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Hyperkinetic heart in severe hypertension: A separate clinical hemodynamic entity
STUDIES IN HYPERTENSION
Hyperkinetic
Heart in Severe Hypertension:
Hemodynamic
M. MOHSEN ROBERT HARRIET
IBRAHIM,
Cleveland,
Clinical
Entity
MD,
FACC
C. TARAZI, MD, FACC P. DUSTAN, MD, FACC
EMMANUEL L. BRAVO, RAY W. GIFFORD, Jr.,
A Separate
MD MD,
FACC
Ohio
A long-term study of established hypertension helped identify a well defined group of 10 patients who differed both clinically and hemodynamically from 59 patients with the more frequent form of this disease. Their cardiac output was significantly increased (P
Whereas augmented cardiac activity is known to occur in patients with mild and borderline essential hypertension,‘-3 the association of increased cardiac output with severe long-term elevation of arterial pressure has not been described. In a previous communication we reported evidence for excessive cardioadrenergic drive in some patients with established hypertension .4 Further study of these and other patients suggested that they represented a separate clinical hemodynamic group. We therefore report here in greater detail their characteristics together with results of studies of autonomic nervous function and possible factors regulating cardiac output. Their response to therapy and incidence of complications during a long follow-up period are also described. Methods Clinical Studies
From the Research Division and the Department of Hypertension and Nephrology, the Cleveland Clinic Foundation and the Cleveland Clinic Educational Foundation, Cleveland, Ohio. This study was supported in part by Grant HL 6835 from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., The John A. Hartford Foundation and the U. A. Whitaker Fund. Manuscript accepted September 19, 1974. Address for reprints: Robert C. Tarazi, MD, Research Division, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44108.
Ten patients were studied; some of the data on eight were reported previously.4 Since this investigation was limited to patients with essential hypertension, one case, reported in our early study, was not included here because the patient had mild proteinuria and kidney biopsy revealed membranoproliferative glomerulonephritis. All patients had complete clinical and laboratory evaluation including creatinine clearance studies and renal arteriography. Ocular fundi were graded according to the Keith-Wagener-Barker classification. Electrocardiographic signs of left ventricular hypertrophy were described as either definite or probable. Definite signs were one or more of the following: R wave in lead aVL greater than 11 mm,5 S wave in lead VI 24 mm or greater,” or sum of the tallest and deepest precordial R and S waves exceeding 45 mm.7 The first two criteria were reported to have no false positives5; for the third criterion, false positives were reported in 1.68 to 7 percent.g When the sum of S in lead VI and R in lead Vg was greater than 35 mm,5 left ventricular hypertrophy was diagnosed as “probable.” Tests for pheochromocytoma and thyroid function were performed in all and tests for
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35
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HYPERKINETIC
TABLE
HEART
IN HYPERTENSION-IBRAHIM
ET AL
I
Clinical Characteristics
BSA (m*)
Age (yr) Case no. &Sex
~~
~
Hypertension
Age at DurationOnset
BloodPressure(Hospital Reading) (mm Hg)
(yr)
(yr)
Family History
Average
Range
2 3 4 5 6 7 8 9
2.41 1.65 1.64 1.82 2.11 2.14 1.83 2.00 2.16
26 13 16 20 12 18 8 10 23
30 33 39 19 22 24 48 39 20
Yes No Yes Yes Yes Yes Yes ? Yes
150/100 155/100 142/91 210/130 187/126 145197 184/104 2201143 139/95
130/86to X30/118 130,'90to196/124 126/86to178/110 140/108to290/140 160/110to 250/160 130/87 to 240/140 150/100to 220/120 150/104to240/162 124/86to 172/120
II 0 II I I II I I
+ 0 + + 0 + * 0
11 0 0 I-II 0 I-II 0 I
II
Base LSB 0 0 Mitral 0 Base 0
+ 0 0 * =t 0 f 0
LSB
0
10
47M
2.10
17
30
No
195/129
142/96 to 236/150
II
+
0
0
+
1.99 0.08
16.2 2.0
30.4 3.4
1731112 9.515.8
138/95to 220/134 3.8/30to 12.1/5.9
Average 46.7 SE 2.4
* Keith-Wagener-Barker classification. + =definite;& = probable;O= absent. BSA = bodysurfacearea; LSB = leftsternalborder;LVH on ECG= = standard error.
Studies
All investigations were performed in a quiet laboratory in the morning with the subjects fasting and resting comfortably supine. Catheters were introduced into an antecubital vein and brachial artery by the Seldinger technique and advanced to the innominate vein or superior vena cava and to the axillary or subclavian artery, respectively. In five patients the catheters were carefully positioned under fluoroscopy at the junction of the superior vena cava and right atrium and in the ascending aorta. Cardiac output was determined at least in triplicate using indocyanine green dye (5 mg) introduced into a transparent tube connected to the venous catheter and then flushed as rapidly as possible into the circulation with 5 to 10 ml of saline solution. Dye-dilution curves were obtained by the usual methods as previously described,‘OJl and blood was reinfused immediately after the inscription of the curve to avoid blood loss. Cardiac output was calculated by the Stewart-Hamilton method. Cardiopulmonary volume was determined in the five patients with centrally positioned catheters as the product of mean transit time (corrected for catheter delay) and blood flow per second. Arterial and venous pressures were
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electrocardiographicevidence ofleftventricularhypertrophy:SE
primary aldosteronism were used when indicated. In all patients, antihypertensive therapy was discontinued for at least 1 month before hospitalization. Although the patients were hospitalized, they were not restricted in diet or activity. The severity of hypertension was indicated by the level of arterial pressure measured in the hospital or the development of cerebrovascular complications; in all patients diastolic pressures measured in the office were consistently greater than 110 mm Hg. The duration of hypertension was documented as closely as possible in each patient by reference to old records, previous hospitalizations, rejections for military service or life insurance and by contact with the family physician when necessary. Hemodynamic
I
LVH on ECG
56M 46M 55F 39M 34M 42M 56F 49F 43M
1
666
Systolic Murmurs .__ Fourth Ocular Heart Grade Maximal Fundi* Sound (I-VI) Intensity
Volume 35
measured using Statham P23DB transducers. Derived variables-total peripheral resistance, stroke volume and mean rate of left ventricular ejection-were calculated by the usual methods. In three patients (Cases 1,9and 10)minute oxygen consumption was measured at the time of hemodynamic study; expired air was collected in 120-L Douglas air bags and contents were analyzed by Beckman oxygen analyzer; results were corrected for standard temperature and pressure. Results of cardiac output measurements were compared with those in two previously described control groups,3 one of 29 normotensive subjects and one of 59 patients with fixed essential hypertension. Values for cardiopulmonary volume were compared with measurements in nine normal volunteers previously described.12 Plasma and Total Blood Volume Plasma volume was determined in the morning after an overnight fast and after the patient had been allowed to rest in the supine position for at least 30 to 45 minutes. It was computed directly by the Volemetron@ from plasma samples obtained 10 minutes after injection of iodine-131, 5 PCi, or iodine-125, 2.5 &!i. Total blood volume was calculated from the plasma volume and venous hematocrit; the latter was detqrmined, by capillary microcentrifugation from four samples of blood drawn without stasis, and appropriate correction factors were used for the differences betwaen large vessel and total body hematocrit.13 The meth@ and calculations, as well as normal values for laboratori, have pre+o&ly been described in detail.14 Volume determinations were usually performed just before the hemodynamic studies or, occasionally, the day before under exactly the same conditions. Results were expressed as percent of normal to allow for sex differences.14 In 9 of the 10 patients, plasma renin activity was determined by a modified Pickens method15 in peripheral blood samples obtained at the time of the blood volume determination.
HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
ET AL.
In nine patients systolic time intervals were determined from simultaneous recordings (100 mm/set) of the external carotid arterial pulse, phonocardiogram and electrocardiograml”; these measurements were obtained either at the same time as the hemodynamic study or occasionally the day before. The following intervals were measured from at least 10 complexes, as previously described*: total electromechanical systole (Q-AZ), left ventricular ejection time (LVET), preejection period (PEP) and isovolumic contraction period (IVCP). Results were compared with values obtained from 1’7 normotensive subjects, and corrections for heart rate calculated according to the equations of Weissler et a1.16
to an early stage, the impressive finding was the severe elevation of arterial pressure at a young age. During their hospital stay the same lability of pressure was observed (Table I). In four patients the weekly hospital averages were generally less impressive than the usual office readings. Grade I to II changes in ocular fundi were present in all but one patient, who had normal eyegrounds. Five patients had cardiac systolic murmurs (Table I). All had vigorous peripheral and carotid arterial pulses. Electrocardiographic signs of left ventricular hypertrophy were definitely present in two patients and “probable” in three more.
Tests of Autonomic
Follow-Up
Systolic Time intervals
Nervous Activity
Tests of autonomic nervous activity were obtained during the hemodynamic study with continuous intraarterial pressure recording; the Valsalva maneuver was performed in duplicate by blowing a mercury column to 40 mm Hg and maintaining it at that level for about 10 seconds. The diastolic pressure overshoot following Valsalva maneuver was expressed both as percent increase over control levels and as a fraction of the reduction in pulse pressure obtained during straining. l7 Results were compared with those in a closely matched group of patients with fixed essential hypertension and a group of normal subjects.r8 Cold pressor test was performed by immersing the patient’s hand to the wrist in ice cold water for 1 minute. Changes in arterial pressure were compared with previously reported results in normal subjects and in patients with essential hypertension.18 Isoproterenol was infused in five patients at sequentially increasing rates (0.01, 0.02 and 0.03 pg/kg per min). Effect of the “0.03 bg” dose level upon heart rate was compared with its effect in 31 patients with essential hypertension and in normal subjects.ig Results Clinical Features
Table I summarizes the important clinical characteristics of the patients studied. Common features were the early age of onset and the long duration of hypertension. Seven patients had a family history of increased arterial pressure. Symptoms of anxiety (“feel nervous,” “worrying a lot,” “have fear episodes”) were the main complaints. Cardiac awareness, rapid heart rate, flushing, pallor, sweating, headaches and dizzy spells were present in different combinations in all patients. Flushing of the neck and upper part of the chest when nervous, manifested by erythematous patches (diencephalic flush), was a common finding. Marked lability of hypertension ranging from almost normal levels of 124/86 to alarming degrees of 300/160 mm Hg during ambulation was characteristic. This gross variability of arterial pressure, in addition to the symptoms mentioned, raised the possibility of pheochromocytoma in all patients. All were carefully studied for that possibility at some stage of their disease; in some, these studies were repeated two or three times to rule out this diagnosis. In patients whose arterial pressure records could be traced
In two patients (Cases 5 and 9) symptoms of transient cerebral ischemic attacks developed during the course of the disease. One (Case 3) had a thrombotic stroke and made a good recovery; cervical angiogram revealed 90 percent stenosis of the origin of the left vertebral artery and a small plaque at the origin of the left internal carotid artery. In one patient (Case 1) the electrocardiographic pattern changed from normal to one of definite left ventricular hypertrophy over a period of 8 years. Effect of Treatment
Different types of treatment, including administration of sedatives and tranquilizers, diuretic agents, propranolol, alpha-methyldopa, hydralazine, guanethidine and reserpine, were used in various combinations and their effects were evaluated on the basis of home and office arterial pressure readings. Blood pressure was difficult to control, especially when judged from office readings; only two patients had diastolic levels below 100 mm Hg in follow-up visits; in the others, office-determined pressure levels averaged 179/120 mm Hg (range 134/102 to 230/160). However, home blood pressure readings, available in six patients, were substantially lower, averaging 141/91 mm Hg (range 130/80 to 155/98). No specifically effective antihypertensive drug could be identified. Although propranolol helped to eliminate tachycardia and many symptoms in most (8 of 10) patients, its effect on arterial pressure was not encouraging when used alone. Doses of up to 320 to 400 mglday were used in some patients without satisfactory control of hypertension. Of particular interest was the persistence of tachycardia or absence of bradycardia despite apparently effective beta adrenergic blockade. One patient (Case 10) persistently had an office-measured heart rate of 136 beatslmin in spite of a regimen of 320 mg/day of propranolol; during a subsequent hemodynamic study an infusion of isoproterenol (0.03 Kg/kg per min) produced effective beta blockade with an average heart rate of 95 beats/ min. Hemodynamic
Studies (Table II)
Arterial pressures at the time of studies ranged between 152/93 and 264/168 mm Hg (mean 212/125).
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Volume 35
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HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
TABLE
ET AL.
II
Hemodynamic Caseno.
Data
BP
N3*12,14*
MAP
123172 z!z 2.8/1.4
HR
89 zt 1.8
1 2 3 4 5 6 7 8 9 10
195/111 152193 216/116 261/146 2641168 165/113 2441136 229/126 155/101 2391144
139 112 149 185 200 130 172 159 119 176
Average SE
2121125 13.517.3
154 9.3
Cl
67 1.7
f
109 106 89 124 65 74 87 118 80 93 95 6.1
SI
TPR
3130 f 77
47 zt 1.0
3737 3955 2377 4563 3041 3337 3192 4644 3648 3480
35 37 27 37 47 45 37 39 46 37 _._~__. 39 1.9
3597 217
29 + 0.8
MRLVE
f
154 3.7
CPV
CO/CPV
649 IJI 23
4.36 + 0.22 6.44 6.32 5.88 6.41 4.43
38 28 63 41 66 39 54 34 33 50
130 147 87 193 160 152 132 181 179 167
580 626 404 712 687 ... ... .. ... ...
45 4.1
153 9.8
602 54.6
TBV
..
PV
CPV/TBV
.. i
... __-5.90 0.38
22.7 1.0
114 66 87 79 96 112 105 124 101 111
119 65 83 75 92 107 95 123 102 112
21.4 29.8 19.6 30.6 26.6
99.5 5.6
97.3 6.0
25.6 2.2
..
* Mean & standard error. BP = blood pressure (mm Hg); Cl = cardiac index (ml/min per m’); CO = cardiac output; CPV = cardiopulmonary volume (ml/m*); HR = heart rate (beats/min); MAP = mean arterial pressure (mm Hg); MRLVE = mean rate of left ventricular ejection (ml/set per ml); N = normal; PV = plasma volume (% of normal); SE = standard error; SI = stroke index (ml/m*); TBV = total blood volume (% of normal); TPR = total peripheral resistance (units per mz)
Cardiac rate varied widely among patients, 65 to 124 beatslmin, but because it was rapid in most, the average-95 f 6.1 beats/min (mean f standard error)was higher than in normal subjects (P
HEH 10
4/
I
2.00 CARDIAC
I
I
1
3.00
4.00
5.00
INDEX
(L/min/m*)
FIGURE 1. Data on cardiac index and mean arterial pressure (MAP) show no correlation between these variables in 10 patients with hyperkinetic circulation.
