction by echocardiography. Circulation 43:480-490, 1971 7. Fortuin NJ, Hood WP Jr, Sherman E, Cralge E: Determinations of left ventricular volumes by ultrasound. Circulation 44575584, 1971 8. Dodge HT, Sandler H, Balleu DW, Lord JR: Use of biplane angiocardiography for the measurement of left ventricular volume in man. Am Heart J 60:762-776, 1960 9. Popp RL, Harrison DC: Ultrasonic cardiac echocardiography for determining stroke volume and valvular regurgitation. Circulation 61:493-502, 1970 10. Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man. Circulation 55:613-618, 1977 11. Feigenbaum H, Popp RL, Chip JN, Haine C: Left ventricular wall thickness measured by ultrasound. Arch Intern Med 121:391-395, 1968 12. Kerber RE, Marcus ML, Ehrhard J, Wilson R, Abboud FM: Correlation between echocardiographically demonstrated segmental dyskinesis and regional myocardial perfusion. Circulation 52: 1097-l 104, 1975
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13. Mashino I, Nelson RR, Cohn JN, Franciosa JA: Ventricular dimensions measured non-invasively by echocardiography in the awake dog. J Appl Physiol41:953-959, 1976 14. Troy BL, Pombo J, Rackley CE: Measurements of left ventricular wall thickness and mass by echocardiography. Circulation 45: 602-611, 1972 15 Conway J, Hatton R: Development of deoxycciticosterone acetate hypertension in the dog. Circ Res 43:Suppl 1:1-82-l-86, 1978 16. Ferrario C, Page I: Current views concerning cardiac output in the genesis of experimental hypertension. Circ Res 43:821-831, 1978 17. Ferrario CM: Contribution of cardiac output and peripheral resistance to experimental renal hypertension, Am J Physiol 226: 711-717.1974 18. Ferrario CM, Blume C, Nadzam GR, McCubbin JW: An externally adjustable renal artery clamp. J Appl Physiol 31:635-637, 1971 19 Geiser EA, Bove KE: Calculation of left ventricular mass and relative wall thickness. Arch Pathol 97:13-21, 1974 20. Sahn DJ, DeMaria A, Kisslo J, Weyman A: The Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978 21. Teichholr LE, Kreulen T, Herman AV, Gorlin R: Problems in echocardiographic volume determinations: echocardiographicangiographic correlations in the presence or absence of asynergy. Am J Cardiol 37:7-l 1, 1976 22 Safar ME, Lehner JP, Vincent MI, Plafnfosse MT, Simon AC: Echocardiographic dimensions in borderline and sustained hypertension. Am J Cardiol 44:932-937, 1979 23. Fowles RE, Martin RP, Popp RL: Erroneous diagnosis of asymmetric septal hypertrophy due to angled interventricular septum (abstr). Am J Cardiol 43:348, 1979
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