Autonomic dysfunction, a risk factor for death >>
Baroreflex or stretch-o-reflex? >>
Gender difference in autonomic function >>
Anticipatory reactions and stroke >>
Implantable loop recorders vs tilt-table test >>
(Click on the reference to view the abstract)
Autonomic Dysfunction and Increased Mortality:
Assessment by Sinus Arrhythmia is as Good as Any Other Autonomic Function
Tests
Several studies have consistently found an association
between autonomic impairment and increased mortality in several populations,
including patients with diabetes, survivors of myocardial infarction, and
unselected middle-aged and elderly subjects.
Different methods have been used to establish autonomic impairment, but
side-to-side comparisons between these tests are not available.
In this study, Gerritsen et al. followed 605 subjects 50-75 years
of age for 9 years. Baseline measurements included a glucose tolerance test and
monitoring of heart rate and continuous finger blood pressure at rest and during
controlled breathing. From these
readings, seven parameters of autonomic function were assessed: resting heart
rate (mean R-R interval), standard deviation of R-R intervals, low frequency
(LF) and high frequency (HF) power of heart rate variability, LF/(LF+HF), mean
difference in R-R interval during deep breathing (EI difference, sinus
arrhythmia), and baroreflex sensitivity using cross-spectra analysis.
Subjects with diabetes and autonomic impairment had twice the risk of
mortality. This association was
consistent for all seven parameters, but not statistically significant for all.
Of interest, EI difference (sinus arrhythmia during deep breathing) was
as good predictor as any of the other parameters.
The elevated risk was not observed in subjects without diabetes,
hypertension or cardiovascular disease.
Gerritsen
J, Dekker JM, TenVoorde BJ, et al. Impaired autonomic
function is associated with increased mortality, especially in subjects with
diabetes, hypertension, or a history of cardiovascular disease.
Diabetes Care 2001;24:1793-1798.
Baroreflex or
Strech-O-reflex?
Impaired baroreflex sensitivity is associated with
hypertension, heart disease, diabetes and other pathological conditions, and may
be an indicator of increased mortality (see previous news).
Traditionally, cardiac-vagal baroreflex sensitivity or gain has been
quantified by the changes in heart rate (or R-R interval) resulting from changes
in blood pressure. “Baroreceptors”, however, do not respond to pressure per
se, but to the mechanical deformation produce by changes in pressure.
Hunt et al. measured beat-to-beat changes in carotid diameter (by
ultrasound) at baseline and during acute changes in blood pressure induced by
bolus injections of phenylephrine or nitroprusside.
There was a significant correlation between carotid diameter and blood
pressure, and this relationship may provide a gain estimate of dynamic
transduction of pressure into a baroreflex stimulus (“mechanical transduction”).
Additional information can be obtained by examining the relationship
between R-R interval and systolic carotid artery diameter (“neural
transduction”). Neither of these
measurements individually correlated with traditional integrated baroreflex gain
(R-R interval/systolic blood pressure). This
novel approach, however, may allow us to dissect abnormalities in these
individual components of baroreflex function in abnormal populations.
It should be noted that systemic administration of vasoactive compounds
also recruit baroreceptors outside the carotid arteries, which also influence
overall baroreflex gain, but could not be examined in this study.
Hunt
BE, Fahy L, Farquhar WB, Taylor JA. Quantification
of mechanical and neural components of vagal baroreflex in humans.
Hypertension 2001;37:1362-1368.
The Importance of Being
Ernst or Ernesta. Gender
Differences in Autonomic Function
Baroreflex sensitivity (BRS) has been found lower and
heart rate variability have been found higher in healthy women than in healthy
men. These measurements of
autonomic function are also impaired in disease states, including hypertension.
Sevre et al. studied 41 hypertensive patients and 34 normotensive
subjects to examine potential gender differences in heart rate variability
(24-hr Holter) and BRS (transfer function of finger blood pressure and R-R
interval). Women were
postmenopausal. Hypertensive
patients had lower total power and high frequency power of heart rate
variability, and lower BRS. After
considering gender, these differences were apparent only in the female group.
The difference in BRS within the female group was twice that within the
male group. Stepwise regression analysis revealed gender, age, HDL-cholesterol
and blood pressure as independent variables affecting BRS and heart rate
variability. The results from this
relatively small study do not negate the importance of impaired autonomic
function as a risk factor in men, but highlight the necessity to examine
potential gender differences in future studies, and to consider more carefully
the potential impact of autonomic impairment on cardiovascular risk in
postmenopausal women.
