- Email: [email protected]
Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertension
Coronary Flow Reserve and Myocardial Diastolic Dysfunction in Arterial Hypertension Maurizio Galderisi, MD, Silvana Cicala, MD, Pio Caso, MD, Luigi De Simone, MD, Arcangelo D’Errico, MD, Antonio Petrocelli, MD, and Oreste de Divitiis, MD The aim of this study was to assess the relation between coronary blood flow and left ventricular (LV) myocardial diastolic dysfunction in arterial hypertension. The study population included 30 hypertensive patients who were free of coronary artery disease and pharmacologic therapies. They underwent standard Doppler echocardiography and color tissue Doppler of the middle posterior septum at baseline and with high-dose dobutamine, and second-harmonic Doppler flow analysis of the distal left anterior descending coronary artery at baseline and after vasodilation by dipyridamole (0.56 mg/kg IV in 4’). Coronary flow reserve (CFR) was estimated as the ratio of hyperemic and baseline diastolic flow velocities. According to CFR, hypertensives were divided into 2 groups: 15 patients with normal CFR (>2) and 15 patients with reduced CFR (<2). The 2 groups were comparable for sex, age, body mass index, baseline heart rate, and blood pressure. LV mass index was greater in hypertensives with reduced CFR (p <0.01). By color tissue Doppler, baseline and high-dose dobutamine sep-
tal systolic velocities did not differ between the 2 groups. The ratio between myocardial velocities in early diastole and at atrial contraction (Em/Am ratio) was lower in patients with reduced CFR, both at baseline (p <0.05) and with high-dose dobutamine (p <0.00001). After adjusting for age, body mass index, LV mass index, and both high-dose dobutamine diastolic blood rate and heart rate by a multiple linear regression analysis, Em/Am ratio at high-dose dobutamine was independently associated with CFR in the overall population ( 0.62, p <0.0005) (cumulative R2 0.38, p <0.0005). In conclusion, this study provides evidence of an independent association between CFR and myocardial diastolic function. In hypertensive patients without coronary artery stenosis, CFR alteration may be a determinant of myocardial diastolic dysfunction or diastolic impairment that should be taken into account as possibly contributing to coronary flow reduction. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;90:860 – 864)
everal factors are involved in reducing coronary flow reserve (CFR) in hypertensive patients. First, S baseline coronary flow may be increased because of
segment changes. Elevations of LV end-diastolic pressure have long been recognized to occur during spontaneous or provoked ischemia.6 – 8 Nevertheless, little is known about the relation between LV diastolic function and coronary flow dynamics.9 To date, CFR may be assessed noninvasively by second-harmonic Doppler echocardiography,10 –12 whereas color tissue Doppler may be used to assess myocardial diastolic function both at rest and during stress.13,14 The present study was designed to investigate the association between LV myocardial diastolic dysfunction and CFR in hypertensives, using both second-harmonic Doppler and color tissue Doppler during dobutamine stress.
higher blood pressure (BP), greater left ventricular (LV) end-systolic stress, and LV hypertrophy.1 Second, the maximal flow response to physiologic or pharmacologic stimuli may be limited by a reduction in the overall maximal cross-sectional area of the microcirculatory bed that is induced by vascular changes in the intramyocardial coronary arteries, increased coronary arteriolar tone, inadequate angiogenesis in LV hypertrophy, endothelial dysfunction, or by extravascular compression.2–5 However, in view of the fact that coronary blood flow occurs predominantly during diastole, it is conceivable that LV diastolic changes also play a role in CFR impairment in hypertensives. In contrast, myocardial ischemia may produce LV diastolic alterations, even before the detection of wall motion and/or electrocardiographic STFrom the Department of Clinical and Experimental Medicine, “Federico II” University of Naples; Medical-Surgical Physiopathology of Cardiopulmunary and Respiratory System and Associated Biotechnologies, Second University of Naples; and Division of Cardiology, Monaldi Hospital, Naples, Italy. Manuscript received April 26, 2002; revised manuscript received and accepted June 6, 2002. Address for reprints: Maurizio Galderisi, MD, Laboratory of Echocardiography, Department of Clinical and Experimental Medicine, Federico II University, Via Andrea d’Isernia, 4, 80122 Naples, Italy. E-mail: [email protected].
