Volume 124 Number
Determinants
5
40. Thomas JD, Wilkins GT, Choong CY, Abascal VM, Palacios IF, Block PC, Weyman AE. Inaccuracy of the mitral pressure half-time immediately following percutaneous mitral valvotomy: dependence on transmitral gradient and left atria1 and ventricular compliance. Circulation 1988;78:980-93. 41. Lavine SJ, Campbell CA, Kloner RA, Gunther SJ. Diastolic filling in acute left ventricular dysfunction: role of the pericardium. J Am Co11Cardiol 1988;12:1326-33. 42. Thomas JD, Weyman AE. Echocardiographic Doppler evaluation of left ventricular diastolic function: physics and physiology. Circulation 1991;977-90.
of
ventricular
relaxation
43. Sabbah HN, Stein PD. Proposed mechanism for depression of maximal rate of left ventricular pressure fall (peak negative dP/dt) during regional myocardial ischemia. Cathet Cardiovast Diagn 1986;12:182-8. 44. Rubenstein JJ, Pohost GM, Dinsmore RE, Harthorne JW. The echocardiographic determination of mitral valve opening and closure: correlation with hemodynamic studies in man. Circulation 1975;51:98-103.
Doppler assessment of right ventricular dynamics in systemic hypertension: Comparison with left ventricular filling
filling
To assess right ventricular filling dynamics in systemic hypertension, pulsed Doppler echocardiographic studies were obtained at the tricuspid and mitral anuli in 43 untreated hypertensive patients, aged 23 to 66 years, and in 42 age-matched normotensive control subjects. In hypertensive patients, the ratio of late to early peak filling velocity and atrial filling fraction were higher, while normalized peak filling rate, one third and one half filling fractions were lower, compared with control values. Right ventricular filling dynamics correlated poorly with age in hypertensive patients, and were unrelated to left ventricular mass or left ventricular wall thickness. Weak correlations were only found between right ventricular wall thickness and right ventricular peak late inflow velocity, first half and first third filling fractions. However, right ventricular filling dynamics were closely related to left ventricular filling dynamics in both hypertensive patients (r = 0.49 to 0.82) and normal individuals (r = 0.55 to 0.86). Thus right ventricular filling dynamics are altered in hypertension, independently of left ventricular mass or blood pressure, are weakly related to right ventricular thickness, but remain closely correlated to left ventricular filling dynamics. (AM HEART J 1992;124:1313.)
Gabriel B. Habib, MD, and William
A. Zoghbi, MD Houston,
Doppler echocardiography has recently provided assessment of right and left ventricular filling dynamics.le5 Parameters of right and left ventricular filling From the Section of Cardiology, Department of Medicine, Baylor College of Medicine, The Methodist Hospital Echocardiography Laboratory, and Veterans Affairs Medical Center. Computational assistance was provided by the CLINFO Project, funded by Grant RR-00350 tutes of Health, Received Reprint College
from the Division Bethesda, Md.
for publication
Nov.
of Research
21, 1991; accepted
Resources, May
National
Insti-
15, 1992.
requests: William A. Zoghbi, MD, Section of Cardiology, Baylor of Medicine, 6535 Fannin, M.S. F-905, Houston, TX 77030.
411140553
Texas
have been shown to be impaired in patients with hypertrophic cardiomyopathy.6l 7 In systemic hypertension, left ventricular filling dynamics have been reported to be abnormal in the presence or absence of left ventricular hypertrophy.s-10 The effects of systemic hypertension on right ventricular function are not well understood. Right ventricular hypertrophy, elevated right-sided pressures, and impaired right ventricular systolic function have been reported in patients with systemic hypertension.l’-l3 Whether right ventricular filling dynamics are altered in hypertensive patients is presently not known. The present study was therefore designed to compare
1313
November
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Habib and Zoghbi
right and left ventricular filling dynamics in hypertensive patients with those of age-matched normotensive subjects, and to determine whether these changes are related to age, heart rate, blood pressure, or left ventricular mass. METHODS Patient population.
The population consisted of 43 patients (24 men and 19 women) with essential hypertension (diastolic blood pressure > 90 mm Hg) for 1 to 20 years who previously received P-blockers, thiazide diuretics, sympatholytic drugs, or angiotensin-converting enzyme inhibitors but had discontinued therapy at least 8 weeks before study participation. Age ranged between 23 and 66 years (43 + 12 years). None had clinical, electrocardiographic, two-dimensional, or Doppler echocardiographic evidence of coronary or valvular heart disease, congestive heart failure, atria1 fibrillation or flutter, atrioventricular block, pulmonary disease, insulin-dependent diabetes mellitus, or renal insufficiency (serum creatinine > 2 mg/dl). Hypertensive patients were age-matched with 42 asymptomatic and apparently healthy subjects who satisfied the aforementioned exclusion criteria. Normotensive subjects were selected among healthy volunteers such that the number of normotensive subjects was almost identical to the number of hypertensive patients in each decade of life between 20 and 70 years. The age of normotensive subjects ranged between 21 and 66 years (43 t 12 years). Normotensive controls had a sitting blood pressure less than X0/90 mm Hg and a normal physical examination, electrocardiogram, and M-mode, two-dimensional, and Doppler echocardiographic studies. Normotensive and hypertensive patients sat still for 30 minutes before vital signs were measured. Blood pressure was obtained by the same examiner using a calibrated cuff sphygmomanometer. Blood pressure was measured twice at 3-minute intervals with the patient in the sitting position for at least 30 minutes. Participation in this study was voluntary and a written informed consent was obtained from each entrant. The study protocol was approved by the Institutional Review Board of Baylor College of Medicine and by the Veterans Affairs Medical Center. Echocardiographic and Doppler studies. Two-dimensional and Doppler echocardiographic studies were performed using a Hewlett-Packard ultrasound system (No. 77020AC, Hewlett-Packard Co., Medical Products Group, Andover, Mass.) equipped with 3.5 or 2.5 MHz transducers and recorded on Yz-inch videotape. Echocardiographic images were obtained from the parasternal and apical windows with the patient in the left lateral recumbent position. Complete M-mode, two-dimensional, and pulse-wave Doppler echocardiographic studies were obtained. All individuals had adequate quality studies for quantitation. M-mode echocardiographic measurements were made according to the guidelines of the American Society of Echocardiography.‘* Left ventricular mass was calculated by the Penn-cube method described by Devereux et a1.15Right ventricular diastolic wall thickness was measured from high-quality M-mode recordings; particular care was taken
American
1992
Heart Journal
to optimize the near gain settings to enhance the definition of the right ventricular anterior wall.” For measurements of ventricular filling dynamics, pulsed Doppler studies were performed using the parasternal and apical windows. Recordings of inflow velocity were obtained at the level of the tricuspid and mitral anuli during quiet and shallow breathing, as previously described.2 Furthermore, since right ventricular filling is significantly affected by respiration,2 all measurements of right ventricular filling dynamics were also obtained during end-tidal apnea. Right ventricular inflow velocity was recorded from the short-axis, low parasternal, and apical four-chamber views. Right ventricular filling dynamics were determined from the window providing the highest velocity recordings at the tricuspid anulus, thus implying the least Doppler angle with flow. This echocardiographic window was the low parasternal view in 75 “0 of the cases. Left ventricular inflow velocity was recorded from the apical four-chamber view, as previously described. ‘3’ No angle correction between the Doppler ultrasound beam and the presumed flow direction was performed for determination of left or right ventricular filling parameters. All Doppler recordings were performed at a sweep speed of 100 mm/set. To assess whether pulmonary artery pressure was similar in the hypertensive patients and control subjects, pulsed Doppler recordings in the right ventricular outflow tract were performed from the short-axis window. The ratio of right ventricular acceleration time to ejection time, an index of pulmonary artery pressure, was determined as described by Kitabatake et a1.16 Doppler-derived
parameters
of
ventricular
filling.
