ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE...
ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE TO DOPPLER ULTRASOUND Akademisk avhandling som med vederbörligt tills tå n d av Rektorsäm betet vid Umeå universitet fö r avläggande av medicine doktorsexamen kommer att offentligen försvaras i Rosa Salen, Tandiäkarhögskolan, Umeå regionsjukhus, fredagen den 19 december 1986, kl 09.15. av DAG TEIEN UMEÅ 1986
ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE …umu.diva-portal.org/smash/get/diva2:815565/FULLTEXT01.pdf · In aortic stenosis as well as in other valvular lesions, it is
Text of ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE...
ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE TO DOPPLERULTRASOUND
Akademisk avhandling som med vederbörlig t t i l ls tå n d av Rektorsämbetet v id Umeå u n ive rs ite t fö r avläggande av medicine doktorsexamen kommer a t t o ffen tligen försvaras i Rosa Salen, Tandiäkarhögskolan, Umeå regionsjukhus, fredagen den 19 december 1986, kl 09.15.
UMEÅ UNIVERSITY MEDICAL DISSERTATIONSNew Series No 177 - ISSN 0346-6612
Assessment of a o rtic stenosis with special reference to Doppler ultrasound
Dag Teien, Department o f C lin ica l Physiology, U n ivers ity o f Umeå, S-901 85 Umeå, Sweden
The severity o f le f t ve n tr icu la r outflow obstruction, the le f t vent r ic u la r function and the occurrence o f concomitant coronary arte ry disease are three important issues in the evaluation o f patients w ith suspected a o rtic stenosis.The sys to lic peak pressure gradient obtained by continuous wave Doppler echocardiography was compared w ith the peak to peak pressure gradient measured at cardiac ca theteriza tion in 58 consecutive pa tien ts . The two measurements agreed favourably; r = 0.85, SEE = 14 mm Hg.The Doppler peak gradient was compared w ith the peak gradient measured at ca theteriza tion by simultaneous recordings in the le f t ve n tr ic le and ascending aorta in 26 patien ts . A close co rre la tion was obtained; r = 0.94, SEE = 9.1 mm Hg.Estimation o f the mean sys to lic pressure drop across the valve from Doppler tracings o f the same pa tien ts , using a simple formula APmean = 0*64 x Appeak, was compared with the invasivemean pressure gradient obtained by planimetry. The mean gradient was accurately estimated, r = 0.91, SEE = 7.6 mm Hg.A o rtic valve area measurements were obtained in 22 patients both by application o f a modified Gorlin formula and by application of the con tinu ity equation using the Doppler derived sys to lic pressure gradient and ve loc ity in tegra l as well as the stroke volume obtained by radionuclide angiography. The noninvasi ve valve area was compared with tha t obtained by invasive reg is tra tions and an excelle n t re la tionsh ip was found; r = 0.95, SEE = 0.13 cm2 by the Gorlin formula and r = 0.94, SEE = 0.14 cm2 by the in teg ra tion method. Exercise ECG was used to estimate the occurrence of coexistent coronary heart disease in 35 patien ts. Patients with s ig n if ic a n t coronary lesions documented by angiography showed a lower mean working capacity, la rger ST depressions and higher e f fo r t angina score during the exercise te s t than patients w ith no or only in s ig n if ic a n t coronary obstructions.Application of simultaneous ECG, phonocardiography and Doppler echocardiography were used to determine the in te rva l between the QRS complex and the m itra l valve opening (Q-MC) and the in te rva l between the a o rtic valve closure and m itra l valve opening (A2 -MO). The ra tio Q-MC/A2 -MO corre lated closely w ith the pu lmonary c a p illa ry wedge pressure measured at ca the te riza tion ; r = 0.94, SEE = 2.9 mm Hg, n = 20.A reduction of invasive investiga tions in the evaluation of patie n ts with a o rtic stenosis is suggested.
Key words: A ortic stenosis, a o rtic valve area, transva ivular pressure drop, coronary heart disease, pulmonary c a p illa ry wedge pressure, Doppler echocardiography, radionuclide angiography
UMEÅ UNIVERSITY MEDICAL DISSERTATIONSNew Series No 177 - ISSN 0346-6612
From The Department o f C lin ica l Physiology Univers ity o f Umeå, Umeå, Sweden
ASSESSMENT OF AORTIC STENOSIS WITH SPECIAL REFERENCE TO DOPPLER ULTRASOUND
Evaluation o f patients with suspected a o rtic stenosis .................. 9The Doppler p rin c ip le ............................................................................. 10The Bernoulli equation ........................................................................... 11
AIMS OF THE STUDY ................................................................. 12
Cardiac catheteriza tion ......................................................................... 14Cineangiography ......................................................................................... 14A ortic valve area ..................................................................................... 15Coronary angiography ............................................................................... 15Estimation o f pulmonary c a p illa ry wedge pressure .......................... 17Radionuclide angiography ....................................................................... 17Noninvasive ca lcu la tion of a o rtic valve area .................................. 18
RESULTS AND DISCUSSION ............................................ 19
Q uantification o f the transva lvu la r pressure differences(Studies I and I I ) ................................................................................... 19The mean gradient (Study I I ) ..................................................... 20Determination o f a o rtic valve area (Study I I I ) ................................. 21The coexistence o f coronary heart disease (CHD) (Study IV) . . . . 23Estimation o f pulmonary c a p illa ry wedge pressure in a o rtic stenosis (Study V) ................................................ 23
