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Relationship Between Left Ventricular Diastolic Function and Atrial Natriuretic Factor in Never-Treated Mild Hypertensives
AJH
1997;10:946 –950
Relationship Between Left Ventricular Diastolic Function and Atrial Natriuretic Factor in Never-Treated Mild Hypertensives Anna Maria Grandi, Paolo Zanzi, Luca Ceriani, Giovanni Gaudio, Andrea Bertolini, Luca Giovanella, Luigina Guasti, Giuseppina Roncari, and Achille Venco
Using digitized M-mode echocardiograms, we evaluated the relationship between plasma atrial natriuretic factor (ANF) and morphofunctional characteristics of the left ventricle (LV) in 24 mild hypertensive men, never treated, with normal renal function. For each subject we collected a blood sample for plasma ANF evaluation and, immediately after, we recorded the LV echocardiogram. All the patients had normal LV diastolic diameter and systolic function; LV hypertrophy was present in 10 patients, 7 of whom had left atrial enlargement, and 13 patients had impaired LV diastolic function. ANF was similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement, whereas ANF was significantly (P < .01) higher in patients with LV diastolic dysfunction than in patients with normal diastolic function. ANF was inversely correlated
with both indices of diastolic function (peak lengthening rate and peak wall thinning rate), whereas it did not correlate with blood pressure, heart rate, end-systolic wall stress, and other LV parameters. In conclusion, from our results, ANF level in never-treated mild hypertensives is related neither to the degree of LV hypertrophy nor to the afterload, expressed as blood pressure or endsystolic wall stress, whereas it is mainly influenced by LV diastolic function: the diastolic impairment induces an increase in ANF level, probably through an increased atrial stretch. Am J Hypertens 1997;10:946 –950 © 1997 American Journal of Hypertension, Ltd.
A
regulation, a role of ANF in the pathophysiology of essential hypertension has been hypothesized, but until now this role has been controversial and is still under investigation.3,4 Several reports showed increased levels of plasma ANF in hypertensives,5–9 whereas others did not10 –12: now there appears to be general agreement that severe hypertension is associated with increased plasma ANF, whereas in patients with mild or moderate and uncomplicated hyperten13 sion the data are contradictory. Despite the fact that some have found significant correlations between plasma ANF levels and blood pressure values,5,7,8,14 –16 a recent study on a very large popu-
trial natriuretic factor (ANF) is a polypeptide secreted from the atria, with natriuretic and vasodilatory actions, which can also inhibit the renin-angiotensin-aldosterone axis.1,2 Because of these actions on blood pressure
Received September 3, 1996. Accepted February 4, 1997. From the Department of Clinical and Biological Sciences (AMG, PZ, GG, AB, LGu, AV), II Faculty of Medicine, University of Pavia, Varese, Italy, and the Department of Nuclear Medicine, Ospedale di Circolo, Varese, Italy (LC, LGi, GR). Address correspondence and reprint requests to Anna Maria Grandi, via Bagaini 15, 21100 Varese, Italy.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Atrial natriuretic factor, essential hypertension, diastolic function, myocardial hypertrophy.
0895-7061/97/$17.00 PII S0895-7061(97)00124-6
AJH–AUGUST 1997–VOL. 10, NO. 8
ATRIAL NATRIURETIC FACTOR AND DIASTOLIC FUNCTION
lation failed to show any correlation.17 Considering that ANF is secreted primarily in response to stimuli that enhance atrial wall stretch,18 factors other than blood pressure may influence plasma ANF release in hypertension. These include duration of hypertension, increase in venous return, left ventricular hypertrophy, as well as systolic or diastolic dysfunction.8,15,16,19,20,23 These studies provided controversial results, probably related to differences in the population studied as regards age, degree of hypertension, presence of end organ damage, dietary sodium intake, previous antihypertensive treatment, and differences in the methods employed, for instance, in evaluating LV hypertrophy by means of ECG criteria, cardiothoracic ratio, or echocardiography. Therefore we considered it of interest to evaluate the relationship between plasma ANF level and the morphofunctional characteristics of the left ventricle (LV) in a group of mild hypertensive men, never treated, with normal renal function and within a narrow range of age. PATIENTS AND METHODS Patients We evaluated 24 men (mean age 41 6 3 years) who had mild essential hypertension (diastolic blood pressure between 95 and 105 mm Hg in at least four measurements taken in different days). The patients have been selected following these criteria: no previous antihypertensive treatment, left ventricular echocardiogram of good quality, normal renal function (plasma creatinine ,1.1 mg/dL; creatinine clearance .95 mL/min/1.73 m2), fasting plasma glucose ,100 mg/dL, body mass index ,25 kg/m2, no clinical, electrocardiographic (ECG) or echocardiographic evidence of coronary artery disease, heart failure, valvular heart diseases, and no systemic illnesses able to induce LV changes per se. Secondary causes of hypertension have been ruled out on the basis of a routine diagnostic workup. For each subject we collected a blood sample for ANF evaluation immediately before the echocardiographic examination; the study was carried out with the patients on their usual daily sodium intake. ANF Determination The patients were kept in a supine and comfortable position for 30 min, between 8:30 and 10:30 AM; blood pressure was then measured by sphygmomanometer and 10 mL of venous blood were collected in EDTA-dipotassium salt tubes containing aprotinin and immediately centrifuged. Plasma was separated and frozen at 220°C. ANF determination was performed by means of a doubleantibody radioimmunoassay based on the competitive method (HANP-Kit, Eiken, Tokyo, Japan). The normal values of plasma ANF are 20 to 60 pg/mL; the intra-
947
and interassay coefficients of variation of this method are consistently less than 15%. Echocardiographic Evaluation The echocardiographic evaluation was performed using a HewlettPackard (Andover, MA) Sonos 1500 with a 2.0/2.5MHz transducer. LV M-mode echocardiograms were recorded under two-dimensional control, at a paper speed of 100 mm/sec, with a simultaneous ECG. The M-mode tracings were evaluated blindly by a single operator who digitized four consecutive cardiac cycles of each echocardiogram, as originally described by Upton and Gibson,24 using a Numosonic 2205 graphic tablet. An IBM (Greenwich, England) personal computer processed digitized data, averaging the four cardiac cycles. We evaluated the following parameters from tracings obtained with an Intel processor 80286: LV end-diastolic diameter and LV end-diastolic diameter index (LV end-diastolic diameter/body surface area), end-diastolic thickness of interventricular septum and posterior wall, LV mass by the Penn convention25 and LV mass index (LV mass/body surface area), peak shortening rate of LV diameter, peak lengthening rate of LV diameter, and peak thinning rate of posterior wall during LV relaxation. We also evaluated left atrial diameter at end-systole, left atrial diameter index (left atrial diameter/body surface area), and LV meridional end-systolic wall stress.26 The normal limits of these parameters in our laboratory have been derived from our evaluation of 200 normal adults. We tested the reproducibility of the echocardiographic measurements on 20 normal subjects (each examined three times by the same ultrasonic technique); the same operator digitized four consecutive cardiac cycles of each echocardiogram. The coefficients of variation were as follows: LV end-diastolic diameter, 0.4%; septal thickness, 3.2%; posterior wall thickness, 3.4%; peak shortening rate, 1.1%; peak lengthening rate, 4.7%; and peak thinning rate, 7.3%. Statistical Analysis The results have been evaluated by means of contrast method, Pearson’s linear correlation coefficient, and stepwise multiple regression analysis. A P , .05 was considered statistically significant. RESULTS All the patients had normal (,56 mm) LV end-diastolic diameter; LV hypertrophy (LV mass index .130 g/m2) due to increased septal and wall thickness was found in 10 patients, 7 of whom had increased left atrial diameter (.40 mm). As regards LV function, peak shortening rate of LV diameter, the index of systolic function, was normal (.1.9/sec). A diastolic impairment (peak lengthening rate ,3.6/sec or peak wall thinning rate ,8.4 cm/sec) was found in 13 patients, 8 of whom had LV hyper-
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AJH–AUGUST 1997–VOL. 10, NO. 8
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TABLE 1. CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF THE PATIENT GROUP Variable
Mean 6 SD
Range
Age (years) BMI (kg/m2) ANF (pg/mL) SBP (mm Hg) DBP (mm Hg) HR (beats/min) LAD (mm) LADi (mm/m2) LVDD (mm) LVDDi (mm/m2) LVMi (g/m2) 2dD/dt (sec21) 1dD/Dt (sec21) dW/dt (cm/sec) ESS (103 dynes/cm2)
41 6 3 24.2 6 0.5 102.5 6 29.5 158 6 8 99 6 3 72 6 6 38 6 6 18.8 6 2.6 49 6 4 26.6 6 2.7 135 6 36 3.6 6 0.7 4.1 6 1.2 10.1 6 2.8 53 6 18
38–44 23.6–24.7 58–174 144–172 95–104 64–80 32–47 15.5–24.5 42–55 22.5–31.4 88–215 2.8–4.9 2.7–6.4 6.3–16.5 24–90
BMI, body mass index; ANF, atrial natriuretic factor; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; LAD, left atrial diameter; LADi, left atrial diameter index; LVDD, LV end-diastolic diameter; LVDDi, left ventricular end-diastolic diameter index; LVMi, LV mass index; 2dD/dt, peak shortening rate of LV diameter; 1dD/dt, peak lengthening rate of LV diameter; dW/dt, peak thinning rate of posterior wall; ESS, LV meridional end-systolic wall stress.
