abnormal cardiovascular regulation in the mitral valve prolapse syndrome

Abnormal Cardiovascular Regulation in the Mitral Valve Prolapse Syndrome

F. ANDREW GAFFNEY, MD, BRUCE C. BASTIAN, MD, LYNDA B. LANE, RN,

W. FRED TAYLOR, MS, JURETA HORTON, PhD, JAMES E. SCHUTTE, PhD,

ROBERT M. GRAHAM, MD, WILLIAM PETTINGER, MD, and C. GUNNAR BLOMQVIST, MD,

With the technical assistance of WILLIE E. MOORE, Jr.

Studies of patients with mitral valve prolapse syndrome have suggested autonomic nervous system dysfunction, but a precise definition of mechanisms is lacking. We measured supine and standing heart rate, blood pressure, cardiac output, oxygen consumption, plasma catecholamines, and blood volume in 23 symptomatic women with both echocardiographic and phonographic signs of MVP and in 17 normal control subjects. An analysis of the results revealed 2 distinct subgroups of patients: those with normal heart rates but increased vasoconstriction (Group I, n = IO) and those with orthostatic tachycardia (Group II, n = 13). Group II patients had heart rates at rest suplne of 97 f 3 compared with 79 f 2 in Group I patients and 78 f 8 in control subjects. Estimated total blood volumes were lowest in Group I patients, intermediate in Group II patients, and highest in control subjects (p <0.05). Other mea-

surements at rest supine were simil,ar in patients and controls. After standing for 5 minutes, patients had a higher mean plasma epinephrine value, diastolic blood pressure (81 f 2 versus 74 f 3 mm Hg, p <0.05), and peripheral resistance (1,878 f 114 versus 1,414 f 92, dynes s cms5, p <O.Ol), wider arteriovenous oxygen difference (6.7 f 0.4 versus 5.3 f 0.5 vol% ), and lower stroke volume index (26 f 2 versus 33 f 2 ml/m*, p <O.Ol) than dld the control subjects. Cardiac output was normal in Group II patients but reduced in Group I patients, who demonstrated marked vasoconstriction. No patient had evidence of a “hyperkinetic” circulatory state. A cycle of decreased forward stroke volume, vasoconstriction, and blood volume contraction appears to be present in at least some symptomatic patients with MVP.

Reports from our 1aboratoryQ and otherss-5 have documented the presence of autonomic nervous system dysfunction in some patients with the mitral valve prolapse (MVP) syndrome, but a precise definition of the regulatory abnormalities has not been presented. Coghlan et al3 reported that some patients appeared to have excessive vagal tone and responsiveness. Bou- doulas et al5 recently suggested that patients with MVP are hyperadrenergic, with increased beta-adrenergic

From the Pauline and Adolph Weinberger Laboratory for Cardiopul- monary Research and the Harry S. Moss Heart Center, Southwestern Medical School, University of Texas Health Science Center, Dallas, Texas. This study was supported by National Heart, Lung, and Blood Institute Young Investigator Award HL 25710, NASA Grant NSG9026, and National Institutes of Health lschemic SCOR Grant HL-17669. Manuscript received January 14, 1983; revised manuscript received May 9. 1983, accepted May IO, 1983.

Address for reprints: F. Andrew Gaffney, MD, University of Texas Heath Science Center, Division of Cardiology H8.122, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

tone and responsiveness. Our previous work provided no evidence for increased beta-adrenergic activity, but rather, suggested that alpha-adrenergic hyperactivity was present. A common feature in all of these reports is that the conclusions were based partly on the response to orthostatic stress produced by head-up tilt,3 standing,*y5 or lower body negative pressure.l Because of differences in findings, we carried out a second set of studies in which the hemodynamic and neuroendocrine responses of patients with MVP to orthostatic stress were analyzed.