Echocardiographic and Doppler measurements were performed using an off-line computer analysis station (EC500, Digisonics, Inc., Houston, Texas) equipped with a digitizing pad and internal calipers and interfaced with the video signal. All measurements were performed by an observer blinded to all clinical data. The Doppler velocity tracings at the tricuspid and mitral valve anuli were digitized using the contour of the darkest portion of the spectral display, and the following parameters were computergenerated, as previously described in detail”: peak early inflow velocity (E) in cm/set; peak late inflow velocity (A) in cm/set; A/E ratio; the time-velocity integral of diastolic inflow velocity; first half filling fraction ( % FF); first third filling fraction (‘4 FF); and atria1 filling fraction (AFF). Furthermore, peak filling rate normalized to stroke volume (NPFR) was derived as defined by Bowman et al.” This was obtained by dividing peak early filling velocity by t.he total time-velocity integral, and is expressed as stroke volume per second (SV/sec). To minimize the effect of respiration on ventricular filling dynamics, Doppler measure-ments were obtained from 7 to 10 consecutive cardiac cycles and were averaged.2 Moreover, right ventricular filling dynamics were obtained during end-tidal apnea in all patients. Statistical analysis. Results were expressed as mean + standard deviation, except as indicated. Comparisons of Doppler measurements in hypertensive patients with those of normotensive controls was performed using
Volume 124 Number 5
Table
Doppler
RV and LVfilling
in
hypertension
1315
I. Clinical and echocardiographic characteristics of normals and hypertensive patients Normals
Age (yr)
Hypertensives
43 k 12 (21-66) 2222 121 k 11 (90-140) 78 + 8 (60-90) 93 k 8 (70-107) 69 f 10 (43-96) 0.7 i- 0.1 (0.5-1.2) 1.1 + 0.1 (0.7-1.5) 0.5 k 0.1 (0.4-0.8) 106 + 35 (55-189) 149 t 26 (108-197) 327 AZ35 (226-387) 0.5 k 0.1 (0.3-0.6)
Sex (M:F) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Heart rate (beats/min) Posterior wall thickness (cm) Septal wall thickness (cm) Right ventricular wall thickness (cm) Left ventricular mass index (gm/m2) AT (msec) ET (msec) AT/ET
43 k 12 (23-66) 24:19 150 + 21* (110-190) 100 + 16* (90-134) 116 k 16* (100-146) 72 k 12 (51-96) 1.1 + 0.2* (0.8-1.9) 1.6 2 0.2* (1.2-1.9) 0.8 F 0.2* (0.6-1.2) 161 * 37* (126-256) 153 + 23 (110-212) 332 t 33 (258-389) 0.5 k 0.1 (0.3-0.6)
Values are expressed as mean t standard deviation, followed by range. AT, Acceleration
time; ET, ejection time. Both AT and ET are measured *p < 0.01 hypertensives versus normals.
Table
II. Doppler-derived
parameters
of right
in the right ventricular
outflow
tract.
and left ventricular filling in hypertensive and normal subjects
Right ventricle Normals
Left ventricle Normals
Hypertensiues
Hypertensives
-~
TV1 (cm) E (cm/src) A (cm/set) A/E ‘5 FF (‘;) I,:, FF ( “0 ) NPFR (S/see) AFF (“Cl DT (msec)
12 44 37 0.9 62 50 3.9 24 142
2~ 2 + 9 i
11
* t + k + +
0.3 10 10 0.8 9 39
12 42 43 1.0 56 43 3.5 38 179
AC3 t 1
+ 16 t 0.3t I 9t r lot
+ 0.6t t 13t f 43*
13 55 48 0.9 63 54 4.2 25 137
t 2 t
11
+ 13 k 0.4 i 9 + 11
i 0.8 I+ 8 + 27
14 52 54 1.1 54 43 3.8 39 190
* 4 2 20* 5 16 f 0.4t f lot AZ12t -t 0.8* * 12t t 56t
All values are expressed as mean ? standard deviation. A, Peak late filling velocity; DT, deceleration time; E, peak early filling velocity; HR, heart rate; NPFR, peak filling rate normalized to stroke stroke volume; TVI, time-velocity integral; !+ FF’, first half filling fraction: 5 I?‘, first third filling fraction: AFF, atria1 filling fraction. *O.Ol < p < 0.05 hypertensives versus normals. tp 5 0.01 hyprrtensives versus normals.
Student’s t testI for unpaired observations if the observations had a normal distribution. Nonparametric statistical analysis using the Wilcoxon rank sum test was used for comparison between groups that did not pass standard tests of normality.
Correlations
between
parameters
of
ventricular filling, age, left ventricular mass, wall thickness, and blood pressure were performed using univariate linear regression analysis. In view of the multiple comparisons between clinical and echocardiographic characteristics of hypertensive and normotensive subjects, statistical significance was set at a p value I 0.01. RESULTS Comparison of Doppler filling dynamics in normals versus hypertensive patients. Table I shows the clini-
cal and echocardiographic characteristics of normal individuals and hypertensive patients. Among 43 hypertensive patients, 30 had mild, eight had mod-
volume;
SV,
erate, and five had severe essential hypertension, defined as sitting diastolic blood pressures of 90 to 105, 106 to 120, and I 121 mm Hg, respectively. Blood pressure (systolic, diastolic, and mean), left ventricular mass index, left ventricular posterior wall thickness, septal wall thickness, and right ventricular anterior wall thickness were higher in hypertensives than in age-matched normal subjects. Heart rate was almost identical in both groups and did not change during the echocardiographic examination. Acceleration time in the right ventricular outflow tract, right ventricular ejection time, and their respective ratio were similar in normal and in hypertensive subjects. Doppler-derived filling parameters are shown in Table II. Compared with normotensive controls, right and left ventricular filling dynamics in hypertensive patients were characterized by decreased
November
1316
Habib and Zoghbi
American
1992
Hearl Journal
Fig. 1. Examples of pulsed Doppler recordings of right ventricular inflow and left ventricular inflow in a normal individual and in an age-matched hypertensive patient (age 28 years). Peak early filling (E) and peak late filling (A) are shown. Note the reduced early filling in the hypertensive patient, with an increased atria1 contribution to filling in both right and left ventricular inflow compared with the normal subject.
Table III. Correlations between parameters of right and left ventricular filling in normal and hypertensive subjects Normal Parameter
E (cm/set) A (cm/set) A/E ‘h FF (%) !/3 FF(%) NPFR (SV/sec) AFF (7;) r, Correlation All correlation
subjects r
Hypertensiue subjects r
0.63 0.63 0.86 0.61 0.66
0.54 0.68 0.56 0.59 0.68
0.55
0.49
0.66
0.82
coefficient; other abbreviations as defined coefficients were significant (p 5 0.01).
in Table
II.
early filling, as assessed by reduced first half and first third filling fractions, and normalized peak filling rate and prolonged deceleration time. An augmentation of the atria1 contribution to ventricular filling was manifested by an increase in atria1 filling fraction. The A/E ratios at the tricuspid and mitral anuli were also higher in hypertensive patients. An example of the changes observed in right and left ventricular filling in hypertension compared with normal blood pressure is shown in Fig. 1. Comparison of right and left ventricular filling dynamics. Table III shows the results of the univariate lin-
ear regression analysis between right and left ven-
tricular filling dynamics of normal and hypertensive subjects. Significant correlations were observed between parameters of right and left ventricular filling in both hypertensive patients (r range, 0.49 to 0.82) and normal subjects (r range, 0.55 to 0.86). Relation of ventricular filling dynamics to age. Table IV shows the results of the correlations between Doppler-derived filling parameters and age in normal and hypertensive patients. In normal subjects, and as previously reported,’ age was an important determinant of Doppler filling parameters of the right and left ventricles. Age was inversely related to parameters of early filling (E, ‘/iLFF, $5 FF, and NPFR) and was directly related to late ventricular filling parameters of both ventricles (AFF and A). Correlation coefficients ranged from -0.46 to 0.82 (p < 0.001) for the right ventricle, and from -0.40 to 0.81 (p < 0.009) for the left ventricle. In contrast, in hypertensive patients, the correlations of Doppler filling parameters with age decreased significantly for both right and left ventricles. No relation was observed between right ventricular filling parameters and age, except for a weak relation with atria1 filling fraction and the A/E ratio. As for left ventricular filling parameters, hypertensive patients had lower correlation coefficients between age and Doppler filling indices compared with those observed in the normal population.
