divergent effects of antihypertensive therapy on cardiovascular responses and left ventricular...

Divergent Effects of Antihypertensive Therapy on Cardiovascular Responses and Left Ventricular Function During Upright Exercise

ROBERT A. BRUCE, MD, FACC REGINALD ELEADY-COLE, MB,

BChir, MRCP*t LOWELL J. BENNETT, MD* FUSAKO KUSUMI, MS

Seattle, Washington

From the Department of Medicine (Cardiolo- gy), University of Washington, Seattle, Wash. These studies were supported in part by Grants in Aid HE09773 and HE05281-13 from the National Heart and Lung Institute, RR37 from the National Institutes of Health, HSOOO92 from the National Center for Health Sciences Research, U.S. Public Health Ser- vice, and an award from Merck, Sharpe and Dohme Company. Manuscript received May 1, 1972: revised manuscript received Juty 1. 1972, accepted July 4, 1972.

*Recipients of the Poncin Scholarship for Medical Research, Seattle First National Bank.

*Recipient of Junior Research Award from World Health Organization.

Address for reprints: Robert A. Bruce, MD. Department of Medicine (Cardiology), Uni- versity Hospital, RG-20. University of Wash- ington, Seattle, Wash. 98195.

Maximal oxygen intake (defined by the highest value observed) during upright exercise increased (P qO.05) in 16 patients with essential hypertension but not In 27 of 50 slightly younger, asymptomatic Negro male workers with high blood pressure. Antihypertensive therapy reduced resting blood pressure (P CO.001) in all and decreased pressure at maximal exercise in workers (P X0.001); but duration of multistage treadmill exercise increased significantly (P CO.001) only in patients. Hemodynamic studies at rest and at graded levels of submaximal exercise on a bicycle ergometer in 15 untreated volur~ teers (6 patients and 7 workers) revealed reduced cardiac output and asymptotic relation to oxygen intake In untreated patients. Dur- ing effective antihypertensive therapy, both systemic and pulmonary arterial mean pressure levels were slightly lower (P X0.001) at rest and during submaximal exercise. In patients, cardiac output at high er work loads increased as noncongestive left ventricular failure was corrected and left ventricular function Improved with treatment. In untreated workers, acute reduction of blood pressure with nitroglycerin increased maximal oxygen intake (P CO.001) but was lneffect- ual during antihypertensive therapy.

In conclusion, antihypertensive therapy reduces pressure and improves ventricular function, but only when hypertension is complicat- ed by clinical manifestations of disease and noncongestive heart fait- ure occurs with exertion. Lesser elevations of the level of blood pressure in asymptomatic persons can be modified by drug therapy, but exercise capacity is not improved.

Since administration of nitroglycerin improves work capacity and cardiovascular performance of patients with coronary disease,’ we considered evaluation of the effects of chemotherapy on hypertensive patients important. Patients with established hypertension, referred for treatment, and asymptomatic healthy workers with increased blood pressure were tested in the course of antihypertensive therapy for changes in maximal oxygen intake and hemodynamic responses to graded levels of upright exercise. Protection against congestive heart failure, as r’eported in clinical studies,* was noted. Since electrocardiographic manifestations of myocardial ischemia were more frequent, the possible relation to myocardial infarction as a compli- cation of otherwise successful treatment emerges.*,3

Material and Methods

Table I shows the physical and circulatory characteristics of 16 clinical patients referred for treatment and studied by Dr. Eleady-Cole. These sed-

708 November 20,1972 The American Journal 01 CARDIOLOGY Volume 30

ANTIHYPERTENSIVE THERAPY AND HEMODYNAMICS DURING EXERCISE-BRUCE ET AL.

