Sympathetic reinnervation after heart transplantation
Several studies have now established that at least partial autonomic
reinnervation occurs in some patients late after transplantation.
Among the evidence in favor of reinnervation, there is functional
normalization of heart rate responses to orthostatic and other challenges (Bernardi
L, et al. Circulation 1995;95:2895), and neurochemical restoration of
cardiac norepinephrine spillover (Kaye DM, et al. Circulation
1993;88:1110). Imaging studies
suggest that, when reinnervation occurs, it is limited to the anterior wall of
the left ventricle. It has been
more difficult to determine the clinical relevance of sympathetic reinnervation.
Even denervated hearts will increase contractility in response to
exercise, mainly due to Frank-Starling mechanisms (stretch induced contraction).
This mechanism, however, does not normalize cardiac response to exercise
in heart transplant patients. The
question addressed in this study is whether reinnervation improves myocardial
function during exercise. Bengel et
al, studied the response to exercise in 29 heart transplant patients.
They measured uptake of [11C]hydroxyephedrine with
positron-emission tomography (PET) to assess the extend and location of
sympathetic innervation, and correlated this information with regional
myocardial function, assessed by radionucleide angiography.
Evidence of reinnervation, limited to the anterior wall, was observed in
16 of 29 patients (4.4 years post surgery compared to 1.7 years in the
denervated group). Hemodynamic
values at rest were similar in the reinnervated and denervated groups, but the
duration of exercise was longer and the peak heart rate was higher in patients
with evidence of reinnervation (still, values were lower compared with those
observed in normal subjects). An
increase in wall motion, which is part of the normal response to exercise,
occurred only in the patients with evidence of reinnervation, and only in the
anterior wall. Thus, sympathetic
reinnervation is associated with improved cardiac performance in heart
transplantation.
Bengel
FM, Ueberfuhr P, Schiepel N, et al. Effect of Sympathetic
Reinnervation on Cardiac Performance after Heart Transplantation.
New Engl J Med 2001;345:731-738.
Resting heart rate is an independent predictor of
sudden death
Abnormalities of the autonomic nervous system (increased
sympathetic/decreased parasympathetic function) are suspected to play a role in
sudden death. In this study, 7079
middle-aged French men, without known ischemic heart disease, were followed-up
for an average of 23 years. Among
the 2083 deaths, 603 were from cardiovascular causes, including 118 sudden
deaths and 192 following myocardial infarction.
The crude risk of sudden death increased linearly with the level of
resting heart rate, increasing up to 3.8-fold in the highest quintile.
After accounting for various known risk factors, resting heart rate
remained an independent risk factor for sudden death, but not for myocardial
infarction.
Jouven
X, Zureik M, Desnos M, et al. Resting
heart rate as a predictive risk factor for sudden death in middle-aged men.
Cardiovasc Res 2001;50:373-378.
Is reducing sympathetic activity with clonidine
beneficial in heart failure?
Several studies have shown that sympathetic activation has a negative
effect on survival in congestive heart failure (e.g., see Kaye DM, et al,
J Am Coll Cardiol 1995;26:1257). It
follows that inhibition of sympathetic activity might be beneficial.
This study measured the effect of relatively short-term (2 month)
administration of clonidine (transdermal patch, 0.2 mg/d) or placebo patch given
in addition to standard treatment with furosemide and enalapril. Patients did not receive either β-blockers or
aldosterone antagonists. Clonidine
reduced plasma norepinephrine by 47% and muscle sympathetic nerve activity (MSNA)
by 27%. No significant change in
heart rate or blood pressure were observed.
Cardiac baroreflex (heart rate) and sympathetic baroreflex (MSNA)
responses to changes in blood pressure were not altered by clonidine. In conclusion, clonidine was effective in reducing
sympathetic activity. This was not
associated with changes in blood pressure, heart rate or baroreflex function.
It is not know if this reduction in sympathetic activity will be
translated in therapeutic benefit, and if so, if it would have an advantage over
treatment with β-blockers.
Grassi
G, Turri C, Seravalle G, et al. Effects
of chronic clonidine administration on sympathetic nerve traffic and baroreflex
function in heart failure. Hypertension 2001;38:286-291.