FUTURE DEVELOPMENT ......................................................................................... 25
GENERAL SUMMARY AND CONCLUSIONS ................................................................ 27
ET = E jection timePCWP = Pulmonary c a p illa ry wedge pressureSV = Stroke volumeSVI = S ysto lic ve loc ity in tegra lVmax = Maximum ve loc ityWmax = Maximum working capacityWmaxN = Predicted normal WmaxWmax% = Wmax • 100/WmaxN
The severity o f le f t ven tricu la r outflow obstruction, the le f t ve n tr ic u la r function and the occurrence o f concomitant coronary arte ry disease are three important issues in the evaluation o f patients w ith suspected a o rtic stenosis.The sys to lic peak pressure gradient obtained by continuous wave Dopp le r echocardiography was compared with the peak to peak pressure gradient measured at cardiac cathe teriza tion in 58 consecutive pa tien ts . The two measurements agreed favourably; r = 0.85, SEE = 14 mm Hg.The Doppler peak gradient was compared w ith the peak gradient measured at ca theteriza tion by simultaneous recordings in the le f t ve n tr ic le and ascending aorta in 26 patien ts. A close co rre la tion was obtained; r = 0.94, SEE = 9.1 mm Hg.Estimation o f the mean sys to lic pressure drop across the valve from Doppler tracings of the same pa tien ts , using a simple formula APmean = 0*64 x Appeak» was compared w ith the invasive mean pressure gradient obtained by planimetry. The mean gradient was accura te ly estimated, r = 0.91, SEE = 7.6 mm Hg.A o rtic valve area measurements were obtained in 22 patients both by application of a modified Gorlin formula and by app lication o f the cont in u ity equation using the Doppler derived sys to lic pressure gradient and ve loc ity in tegra l as well as the stroke volume obtained by rad ionuclide angiography. The noninvasi ve valve area was compared with tha t obtained by invasive re g is tra tions and an excellent re la tionsh ip was found; r = 0.95, SEE = 0.13 cm2 by the Gorlin formula and r = 0.94, SEE =0.14 cm2 by the in teg ra tion method.Exercise ECG was used to estimate the occurrence o f coexistent coronary heart disease in 35 pa tien ts . Patients w ith s ig n if ic a n t coronary lesions documented by angiography showed a lower mean working capacity, la rger ST depressions and higher e f fo r t angina score during the exercise te s t than patients w ith no or only in s ig n if ic a n t coronary obstructions .Application o f simultaneous ECG, phonocardiography and Doppler echocardiography were used to determine the in te rva l between the QRS complex and the m itra l valve opening (Q-MC) and the in te rva l between the a o rtic valve closure and m itra l valve opening (A2 -MO). The ra tio Q-MC/A2 - MO correlated closely w ith the pulmonary c a p illa ry wedge pressure measured at ca the te riza tion ; r = 0.94, SEE = 2.9 mm Hg, n = 20.A reduction o f invasive investiga tions in the evaluation o f patients with a o rtic stenosis is suggested.
Key words: A ortic stenosis, a o rtic valve area, transva ivular pressure drop, coronary heart disease, pulmonary c a p illa ry wedge pressure, Doppler echocardiography, radionuclide angiography
The present study is based on the fo llow ing papers, which w il l be referred to by th e ir Roman numerals.
I Teien D, Eriksson P. Q uantifica tion o f transva ivular pressure d i f ferences in a o rtic stenosis by Doppler ultrasound.In t J Cardiol 1985;7:121-6.
I I Teien D, Karp K, Eriksson P. Noninvasi ve estimation of the meanpressure d ifference in a o rtic stenosis by Doppler ultrasound.Br Heart J 1986 (in press).
I I I Teien D, Karp K, Eriksson P, B je rle P, Österman G. Noninvasi ve determ ination o f the va lvu la r area in a o rtic valve disease by Doppler echocardiography and radionuclide angiography.Manuscript
IV Linderholm H, Österman G, Teien D. Detection o f coronary artery disease by means o f exercise ECG in patients w ith a o rtic stenosis. Acta Med Scand 1985;218:181-8.
V Teien D, Karp K, Eriksson P. Estimation o f pulmonary c a p illa ry wedge pressure in a o rtic stenosis by combined ECG, phonocardiography and Doppler echocardiography.J Cardiovasc U1trasonography (in press).
Evaluation o f patients w ith suspected aort ic stenosisSeveral factors have to be taken in to consideration in the evaluationo f patients with a o rtic stenosis, p a r t ic u la r ly the severity o f outflowobstruction, le f t ve n tricu la r performance and concomitant coronaryheart disease. An accurate assessment is crucia l since surgery may belife -s a v in g .
The sys to lic pressure gradient across the valve is a measure o f obs truc tion to flow . The sys to lic pressure gradient is , however, alsodependent on le f t ven tricu la r stroke volume, i.e . the sys to lic flowacross the valve. Patients w ith a compromised le f t ven tricu la r function may show a low gradient despite a small valve area. The a o rtic valve area is thus an important e n tity and i t should be calculated in a llpatients in whom there is any doubt about the severity o f the lesion. L e ft ven tricu la r performance may be assessed by measuring the e jection fra c tio n , stroke volume or cardiac output, and the pulmonary ca p illa ry wedge pressure.
The occurrence o f concomitant s ig n if ic a n t coronary heart disease is another major issue. There are c o n flic t in g reports regarding the prevalence of coronary heart disease in patients with a o rtic stenosis and the s ign ificance o f coronary atheromatosis in th is se tting is disputed (1-11). Angina pectoris is a frequent complaint in patients with a o rtic stenosis both w ith and w ithout angiographic evidence of obstructive coronary a rte ry lesions. On the other hand, a negative h is to ry o f e ffo r t re la ted chest pain does not ru le out s ig n if ic a n t coronary obstructions even i f th is combination is rare (1-11).