TABLE I

NS NS

NS

<O.Ol <O.OOl

NS

NS NS <0.05 NS NS NS <O.Ol <O.OOl <O.Ol

Physical and Circulatory Characteristics of Hypertensive Men Aged 24 to 64 Years

16 Patients 27 Workers P

Basis for study

Blood pressure at rest (criteria for admission) (mm Hg)

Age Or) Weight (kg) Grade I (KW) retinopathy (no.) LVH by ECG (no.) Mean resting values (sitting)

Heart rate (beats/min) Systolic pressure (mm Hg) Diastolic pressure (mm Hg)

Mean values during multistage treadmill test Stage I

Heart rate (beats/mln) Systolic pressure (mm Hg)

Maximal stage Heart rate (beats/min) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Pressure-rate product/100 Change in heart rate (beats/mm) Change in systolic pressure (mm Hg) Vo,max, [ml/(kg-min)] Duration (set) Functional aerobic impairment 6)

Referred for treatment

Systolic >150 Diastolic >lOO

50 f 10 72.3 f 12.9

3 (19%) 1(6%)

a2 f la 172 f 20 113 & 10

135 f 21 191* 22

160 f 23 2l2It 23 102 f 19 344+ 60 a2 + 31 48 f 35

23.1 f 5.7 317 f 156 34 * 20

Identified by screening BP

Systolic >160 Diastolic >90

46 f 10 a2 f 15 0 0

a0 z?z 16 152 f 18 loo* 9

134* 17 195k 28

172 +z 17 220 f 40 a9 f 16

375 z!z 74 92f 20 68& 30

29.7 f 6.1 490 f 116

17 f 13

BP = blood pressure; KW = Keith, Wagener and Barker classification; LVH = left ventricular hypertrophy.

entary hypertensive patients (11 men and 5 women of 50 f 10 years of age) were considered to have benign essential hypertension after clinical evaluation. There was no evidence of any primary cause. The patients had no clini- cally detectable coronary heart disease, congestive heart failure, stroke, varicose veins, significant obesity or diabetes mellitus. Initial resting blood pressure, which was recorded as the median of 7 consecutive measurements obtained with a clinical sphygmomanometer, with diastolic pressures defined by fiih Korotkoff sound, averaged 1721 113 mm Hg. Dr. George Aagaard, the attending physician, defined the “optimal therapy” as the therapeutic regi- men required to reduce blood pressure and restore a feel- ing of well-being without untoward symptoms, especially those due to orthostatic hypotension. The drugs used in- cluded hydrochlorothiazide or chlorothiazide, reserpine, methyl dopa and clonidine, individually or in combina- tion, in doses sufficient to lower blood pressure consistent- ly. Some patients were fiit studied after drug therapy and others before treatment, to avoid a systematic bias in the sequential tests.

Eight patients (aged 31 to 59 years, mean 46.9 * 11.1 years) volunteered for additional hemodynamic studies. None had azotemia or more than grade 1 retinopathy. Besting blood pressure averaged 161/107 mm Hp. Chest roentgenogram revealed that 4 patients had slight cardio- megaly. One had electrocardiographic evidence of left ventricular hypertrophy.

Besting blood pressures of 260 Negro male employees of the University of Washington and the Seattle Post Office

were screened by Dr. Bennett. Fifty subjects (19 percent) had hypertension, defined as a systolic pressure of 160 mm Hg or more or a diastolic pressure of 96 mm Hg or more by fifth Korotkoff sound, or both, on 3 occasions, twice when they were sitting and once when resting supine. Twenty-seven (54 percent) who voluntarily participated in this study had a mean age of 46 f 10 years and a mean resting pressure of 152/100 mm Hg (Table I). Only 5 had prior elevations of blood pressure level; 1 had previ- ous antihypertensive therapy, but none was currently receiving therapy. All were asymptomatic, without congestive heart failure, coronary disease, stroke, diabetes mellitus or significant obesity. None had azotemia, proteinur- ia, greater than grade 1 retinopathy or electrocardiographic evidence of myocardial infarction. After undergoing treadmill exercise to a point of maximal tolerance, the workers were randomly assigned to a “treatment” or “pla- cebo” subgroup. They were then treated for 3 months with hydrochlorothiazide, 50 mg daily, or, if clinical response was poor, hydrochlorothiazide plus reserpine, 0.25 mg daily, was added before repeating the treadmill exercise test. Each subject was then assigned to the opposite regi- men for the next 3 months, and maximal exercise testing was repeated. Interim history, blood pressure measurements were obtained and fundoscopic examinations performed on each occasion of testing.

