central blood volume: a determinant of early cardiac adaptation in arterial hypertension?

1692 JACC Vol. 26, No. 7 December 1995:1692-8

HYPERTENSION

Central Blood Volume: A Determinant of Early Cardiac Adaptation in Arterial Hypertension?

R O L A N D E. S C H M I E D E R , MD, H A N S P. S C H O B E L , MD, F R A N Z H. M E S S E R L I , MD, FACC*

Narnberg, Germany and New Orleans, Louisiana

Objectives. This study was undertaken to assess the influence of the fluid volume state on cardiac adaptation to hypertension.

Background. Left ventricular hypertrophy is an important predictor of hypertensive complications. We analyzed volume status and its impact on cardiac structural changes in early hypertension.

Methods. In 33 normotensive subjects, 40 patients with borderline hypertension and 63 patients with established essential hypertension, mean arterial pressure was measured invasively; total blood volume was measured by iodine-125-1abeled plasma albumin and hematocrit; central blood volume by indocyanine green dye dilution curve; and diastolic diameter and left ventricular mass by two-dimensional-guided M-mode echocardiography.

Results. Central blood volume was -20% higher in patients with stage I borderline hypertension than in normotensive subjects ([mean ± SD] 3,001 ± 663 vs. 2,493 -+ 542 ml, p < 0.05),

whereas total blood volume was similar in all three groups. This shift in intravascular volume toward the cardiopulmonary circulation was accompanied by a significant increase in diastolic diameter (5.29 + 0.80 vs. 4.86 -+ 0.77 cm, p < 0.05) and in left ventricular mass (239.4 ± 90.6 vs. 183.5 -+ 68.8 g, p < 0.05) in patients with borderline hypertension compared with subjects with normotension. In patients with established essential hyper. tension, volume status of stroke volume and diastolic dimension returned to normal values, whereas left ventricular mass increased further.

Conclusions. We conclude that the early phase of hypertension is characterized by centripetal distribution of intravascnlar volume, leading to an increased preload to the left ventricle. This change in volume status appears to be related to cardiac struc- turai adaptation to an increase in arterial pressure.

(J Am Coil Cardiol 1995;26:1692-8)

Left ventricular hypertrophy is the hallmark of early cardiac structural adaptation in essential hypertension. Although myo- cardial hypertrophy was previously regarded as a compensa- tory, and thus physiologically necessary, process for offsetting increased wall stress of the left ventricle (1-4), it is well accepted that left ventricular hypertrophy is also a powerful independent risk factor for congestive heart failure, coronary artery disease and sudden cardiac death (5-8). Recent re- search indicates that left ventricular mass is a stronger predictor of hypertensive complications than blood pressure or other conventional risk factors (9) and that reduction of left ventricular hypertrophy by antihypertensive treatment improves prog- nosis (10).

The common view that the increase in left ventricular mass and the development of left ventricular hypertrophy are caused by an increase in afterload subsequent to functional and structural changes in the arterial vascular bed (11-14) is now challenged by evidence indicating that left ventricular hypertrophy closely parallels peripheral vascular changes and may

From the Department of Medicine, Universitat Erlangen-Niirnberg, Niirn- berg, Germany; and *Department of Internal Medicine, Section of Hypertensive Diseases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana.

Manuscript received October 19, 1994; revised manuscript received May I 1, 1995, accepted July 13, 1995.

Address for corresr)ondencc: Dr. Franz H. Messcrli, Ochsner Clinic. 1514 Jefferson Highway, New Orleans, Louisiana 70121.

already be detectable in early phases of hypertension (15-17), even before afterload becomes increased. Experimental data by Friberg et al. (18) showed that in rats, eccentric cardiac hypertrophy may develop rapidly in response to an increase in preioad, suggesting that the volume load of the heart may be an important factor in regulating the level of left ventricular mass. Other investigators (19-21) also provided evidence that hemodynamic volume load may be a stimulus to hypertensive left ventricular hypertrophy, in human as well as animal studies. This view is supported by a previous study from our laboratory (22) showing that total blood volume was a strong and pressure-independent predictor for chamber volume and left ventricular mass. Other factors proposed as influencing the pathogenesis of left ventricular hypertrophy, either through hemodynamic mechanisms or by directly promoting cardiac myocyte growth, are sodium intake (23,24), whole-blood viscosity (25,26) and neurohumoral substances.