Methods

Patients: The patient group consisted of 23 women aged 36 f 2 years (mean age f standard error) (range 21 to 60). Patient characteristics are shown in Table I. All patients had presented for medical care because of symptoms commonly associated with MVP such as chest pain, palpitations, easy fatigability, and near-syncope, often in response to orthostatic

316

August 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52 317

stress. None had clinical evidence of significant mitral regurgitation, coronary artery disease, hypertension, diabetes mellitus, or alcoholism. None of the subjects in this study group met Diagnostic Standards Manual-III criteria for panic disorder. Neuroactive medications were discontinued at least 1 week before study. MVP was diagnosed by 2-dimensional (2-D) echocardiography and phonocardiography.l Criteria for echocardiographic diagnosis included prolapse of 1 or both leaflets behind an imaginary line through the mitral anulus in either the apical 4-chamber or the parasternal long-axis views. All subjects had persistent auscultatory findings including isolated single or multiple nonejection clicks with or without the murmur of mitral regurgitation. No subject with “silent” or “echo-only” MVP was included. Family studies in more than half the subjects confirmed the familial nature of the disorder.

Control subjects for the hemodynamic studies were 17 women, mean age 27 f 1 years. All were healthy nonsmokers, taking no cardio- or neuroactive medications. They were employees of the University of Texas Health Science Center or the Parkland Memorial Hospital in Dallas, Texas. Most were sedentary and none participated regularly in athletics.

Procedures: Heart rate was measured by the electrocar- diogram and displayed digitally on a beat-to-beat basis (Quinton Cardiotachometer, model 511). Indirect arterial blood pressure was measured semiautomatically with a device that records simultaneous cuff pressure and Korotkov sounds (Narco Bio-Systems Elec-tro-Sphygmomanometer, PE-300). Cardiac output was measured with an acetylene rebreathing technique previously validated in our laboratory. The coef- ficient of variation when compared with simultaneous indo- cyanine green cardiac outlputs was 4.3% over a range of 4 to 19 liters/min.6 Oxygen consumption and cardiac output were simultaneously measured to calculate arteriovenous oxygen differences. Plasma catecholamines were measured by a ra- dioenzymatic technique.:’ Plasma volume was measured by standard dilution techniques using either human serum al- bumin tagged with iodine-125 (RISA) or Evans blue dye.sg Iodine-125 was used in 4 of 23 patients and 3 of 17 control subjects. Measurement of plasma volume by both RISA and Evans blue methods in 7 subjects revealed a nonsignificant mean difference of 183 f 104 ml (RISA values being higher). Total blood volume was estimated from measurement of plasma volume and peripheral venous hematocrit corrected for trapped plasma and the difference between central and peripheral venous hematocrit.lOJl

Protocol: The study was approved by the local Human Research Review Committee. Each subject gave informed written consent before study. Although most patients and subjects had participated in similar hemodynamic studies previously, care was taken to familiarize each person with the laboratory procedures and equipment. This familiarization was always accomplished a day before the study was performed. Testing of patients and control subjects was performed concurrently.

On the first day of stucly, a small needle was placed in an arm vein and kept open with heparinized saline solution. Baseline cardiac output, heart rate, and blood pressure were measured. After at least :!O minutes of supine rest, a venous blood sample was drawn for plasma catecholamine determination. Hemodynamic measurements were then repeated. The subject then stood quietly for 5 minutes, after which catecholamine sampling and lnemodynamic measurements were again repeated.

Measurement of plasma volume was performed on a second day with the subject at rest supine for approximately 1 hour. Hematocrit was determined on simultaneously obtained peripheral blood samples.

TABLE I Subject Characteristics

&e (yr) l

Mitral Valve Prolapse

Group I Group II (HR <lOO) (HR 2 100)

39.0’: 4.1 33.5’: 2 4

Normal Control

Subjects

17 26.9 f 1.0

Height (cm) 167.7 f 2.0 167.6 f 2:2 167.8 f 1.8

&$$9 56.8 f 2.3 55.7 f 2.6 58.6 f 1.6 1.64 f 0.03 1.62 f 0.04 1.66 f 0.03

l p <O.Ol. BSA = body surface area; HR = heart rate.

