Non-Beta-Adrenergic-Mediated Peripheral Circulatory Hyperkinesia in Hyperthyroidism Paul Valensi, M.D. Alain Simon, M.D. Isabelle Pithois-Merli, M.D. and Jaime Levenson, M.D.
PARIS and
BONDY, FRANCE
Abstract
Systolic time intervals and brachial circulation, evaluated by pulsed Doppler in terms of arterial diameter, blood velocity and flow, and vascular resistance, were studied in 12 hyperthyroid patients and in 12 normal controls. In patients, arterial circulation was studied before and during mechanical exclusion of the hand, and hemodynamic measurements were repeated after beta-blocker treatment and after obtainment of euthyroid state. Compared with controls, patients had higher heart rate (P < 0.001), lower systolic time intervals (P < 0.05, P < 0.01), and higher blood velocity (P < 0.05). Beta blockade decreased heart rate (P < 0.05, P < 0.001) but did not change systolic time intervals and arterial circulation. Euthyroid state decreased heart rate (P < 0.01), preejection period (P < 0.01), and blood velocity (P < 0.01) and flow (P < 0.05). The decreases in velocity and flow before hand exclusion when euthyroid state was obtained were correlated with hyperthyroid values of velocity and flow respectively (r = 0.85, r = 0.90, P < 0.01, P < 0.001). Vascular resistance during hand exclusion was correlated negatively with serum 3 T level during hyperthyroid and euthyroid states. Thus, thyroid hormones but not beta-adrenoreceptors participate in the peripheral hyperkinesia of hyperthyroidism.
From the Centre de Médecine Préventive Cardiovasculaire, INSERM U 28, Hôpital Broussais, Paris, and the Department of Endocrinology-Diabetology-Nutrition, Hopital Jean Verdier, Bondy, France
996
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
997 TABLE I Clinical Characteristics of Controls and Patients
Values
are mean
t 1 SEM; *P < 0.05.
Introduction The cardiovascular manifestations of hyperthyroidism are classically characterized by an enhanced myocardial contractility’~ and are considered mainly dependent on an increased sympathoadrenal activity on the basis that they are relieved by beta-blocker treatment.s’6 But all7 the cardiac manifestations cannot be explained by increased sympathoadrenal activity alone ; experimental studies suggest that the thyroid hormones may have direct effects on the heart.&dquo;’ In contrast, the manifestations of hyperthyroidism on peripheral vasculature have been poorly investigated; some studies based on the observation of increased muscle blood flow9 or decreased total peripheral resistance’° suggest a peripheral vasodilation. Such a vasodilation could not be explained only by an increase in the metabolic requirement of the tissue9 and might also be mediated by the alpha adrenergic system,&dquo; but globally, the features of peripheral effects of hyperthyroidism and its mechanisms remain unclear. Thus, the aims of this study were to perform a careful evaluation of brachial artery circulation in 12 hyperthyroid patients and in 12 normal controls, determine the potential role of the beta-adrenergic system and of thyroid hormones, and assess the part of the brachial circulation related to skin and subcutaneous tissues and that related to the muscle circulatory bed.’2’’3
Materials and Methods Patients Twelve hyperthyroid patients were selected for the study. Eight of them had Graves’ disease and the 4 others had nodular toxic goiter. Thyrotoxicosis was assessed on clinical data and confirmed in all cases by hormone assays. Twelve normal age- and sex-matched controls without history of thyroid disorder also entered the investigation. All the subjects had a sinus rhythm and none had congestive heart failure, valvular or coronary artery disease, or arterial hypertension on the basis of history, physical examination, electrocardiogram, and chest radiograph. All hyperthyroid patients were investigated before any beta-blocker or antithyroid treatment. Clinical characteristics of controls and patients are given in Table I. After giving informed consent, the normal controls and the hyperthyroid patients were referred to the hemodynamic laboratory for performance of the noninvasive arterial measurements in the beginning of the afternoon after a light lunch. Brachial Measurements The study was performed with the subjects supine in a warm and quiet room. The right upper limb was kept at the midthoracic level in a controlled environment at 20 ± 1 ° C with the
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
998 TABLE III
Comparison of Brachial Hemodynamics Between Controls
TABLE II
Comparison of Central Hemodynamics
and Patients
Between Controls
and Patients
Values are mean t 1 SEM; *P < 0.05, For abbreviations, see methods.