trophy (Table 1). Using the contrast method, we evaluated ANF levels in the patients grouped on the basis of 1) normal or increased LV mass index, 2) normal or increased left atrial diameter, and 3) normal or impaired diastolic function. ANF was similar between subjects with and without LV hypertrophy (112 6 35 v 99 6 34 pg/mL) and between subjects with and without left atrial enlargement (104 6 31 v 107 6 36 pg/ mL), whereas ANF was significantly (P , .01) higher in patients with LV diastolic impairment (124 6 35 pg/mL) than in patients with normal LV diastolic function (87 6 27 pg/mL). Plasma ANF values were inversely correlated with both indexes of LV diastolic function: peak lengthening rate r 5 20.58, P , .01 (Figure 1), peak thinning rate r 5 20.61, P , .005 (Figure 2). ANF did not correlate with blood pressure (systolic r 5 0.11, diastolic r 5 0.14, P 5 NS), LV end-diastolic diameter (r 5 0.07, P 5 NS), LV end-diastolic diameter index (r 5 0.14, P 5 NS), LV mass index (r 5 0.12, P 5 NS), left atrial diameter (r 5 0.10, NS), left atrial diameter index (r 5 0.08, P 5 NS), peak shortening rate (r 5 0.06, P 5 NS), or end-systolic wall stress (r 5 0.15, P 5 NS). Using a stepwise multiple regression analysis with ANF as the dependent variable and age, blood pressure, and echocardiographic parameters as independent variables, only the peak thinning rate of the posterior wall influenced ANF level independently (P , .001).
FIGURE 1. Correlation between plasma ANF values and peak lengthening rate of LV diameter.
DISCUSSION In designing this study, we tried to avoid some potentially confounding factors in first selecting patients who were never treated with antihypertensive therapy, as many drugs have been proved to significantly influence LV anatomy and function27,28 and, according to recent studies,29,30 probably affected plasma ANF concentration. We also paid attention to obtain a homogeneous group of patients: lean men with mild hypertension, normal renal function, and within a narrow range of age, as an increase in ANF with aging has been demonstrated.6,8,16 Obviously these criteria significantly reduced the number of patients eligible for the study, but they also eliminated some possible bias. Instead of indices derived from Doppler transmitral flow, we evaluated LV diastolic function by means of peak lengthening rate of the LV diameter and peak thinning rate of the posterior wall, both obtained from digitized M-mode echocardiography. These two parameters have been proved more specific than Dopp-
FIGURE 2. Correlation between plasma ANF values and peak thinning rate of LV posterior wall.
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ATRIAL NATRIURETIC FACTOR AND DIASTOLIC FUNCTION
ler indices in discriminating between normal and abnormal diastole in patients with myocardial hypertrophy; moreover, the parameters are less influenced by age and by events during isovolumic relaxation.31 According to our results, plasma ANF level in never-treated mild hypertensives is mainly influenced by LV diastolic function. In fact, ANF concentration is significantly higher in patients with LV diastolic dysfunction than in patients with normal diastole, whereas when grouping patients on the basis of LV mass index or left atrial diameter, ANF level is similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement. Moreover ANF values significantly correlate only with the indices of LV diastolic function: the lower the peak lengthening rate and peak wall thinning rate, the higher the ANF level. The latter does not correlate with blood pressure, LV mass, LV diastolic diameter, left atrial diameter, peak shortening rate, index of systolic function, or end-systolic wall stress, index of afterload. Finally, from multiple regression analysis, we found that only peak wall thinning rate independently influences plasma ANF values. The diastolic impairment may be responsible for increased atrial stretch and thereby stimulation of ANF release. The lack of correlation between ANF and left atrial size, in our opinion, does not stand against this hypothesis because the atrial enlargement develops as a consequence of chronic increased stretch, which is initially associated with normal atrial size. Our data confirm the results of two previous studies, carried out in mild-to-moderate hypertensives, by means of Doppler indices21,22 but are partially different from the results of Ganau and coworkers,16 which were obtained using the same digitized M-mode method. These workers found in hypertensives a significant direct correlation between ANF levels and age, left atrial size, and systolic pressure, whereas ANF did not correlate with LV