A noninvasi ve procedure to screen patients w ith suspected a o rtic valve lesions in respect to the severity of obstruction, le f t ven tricu la r function and concomitant coronary disease is thus desirable. In additio n , the accuracy o f the noninvasive procedures should allow the use of invasive methods to be minimized. The advent o f Doppler ultrasound is an important step in th is d irec tion (12).
The Doppler p rin c ip leThe Doppler e ffe c t was described in the f i r s t h a lf o f the 19th century by Christian Johann Doppler (1803-1853). I t applies to a ll wave-forms including sound. Several i l lu s tra t io n s have been used to exemplify th is phenomenon. One example is a row boat; when the boat is sta tionary a certa in frequency o f the sea waves is f e l t in the boat. I f the boat is rowed against the waves a sensation o f increased wave frequency is experienced, while the opposite is true when the boat is rowed in the other d irec tion . The difference in frequency f e l t when the boat is moving and not moving is the Doppler s h if t or the Doppler frequency. The Doppler frequency can be used to calcu la te the ve loc ity o f the boat provided tha t the frequency o f the waves is known.
In Doppler echocardiography a transducer emits ultrasound with a known frequency (usually 1-10 MHz). The moving blood c e lls act as re fle c to rs and the ve loc ity o f the blood corpuscules can be calculated from the Doppler equation,
c • A f v = --------------------------
2 • f • cosa
v = ve loc ity o f the blood c = ve loc ity o f sound in tissues
A f = the frequency s h if t o f re flec ted ultrasound f = ultrasound frequencyc*= angle o f incidence between the u ltrason ic beam and ve loc ity
vectors o f the moving blood
A small angle o f incidence between the blood flow and the u ltrason ic beam is c r i t ic a l to obtain accurate estimation o f the flow ve lo c ity . In a o rtic stenosis as well as in other va lvu lar lesions, i t is usually possible to obtain a transducer position w ith an angle less than 15°, which gives a cosine o f more than 0.95. I t is , however, o f the utmost
importance to t ry many d iffe re n t transducer positions to minimize the angle.
The Bernoulli equationThis equation is essential in Doppler echocardiography because i t denotes the re la tion between the d ifference in blood ve loc ity and the pressure d ifference between the two sides o f an obstructive lesion (13).
p - p2 = 1/2 p (V22 - v i2) + p 2 \ i l d r+ R (v)dt
flow ac- visciouscel e ra ti on f r i c t i on
S u ffix 1 denotes the position p r io r to the obstruction and s u ff ix 2 post the obstruction.
Pl = pressure p r io r to obstruction P2 = pressure post to obstruction P = mass density o f blood per u n it volume v i = ve loc ity p r io r to obstruction V2 = ve loc ity in the je t
The second term on the r ig h t side o f the equation represents the pressure drop caused by changes o f the ve loc ity w ith time. The la s t term represent viscous losses. I t has been shown (12-13) tha t the two la s t paragraphs can be omitted when the equation is applied to the pressures and dimensions found in s tenotic valve disease. Since the ve loc ity p r io r to a stenosis is small compared with the ve loc ity in the je t i t can also be neglected in most cases with obstruction loca lized to the va lvu lar plane. The equation can then be w ritte n ,
Ap = 4 (Vmax)2
Ap = pressure drop across the stenosis Vmax = maximal ve loc ity in the je t
The v a lid ity of the s im p lifie d equation has been tested by several authors (12-17) and Hatle and Angelsen (18) have presented a deta iled discussion on th is subject in th e ir excellent textbook.
AIMS OF THE STUDY
To evaluate the a p p lic a b ility o f Doppler ultrasound fo r quan tifica tion o f pressure d ifference across the valve in patients w ith suspected a o rtic stenosis.
To evaluate a simple method to estimate the mean pressure d ifference in a o rtic stenosis from Doppler trac ings.
To noninvasively estimate the a o rtic valve area by combining Doppler echocardiography and radionuclide angiography in patients w ith a o rtic valve disease.
To evaluate the usefulness o f the standard exercise te s t to id e n tify coexistant coronary heart disease in patients w ith a o rtic stenosis.
To noninvasi vely estimate the pulmonary c a p illa ry wedge pressure in patie n ts w ith a o rtic stenosis.
Study IIn th is study 58 consecutive patients were included. They were re ferred fo r evaluation o f suspected a o rtic stenosis. Nineteen patients had s ig n if ic a n t a o rtic regurg ita tion and three o f them also had m itra l regurg ita tio n according to angiography. No patien t was excluded on grounds o f imperfect Doppler recordings.
Studies I I , I I ITwenty-six consecutive patients examined fo r suspected a o rtic stenosis were included. There were 15 patients w ith pure a o rtic stenosis or only minimal a o rtic regu rg ita tion , 8 had stenosis w ith moderate or moderately severe regurg ita tion and 3 had severe regu rg ita tion . Of the 26 pat ie n ts , 14 had m itra l regu rg ita tio n , which was moderate in 2 and m in imal in 12. No patien t included in Studies I I and I I I was recru ited from Study I . Four patients were excluded in Study I I I as they d id not fu l ly complete the invasive protocol o f the study.
Study IVIn th is study, 35 patients were included, mainly those p a rtic ip a tin g in Study I . However, patients w ith a o rtic or m itra l regurg ita tion were ex- cl uded.
Study VTwenty consecutive patients were included, 18 o f them from Studies I I and I I I .