Continuous positive airway pressure (CPAP),
another way of decreasing sympathetic tone in heart failure
Sleep apnea is a common finding in congestive
heart failure patients, may adversely affect cardiovascular pathophysiology and
may contribute to increased sympathetic activity. There is interest, therefore, to determine if treatment of
sleep apnea with CPAP will have a beneficial effect in congestive heart failure.
In this study, Kaye et al report that CPAP (10 cm H2O
for 10 minutes) acutely reduced cardiac output (4.8 to 4.4 L/min) and cardiac
norepinephrine spillover (370 to 299 pmol/min), without affecting systemic
norepinephrine spillover. Further studies are warranted to determine the potential
beneficial effect of CPAP in congestive heart failure patients.
Kaye
DM, Mansfield D, Aggarwal A, et. al. Acute
effects of continuous positive airway pressure on cardiac sympathetic tone in
congestive heart failure. Circulation
2001;103:2336-2338.
Mechanisms of the beneficial effects of β-blockade
in heart failure
Despite the initial fears that β-blockade
would reduce myocardial contractility and be detrimental in patients with
congestive heart failure, it is now well established that β-blockers
paradoxically improve outcome of this condition.
However, the mechanism that explained this beneficial effect remains
unclear. In this study, the
non-selective β1- β2- adrenoreceptor blocker
Carvedilol (titrated to up to 50mg/d for 3 months) reduced heart rate (80 to 64)
and improved left ventricular ejection fraction (17 to 28%).
These beneficial effects were not explained by blockade of presynaptic
β2-adrenoreceptors that promote norepinephrine release, because
cardiac and systemic norepinephrine spillover remained elevated compared to
normal values and unchanged from baseline measurements.
This was also not explained by decreased oxygen consumption, and left
ventricular stroke work increased after adjustment of heart rate (87 to 119 g
• m/beat). These results suggest
that the mechanism of action is direct protection of the toxic effects of
catecholamines in the heart. It
should be noted that Carvedilol differs from other β-blockers in that it
also blocks α1-adrenergic receptors and induces vasodilation.
Whether this contributes to its beneficial effect is not know.
Neither cardiac output nor blood pressure changed significantly in this
study.
Kaye
DM, Johnston L, Vaddadi G, et al. Mechanisms of carvedilol action in human congestive
heart failure. Hypertension
2001;37:1216-1221.
Cardiac “atrophy” after bed-rest:
A non-neural mechanism for orthostatic intolerance?
Prolonged bed rest is associated with orthostatic
intolerance, which is characterized by a greater than normal reduction in stroke
volume during upright posture. Bed rest is also associated with reduced blood volume,
raising the possibility that hypovolemia can explain this decrease in stroke
volume. Alternatively, this group
has previously shown that the heart becomes less “distensible” after 2 weeks
of bed rest at –6˚ head-down tilt, and suggested that this mechanism
explains a diminished end-diastolic volume (for any given filling pressure)
while upright. The purpose of this
study was to determine if these cardiac abnormalities could be reproduced by
acute hypovolemia with furosemide. Normal
volunteers were subjected either to acute hypovolemia with furosemide 20 mg iv
or to 18 days of head-down tilt. Orthostatic
tolerance was determined by the response to lower body negative pressure. Both
maneuvers reduced orthostatic tolerance (bed rest by 27%, hypovolemia by 18%)
and induced a similar reduction in blood volume.
However, left ventricular end-diastolic volume decreased by 20% after bed
rest, and by 7% after hypovolemia. Moreover,
stroke volume was reduced more after bed rest than after hypovolemia, and the
Starling curve was shifted to the left after bed rest but not after hypovolemia.
The authors conclude that hypovolemia alone cannot totally explain the
hemodynamic abnormalities produced by bed rest, and that myocardial remodeling
contributes to the orthostatic intolerance of bed rest.
Perhonen
MA, Zuckerman JH and Levine BD. Deterioration
of left ventricular chamber performance after bed rest : "cardiovascular
deconditioning" or hypovolemia? Circulation
2001;103:1851-1857.
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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