hypertrophy and LV peak filling rate. The partially different findings are probably related to significant differences between the groups of patients studied, as our never-treated subjects were younger, in a narrow range of both age and blood pressure values, with greater LV hypertrophy and a significant impairment of diastolic function, whereas the patients evaluated by Ganau and coworkers had peak filling rate similar to normotensives. Our results do not support a direct link between myocardial hypertrophy and plasma ANF levels. The lack of correlation between ANF and LV mass is in keeping with some studies,16,23 whereas others have found a direct correlation between the two parameters.8,15,20 –22 However, some of these studies have been carried out assessing LV mass by means of ECG criteria or cardiothoracic ratio, far less sensitive
949
than echocardiography. The majority of the patients examined had been previously treated with antihypertensive drugs, with possible changes in LV mass and ANF level. Finally, some patients had severe hypertension with myocardial hypertrophy greater than our subjects. Therefore, we cannot exclude the possibility that severe LV hypertrophy might induce an increase of plasma ANF levels; however, our data indicate that in mild hypertension myocardial mass is not a major independent stimulus to ANF release. In agreement with recent studies on mild-to-moderate hypertension,13,17 we have not found any correlation between ANF and blood pressure; moreover ANF does not correlate with afterload, expressed as end-systolic wall stress. From these data, at least in mild hypertensives, the increase in blood pressure seems not to influence plasma ANF level per se. In conclusion, our study shows that, in nevertreated mild hypertension, plasma ANF level is not significantly affected by myocardial mass or afterload, but is mainly influenced by diastolic function. The diastolic impairment can raise ANF release probably through an increase of atrial stretch. REFERENCES 1.
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Burnett JC, Jr., Granger JP, Opgenorth TJ: Effects of synthetic atrial natriuretic factor on renal function and renin release. Am J Physiol 1984;247:F863– 866. Laragh JH: Atrial natriuretic hormone, the renin-aldosterone axis and blood pressure-electrolyte homeostasis. N Engl J Med 1985;313:1330 –1340. Bruun NE: On the role of atrial natriuretic factor in normotensive and hypertensive man. Danish Med Bull 1993;40:582– 600. Richards AM: The natriuretic peptides and hypertension. J Int Med 1994;235:543–560. Sugawara A, Nakao K, Sakamoto M, et al: Plasma concentration of atrial natriuretic polypeptide in essential hypertension. Lancet 1985;ii:1426 –1427. Sagnella GA, Markandu ND, Shore AC, MacGregor GA: Raised circulating levels of atrial natriuretic peptide in essential hypertension. Lancet 1986;i:179 –181. MacGregor GA, Sagnella GA, Markandu ND, et al: Raised plasma levels of atrial natriuretic peptide in subjects with untreated essential hypertension. J Hypertens 1986;4(suppl 6):S567–S569. Montorsi P, Tonolo G, Polonia J, et al: Correlates of plasma natriuretic factor in health and hypertension. Hypertension 1987;10:570 –576. Wambach G, Gotz S, Suckau G, Kaufmann W: Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake. Klin Wochenschr 1987;65:232–237. Zachariah PK, Burnett JC, Jr., Ritter SG, et al: Atrial natriuretic peptide in human essential hypertension. Mayo Clin Proc 1987;62:782–786. Nilsson P, Lindholm L, Schersten B, et al: Atrial natriuretic peptide and blood pressure in a geographically defined population. Lancet 1987;ii:883– 885.
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12.
Larochelle P, Cusson JR, Gutkowska J, et al: Plasma atrial natriuretic factor concentrations in essential and renovascular hypertension. Br Med J 1987;294:1249 – 1252.
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Hollister AS, Inagami T: Atrial natriuretic factor and hypertension. A review and metaanalysis. Am J Hypertens 1991;4:850 – 865.
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Richards AM, Tonolo G, Tillman D, et al: Plasma atrial natriuretic peptide in stable and accelerated essential hypertension. J Hypertens 1986;4:790 –791.
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Pontremoli R, Bezante GP, Robaudo C, et al: Cardiac diastolic abnormalities and atrial natriuretic factor in essential hypertension. Eur Heart J 1993;14:910 –914.
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Lucarini AR, Favilla S, Marini C, et al: Atrial natriuretic factor in essential hypertension: echocardiographic and humoral correlates. Clin Cardiol 1992;15:353–356.