All patients and workers performed a multistage treadmill test of submaximal and maximal exercise to a level of “symptom-limited capacity”.’ A bipolar CBs electrocardiogram was monitored with an oscilloscope and recorded

November 20.1972 The American Journal of CARDIOLOGY Volume 30 769

ANTIHYPERTEN~IVE THERAPY AND HEMODYNAMICS DURING EXERCISE-BRUCE ET AL.

TABLE II

Hemodynemic Characteristics Before and During Antihypertensive Therapy

Exercise

Before Antihypertensive Therapy (no. = 8)

Rest 1 2 3

During Antihypertensive Therapy (no. = 8)

- P Valuet Rest 1 2 3 P Valuet

A. Hypertensive Patients* -___

Work load (watts) 0 31+ 6 85 * 14 lO4z1~ 16 . . . 0 31+7 81 z!z 16 109 * 19 . . .

90, (ml/mm) 315 & 23 823 f 88 1443 i 107 1593 f 148 . . . 302 Z!I 36 854 & 67 1448 i 142 1548 f 247 NS ?TJ Vo, max 16 f 2 42 z!z 8 79 f 11 87 j, 11 . . . 15 * 3 42& 5 74 i 13 72~ 14 <O.Ol

Q (liters/min) 5.7zt 1.5 8.4ztz 1.2 11.9& 0.8 12.4zt 0.7 . . . 5.0 f 1.2 9.1+ 0.9 13.3zt 1.9 13.7 ziz 2.4 NS a-v 0, diff (ml/liter) 58 f 14 99 z!C 11 122 f 10 128 f 8 . . . 62zt 8 94zt-7 111 f 9 115 * 10 <O.OOl SV (ml) 64zt 11 78 f 10 86 f 7 84+8 . . . 59 f 11 81+ 11 97 f 13 95* 12 <0.02 HR (beats/min) 89 XIY 17 109 f 18 140 f 16 150 f. 16 . . . 84 f 12 114 f 14 138i21 144zt225 NS

S& P (mm Hg) 135 X!I 16 145 i 13 152 i 11 158 zk 10 . . . 121 IrI 9 131 i 15 144i 11 1401 13 <O.Ol E P (mm Hg) 15* 3 22* 3 31* 5 31*5 . . . 12* 2 18 f 3 27 z& 6 24 f 6 <O.OOl Est LVEDP (mm Hg) 10 f 2 14+ 2 21zt 3 21&3 . . . 8f2 11* 2 18 f 5 14 f 4 <O.OOl

SV/ti 4.6zrz 1.9 3.6zt 0.6 2.8& 0.3 2.7+ 0.4 . . . 5.1 f 1.1 4.5~tO.5 3.8ztl.O 4.0~1~0.5 <O.OOOl PR/lOO 118 z!z 26 155 f 25 2O6*31 234zt 30 . . . 99 zt 6 147 f 20 188 f 38 2O6z!z48 NS s R set (dyne cm-e) 1988 & 666 1375 f 341 988 f 83 938f 74 . . . 2554 zt 780 1425 zt 125 1103 f 132 1038 & 126 NS G R (dyne seccm+) 219 & 62 211 Z!G 41 205 i 28 199 * 30 ..* 197 * 40 160 + 28 165 f 50 147 * 33 .NS

STB&) lzt 58 -66 f 108 -122 f 141-124 z+z 138 . . . -14+ 30 -20 + 45 -41 C!Z 39 -61 f 53 NS

