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2001; Volume 11(5) from Clinical Autonomic Research                                           
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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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Perhonen MA, Zuckerman JH, Levine BD. Deterioration of left ventricular chamber performance after bed rest : "cardiovascular deconditioning" or hypovolemia? Circulation. 2001;103:1851-57.
Abstract: BACKGROUND: Orthostatic intolerance after bed rest is characterized by hypovolemia and an excessive reduction in stroke volume (SV) in the upright position. We studied whether the reduction in SV is due to a specific adaptation of the heart to head-down tilt bed rest (HDTBR) or acute hypovolemia alone. METHODS AND RESULTS: We constructed left ventricular (LV) pressure-volume curves from pulmonary capillary wedge pressure and LV end-diastolic volume and Starling curves from pulmonary capillary wedge pressure and SV during lower body negative pressure and saline loading in 7 men (25+/-2 years) before and after 2 weeks of -6 degrees HDTBR and after the acute administration of intravenous furosemide. Both HDTBR and hypovolemia led to a similar reduction in plasma volume. However, baseline LV end-diastolic volume decreased by 20+/-4% after HDTBR and by 7+/-2% after hypovolemia (interaction P<0.001). Moreover, SV was reduced more and the Starling curve was steeper during orthostatic stress after HDTBR than after hypovolemia. The pressure-volume curve showed a leftward shift and the equilibrium volume of the left ventricle was decreased after HDTBR; however, after hypovolemia alone, the curve was identical, with no change in equilibrium volume. Lower body negative pressure tolerance was reduced after both conditions; it decreased by 27+/-7% (P<0.05) after HDTBR and by 18+/-8% (P<0.05) after hypovolemia. CONCLUSIONS: Chronic HDTBR leads to ventricular remodeling, which is not seen with equivalent degrees of acute hypovolemia. This remodeling leads to a greater decrease in SV during orthostatic stress after bed rest than hypovolemia alone, potentially contributing to orthostatic intolerance

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