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Upton MT, Gibson DG: The study of left ventricular function from digitised echocardiograms. Prog Cardiovasc Dis 1978;20:359 –384.
Kohno M, Yasanuri K, Matsura T, et al: Circulating atrial natriuretic polypeptyde in essential hypertension. Am Heart J 1987;113:1160 –1163.
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Devereux RB, Reichek N: Echocardiographic determination of left ventricular mass in man: validation of the method. Circulation 1977;55:613– 618.
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Ganau A, Devereux RB, Atlas SA, et al: Plasma atrial natriuretic factor in essential hypertension: relation to cardiac size, function and systemic hemodynamics. J Am Coll Cardiol 1989;14:715–724.
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Wilson JR, Reichek N, Hirshfeld J: Noninvasive assessment of load reduction in patients with asymptomatic aortic regurgitation. Am J Med 1980;68:664 – 674.
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Flickinger AL, Burnett JC, Jr., Turner ST: Atrial natriuretic peptide and blood pressure in a populationbased sample. Mayo Clin Proc 1995;70:1015–1017.
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Brooks SE, Zimmerman RS, Schwab TR, et al: Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res 1988;62:191–195.
Grandi AM, Venco A, Bertolini A, et al: Left ventricular function after reversal of myocardial hypertrophy in systemic hypertension and response to acute increase of afterload by cold pressor test. Am J Cardiol 1992;69: 1439 –1441.
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Dahlof B, Pennert K, Hansson L: Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens 1992; 5:95–110.
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Erbas B, Ozdemir O, Pasaoglu I, et al: Short- and longterm effects of felodipine on circulating endothelin and atrial natriuretic peptide levels in essential hypertension. Nephron 1993;63:363–364.
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Papadopoulos CL, Kokkas BA, Kotridis PS, et al: The effect of beta 1-blocker bisoprolol on atrial natriuretic peptide plasma levels in hypertensive patients. Int J Angiol 1995;4:165–168.
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Lee CH, Hogan JC, Gibson DG: Diastolic disease in left ventricular hypertrophy: comparison of M mode and Doppler echocardiography for the assessment of rapid ventricular filling. Br Heart J 1991;65:194 –200.
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Dessı`-Fulgheri P, Palermo M, Di Noto G, et al: Plasma levels of atrial natriuretic factor in mild to moderate hypertensives without signs of left ventricular hypertrophy: correlation with the known duration of hypertension. J Hum Hypertens 1988;2:177–182.
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Wambach G, Bonner G, Stimpel M, Kaufmann W: Relationship between plasma atrial natriuretic peptide and left atrial and ventricular involvement in essential hypertension. J Hypertens 1988;6:573–577.
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Dessı`-Fulgheri P, Palermo R, Di Noto G, et al: High levels of plasma atrial natriuretic factor and impaired left ventricular diastolic function in hypertensives without left ventricular hypertrophy. J Hypertens 1992; 10:161–165.
1997;10:946 –950
Relationship Between Left Ventricular Diastolic Function and Atrial Natriuretic Factor in Never-Treated Mild Hypertensives Anna Maria Grandi, Paolo Zanzi, Luca Ceriani, Giovanni Gaudio, Andrea Bertolini, Luca Giovanella, Luigina Guasti, Giuseppina Roncari, and Achille Venco
Using digitized M-mode echocardiograms, we evaluated the relationship between plasma atrial natriuretic factor (ANF) and morphofunctional characteristics of the left ventricle (LV) in 24 mild hypertensive men, never treated, with normal renal function. For each subject we collected a blood sample for plasma ANF evaluation and, immediately after, we recorded the LV echocardiogram. All the patients had normal LV diastolic diameter and systolic function; LV hypertrophy was present in 10 patients, 7 of whom had left atrial enlargement, and 13 patients had impaired LV diastolic function. ANF was similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement, whereas ANF was significantly (P < .01) higher in patients with LV diastolic dysfunction than in patients with normal diastolic function. ANF was inversely correlated
with both indices of diastolic function (peak lengthening rate and peak wall thinning rate), whereas it did not correlate with blood pressure, heart rate, end-systolic wall stress, and other LV parameters. In conclusion, from our results, ANF level in never-treated mild hypertensives is related neither to the degree of LV hypertrophy nor to the afterload, expressed as blood pressure or endsystolic wall stress, whereas it is mainly influenced by LV diastolic function: the diastolic impairment induces an increase in ANF level, probably through an increased atrial stretch. Am J Hypertens 1997;10:946 –950 © 1997 American Journal of Hypertension, Ltd.