B. Hypertensive Workers*

Before Hypertensive Therapy (no. = 7) During Antihypertensive Therapy (no. = 7)

Work load (watts) 0 54 & 10 96 rt 19 125 f 31

00, (ml/min) 311 f 71 1088 f 168 1620 ZIX 283 1838 f 430 96 Vo, max 13* 3 45* 4 68z!z 8 76f 9 Q (liters/min) 5.1ztz 2.110.4& 2.0 13.2& 3.2 14.4& 3.6

(P<O.5) a-v OS diff (ml/liter) 63 f 11 105 f 9 123 zt 4 130 f 3 SV (ml) 61 Z!C 22 89 f 17 92 f 19 86 f 17 HR (beatsfmin) 89 i 18 118 i 18 145 i 16 165 f 23

S2 P (mm Hg) 127 f 18 145 z?z 28 158 z!z 19 fi P (mm Hg) llf 3 22 f 4 26zt 3

(P<O.o4) Est LVEDP (mm Hg) llf 2 20* 3 24+ 2

sv /PA 5.9zt 3.0 4.2f 1.1 3.6 ZII 1.0 (P<O .Ol)

PR/lOO 110 i 31 171 f 48 229 + 43 a R set cm (dyne -“) 2186 f 633 1147 f 337 1014 f 289 PA R set (dyne cm-‘) 193 f 74 169 f 37 165 f 47

166 z+z 13 31+ 6

27% 5

2.8 z!z 0.8 (P<O.O3) 272 f 42 964 + 231 176 f 41

(P<O.Ol)

STB (I1v) 46* 53 23& 43 -33zt 43 -59 f 59

. . . 0 55 f 11 95 f 21 125 + 31 . . .

. . . 292 * 48 1058 f 119 1497 zip 255 1748 f 357 <O.Ol . . . 12 f 2 44*7 62f 6 72+5 NS . . . 4.4+ 1.8 lO.lzt 1.9 12.4f 2.6 14.8+ 2.9 <O.Ol

. . . 57 f 7 104 ZIY 13 121 f 11 128 f 12 NS

. . . 69 f 27 94 f 17 94 f 18 91 YIZ 10 NS

. . . 79& 13 112 i 22 134 i 22 152 f 23 <O.OOl

. . . 127 f 17 149 zt 22 161 f 22 165 f 19 NS

. . . 14zt 3 25zt 3 26 f 4 28&t NS

. . . 13rt 2 22f 3 24f 3 25zt4 NS

. . . 5.1 f 2.1 3.7zt 0.5 3.6f 0.8 3.3+ 0.7 NS

. . . 99 f 22 165 f 32 212 f 26 247 ziz 25 <O.OOl

. . . 2658 f 1140 1214 f 365 1093 z& 359 lOO2 & 298 NS

. . . 223 & 69 MC29 173 f 46 170 +z 48 <0.02

. * . 60 f 56 54f 54 -22 f 53 -47 f 58 NS

C. Acute Effects of Nitroglycerin in Hypertensive Workers*

Work load (watts)

$0, (ml/min) % Vp, max

Q (liters/min)

a-v OI diff (ml/liter) SV (ml) HR (beats/min)

s P (mm Hg) PA P (mm Hg) Est LVEDP

Without Antihypertensive Therapy (no. = 6) With Antihypertensive Therapy (no. = 5)

. . . 60 f 14 1OO+20 131+ 32 . . . . . . 55 f 11 95 f 21 125 f 35 . . .