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©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 October 15, 2002
METHODS
Study population: Between September 1998 and December 2000, 147 patients affected by newly diagnosed, never-treated arterial hypertension (World Health Organization/International Society of Hypertension grade 1 to 2) were screened at our outpatient clinic. Patients were defined as hypertensive if their diastolic BP was ⱖ90 mm Hg (mean of 3 different measurements on 3 different visits). Exclusion criteria were coronary artery disease (absence of angina pectoris and negative findings on the electrocardiogram at rest, maximal treadmill exercise electrocardiography, and stress perfusion scintigraphy), diabetes mellitus, heart failure, valvular heart disease, atrial fibrillation, 0002-9149/02/$–see front matter PII S0002-9149(02)02708-X
CFR DETERMINATION: CFR assessment was performed by an Acuson Hypertensives Hypertensives Sequoia system (Acuson CorporaWith CFR ⱖ2 With CFR ⬍2 tion, Mountain View, California), usVariable (n ⫽ 15) (n ⫽ 15) p Value ing a transducer with second-harmonic Men/women 12/3 12/3 NS capability (1.7 MHz transmitting and Age (yrs) 53 ⫾ 6 53 ⫾ 5 NS 3.5 MHz receiving). The visualization 28 ⫾ 3 28 ⫾ 4 NS Body mass index (kg/m2) of the distal portion of the left anterior Baseline systolic BP (mm Hg) 145 ⫾ 7 151 ⫾ 14 NS descending artery was performed usBaseline diastolic BP (mm Hg) 99 ⫾ 3 101 ⫾ 4 NS Baseline heart rate (beat/min) 75 ⫾ 5 75 ⫾ 8 NS ing the standard method10 –12 with a Dobutamine systolic BP (mmHg) 160 ⫾ 5 171 ⫾ 17 ⬍0.05 contrast agent (Levovist, SHU-508A, Dobutamine diastolic BP (mmHg) 98 ⫾ 5 100 ⫾ 5 NS Schering AG, Berlin, Germany)11 in Dobutamine heart rate (beats/min) 134 ⫾ 5 135 ⫾ 7 NS case of suboptimal color Doppler imaging. By placing the sample volume on the color signal, spectral Doppler of and inadequate echocardiograms. Using these criteria, the left anterior descending artery showed the characterafter the approval of the Institutional Ethics Commit- istic biphasic flow pattern with larger diastolic and tee and the informed consent of each patient, 30 hy- smaller systolic components. Coronary diastolic peak pertensives (24 men, 6 women; mean age 53.1 years) velocities were measured at baseline and after dipyridformed the final study group. According to CFR, amole (0.56 mg/kg over 4 minutes) by averaging the hypertensives were divided into 2 groups: 15 with highest 3 Doppler signals for each measurement. CFR normal CFR (ⱖ2) and 15 with impaired CFR (⬍2). was defined as the ratio of hyperemic to basal diastolic Procedures: Hypertensives underwent standard peak velocities. All images were analyzed off-line by 2 echocardiography and color tissue Doppler dobut- observers blinded to the other data. Our CFR reproducamine stress on the same day but CFR determination ibility has been previously tested,18 with an intraobserver on a different day. variability of 1.9% and interobserver variability of 4.2%. TRANSTHORACIC ECHOCARDIOGRAPHY: Standard Statistical analysis: The analyses were performed by echocardiography was performed by a System FiVe, SPSS for Windows release 8.0 (Chicago, Illinois). The Vingmed Sound AB machine (GE, Horten, Norway), t test for unpaired data was used to assess intergroup using a 2.5-MHz transducer equipped with second- differences. Univariate relations were tested by Pearharmonic capability. M-mode was performed accord- son’s method. Prediction of variables was obtained by ing to the methods of our laboratory.15 Doppler in- stepwise, forward, multiple regression including podexes of LV diastolic function were measured accord- tential confounders. A p value of ⬍0.05 was considing to the standard techniques.16 ered significant. COLOR TISSUE DOPPLER DOBUTAMINE STRESS: Color tissue Doppler dobutamine echocardiography was recorded using the same System FiVe Vingmed instruRESULTS ment. Dobutamine protocol was performed according Characteristics of the population are listed in Table 17 to standard methods. Color tissue Doppler acquisi1. High-dose dobutamine systolic BP was higher in tion of longitudinal myocardial velocities from the posterior septum in the apical 4-chamber view was patients with CFR ⬍2. No patient complained of chest performed in real-time and superimposed on 2-dimen- pain and no ST changes occurred using both stressors. sional images at rest and after administration of high- Analyses of the Doppler echocardiographic data are dose dobutamine. The images were stored digitally listed in Table 2. Relative wall thickness and LV mass and the analysis was performed off-line on cine index were higher in patients with CFR ⬍2. Doppler loops.13,14 The region of interest was the middle pos- indexes were similar between the 2 groups. The results of the dobutamine test and color tissue terior septum where the myocardial velocity profile Doppler are listed in Table 3. Sm velocities were was obtained at rest and during administration of high-dose dobutamine. The typical color tissue Dopp- similar between the 2 groups at rest or with high-dose ler pattern comprises a positive mean systolic velocity dobutamine. In diastole, Em/Am was mildly lower at (Sm) and 2 negative mean diastolic velocities—1 dur- baseline (p ⬍0.05) and highly significantly reduced ing early diastole (Em) and another during atrial con- with high-dose dobutamine (p ⬍0.00001) in hypertentraction (Am). The choice of the middle posterior sives with abnormal CFR. Figure 1 shows a patient septum for color tissue Doppler was based on the with normal CFR; despite a faster heart rate, septal assumption that the perfusion of this myocardial seg- Em/Am was marginally modified from baseline (1.00) ment is provided by a branch of the left anterior to adminstration of high-dose dobutamine (0.99). Figdescending artery, where CFR was also determined. ure 2 shows a patient with reduced CFR where the Our color tissue Doppler reproducibility has been septal Em/Am ratio at rest (0.89) decreased with highpreviously reported18; the intra- and interobserver dose dobutamine (0.71). Relation between CFR and color tissue Doppler: In variabilities were ⬍3% and ⬍6%, respectively, for all the measurements, both at baseline and with high-dose the overall population CFR was not related to standard dobutamine. Doppler diastolic measurements. Among baseline TABLE 1 Characteristics of the Study Population