The provocative findings of de Simone et al. (27), that echocardiographic left ventricular mass in normotensive adults predicts future development of arterial hypertension, suggest that cardiac involvement may even precede clinically detectable hypertension. This observation was confirmed by Iso et al. (28) and Post et al. (29). Thus, the time of onset and the interaction of various underlying pathogenetic mechanisms of hypertensive heart disease are still unknown. To elucidate some of these questions, we evaluated cardiovascular and humoral findings in patients with borderline hypertension and

q"~1995 by the American ('~,llcg~ L~I ( :~~l~,~l~, [)735-1097/95/$9.5[] 0735-1097(95)00387-J

JACC Vol. 26. No. 7 SCHMIEDER ET AL. 1693 December 1995:1692-8 CENTRAL BLOOD VOLUME IN HYPERTENSION

compared them with normotensive control subjects and patients with established essential hypertension.

M e t h o d s

Study group. Included in the study were 136 subjects (mean [+SD] age 39.5 _+ ll.8 years; 90 men, 46 women; 104 white, 32 black): 33 normotensive volunteers, 40 patients with borderline hypertension and 63 patients with established hypertension. Secondary causes of arterial hypertension were excluded by clinical evaluation. No patient had clinical signs of advanced hypertensive target organ damage, congestive heart failure, coronary artery disease or valvular and congenital cardiac lesions. All patients either had never been treated with antihypertensive medication or had discontinued it at least 4 weeks before being examined. Informed written consent was obtained before the study, and the protocol was approved by the Institutional Clinical Investigation Committee.

Patients were considered to have borderline hypertension if some diastolic blood pressure values were >90 and some <90 mm Hg but were <95 mm Hg during at least four readings of ambulatory blood pressure measurements in the outpatient clinic (office blood pressure). Patients were considered to have established hypertension if their office diastolic blood pressure in the outpatient clinic was consistently >95 mm Hg. Office diastolic blood pressure values of the normotensive subjects were consistently <90 mm Hg.

Echocardiography. Two-dimensional M-mode echocardiographic studies were conducted by standard methods, as previously outlined (30), by using an ultrasonoscope (Toshiba) interfaced with a strip chart recorder. All echocardiograms were recorded in the third or fourth interspace lateral to the left sternal border with the patient in the supine position. All echocardiograms were independently read by two physicians blinded to the characteristics, including the office blood pressure values, according to the standards of the American Society of Echocardiography (31). The coefficient variation of intra- and interobserver reproducibility was <5% for left ventricular dimensions and <10% for left ventricular wall thickness. Left ventricular structure was evaluated by septal and posterior wall thicknesses and systolic and diastolic diam- eters measured at the onset of the ORS complex. Left ventricular mass was calculated according to the standard formula of Troy et al. (32), which takes both septal and posterior wall thicknesses into account. However, left ventricular mass deter- mined by this method needs to be adjusted by the regression PENN cube left ventricular mass of 0.80 (ASE cube left ventricular mass) plus 0.6 g to avoid systematic overestimation (33-36).

Hemodynamic, volume and humoral measurements. He- modynamic evaluation was performed after overnight fasting as previously described (37). There was a maximum of 7 to l0 days between the office blood pressure screening and the hemodynamic study. Within this period the subjects were asked to maintain a stable life-style with regard to drinking and

Table 1. Demographic Characteristics in Normotensive Control Subjects and Patients With Borderline Hypertension or Established Essential Hypertension

NT BH EH (n = 33) (n = 40) (n = 63)