Statistical analysis was performed with the use of the Sta- tistical Analysis Systems programs.12 Because an initial analysis of the results revealed the presence of 2 hemody- namically distinct subsets of patients, an analysis of variance was used to test for differences between the control subjects, the patients with normal supine and standing heart rates (Group I), and those with tachycardia when standing (Group II). Results are expressed as the mean f standard error of the mean. Differences were statistically significant to a level of probability of p <0.05.

Results

Supine: Cardiac and stroke volume indexes, calculated arteriovenous oxygen differences, and total peripheral resistance for patients and control subjects were not significantly different (Fig. 1). Mean arterial pressure was higher in the patients. Heart rate was increased only in the patients with standing tachycardia (Group II). Mean plasma norepinephrine levels were similar, but plasma epinephrine levels were significantly higher in patients compared with the control subjects (31 f 5.7 versus 11 f 3.7 pg/ml, p <O.Ol). These values, although at the lower limits of detectability, correlated significantly with heart rate (p <O.OOl) and systolic blood pressure (p <O.OOl).

Standing: As expected, cardiac indexes decreased significantly on standing in both patients and control subjects; Group I patients had lower mean cardiac indexes than did Group II patients or control subjects. Both patient groups had a higher mean diastolic arterial blood pressure (81 f 3, 79 f 2, and 72 f 2 mm Hg, p <0.05, respectively), with a subnormal stroke volume index (p <0.05). Plasma norepinephrine levels increased in all groups. Again, the intergroup differences were not statistically significant, but several individual patients had very large increases on standing, and there was a downward progression from Group II patients with tachycardia to normal control subjects (Fig. 2). Plasma epinephrine levels were not significantly different from values obtained in the supine position. Measurements of heart rate, blood pressure, and stroke volume also showed large interindividual differences among the patients. Total peripheral resistance (Fig. 1) was significantly higher in Group I patients, with no tachycardia; Group II patients had intermediate values, whereas the controls had the lowest. An identical pattern was seen for calculated arteriovenous oxygen difference (6.90 f O-60,6.77 f 0.39, and 5.70 f 0.26 vol%, respectively).

318 CARDIOVASCULAR REGULATION IN MITRAL VALVE PROLAPSE

^a 2 .E a3MVPS HR 2100 440 -

0 MVPS HR <400 Y

L 0 Control p 405 - 5 cxro’r

2 B 400- bi 20- m

g go-

J 80- 9 “w 70- hP 44

5 60-

5 “; ?ze g* --kbl ,2_ .; . . . ,i

;: j ”

E 10 - f?j

Y f q ‘g _

SUPINE STANDING SUPINE STANDING SUPINE STANDING

* 4

2.5 -

$

9 2.0 - I -

FIGURE 1. Hemodvnamic and neuroendocrine measurements in patients with normal heart rates (Group I), patients with orthostatic tachycardia (Group II), and normal control subjects. MVPS = mitral valve prolapse svndrome: HP = heart rate. Values are mean f 1 stan-

SUPINE STANDING SUPINE STANDING SUPINE STANDING d&d error.

Plasma volume: Overall, patients had a significantly higher hematocrit (40.3 f 0.9 versus 37.6 f 0.6%, p <0.02) and lower plasma volume, both in absolute terms (2,836 f 82 versus 3,222 f 123 ml, p <O.Ol) and when corrected for height (17.0 f 0.5 versus 19.2 f 0.7 ml/cm, p <O.Ol). There were similar differences in absolute blood volume and when correction was made for height or body surface area.i3 Group I patients, who had the highest total peripheral resistance, had the lowest blood volumes, 4,012 f 100 ml, Group II patients had intermediate values, 4,406 f 133 ml, and control subjects had 4,798 f 231 ml (p <0.05).