Volume 124 Number
Table
Doppler
5
IV. Correlations
between
ventricular
filling
dynamics,
RV and LVfilling
age, and heart rate in normals
Right ventricle Hypertensives
Normals
E A
A/E ‘4 FF ‘~3 FF NPFR AFF
Left
Hypertensives
HR
Age
HR
A.@
HR
Age
HR
-0.61 0.60 0.82 -0.63 -0.46 -0.54 0.72
NS NS 0.49 -0.50 -0.57 NS NS
NS NS 0.38 NS NS NS 0.40
NS NS NS -0.47 -0.55 NS NS
-0.66 0.57 0.81 -0.66 -0.40 -0.73 0.73
-0.36 0.47 0.49 -0.54 -0.61 NS NS
-0.40 0.31 0.65 -0.49 -0.28 -0.53 0.64
NS NS NS -0.41 -0.45 NS NS
hypertension on ventricular filling dynamics were different in younger versus older patients, we calculated paired differences in filling parameters between hypertensive patients and age-matched normotensive subjects. Paired differences among patients younger than 45 years were compared with those of older individuals. Among 43 hypertensive patients, 25 were less than 45 years of age; among 42 normotensive subjects, 26 were less than 45 years of age. Greater alterations in right ventricular filling dynamics were observed in the younger compared with the older individuals. Respective paired differences in younger versus older subjects for the various parameters were as follows (all p < 0.05)-A/E: 0.29 t- 0.44 versus 0.02 * 0.31; C/2FF: 9 I~I 14% versus 0 -+ 8% ; l/3 FF: 11 + 16% versus 0 + 10% ; NPFR: 0.7 + 1 SV/sec versus 0.01 f 0.5 SV/sec. In contrast, the alterations in left ventricular filling parameters with hypertension were similar in the younger and older age groups. Relation of filling dynamics to heart rate. In the normal subjects, and as previously demonstrated,2 heart rate was a weaker determinant of Doppler filling parameters when compared with age (Table IV). The highest correlations were observed with first half and first third filling fraction for both the right and left ventricles (r range, -0.50 to -0.61). In hypertensive patients, heart rate remained an important determihalf
ventricle
Age
Effect of hypertension on filling dynamics in younger versus older patients. To assess whether the effects of
of first
1317
and hypertensives
Normals
Values represent sigmficant correlation coefficients (p < 0.01) of the univariate regression analysis in normal and hypertensive subjects. HR. Heart rate; NS, correlation not statistically significant; other abbreviations as in Table II.
nant
in hypertension
and first
third
filling
fraction
only,
for both ventricles. Relation between filling dynamics and left ventricular mass, left and right ventricular wall thickness, and blood pressure. Univariate linear regression analysis be-
tween right. or left ventricular
filling parameters
and
of ventricular
filling parameters
versus age and heart
rate
left ventricular mass, left ventricular posterior wall thickness, and septal wall thickness showed no significant correlations, except for a weak correlation between left ventricular first third filling fraction and posterior or septal wall thickness (r = -0.47,~ = 0.04, and r = -0.49, p = 0.03, respectively). A weak correlation was also found between right ventricular anterior wall thickness and right ventricular peak late inflow velocity, one half and one third filling fraction (r = 0.39, -0.41, and -0.40, respectively; p = 0.03 to 0.04), but not with any other filling parameters. No correlation was found between right or left ventricular filling dynamics and systolic, diastolic, or mean blood pressure. DISCUSSION
This study demonstrates that Doppler-derived parameters of right ventricular filling dynamics are altered in hypertensive patients compared with ageand heart rate-matched controls. The changes in right ventricular filling dynamics with hypertension alter the usual relation of age with parameters of diastolic filling and are more pronounced in younger individuals. Doppler echocardiographic tricular diastolic function.
evaluation
of right
ven-
Validation of Doppler-derived left ventricular filling parameters has been accomplished by comparison with cineangiography,’ hemodynamic techniques,* and radionuclide angiography.3, 5 Although right ventricular geometry has hampered evaluation of right ventricular function for many years, Doppler echocardiography has recently allowed the assessment of right ventricular filling. Abnormalities of right ventricular diastolic filling have been described in hypertrophic cardiomyopathy, in coronary artery disease involving the right
1318
Habib
and Zoghbi
American
ventricular branch, and in patients with inferior myocardial infarction.lg$ 2o Doppler-derived right ventricular filling dynamics have not, until recently, been well characterized in a normal population.‘, “I We2 have recently demonstrated the dependence of Doppler parameters of right ventricular filling on age, heart rate, and respiration in a normal adult population. The present study was specifically designed to evaluate right ventricular filling dynamics in hypertensive patients by controlling for these potential confounding variables. Matching for age was achieved by random selection of an equal number of hypertensive and normotensive subjects in each decade of age. Heart rates were almost identical in both groups. Finally, right ventricular Doppler recordings were performed at end-tidal apnea to minimize the effects of respiration on filling dynamics. Compared with normal individuals, hypertensive patients had diminished early filling, as assessed by normalized peak filling rate, first third and first half filling fraction, and deceleration time, with a compensatory increase in the atria1 contribution to filling. This Doppler pattern of inflow velocity has recently been associated with impaired ventricular relaxation.“, ‘” Right ventricular performance in systemic sion. In a study evaluating right ventricular
hyperten-
function in patients with uncomplicated essential hypertension, Ferlinzi” observed that right atria1 and right ventricular end-diastolic pressures were higher, and right ventricular ejection fraction was lower compared with those of normal control subjects. Right ventricular hypertrophy, previously reported in patients with essential hypertension using M-mode echocardiography,” was confirmed in the present study. Although abnormalities of diastolic function and filling parameters have been well described for the left ventricle in hypertension,s-10 there is a paucity of data regarding right ventricular diastolic function in systemic hypertension. Recently, Chakko et a1.23reported alterations in right ventricular filling parameters in 32 patients with mild untreated hypertension compared with 10 normal controls. Patients with moderate or severe hypertension and women were excluded; Doppler recordings of tricuspid flow velocities were analyzed without consideration of the effects of respiration, and the potential effect of heart rate on filling dynamics was not evaluated. The present study specifically addresses these limitations and further substantiates the findings of altered right ventricular filling in systemic hypertension compared with the findings in age-matched and heart rate-matched controls. With increasing age in a normal population, a pro-
November 1992 Heart Journal
gressive decrease in early right and left ventricular filling occurs, with a compensatory increase in late filling,“, 24,25 and this is compatible with delayed ventricular relaxation. 4*22 In this study, systemic hypertension altered the accepted relation of age with ventricular filling dynamics. Right ventricular filling parameters were, for the most part, no longer related to age. However, alterations in right ventricular filling were more pronounced in the younger hypertensive patients. As for the left ventricle, the correlations of filling parameters with age were weaker in the hypertensive group compared with the controls, but remained statistically significant. These findings are compatible with those of previous reportsZ4, E showing that the effect of age on left ventricular filling is attenuated in the presence of left ventricular disease. In hypertensive patients, heart rate did not alter any filling parameter except for first half and first third filling fractions, which were weakly related to heart, rate. As reported for the left ventricle26, 27 and more recently for the right ventricle,“” changes in filling dynamics observed with hypertension related poorly to left ventricular mass, wall thickness, and blood pressure. Advantages and limitations of this study. Doppler echocardiography allows the noninvasive evaluation of ventricular filling dynamics. This method is especially useful in evaluating right ventricular filling, because M-mode and two-dimensional echocardiography are both limited in this regard and because gated radionuclide angiography has difficulties separating the right atrium from the right ventricle. However, several limitations and sources of error are present with the Doppler technique. The crosssectional area of the valve anulus changes during diastole and has been found to increase by approximately 12 “; from the onset to the end of diastole for the mitral anulus.28 A similar behavior during the cardiac cycle has been observed with the tricuspid anulus.2g Another source of error is the beat-to-beat variability in flow dynamics, especially in the right side, caused by respiration. Measurements of right ventricular filling dynamics were performed during apnea to minimize this error. To avoid underestimation of velocity by the Doppler technique caused by a significant angle of incidence, multiple windows were used to record the flow velocity at the tricuspid anulus, with measurements performed from the window providing the highest velocities. Nevertheless, it should be emphasized that the latter error predominantly affects absolute measurements of velocity or velocity integral and to a lesser degree the parameters derived as ratios of velocities or time-velocity inte-
