| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575
Submitted 13 March 2003 ; accepted in final form 21 April 2003
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
sympathetic nerve activity; cardiac dysfunction
Therefore, the concept of statin effects on neurohormonal stimulation in heart failure remains to be specified with regard to vagal activity. This study sought to determine the sympathovagal balance in an animal model for CHF with and without statin treatment by using heart rate (HR) variability (HRV). As HRV is mainly determined by vagal efferent activity (4), HRV measurements in conjunction with our laboratory's previous results of sympathetic nerve recordings (15) from CHF animals with and without statin therapy may allow for insights into sympathovagal balance in this disease state. In addition to HRV, power spectral analysis (PSA) was used to differentiate between vagal and sympathetic components of sinus node modulation. A third technique to dissect autonomic tone employed in this study was the selective blockade of either the sympathetic or parasympathetic component of resting HR. We hypothesize that statins increase the depressed HRV found in a model of CHF, reflecting an increase of cardiac vagal tone in CHF.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
Surgery for CHF model. Normolipidemic rabbits underwent sterile thoracic instrumentation, as previously described (10). In brief, the trachea was intubated, and the rabbits were anesthetized with isoflurane. A left thoracotomy was performed in the third intercostal space. After the pericardium was opened, a pair of 5-MHz, 2-mm piezoelectric crystals were sutured to the epicardial surface of the left ventricle across the base of the short axis to chronically record the changes in left ventricular dimensions. A pacing electrode was sutured to the epicardium of the left ventricle. A reference electrode was secured to the left atrium. In some rabbits, an arterial catheter was inserted into the descending thoracic aorta. The chest was closed and evacuated. Rabbits were allowed to recover for 2 wk before entering into the study.
The induction of experimental CHF and the respective treatment occurred
concurrently over 
3 wk. CHF was induced by rapid cardiac pacing at 100
beats above the rabbits' resting HR, up to a maximum rate of 340 beats/min, by
using an external pacing unit of our own design. Cardiac dimensions (end
diastolic, end systolic, and mean diameter) and the first derivative of
diameter were recorded in the conscious state with the pacemaker turned off
for at least 20 min. In addition to a left ventricular dimension change,
clinical signs of CHF, such as ascites, pulmonary congestion, and cachexia,
were symptoms of this CHF model.
Evaluation of HRV. After the pacemaker was turned off for
20–30 min, HR was recorded from the ECG taken directly off the cardiac
pacing electrodes of awake animals. The cardiac tachogram was calculated on a
beat-to-beat basis by using the Powerlab system and Chart software
(ADInstruments, Milford, MA). HRV was analyzed by using the HRV extension for
Chart 4 at a sampling frequency of 1 kHz for a 5-min ECG recording. This
recording was separated into 1-min segments and analyzed for the SD of
R-wave-R-wave intervals and the standard deviation of the differences between
adjacent intervals (SD of 
R-wave-R-wave). Results are the mean values
derived from the same 5-min recording. Ectopic beats and artifacts were
eliminated (cycle-length cutoff for ectopics was <150 and >350 ms, and
for artifacts <100 and >400 ms). PSA in the frequency domain was
performed by fast Fourier transformation. For the rabbit, frequency cutoffs of
0.0625–0.1875 Hz were considered as the low-frequency (LF) band and
0.1875–0.5625 Hz as the high-frequency (HF) band
(11). Total power integrated
the whole spectrum.
Specific autonomic blockade. To block vagal influences, intravenous atropine methyl bromide (ATR; 0.2 mg/kg) was used. To block sympathetic inputs to the sinoatrial node, 1 mg/kg metoprolol bitartrate (MET) was given. ECG recordings obtained 20 min after injection of ATR or MET were analyzed for changes in HR, HRV, as well as PSA. Only one experiment per day using ATR or MET was performed.
Statistical analysis. The data for each group are expressed as means ± SE. Differences among groups were assessed by using a one-way ANOVA for repeated measures. Post hoc analysis consisted of the Tukey-Kramer multicomparisons test. A P value of <0.05 was considered statistically significant.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
|
HRV. HRV was found depressed in the CHF condition, as well as in the two lower doses of simvastatin-treated CHF animals, compared with normal controls. In contrast, HRV in CHF animals treated with 3 mg · kg-1 · day-1 simvastatin was not statistically different from that in normal controls (Fig. 1).
|
PSA. Total power derived from PSA of the frequency domain was lower in both CHF controls, as well as CHF animals on the two lower doses of simvastatin. However, similar to HRV, the CHF group taking the highest dose of simvastatin was not statistically different from normal controls (Fig. 2). Both LF and HF were depressed in CHF rabbits; however, they tended to increase on the two higher doses of simvastatin, resulting in no change in the LF-to-HF ratio (Table 2).
|
|
Autonomic blockade and reflex assessment. There were no differences in indexes of HRV or PSA detectable after either MET or ATR blockade (Tables 3 and 4). In the CHF group on the lowest simvastatin dose, too few appropriate ECG recordings were obtained for statistical analysis.