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TABLE 2 Standard Doppler Echocardiographic Analysis Variable
Hypertensives With CFR ⱖ2
Septal wall thickness (mm) Posterior wall thickness (mm) LV internal diastolic diameter (mm) LV internal systolic diameter (mm) Endocardial fractional shortening (%) Relative diastolic wall thickness LV mass index (g/m2.7) Peak E velocity (m/s) Peak A velocity (m/s) Peak E/A ratio E-wave deceleration time (ms) Isovolumic relaxation time (ms)
10 9 52 36 31 0.36 41 0.54 0.56 0.96 187 84
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 1 6 4 5 0.08 9 0.15 0.06 0.3 30 21
Hypertensives With CFR ⬍2
p Value
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
⬍0.01 ⬍0.05 NS NS NS ⬍0.01 ⬍0.01 NS NS NS NS NS
12 10 51 35 32 0.42 53 0.58 0.66 0.89 201 90
1 1 6 5 5 0.06 10 0.08 0.12 0.15 51 41
CFR level, with the cut-off point for normal CFR ⱖ2.11 The main findings of the study are: (1) hypertensives with abnormal CFR have a lower myocardial Em/Am ratio at baseline and particularly with highdose dobutamine, and (2) an association between CFR and Em/Am with high-dose dobutamine is evident in all of the hypertensive patients, independent of clinical and echocardiographic variables. Myocardial diastolic dysfunction in hypertensives with reduced CFR: To
our knowledge, no association between CFR and Doppler-derived LV diastolic function has previously TABLE 3 Color Tissue Doppler Analysis at Baseline and With High-dose been found. Accordingly, transmitral Dobutamine diastolic measurements were not sigHypertensives Hypertensives nificantly different in our hypertenVariable With CFR ⱖ2 With CFR ⬍2 p Value sives with normal or altered CFR. Baseline Color tissue Doppler provides addi8⫾1 5⫾2 ⬍0.0005 Em velocity (cm/s) tional information about myocardial Am velocity (cm/s) 7 ⫾ 0.8 7⫾2 NS function also during dobutamine Em/Am ratio 1 ⫾ 0.11 0.78 ⫾ 0.38 ⬍0.05 Sm velocity (cm/s) 5 ⫾ 0.5 5 ⫾ 0.7 NS stress. Color tissue Doppler-derived High-dose dobutamine Em velocity may be considered an Em velocity (cm/s) 9⫾2 6⫾2 ⬍0.001 index of myocardial relaxation, Am velocity (cm/s) 9⫾2 11 ⫾ 2 ⬍0.02 whereas Am velocity reflects atrial Em/Am ratio 0.99 ⫾ 0.14 0.63 ⫾ 0.24 ⬍0.00001 activity and probably intrinsic disSm velocity (cm/s) 11 ⫾ 1 11 ⫾ 2 NS tensibility of LV myocardial fibers. Of note, alterations of LV relaxation in arterial hypertension may be due color tissue Doppler measurements, CFR was posi- either to increased afterload or to changes in LV tively related to Em (r ⫽ 0.45, p ⬍0.01), whereas the structure.15,19 In the present study, the septal Em/Am relation with Am (r ⫽ 0.10), Em/Am (r ⫽ 0.25), and Sm ratio was lower in patients with reduced CFR already (r ⫽ ⫺0.12) were not significant. Among high-dose at baseline and much more with high-dose dobutdobutamine measurements, Em (r ⫽ 0.39, p ⬍0.05), amine. Em/Am reduction was mainly due, both at Am (r ⫽ ⫺0.41, p ⬍0.05), and Em/Am (r ⫽ 0.62, baseline and during stress, to the decrease of Em p ⬍0.0005) (Figure 3), but not Sm (r ⫽ ⫺0.10), had velocity, whereas the Am increase had a role only with univariate relations with CFR. High-dose dobutamine high-dose dobutamine. Em/Am was related to high-dose dobutamine heart Association between CFR and color tissue Doppler rate (r ⫽ ⫺0.37, p ⬍0.05), diastolic BP (r ⫽ ⫺0.40, Em/Am ratio: A strong positive association between the p ⬍0.05), and to LV mass index (r ⫽ ⫺0.42, p high-dose dobutamine Em/Am ratio and CFR was ⬍0.02), whereas the relations with age and body mass found in the entire hypertensive population. This asindex (r ⫽ ⫺0.32 and r ⫽ ⫺0.14, respectively) were sociation may be interpreted in 2 ways. First, it can be not significant. A stepwise forward multilinear regres- hypothesized that myocardial diastolic dysfunction sion model was performed to analyze the relation that negatively affects CFR. LV diastolic function contriboccurred between CFR and high-dose dobutamine utes to regulate the relation between coronary flow Em/Am after adjusting for age, LV mass index, and and pressure perfusion. The diastolic time fraction is a both high-dose dobutamine heart rate and diastolic determinant of coronary flow increase when the autoBP. By this model, Em/Am ratio and CFR were inde- regulatory mechanism is exhausted because larger pendently associated ( 0.62, p ⬍0.0005) (cumulative fractional diastolic time occurs at lower perfusion R2 0.38, p ⬍0.0005). pressure, in the presence as well as in the absence of coronary stenosis.20 The impairment of LV relaxation has shown an adverse impact on early diastolic coroDISCUSSION The present study used color tissue Doppler13,14 nary flow in dogs21 but also in humans.9 This mechand CFR determination10 –12 to evaluate the possible anism can be important also in hypertensives without association between LV myocardial diastolic function coronary artery disease. Coronary microvessel damand CFR in arterial hypertension where changes in age, probably due also to extravascular diastolic comafterload and LV structure may influence both LV pression,22 may not be evident at baseline, but can diastolic properties and coronary blood flow supply. become overt with faster heart rates.9 Alternatively, a Hypertensives were divided into 2 groups according to reduced CFR may itself affect LV diastolic properties. 862 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 1. Myocardial septal Em/Am ratio at baseline and with high-dose dobutamine (DOB) in a patient with normal CFR (>2). Upper panels, coronary artery flow velocity in the left descending coronary artery at baseline and with a normal increase with dipyridamole (DIP). Lower panels, with high-dose dobutamine, despite the increase in heart rate, the Em/Am ratio at the mid-part of the posterior septum is marginally modified because of a mild increase in Em and Am. The myocardial systolic velocity (Sm) shows a normal increase with dobutamine.