Sevre
K, Lefrandt JD, Nordby G, et al. Autonomic
function in hypertensive and normotensive subjects.
Hypertension 2001;37:1351-1356.
Anticipatory Systolic Pressor
Response Correlates with Stroke
Systolic hypertension is a known risk factor for
stroke. It has been proposed that
individuals who show frequent, large blood pressure and heart rate responses to
psychological stress, are at higher risk of cardiovascular disease, the
cardiovascular reactivity hypothesis. In
this study, Everson et al., tested this hypothesis in 2,303 Finish men
(53±5 years of age) participating in a population-based, longitudinal study of
risk factors for cardiovascular disease. Blood
pressure reactivity was calculated as the difference between blood pressure
measured during the anticipatory phase of an exercise tolerance test, and the
resting blood pressure measured one week earlier.
Men with an exaggerated systolic reactivity (greater than or equal to a
20mm Hg) had 72% greater risk of any stroke, and 87% greater risk of ischemic
stroke. Low socioeconomic status
has been previously shown to be associated with increased risk of stroke. In this study, men who were high reactors and poorly educated
were nearly 3 times more likely to suffer a stroke than better educated, less
reactive men. The association
between anticipatory pressor response and stroke remained significant after
adjustment for age, exercise tolerance, resting blood pressure, smoking, alcohol
consumption, body mass index, hypercholesterolemia, use of antihypertensives and
diabetes. The assumption underlying
these conclusions is that the anticipatory blood pressure before exercise is an
adequate surrogate for cardiovascular reactivity. Further studies that test this association directly will be
of great interest, as would be to determine if a similar association is seen in
Finish women (see previous news).
Everson
SA, Lynch JW, Kaplan GA, et al., Stress-induced blood pressure reactivity and
incident stroke in middle-age men. Stroke
2001;32:1263-1270.
Role of Implantable Loop
Recorder and Tilt-Test in Defining the Mechanism of Neurogenic Syncope. Is there a “Gold Standard”?
Head-up tilt is used in the diagnosis of syncope
under the assumption that the procedure will reproduce the mechanisms underlying
spontaneous neurogenic syncope. Moya
et al. tested this assumption by evaluating patients with syncope and
either positive (n=29) or negative (n=82) tilt table test results.
Average age was 63, duration of disease 4 years, and patients had an
average of 4 episodes in the last 2 years.
All were monitored with an implantable loop (40 minutes before and 2
minutes after activation) recorder. Syncope
did not recur in 66% of patients and recurred in 32 patients only.
Of these, episodes of asystole or bradycardia were documented by the loop
recorder in 19 (60%). The other 13
patients had either normal sinus rhythm, sinus tachycardia, or atrial
tachycardia (in one). Based on
these results, a permanent pacemaker was implanted at the end of the study in 14
patients. The following
observations were made. Presyncopal
episodes, as defined by the patients, were not associated with demonstrable
heart rhythm abnormalities other than tachycardia.
Episodes of spontaneous bradycardia/asystole were either gradual in onset
or were preceded by tachycardia (it had been suggested that these patterns
differentiate between true syncope or false positive syncope at tilt).
Patients with a mixed cardioinhibitory/vasodepressor response to tilt
without asystole were subsequently found to have spontaneous asystole during
monitoring. The
“cardiovascular” pattern of spontaneous syncope determined by the loop
recorder appeared to be consistent in the few patients who had repeated syncopal
episodes. These observations, however, remain anecdotal because of the few
patients involved. Therefore, an
implantable loop recorder can aid in the diagnosis of neurogenic syncope, but
our clinical ability to predict which patients will have recurrent syncope
remains poor. Implantable loop
recorders may be particularly useful in patients having a negative tilt test
result and in the decision to implant a permanent pacemaker.
The presence of bradycardia or asystole documented by loop recordings, in
the absence of structural heart disease, suggests neurogenic syncope.
The absence of bradycardia, however, cannot rule out a pure vasodepressor
syncope. In this relatively small
subject population, none of the patients with a positive tilt test result were
found subsequently to have cardiogenic syncope, suggesting that the tilt test
remains an acceptable diagnostic tool. However,
it is possible that the hemodynamic pattern diagnosed by tilt testing may differ
from that occurring during spontaneous events.