|
|
Resting HR changed significantly less in CHF control animals after ATR injection compared with normal subjects. However, compared with normal subjects, no significant HR changes were found in simvastatin-treated CHF animals after ATR (Table 3). MET unveiled no differences in baseline HR between groups (Table 4).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
Heart failure state. The baseline hemodynamics summarized in Table 1 indicate a reduced systolic function for all CHF animals, as evaluated by lower fractional shortening and negative maximal first derivative of cardiac shortening. These parameters were not influenced by statin treatment. All ECG recordings for the determination of HRV were obtained after at least 3 wk of recovery from surgery for the implantation of pacing leads and dimension crystals. Therefore, surgical stress was negligible. All experiments were carried out in the conscious state in trained animals.
HRV. HRV has been used as a noninvasive marker of autonomic outflow to the heart in a variety of disease states (18). A depressed short-term HRV may indicate a poorer prognosis in the CHF condition (8). In the present study, simvastatin reversed the HRV, implying a possible improvement in prognosis that may be related to a restoration of vagal tone. Similarly, hypercholesterolemic patients with coronary artery disease treated for 2 yr with atorvastatin exhibited an increased HRV (14), and survivors of a myocardial infarction using statins expressed a higher HRV than their nonusing counterparts (16). Thus the overall increase of HRV in this model of CHF supports the concept of a beneficial effect of statins on neurohumoral stimulation.
PSA. Total spectral power exhibited a pattern similar to the HRV
results. Total power was restored in CHF rabbits on simvastatin doses similar
to those that were used to lower cholesterol in hyperlipidemic animal models
(1,
17). However, there was a
concurrent reversal in the high- and low-spectral-frequency components.
Although it may seem paradoxical that both HF and LF components are reversed
by simvastatin treatment, depressions of both the LF and HF band were reported
in severe CHF (19) and may be
due to an 
-adrenergic-receptor downregulation
(20). Therefore, caution
should be used when drawing conclusions from the LF data with regard to
sympathetic contributions in this CHF model. As a unique finding that is
probably restricted to the heart failure state, simvastatin reverses the
depressed indexes of PSA for both the LF and the HF band. Future studies need
to confirm and mechanistically elucidate these findings.
Autonomic blockade. Pharmacological interventions to block one
component of the autonomic nervous system unveiled no significant changes in
HRV and power spectral indexes. Indirectly, this may demonstrate the need for
both components to explain the data found in the unblocked condition.
Therefore, both vagal restoration and sympathetic withdrawal may concurrently
contribute to the effects displayed in
Table 2. Neither component
alone may be sufficient to achieve significant changes in HRV and total power.
After ATR administration, CHF animals showed less HR change, demonstrating
vagal depression under normal conditions. Conversely, simvastatin-treated CHF
animals exhibited a reversal in this abnormality. After 
-adrenergic
blockade, no differences were observed among groups. The exact cellular
mechanisms by which statins evoke salutary neural effects are not known.
Whereas lipid status was found unchanged
(15), the results may be
mediated by the antioxidant capacity of statins
(2,
21), which, in turn, may
augment cardiovascular reflex sensitivities
(3,
12) and increase NO
bioavailability via reduced degradation. In addition, statin's regulatory
effects include a functional increase of endothelial NO synthesis via less
isoprenylation of Rho-kinase
(9). Enhanced NO synthase in
areas related to integration of sympathetic nerve activity may also lead to a
reduction of sympathetic neural outflow
(6,
7).
In summary, the present study provides the first data showing a potent effect of statin therapy on HRV in the CHF state. Both power spectral and HRV data suggest that statins can restore autonomic function in CHF. Partial normalization of sympathovagal imbalance may be a significant component of the effects of statins on neurohumoral stimulation in CHF. Future studies are needed to confirm these proposed actions of statins on neurohumoral activation in CHF patients.
|
DISCLOSURES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  M.S. Kostapanos, E.N. Liberopoulos, J.A. Goudevenos, D.P. Mikhailidis, and M.S. Elisaf Do statins have an antiarrhythmic activity? Cardiovasc Res, July 1, 2007; 75(1): 10 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bauersachs, K. Hiss, D. Fraccarollo, U. Laufs, and H. Ruetten Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects Cardiovasc Res, December 1, 2006; 72(3): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. H. Zucker Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure Hypertension, December 1, 2006; 48(6): 1005 - 1011. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ramasubbu and D. L. Mann The Emerging Role of Statins in the Treatment of Heart Failure J. Am. Coll. Cardiol., January 17, 2006; 47(2): 342 - 344. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gao, W. Wang, Y.-L. Li, H. D. Schultz, D. Liu, K. G. Cornish, and I. H. Zucker Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure: Roles of Angiotensin II Type 1 Receptors and NAD(P)H Oxidase Circulation, September 20, 2005; 112(12): 1763 - 1770. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