FIGURE 2. Myocardial septal Em/Am ratio at baseline and with high-dose dobutamine (DOB) in a patient with reduced CFR (<2). Upper panels, the flow velocity increase in the left descending coronary artery with dipyridamole (DIP) is impaired. Lower panels, with high-dose dobutamine, the Em at the midpart of the posterior septum shows minimal change, whereas Am has a greater increase, resulting in a reduction of the Em/Am ratio. The increase in myocardial systolic velocity is normal, similar to that seen in Figure 1.
In the ischemic process, LV diastolic dysfunction occurs early, before evidence of wall motion abnormalities and LV systolic failure.23 The main diastolic alteration due to ischemia is a delayed myocardial relaxation associated with lower transmitral gradient pressure at the time of the mitral opening that results in less early diastolic filling. This mechanism may be crucial in hypertensives, due to both pressure overload and LV hypertrophy. In our study, CFR was significantly related only to Em at rest but it was positively related to Em and Em/Am and negatively with Am with high-dose dobutamine.
The association between CFR and the Em/Am ratio was tested by a multilinear regression analysis adjusting for several confounders. Age, heart rate, and diastolic BP were included as possible determinants because of their physiologic influence on both LV diastolic function19,24 and CFR.25,26 The role of LV mass was assessed because of the adverse effect of LV hypertrophy on both myocardial flow27 and LV diastolic properties.28 However, the association between CFR and myocardial diastolic function remained independent of the influence exerted by all these variables. These data are consistent with previ-
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8. Wijns W, Serruys PW, Slager CJ, Grimm J, Krayenbuehl HP, Huhenoltz PG, Hess OM. Effect of coronary occlusion during percutaneous transluminal angioplasty on humans on left ventricular chamber stiffness and regional diastolic pressure-radius relation. J Am Coll Cardiol 1986;7:455– 463. 9. Masuyama T, Uematsu M, Doi Y, Yamamoto K, Mano T, Naito J, Kondo H, Nagano R, Hori M, Kamada T. Abnormal coronary dynamics at rest and during tachycardia associated with impaired left ventricular relaxation in humans: implications for tachycardia-induced myocardial ischemia. J Am Coll Cardiol 1994;24:1625–1632. 10. Lambertz H, Tries HP, Stein T, Lethen H. Noninvasive assessment of coronary flow reserve with transthoracic signal-enhanced Doppler echocardiography. J Am Soc Echocardiogr 1999;12:186 –195. 11. Caiati C, Montaldo C, Zedda N, Bina A, Iliceto S. A new non-invasive method for coronary flow reserve assessment: contrast-enhanced transthoracic second harmonic echo Doppler. Circulation 1999;99:771–778. 12. Hozumi T, Yoshida K, Ogata Y, Akasaka T, Asami Y, Morioka S. Noninvasive assessment of significant left anterior descending coronary artery coronary stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography. Circulation 1998;97:1557–1562. 13. Pasquet A, Armstrong G, Beachler L, Lauer MS, Marwick TH. Use of segmental tissue Doppler velocity to FIGURE 3. Positive association between the CFR and high-dose dobutamine (Dob) quantitative exercise echocardiography. J Am Soc EchocarEm/Am ratio in the overall hypertensive population. diogr 1999;12:901–912. 14. Pasquet A, Armstrong G, Rimmerman C, Marwick TH. Correlation of myocardial Doppler velocity response to exercise with independent evidence of myocardial ischemia ous observations showing early alterations of CFR and by dual-isotope single-photon emission computed tomography. Am J Cardiol –542. LV diastolic function in arterial hypertension, even 2000;85:536 15. Galderisi M, Petrocelli A, Alfieri A, Garofalo M, de Divitiis O. Impact of 15,19 before the development of LV hypertrophy. ambulatory blood pressure on left ventricular diastolic dysfunction arterial sysClinical implications: These findings have clinical temic hypertension. Am J Cardiol 1996;77:579 –601. 16. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recomimpact and provide information about the relations mendations for quantification of Doppler echocardiography: a report from the between myocardial diastolic function and coronary Doppler quantification task force of the nomenclature and standard committee of American Society of Echocardiography. J Am Soc Echocardiogr 2002;15: blood flow supply in patients with hypertension. A the 167–184. CFR reduction might be potentially responsible for 17. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echoLV diastolic failure, even in absence of coronary heart cardiography: recommendations for perfomance and interpretation of stress echoStress Echocardiography Task Force of the Nomenclature and disease. LV diastolic failure is very frequent in hyper- cardiography. Standards Committee of the American Society of Echocardiography. J Am Soc 29 tensives. Alternatively, myocardial diastolic impair- Echocardiogr 1998;11:97–104. ment has to be taken into account as a possibly influ- 18. Galderisi M, Cicala S, De Simone L, Caso P, Petrocelli A, Pietropaolo I, Celentano A, Mininni N, de Divitiis O. Impact of myocardial diastolic dysfuncence on coronary flow reduction, and thus, angina tion on coronary flow reserve in hypertensive patients with left ventricular pectoris in hypertensive patients who do not have hypertrophy. Ital Heart J 2001;2:677–684. 19. Inouye I, Massie B, Loge D, Topic N, Silverstein D, Simpson P, Toubau JF. evidence of coronary artery stenosis. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120 –126. Acknowledgment: The investigators are indebted to 20. Merkus D, Kajiya F, Vink H, Vergroesen I, Dankelman J, Goto M, Spaan Prolonged diastolic time fraction protects myocardial perfusion when corLiv Hatle, MD, for scientific comments, critical sug- JAE. onary blood flow is reduced. Circulation 1999;100:75–81. gestions, and valuable review of the manuscript. 21. Domalik-Wawrzynski LJ, Powell WJ, Guerrero L, Palacios I. Effect of changes in ventricular relaxation on early diastolic coronary blood flow. Circ Res 1987;61:747–756. 1. Polese A, De Cesare N, Montorsi P, Fabbiocchi F, Guazzi M, Loaldi A, Guazzi 22. Breisch E, White FC Nimmo LE, Bloor CM. Cardiac vasculature and flow MD. Upward shift of the lower range of coronary flow autoregulation in hyperduring pressure overload hypertrophy. Am J Physiol 1986;251:H1031–H1037. tensive patients with hypertrophy of the left ventricle. Circulation 1991;83:845– 23. Picano E. Symptoms and signs of myocardial ischemia. In: Picano E, ed. 853. Stress Echocardiography. Berlin: Springer-Verlag, 1994:20 –31. 2. Brush JE, Canon RO, Schenke WH, Bonow RO, Leon MB, Maron BJ, Epstein 24. Galderisi M, Benjamin EJ, Evans JC, D’Agostino RB, Fuller DL, Lehman B, SE. Angina due to coronary microvascular disease in hypertensive patients Levy D. Impact of heart rate and PR interval on Doppler indexes of diastolic without left ventricular hypertrophy. N Engl J Med 1988;319:1302–1307. filling in an elderly cohort (The Framingham Heart Study). Am J Cardiol 3. Schwartzkopff B, Motz W, Frenzel H, Vogt M, Knauer S, Strauer BE. 1993;72:1183–1187. Structural and functional alterations of the intramyocardial coronary arterioles in 25. Czernin J, Muller P, Chan S, Bruken RC, Porenta G, Krivokapich J, Chen K, patients with arterial hypertension. Circulation 1993;88:993–1003. Chan A, Phelps ME, Schelbert HR. Influence of age and hemodynamics on 4. Vogt M, Motz W, Strauer BE. Coronary hemodynamics in hypertensive heart myocardial blood flow and flow reserve. Circulation 1993;88:62–69. disease. Eur Heart J 1992;13(suppl D):44 –49. 26. Mc Ginn AL, White CW, Wilson RF. Interstudy variability of coronary flow 5. Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, reserve. Influence of heart rate, arterial pressure, and ventricular preload. CircuGanz P, Alexander RW. Hypertension and left ventricular hypertrophy are lation 1990;82:1815–1825. associated with impaired endothelium-mediated relaxation in human coronary 27. Hamasaki S, Al Suwaidi J, Higano ST, Miyauchi K, Holmes DR Jr, Lerman resistance vessels. Circulation 1993;87:86 –93. A. Attenuated coronary flow reserve and vascular remodeling in patients with 6. El-Said E-SM, Roeland J, Fioretti PM. Abnormal left ventricular early diastolic hypertension and left ventricular hypertrophy. J Am Coll Cardiol 2000;35:1654 – filling during dobutamine stress Doppler echocardiography is a sensitive indicator 1660. of significant coronary artery disease. J Am Coll Cardiol 1994;24:1618 –1624. 28. Fouad FM, Slominski JM, Tarazi RC. Left ventricular diastolic filling in 7. Fujibashi Y, Yamazaki S, Chang BL, Rajagopalan R, Meerbaum S, Corday E. hypertension: relation to left ventricular mass and systolic function. J Am Coll Comparative echocardiographic study of recovery of diastolic versus systolic Cardiol 1984;3:1500 –1506. function after brief period of coronary occlusion: differential effects of intrave29. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis nous nifedipine administered before and during occlusion. J Am Coll Cardiol of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 1985;6:1289 –1298. 1995;26:1565–1574.
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tal systolic velocities did not differ between the 2 groups. The ratio between myocardial velocities in early diastole and at atrial contraction (Em/Am ratio) was lower in patients with reduced CFR, both at baseline (p <0.05) and with high-dose dobutamine (p <0.00001). After adjusting for age, body mass index, LV mass index, and both high-dose dobutamine diastolic blood rate and heart rate by a multiple linear regression analysis, Em/Am ratio at high-dose dobutamine was independently associated with CFR in the overall population ( 0.62, p <0.0005) (cumulative R2 0.38, p <0.0005). In conclusion, this study provides evidence of an independent association between CFR and myocardial diastolic function. In hypertensive patients without coronary artery stenosis, CFR alteration may be a determinant of myocardial diastolic dysfunction or diastolic impairment that should be taken into account as possibly contributing to coronary flow reduction. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;90:860 – 864)
everal factors are involved in reducing coronary flow reserve (CFR) in hypertensive patients. First, S baseline coronary flow may be increased because of
segment changes. Elevations of LV end-diastolic pressure have long been recognized to occur during spontaneous or provoked ischemia.6 – 8 Nevertheless, little is known about the relation between LV diastolic function and coronary flow dynamics.9 To date, CFR may be assessed noninvasively by second-harmonic Doppler echocardiography,10 –12 whereas color tissue Doppler may be used to assess myocardial diastolic function both at rest and during stress.13,14 The present study was designed to investigate the association between LV myocardial diastolic dysfunction and CFR in hypertensives, using both second-harmonic Doppler and color tissue Doppler during dobutamine stress.