**P < 0.01,
***P < 0.001. Values
are mean
t 1
SEM; *P < 0.05.
hand relaxed and opened. After ten minutes of rest, systemic blood pressure was determined in the left upper limb as the mean of at least three measurements by standard sphygmomanometric procedure. The brachial artery circulation was studied by means of a bidimensional pulsed Doppler velocimeter with a frequency of 8 MHz pulsed at 15 kHz and with two important features previously described.’2’’4 The first was a double-transducer probe permitting adjustment of the incident angle of the ultrasonic beam at 60 ± 1 ° to the arterial axis to quantify precisely the blood velocity inside the artery. The precision of the ultrasound angle was improved by carefully fixing the Doppler probe over the course of the brachial artery by means of a stereotaxis device placed around the upper limb. The second feature of the velocimeter was a range-gated time system of reception enabling adjustment of the interval between two successively emitted pulses as well as the size and the depth of the measurement volume. By moving the smallest measurement volume across the arterial lumen electronically, it was possible to locate precisely the proximal and the distal wall of the artery corresponding respectively to the first and the last Doppler signals received and to deduce by a simple difference the internal diameter of the brachial artery. Once the arterial diameter was determined, the velocity of the whole arterial blood column was measured by increasing the width of the measurement volume to the value of the diameter and by superimposing it on the lumen of the artery; the recording of the instantaneous blood velocity curve enabled the systolic peak velocity during systole to be measured. The mean blood velocity (VM) was obtained from electronic integration of the instantaneous blood velocity curve and was used to calculate the mean blood flow in the brachial artery (Q) according to the formula Q=(-rrU/4) x VM where D is the internal diameter. All determinations of arterial diameter and blood velocity were repeated at least twice in each patient for each probe with a reproducibility of 7 ± 2 % and 5 ~ 2 % (means z SEM).‘4 Diameter was expressed in centimeters (cm), blood velocity in centimeters per second (cm/s), and blood flow in milliters per minute (mL/min). Vascular resistance of the arterial distal bed to the brachial artery was calculated by dividing mean arterial pressure (calculated as one third of the sum of systolic pressure and twice the diastolic pressure) by the brachial artery mean blood flow.’2 Additionally, in order to discriminate the part of the brachial
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
999
FIG. 1. Correlation between baseline values of
brachial artery diameter and T3 serum level in the hyper-
thyroid patients
group.
circulation related to skin and subcutaneous tissues and that related to the muscle circulatory bed, measurements were performed in hyperthyroid patients with the circulation of the hand stopped by inflation of a cuff around the wrist to 250 mmHg at least one minute before the measurements
122
Determination of Systolic Time Intervals The systolic time intervals were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, and carotid arterial pulse by means of a multichannel system.&dquo; Care was taken to ensure that the beginning and the end of the determinations always coincided with the same phase of respiration. The following intervals of the left ventricular systolic cycle were measured or calculated.&dquo; QS2: The total electromechanical interval was measured from the onset of the QRS complex to the initial high-frequency vibration of the aortic component of the second heart sound. LVET: The left ventricular ejection time measured from the beginning of the upstroke to the trough of the incisura of the carotid arterial pulse tracing. PEP: The preejection period was derived by subtracting LVET from the QS2 interval. The PEP/LVET ratio was also calculated. All intervals were calculated as the average of measurements made on 10 consecutive heart beats. Heart rate was derived from the average R-R interval. PEP and LVET were corrected for heart rate according to the standard formula. Hormonal Assays Fasting serum thyroxin (T4), triiodothyronine (T3), and plasma thyrotropin (TSH) were determined by radioimmunoassay kits at 8 AM in the morning. Free T4 index (FT4I) was
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
1000
FIG. 2. Effects of beta blockers (propranolol and atenolol) n number of patients. *P < 0.05, **P < 0.01,
hemodynamics;
=
for 7 0.001.