Volume 124 Number 5
grals. As for measurement of right ventricular wall thickness, it is well known that this can be a difficult determination because of the proximity of the right ventricular wall to the transducer and because of the small thickness of the wall. In this study, we have attempted to optimize this measurement by adjusting the near gains to allow definition of right ventricular wall thickness. Possible mechanisms of altered right ventricular filling in systemic hypertension. The mechanism for
altered right ventricular filling dynamics in hypertensive patients is unclear. Although right ventricular pressure overload with elevated pulmonary artery pressure has been reported in systemic hypertension I2 the finding of normal acceleration time-toejeciion time ratios in the right ventricular outflow renders this mechanism less likely.16 Right and left ventricular filling dynamics were closely correlated in hypertensive patients and in normal individuals, suggesting the diastolic interdependence of the two ventricles through a shared interventricular septurnso. 31 or the presence of biventricular hypertrophy. The presence of right ventricular hypertrophy documented in this study and by previous investigators” and the correlation of right ventricular filling dynamics with right ventricular anterior wall thickness, albeit weak, suggest that alteration of right ventricular filling dynamics in uncomplicated systemic hypertension may be the result, at least in part, of right ventricular hypertrophy. The mechanism of right ventricular hypertrophy in systemic hypertension is unknown. Development of cardiac hypertrophy may be mediated by a variety of local and systemic factors. By far, the most important local factor mediating cardiac hypertrophy is pressure overload. Systemic factors have recently been recognized as important mediators of cardiac hypertrophy and include growth factors,32 protooncogenes,3”, 33 catecholamines,34> 35 and angiotension II.3”r 37 Experimental pressure overload may lead to the accumulation in the myocardium of peptide growth factors, which differentially and selectively activate fetal cardiac growth genes,38s 3g resulting in cardiac hypertrophy. Thus cardiac hypertrophy induced by left ventricular pressure overload may not theoretically be restricted to the left ventricle, since growth fact,ors or other trophic peptides may accumulate throughout the myocardium. Although this hypothesis was recently challenged by Cooper et a1.,40 the concept of biventricular hypertrophy in uncomplicated systemic hypertension is supported by our observations of increased right ventricular wall thickness in untreated hypertensive subjects and by the
Doppler RV and LV filling in hypertension
1319
similar findings of previous reports.” Additional studies are needed to further elucidate the mechanisms of altered right ventricular filling and right ventricular hypertrophy in systemic hypertension. The tance.
authors
thank
Ruth
Negron
for her expert
secretarial
assis-
REFERENCES
1. Rokey R, Kuo MC, Zoghbi WA, Limacher MC, Quinones MA. Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985;71:543-50. 2. Zoghbi WA, Habib G, Quinones MA. Doppler assessment of right ventricular filling in a normal population: comparison with left ventricular filling dynamics. Circulation 1990; 82:1316-24. 3. Spirit0 P, Maron BJ, Bonow RO. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Co11 Cardiol 1986;7:518-26. 4. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic functions: new insights from a combined hemodynamic and Doppler echocardioaranhic studv. J Am Co11 Cardiol 1988:12:426-40. 5. Friedman BJ,-Brinkovi-c N, Miles H, Shih WJ, Massoleni A, DeMaria AN. Assessment of left ventricular diastolic function: comparison of Doppler echocardiography and gated blood pool scintigraphy. J Am Co11 Cardiol 1986;8:1348-54. 6. Takenaka K, Dabestani A, Gardin JM, Russell D, Clark S, Allfie A, Henry WL. Left ventricular filling in hypertrophic cardiomyopathy: a pulsed Doppler echocardiographic study. J Am Co11 Cardiol 1986;7:1263-71. 7. Okamoto M, Kinoshita N, Miyatake K, Nagata S, Beppu S, Park YD, Pyon ZF, Sakakibara H, Nimura Y. Analysis of diastolic filling of the right ventricle in hypertrophic cardiomyopathy: a study with two-dimensional Doppler echocardiography. J Cardiography 1983;13:79-88. 8. Inouye I, Massie B, Loge D, et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120-6. 9. Fouad FM, Slominiski JM, Tarazi RC. Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function. J Am Co11 Cardiol 1984;3:1500-6. 10. Caruana M, Al-Khawaja I, Lahiri A, Lewis J, Raftery EB. Radionuclide measurements of diastolic function for assessing early left ventricular abnormalities in the hypertensive patient. Br Heart J 1988;59:218-26. 11. Nunez BD, Messerli FH, Amodco C, Garavaglia GE, Schneider RE, Frohlich ED. Biventricular cardiac hypertrophy in essential hypertension. AM HEART J 1987;114:813-7. 12. Olivari MT, Florentini C, Polese A, Guazzi MD. Pulmonary hemodynamics and right ventricular function in hypertension. Circulation 1978;57:1185-90. 13. Ferlinz J. Right ventricular performance in essential hypertension. Circulation 1980;61:156-62. 14. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-82. 15. Devereux RB, Alonsono DRD, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichete N. Echocardiographic assessment of left ventricular hypertrophy. Comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 16. Kitabatake A, Inoue M, Asao M, et al. Non-invasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983;68:302-9.
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17. Bowman LK, Lee FA, Jaffe CC, Mattera J, Wackers FJ, Zaret BL. Peak filling rate normalized to mitral stroke volume. A new Doppler echocardiographic filling index validated by radionuclide angiographic techniques. J Am Co11 Cardiol 1988;12:937-43. 18. Snedecor GW, Cochran WG. Multiple linear regression. In: Statistical methods. 7th ed. Ames: Iowa State Universitv Press, 1980:334-61. 19. Fuji J, Yazaki Y, Hitoshi S, Tadanori A, Watanabe H, Kato K. Noninvasive assessment of left and right ventricular filling in myocardial infarction with a two-dimensional Doppler echocardiographic method. J Am Co11Cardiol1985;5:1155-60. 20. Isobe M, Yaraki Y, Takaku F, Hara K, Kashida M, Yamajuchi T, Machii K. Right ventricular filling detected by pulsed wave Doppler echocardiography during the convalescent stage of inferior wall acute myocardial infarction. Am J Cardiol 1987:59:1245-50. 21. Riggs TW, Rodriguez R, Snider AR, Batton D, Pollock J, Sharu EJ. Dounler echocardioaanhic evaluation of rieht and left ventricular diastolic function in normal neonate: J Am Co11 Cardiol 1989;13:700-5. 22. Choong CY, Abascal VM, Thomas JD, Guerro JL, McGlew S, Weyman AE. Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 1988; 78672-83. 23. Chakko S, de Marchena E, Kessler KM, Materson BJ, Myerburg RJ. Right ventricular diastolic function in systemic hypertension. Am J Cardiol 1990;65:1117-20. 24. Kuo LC, Quinones MA, Rokey R, &tori M, Abinader EG, Zoghbi WA. Quantification of atrial contribution to left ventricular filling by pulsed Doppler echocardiography and the effect of age in normal and diseased hearts. Am J Cardiol 1987;59:1174-8. 25. Sartori MP, Quinones MA, Kuo LC. Relation of Doppler derived left ventricular filling parameters to age and radius/ thickness ratio in normal and pathologic states. Am J Cardiol 1987;59:1179-82. 26. Szlachcic J, Tubau JF, O’Kelly B, Massie BM. Diastolic abnormalities in hypertension are not explained by LVH alone [Abstract]. J Am Co11 Cardiol 1989;13:59A. 27. Cooper JW, Awad MM, Shah VK, Chopra HK, Daruwala D, Nanda NC. Are Doppler indices of diastolic filling affected by left ventricular hypertrophy? [Abstract]. J Am Co11 Cardiol 1989;13:209A.