Age (yr) 33 -+ 10 35 ± 4 45 ± ll*l Race (white/black) 28/5 34/6 42/21 Gender (male/female) 22/11 32/8 36/27 Weight (kg) 80 ± 18 85 ± 19 81 ± 18 Height (cm) 171 ± 10 176 ± 10':~ 171 ± 10 Body mass index (kg/m 2) 27.2 ± 5.8 27.3 ± 5.2 27.8 ± 5.8 Body surface area (m 2) 1.9 ± 0.2 2.0 _+ 0.2 1.9 ± 0.2

*p < 0.05 versus normotensive control subjects (NT). tp < 0.05 versus patients with borderline hypertension (BH). *p < 0.05 versus patients with established essential hypertension (EH). Data presented are mean value + SD or number of subjects.

eating habits. Briefly, catheters were inserted into a brachial artery and an antecubital vein and advanced to the ascending aorta and superior vena cava, respectively. Thus, arterial pressure was measured continuously, simultaneously with the recording of the electrocardiogram (lead Ill). Cardiac output was measured in triplicate with the indocyanine green dye technique. Stroke volume and total peripheral resistance were calculated by standard formulas. Plasma volume was measured during the hemodynamic study with iodine-125-1abeled plasma serum albumin (38). Total blood volume was estimated from the plasma volume and hematocrit: Total blood volume = Plasma volume/(100 - Hematocrit), with the hematocrit having been adjusted by the correction factor 0.91 for total body hematocrit. Central blood volume was assessed from the indocyanine green dye dilution curve by calculating the prod- uct of mean transit time and blood flow per second as previously outlined in detail (39,40). When the patients had been recumbent for at least 1 h after the insertion of the catheters, blood was withdrawn into ice-cooled tubes and stored at -21°C for later determinations of circulating plasma norepinephrine and epinephrine levels (radioenzymatic assay) and plasma renin activity (radioimmunoassay).

Statistics. One-way analysis of variance and the Bonfer- roni correction were used to evaluate any significant difference between the groups. Statistical significance was considered to be p < 0.05 (two-tailed). All data are expressed as mean value _+ 1 SD, unless otherwise specified.

Resul t s

Demographic characteristics. There were no significant differences in gender, race, weight, body mass index or body surface area between the normotensive control and borderline and established essential hypertension groups (Table 1). Pa- tients with established hypertension were older than the normotensive subjects and the patients with borderline hypertension (p < 0.05), and the borderline hypertensive group was taller than the other two groups (p < 0.05) (Table 1).

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Table 2. Hemodynamic, Volume and Humoral Findings in Normotensive Subjects and Patients With Borderline Hypertension or Established Essential Hypertension

NT BH EH p Value

Systolic arterial pressure (mm Hg) 121.7 - 10.1 132.4 _+ 13.3" 157.5 -+ 13.2"f <0.0001 Diastolic arterial pressure (ram Hg) 72.2 + 6.8 78.5 _+ 7.4* 88.4 _+ 8.1*f <0.0001

Mean arterial pressure (mm Hg) 882 -+ 7.4 %.5 + 8.7* 111.4 _+ 8.2** <0.0001

Heart rate (beats/rain) 68.0 + 9.0 66.1 + 10.3 68.9 _+ 9.8 NS

Cardiac output (liters/rain) 5.8 +_ 1.5 6.6 _+ 1.6'$ 5.8 -+ 1.3 <0.02 Cardiac index (liters/rain per mZ) 3.1 + 0.7 3.3 _+ 0.8 3.0 _+ 0.6 NS

Stroke volume (ml/min) 87.0 + 22.2 100.7 + 22.1'$ 85.2 +_ 19.9 0.001

Total blood volume (ml) 4,795 _+ 888 5,(}51 *_ 916 4,642 + 1023 NS

Plasma volume (ml) 2,911 + 566 3,071 _+ 539 2,867 +- 577 NS

Central blood volume (ml) 2,493 ~ 542 3,{X)I _+ 663*$ 2,626 _+ 516 0.001 Total blood volume/height (ml/cm) 27.9 * 4.1 28.6 _+ 4. I 27.1 _+ 5.1 NS