higher blood pressure (BP), greater left ventricular (LV) end-systolic stress, and LV hypertrophy.1 Second, the maximal flow response to physiologic or pharmacologic stimuli may be limited by a reduction in the overall maximal cross-sectional area of the microcirculatory bed that is induced by vascular changes in the intramyocardial coronary arteries, increased coronary arteriolar tone, inadequate angiogenesis in LV hypertrophy, endothelial dysfunction, or by extravascular compression.2–5 However, in view of the fact that coronary blood flow occurs predominantly during diastole, it is conceivable that LV diastolic changes also play a role in CFR impairment in hypertensives. In contrast, myocardial ischemia may produce LV diastolic alterations, even before the detection of wall motion and/or electrocardiographic STFrom the Department of Clinical and Experimental Medicine, “Federico II” University of Naples; Medical-Surgical Physiopathology of Cardiopulmunary and Respiratory System and Associated Biotechnologies, Second University of Naples; and Division of Cardiology, Monaldi Hospital, Naples, Italy. Manuscript received April 26, 2002; revised manuscript received and accepted June 6, 2002. Address for reprints: Maurizio Galderisi, MD, Laboratory of Echocardiography, Department of Clinical and Experimental Medicine, Federico II University, Via Andrea d’Isernia, 4, 80122 Naples, Italy. E-mail: [email protected].
860
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 October 15, 2002
METHODS
Study population: Between September 1998 and December 2000, 147 patients affected by newly diagnosed, never-treated arterial hypertension (World Health Organization/International Society of Hypertension grade 1 to 2) were screened at our outpatient clinic. Patients were defined as hypertensive if their diastolic BP was ⱖ90 mm Hg (mean of 3 different measurements on 3 different visits). Exclusion criteria were coronary artery disease (absence of angina pectoris and negative findings on the electrocardiogram at rest, maximal treadmill exercise electrocardiography, and stress perfusion scintigraphy), diabetes mellitus, heart failure, valvular heart disease, atrial fibrillation, 0002-9149/02/$–see front matter PII S0002-9149(02)02708-X
CFR DETERMINATION: CFR assessment was performed by an Acuson Hypertensives Hypertensives Sequoia system (Acuson CorporaWith CFR ⱖ2 With CFR ⬍2 tion, Mountain View, California), usVariable (n ⫽ 15) (n ⫽ 15) p Value ing a transducer with second-harmonic Men/women 12/3 12/3 NS capability (1.7 MHz transmitting and Age (yrs) 53 ⫾ 6 53 ⫾ 5 NS 3.5 MHz receiving). The visualization 28 ⫾ 3 28 ⫾ 4 NS Body mass index (kg/m2) of the distal portion of the left anterior Baseline systolic BP (mm Hg) 145 ⫾ 7 151 ⫾ 14 NS descending artery was performed usBaseline diastolic BP (mm Hg) 99 ⫾ 3 101 ⫾ 4 NS Baseline heart rate (beat/min) 75 ⫾ 5 75 ⫾ 8 NS ing the standard method10 –12 with a Dobutamine systolic BP (mmHg) 160 ⫾ 5 171 ⫾ 17 ⬍0.05 contrast agent (Levovist, SHU-508A, Dobutamine diastolic BP (mmHg) 98 ⫾ 5 100 ⫾ 5 NS Schering AG, Berlin, Germany)11 in Dobutamine heart rate (beats/min) 134 ⫾ 5 135 ⫾ 7 NS case of suboptimal color Doppler imaging. By placing the sample volume on the color signal, spectral Doppler of and inadequate echocardiograms. Using these criteria, the left anterior descending artery showed the characterafter the approval of the Institutional Ethics Commit- istic biphasic flow pattern with larger diastolic and tee and the informed consent of each patient, 30 hy- smaller systolic components. Coronary diastolic peak pertensives (24 men, 6 women; mean age 53.1 years) velocities were measured at baseline and after dipyridformed the final study group. According to CFR, amole (0.56 mg/kg over 4 minutes) by averaging the hypertensives were divided into 2 groups: 15 with highest 3 Doppler signals for each measurement. CFR normal CFR (ⱖ2) and 15 with impaired CFR (⬍2). was defined as the ratio of hyperemic to basal diastolic Procedures: Hypertensives underwent standard peak velocities. All images were analyzed off-line by 2 echocardiography and color tissue Doppler dobut- observers blinded to the other data. Our CFR reproducamine stress on the same day but CFR determination ibility has been previously tested,18 with an intraobserver on a different day. variability of 1.9% and interobserver variability of 4.2%. TRANSTHORACIC ECHOCARDIOGRAPHY: Standard Statistical analysis: The analyses were performed by echocardiography was performed by a System FiVe, SPSS for Windows release 8.0 (Chicago, Illinois). The Vingmed Sound AB machine (GE, Horten, Norway), t test for unpaired data was used to assess intergroup using a 2.5-MHz transducer equipped with second- differences. Univariate relations were tested by Pearharmonic capability. M-mode was performed accord- son’s method. Prediction of variables was obtained by ing to the methods of our laboratory.15 Doppler in- stepwise, forward, multiple regression including podexes of LV diastolic function were measured accord- tential confounders. A p value of ⬍0.05 was considing to the standard techniques.16 ered significant. COLOR TISSUE DOPPLER DOBUTAMINE STRESS: Color tissue Doppler dobutamine echocardiography was recorded using the same System FiVe Vingmed instruRESULTS ment. Dobutamine protocol was performed according Characteristics of the population are listed in Table 17 to standard methods. Color tissue Doppler acquisi1. High-dose dobutamine