. . . 1112 +z 212 1614 i 346 1943 z!z 450 NS . . . 980 f 230 1545 f 310 1823 f 410 NS

. . . 46+6 66*7 79zt 5 NS . . . 38*4 60 zrz 7 71+5 NS

(P<O.O5) . . . 10.3+ 2.4 13.0+ 3.5 14.5+ 3.6 NS . . . 9.2zt 2.4 13.6 f 3.0 14.4 f 3.5 NS . . . 111 f 10 126 f 7 134 z?z 6 <O.Ol . . . 108 f 6 115 f 11 l28zr111 NS . . . 79* 19 87 f 19 84+ 16 <0.02 . . . 76 f 21 94 f 14 86 f 11 <0.05 . . . 137 f 13 150 f 17 174* 14 <O.Ol . . . 123 -I 21 142 f 18 160 f 21 <O.OOl

. . . 133 f 13 150 * 12 155 f 15 <O.Ol . . . l28zt 18 146+20 145 f 24 <O.OOl

. . . 16+ 5 21* 3 25 I!.Z 5 <O.OOl . . . 20* 4 24z?z 5 24z!z 4 <O.OOl

. . . 15 f 3 20* 2 22 f 4 <O.OOl . . . 18f 3 22rt 4 22+ 3 <O.OOl

(continued)

770 November 20,1972 The American Journal of CARDIOLOGY Volume 30

ANTlHYPERTENSIVE THERAPY AND HEMODYNAMICS DURING EXERCISE--BRUCE ET AL.

TABLE II (continued)

Hemodynamic Characteristics Before and During Antihypertensive Therapy

Exercice

Before Antihypertensive Therapy (no. = 8) During Antihypertensive Therapy (no. = 8) .--_ ~_._

Rest 1 2 3 PValuet Rest 1 2 3 P Valuet --. -. -.~ ---

SV/PA . . . 4.2f 1.0 3.6f 1.0 2.8& 0.7 <O.OOl . . . 3.9zt 1.3 4.0 f 0.8 3.7 + 0.6 NS

(PCO.05) PR/lOO . . . 17lk 48 224 f 34 268zk 23 NS . . . 155 +I 28 205 I 25 229 * 37 <O.Ol % R (dyne set cm -6) . . . 1090 f 280 985 k 274 898 + 258 NS . . . 1195 f 447 905 rt 291 844 f 260 NS l%R(dyneseccm-6) . . . 134f 49 139 t 44 141f 46 <O.OOl . . . 184~1176 138 z?z 44 141+ 47 <0.02

STB Gtv) . . . 3* 29 -9 f: 37 -33zk 87 NS . . . 20f 27 -15zk 25 -121k 84 NS

* Age range 35 to 55 years (mean 45.8).

i Pvalue in A and B refers to probability of difference between means for all periods of observation of treated patients with chronic

hypertension vs. untreated control subjects; in C, Pvalue refers to probability of difference between means for all periods of observation with and without nitroglycerin.

a-v Ot diff = arterlovenous oxygen difference; HR = heart rate; LVEDP = left-ventricular end-diastolic pressure; NS = not significant. % P = pulmonary-arterial pressure; fi R = pulmonary-arterial resistance; PR = pressure-rate product (see text); 0 = cardiac output; $% P = mean systemic-arterial pressure; SA R = mean systemic-arterial resistance; STB = S-T segment at 50 to 69 msec after nadir of S; SV = stroke volume; 90, = oxygen consumption per minute.

directly on paper at 1 minute intervals for immediate qualitative assessment of electrocardiographic changes. Magnetic tape recordings were subsequently averaged by computer for 100 consecutive S-T segment responses at selected intervals. Methods are recorded elsewhere.s One minute samples of expiratory air were collected during the final 2 to 4 minutes of exercise; oxygen intake was calcu- lated from the volume of expired air and concentrations of oxygen, with and without absorption of carbon dioxide.* Blood pressure was recorded with a clinical sphygmomanometer while the subject sat at rest before exercise, 2 l/2 minutes later at the lowest work load of exercise (1.7 miles/hour, 10 percent gradient), and immediately after maximal exercise, while sitting. After resting.for 30 to 40 minutes, most hypertensive workers were given nitroglycerin, 0.4 mg sublingually, and retested for possible changes in cardiovascular performance.