Cardiac cat he te riza tionIn a ll studies the pressure curves were recorded by liq u id f i l le d catheters connected to mechanoelectrical transducers in terfaced with an UY recorder and ca lib ra ted against a hydrostatic standard. Cardiac output was measured by the d ire c t Fick method. No premedication was given. The fo llow ing sys to lic pressure differences were calculated:a) the peak to peak gradient which is the d ifference between the peak sys to lic pressure in the le f t ve n tr ic le and the peak sys to lic pressure in the aorta,b) the peak pressure d ifference which is the la rgest instantaneous systo l ic pressure d iffe rence,c) the mean gradient which is the d ifference between the mean sys to lic pressure in the le f t ve n tr ic le and the mean sys to lic pressure in the ascending aorta. I t was calculated by in teg ra ting the area between the le f t ve n tric le and the a o rtic pressure recordings (19).
A single catheter was used in Study I and th is catheter was positioned in the le f t ven tric le and subsequently a pull-back procedure was performed. Two catheters were used in Studies I I and I I I , one catheter was positioned w ith the t ip in the le f t ve n tric le and the other in the ascending aorta.
In Study V, the wedge position o f the catheter was confirmed by typ ica l phasic wave form and fluoroscopic determination of the s ite o f the catheter t ip . The mean pulmonary c a p illa ry wedge pressure was obtained
by e lec tron ic damping o f the s igna l.
CineangiographyLe ft ventriculography and aortography were performed in the 45° r ig h t and 45° le f t an te rio r oblique pro jections. Le ft ven tricu la r end-dia- s to lic and end-systo lic volumes were calculated using a computer system with a biplane e llip s o id method, or in cases w ith a deformed ven tricu la r cav ity , a biplane in teg ra tion method. The stroke volume was calculated as the d ifference between them (20). The severity of a o rtic and
m itra l regurg ita tion was assessed as described by Dexter and Grossman (19). Le ft ven tricu la r motion score (LVMS) was calculated v isu a lly according to the motion of d if fe re n t wall segments (21). The le f t vent r ic le was thereby divided in to seven segments according to the American Heart Association (22). The motion o f each segment was graded as fo llow s: normal motion = 0, hypokinesia = 1, akinesia = 2, dyskinesia = 3 po in ts. By adding these points LVMS was obtained.
A o rtic valve areaThe a o rtic valve area was calculated according to Gorlin and G orlin(23):
A V A = ^ ________________________ .
ET • 44.5 VApmean
AVA = a o rtic valve areaSV = stroke volumeET = e jection timeAp mean = mean sys to lic gradient
Both the Fick (or net) and the cineangiographic (or to ta l) stroke volume were used in the ca lcu la tions of the valve area.
Coronary angiographyCoronary angiography was carried out according to Judkins' technique(24). Obstruction o f a coronary vessel resu lting in a decrease o f the transsectional area by more than 75% was regarded as a s ig n if ic a n t stenosis. Calculation o f myocardial coronary obstruction score is a method employed to estimate the degree o f a r te r ia l obstruction, and i t includes an evaluation o f the myocardial mass subserved by the stenotic vessel (21). The maximal score is 15 which indicates occlusion o f a ll coronary a rte r ie s .
Routine ECG. A 12-lead ECG (aVL, I , -aVR, I I aVF, I I I , and V ^g) was recorded using a d ire c t w r it in g ECG-recorder (Mingograph, Siemens Elema).
Phonocardiography. Phonocardiography was recorded together with the ECG and Doppler recording. A 500-1000 Hz f i l t e r was used.
Exercise te s t . A standard exercise ECG te s t was performed (25). Maximum working capacity (Wmax) according to Strandell (26) was calculated and compared with the predicted normal maximum working capacity (WmaxN) (Linderholm, unpublished observations). Wmax as a percentage o f WmaxN has been used as an index o f physical performance (Wmax%). ST depression during exercise was measured as the d ifference between ST levels during maximum work and at res t. The ra t io 100 x STdepression/ Wmax% was used as an index o f coronary insu ffic iency (C I-index). E ffo r t angina during the exercise te s t was recorded and an e f fo r t angina score was defined. 0 = No angina during or a fte r the exercise te s t, 1 = Typical or atypical angina during exercise but no angina a fte r exercise, 2 = Typical or atyp ica l angina during exercise which disappears w ith in 5 minutes a fte r exercise, 3 = Typical or atypical angina during exercise which pers is ts fo r more than 5 minutes a fte r exercise.
Doppi er echocardi ography. Continuous wave Doppler examinations were performed using a Pedof system w ith a 2.0 MHz nonimaging transducer (Vingmed A/S). Flow ve lo c itie s up to 6 m/s corresponding to a pressure d ifference o f approximately 140 mm Hg can be measured with th is equipment. Spectral frequency analysis was not available fo r these studies.
In Studies I and IV the investiga tions were performed p rio r to the in vasive inves tiga tion , usually one day before. In Studies I I , I I I and V the examinations were carried out w ith in one hour o f the subsequent in vasive procedure. Some patients have been examined simultaneously by noninvasi ve and invasive methods.
The maximal flow ve lo c ity was recognized by lis te n in g to an audio signal o f a lte rna ting p itch from the loudspeaker in the apparatus (the higher the p itch , the higher the ve lo c ity ) and observing recorded ve l
o c ity p ro file s .
Doppler gradients. The s im p lifie d Bernoulli formula was used to calcula te the peak pressure gradient from the recorded peak ve loc ity in Stu
dies I-Y (13).16
Estimation o f pulmonary c a p illa ry wedge pressureCombined ECG, phonocardiogram and Doppler amplitude recordings were applied to record the Q-MC and A2 -MO in te rva ls . The Q-MC was measured as the in te rva l between the onset o f the QRS complex and the top o f the amplitude signal o f the m itra l valve closure. The A2 -MO in te rva l was measured as the in te rva l between the onset o f the second heart sound and the beginning o f the amplitude signal o f the m itra l valve opening.
These in te rva ls as well as the quotient Q-MC/A2 -MO were compared with the mean c a p illa ry wedge pressure measured at ca the te riza tion .
