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Research Highlights from the Literature

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2001; Volume 11(6) from Clinical Autonomic Research                                           
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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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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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