American
1992
Heart Journal
28. Ormiston JA, Shah PM, Tei C, Wong M. Size and motion (11 the mitral valve annulus in man. I. A two-dimensional echocardiographic method and findings in normal subjects. Circulation 1981;64:113-20. 29. Tei C, Pilgrim JP, Shah PM, Ormiston JA, Wong MW. The tricuspid valve annulus: study of size and motion in normal subjects and in patients with tricuspid regurgitation. Circulation 1982;66:665-71. 30. Bove A, Santamore W. Ventricular interdependence. Prog Cardiovasc Dis 1981;23:365-87. 31. Weber KT, Janicki JS, Shroff LS, Fishman AP. Contractile mechanisms and interaction of the right and left ventricles. Am J Cardiol 1981;41:686-95. 32. Izumo S, Nadal-Ginard B, Mahdavi V. Proto-oncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Nat1 Acad Sci USA 1988;85:339-43. 33. Komuro M, Kurabyashi M, Takaku F, Yazaki Y. Expression of cellular oncogenes in the myocardium during the developmental stage and pressure-overload hypertrophy of the rat heart. Circ Res 1988;62:1075-9. 34. Strauer BE, Bayer F, Brecht HM, Motz W. The influence of sympathetic nervous activity on regression of cardiac hypertrophy. J Hypertens 1985;3(suppl4):S39-44. 35. Ganguly PK, Lee SL, Beamish RE, Dhalla NS. Altered sympathetic system and adrenoceptors during the development of cardiac hypertrophy. AM HEART J 1989;118:520-5. 36. Baker KM, Chernin MI, Wixson SK, Aceto JF. Reninangiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am J Physiol 1990;259:H324-32. 37. Linz W, Scholkens BA, Ganten D. Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats. Clin Exp Hypertens 1989;11:1325-50. 38. Schwartz K, de la Bastie D, Bouveret P, Oliviero P, Alonso S, Buckingham M. L-skeletal muscle actin mRNAs accumulate in hypertrophied adult rat hearts. Circ Res 1986;59:551-5. 39. Parker TG, Packer SE, Schneider MD. Peptide growth factors can provoke “fetal” contractile protein gene expression in rat cardiac myocytes. J Clin Invest 1990;85:507-14. 40. Cooper G, Kent RL, Uboh CE, Thompson EW, Marino TA. Hemodynamic versus adrenergic control of cat right ventricular hypertrophy. J Clin Invest 1985;75:1403-14.
Determinants
5
40. Thomas JD, Wilkins GT, Choong CY, Abascal VM, Palacios IF, Block PC, Weyman AE. Inaccuracy of the mitral pressure half-time immediately following percutaneous mitral valvotomy: dependence on transmitral gradient and left atria1 and ventricular compliance. Circulation 1988;78:980-93. 41. Lavine SJ, Campbell CA, Kloner RA, Gunther SJ. Diastolic filling in acute left ventricular dysfunction: role of the pericardium. J Am Co11Cardiol 1988;12:1326-33. 42. Thomas JD, Weyman AE. Echocardiographic Doppler evaluation of left ventricular diastolic function: physics and physiology. Circulation 1991;977-90.
of
ventricular
relaxation
43. Sabbah HN, Stein PD. Proposed mechanism for depression of maximal rate of left ventricular pressure fall (peak negative dP/dt) during regional myocardial ischemia. Cathet Cardiovast Diagn 1986;12:182-8. 44. Rubenstein JJ, Pohost GM, Dinsmore RE, Harthorne JW. The echocardiographic determination of mitral valve opening and closure: correlation with hemodynamic studies in man. Circulation 1975;51:98-103.
Doppler assessment of right ventricular dynamics in systemic hypertension: Comparison with left ventricular filling
filling
To assess right ventricular filling dynamics in systemic hypertension, pulsed Doppler echocardiographic studies were obtained at the tricuspid and mitral anuli in 43 untreated hypertensive patients, aged 23 to 66 years, and in 42 age-matched normotensive control subjects. In hypertensive patients, the ratio of late to early peak filling velocity and atrial filling fraction were higher, while normalized peak filling rate, one third and one half filling fractions were lower, compared with control values. Right ventricular filling dynamics correlated poorly with age in hypertensive patients, and were unrelated to left ventricular mass or left ventricular wall thickness. Weak correlations were only found between right ventricular wall thickness and right ventricular peak late inflow velocity, first half and first third filling fractions. However, right ventricular filling dynamics were closely related to left ventricular filling dynamics in both hypertensive patients (r = 0.49 to 0.82) and normal individuals (r = 0.55 to 0.86). Thus right ventricular filling dynamics are altered in hypertension, independently of left ventricular mass or blood pressure, are weakly related to right ventricular thickness, but remain closely correlated to left ventricular filling dynamics. (AM HEART J 1992;124:1313.)
Gabriel B. Habib, MD, and William
A. Zoghbi, MD Houston,
Doppler echocardiography has recently provided assessment of right and left ventricular filling dynamics.le5 Parameters of right and left ventricular filling From the Section of Cardiology, Department of Medicine, Baylor College of Medicine, The Methodist Hospital Echocardiography Laboratory, and Veterans Affairs Medical Center. Computational assistance was provided by the CLINFO Project, funded by Grant RR-00350 tutes of Health, Received Reprint College
from the Division Bethesda, Md.
for publication
Nov.
of Research
21, 1991; accepted
Resources, May
National
Insti-
15, 1992.
requests: William A. Zoghbi, MD, Section of Cardiology, Baylor of Medicine, 6535 Fannin, M.S. F-905, Houston, TX 77030.
411140553
Texas
have been shown to be impaired in patients with hypertrophic cardiomyopathy.6l 7 In systemic hypertension, left ventricular filling dynamics have been reported to be abnormal in the presence or absence of left ventricular hypertrophy.s-10 The effects of systemic hypertension on right ventricular function are not well understood. Right ventricular hypertrophy, elevated right-sided pressures, and impaired right ventricular systolic function have been reported in patients with systemic hypertension.l’-l3 Whether right ventricular filling dynamics are altered in hypertensive patients is presently not known. The present study was therefore designed to compare
1313
November
1314
Habib and Zoghbi
right and left ventricular filling dynamics in hypertensive patients with those of age-matched normotensive subjects, and to determine whether these changes are related to age, heart rate, blood pressure, or left ventricular mass. METHODS Patient population.