S ysto lic ve loc ity in tegra l (SVI). The area under the maximum ve loc ity recording was manually in tegrated to obtain the sys to lic ve loc ity in te g ra l. This measure represents the distance covered by the stroke volume per beat.Analysis o f flow in a o rtic stenosis indicates tha t the ve loc ity p ro f ile is f la t (18). The a o rtic valve area can therefore also be calculated as the re la tion between stroke volume and sys to lic ve loc ity in tegra l (SV/ SVI).
Radionuclide angiographyA non-geometric attenuation-corrected technique was used to determine absolute le f t ven tricu la r end-d iasto lic and end-systo lic volumes from ECG-gated blood pool studies (27).Red blood ce ll la b e llin g in vivo was accomplished by intravenous adm in is tra tion o f stannous pyrophosphate followed a fte r 20 minutes by adm inistration of 740 MBq technetium-99m pertechnetate. Le ft ventricula r depth (d) in the le f t an te rio r oblique 45° pro jection was measured, and used according to a previously described technique fo r attenuation correction (27). In accordance w ith previous reports (28) and our own experience an attenuation c o e ffic ie n t (fi) o f 0.13 cm“ 1 was used.Each cardiac cycle was divided in to 24 frames w ith ECG-gating and data were co llected using a Portacamera l ie (General E le c tr ic ) w ith a high reso lution pa ra lle l hole co llim a to r in terfaced w ith a Gamma 11 computer system (D ig ita l Equipment Corporation) fo r 10 minutes in the LAO 45° pro jection with the patients in the supine pos ition . Approximately 500 to 1000 cardiac cycles were co llected depending on the actual heart ra te . No arrhythmia re jec tion was used.
Regions o f in te re s t were manually drawn around the le f t ve n tric le in the end-d iasto lic and the end-systo lic frames, with a manually drawn poste ro-la te ra l region in the end-systo lic frame fo r background correctio n .
Immediately before data co lle c tio n in the LAO 45° view a 10 ml venous blood sample was drawn from the patients arm contra la te ra l to the in je c tio n s ite . The blood sample was contained in a Petri dish and the a c t iv ity was counted with the same gammacamera equipment fo r 3 minutes to obtain the spec ific a c t iv ity in the blood, corrected fo r background in the f ie ld and also corrected fo r decay to midtime o f the sampling from the le f t an te rio r oblique view. Le ft ven tricu la r stroke volume (SY) was the rea fte r calculated according to the formula:
5 y - 1 (end-d iasto lic counts - end-systo lic counts) x 1.8 x 106
e“ ^ counts in blood sample x cycles co llected x frame time
The procedure was previously validated against stroke volume determination by cineangiography and there was close agreement between the two methods in lin e w ith previous reports (29, 30).
Noninvasive ca lcu la tions o f a o rtic valve areaCalculations of the a o rtic valve area from noninvasive data was accomplished by two d iffe re n t approaches. A modified Gorlin equation derived by resu lts from Study I I was used,
AVA = SV/(ET x 71.2 x Ymax)
Furthermore, according to the con tinu ity equation (31-33):
AVA = SV/SVI
AVA = a o rtic valve area SV = stroke volume ET = le f t ven tricu la r e jection time SVI = sys to lic ve loc ity in teg ra l
RESULTS AND DISCUSSION
Q uantifica tion o f the transva lvu lar pressure d if fe rence(Studies I , I I ) Study I was carried out to examine the a p p lic a b ility o f sys to lic pressure d ifference estimation by Doppler ultrasound in a consecutive series o f patients with a o rtic stenosis. The peak gradient calculated from the Doppler recordings was compared with the peak to peak gradient measured at ca the te riza tion . Noninvasi ve and invasive pressure grad ients showed an acceptable co rre la tio n , r = 0.85, SEE = + 14 mm Hg. The Doppler peak gradient exceeded the invasive peak to peak gradient in some pa tien ts . Although i t was rea lized tha t the peak to peak gradient and the Doppler peak gradient were conceptually d iffe re n t the p o s s ib ili t y o f a large d ifference between the two pressure differences was not fu l ly appreciated. On the other hand, there was an obvious underestimation o f the pressure d ifference in several patients w ith severe stenos is . The patients were examined in 1982 and 1983. The number o f reports in the lite ra tu re at tha t time was lim ite d and only involved small series o f patients and children (who are more easily examined). In add ition , patients had often been excluded because o f unsatisfactoryDoppler recordings (34, 35).
In 1985, when Studies I I and I I I were performed i t was apparent tha t a more refined invasive procedure had to be adopted. A dual catheter technique was used and the Doppler gradient was compared with the in stantaneous peak gradient measured at ca the te riza tion . A co rre la tion r = 0.94, SEE = + 9.1 mm Hg was obtained in Study I I . A difference o f up to 48 mm Hg between the peak and the peak to peak gradient was also observed. Differences o f th is magnitude have also been reported by Krafchek (36). Since H atle 's (12) o rig ina l report numerous studies have been reported, and today Doppler ultrasound is a generally accepted method to estimate the peak gradient in a o rtic stenosis (37-40). In most studies comparisons have been made with gradients measured by f lu id f i l le d catheters. However, the accuracy o f the reference method must also be considered. The f id e l i t y o f a f lu id f i l le d catheter pressure measurement systems and the presence o f catheter induced a rte facts are thus important considerations. O sc illa tions may lead to errors inestimation of peak and mean pressure gradients. When a single catheter
study is performed, i t is necessary to superimpose the a o rtic trac ing onto the recording from the le f t ve n tr ic le and small errors in the tim ing may re s u lt in large differences in the gradients. In add ition , measurement o f the gradient is based on nonsimultaneous beats. Id e a lly , simultaneous reg is tra tions from the le f t ve n tric le and the ascending aorta using micromanometertipped catheters should be undertaken. Simultaneous invasive and Doppler recordings would seem idea l, but the Doppler investiga tion may be hindered by d i f f ic u l t ie s in getting the pa tien t in an optimal position in the ca theteriza tion laboratory. Smith et al (40) even reported closer corre la tions between noninvasi ve and invasive data when the noninvasi ve tests were carried out at a separate time in the noninvasi ve laboratory. Of course, th is only holds true i f the patien t is in a stable hemodynamic condition . Some o f the discrepancies between Doppler and invasive measurements reported may thus be explained by inaccuracies in the reference method. A perfect Doppler recording might even render a bette r measurement o f the pressure d i f ference than tha t achieved by a pull-back procedure using a f lu id f i l le d catheter.