Eight patients and 7 workers participated in hemodynamic studies at rest and at graded levels of submaximal work loads on a bicycle ergometer. Right heart catheterization was performed percutaneously with either a poly- vinyl catheter or a Swan-Ganz catheter inserted into an antecubital vein and advanced, with pressure monitoring, into the main pulmonary artery.6 Another catheter was introduced percutaneously into either the radial or the brachial artery. Zero pressure levels were adjusted to the fourth intercostal space at the mid-clavicular line ante- riorly. Pulmonary and systemic arterial pressures were recorded with Statham pressure transducers, Honeywell carrier amplifiers and a direct-writer oscillograph. Mean arterial pressure was derived by a second-order low-pass filter with a 0.16 Hz cut-off frequency.

Pressures and direct Fick cardiac output determinations were obtained during the minute of rest and of upright exercise at 43 and 79 percent of individually measured maximal oxygen intake in patients, and at 45, 68 and 76 percent of maximal oxygen intake in workers, as described previously.7 Work loads 1 and 2 continued for 5 to 7 minutes and work load 3 for 4 minutes. The subjects rested

for 20 minutes between the fit 2 work loads, and for 30 minutes before the last work load. After resting another hour, the hypertensive workers received nitroglycerin, 0.4 mg sublingually, and repeated the same exercise proce- dure.

Left ventricular end-diastolic pressure was estimated from mean pulmonary arterial pressure and stroke volume by regression equation (estimated left ventricular end- diastolic pressure = [mean pulmonary arterial pressure + 1.33 - 0.05 stroke volume)/1.34).s Hemodynamic afterload on myocardial metabolism was assessed by product of heart rate and mean systemic arterial pressure/lOO. Afterload was overestimated whenever peripheral vasodi- lation, induced by drug therapy, redistributed blood volume into peripheral vessels. As a consequence, diastolic filling volume and pressure, as well as the systolic wall tension of the left ventricle, diminished in the upright posture. Ratio of stroke volume to mean pulmonary arterial pressure revealed changes in ventricular compliance in diastole and myocardial contractility in systole. (None of the subjects had pulmonary hypertension, mitral ste- nosis or pericardial constriction to affect pulmonary arterial pressure.)

Plotting the sequential relation of stroke volume to mean pulmonary arterial pressure and product of heart rate and mean systemic arterial pressure/100 at rest and graded levels of upright exercise showed a curve of left ventricular function; effects of drug therapy were mani- fested by a displacement of this function curve.

Differences in variables were evaluated by the unpaired t test; changes resulting from therapy were assessed by the paired t test.

Results

Major responses during the experimental condi- tions of selection and study are summarized in Table II, A to C, and Figures 1 to 5.

Changes in circulation and aerobic capacity at maximal exercise: Treatment of patients de-

November 2O,lg72 The American Journal oi CARDIOLOGY Volume 30 771


I Patlents (N=16-12) 1 Workers CN:27.18) 1

I” ; 200

r

2150 :

&

VlOO

E 5

2 50 In

0

t With Sphygmomanometer . Multistage TreadmIll

FIGURE 1. Effects of long-term antihypertensive therapy for 3 months on systolic (S) and diastolic (D) systemic arterial pressures at rest and during maximal exercise in patients and workers. Changes in mean talues indicated.

Patients

represented by -0, with probability

Workers

Dura tlon

- 0 .5 . 1.5 2.0 90, max L/mln

I 0 2 4 6 6 10

Minutes

0 .5 1.0 1.5 2.0 2.5 i/o2 max L/mln

FIGURE 2. Effects of chronic antihypertensive therapy on exercise capacity. Graph shows duration of exercise and oxygen intake during maximal exercise in patients and workers.