A
regulation, a role of ANF in the pathophysiology of essential hypertension has been hypothesized, but until now this role has been controversial and is still under investigation.3,4 Several reports showed increased levels of plasma ANF in hypertensives,5–9 whereas others did not10 –12: now there appears to be general agreement that severe hypertension is associated with increased plasma ANF, whereas in patients with mild or moderate and uncomplicated hyperten13 sion the data are contradictory. Despite the fact that some have found significant correlations between plasma ANF levels and blood pressure values,5,7,8,14 –16 a recent study on a very large popu-
trial natriuretic factor (ANF) is a polypeptide secreted from the atria, with natriuretic and vasodilatory actions, which can also inhibit the renin-angiotensin-aldosterone axis.1,2 Because of these actions on blood pressure
Received September 3, 1996. Accepted February 4, 1997. From the Department of Clinical and Biological Sciences (AMG, PZ, GG, AB, LGu, AV), II Faculty of Medicine, University of Pavia, Varese, Italy, and the Department of Nuclear Medicine, Ospedale di Circolo, Varese, Italy (LC, LGi, GR). Address correspondence and reprint requests to Anna Maria Grandi, via Bagaini 15, 21100 Varese, Italy.
© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
KEY WORDS:
Atrial natriuretic factor, essential hypertension, diastolic function, myocardial hypertrophy.
0895-7061/97/$17.00 PII S0895-7061(97)00124-6
AJH–AUGUST 1997–VOL. 10, NO. 8
ATRIAL NATRIURETIC FACTOR AND DIASTOLIC FUNCTION
lation failed to show any correlation.17 Considering that ANF is secreted primarily in response to stimuli that enhance atrial wall stretch,18 factors other than blood pressure may influence plasma ANF release in hypertension. These include duration of hypertension, increase in venous return, left ventricular hypertrophy, as well as systolic or diastolic dysfunction.8,15,16,19,20,23 These studies provided controversial results, probably related to differences in the population studied as regards age, degree of hypertension, presence of end organ damage, dietary sodium intake, previous antihypertensive treatment, and differences in the methods employed, for instance, in evaluating LV hypertrophy by means of ECG criteria, cardiothoracic ratio, or echocardiography. Therefore we considered it of interest to evaluate the relationship between plasma ANF level and the morphofunctional characteristics of the left ventricle (LV) in a group of mild hypertensive men, never treated, with normal renal function and within a narrow range of age. PATIENTS AND METHODS Patients We evaluated 24 men (mean age 41 6 3 years) who had mild essential hypertension (diastolic blood pressure between 95 and 105 mm Hg in at least four measurements taken in different days). The patients have been selected following these criteria: no previous antihypertensive treatment, left ventricular echocardiogram of good quality, normal renal function (plasma creatinine ,1.1 mg/dL; creatinine clearance .95 mL/min/1.73 m2), fasting plasma glucose ,100 mg/dL, body mass index ,25 kg/m2, no clinical, electrocardiographic (ECG) or echocardiographic evidence of coronary artery disease, heart failure, valvular heart diseases, and no systemic illnesses able to induce LV changes per se. Secondary causes of hypertension have been ruled out on the basis of a routine diagnostic workup. For each subject we collected a blood sample for ANF evaluation immediately before the echocardiographic examination; the study was carried out with the patients on their usual daily sodium intake. ANF Determination The patients were kept in a supine and comfortable position for 30 min, between 8:30 and 10:30 AM; blood pressure was then measured by sphygmomanometer and 10 mL of venous blood were collected in EDTA-dipotassium salt tubes containing aprotinin and immediately centrifuged. Plasma was separated and frozen at 220°C. ANF determination was performed by means of a doubleantibody radioimmunoassay based on the competitive method (HANP-Kit, Eiken, Tokyo, Japan). The normal values of plasma ANF are 20 to 60 pg/mL; the intra-
947