The mean gradient (Study I I )The mean gradient describes the degree o f pressure drop throughout systo le , and i t is usually included in hydraulic o r if ic e formulas. The area between the le f t ve n tr icu la r and a o rtic pressure curves is in te grated to determine the mean gradient. The corresponding Doppler gradient can be calculated by tra n s fe rrin g the ve loc ity curve to a pressure drop curve by applying the Bernoulli equation. This is a burdensome procedure invo lv ing numerous measurements of the instantaneous ve loc it ie s at short in te rva ls throughout systo le. The instantaneos ve lo c itie s then have to be squared and the re su ltin g pressure drop curve p lo tted . The mean pressure d ifference can then be obtained by planimetry. Good co rre la tion has been reported (36 41) between invasive and noninvasi ve measurements of the mean pressure gradient. The complicated procedure involved has, however, stimulated an in te re s t in find ing a simpler method o f assessment. Zhang e t al (41) reported a formula in which thepeak and mean ve loc ity were included: Apm = 8 V2m [Vp/(V p +
Ym) ] where APm is the mean7 gradient, vp is the peak sys to lic ve lo c ity , and Vm is the mean sys to lic ve lo c ity . We observed tha t in
most patients the p lo tted pressure drop curve had a configuration very s im ila r to a sine wave. Applied to a pressure drop curve th is means tha t the mean pressure gradient is equivalent to 2/7T m u ltip lie d by the peak gradient according to basic trigonom etric p rin c ip le s . Others (33, 41) have considered the ve loc ity curve to be symmetrical fo r p ractica l purposes. Our resu lts showed tha t there was no s ig n if ic a n t d ifference between the mean gradient obtained by planimetry a t ca the te riza tion and tha t obtained by m u ltip ly ing the peak gradient by 2/7T.
Of course the curves cannot inva riab ly be regarded as a sine wave. Intheory i t may be tr ia n g u la r a t one extreme and rectangular a t the othe r, resu lting in a mean pressure gradient ranging between 1/3 and 1 o fthe peak gradient. These hypothetical s itua tions were not encountered in our material and do not seem to represent a major problem. Moreover, a s im p lif ica tio n should indeed be simple.
A p o s s ib il ity to modify the G orlin equation is also given by the simple re la tio n between mean and peak pressure gradient. When 0.64 x 4(Vmax)2 is substitu ted fo r A p mean, the equation is transformed to : AVA = SV/(ET x 71.2 x Ymax), a formula very s im ila r to tha t suggested by Ohlsson et al (42).
Determination o f a o rtic valve area (Study I I I )The Gorlin equation was used to calcu la te the a o rtic valve area from invasive data. Stroke volumes measured by le f t ventriculography were used since a o rtic regurg ita tion was a frequent find ing in our pat ie n ts . In the absence o f s ig n if ic a n t m itra l regurg ita tion th is method gives the actual flow across the a o rtic valve. In the noninvasi ve stucjy both the modified Gorlin equation and the in teg ra tion method were used. In both stroke volume was obtained by radionuclide angiography, which lik e cineangiography gives the to ta l stroke volume. Close co rre la tions w ith the invasive data were obtained, r = 0.95, SEE = + 0.13 cm2 by the modified Gorlin equation and r = 0.94, SEE = +_ 0.14 cm2 by the in teg ra
tion method. The two noninvasive tests gave almost iden tica l re su lts , r = 0.98, SEE = +_ 0.09 cm2. More important, a ll patients w ith an a o rtic valve area o f less than 1 cm2 by the invasive study were id e n tif ie d by both the noninvasive procedures.
There are some previous reports o f valve area ca lcu la tions in which Doppler ultrasound was used to measure the mean gradient or the SVI (or both). The princ ipa l d ifference between these studies is the method chosen to estimate the stroke volume. Skjärpe et al (31), Zhang et al (32) and Zoghbi e t al (33) used a combined echo and Doppler ultrasound method to calcu late the stroke volume. The stroke volume can be estimated from the flow through pulmonary annulus, m itra l annulus and through the a o rtic annulus d ire c tly below the obstruction. When stroke volume is calculated using flow through the m itra l valve, patients w ith s ig n if ic a n t a o rtic and/or m itra l regurg ita tion has to be excluded, since the actual a o rtic flow is needed.
Ohlson et al (42) used a CO2 rebreathing technique, which gives the e ffe c tiv e (or net) stroke volume. This technique has the same l im ita tio n s , the a o rtic flow being undervalued in patients w ith a o rtic regurg ita tio n . I t seems a ttra c tiv e to use the stroke volume through the aort ic annulus because no pa tien t needs to be excluded because of a o rtic or m itra l regu rg ita tion . Skjärpe e t al (31), however, stress tha t th is approach is d i f f i c u l t to handle and subject to s ig n if ic a n t e rro rs .