systolic BP was higher in tion of longitudinal myocardial velocities from the posterior septum in the apical 4-chamber view was patients with CFR ⬍2. No patient complained of chest performed in real-time and superimposed on 2-dimen- pain and no ST changes occurred using both stressors. sional images at rest and after administration of high- Analyses of the Doppler echocardiographic data are dose dobutamine. The images were stored digitally listed in Table 2. Relative wall thickness and LV mass and the analysis was performed off-line on cine index were higher in patients with CFR ⬍2. Doppler loops.13,14 The region of interest was the middle pos- indexes were similar between the 2 groups. The results of the dobutamine test and color tissue terior septum where the myocardial velocity profile Doppler are listed in Table 3. Sm velocities were was obtained at rest and during administration of high-dose dobutamine. The typical color tissue Dopp- similar between the 2 groups at rest or with high-dose ler pattern comprises a positive mean systolic velocity dobutamine. In diastole, Em/Am was mildly lower at (Sm) and 2 negative mean diastolic velocities—1 dur- baseline (p ⬍0.05) and highly significantly reduced ing early diastole (Em) and another during atrial con- with high-dose dobutamine (p ⬍0.00001) in hypertentraction (Am). The choice of the middle posterior sives with abnormal CFR. Figure 1 shows a patient septum for color tissue Doppler was based on the with normal CFR; despite a faster heart rate, septal assumption that the perfusion of this myocardial seg- Em/Am was marginally modified from baseline (1.00) ment is provided by a branch of the left anterior to adminstration of high-dose dobutamine (0.99). Figdescending artery, where CFR was also determined. ure 2 shows a patient with reduced CFR where the Our color tissue Doppler reproducibility has been septal Em/Am ratio at rest (0.89) decreased with highpreviously reported18; the intra- and interobserver dose dobutamine (0.71). Relation between CFR and color tissue Doppler: In variabilities were ⬍3% and ⬍6%, respectively, for all the measurements, both at baseline and with high-dose the overall population CFR was not related to standard dobutamine. Doppler diastolic measurements. Among baseline TABLE 1 Characteristics of the Study Population
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TABLE 2 Standard Doppler Echocardiographic Analysis Variable
Hypertensives With CFR ⱖ2
Septal wall thickness (mm) Posterior wall thickness (mm) LV internal diastolic diameter (mm) LV internal systolic diameter (mm) Endocardial fractional shortening (%) Relative diastolic wall thickness LV mass index (g/m2.7) Peak E velocity (m/s) Peak A velocity (m/s) Peak E/A ratio E-wave deceleration time (ms) Isovolumic relaxation time (ms)
10 9 52 36 31 0.36 41 0.54 0.56 0.96 187 84
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
2 1 6 4 5 0.08 9 0.15 0.06 0.3 30 21
Hypertensives With CFR ⬍2
p Value
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
⬍0.01 ⬍0.05 NS NS NS ⬍0.01 ⬍0.01 NS NS NS NS NS
12 10 51 35 32 0.42 53 0.58 0.66 0.89 201 90
1 1 6 5 5 0.06 10 0.08 0.12 0.15 51 41
CFR level, with the cut-off point for normal CFR ⱖ2.11 The main findings of the study are: (1) hypertensives with abnormal CFR have a lower myocardial Em/Am ratio at baseline and particularly with highdose dobutamine, and (2) an association between CFR and Em/Am with high-dose dobutamine is evident in all of the hypertensive patients, independent of clinical and echocardiographic variables. Myocardial diastolic dysfunction in hypertensives with reduced CFR: To
our knowledge, no association between CFR and Doppler-derived LV diastolic function has previously TABLE 3 Color Tissue Doppler Analysis at Baseline and With High-dose been found. Accordingly, transmitral Dobutamine diastolic measurements were not sigHypertensives Hypertensives nificantly different in our hypertenVariable With CFR ⱖ2 With CFR ⬍2 p Value sives with normal or altered CFR. Baseline Color tissue Doppler provides addi8⫾1 5⫾2 ⬍0.0005 Em velocity (cm/s) tional information about myocardial Am velocity (cm/s) 7 ⫾ 0.8 7⫾2 NS function also during dobutamine Em/Am ratio 1 ⫾ 0.11 0.78 ⫾ 0.38 ⬍0.05 Sm velocity (cm/s) 5 ⫾ 0.5 5 ⫾ 0.7 NS stress. Color tissue Doppler-derived High-dose dobutamine Em velocity may be considered an Em velocity (cm/s) 9⫾2 6⫾2 ⬍0.001 index of myocardial relaxation, Am velocity (cm/s) 9⫾2 11 ⫾ 2 ⬍0.02 whereas Am velocity reflects atrial Em/Am ratio 0.99 ⫾ 0.14 0.63 ⫾ 0.24 ⬍0.00001 activity and probably intrinsic disSm velocity (cm/s) 11 ⫾ 1 11 ⫾ 2 NS tensibility of LV myocardial fibers. Of note, alterations of LV relaxation in arterial hypertension may be due color tissue Doppler measurements, CFR was posi- either to increased afterload or to changes in LV tively related to Em (r ⫽ 0.45, p ⬍0.01), whereas the structure.15,19 In the present study, the septal Em/Am relation with Am (r ⫽ 0.10), Em/Am (r ⫽ 0.25), and Sm ratio was lower in patients with reduced CFR already (r ⫽ ⫺0.12) were not significant. Among high-dose at baseline and much more with high-dose dobutdobutamine measurements, Em (r ⫽ 0.39, p ⬍0.05), amine. Em/Am reduction was mainly due, both at Am (r ⫽ ⫺0.41, p ⬍0.05), and Em/Am (r ⫽ 0.62, baseline and during stress, to the decrease of Em p ⬍0.0005) (Figure 3), but not Sm (r ⫽ ⫺0.10), had velocity, whereas the Am increase had a role only with univariate relations with CFR. High-dose