Moya
A, Brignole M, Menozzi C, et al. Mechanism
of syncope in patients with isolated syncope and in patients with tilt-positive
syncope. Circulation
2001;104:1261-1267.
Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG,
Reichart B, Schwaiger M. Myocardial efficiency and sympathetic reinnervation
after orthotopic heart transplantation: a noninvasive study with positron
emission tomography. Circulation. 2001;103:1881-86.
Abstract: BACKGROUND: The lack of cardiac catecholamine uptake and storage
caused by sympathetic denervation may influence performance of the transplanted
heart. Reinnervation, occurring late after transplantation, may partially
resolve these effects. In this study, oxidative metabolism and its relation to
cardiac work were compared in allografts and normal and failing hearts, and the
effects of sympathetic reinnervation were evaluated. METHODS AND RESULTS:
Twenty-seven nonrejecting, symptom-free transplant recipients, 11 healthy
control subjects, and 10 patients with severe dilated cardiomyopathy underwent
PET with (11)C acetate for assessment of oxidative metabolism by the clearance
constant k(mono) and radionuclide angiography or MRI for measurement of
ventricular function, geometry, and work. Efficiency was estimated noninvasively
by a work-metabolic index [WMI=(stroke volumexheart ratexsystolic pressure)/k(mono)].
In 14 of 27 transplants, presence of regional reinnervation was identified with
PET and the catecholamine analogue (11)C hydroxyephedrine (extent, 24+/-14% of
left ventricle). The WMI was comparable in normal subjects and reinnervated and
denervated transplants (6.2+/-2.3 versus 4.9+/-2.0 versus 4.9+/-1.2. 10(6) mm
Hg. mL; P=NS) and significantly lower in cardiomyopathy patients (3.0+/-1.3.
10(6) mm Hg. mL; P<0.001). For normal subjects and transplant recipients, the
WMI was significantly correlated with afterload (peripheral vascular resistance;
r=-0.65, P<0.01), preload (end-diastolic volume; r=0.78, P<0.01), and
stroke volume (r=0.81, P<0.01) but not with hydroxyephedrine retention
(transplants only; r=0.09, P=NS). CONCLUSIONS: After transplantation, cardiac
efficiency is improved compared with failing hearts and comparable to normal
hearts. Differences between denervated and reinnervated allografts were not
surveyed. Additionally, the dependency on loading conditions and contractility
was preserved, suggesting that normal regulatory interactions for efficiency are
intact and that sympathetic tone does not play a role under resting conditions.
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Jouven X, Zureik M, Desnos M, Guerot C,
Ducimetiere P. Resting heart rate as a predictive risk factor for sudden
death in middle-aged men. Cardiovasc Res. 2001;50:373-78.
Abstract: OBJECTIVE: A relative hyperadrenergic tone related to abnormalities of
the autonomic nervous system is suspected in the mechanisms of sudden death.
Therefore, we assessed the role of an elevated basal heart rate in the
occurrence of sudden death in a long-term cohort study. METHODS: 7746 subjects
aged 42--53 years, underwent ECG and physical examination conducted by a
physician under standardized conditions, provided blood samples for laboratory
tests, and answered questionnaires administered by trained interviewers. The
vital status was obtained from specific inquiries up to the time of retirement
and then by death certificates. Men with known ischemic heart disease were
further excluded from analysis which was conducted on the 7079 remaining
subjects. RESULTS: After an average follow-up period of 23 years, there were
2083 deaths, among which were 603 cardiovascular deaths including 118 sudden
deaths and 192 following myocardial infarction. The crude risk of sudden death
increased linearly with the level of resting heart rate and the risk in men in
the highest quintile of heart rate was 3.8 fold than in those in the lowest
quintile, whereas rates were approximatively twice higher for fatal myocardial
infarction, cardiovascular and total mortality (all P<0.01). When age, body
mass index, systolic blood pressure, tobacco consumption, parental history of
myocardial infarction and parental history of sudden death, cholesterol level,
diabetic status, and sport activity were simultaneously entered into the
survival model, resting heart rate remained an independent risk factor for
sudden death (P=0.03) but not for fatal myocardial infarction. CONCLUSION: An
elevated heart rate at rest was confirmed as an independent risk factor for
sudden death in middle-aged men.