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PATIENTS
FEH 59
PATIENTS
FIGURE 2. Hemodynamic characteristics of hyperkinetic essential hypertension. Both mean arterial pressure (MAP) and cardiac index (Cl) were significantly higher in the hypertensive patients with hyperkinetic circulation than in the 59 patients with fixed essential hypertension; data for the latter were derived from a previous study from this laboratory.3 FEH and HEH = fixed and hyperkinetic essential hypertension; N = normal values for laboratory; TPR = total peripheral resistance. Bars indicate standard error.
HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
TABLE
III
TABLE
Systolic Time intervals
Caseno.
PEP
(msec)
IVCP
IV
Results of Tests of Autonomic
LVET,
PEP/ LVET
Nervous Activity* Patients with Hypertension
DBP/IVCP (mm Hg/sec)
Hyperkinetic Essential
Essential N 1 2 3 4 5 6 7 8 9 Average SE
104 f2.8 96 73 85 94 118 115 122 70 113 101 7
38 Al.2 26 21 19 32 46 42 42 20 48 34 4
405 h3.9 425 449 418 402 397 435 399 360 408 409 8
0.355 kO.014 0.373 0.267 0.333 0.441 0.398 0.359 0.442 0.312 0.403 0.372 0.019
2116 f78 4538 5714 5684 4531 3491 2619 2762 6200 2083 4113 460
ET AL.
no.
Normal Subjects
Response no. Response no. Response
Valsalva maneuver
DBP/IVCP = rate of rise of isovolumic pressure; IVCP = isovolumic contraction period; LVET = left ventricular ejection time; LVET, = left ventricular ejection time corrected for heart rate’s; N = normal for laboratory (mean + standard error); PEP = preejection period.
the hemodynamic findings in patients with hyperkinetic essential hypertension and those in 59 patients with established essential hypertension. The hyperkinetic group had a higher level of mean arterial pressure (P <0.005)and cardiac output (P
y0 increase in diastolic BP (overshoot) Valsalva index (% increase in diastolic BP& decrease in PP) Cold pressor test % increase in diastolic BP lsoproterenol (0.03
9
&z/kg Per r-W Increase in HR (beatslmin) % increase in HR
30
9
23
25
29t
25
1.35
9
0.61
9
0.40
7
20t
5
15
15
23t
31
28
5
22
15
20t
31
37
5
25
...
...
* The only significant difference was found in Valsalva index for the two hypertensive groups (P
28
26
>
24
=
22
z ;
71
20
I HEH
FEH
HEH
FEH
FIGURE 3. Cardiopulmonary volume (CPV) in hyperkinetic hypertension. There was no significant difference between the distribution of intravascular volume expressed as the ratio of cardiopulmonary to total blood volume (CPVITBV) in patients with hyperkinetic and fixed essential hypertension. However, the ratio of cardiac output to cardiopulmonary volume (COXPV), which is an index of cardiac performance,‘* was significantly higher in patients with hyperkinetic hypertension (P <0.005). Abbreviations as in Figure 2.
tricular rate of pressure rise (dP/dt),20 cantly elevated (P
was signifi-
Nervous Activity (Table IV)
No significant differences were found between the two hypertensive groups either in the diastolic pressure overshoot (percent diastolic pressure increase over the control pressure) or in the Valsalva index. However, when compared with normal subjects both groups had significantly lower Valsalva indexes (P <0.025 for hyperkinetic and P <0.05 for fixed essen-
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HYPERKINETIC
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IN HYPERTENSION-IBRAHIM
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tial hypertension). Arterial pressure response to the cold pressor test was decreased compared with the response in control subjects. However, statistical analysis was difficult because of the limited data. Responses of heart rate to isoproterenol infusion were not different from those of other hypertensive patients or normal subjects.
ta adrenergic state, who also had increased cardiac output and symptoms of cardiac awareness,ls responses to isoproterenol infusion in our group provided no evidence of beta receptor hypersensitivity. Further, the patients described here had a much higher arterial pressure than most of those with a “hyperbeta state.” Arterial pressure responses to cold were within normal limits, and the diastolic pressure response to the Valsalva maneuver was low in both hypertensive groups, possibly a reflection of the difference in age from normal control subjects23 (mean age of normal subjects 35 years). Hemodynamic characteristics: The hemodynamic pattern in these patients with chronic hypertension was at variance with the usual theories regarding essential hypertension. The prevailing concept, repeatedly suggested from many laboratories 21,24,25is a change in the hemodynamic pattern as the ‘years go by, from one of increased flow and normal resistance in the early phase to one of reduced flow and increased resistance in later and more advanced phases. Patients with labile, borderline hypertension, when followed up for a long time, tended to have reduced cardiac output.24 Unfortunately, we do not know the hemodynamic characteristics of our 10 patients when hypertension first developed; however, their high level of output 10 to 20 years after the onset of hypertension suggests that they formed a separate hemodynamic entity. The increase in cardiac output was particularly impressive in view of the highly increased blood pressure. Cardiac output was determined in two patients during a spontaneous hypertensive episode; in one, the increase in pressure was accompanied by an increase in output, but in the other it was associated with an increase in resistance, so that no firm conclusions could be reached regarding the fluctuations in blood pressure. However, the lack of correlation of pressure with output (Fig. 1) suggests that, as in other forms of secondary hypertension with similar hemodynamic characteristics,26 peripheral resistance was more important than cardiac output. Role of anxiety: Anxiety, although difficult to quantitate, undoubtedly played an important role in many of the patients’ symptoms. However, its relation to increased cardiac output and pressure was not clear. When measured, oxygen consumption was normal rather than elevated, as would be expected with anxiety.27 Furthermore, sedatives and tranquilizers failed to reduce arterial pressure or alleviate subjective complaints. Nevertheless, if anxiety were the only cause of the elevated cardiac output, this hemodynamic pattern would still represent a different response to the stress of the test from that seen in subjects with a normal cardiac index. De Quattro2s described autonomic hyperactivity, hypertension and excessive norepinephrine excretion in four patients without pheochromocytoma and related his findings to unidentified forms of stress. Physiologic responses to stress, which are normally protective and adaptive,