given orally ***P
PARIS and
BONDY, FRANCE
Abstract
Systolic time intervals and brachial circulation, evaluated by pulsed Doppler in terms of arterial diameter, blood velocity and flow, and vascular resistance, were studied in 12 hyperthyroid patients and in 12 normal controls. In patients, arterial circulation was studied before and during mechanical exclusion of the hand, and hemodynamic measurements were repeated after beta-blocker treatment and after obtainment of euthyroid state. Compared with controls, patients had higher heart rate (P < 0.001), lower systolic time intervals (P < 0.05, P < 0.01), and higher blood velocity (P < 0.05). Beta blockade decreased heart rate (P < 0.05, P < 0.001) but did not change systolic time intervals and arterial circulation. Euthyroid state decreased heart rate (P < 0.01), preejection period (P < 0.01), and blood velocity (P < 0.01) and flow (P < 0.05). The decreases in velocity and flow before hand exclusion when euthyroid state was obtained were correlated with hyperthyroid values of velocity and flow respectively (r = 0.85, r = 0.90, P < 0.01, P < 0.001). Vascular resistance during hand exclusion was correlated negatively with serum 3 T level during hyperthyroid and euthyroid states. Thus, thyroid hormones but not beta-adrenoreceptors participate in the peripheral hyperkinesia of hyperthyroidism.
From the Centre de Médecine Préventive Cardiovasculaire, INSERM U 28, Hôpital Broussais, Paris, and the Department of Endocrinology-Diabetology-Nutrition, Hopital Jean Verdier, Bondy, France
996
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
997 TABLE I Clinical Characteristics of Controls and Patients
Values
are mean
t 1 SEM; *P < 0.05.
Introduction The cardiovascular manifestations of hyperthyroidism are classically characterized by an enhanced myocardial contractility’~ and are considered mainly dependent on an increased sympathoadrenal activity on the basis that they are relieved by beta-blocker treatment.s’6 But all7 the cardiac manifestations cannot be explained by increased sympathoadrenal activity alone ; experimental studies suggest that the thyroid hormones may have direct effects on the heart.&dquo;’ In contrast, the manifestations of hyperthyroidism on peripheral vasculature have been poorly investigated; some studies based on the observation of increased muscle blood flow9 or decreased total peripheral resistance’° suggest a peripheral vasodilation. Such a vasodilation could not be explained only by an increase in the metabolic requirement of the tissue9 and might also be mediated by the alpha adrenergic system,&dquo; but globally, the features of peripheral effects of hyperthyroidism and its mechanisms remain unclear. Thus, the aims of this study were to perform a careful evaluation of brachial artery circulation in 12 hyperthyroid patients and in 12 normal controls, determine the potential role of the beta-adrenergic system and of thyroid hormones, and assess the part of the brachial circulation related to skin and subcutaneous tissues and that related to the muscle circulatory bed.’2’’3
Materials and Methods Patients Twelve hyperthyroid patients were selected for the study. Eight of them had Graves’ disease and the 4 others had nodular toxic goiter. Thyrotoxicosis was assessed on clinical data and confirmed in all cases by hormone assays. Twelve normal age- and sex-matched controls without history of thyroid disorder also entered the investigation. All the subjects had a sinus rhythm and none had congestive heart failure, valvular or coronary artery disease, or arterial hypertension on the basis of history, physical examination, electrocardiogram, and chest radiograph. All hyperthyroid patients were investigated before any beta-blocker or antithyroid treatment. Clinical characteristics of controls and patients are given in Table I. After giving informed consent, the normal controls and the hyperthyroid patients were referred to the hemodynamic laboratory for performance of the noninvasive arterial measurements in the beginning of the afternoon after a light lunch. Brachial Measurements The study was performed with the subjects supine in a warm and quiet room. The right upper limb was kept at the midthoracic level in a controlled environment at 20 ± 1 ° C with the
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
998 TABLE III
Comparison of Brachial Hemodynamics Between Controls
TABLE II
Comparison of Central Hemodynamics
and Patients
Between Controls
and Patients
Values are mean t 1 SEM; *P < 0.05, For abbreviations, see methods.