Plasma volume/height (ml/cm) 17.0 + 2.8 17.4 _+. 2.5 16.8 _+ 2.9 NS

Central blood volume/height (ml/cm) 14.6 +_ 2.8 16.9 _+ 3.4*$ 15.2 z 2.6 0.003

Stroke volume/height (ml/cm) 0.51 ± 0.11 0.57 _+ 0.11'$ 0.50 + 0.11 0.005

Total peripheral resistance (U) 16.1 + 4.4 15.4 _+ 4.0 20.1 _+ 4.6*? <0.0001

Norepinephrine 267 + 157 341 +_ 172 299 + 128 NS

Epinephrine 1il9 + 65 143 _+ 1125 71 +_ 73 <0.05

Renin 0.ql + 1.1 1.0 _+ 0.8 1/.95 _+ 1.2 NS

*p < 0.05 versus normotensive control subjects (NT). *p < 0.05 versus patients with borderline hypertension (BH). Sp < 0.05 versus patients with established essential hypertension (EH). Data presented are mean value +_ SD.

Hemodynamic, volume and humoral findings. Arterial pressure measured invasively was higher in the patients with borderline hypertension and established hypertension than in the normotensive subjects (Table 2, Fig. 1). Stroke volume was significantly increased in patients with borderline hypertension compared with the normotensive subjects and the patients with established hypertension (100.7 _+ 22.1 vs. 87.0 + 22.2 and 85.2 _+ 19.9 ml, respectively, p < 0.05) (Table 2, Fig. 1). The increase in stroke volume in this group was accompanied by a significant increase in cardiac output (6.6 _+ 1.6 vs. 5.8 _+ 1.5 liters/rain in the normotensive group and 5.8 _+ 1.3 liters/rain in

Figure 1. Differences in central blood volume (CBV), total blood volume (TBV), stroke volume (SV) and cardiac output (CO) among the three study groups. BH = patients with borderline hypertension; EH = patients with essential hypertension; NT = normotensive control subjects.

CBV (ml) . + TBV (ml)

6000~

SV (ml) CO (I/rain)

NT BH EH NT BH EH

* p<O.05 vs NT + p<0.05 vs EH

the group with established hypertension, p < 0.05) (Table 2, Fig. 1). Total peripheral resistance was significantly increased in the patients with established hypertension compared with the other two groups (p < 0.001) (Table 2).

Patients with borderline hypertension showed a marked increase in central blood volume that was -20% higher than that in the normotensive control subjects (3,001 + 663 vs. 2,493 + 542 ml, p < 0.05) (Table 2, Fig. 1), whereas plasma volume and total blood volume were similar in all three groups, indicating a shift of the circulating intravascular volume toward the cardiopulmonary circulation in early hypertension. When corrected for differences in body height, total blood volume and plasma volume were again not different among the groups. In contrast, central blood volume corrected for height still showed an increase in the patients with borderline hypertension compared with the normotensive subjects and those with established hypertension (116.9 _+ 3.4 vs. 14.6 +_ 2.8 and 15.2 _+ 2.6 ml/cm, respectively, p < 0.05) (Table 2). Although somewhat higher in the patients with borderline hypertension, norepinephrine and renin levels were not significantly different in the other groups. However, epinephrine levels were higher in patients with borderline hypertension than in those with established hypertension (p < 0.05) but was not significantly different in the normotensive control group (Table 2).

Eehocardiographic findings. As expected, echocardiographic determination of septal and posterior wall thickness revealed higher values in patients with established essential hypertension than in the other groups (Table 3, Fig. 2). Compared with the normotensive subjects, those with borderline hypertension exhibited an increase in septal thickness (9.9 +_ 1.8 vs. 8.8 + 1.9 ram, p < 0.05) (Table 3, Fig. 2) but not in posterior wall thickness. Furthermore, there was also a

JACC Vol. 26, No. 7 SCHMIEDER ET AL. 1695 December 1995:1692-8 CENTRAL BLOOD VOLUME IN HYPERTENSION

Table 3. Echocardiographic Findings in Normotensive Control Subjects and Patients With Borderline Hypertension or Established Essential Hypertension