The population consisted of 43 patients (24 men and 19 women) with essential hypertension (diastolic blood pressure > 90 mm Hg) for 1 to 20 years who previously received P-blockers, thiazide diuretics, sympatholytic drugs, or angiotensin-converting enzyme inhibitors but had discontinued therapy at least 8 weeks before study participation. Age ranged between 23 and 66 years (43 + 12 years). None had clinical, electrocardiographic, two-dimensional, or Doppler echocardiographic evidence of coronary or valvular heart disease, congestive heart failure, atria1 fibrillation or flutter, atrioventricular block, pulmonary disease, insulin-dependent diabetes mellitus, or renal insufficiency (serum creatinine > 2 mg/dl). Hypertensive patients were age-matched with 42 asymptomatic and apparently healthy subjects who satisfied the aforementioned exclusion criteria. Normotensive subjects were selected among healthy volunteers such that the number of normotensive subjects was almost identical to the number of hypertensive patients in each decade of life between 20 and 70 years. The age of normotensive subjects ranged between 21 and 66 years (43 t 12 years). Normotensive controls had a sitting blood pressure less than X0/90 mm Hg and a normal physical examination, electrocardiogram, and M-mode, two-dimensional, and Doppler echocardiographic studies. Normotensive and hypertensive patients sat still for 30 minutes before vital signs were measured. Blood pressure was obtained by the same examiner using a calibrated cuff sphygmomanometer. Blood pressure was measured twice at 3-minute intervals with the patient in the sitting position for at least 30 minutes. Participation in this study was voluntary and a written informed consent was obtained from each entrant. The study protocol was approved by the Institutional Review Board of Baylor College of Medicine and by the Veterans Affairs Medical Center. Echocardiographic and Doppler studies. Two-dimensional and Doppler echocardiographic studies were performed using a Hewlett-Packard ultrasound system (No. 77020AC, Hewlett-Packard Co., Medical Products Group, Andover, Mass.) equipped with 3.5 or 2.5 MHz transducers and recorded on Yz-inch videotape. Echocardiographic images were obtained from the parasternal and apical windows with the patient in the left lateral recumbent position. Complete M-mode, two-dimensional, and pulse-wave Doppler echocardiographic studies were obtained. All individuals had adequate quality studies for quantitation. M-mode echocardiographic measurements were made according to the guidelines of the American Society of Echocardiography.‘* Left ventricular mass was calculated by the Penn-cube method described by Devereux et a1.15Right ventricular diastolic wall thickness was measured from high-quality M-mode recordings; particular care was taken
American
1992
Heart Journal
to optimize the near gain settings to enhance the definition of the right ventricular anterior wall.” For measurements of ventricular filling dynamics, pulsed Doppler studies were performed using the parasternal and apical windows. Recordings of inflow velocity were obtained at the level of the tricuspid and mitral anuli during quiet and shallow breathing, as previously described.2 Furthermore, since right ventricular filling is significantly affected by respiration,2 all measurements of right ventricular filling dynamics were also obtained during end-tidal apnea. Right ventricular inflow velocity was recorded from the short-axis, low parasternal, and apical four-chamber views. Right ventricular filling dynamics were determined from the window providing the highest velocity recordings at the tricuspid anulus, thus implying the least Doppler angle with flow. This echocardiographic window was the low parasternal view in 75 “0 of the cases. Left ventricular inflow velocity was recorded from the apical four-chamber view, as previously described. ‘3’ No angle correction between the Doppler ultrasound beam and the presumed flow direction was performed for determination of left or right ventricular filling parameters. All Doppler recordings were performed at a sweep speed of 100 mm/set. To assess whether pulmonary artery pressure was similar in the hypertensive patients and control subjects, pulsed Doppler recordings in the right ventricular outflow tract were performed from the short-axis window. The ratio of right ventricular acceleration time to ejection time, an index of pulmonary artery pressure, was determined as described by Kitabatake et a1.16 Doppler-derived
parameters
of
ventricular
filling.
Echocardiographic and Doppler measurements were performed using an off-line computer analysis station (EC500, Digisonics, Inc., Houston, Texas) equipped with a digitizing pad and internal calipers and interfaced with the video signal. All measurements were performed by an observer blinded to all clinical data. The Doppler velocity tracings at the tricuspid and mitral valve anuli were digitized using the contour of the darkest portion of the spectral display, and the following parameters were computergenerated, as previously described in detail”: peak early inflow velocity (E) in cm/set; peak late inflow velocity (A) in cm/set; A/E ratio; the time-velocity integral of diastolic inflow velocity; first half filling fraction ( % FF); first third filling fraction (‘4 FF); and atria1 filling fraction (AFF). Furthermore, peak filling rate normalized to stroke volume (NPFR) was derived as defined by Bowman et al.” This was obtained by dividing peak early filling velocity by t.he total time-velocity integral, and is expressed as stroke volume per second (SV/sec). To minimize the effect of respiration on ventricular filling dynamics, Doppler measure-ments were obtained from 7 to 10 consecutive cardiac cycles and were averaged.2 Moreover, right ventricular filling dynamics were obtained during end-tidal apnea in all patients. Statistical analysis. Results were expressed as mean + standard deviation, except as indicated. Comparisons of Doppler measurements in hypertensive patients with those of normotensive controls was performed using
Volume 124 Number 5
Table
Doppler
RV and LVfilling
in
hypertension
1315
I. Clinical and echocardiographic characteristics of normals and hypertensive patients Normals
Age (yr)
Hypertensives
43 k 12 (21-66) 2222 121 k 11 (90-140) 78 + 8 (60-90) 93 k 8 (70-107) 69 f 10 (43-96) 0.7 i- 0.1 (0.5-1.2) 1.1 + 0.1 (0.7-1.5) 0.5 k 0.1 (0.4-0.8) 106 + 35 (55-189) 149 t 26 (108-197) 327 AZ35 (226-387) 0.5 k 0.1 (0.3-0.6)
Sex (M:F) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Heart rate (beats/min) Posterior wall thickness (cm) Septal wall thickness (cm) Right ventricular wall thickness (cm) Left ventricular mass index (gm/m2) AT (msec) ET (msec) AT/ET
43 k 12 (23-66) 24:19 150 + 21* (110-190) 100 + 16* (90-134) 116 k 16* (100-146) 72 k 12 (51-96) 1.1 + 0.2* (0.8-1.9) 1.6 2 0.2* (1.2-1.9) 0.8 F 0.2* (0.6-1.2) 161 * 37* (126-256) 153 + 23 (110-212) 332 t 33 (258-389) 0.5 k 0.1 (0.3-0.6)
Values are expressed as mean t standard deviation, followed by range. AT, Acceleration
time; ET, ejection time. Both AT and ET are measured *p < 0.01 hypertensives versus normals.
Table
II. Doppler-derived
parameters
of right
in the right ventricular
outflow
tract.
and left ventricular filling in hypertensive and normal subjects
Right ventricle Normals
Left ventricle Normals
Hypertensiues
Hypertensives
-~
TV1 (cm) E (cm/src) A (cm/set) A/E ‘5 FF (‘;) I,:, FF ( “0 ) NPFR (S/see) AFF (“Cl DT (msec)
12 44 37 0.9 62 50 3.9 24 142
2~ 2 + 9 i
11
* t + k + +
0.3 10 10 0.8 9 39
12 42 43 1.0 56 43 3.5 38 179
AC3 t 1
+ 16 t 0.3t I 9t r lot
+ 0.6t t 13t f 43*
13 55 48 0.9 63 54 4.2 25 137
t 2 t
11
+ 13 k 0.4 i 9 + 11
i 0.8 I+ 8 + 27
14 52 54 1.1 54 43 3.8 39 190
* 4 2 20* 5 16 f 0.4t f lot AZ12t -t 0.8* * 12t t 56t
All values are expressed as mean ? standard deviation. A, Peak late filling velocity; DT, deceleration time; E, peak early filling velocity; HR, heart rate; NPFR, peak filling rate normalized to stroke stroke volume; TVI, time-velocity integral; !+ FF’, first half filling fraction: 5 I?‘, first third filling fraction: AFF, atria1 filling fraction. *O.Ol < p < 0.05 hypertensives versus normals. tp 5 0.01 hyprrtensives versus normals.
Student’s t testI for unpaired observations if the observations had a normal distribution. Nonparametric statistical analysis using the Wilcoxon rank sum test was used for comparison between groups that did not pass standard tests of normality.
Correlations
between
parameters
of
ventricular filling, age, left ventricular mass, wall thickness, and blood pressure were performed using univariate linear regression analysis. In view of the multiple comparisons between clinical and echocardiographic characteristics of hypertensive and normotensive subjects, statistical significance was set at a p value I 0.01. RESULTS Comparison of Doppler filling dynamics in normals versus hypertensive patients. Table I shows the clini-
cal and echocardiographic characteristics of normal individuals and hypertensive patients. Among 43 hypertensive patients, 30 had mild, eight had mod-
volume;
SV,
erate, and five had severe essential hypertension, defined as sitting diastolic blood pressures of 90 to 105, 106 to 120, and I 121 mm Hg, respectively. Blood pressure (systolic, diastolic, and mean), left ventricular mass index, left ventricular posterior wall thickness, septal wall thickness, and right ventricular anterior wall thickness were higher in hypertensives than in age-matched normal subjects. Heart rate was almost identical in both groups and did not change during the echocardiographic examination. Acceleration time in the right ventricular outflow tract, right ventricular ejection time, and their respective ratio were similar in normal and in hypertensive subjects. Doppler-derived filling parameters are shown in Table II. Compared with normotensive controls, right and left ventricular filling dynamics in hypertensive patients were characterized by decreased
November
1316
Habib and Zoghbi
American
1992
Hearl Journal
Fig. 1. Examples of pulsed Doppler recordings of right ventricular inflow and left ventricular inflow in a normal individual and in an age-matched hypertensive patient (age 28 years). Peak early filling (E) and peak late filling (A) are shown. Note the reduced early filling in the hypertensive patient, with an increased atria1 contribution to filling in both right and left ventricular inflow compared with the normal subject.