Renin Levels Peripheral plasma renin levels, determined in nine patients, ranged from undetectable to definitely elevated. Compared with normal values for our laboratory (average 1.2 ng/ml, range 0.4 to 2.7 in patients consuming an unrestricted hospital diet), plasma renin activity was low in two patients (undetectable in Case 9 and 0.12 ng/ml in Case 3). It was within normal limits in five, ranging from 1.0 in Case 8 to 2.3 in Case 10; however, four of these patients (Cases 1, 6, 8 and 10) were definitely hypervolemic (Table II) and their renin levels, although within the normal range, could be considered elevated for the degree of hypervolemia. l5 Two patients had definitely elevated plasma renin activity: 3.0 ng/ml in Case 7 and 6.7 in Case 5. The two patients with low renin levels had a lower blood pressure than the others, but there was otherwise no evident correlation between pressure levels and renin activity. Discussion The presence of a hyperkinetic heart and increased cardiac output has been described in early borderline and in normotensive subjects with hypertension1,2 the hyperkinetic heart syndrome.22 Patients with severe long-standing hypertension had either a normal or reduced cardiac output. 21 In this study the combination of hyperkinetic heart and chronic severe elevation of arterial pressure identified a separate group of hypertensive patients who had common clinical and physiologic characteristics. Hypertension in this group was difficult to control and was always symptomatic. Complaints of anxiety, unusual cardiac awareness, excessive perspiration and skin flushing were present in all. Variability of arterial pressure was a constant feature to the extent that pheochromocytoma was the provisional diagnosis in all patients. Systolic cardiac murmurs were common, and most subjects had sinus tachycardia. Hemodynamic studies and measurements of systolic time intervals indicated that increased cardiac output was associated with augmented myocardial contractility. The rate of rise of isovolumic pressure (DBP/IVCP), which corresponds to maximal intraventricular rate of pressure rise (dP/dt),20 was elevated in eight of nine patients. The preejection period and isovolumic contraction period were shortened in five patients in spite of the severity of hypertension. Measurements of cardiopulmonary volume provided additional evidence of enhanced cardiac performance by documenting a high ratio between cardiac output and cardiopulmonary volume.12 In contrast to hypertensive patients with hyperbe-
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may persist to a pathologic degree for various reasons. Role of increased cardiac output: Our early studies suggested that the increased heart action in this group was the result of increased adrenergic activity.4 This cardiac factor alone could not explain the high cardiac output, because without increased venous filling, maximal sympathetic cardiac stimulation can increase cardiac output only slightly.2g Our data indicated that increased myocardial contractility and central redistribution were both responsible for augmentation of cardiac output. However, the importance of the role played by each varied in the individual patient. Two patients manifested a dissociation between cardiac output and myocardial contractility. In Patient 3, contractility was increased, as evidenced by the elevated DBP/IVCP ratio, shortened preejection and isovolumic contraction periods and the high ratio between cardiac output and cardiopulmonary volume with a low cardiac output. In Patient 9, cardiac output was increased in the presence of normal contractility. This dissociation has been described before.30 Other cardiogenic factors: The close association of augmented cardiac activity and increased arterial pressure suggested that the heart might be involved in the genesis and maintenance of systemic hypertension in these patients. Because of increased peripheral resistance, mechanisms other than simple increase in cardiac output have still to be investigated. A neuroendocrine function of the heart has been described.“l An increase in systemic pressure due to liberation of excessive amounts of cardiac norepinephrine followed isolated cardiac sympathetic stimulation.sl Spinal sympa thetic reflexes arising from the
HEART
IN HYPERTENSION-IBRAHIM
ET AL.
heart were responsible for elevation of arterial pressure in spinal experimental animals.32 Recently, Liard et a1.33 were able to induce sustained hypertension by stellate ganglion stimulation in conscious dogs; the increase in pressure was maintained for the duration of stimulation and could not be prevented by administration of propranolol. Clinical implications: The identification of this type of hypertension raised important prognostic and therapeutic questions. Our initial impression of its possible benign nature in relation to cardiac disease was not borne out by the addition of new patients to the small original series. Marked lability of this type of hypertension and the occasional recording of relatively low values should not obscure its seriousness as indicated by the high incidence of cerebrovascular complications. The presence of increased heart rate and augmented cardiac activity was an important stimulus to try beta adrenergic blockade. However, the response of arterial pressure to propranolol alone was disappointing. This finding should not necessarily contradict the hypothesis of a cardiac factor since beta adrenergic blocking agents reduce arterial pressure by mechanisms other than simple changes in cardiac output.34 Furthermore, complete abolition of sympathetic impulses to the heart diminishes the strength of ventricular contraction by only 10 to 20 percent.35 Despite the failure of propranolol as sole treatment agent, the drug was a required part of the antihypertensive regimen. Cardiac decompensation did not occur with its use inany of these patients; the rarity of heart failure due to beta adrenergic blockade in hypertension has already been noted in many other reports.34,36y37
References
5.
6. 7. 6.
9.
10.
Eich RH, Peters RJ, Cuddy RP, et al: The hemodynamics of labile hypertension. Am Heart J 63:188-195, 1962 Julius S, Conway J: Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 38: 282-288, 1968 Frohlich ED, Tarazi RC, Dustan HP: Re-examination of the hemodynamics of hypertension. Am J Med Sci 2579-23, 1969 lbrahlm MM, Tarazi RC, Dustan HP, et al: Cardioadrenergic factor in essential hypertension. Am Heart J 88: 724-732, 1974 Sokolow M, Lyon TP: The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 37:161-186, 1949 Wilson FN, Johnston FD, Rosenbaum FF, et al: The precordial electrocardiogram. Am Heart J 27: 19-85, 1944 McPhie J: Left ventricular hypertrophy: electrocardiographic diagnosis. Austral Ann Med 7:317-321, 1958 Kllty SE, Lepeschkin E: Effect of body build on the QRS voltage of the electrocardiogram in normal men: its significance in the diagnosis of left ventricular hypertrophy. Circulation 31:77-84, 1965 Romhilt DW, Bove KE, Norris RJ, et al: A critical appraisal of the electrocardiographic criteria for the diagnosis of left ventricular hypertrophy. Circulation 40:185-195, 1969 Frohllch ED, Ulrych M, Tarazl RC, et al: A hemodynamic comparison of essential and renovascular hypertension. Cardiac output and total peripheral resistance-supine and tilted patients. Circulation 35:289-297, 1967
11. Ulrych M, Frohlich ED, Tarazi RC, et al: Cardiac output and distribution of blood volume in central and peripheral circulations in hypertensive and normotensive man. Br Heart J 31570-574. 1969 12. Tarari RC, lbrahim MM, Dustan HP, et al: Cardiac factors in hypertension. Circ Res 34: Suppl 1:213-221, 1974 13. Chaplin H Jr, Mollison PL, Vetter H: The body venous hematocrit ratio: its constancy over a wide hematocrit range. J Clin Invest 32:1309-1316, 1953 14. Tarazi RC, Dustan HP, Frohlich ED, et al: Plasma volume and chronic hypertension. Arch Intern Med 125:835-842, 1970 15. Dustan HP, Tarazi RC, Frohlich ED: Functional correlates of plasma renin activity in hypertensive patients. Circulation 41: 555-567, 1970 16. Weissler AM, Harris WS, Schoenfeld CD: Systolic time intervals in heart failure in man. Circulation 37:149-159, 1968 17. Sharpey-Schafer EP: Effects of Valsalva’s maneuver on the normal and failing circulation. Br Med J 2:693-695, 1955 18. Frohllch ED, Tarazi RC, Dustan HP: Hyperdynamic P-adrenergic circulatory state. Increased @-receptor responsiveness. Arch Intern Med 123: 1-7, 1969 19. George CF, Conolly ME, Fenyvesl T, et al: Intravenously administered isoproterenol sulfate dose-response curves in man. Arch Intern Med 130:361-364, 1972 20 Landry AB Jr, Goodyer AVN: Rate of rise of left ventricular pressure. Indirect measurement and physiologic significance. Am J Cardiol 15:860-664, 1965
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21.