dobutamine high-dose dobutamine. Em/Am was related to high-dose dobutamine heart Association between CFR and color tissue Doppler rate (r ⫽ ⫺0.37, p ⬍0.05), diastolic BP (r ⫽ ⫺0.40, Em/Am ratio: A strong positive association between the p ⬍0.05), and to LV mass index (r ⫽ ⫺0.42, p high-dose dobutamine Em/Am ratio and CFR was ⬍0.02), whereas the relations with age and body mass found in the entire hypertensive population. This asindex (r ⫽ ⫺0.32 and r ⫽ ⫺0.14, respectively) were sociation may be interpreted in 2 ways. First, it can be not significant. A stepwise forward multilinear regres- hypothesized that myocardial diastolic dysfunction sion model was performed to analyze the relation that negatively affects CFR. LV diastolic function contriboccurred between CFR and high-dose dobutamine utes to regulate the relation between coronary flow Em/Am after adjusting for age, LV mass index, and and pressure perfusion. The diastolic time fraction is a both high-dose dobutamine heart rate and diastolic determinant of coronary flow increase when the autoBP. By this model, Em/Am ratio and CFR were inde- regulatory mechanism is exhausted because larger pendently associated ( 0.62, p ⬍0.0005) (cumulative fractional diastolic time occurs at lower perfusion R2 0.38, p ⬍0.0005). pressure, in the presence as well as in the absence of coronary stenosis.20 The impairment of LV relaxation has shown an adverse impact on early diastolic coroDISCUSSION The present study used color tissue Doppler13,14 nary flow in dogs21 but also in humans.9 This mechand CFR determination10 –12 to evaluate the possible anism can be important also in hypertensives without association between LV myocardial diastolic function coronary artery disease. Coronary microvessel damand CFR in arterial hypertension where changes in age, probably due also to extravascular diastolic comafterload and LV structure may influence both LV pression,22 may not be evident at baseline, but can diastolic properties and coronary blood flow supply. become overt with faster heart rates.9 Alternatively, a Hypertensives were divided into 2 groups according to reduced CFR may itself affect LV diastolic properties. 862 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 1. Myocardial septal Em/Am ratio at baseline and with high-dose dobutamine (DOB) in a patient with normal CFR (>2). Upper panels, coronary artery flow velocity in the left descending coronary artery at baseline and with a normal increase with dipyridamole (DIP). Lower panels, with high-dose dobutamine, despite the increase in heart rate, the Em/Am ratio at the mid-part of the posterior septum is marginally modified because of a mild increase in Em and Am. The myocardial systolic velocity (Sm) shows a normal increase with dobutamine.
FIGURE 2. Myocardial septal Em/Am ratio at baseline and with high-dose dobutamine (DOB) in a patient with reduced CFR (<2). Upper panels, the flow velocity increase in the left descending coronary artery with dipyridamole (DIP) is impaired. Lower panels, with high-dose dobutamine, the Em at the midpart of the posterior septum shows minimal change, whereas Am has a greater increase, resulting in a reduction of the Em/Am ratio. The increase in myocardial systolic velocity is normal, similar to that seen in Figure 1.
In the ischemic process, LV diastolic dysfunction occurs early, before evidence of wall motion abnormalities and LV systolic failure.23 The main diastolic alteration due to ischemia is a delayed myocardial relaxation associated with lower transmitral gradient pressure at the time of the mitral opening that results in less early diastolic filling. This mechanism may be crucial in hypertensives, due to both pressure overload and LV hypertrophy. In our study, CFR was significantly related only to Em at rest but it was positively related to Em and Em/Am and negatively with Am with high-dose dobutamine.
The association between CFR and the Em/Am ratio was tested by a multilinear regression analysis adjusting for several confounders. Age, heart rate, and diastolic BP were included as possible determinants because of their physiologic influence on both LV diastolic function19,24 and CFR.25,26 The role of LV mass was assessed because of the adverse effect of LV hypertrophy on both myocardial flow27 and LV diastolic properties.28 However, the association between CFR and myocardial diastolic function remained independent of the influence exerted by all these variables. These data are consistent with previ-
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Galderisi M, Petrocelli A, Alfieri A, Garofalo M, de Divitiis O. Impact of 15,19 before the development of LV hypertrophy. ambulatory blood pressure on left ventricular diastolic dysfunction arterial sysClinical implications: These findings have clinical temic hypertension. Am J Cardiol 1996;77:579 –601. 16. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recomimpact and provide information about the relations mendations for quantification of Doppler echocardiography: a report from the between myocardial diastolic function and coronary Doppler quantification task force of the nomenclature and standard committee of American Society of Echocardiography. J Am Soc Echocardiogr 2002;15: blood flow supply in patients with hypertension. A the 167–184. CFR reduction might be potentially responsible for 17. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. 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