Discussion

The present study demonstrates that a subgroup of patients with MVP, characterized by the presence of symptoms and both echocardiographic and ausculta-

MITRAL VALVE PROLAPSE CONTROL SYNDROME

; 4400-

e 4200-

8 1000 -

P 800 -

z 8 600 -

h

400 -

200- :s

0’ c I

Supine Standing Supine Standing

FIGURE 2. Supine and standing plasma ncrepinephrine values for each patient and each normal control subject.

tory/phonographic signs of prolapse, have an abnormal response to orthostatic stress. They develop excessive vasoconstriction and, in some cases, tachycardia, and maintain a higher mean arterial blood pressure (standing) than do normal control subjects. By them- selves, heart rate and blood pressure data suggest a hyperkinetic response, but when examined relative to the overall hemodynamic response, a different pattern emerges. Stroke volume tends to be slightly lower in the supine position, and on standing is significantly lower in both groups of patients with MVP. In Group II patients, there is tachycardia on standing, and cardiac output is maintained at normal levels. In Group I patients, the response is actually hypokinetic, as reflected in the tendency toward wider calculated arteriovenous oxygen differences in the patient group in the upright position. Group I patients, when standing, seem to compensate for decreased forward stroke volume by vasoconstriction. However, if the patients had a purely compensatory response, their blood pressure should have been slightly lower than normal, rather than significantly higher than the control group values.

The hemodynamic heterogeneity of the patients makes interpretation of the average norepinephrine responses difficult. Other investigators have found small but significant differences between patients with MVP and control subjects4p5 Our patients also tended to have higher plasma norepinephrine levels, but interindividual variations were large and the intergroup differences did not reach statistical significance (Fig. 2). Whether or not a group difference will be recorded is determined in large part by the number of patients in the study who have orthostatic intolerance and tachycardia as major complaints. The finding that certain patients with MVP have tachycardia and increased norepinephrine levels on standing does not constitute proof of beta-adrenergic hyperactivity, that is, an ab-

August 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52 319

normal hemodynamic state primarily attributable to abnormal levels of beta-adrenergic stimulation. Patients with the higher norepinephrine levels also had the higher heart rates which served to maintain cardiac output to a more normal degree than did the “normal” heart rate. The 13 patients with the highest norepinephrine levels and standing heart rates over 100 beats/min (Group II patients) had a mean cardiac index of 2.9 f 0.2 liters/min/n-?, whereas the patients (Group I) with standing heart. rates under 100 had a significantly lower cardiac index (2.3 f 0.2 liters/min/m2). Other investigators4y5 noted an apparently inappro- priate response in patients with MVP on standing, but cardiac output measurements were not performed. The lack of cardiac output data led to the conclusion that a hyperkinetic state was present, whereas the present study suggests that the heart rate response is reasonably appropriate considering the stimulus, that is, an orthostatic blood volume shift producing a low forward stroke volume. The increase in arterial pressure above normal levels during orthostatic stress despite a substantial decrease in cardiac output has been noted previously1 and suggests an abnormal alpha-adrenergic responsiveness with a:ppropriate beta-adrenergic activity. The alpha-adrenergic hyperactivity in the upright position may eventually lead to a chronic state of vasoconstriction and increased plasma catecholamine levels. The fact that orthostatic intolerance in some patients with pheochromocytoma provides some support for the hypothesis that a neuroendocrine postural response that is beneficial on a short-term basis may contribute to a chronic state of orthostatic intolerance.14 Similar changes may also be seen in subjects rendered hypovolemic by prolonged bed rest or space travel.15