22. 23. 24. 25. 26.
27.
28.
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Frohlich
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ED, Kozul VJ, Tarazi
ET AL.
RC, et al: Physiologic
compari-
29.
Guyton AC, Jones CE, Coleman TG: Circulatory Physiology: Cardiac Output and its Regulation. Philadelphia, WB Saunders, 1973, p 141 30. Braunwald E: On the difference between the heart’s output and its contractile state. Circulation 43: 171-174, 1971 31. Braunwald E, Harrison DC, Chidsey CA: The heart as an endocrine organ. Am J Med 36:1-4, 1964 32. Malliani A, Peterson DF, Bishop VS, et al: Spinal sympathetic cardiocardiac reflexes. Circ Res 30:158-166, 1972 33. Liard JF, Tarazl RC, Ferrario CM, et al: Hemodynamic and humoral characteristics of hypertension induced by prolonged stellate stimulation in conscious dogs. Circ Res, in press 34. Tarazi RC, Dustan HP: Beta-adrenergic blockade in hypertension! practical and theoretical implications of long-term hemodynamic variations. Am J Cardiol 29:633-640, 1972 35. Guyton AC, Jones CE, Coleman TG: In Ref 29, p 308 36. Prlchard BNC: Propranolol as an antihypertensive agent. Am Heart J 79:128-133, 1970 37. Buhler FR, Laragh JH, Baer L, et al: Propranolol inhibition of renin secretion. N Engl J Med 287:1209-1214, 1972
son of labile and essential hypertension. Circ Res 26 and 27: Suppl I:%-63 1970 Gorlin R, Br&hfeld N, Turner JO, et al: The idiopathic high cardiac output state. J Clin Invest 38:2144-2153, 1959 Appenzeller 0, Descarrles L: Circulatory reflexes in patients with cerebrovascular disease. N Engl J Med 271:820-823, 1964 Elch RH, Cuddy RP, Smulyan H, et al: Hemodynamics in labile hypertension. A follow-up study. Circulation 34:229-307, 1966 Lund-Johanssen P: Hemodynamics in early essential hypertension. Acta Med Stand 181: Suppl 482:9-101, 1967 Tarazi RC, lbrahim MM, Bravo EL, et al: Hemodynamic characteristics of primary aldosteronism. N Engl J Med 289:13301335,1973 Stead EA, Warren JV, Merrill AJ, et al: The cardiac output in male subjects as measured by the technique of right atrial catheterization. Normal values with observations on the effects of anxiety and tilting. J Clin Invest 24:326-331, 1945 De Quattro V: Evaluation of increased norepinephrine excretion in hypertension using L-dopa-3H. Circ Res 28:84-97. 197 1
May 1975
The American
Journal
of CARDIOLOGY
Volume
35
Hyperkinetic
Heart in Severe Hypertension:
Hemodynamic
M. MOHSEN ROBERT HARRIET
IBRAHIM,
Cleveland,
Clinical
Entity
MD,
FACC
C. TARAZI, MD, FACC P. DUSTAN, MD, FACC
EMMANUEL L. BRAVO, RAY W. GIFFORD, Jr.,
A Separate
MD MD,
FACC
Ohio
A long-term study of established hypertension helped identify a well defined group of 10 patients who differed both clinically and hemodynamically from 59 patients with the more frequent form of this disease. Their cardiac output was significantly increased (P
Whereas augmented cardiac activity is known to occur in patients with mild and borderline essential hypertension,‘-3 the association of increased cardiac output with severe long-term elevation of arterial pressure has not been described. In a previous communication we reported evidence for excessive cardioadrenergic drive in some patients with established hypertension .4 Further study of these and other patients suggested that they represented a separate clinical hemodynamic group. We therefore report here in greater detail their characteristics together with results of studies of autonomic nervous function and possible factors regulating cardiac output. Their response to therapy and incidence of complications during a long follow-up period are also described. Methods Clinical Studies
From the Research Division and the Department of Hypertension and Nephrology, the Cleveland Clinic Foundation and the Cleveland Clinic Educational Foundation, Cleveland, Ohio. This study was supported in part by Grant HL 6835 from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md., The John A. Hartford Foundation and the U. A. Whitaker Fund. Manuscript accepted September 19, 1974. Address for reprints: Robert C. Tarazi, MD, Research Division, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44108.
Ten patients were studied; some of the data on eight were reported previously.4 Since this investigation was limited to patients with essential hypertension, one case, reported in our early study, was not included here because the patient had mild proteinuria and kidney biopsy revealed membranoproliferative glomerulonephritis. All patients had complete clinical and laboratory evaluation including creatinine clearance studies and renal arteriography. Ocular fundi were graded according to the Keith-Wagener-Barker classification. Electrocardiographic signs of left ventricular hypertrophy were described as either definite or probable. Definite signs were one or more of the following: R wave in lead aVL greater than 11 mm,5 S wave in lead VI 24 mm or greater,” or sum of the tallest and deepest precordial R and S waves exceeding 45 mm.7 The first two criteria were reported to have no false positives5; for the third criterion, false positives were reported in 1.68 to 7 percent.g When the sum of S in lead VI and R in lead Vg was greater than 35 mm,5 left ventricular hypertrophy was diagnosed as “probable.” Tests for pheochromocytoma and thyroid function were performed in all and tests for
May 1975
The American
Journal of CARDIOLOGY
Volume
35
667
HYPERKINETIC
TABLE
HEART
IN HYPERTENSION-IBRAHIM
ET AL
I
Clinical Characteristics
BSA (m*)
Age (yr) Case no. &Sex
~~
~
Hypertension
Age at DurationOnset
BloodPressure(Hospital Reading) (mm Hg)
(yr)
(yr)
Family History
Average
Range
2 3 4 5 6 7 8 9
2.41 1.65 1.64 1.82 2.11 2.14 1.83 2.00 2.16
26 13 16 20 12 18 8 10 23
30 33 39 19 22 24 48 39 20
Yes No Yes Yes Yes Yes Yes ? Yes
150/100 155/100 142/91 210/130 187/126 145197 184/104 2201143 139/95
130/86to X30/118 130,'90to196/124 126/86to178/110 140/108to290/140 160/110to 250/160 130/87 to 240/140 150/100to 220/120 150/104to240/162 124/86to 172/120
II 0 II I I II I I
+ 0 + + 0 + * 0
11 0 0 I-II 0 I-II 0 I
II
Base LSB 0 0 Mitral 0 Base 0
+ 0 0 * =t 0 f 0
LSB
0
10
47M
2.10
17
30
No
195/129
142/96 to 236/150
II
+
0
0
+
1.99 0.08
16.2 2.0
30.4 3.4
1731112 9.515.8
138/95to 220/134 3.8/30to 12.1/5.9
Average 46.7 SE 2.4
* Keith-Wagener-Barker classification. + =definite;& = probable;O= absent. BSA = bodysurfacearea; LSB = leftsternalborder;LVH on ECG= = standard error.