! ‘f@ Antihypertensive 5,

(N=lB)

Rest Max Exe;

n-10

FIGURE 3. Effects of acute nitroglycerin therapy in workers with hypertension. Graph shows effects of nitroglycerin on systemic pressures, both systolic (S) and diastolic (D) at rest and during maximal exercise. The reductions in pressure are insig- nificant when workers are already receiving antihypertensive therapy.

creased systolic and diastolic blood pressures at rest (P <O.OOl) but not during maximal exercise (Fig. 1, Table I). Systolic and diastolic pressures in workers decreased with antihypertensive therapy both at rest and during maximal exercise (P CO.001).

Heart rates of patients were unchanged with therapy, whereas workers showed a slight reduction in resting heart rate with therapy (P cO.05). The pressure-rate product decreased significantly in both groups at rest and during submaximal and maximal exercise (Table II, A and B).

Mean duration of multistage treadmill exercise increased significantly (from 5.23 to 6.60 minutes) in patients (P <O.OOl) but insignificantly (from 8.17 to 8.65 minutes) in workers (Fig. 2). Maximal oxygen intake increased slightly in patients (P cO.05) with drug therapy, but remained at the same higher level in workers (Fig. 2).

Acute effects of nitroglycerin on responses to maximal exercise: Nitroglycerin given to workers reduced systolic and diastolic blood pressures (P <O.OOl) (Fig. 3) and increased maximal oxygen intake from 29.7 to 31.5 ml/(kg-min) (P <O.OOl) (Table IIC).

Although heart rate was faster (P X0.001), pressure-rate product was unchanged at rest and decreased with exercise. Duration of exercise increased slightly from 8.17 to 8.73 minutes (P <0.05), whereas functional aerobic impairment decreased from 17 to 11 percent (P <O.OOl). Nitroglycerin with chronic antihypertensive therapy decreased systolic pressures only (P <O.OOl), but neither resting nor maximal heart rate changed. Duration of exercise increased by only 12 seconds; functional aerobic impairment diminished 2 percent.

Changes in hemodynamic responses to upright exercise: During antihypertensive therapy, patients showed reduced systemic and pulmonary arterial pressures at rest and at all levels of exercise (Fig. 4). Estimated left ventricular end-diastolic pressure, pressure-rate product and percent maximal oxygen intake diminished at each work load. With therapy, cardiac output and stroke volume diminished at rest, but increased with higher, work loads of exercise as left ventricular preload and afterload were modified. Peripheral resistance was reduced only during exercise. Heart rates were lower and arterial mixed ve- nous oxygen difference was reduced with treatment (P <O.OOl). Unexpectedly, workers showed no significant hemodynamic changes with chronic antihypertensive therapy. At the lowest work load, ratio of stroke volume to mean pulmonary arterial pressure increased with nitroglycerin but diminished with chronic antihypertensive therapy (Fig. 5).

Discussion

Earlier studies revealed different hemodynamic patterns in relation to severity of hypertensions-17 and age.12J6,17 Maximal exercise testing evoked no impairment in younger patients with increased blood



FIGURE 4. Hemodynamic responses to upright exercise on Monark bicycle ergometer in patients and Workers. Graph compares effects of antihypertensive therapy (and nitroglycerin) on cardiac output, systemic and pulmonary arterial pressures at rest and during 3 levels of upright exercise. Pressures are reduced in both groups but. in patients, cardiac output increases at higher work loads only.

FIGURE 5. Changes in left ventricular function and S-T segment responses. Graph shows divergent 8ff8CtS Of therapy on hemodynamic and electrocardiographic ind8X8S of left ventricular function. Note improvement in function, with more suggestion of ischemia in patients, and opposite effects, especially with nitroglycerin. in workers.