P NT BH EH Value

Septal thickness (ram) Posterior wall thickness (mm) Diastolic diameter (cm) Systolic diameter (cm) Left ventricular mass (g) Left ventricular mass index (g/m 2) Left ventricular mass/height (g/m) Relative wall thickness (2 PWT/DD)

8.8 -+ 1.9 9.9 _+ 1.8" 11.1 • 2.2"t <0.001 8.4 -+ 1.4 9.0 _+ 1.3 10.0 --- 1.5'? <0.001

4.86 -+ 0.77 5.29 _+ 0.80*¢ 4.79 ± 0.60 0.002 3.13 +- 0.63 3.50 _+ 0.62':~ 3.10 --- 0.54 0.003

183.5 -+ 68.8 239.4 +_ 90.6* 232.4 -- 67.4* 0.003 96.4 _+ 36.5 122.2 _+ 53.7* 121.9 ± 37.0* 0.01 108 -+ 41 138 _+ 57* 137 ± 39* 0.007

0.36 - 0.02 0.35 -+ 0.01 0.42 ± 0.008'~" <0.001

*p < 0.05 versus normotensive control subjects (NT). ~p < 0.05 versus patients with borderline hypertension (BH). :~p < 0.05 versus patients with established essential hypertension (EH). Data presented are mean value _+ SD. DD = diastolic diameter; PWT - posterior wall thickness.

significant increase in left ventricular end-diastolic diameter in patients with borderline hypertension compared with normotensive subjects (5.29 _+ 0.80 vs. 4.86 ___ 0.77 cm, p < 0.05) (Table 3, Fig. 2). Most important, in comparison with the normotensive subjects, left ventricular mass was significantly increased not only in the patients with established hypertension but also in those with borderline hypertension (239.4 _+ 90.6 vs. 183.5 -+ 68.8 g, p < 0.05) (Table 3, Fig. 2).

Influence of gender on findings in borderline hypertension. Because women have a lower blood volume and cardiac output than men, we addressed the question of whether this variation in gender distribution may have had any influence on the results (Table 1). The male borderline hypertensive group exhibited increases in central blood volume (3,212 _ 660 vs. 2,693 _ 496 ml, p < 0.05), diastolic diameter (5.22 _+ 0.66 vs. 4.86 __+ 0.67 cm) and left ventricular mass (236.2 -+ 68.1 vs. 190.4 -+ 69.3 g) compared with the male normotensive group. In the female borderline hypertensive group compared with the female normotensive group, a trend was also found for an

Figure 2. Differences in septal thickness (ST), posterior wall thickness (PWT), left ventricular end-diastolic dimension (LVEDD) and left ventricular mass (LVM) among the three groups. Other abbreviations as in Figure 1.

ST (mm) . + PWT (ram) . +

11; * 10

LVEDD (cm) LVM (g)

6 300

2O0

100

NT BH EH NT BH EH

• p<o.05 vs NT + p<0.05 E]H vs EH

increase in central blood volume (2,446 ___ 297 vs. 2,133 _ 447 ml) and diastolic diameter (5.38 _+ 1.23 vs. 4.87 _.+ 0.99 cm); however, statistical significance was not reached because of the small sample size (n = 8). Nevertheless, the increase in left ventricular mass (261.9 - 145.8 vs. 169.6 - 68.9 g) was significant (p < 0.05), even with this small number of female patients. Thus, the findings in the female borderline hypertensive patients appeared to parallel those seen in the group of male borderline hypertensive patients. This subanalysis sug- gests that the variation in gender distribution had no major influence on the main results of the study.