Estimation o f le f t ve n tricu la r stroke volume by radionuclide angiography has the same lim ita t io n in respect to m itra l regu rg ita tion . In our study there was a close co rre la tion between stroke volume estimated by the isotope technique and le f t ventriculography, r = 0.91, SEE + 9.9 ml. In add ition , the e jection fra c tio n is obtained and regional vent r ic u la r function can be assessed.
The present study concerned patients with a o rtic stenosis. Doppler examinations have shown tha t the so ca lled iso la ted a o rtic stenosis is a r a r i ty ; most patients show some degree o f concomitant regurg ita tion . A high percentage of leaking valves has been reported also in healthy ind iv idua ls . There were only 4 out of the 26 patients who did not show e ith e r a o rtic or m itra l regurg ita tion in Studies I I and I I I . This has important im plications fo r ca lcu la tions o f the a o rtic valve area as discussed previously. The diagnosis a o rtic regurg ita tion may be d i f f i c u lt and we believe tha t Doppler is the most sens itive method. However, quan tifica tion o f va lvu lar regurg ita tion is often d i f f ic u l t . Angio
graphy has been regarded as the gold standard in many studies but when the severity o f regurg ita tion is divided in to four grades there is a considerable overlap (C ro ft e t a l, 43). Grading o f a o rtic regurg ita tion w ith pulsed wave Doppler technique has been described (44-45) but the v a lid ity o f these approaches is doubtful (46, 47). In our experience discrepancies between angiographic gradings and tha t o f pulsed Doppler are often observed. Continuous wave Doppler has also been used fo r th is purpose (48). There is s t i l l no optimal method fo r accurate qu a n tifica tion o f regurg itan t les ions.
The coexistence o f coronary heart disease (CHD) (Study IV)The reported prevalence o f coronary heart disease in a o rtic stenosis shows considerable va ria tion w ith figures ranging between 20-60% (49-
55). In Study IV, 43% o f the patients had s ig n if ic a n t CHD. This is in agreement w ith a la rger study recently published from our hospital (49), where 37% o f 221 patients w ith a o rtic valve disease had s ig n i f i cant CHD.
I t is controversia l whether coronary angiography should be carried out in a ll patients despite the absence o f angina pectoris (49-55). A screening procedure to id e n tify patients w ith c l in ic a l ly s ig n if ic a n t CHD would be desirable. A standard ECG exercise te s t fo r th is purpose was examined. The coronary insu ffic iency-index was able to separate patie n ts w ith and w ithout CHD fa ir ly accurate. When an index 3 and an index < 3 was used to id e n tify those patients w ith and w ithout CHD, 11 out o f 15 patients w ith CHD and 18 out o f 19 w ithout CHD could be ident i f ie d . When the presence o f angina at the exercise te s t was included the s e n s it iv ity o f the te s t was somewhat enhanced. About 50% of the angiographies may be omitted when these c r ite r ia are used. On the other hand, approximately 15% o f the patients w ith CHD would be missed which is not acceptable and our po licy is to perform coronary angiography in a ll patients aged 40 years or more regardless o f a h is to ry o f angina.
Estimation o f pulmonary c a p illa ry pressure in a o rtic stenosis (Study V) An estimate of le f t ve n tr icu la r performance is valuable and often achieved by combined evaluation o f two-dimensional echocardiography,
radionuclide angiography, and le f t ventriculography. The pulmonary ca p illa ry wedge pressure provides an estimate o f the le f t ven tricu la r end-d iasto lic pressure. An abnormally elevated pulmonary c a p illa ry wedge pressure in the presence o f other signs o f depressed ven tricu la r function , i .e . reduced cardiac output, e jection fra c tio n , or stroke work indicates tha t c o n tra c t i l i ty is probably impaired (56) However, a reduced ven tricu la r compliance caused by e.g. hypertrophy may elevate the f i l l i n g pressure while the end-d iasto lic volume remains normal(56). Despite these d i f f ic u l t ie s the pulmonary ca p illa ry wedge pressure might add inform ation, p a rtic u la r ly in patients w ith coexisting valvula r lesions or ischemic myocardial in ju r ie s .
The A2 -MO in te rva l decreased and the Q-MC in te rva l increased in patie n ts with m itra l stenosis when the degree o f obstruction increased(57). Further studies showed tha t these in te rva ls were useful fo r e s t imation o f the pulmonary c a p illa ry pressure in va lvu lar diseases other than m itra l stenosis even i f there are some c o n flic t in g resu lts reported (58-63). In those studies, the in te rva ls have been recorded using M-mode echocardiography. In Study V, the Doppler amplitude signal o f the m itra l valve was used, since in our experience the measurement points were more easily id e n tif ie d by Doppler than by M-mode echocar
diography. The in te rva ls were combined to a quotient
A2 - MOwhich compared favourable w ith the mean pulmonary c a p illa ry wedge pressure at ca the te riza tion , r = 0.94, SEE = +_ 2.9 mm Hg. The method accura te ly separated those patients w ith a normal or near normal pulmonary c a p illa ry wedge pressure from those w ith an elevated wedge pressure.
We believe tha t the measurement points o f the amplitude signals corresponds to the s ta r t and end o f the flow through the m itra l valve as indicated by the mean ve lo c ity s igna l. The exact re la tio n to the pressure crossover o f the le f t ve n tr icu la r pressure curve and le f t atrium / pulmonary c a p illa ry wedge pressure curves remains to be c la r if ie d .