Studies
All investigations were performed in a quiet laboratory in the morning with the subjects fasting and resting comfortably supine. Catheters were introduced into an antecubital vein and brachial artery by the Seldinger technique and advanced to the innominate vein or superior vena cava and to the axillary or subclavian artery, respectively. In five patients the catheters were carefully positioned under fluoroscopy at the junction of the superior vena cava and right atrium and in the ascending aorta. Cardiac output was determined at least in triplicate using indocyanine green dye (5 mg) introduced into a transparent tube connected to the venous catheter and then flushed as rapidly as possible into the circulation with 5 to 10 ml of saline solution. Dye-dilution curves were obtained by the usual methods as previously described,‘OJl and blood was reinfused immediately after the inscription of the curve to avoid blood loss. Cardiac output was calculated by the Stewart-Hamilton method. Cardiopulmonary volume was determined in the five patients with centrally positioned catheters as the product of mean transit time (corrected for catheter delay) and blood flow per second. Arterial and venous pressures were
May 1975
The American Journal of CARDIOLOGY
0
electrocardiographicevidence ofleftventricularhypertrophy:SE
primary aldosteronism were used when indicated. In all patients, antihypertensive therapy was discontinued for at least 1 month before hospitalization. Although the patients were hospitalized, they were not restricted in diet or activity. The severity of hypertension was indicated by the level of arterial pressure measured in the hospital or the development of cerebrovascular complications; in all patients diastolic pressures measured in the office were consistently greater than 110 mm Hg. The duration of hypertension was documented as closely as possible in each patient by reference to old records, previous hospitalizations, rejections for military service or life insurance and by contact with the family physician when necessary. Hemodynamic
I
LVH on ECG
56M 46M 55F 39M 34M 42M 56F 49F 43M
1
666
Systolic Murmurs .__ Fourth Ocular Heart Grade Maximal Fundi* Sound (I-VI) Intensity
Volume 35
measured using Statham P23DB transducers. Derived variables-total peripheral resistance, stroke volume and mean rate of left ventricular ejection-were calculated by the usual methods. In three patients (Cases 1,9and 10)minute oxygen consumption was measured at the time of hemodynamic study; expired air was collected in 120-L Douglas air bags and contents were analyzed by Beckman oxygen analyzer; results were corrected for standard temperature and pressure. Results of cardiac output measurements were compared with those in two previously described control groups,3 one of 29 normotensive subjects and one of 59 patients with fixed essential hypertension. Values for cardiopulmonary volume were compared with measurements in nine normal volunteers previously described.12 Plasma and Total Blood Volume Plasma volume was determined in the morning after an overnight fast and after the patient had been allowed to rest in the supine position for at least 30 to 45 minutes. It was computed directly by the Volemetron@ from plasma samples obtained 10 minutes after injection of iodine-131, 5 PCi, or iodine-125, 2.5 &!i. Total blood volume was calculated from the plasma volume and venous hematocrit; the latter was detqrmined, by capillary microcentrifugation from four samples of blood drawn without stasis, and appropriate correction factors were used for the differences betwaen large vessel and total body hematocrit.13 The meth@ and calculations, as well as normal values for laboratori, have pre+o&ly been described in detail.14 Volume determinations were usually performed just before the hemodynamic studies or, occasionally, the day before under exactly the same conditions. Results were expressed as percent of normal to allow for sex differences.14 In 9 of the 10 patients, plasma renin activity was determined by a modified Pickens method15 in peripheral blood samples obtained at the time of the blood volume determination.
HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
ET AL.
In nine patients systolic time intervals were determined from simultaneous recordings (100 mm/set) of the external carotid arterial pulse, phonocardiogram and electrocardiograml”; these measurements were obtained either at the same time as the hemodynamic study or occasionally the day before. The following intervals were measured from at least 10 complexes, as previously described*: total electromechanical systole (Q-AZ), left ventricular ejection time (LVET), preejection period (PEP) and isovolumic contraction period (IVCP). Results were compared with values obtained from 1’7 normotensive subjects, and corrections for heart rate calculated according to the equations of Weissler et a1.16
to an early stage, the impressive finding was the severe elevation of arterial pressure at a young age. During their hospital stay the same lability of pressure was observed (Table I). In four patients the weekly hospital averages were generally less impressive than the usual office readings. Grade I to II changes in ocular fundi were present in all but one patient, who had normal eyegrounds. Five patients had cardiac systolic murmurs (Table I). All had vigorous peripheral and carotid arterial pulses. Electrocardiographic signs of left ventricular hypertrophy were definitely present in two patients and “probable” in three more.
Tests of Autonomic
Follow-Up
Systolic Time intervals
Nervous Activity
Tests of autonomic nervous activity were obtained during the hemodynamic study with continuous intraarterial pressure recording; the Valsalva maneuver was performed in duplicate by blowing a mercury column to 40 mm Hg and maintaining it at that level for about 10 seconds. The diastolic pressure overshoot following Valsalva maneuver was expressed both as percent increase over control levels and as a fraction of the reduction in pulse pressure obtained during straining. l7 Results were compared with those in a closely matched group of patients with fixed essential hypertension and a group of normal subjects.r8 Cold pressor test was performed by immersing the patient’s hand to the wrist in ice cold water for 1 minute. Changes in arterial pressure were compared with previously reported results in normal subjects and in patients with essential hypertension.18 Isoproterenol was infused in five patients at sequentially increasing rates (0.01, 0.02 and 0.03 pg/kg per min). Effect of the “0.03 bg” dose level upon heart rate was compared with its effect in 31 patients with essential hypertension and in normal subjects.ig Results Clinical Features
Table I summarizes the important clinical characteristics of the patients studied. Common features were the early age of onset and the long duration of hypertension. Seven patients had a family history of increased arterial pressure. Symptoms of anxiety (“feel nervous,” “worrying a lot,” “have fear episodes”) were the main complaints. Cardiac awareness, rapid heart rate, flushing, pallor, sweating, headaches and dizzy spells were present in different combinations in all patients. Flushing of the neck and upper part of the chest when nervous, manifested by erythematous patches (diencephalic flush), was a common finding. Marked lability of hypertension ranging from almost normal levels of 124/86 to alarming degrees of 300/160 mm Hg during ambulation was characteristic. This gross variability of arterial pressure, in addition to the symptoms mentioned, raised the possibility of pheochromocytoma in all patients. All were carefully studied for that possibility at some stage of their disease; in some, these studies were repeated two or three times to rule out this diagnosis. In patients whose arterial pressure records could be traced
In two patients (Cases 5 and 9) symptoms of transient cerebral ischemic attacks developed during the course of the disease. One (Case 3) had a thrombotic stroke and made a good recovery; cervical angiogram revealed 90 percent stenosis of the origin of the left vertebral artery and a small plaque at the origin of the left internal carotid artery. In one patient (Case 1) the electrocardiographic pattern changed from normal to one of definite left ventricular hypertrophy over a period of 8 years. Effect of Treatment
Different types of treatment, including administration of sedatives and tranquilizers, diuretic agents, propranolol, alpha-methyldopa, hydralazine, guanethidine and reserpine, were used in various combinations and their effects were evaluated on the basis of home and office arterial pressure readings. Blood pressure was difficult to control, especially when judged from office readings; only two patients had diastolic levels below 100 mm Hg in follow-up visits; in the others, office-determined pressure levels averaged 179/120 mm Hg (range 134/102 to 230/160). However, home blood pressure readings, available in six patients, were substantially lower, averaging 141/91 mm Hg (range 130/80 to 155/98). No specifically effective antihypertensive drug could be identified. Although propranolol helped to eliminate tachycardia and many symptoms in most (8 of 10) patients, its effect on arterial pressure was not encouraging when used alone. Doses of up to 320 to 400 mglday were used in some patients without satisfactory control of hypertension. Of particular interest was the persistence of tachycardia or absence of bradycardia despite apparently effective beta adrenergic blockade. One patient (Case 10) persistently had an office-measured heart rate of 136 beatslmin in spite of a regimen of 320 mg/day of propranolol; during a subsequent hemodynamic study an infusion of isoproterenol (0.03 Kg/kg per min) produced effective beta blockade with an average heart rate of 95 beats/ min. Hemodynamic
Studies (Table II)
Arterial pressures at the time of studies ranged between 152/93 and 264/168 mm Hg (mean 212/125).