Table III. Correlations between parameters of right and left ventricular filling in normal and hypertensive subjects Normal Parameter
E (cm/set) A (cm/set) A/E ‘h FF (%) !/3 FF(%) NPFR (SV/sec) AFF (7;) r, Correlation All correlation
subjects r
Hypertensiue subjects r
0.63 0.63 0.86 0.61 0.66
0.54 0.68 0.56 0.59 0.68
0.55
0.49
0.66
0.82
coefficient; other abbreviations as defined coefficients were significant (p 5 0.01).
in Table
II.
early filling, as assessed by reduced first half and first third filling fractions, and normalized peak filling rate and prolonged deceleration time. An augmentation of the atria1 contribution to ventricular filling was manifested by an increase in atria1 filling fraction. The A/E ratios at the tricuspid and mitral anuli were also higher in hypertensive patients. An example of the changes observed in right and left ventricular filling in hypertension compared with normal blood pressure is shown in Fig. 1. Comparison of right and left ventricular filling dynamics. Table III shows the results of the univariate lin-
ear regression analysis between right and left ven-
tricular filling dynamics of normal and hypertensive subjects. Significant correlations were observed between parameters of right and left ventricular filling in both hypertensive patients (r range, 0.49 to 0.82) and normal subjects (r range, 0.55 to 0.86). Relation of ventricular filling dynamics to age. Table IV shows the results of the correlations between Doppler-derived filling parameters and age in normal and hypertensive patients. In normal subjects, and as previously reported,’ age was an important determinant of Doppler filling parameters of the right and left ventricles. Age was inversely related to parameters of early filling (E, ‘/iLFF, $5 FF, and NPFR) and was directly related to late ventricular filling parameters of both ventricles (AFF and A). Correlation coefficients ranged from -0.46 to 0.82 (p < 0.001) for the right ventricle, and from -0.40 to 0.81 (p < 0.009) for the left ventricle. In contrast, in hypertensive patients, the correlations of Doppler filling parameters with age decreased significantly for both right and left ventricles. No relation was observed between right ventricular filling parameters and age, except for a weak relation with atria1 filling fraction and the A/E ratio. As for left ventricular filling parameters, hypertensive patients had lower correlation coefficients between age and Doppler filling indices compared with those observed in the normal population.
Volume 124 Number
Table
Doppler
5
IV. Correlations
between
ventricular
filling
dynamics,
RV and LVfilling
age, and heart rate in normals
Right ventricle Hypertensives
Normals
E A
A/E ‘4 FF ‘~3 FF NPFR AFF
Left
Hypertensives
HR
Age
HR
A.@
HR
Age
HR
-0.61 0.60 0.82 -0.63 -0.46 -0.54 0.72
NS NS 0.49 -0.50 -0.57 NS NS
NS NS 0.38 NS NS NS 0.40
NS NS NS -0.47 -0.55 NS NS
-0.66 0.57 0.81 -0.66 -0.40 -0.73 0.73
-0.36 0.47 0.49 -0.54 -0.61 NS NS
-0.40 0.31 0.65 -0.49 -0.28 -0.53 0.64
NS NS NS -0.41 -0.45 NS NS
hypertension on ventricular filling dynamics were different in younger versus older patients, we calculated paired differences in filling parameters between hypertensive patients and age-matched normotensive subjects. Paired differences among patients younger than 45 years were compared with those of older individuals. Among 43 hypertensive patients, 25 were less than 45 years of age; among 42 normotensive subjects, 26 were less than 45 years of age. Greater alterations in right ventricular filling dynamics were observed in the younger compared with the older individuals. Respective paired differences in younger versus older subjects for the various parameters were as follows (all p < 0.05)-A/E: 0.29 t- 0.44 versus 0.02 * 0.31; C/2FF: 9 I~I 14% versus 0 -+ 8% ; l/3 FF: 11 + 16% versus 0 + 10% ; NPFR: 0.7 + 1 SV/sec versus 0.01 f 0.5 SV/sec. In contrast, the alterations in left ventricular filling parameters with hypertension were similar in the younger and older age groups. Relation of filling dynamics to heart rate. In the normal subjects, and as previously demonstrated,2 heart rate was a weaker determinant of Doppler filling parameters when compared with age (Table IV). The highest correlations were observed with first half and first third filling fraction for both the right and left ventricles (r range, -0.50 to -0.61). In hypertensive patients, heart rate remained an important determihalf
ventricle
Age
Effect of hypertension on filling dynamics in younger versus older patients. To assess whether the effects of
of first
1317
and hypertensives
Normals
Values represent sigmficant correlation coefficients (p < 0.01) of the univariate regression analysis in normal and hypertensive subjects. HR. Heart rate; NS, correlation not statistically significant; other abbreviations as in Table II.
nant
in hypertension
and first
third
filling
fraction
only,
for both ventricles. Relation between filling dynamics and left ventricular mass, left and right ventricular wall thickness, and blood pressure. Univariate linear regression analysis be-
tween right. or left ventricular
filling parameters
and
of ventricular
filling parameters
versus age and heart
rate
left ventricular mass, left ventricular posterior wall thickness, and septal wall thickness showed no significant correlations, except for a weak correlation between left ventricular first third filling fraction and posterior or septal wall thickness (r = -0.47,~ = 0.04, and r = -0.49, p = 0.03, respectively). A weak correlation was also found between right ventricular anterior wall thickness and right ventricular peak late inflow velocity, one half and one third filling fraction (r = 0.39, -0.41, and -0.40, respectively; p = 0.03 to 0.04), but not with any other filling parameters. No correlation was found between right or left ventricular filling dynamics and systolic, diastolic, or mean blood pressure. DISCUSSION
This study demonstrates that Doppler-derived parameters of right ventricular filling dynamics are altered in hypertensive patients compared with ageand heart rate-matched controls. The changes in right ventricular filling dynamics with hypertension alter the usual relation of age with parameters of diastolic filling and are more pronounced in younger individuals. Doppler echocardiographic tricular diastolic function.