Accurate determination o f the a o rtic sys to lic pressure drop can be achieved by Doppler ultrasound in most pa tien ts . S o fis ti cation of the transducers/receivers and s t i l l be tte r signal analysis can be expected. This may optimize the recordings in patients in whom d if f ic u l t ie s in obtaining s u ff ic ie n t signals are encountered today. The colour Doppler system might make the exact area o f in te re s t simpler to id e n tify and w il l speed up the examination. On the other hand, the s ingle nonimaging transducers s t i l l w i l l have i t s d e fin ite place in experienced hands. In our experience, i t is often quicker to obtain good Doppler recordings when a single transducer is used, at least when compared to duplex transducers. According to wellknown psychological mechanisms (64), i t is d i f f i c u l t to concentrate on two tasks simultaneously, i .e . both a 2D-picture and a high q u a lity sound signal (Doppler).
Regarding stroke volume determination more re fined methods fo r separate le f t and r ig h t ven tricu la r output w il l be developed. Tickner et al (65) have developed a so ca lled microbubble technique, which seems promising. This technique may also be applied fo r estimation o f righ ts ided cardiac pressures.
Id e n tif ic a tio n of patients with coronary heart disease in conjunction w ith a o rtic stenosis can be done w ith some degree o f ce rta in ty applying the described work te s t procedure. I t w il l be in te re s tin g whether the resu lts reported in Study V w il l be validated in a la rger group o f patie n ts with and w ithout concomitant a o rtic regu rg ita tion . Such a study
is in progress.
Kemper et al (66) have in jected H2 O2 in the a o rtic root in dogs and have been able to evaluate regional wall perfusion. H2O2 or s im ila r echogenic substances may be developed in the fu ture fo r th is purpose. Even echogenic "bubbles" in jected on the venous side and passing through the pulmonary c ircu la tio n to the le f t side o f the heart have been described (67). Probably we w il l see fu rth e r development in the f ie ld o f echo "con tras t".
The application o f exercise nuclear angiography and myocardial s c in t igraphy to detect coronary heart disease in patients w ith a o rtic stenosis have been reported (68, 69) and fu rth e r advancement can be expected with th is technique. The a p p lic a b ility o f d ig ita l subtraction angiography of coronary lesions is another in te res ting issue.
The use o f Doppler in the evaluation o f coronary c ircu la tio n w il l be an expanding f ie ld . Gramiak et al (70) have recently published a study o f Doppler examination o f le f t coronary a r te r ia l blood flow. The introduction of colour Doppler system may even make diagnosis o f s ig n if ic a n t coronary heart disease possible. At least central major obstruction may be id e n tif ie d . The combination o f echo dimension measurements and Doppler ve loc ity recordings to obtain coronary volume flow in analogy w ith stroke volume estimation may lead to fu rth e r progress in the non- invasive estimation o f coronary heart disease. However, coronary angiography is not l ik e ly to be fu l ly replaced by noninvasive procedures.
When i t comes to the evaluation o f a o rtic regurg ita tion i t is the colour Doppler system which w il l be most in te re s tin g . I t is important, however, to rea lize tha t the same evaluation is available with conventiona l Doppler but the colour system may make i t easier to detect a regurg ita tion and w il l probably speed up the investiga tion . Even i f i t is well known i t is worth mentioning tha t the red "stream" coming towards you from the a o rtic valves (apical view) is not a volume o f blood but blood ve lo c ity .
GENERAL SUMMARY AND CONCLUSIONS
The present study reports on noninvasi ve evaluation o f patients w ith suspected a o rtic stenosis w ith emphasis on Doppler ultrasound. The degree o f outflow obstruction can be s a t is fa c to r ily evaluated as fa r as the peak gradient and the mean gradient are concerned. The determination of a o rtic valve area can be accomplished by combining radioisotope technique with Doppler trac ings.
Noninvasi ve estimation o f the pulmonary ca p illa ry wedge pressure seems to be a feasib le procedure.
Today there is no generally accepted method to reduce the number of coronary angiographies. The method described may serve as a screening procedure but we feel tha t coronary angiography s t i l l have to be recommended as a part o f the standard evaluation program.
I t is important to rea lize tha t not a ll patients can be s a t is fa c to r ily evaluated by noninvasi ve methods and therefore invasive procedures should be carried out whenever there is any remaining doubt about the severity o f the va lvu la r les ion.
I t is suggested tha t the prelim inary evaluation o f patients w ith suspected a o rtic stenosis should include a standard ECG, a bicycle ergo- meter te s t, Doppler and two-dimensional echocardiography. These examinations make i t possible to accurately estimate the pressure gradientand to make a fa i r assessment o f the le f t ven tricu la r function .Assessment o f the valve area is also possible by Doppler and tw o-d imensional echocardiography alone, but radionuclide angiography is a useful approach. Before surgery, coronary angiography should probablybe undertaken in patients aged 40 years or more.
I want to express my sincere gra titude to :
My w ife Anne-B ritt, who is very much my w ife .
Acting Professor Per B je rle , fo r his wholehearted support, enthusiasm and pos itive c r it ic is m ,
Professor Emeritus Håkan Linderholm, whose extensive knowledge o f c lin ic a l physiology has been to a great help,
Dr. K je ll Karp and Dr. Peter Eriksson, who have been my closest coworkers and friends and our combined e ffo r ts have made th is study poss ib le ,
Dr. Göran Österman, fo r his a b i l i t y to de live r the gold standard o f radiology,
Dr. Harold Lake, Newcastle upon Tyne, whom I learned to know during my Yemenitic adventure. He has corrected the language,
Inger G. Andersson and Loi ornai Örnehult, who typed and retyped themanuscript in an excellent way,
The laboratory technicians and other s ta f f a t the Department o f C lin ical Physiology and the section o f Nuclear Medicine fo r th e ir kindest cooperation throughout the study.
This study was supported by grants from the Faculty o f Medicine, Unive rs ity o f Umeå, and the National Association fo r Heart and Lung Pat ie n ts .
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