**P < 0.01,
***P < 0.001. Values
are mean
t 1
SEM; *P < 0.05.
hand relaxed and opened. After ten minutes of rest, systemic blood pressure was determined in the left upper limb as the mean of at least three measurements by standard sphygmomanometric procedure. The brachial artery circulation was studied by means of a bidimensional pulsed Doppler velocimeter with a frequency of 8 MHz pulsed at 15 kHz and with two important features previously described.’2’’4 The first was a double-transducer probe permitting adjustment of the incident angle of the ultrasonic beam at 60 ± 1 ° to the arterial axis to quantify precisely the blood velocity inside the artery. The precision of the ultrasound angle was improved by carefully fixing the Doppler probe over the course of the brachial artery by means of a stereotaxis device placed around the upper limb. The second feature of the velocimeter was a range-gated time system of reception enabling adjustment of the interval between two successively emitted pulses as well as the size and the depth of the measurement volume. By moving the smallest measurement volume across the arterial lumen electronically, it was possible to locate precisely the proximal and the distal wall of the artery corresponding respectively to the first and the last Doppler signals received and to deduce by a simple difference the internal diameter of the brachial artery. Once the arterial diameter was determined, the velocity of the whole arterial blood column was measured by increasing the width of the measurement volume to the value of the diameter and by superimposing it on the lumen of the artery; the recording of the instantaneous blood velocity curve enabled the systolic peak velocity during systole to be measured. The mean blood velocity (VM) was obtained from electronic integration of the instantaneous blood velocity curve and was used to calculate the mean blood flow in the brachial artery (Q) according to the formula Q=(-rrU/4) x VM where D is the internal diameter. All determinations of arterial diameter and blood velocity were repeated at least twice in each patient for each probe with a reproducibility of 7 ± 2 % and 5 ~ 2 % (means z SEM).‘4 Diameter was expressed in centimeters (cm), blood velocity in centimeters per second (cm/s), and blood flow in milliters per minute (mL/min). Vascular resistance of the arterial distal bed to the brachial artery was calculated by dividing mean arterial pressure (calculated as one third of the sum of systolic pressure and twice the diastolic pressure) by the brachial artery mean blood flow.’2 Additionally, in order to discriminate the part of the brachial
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
999
FIG. 1. Correlation between baseline values of
brachial artery diameter and T3 serum level in the hyper-
thyroid patients
group.
circulation related to skin and subcutaneous tissues and that related to the muscle circulatory bed, measurements were performed in hyperthyroid patients with the circulation of the hand stopped by inflation of a cuff around the wrist to 250 mmHg at least one minute before the measurements
122
Determination of Systolic Time Intervals The systolic time intervals were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, and carotid arterial pulse by means of a multichannel system.&dquo; Care was taken to ensure that the beginning and the end of the determinations always coincided with the same phase of respiration. The following intervals of the left ventricular systolic cycle were measured or calculated.&dquo; QS2: The total electromechanical interval was measured from the onset of the QRS complex to the initial high-frequency vibration of the aortic component of the second heart sound. LVET: The left ventricular ejection time measured from the beginning of the upstroke to the trough of the incisura of the carotid arterial pulse tracing. PEP: The preejection period was derived by subtracting LVET from the QS2 interval. The PEP/LVET ratio was also calculated. All intervals were calculated as the average of measurements made on 10 consecutive heart beats. Heart rate was derived from the average R-R interval. PEP and LVET were corrected for heart rate according to the standard formula. Hormonal Assays Fasting serum thyroxin (T4), triiodothyronine (T3), and plasma thyrotropin (TSH) were determined by radioimmunoassay kits at 8 AM in the morning. Free T4 index (FT4I) was
Downloaded from ang.sagepub.com at UCSF LIBRARY & CKM on June 12, 2015
1000
FIG. 2. Effects of beta blockers (propranolol and atenolol) n number of patients. *P < 0.05, **P < 0.01,
hemodynamics;
=
for 7 0.001.
given orally ***P