and interassay coefficients of variation of this method are consistently less than 15%. Echocardiographic Evaluation The echocardiographic evaluation was performed using a HewlettPackard (Andover, MA) Sonos 1500 with a 2.0/2.5MHz transducer. LV M-mode echocardiograms were recorded under two-dimensional control, at a paper speed of 100 mm/sec, with a simultaneous ECG. The M-mode tracings were evaluated blindly by a single operator who digitized four consecutive cardiac cycles of each echocardiogram, as originally described by Upton and Gibson,24 using a Numosonic 2205 graphic tablet. An IBM (Greenwich, England) personal computer processed digitized data, averaging the four cardiac cycles. We evaluated the following parameters from tracings obtained with an Intel processor 80286: LV end-diastolic diameter and LV end-diastolic diameter index (LV end-diastolic diameter/body surface area), end-diastolic thickness of interventricular septum and posterior wall, LV mass by the Penn convention25 and LV mass index (LV mass/body surface area), peak shortening rate of LV diameter, peak lengthening rate of LV diameter, and peak thinning rate of posterior wall during LV relaxation. We also evaluated left atrial diameter at end-systole, left atrial diameter index (left atrial diameter/body surface area), and LV meridional end-systolic wall stress.26 The normal limits of these parameters in our laboratory have been derived from our evaluation of 200 normal adults. We tested the reproducibility of the echocardiographic measurements on 20 normal subjects (each examined three times by the same ultrasonic technique); the same operator digitized four consecutive cardiac cycles of each echocardiogram. The coefficients of variation were as follows: LV end-diastolic diameter, 0.4%; septal thickness, 3.2%; posterior wall thickness, 3.4%; peak shortening rate, 1.1%; peak lengthening rate, 4.7%; and peak thinning rate, 7.3%. Statistical Analysis The results have been evaluated by means of contrast method, Pearson’s linear correlation coefficient, and stepwise multiple regression analysis. A P , .05 was considered statistically significant. RESULTS All the patients had normal (,56 mm) LV end-diastolic diameter; LV hypertrophy (LV mass index .130 g/m2) due to increased septal and wall thickness was found in 10 patients, 7 of whom had increased left atrial diameter (.40 mm). As regards LV function, peak shortening rate of LV diameter, the index of systolic function, was normal (.1.9/sec). A diastolic impairment (peak lengthening rate ,3.6/sec or peak wall thinning rate ,8.4 cm/sec) was found in 13 patients, 8 of whom had LV hyper-
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TABLE 1. CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF THE PATIENT GROUP Variable
Mean 6 SD
Range
Age (years) BMI (kg/m2) ANF (pg/mL) SBP (mm Hg) DBP (mm Hg) HR (beats/min) LAD (mm) LADi (mm/m2) LVDD (mm) LVDDi (mm/m2) LVMi (g/m2) 2dD/dt (sec21) 1dD/Dt (sec21) dW/dt (cm/sec) ESS (103 dynes/cm2)
41 6 3 24.2 6 0.5 102.5 6 29.5 158 6 8 99 6 3 72 6 6 38 6 6 18.8 6 2.6 49 6 4 26.6 6 2.7 135 6 36 3.6 6 0.7 4.1 6 1.2 10.1 6 2.8 53 6 18
38–44 23.6–24.7 58–174 144–172 95–104 64–80 32–47 15.5–24.5 42–55 22.5–31.4 88–215 2.8–4.9 2.7–6.4 6.3–16.5 24–90
BMI, body mass index; ANF, atrial natriuretic factor; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; LAD, left atrial diameter; LADi, left atrial diameter index; LVDD, LV end-diastolic diameter; LVDDi, left ventricular end-diastolic diameter index; LVMi, LV mass index; 2dD/dt, peak shortening rate of LV diameter; 1dD/dt, peak lengthening rate of LV diameter; dW/dt, peak thinning rate of posterior wall; ESS, LV meridional end-systolic wall stress.
trophy (Table 1). Using the contrast method, we evaluated ANF levels in the patients grouped on the basis of 1) normal or increased LV mass index, 2) normal or increased left atrial diameter, and 3) normal or impaired diastolic function. ANF was similar between subjects with and without LV hypertrophy (112 6 35 v 99 6 34 pg/mL) and between subjects with and without left atrial enlargement (104 6 31 v 107 6 36 pg/ mL), whereas ANF was significantly (P , .01) higher in patients with LV diastolic impairment (124 6 35 pg/mL) than in patients with normal LV diastolic function (87 6 27 pg/mL). Plasma ANF values were inversely correlated with both indexes of LV diastolic function: peak lengthening rate r 5 20.58, P , .01 (Figure 1), peak thinning rate r 5 20.61, P , .005 (Figure 2). ANF did not correlate with blood pressure (systolic r 5 0.11, diastolic r 5 0.14, P 5 NS), LV end-diastolic diameter (r 5 0.07, P 5 NS), LV end-diastolic diameter index (r 5 0.14, P 5 NS), LV mass index (r 5 0.12, P 5 NS), left atrial diameter (r 5 0.10, NS), left atrial diameter index (r 5 0.08, P 5 NS), peak shortening rate (r 5 0.06, P 5 NS), or end-systolic wall stress (r 5 0.15, P 5 NS). Using a stepwise multiple regression analysis with ANF as the dependent variable and age, blood pressure, and echocardiographic parameters as independent variables, only the peak thinning rate of the posterior wall influenced ANF level independently (P , .001).