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Grassi G, Turri C,
Seravalle G, Bertinieri G, Pierini A, Mancia G. Effects of chronic clonidine
administration on sympathetic nerve traffic and baroreflex function in heart
failure. Hypertension. 2001;38:286-91.
Abstract: Congestive heart failure is characterized by a sympathetic activation
that is coupled with a baroreflex impairment. Whether these alterations are
affected by clonidine is unknown. In 26 normotensive patients age 58.0+/-1.1
years (mean+/-SEM) affected by congestive heart failure (New York Heart
Association functional class II or III) and treated with furosemide and
enalapril, we measured mean arterial pressure, heart rate, venous plasma
norepinephrine, and muscle sympathetic nerve traffic (microneurography) at rest
and during baroreceptor stimulation and deactivation caused by stepwise
intravenous infusions of phenylephrine and nitroprusside, respectively.
Measurements were repeated after a 2-month administration of transdermal
clonidine patch (14 patients) or placebo (12 patients) according to a
double-blind, randomized sequence. Clonidine caused a slight, nonsignificant
reduction in mean arterial pressure and heart rate without affecting exercise
capacity and echocardiographically determined left ventricular ejection
fraction. In contrast, both plasma norepinephrine and sympathetic nerve traffic
were significantly reduced (-46.8% and -26.7%, respectively; P<0.01 for
both). This reduction was coupled with no change in cardiac and sympathetic
baroreflex responses. Transdermal placebo administration for a 2-month period
did not affect any of the above-mentioned variables. Thus, in congestive heart
failure patients who are undergoing conventional drug treatment, chronic
clonidine administration exerts marked sympathoinhibitory effects without
adversely affecting cardiac functions and clinical state. Whether this leads to
further therapeutic benefits remains to be tested.
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Kaye DM, Mansfield D, Aggarwal A, Naughton MT,
Esler MD. Acute effects of
continuous positive airway pressure on cardiac sympathetic tone in congestive
heart failure. Circulation. 2001;103:2336-38.
Abstract: BACKGROUND: Depressed ventricular performance and neurohormonal
activation are key pathophysiological features of congestive heart failure (CHF).
Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers
exert beneficial effects in CHF, mortality remains unacceptably high, and the
development of further therapeutic approaches is warranted. Recent data suggest
that continuous positive airway pressure (CPAP) may be of benefit in the
treatment of CHF, although the mechanism for this action is incompletely
understood. Methods and RESULTS:In the present study, we examined the effect of
short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz
catheter) and total systemic and cardiac sympathetic activity (norepinephrine
spillover method) in 14 CHF patients in New York Heart Association class III.
The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3
to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac
norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although
total systemic norepinephrine spillover was unchanged. CONCLUSION:The short-term
application of CPAP results in an inhibition of cardiac sympathetic nervous
activity. Further investigation into the potential value of long-term CPAP in
CHF patients is warranted.
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Kaye DM, Johnston L, Vaddadi
G, Brunner-LaRocca H, Jennings GL, Esler MD. Mechanisms of carvedilol action
in human congestive heart failure. Hypertension. 2001;37:1216-21.
Abstract: The precise mechanism by which beta-adrenoceptor blockers exert their
beneficial actions in patients with heart failure remains unclear. Several
possibilities have been proposed, including heart rate reduction,
beta2-adrenoceptor-mediated modulation of catecholamine release, antagonism of
the receptor-mediated toxic actions of norepinephrine on the myocardium, and
favorable effects on myocardial energetics. In the present study we evaluated
the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and
cardiac norepinephrine spillover (isotope dilution method), and myocardial
metabolism (myocardial oxygen consumption and carbon dioxide release) in 10
patients with severe congestive heart failure. Although carvedilol treatment was
associated with a significant improvement in left ventricular ejection fraction
(17+/-1% to 28+/-3%; P<0.01) and left ventricular stroke work (87+/-13 to
119+/-21 g. m per beat; P<0.05), this effect was unrelated to changes in
total systemic or cardiac norepinephrine spillover. The rise in left ventricular
stroke work was accompanied by a modest rise in myocardial oxygen consumption
per beat (0.33+/-0.04 to 0.42+/-0.04; P=0.05), although contractile efficiency
was unchanged. The favorable effects of carvedilol on ventricular function in
the failing heart are not explained by alterations in norepinephrine release or
by changes in myocardial contractile efficiency.
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