A possible link between excessive vasoconstriction, hypovolemia, and MVP is presented in Figure 3. A large postural reduction in forward stroke volume leads to marked vasoconstriction and increased catecholamine release. This chronic vasoconstriction leads to hypovolemia, which produces an even greater reduction in forward stroke volume in the presence of MVP. A vi- cious cycle is establish.ed. Substantial mitral regurgitation is not a prerequisite. The increasing volume contained by the ballooning leaflets with decreasing ventricular size may produce, for any given reduction in left ventricular filling pressure, an exaggerated decrease in resting fiber length, fiber shortening, and forward stroke volume. Our preliminary finding of a marked reduction in left ventricular end-diastolic volume in patients with MVP with upright rest or exercise supports the concept that decreased ventricular filling in the upright position is a prominent feature in the pathophysiologic mechanisms of this syndrome.2 Semiquantitative measurement of leg volume changes during orthostatic stress produced by lower body negative pressure showed that patients with MVP did not have excessive blood pooling in their legs,’ suggesting that the decrease in total blood volume is an important component of orthostatic intolerance in patients with MVP.

Such a decrease in blood volume might also be at least a partial explanation for the recent findings of Devereux et al,16 who noted significantly lower sitting blood

Mitral Valve Prolapse

Decreased Ventricular /’ \ Decreased Forward Volume and Fiber Stroke Volume

Length

T

Decreased \

Blood Volume

Chronic W Increased Heart Rate, Vasoconstriction Contractility and

Vasoconstriction

FIGURE 3. A proposed pathophysiology of orthostatic intolerance in symptomatic patients with mitral valve prolapse (MVP). A large myxomatous mitral valve would clearly have a facilitative role, but it is not necessary in order to have MVP or MVP symptoms related to rxthoetetic intolerance.

pressure in a large number of patients with MVP. The presence of an increased frequency of palpitations in Devereux’s MVP patientsi as well as ours1 may reflect the presence of orthostatic intolerance as recently reported by Santos et al. is Such patients are commonly seen and, in addition to palpitations, give a history of near-syncope or syncope, but an ambulatory electro- cardiographic recording often shows only sinus tachycardia. Unless a diary of patient activity is available, the extent of tachycardia without exertion or excitement is often not appreciated.

The existence of parasympathetic and alpha-adrenergic dysfunction in some patients with MVP suggests a primary abnormality affecting the autonomic nervous system. Two-dimensional echocardiographic studies in our patients, who all had auscultatory signs of prolapse, revealed a wide spectrum of mitral leaflet size and degree of valvular prolapse. These factors appear to be unrelated to the degree of symptoms present. Jeresatylg noted a similar lack of correlation between symptoms and the degree of prolapse, which suggests that at most, the prolapsing valve plays a facilitating role in producing these orthostatic symptoms, but that it is not their primary cause. This subgroup of patients with orthostatic intolerance clearly has a syndrome con- sisting of distinctive anthropometric characteristics,20 autonomic dysfunction,1-5 and myxomatous degener- ation of the mitral valve. Whether MVP is causally related to the symptoms of the patients in the present study is not known. Additionally, the presence of chronic vasoconstriction, hypovolemia, and orthostatic and exercise intolerance in similar patients without MVP (personal observation) suggests that the pathophysiologic mechanisms are by no means specific to MVP, but rather, explain the symptoms found in a va- riety of cardiac disorders. Data from other investigators provide some support for the hypothesis that there are other subgroups of patients with anatomically normal mitral valves, but with symptoms and signs of the MVP syndrome because of autonomic dysfunction including an increased inotropic state with reduced left ventric-

320 CARDIOVASCULAR REGULATION IN MITRAL VALVE PROLAPSE

ular volume. Wooley21 reported the clinical similarities between patients with MVP and hyperkinetic syn- dromes, such as the vasoregulatory asthenia described by Holmgren et a122 and the hyperkinetic heart syndrome reported by Gorlin.23 Whether some of these patients classified as hyperkinetic actually have mid- systolic clicks, murmurs, and echocardiographic evidence of MVP is not known.

Acknowledgment: We thank James T. Willerson, MD, for his advice and encouragement, Kent Dana, MS, and Nancy Plummer, MS, for statistical advice, and Carolyn Donahue for her expert assistance in preparing the manuscript.

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abnormal cardiovascular regulation in the mitral valve prolapse syndrome

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