May 1975
The American Journal of CARDIOLOGY
Volume 35
669
HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
TABLE
ET AL.
II
Hemodynamic Caseno.
Data
BP
N3*12,14*
MAP
123172 z!z 2.8/1.4
HR
89 zt 1.8
1 2 3 4 5 6 7 8 9 10
195/111 152193 216/116 261/146 2641168 165/113 2441136 229/126 155/101 2391144
139 112 149 185 200 130 172 159 119 176
Average SE
2121125 13.517.3
154 9.3
Cl
67 1.7
f
109 106 89 124 65 74 87 118 80 93 95 6.1
SI
TPR
3130 f 77
47 zt 1.0
3737 3955 2377 4563 3041 3337 3192 4644 3648 3480
35 37 27 37 47 45 37 39 46 37 _._~__. 39 1.9
3597 217
29 + 0.8
MRLVE
f
154 3.7
CPV
CO/CPV
649 IJI 23
4.36 + 0.22 6.44 6.32 5.88 6.41 4.43
38 28 63 41 66 39 54 34 33 50
130 147 87 193 160 152 132 181 179 167
580 626 404 712 687 ... ... .. ... ...
45 4.1
153 9.8
602 54.6
TBV
..
PV
CPV/TBV
.. i
... __-5.90 0.38
22.7 1.0
114 66 87 79 96 112 105 124 101 111
119 65 83 75 92 107 95 123 102 112
21.4 29.8 19.6 30.6 26.6
99.5 5.6
97.3 6.0
25.6 2.2
..
* Mean & standard error. BP = blood pressure (mm Hg); Cl = cardiac index (ml/min per m’); CO = cardiac output; CPV = cardiopulmonary volume (ml/m*); HR = heart rate (beats/min); MAP = mean arterial pressure (mm Hg); MRLVE = mean rate of left ventricular ejection (ml/set per ml); N = normal; PV = plasma volume (% of normal); SE = standard error; SI = stroke index (ml/m*); TBV = total blood volume (% of normal); TPR = total peripheral resistance (units per mz)
Cardiac rate varied widely among patients, 65 to 124 beatslmin, but because it was rapid in most, the average-95 f 6.1 beats/min (mean f standard error)was higher than in normal subjects (P
HEH 10
4/
I
2.00 CARDIAC
I
I
1
3.00
4.00
5.00
INDEX
(L/min/m*)
FIGURE 1. Data on cardiac index and mean arterial pressure (MAP) show no correlation between these variables in 10 patients with hyperkinetic circulation.
670
May 1975
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Volume 35
PATIENTS
FEH 59
PATIENTS
FIGURE 2. Hemodynamic characteristics of hyperkinetic essential hypertension. Both mean arterial pressure (MAP) and cardiac index (Cl) were significantly higher in the hypertensive patients with hyperkinetic circulation than in the 59 patients with fixed essential hypertension; data for the latter were derived from a previous study from this laboratory.3 FEH and HEH = fixed and hyperkinetic essential hypertension; N = normal values for laboratory; TPR = total peripheral resistance. Bars indicate standard error.
HYPERKINETIC HEART IN HYPERTENSION-IBRAHIM
TABLE
III
TABLE
Systolic Time intervals
Caseno.
PEP
(msec)
IVCP
IV
Results of Tests of Autonomic
LVET,
PEP/ LVET
Nervous Activity* Patients with Hypertension
DBP/IVCP (mm Hg/sec)
Hyperkinetic Essential
Essential N 1 2 3 4 5 6 7 8 9 Average SE
104 f2.8 96 73 85 94 118 115 122 70 113 101 7
38 Al.2 26 21 19 32 46 42 42 20 48 34 4
405 h3.9 425 449 418 402 397 435 399 360 408 409 8
0.355 kO.014 0.373 0.267 0.333 0.441 0.398 0.359 0.442 0.312 0.403 0.372 0.019
2116 f78 4538 5714 5684 4531 3491 2619 2762 6200 2083 4113 460
ET AL.
no.
Normal Subjects
Response no. Response no. Response
Valsalva maneuver
DBP/IVCP = rate of rise of isovolumic pressure; IVCP = isovolumic contraction period; LVET = left ventricular ejection time; LVET, = left ventricular ejection time corrected for heart rate’s; N = normal for laboratory (mean + standard error); PEP = preejection period.
the hemodynamic findings in patients with hyperkinetic essential hypertension and those in 59 patients with established essential hypertension. The hyperkinetic group had a higher level of mean arterial pressure (P <0.005)and cardiac output (P
y0 increase in diastolic BP (overshoot) Valsalva index (% increase in diastolic BP& decrease in PP) Cold pressor test % increase in diastolic BP lsoproterenol (0.03
9
&z/kg Per r-W Increase in HR (beatslmin) % increase in HR
30
9
23
25
29t
25
1.35
9
0.61
9
0.40
7
20t
5
15
15
23t
31
28
5
22
15
20t
31
37
5
25
...
...
* The only significant difference was found in Valsalva index for the two hypertensive groups (P
28
26
>
24
=
22
z ;
71
20
I HEH
FEH
HEH
FEH
FIGURE 3. Cardiopulmonary volume (CPV) in hyperkinetic hypertension. There was no significant difference between the distribution of intravascular volume expressed as the ratio of cardiopulmonary to total blood volume (CPVITBV) in patients with hyperkinetic and fixed essential hypertension. However, the ratio of cardiac output to cardiopulmonary volume (COXPV), which is an index of cardiac performance,‘* was significantly higher in patients with hyperkinetic hypertension (P <0.005). Abbreviations as in Figure 2.
tricular rate of pressure rise (dP/dt),20 cantly elevated (P
was signifi-
Nervous Activity (Table IV)
No significant differences were found between the two hypertensive groups either in the diastolic pressure overshoot (percent diastolic pressure increase over the control pressure) or in the Valsalva index. However, when compared with normal subjects both groups had significantly lower Valsalva indexes (P <0.025 for hyperkinetic and P <0.05 for fixed essen-
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Volume 35
671
HYPERKINETIC
HEART
IN HYPERTENSION-IBRAHIM
ET AL.
tial hypertension). Arterial pressure response to the cold pressor test was decreased compared with the response in control subjects. However, statistical analysis was difficult because of the limited data. Responses of heart rate to isoproterenol infusion were not different from those of other hypertensive patients or normal subjects.