FIGURE 1. Correlation between plasma ANF values and peak lengthening rate of LV diameter.
DISCUSSION In designing this study, we tried to avoid some potentially confounding factors in first selecting patients who were never treated with antihypertensive therapy, as many drugs have been proved to significantly influence LV anatomy and function27,28 and, according to recent studies,29,30 probably affected plasma ANF concentration. We also paid attention to obtain a homogeneous group of patients: lean men with mild hypertension, normal renal function, and within a narrow range of age, as an increase in ANF with aging has been demonstrated.6,8,16 Obviously these criteria significantly reduced the number of patients eligible for the study, but they also eliminated some possible bias. Instead of indices derived from Doppler transmitral flow, we evaluated LV diastolic function by means of peak lengthening rate of the LV diameter and peak thinning rate of the posterior wall, both obtained from digitized M-mode echocardiography. These two parameters have been proved more specific than Dopp-
FIGURE 2. Correlation between plasma ANF values and peak thinning rate of LV posterior wall.
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ler indices in discriminating between normal and abnormal diastole in patients with myocardial hypertrophy; moreover, the parameters are less influenced by age and by events during isovolumic relaxation.31 According to our results, plasma ANF level in never-treated mild hypertensives is mainly influenced by LV diastolic function. In fact, ANF concentration is significantly higher in patients with LV diastolic dysfunction than in patients with normal diastole, whereas when grouping patients on the basis of LV mass index or left atrial diameter, ANF level is similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement. Moreover ANF values significantly correlate only with the indices of LV diastolic function: the lower the peak lengthening rate and peak wall thinning rate, the higher the ANF level. The latter does not correlate with blood pressure, LV mass, LV diastolic diameter, left atrial diameter, peak shortening rate, index of systolic function, or end-systolic wall stress, index of afterload. Finally, from multiple regression analysis, we found that only peak wall thinning rate independently influences plasma ANF values. The diastolic impairment may be responsible for increased atrial stretch and thereby stimulation of ANF release. The lack of correlation between ANF and left atrial size, in our opinion, does not stand against this hypothesis because the atrial enlargement develops as a consequence of chronic increased stretch, which is initially associated with normal atrial size. Our data confirm the results of two previous studies, carried out in mild-to-moderate hypertensives, by means of Doppler indices21,22 but are partially different from the results of Ganau and coworkers,16 which were obtained using the same digitized M-mode method. These workers found in hypertensives a significant direct correlation between ANF levels and age, left atrial size, and systolic pressure, whereas ANF did not correlate with LV hypertrophy and LV peak filling rate. The partially different findings are probably related to significant differences between the groups of patients studied, as our never-treated subjects were younger, in a narrow range of both age and blood pressure values, with greater LV hypertrophy and a significant impairment of diastolic function, whereas the patients evaluated by Ganau and coworkers had peak filling rate similar to normotensives. Our results do not support a direct link between myocardial hypertrophy and plasma ANF levels. The lack of correlation between ANF and LV mass is in keeping with some studies,16,23 whereas others have found a direct correlation between the two parameters.8,15,20 –22 However, some of these studies have been carried out assessing LV mass by means of ECG criteria or cardiothoracic ratio, far less sensitive
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than echocardiography. The majority of the patients examined had been previously treated with antihypertensive drugs, with possible changes in LV mass and ANF level. Finally, some patients had severe hypertension with myocardial hypertrophy greater than our subjects. Therefore, we cannot exclude the possibility that severe LV hypertrophy might induce an increase of plasma ANF levels; however, our data indicate that in mild hypertension myocardial mass is not a major independent stimulus to ANF release. In agreement with recent studies on mild-to-moderate hypertension,13,17 we have not found any correlation between ANF and blood pressure; moreover ANF does not correlate with afterload, expressed as end-systolic wall stress. From these data, at least in mild hypertensives, the increase in blood pressure seems not to influence plasma ANF level per se. In conclusion, our study shows that, in nevertreated mild hypertension, plasma ANF level is not significantly affected by myocardial mass or afterload, but is mainly influenced by diastolic function. The diastolic impairment can raise ANF release probably through an increase of atrial stretch. REFERENCES 1.
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