evaluation
of right
ven-
Validation of Doppler-derived left ventricular filling parameters has been accomplished by comparison with cineangiography,’ hemodynamic techniques,* and radionuclide angiography.3, 5 Although right ventricular geometry has hampered evaluation of right ventricular function for many years, Doppler echocardiography has recently allowed the assessment of right ventricular filling. Abnormalities of right ventricular diastolic filling have been described in hypertrophic cardiomyopathy, in coronary artery disease involving the right
1318
Habib
and Zoghbi
American
ventricular branch, and in patients with inferior myocardial infarction.lg$ 2o Doppler-derived right ventricular filling dynamics have not, until recently, been well characterized in a normal population.‘, “I We2 have recently demonstrated the dependence of Doppler parameters of right ventricular filling on age, heart rate, and respiration in a normal adult population. The present study was specifically designed to evaluate right ventricular filling dynamics in hypertensive patients by controlling for these potential confounding variables. Matching for age was achieved by random selection of an equal number of hypertensive and normotensive subjects in each decade of age. Heart rates were almost identical in both groups. Finally, right ventricular Doppler recordings were performed at end-tidal apnea to minimize the effects of respiration on filling dynamics. Compared with normal individuals, hypertensive patients had diminished early filling, as assessed by normalized peak filling rate, first third and first half filling fraction, and deceleration time, with a compensatory increase in the atria1 contribution to filling. This Doppler pattern of inflow velocity has recently been associated with impaired ventricular relaxation.“, ‘” Right ventricular performance in systemic sion. In a study evaluating right ventricular
hyperten-
function in patients with uncomplicated essential hypertension, Ferlinzi” observed that right atria1 and right ventricular end-diastolic pressures were higher, and right ventricular ejection fraction was lower compared with those of normal control subjects. Right ventricular hypertrophy, previously reported in patients with essential hypertension using M-mode echocardiography,” was confirmed in the present study. Although abnormalities of diastolic function and filling parameters have been well described for the left ventricle in hypertension,s-10 there is a paucity of data regarding right ventricular diastolic function in systemic hypertension. Recently, Chakko et a1.23reported alterations in right ventricular filling parameters in 32 patients with mild untreated hypertension compared with 10 normal controls. Patients with moderate or severe hypertension and women were excluded; Doppler recordings of tricuspid flow velocities were analyzed without consideration of the effects of respiration, and the potential effect of heart rate on filling dynamics was not evaluated. The present study specifically addresses these limitations and further substantiates the findings of altered right ventricular filling in systemic hypertension compared with the findings in age-matched and heart rate-matched controls. With increasing age in a normal population, a pro-
November 1992 Heart Journal
gressive decrease in early right and left ventricular filling occurs, with a compensatory increase in late filling,“, 24,25 and this is compatible with delayed ventricular relaxation. 4*22 In this study, systemic hypertension altered the accepted relation of age with ventricular filling dynamics. Right ventricular filling parameters were, for the most part, no longer related to age. However, alterations in right ventricular filling were more pronounced in the younger hypertensive patients. As for the left ventricle, the correlations of filling parameters with age were weaker in the hypertensive group compared with the controls, but remained statistically significant. These findings are compatible with those of previous reportsZ4, E showing that the effect of age on left ventricular filling is attenuated in the presence of left ventricular disease. In hypertensive patients, heart rate did not alter any filling parameter except for first half and first third filling fractions, which were weakly related to heart, rate. As reported for the left ventricle26, 27 and more recently for the right ventricle,“” changes in filling dynamics observed with hypertension related poorly to left ventricular mass, wall thickness, and blood pressure. Advantages and limitations of this study. Doppler echocardiography allows the noninvasive evaluation of ventricular filling dynamics. This method is especially useful in evaluating right ventricular filling, because M-mode and two-dimensional echocardiography are both limited in this regard and because gated radionuclide angiography has difficulties separating the right atrium from the right ventricle. However, several limitations and sources of error are present with the Doppler technique. The crosssectional area of the valve anulus changes during diastole and has been found to increase by approximately 12 “; from the onset to the end of diastole for the mitral anulus.28 A similar behavior during the cardiac cycle has been observed with the tricuspid anulus.2g Another source of error is the beat-to-beat variability in flow dynamics, especially in the right side, caused by respiration. Measurements of right ventricular filling dynamics were performed during apnea to minimize this error. To avoid underestimation of velocity by the Doppler technique caused by a significant angle of incidence, multiple windows were used to record the flow velocity at the tricuspid anulus, with measurements performed from the window providing the highest velocities. Nevertheless, it should be emphasized that the latter error predominantly affects absolute measurements of velocity or velocity integral and to a lesser degree the parameters derived as ratios of velocities or time-velocity inte-
Volume 124 Number 5
grals. As for measurement of right ventricular wall thickness, it is well known that this can be a difficult determination because of the proximity of the right ventricular wall to the transducer and because of the small thickness of the wall. In this study, we have attempted to optimize this measurement by adjusting the near gains to allow definition of right ventricular wall thickness. Possible mechanisms of altered right ventricular filling in systemic hypertension. The mechanism for
altered right ventricular filling dynamics in hypertensive patients is unclear. Although right ventricular pressure overload with elevated pulmonary artery pressure has been reported in systemic hypertension I2 the finding of normal acceleration time-toejeciion time ratios in the right ventricular outflow renders this mechanism less likely.16 Right and left ventricular filling dynamics were closely correlated in hypertensive patients and in normal individuals, suggesting the diastolic interdependence of the two ventricles through a shared interventricular septurnso. 31 or the presence of biventricular hypertrophy. The presence of right ventricular hypertrophy documented in this study and by previous investigators” and the correlation of right ventricular filling dynamics with right ventricular anterior wall thickness, albeit weak, suggest that alteration of right ventricular filling dynamics in uncomplicated systemic hypertension may be the result, at least in part, of right ventricular hypertrophy. The mechanism of right ventricular hypertrophy in systemic hypertension is unknown. Development of cardiac hypertrophy may be mediated by a variety of local and systemic factors. By far, the most important local factor mediating cardiac hypertrophy is pressure overload. Systemic factors have recently been recognized as important mediators of cardiac hypertrophy and include growth factors,32 protooncogenes,3”, 33 catecholamines,34> 35 and angiotension II.3”r 37 Experimental pressure overload may lead to the accumulation in the myocardium of peptide growth factors, which differentially and selectively activate fetal cardiac growth genes,38s 3g resulting in cardiac hypertrophy. Thus cardiac hypertrophy induced by left ventricular pressure overload may not theoretically be restricted to the left ventricle, since growth fact,ors or other trophic peptides may accumulate throughout the myocardium. Although this hypothesis was recently challenged by Cooper et a1.,40 the concept of biventricular hypertrophy in uncomplicated systemic hypertension is supported by our observations of increased right ventricular wall thickness in untreated hypertensive subjects and by the
Doppler RV and LV filling in hypertension
1319
similar findings of previous reports.” Additional studies are needed to further elucidate the mechanisms of altered right ventricular filling and right ventricular hypertrophy in systemic hypertension. The tance.
authors
thank
Ruth
Negron
for her expert
secretarial
assis-
REFERENCES
1. Rokey R, Kuo MC, Zoghbi WA, Limacher MC, Quinones MA. Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985;71:543-50. 2. Zoghbi WA, Habib G, Quinones MA. Doppler assessment of right ventricular filling in a normal population: comparison with left ventricular filling dynamics. Circulation 1990; 82:1316-24. 3. Spirit0 P, Maron BJ, Bonow RO. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Co11 Cardiol 1986;7:518-26. 4. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic functions: new insights from a combined hemodynamic and Doppler echocardioaranhic studv. J Am Co11 Cardiol 1988:12:426-40. 5. Friedman BJ,-Brinkovi-c N, Miles H, Shih WJ, Massoleni A, DeMaria AN. Assessment of left ventricular diastolic function: comparison of Doppler echocardiography and gated blood pool scintigraphy. J Am Co11 Cardiol 1986;8:1348-54. 6. Takenaka K, Dabestani A, Gardin JM, Russell D, Clark S, Allfie A, Henry WL. Left ventricular filling in hypertrophic cardiomyopathy: a pulsed Doppler echocardiographic study. J Am Co11 Cardiol 1986;7:1263-71. 7. Okamoto M, Kinoshita N, Miyatake K, Nagata S, Beppu S, Park YD, Pyon ZF, Sakakibara H, Nimura Y. Analysis of diastolic filling of the right ventricle in hypertrophic cardiomyopathy: a study with two-dimensional Doppler echocardiography. J Cardiography 1983;13:79-88. 8. Inouye I, Massie B, Loge D, et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120-6. 9. Fouad FM, Slominiski JM, Tarazi RC. Left ventricular diastolic function in hypertension: relation to left ventricular mass and systolic function. J Am Co11 Cardiol 1984;3:1500-6. 10. Caruana M, Al-Khawaja I, Lahiri A, Lewis J, Raftery EB. Radionuclide measurements of diastolic function for assessing early left ventricular abnormalities in the hypertensive patient. Br Heart J 1988;59:218-26. 11. Nunez BD, Messerli FH, Amodco C, Garavaglia GE, Schneider RE, Frohlich ED. Biventricular cardiac hypertrophy in essential hypertension. AM HEART J 1987;114:813-7. 12. Olivari MT, Florentini C, Polese A, Guazzi MD. Pulmonary hemodynamics and right ventricular function in hypertension. Circulation 1978;57:1185-90. 13. Ferlinz J. Right ventricular performance in essential hypertension. Circulation 1980;61:156-62. 14. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-82. 15. Devereux RB, Alonsono DRD, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichete N. Echocardiographic assessment of left ventricular hypertrophy. Comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 16. Kitabatake A, Inoue M, Asao M, et al. Non-invasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983;68:302-9.
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