Patrents Workers

- UntWJted CO”trOlS -0 Chrome TreJt”Wnt

I I I I 0 500 1000 1500 2CCC 0 5Dcl 1000 1500 2DCD

Oxygen Intake, ml/mm Oxygen Intake, mvmin

I”200 200

E

$ 150 - Systemic Pco2 150 - t /---9

,_/c- /&%I~’

m $ too- 100 -

r Q

$ 50- 5o 5 P”‘m~‘P~ool j 1 pcoo,

0 5 10 15 20 0 5 10 15 20

Cardiac Output, l_/mln Cardrac Output, L/mm

Patrents Workers v uP’,tI-tJtd Controls

W--o Chronr TreJtmcnt

6-d Nltroglycerln

6- 6- Rest

Rest 1

4- *oo’

2- 1 2 3 EXeKlSe Exercise

1 0 100 200 300 200 300 400

PR/lOO PR/lOO

100 100 Rest

n Rest

5 O-

b I b -lOO- 5

EXerClSc m Exercrse

L -2oo- -200 -

0 L

50 100 150 200 0 50 loo 150 200 Heart Rate Heart Rate

November 20.1972 The American Journal ot CARDIOLOGY Volume 30 773


pressures and showed progressively greater impairment in older patients with higher levels of hypertension, left ventricular hypertrophy, retinopathy and coronary heart disease.l? Sannerstedt16 found that hypertensive patients with retinopathy had a greater increase in arterial pressure and peripheral resistance and a smaller increase in cardiac output with exercise in the upright posture. In our study, ‘both workers and patients exhibited the divergent hemodynamic patterns noted in earlier reports. Ini- tially, the slightly younger, asymptomatic workers had lower systolic and diastolic pressures at rest and with maximal exercise, greater exercise capacity, longer exercise duration and greater maximal cardiac output. In workers, at a work load averaging 78 percent of maximal oxygen intake, values for arteriovenous oxygen difference were 8 ml/liter lower and those for cardiac output and heart rate 2.5 liters/min and 25 beats, respectively, higher than values observed in patients. There was a greater difference in cardiac output ‘(21 percent) than in arteriovenous oxygen difference (6.5 percent), and a greater difference in heart rate (18 percent) than in stroke volume (7 percent). In both groups, the greatest stroke volume was observed at an intermediate work load level, and this volume diminished slightly as the lim- its of ventricular compliance and contractility were exceeded at the highest work load level.

In both groups, chronic antihypertensive therapy significantly reduced systemic and pulmonary arterial mean pressures. Although increased pulmonary arterial pressure in the supine position has been observed with exercise in older hypertensive patients,12 reduction of pulmonary arterial pressure with therapy has not been reported to our knowledge. Estimat- ed end-diastolic pressure of the left ventricle showed

a statistically significant hemodynamic change with antihypertensive therapy, whereas the pressure-rate product at submaximal exercise diminished and the stroke volume to mean pulmonary arterial pressure ratio increased. Since only the cardiac output of treated patients increased at work loads of 70 to 80 percent of maximal oxygen intake, this response represented improved cardiovascular efficiency. The finding suggests greater left ventricular diastolic compliance and greater contractile force during antihypertensive treatment. Functional aerobic impairment also diminished toward normal as duration of exercise lengthened.

Curiously, the workers showed little benefit from antihypertensive therapy. Oxygen intake, cardiac output and heart rate decreased slightly. The stroke volume to mean pulmonary arterial pressure ratio was slightly lower at rest and at moderate work. The condition of the workers was not refractory, because greater changes were observed acutely with nitroglycerin, except when the workers were already receiving chronic antihypertensive therapy. Nevertheless, myocardial ischemia, especially when treatment was combined with nitroglycerin, increased as pressure decreased.

Since these studies document differences in hemodynamic responses to exercise between the earliest and intermediate phases of hypertensive cardiovascular disease, the reported protection of antihypertensive therapy in patients against congestive heart failure is more readily understood.2

Acknowledgment We acknowledge the clinical supervision and manage-

ment of the hypertensive patients by Dr. George Aagaard, and thank Alison Ross for editing and Jacqueline Eddy for typing the manuscript.

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divergent effects of antihypertensive therapy on cardiovascular responses and left ventricular...

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