ta adrenergic state, who also had increased cardiac output and symptoms of cardiac awareness,ls responses to isoproterenol infusion in our group provided no evidence of beta receptor hypersensitivity. Further, the patients described here had a much higher arterial pressure than most of those with a “hyperbeta state.” Arterial pressure responses to cold were within normal limits, and the diastolic pressure response to the Valsalva maneuver was low in both hypertensive groups, possibly a reflection of the difference in age from normal control subjects23 (mean age of normal subjects 35 years). Hemodynamic characteristics: The hemodynamic pattern in these patients with chronic hypertension was at variance with the usual theories regarding essential hypertension. The prevailing concept, repeatedly suggested from many laboratories 21,24,25is a change in the hemodynamic pattern as the ‘years go by, from one of increased flow and normal resistance in the early phase to one of reduced flow and increased resistance in later and more advanced phases. Patients with labile, borderline hypertension, when followed up for a long time, tended to have reduced cardiac output.24 Unfortunately, we do not know the hemodynamic characteristics of our 10 patients when hypertension first developed; however, their high level of output 10 to 20 years after the onset of hypertension suggests that they formed a separate hemodynamic entity. The increase in cardiac output was particularly impressive in view of the highly increased blood pressure. Cardiac output was determined in two patients during a spontaneous hypertensive episode; in one, the increase in pressure was accompanied by an increase in output, but in the other it was associated with an increase in resistance, so that no firm conclusions could be reached regarding the fluctuations in blood pressure. However, the lack of correlation of pressure with output (Fig. 1) suggests that, as in other forms of secondary hypertension with similar hemodynamic characteristics,26 peripheral resistance was more important than cardiac output. Role of anxiety: Anxiety, although difficult to quantitate, undoubtedly played an important role in many of the patients’ symptoms. However, its relation to increased cardiac output and pressure was not clear. When measured, oxygen consumption was normal rather than elevated, as would be expected with anxiety.27 Furthermore, sedatives and tranquilizers failed to reduce arterial pressure or alleviate subjective complaints. Nevertheless, if anxiety were the only cause of the elevated cardiac output, this hemodynamic pattern would still represent a different response to the stress of the test from that seen in subjects with a normal cardiac index. De Quattro2s described autonomic hyperactivity, hypertension and excessive norepinephrine excretion in four patients without pheochromocytoma and related his findings to unidentified forms of stress. Physiologic responses to stress, which are normally protective and adaptive,
Renin Levels Peripheral plasma renin levels, determined in nine patients, ranged from undetectable to definitely elevated. Compared with normal values for our laboratory (average 1.2 ng/ml, range 0.4 to 2.7 in patients consuming an unrestricted hospital diet), plasma renin activity was low in two patients (undetectable in Case 9 and 0.12 ng/ml in Case 3). It was within normal limits in five, ranging from 1.0 in Case 8 to 2.3 in Case 10; however, four of these patients (Cases 1, 6, 8 and 10) were definitely hypervolemic (Table II) and their renin levels, although within the normal range, could be considered elevated for the degree of hypervolemia. l5 Two patients had definitely elevated plasma renin activity: 3.0 ng/ml in Case 7 and 6.7 in Case 5. The two patients with low renin levels had a lower blood pressure than the others, but there was otherwise no evident correlation between pressure levels and renin activity. Discussion The presence of a hyperkinetic heart and increased cardiac output has been described in early borderline and in normotensive subjects with hypertension1,2 the hyperkinetic heart syndrome.22 Patients with severe long-standing hypertension had either a normal or reduced cardiac output. 21 In this study the combination of hyperkinetic heart and chronic severe elevation of arterial pressure identified a separate group of hypertensive patients who had common clinical and physiologic characteristics. Hypertension in this group was difficult to control and was always symptomatic. Complaints of anxiety, unusual cardiac awareness, excessive perspiration and skin flushing were present in all. Variability of arterial pressure was a constant feature to the extent that pheochromocytoma was the provisional diagnosis in all patients. Systolic cardiac murmurs were common, and most subjects had sinus tachycardia. Hemodynamic studies and measurements of systolic time intervals indicated that increased cardiac output was associated with augmented myocardial contractility. The rate of rise of isovolumic pressure (DBP/IVCP), which corresponds to maximal intraventricular rate of pressure rise (dP/dt),20 was elevated in eight of nine patients. The preejection period and isovolumic contraction period were shortened in five patients in spite of the severity of hypertension. Measurements of cardiopulmonary volume provided additional evidence of enhanced cardiac performance by documenting a high ratio between cardiac output and cardiopulmonary volume.12 In contrast to hypertensive patients with hyperbe-
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35
HYPERKINETIC
may persist to a pathologic degree for various reasons. Role of increased cardiac output: Our early studies suggested that the increased heart action in this group was the result of increased adrenergic activity.4 This cardiac factor alone could not explain the high cardiac output, because without increased venous filling, maximal sympathetic cardiac stimulation can increase cardiac output only slightly.2g Our data indicated that increased myocardial contractility and central redistribution were both responsible for augmentation of cardiac output. However, the importance of the role played by each varied in the individual patient. Two patients manifested a dissociation between cardiac output and myocardial contractility. In Patient 3, contractility was increased, as evidenced by the elevated DBP/IVCP ratio, shortened preejection and isovolumic contraction periods and the high ratio between cardiac output and cardiopulmonary volume with a low cardiac output. In Patient 9, cardiac output was increased in the presence of normal contractility. This dissociation has been described before.30 Other cardiogenic factors: The close association of augmented cardiac activity and increased arterial pressure suggested that the heart might be involved in the genesis and maintenance of systemic hypertension in these patients. Because of increased peripheral resistance, mechanisms other than simple increase in cardiac output have still to be investigated. A neuroendocrine function of the heart has been described.“l An increase in systemic pressure due to liberation of excessive amounts of cardiac norepinephrine followed isolated cardiac sympathetic stimulation.sl Spinal sympa thetic reflexes arising from the
HEART
IN HYPERTENSION-IBRAHIM
ET AL.
heart were responsible for elevation of arterial pressure in spinal experimental animals.32 Recently, Liard et a1.33 were able to induce sustained hypertension by stellate ganglion stimulation in conscious dogs; the increase in pressure was maintained for the duration of stimulation and could not be prevented by administration of propranolol. Clinical implications: The identification of this type of hypertension raised important prognostic and therapeutic questions. Our initial impression of its possible benign nature in relation to cardiac disease was not borne out by the addition of new patients to the small original series. Marked lability of this type of hypertension and the occasional recording of relatively low values should not obscure its seriousness as indicated by the high incidence of cerebrovascular complications. The presence of increased heart rate and augmented cardiac activity was an important stimulus to try beta adrenergic blockade. However, the response of arterial pressure to propranolol alone was disappointing. This finding should not necessarily contradict the hypothesis of a cardiac factor since beta adrenergic blocking agents reduce arterial pressure by mechanisms other than simple changes in cardiac output.34 Furthermore, complete abolition of sympathetic impulses to the heart diminishes the strength of ventricular contraction by only 10 to 20 percent.35 Despite the failure of propranolol as sole treatment agent, the drug was a required part of the antihypertensive regimen. Cardiac decompensation did not occur with its use inany of these patients; the rarity of heart failure due to beta adrenergic blockade in hypertension has already been noted in many other reports.34,36y37
References
5.
6. 7. 6.
9.
10.
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