"Stage I" versus "stage II" borderline hypertension. To define more accurately the point at which the first hemodynamic and cardiac structural changes occur in the evolution of essential hypertension, we performed a subanalysis of the data by subdassifying the patients with borderline hypertension into two groups according to their blood pressure pattern during invasive measurement at rest in the hemodynamic laboratory: stage I borderline hypertension (n = 28) = normal diastolic pressure (i.e., <90 mm Hg); and stage II borderline hypertension (n -- 12) = diastolic blood pressure >90 mm Hg. Compared with normotensive control subjects, stage I borderline hypertensive patients were characterized by significant increases in stroke volume (102.6 _ 19.9 vs. 87.0 -+ 22.2 ml/min, p < 0.05) and central blood volume (3,060 _ 679 vs. 2,493 +_ 542 ml, p < 0.05), whereas total blood volume and plasma volume were unchanged (Table 4). These differences persisted when corrected for body height. The main echocardiographic findings seen in the group with borderline hypertension as a whole (Table 3, Fig. 2) could be detected in the stage I borderline hypertensive patients. Compared with normotensive subjects, left ventricular end-diastolic diameter and left ventricular mass were significantly increased in patients with stage I borderline hypertension (5.26 _ 0.84 vs. 4.86 + 0.77 cm, p < 0.05; 237.8 _ 93.3 vs. 183.5 _+ 68.8 g, p < 0.05, respectively) (Table 4). Stage II borderline hypertension, characterized by constantly elevated pressure values at rest, appeared to be somewhat intermediate between stage I borderline hypertension and established hypertension, although no significant

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Table 4. Hemodynamic, Volume and Echocardiographic Findings in Patients With Stage I and II Borderline Hypertension, Normotensive Control Subjects and Patients With Established Essential Hypertension

BH

NT Stage I Stage II EH p In = 33) (n = 28) (n - 12) (n = 43) Value

Mean arterial pressure (mm Hg)

Cardiac output (liters/min)

Stroke volume (ml/min)

Central blood volume (ml)

Total blood volume (ml)

Plasma volume (ml) Total blood volume/Seight (ml/cm)

Plasma volume/height (ml/cm)

Central blood volume/height (ml/cm) Septal thickness (ram)

Posterior wall thickness (mm) Diastolic diameter (cm)

Left ventricular mass (g)

Left ventricular mass/height (gc'cm)

88.7 +_ 7.4 92.3 _+ 6.7 106.2 ± 2.8"? 111.4 ± 8.2*$ <0.001

5.8 = 1.5 6.6 _+ 1.6 6.6 ± 1.7 5.8 ± 1.3 NS

87.0 _~ 22.2 102.6 + 19.9"§ 96.2 _+ 27.1 85.2 ± 19.9 <0.003

2,493 + 542 3,(160 + 679*§ 2,880 _+ 640 2,626 ± 516 0.002 4,795 z 888 5,1184 2-- 910 4,968 _+ 968 4,641 + 1023 NS

2,911 = 566 3,1N9 _+ 530 3,005 ± 579 2,867 + 577 NS

27.9 = 4.1 28.7 z 4.1 28.4 + 4.4 27.1 ± 5.1 NS

17.0 + 2.8 17.5 z 2.5 17.1 ± 2.7 16.8 ± 2.9 NS

14.6 = 2.8 17.2 ± 3.5*§ 16.4 ± 3.1 15.2 ± 2.6 0.006

8.8 - 1.9 9.9 +_ 1.9' 9.8 ± 1.7 11.1 + 2.2*$ <0.0001

8.4 + 1.4 9.11 --_ 1.3 9.0 ± 1.3 10.0 ± 1.5'$ <0.0001

4.86 ~ 11.77 5.26 = 0.84*§ 5.35 ± 0.74 4.79 ± 0.60 <0.007

183.5 _+ 68.8 237.8 z 93.3* 243.2 ± 87.8 232.4 ± 67.4* 0.009

1.1 + 0.4 1.4 = 0.6* 1.4 ± 0.6 1.4 _+ 0.4* 0.02

*p < 0.05 versus normotensive control subjects (NT). ?p < 0.05 versus patients with stage 1 borderline hypertension (BH). Sp < 0.05 versus patients with stage II borderline hypertension. §p < 0.05 versus patients with established essential hypertension (EH). Data presented are mean value ± SD.

difference was observed between stage I and stage II borderline hypertension (Table 4).

D i s c u s s i o n

The present cross-sectional study focused on the hemodynamic, volume and cardiac structural differences between a normotensive control group and patients with different degrees of arterial hypertension.

Borderline hypertension, known to be associated with a higher risk of established hypertension and for excessive cardiovascular morbidity and mortality (4:1,42) was characterized hemodynamically by increases in central blood volume, stroke volume and cardiac output, indicating a centripetal redistribution of total blood volume. Echocardiographically, diastolic diameter and left ventricular mass were increased, demonstrating an eccentric type of cardiac remodeling.

Pathophysiologic mechanisms. Our data confirm previous findings from this laboratory (43) showing that patients with borderline hypertension exhibit a cardiopulmonary redistribution of intravascular volume. Furthermore, the subclassifica- tion of the patients with borderline hypertension allowed us to define more exactly the point at which the first hemodynamic and cardiac structural changes occur in the evolution of essential hypertension. Thus, a shift in the circulating intravascular volume toward the cardiopulmonary circulation, as indi- cated by a marked increase in central blood volume, was already evident in patients with stage I borderline hypertension. Central blood volume was still significantly increased in this early phase of hypertension, although plasma volume, total blood volume, weight, body mass index and body surface area were not significantly different among the groups. This centripetal redistribution of the intravascular volume implies the active participation of the capacitance vessels, suggesting vc-

nous constriction in the patients with early borderline hypertension. The underlying pathophysiologic mechanism for this increase in peripheral venous tone may be an increase in sympathetic vasoconstrictor activity. Indeed, evidence from measurements of plasma catecholamines, from responses to adrenergic agonists and antagonists and, more recently, from direct measurements of sympathetic nerve activity to the muscle circulation (44-50) indicates that sympathetic activity is increased in borderline hypertension. Plasma catecholamine levels, although not the best measure of sympathetic activity (51), in the present study at least indicate a trend toward higher values in the group with borderline hypertension.

Central blood volume, stroke volume and cardiac output levels in the patients with established hypertension were very similar to those observed in the normotensive control subjects. Because of the relatively small sample size in the stage II borderline hypertension group (i.e., the patients with presum- ably more advanced hypertensive disease), caution must be taken when making statements about any differences or lack of differences between this group and the other groups. Never- theless, the data obtained at least indicate that the initial shift in intravenous volume to the cardiopulmonary circulation that characterizes the very early phase of essential hypertension (i.e., stage I borderline hypertension) tends to return to normal as the disease progresses. Similarly, our data support the concept that after an initial increase, cardiac output decreases toward normal values, and peripheral resistance increases as the disease evolves, indicating a shift from a high volume/ cardiac output hypertension to a high total peripheral resistance hypertension (52).

Effect on cardiac structure. In a further extension of earlier data from this laboratory, we were able to document that the hemodynamic and volume changes in borderline hypertension go hand in hand with cardiac structural changes.

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Left ventricular mass together with left ventricular end- diastolic diameter was significantly increased in this group, having been already evident in patients with stage I borderline hypertension. In the patients with established hypertension, left ventricular mass remained elevated, whereas left ventricular end-diastolic diameter decreased toward normal, giving rise to the classic form of concentric left ventricular hypertrophy. A limitation of the study was the fact that the two- dimensional M-mode echocardiographic technique is not suf- ficiently accurate to distinguish load-dependent changes in dimension (Frank-Starling mechanism) from "true" shifts in the pressure-volume relation, which would require more de- tailed invasive hemodynamic measurements. Nevertheless, the M-mode echocardiographic technique is a commonly performed and accepted means of accurately measuring cardiac diameter and wall thickness. By using this technique, we could show that in borderline hypertensive patients these measures are increased, so the ratio between wall thickness and diastolic diameter remains normal. Data supporting an increase in plasma volume in hypertensive patients with eccentric left ventricular hypertrophy and a decrease in patients with concentric left ventricular remodeling have been provided by Ganau et al. (53,54).

Conclusions. Taken together, the present data add to the growing evidence that hypertensive disease encompasses more than increased blood pressure, even to the extent that cardiovascular function and structure may be affected before blood pressure is markedly elevated or total peripheral resistance is increased.

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central blood volume: a determinant of early cardiac adaptation in arterial hypertension?

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