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This Article Abstract Full Text (PDF) Free All Versions of this Article: 95/2/700    most recent 00265.2003v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Pliquett, R. U. Articles by Zucker, I. H. Search for Related Content PubMed PubMed Citation Articles by Pliquett, R. U. Articles by Zucker, I. H.

Statin therapy restores sympathovagal balance in experimental heart failure

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

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Inhibitors of hydroxymethylglutaryl-CoA reductase or statins have been shown to alleviate endothelial dysfunction. Their effects on constitutive nitric oxide synthase in the central nervous system may hypothetically affect the autonomic balance in sympathoexcitatory states, such as chronic heart failure (CHF). To address this issue, simvastatin (SIM) (0.3, 1.5, or 3 mg · kg^-1 · day^-1 po) was given to rabbits with pacing-induced CHF over a 3-wk period. Normal and CHF vehicle-treated rabbits served as controls. Autonomic balance was assessed by measuring heart rate variability, including power spectral analysis (PSA). In addition, changes in resting heart rate were assessed before and after vagal and sympathetic autonomic blockade by atropine and metoprolol, respectively. The SD for all intervals was 8.9 ± 0.7 ms in normal, 4.9 ± 0.6 ms in CHF (P < 0.01), 3.8 ± 0.6 ms in CHF with 0.3 mg · kg^-1 · day^-1 SIM (P < 0.001), 5.7 ± 0.9 in CHF with 1.5 mg · kg^-1 · day^-1 SIM (P < 0.05), and 7.2 ± 0.5 in CHF with 3.0 mg · kg^-1 · day^-1 SIM. Similarly, total power was 40.5 ± 6.3 ms² in normal, 10.1 ± 3.0 ms² in CHF (P < 0.01), 6.0 ± 1.6 ms² in CHF with 0.3 mg · kg^-1 · day^-1 SIM (P < 0.01), 13.2 ± 3.9 ms² in CHF with 1.5 mg · kg^-1 · day^-1 SIM (P < 0.05), and 22.0 ± 3.0 ms² in CHF with 3.0 mg · kg^-1 · day^-1 SIM. Both PSA data for low (0.625–0.1875 Hz) and high frequencies (0.1875–0.5625 Hz) showed recovery in CHF animals on medium and high SIM doses without changes in the low-to-high-frequency ratio. SIM beneficially affects autonomic tone in CHF as seen by the reversal of depressed HRV and total power of PSA. These data have important implications for the treatment of patients with autonomic imbalance.

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

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Animals. Measurements of HR and HRV were carried out as a post hoc analysis on 54 male New Zealand White rabbits weighing between 3.0 and 3.5 kg. Results of baroreflex sensitivity and sympathetic nerve recordings from those rabbits have been published previously (15). All experiments were reviewed and approved by the University of Nebraska Medical Center Institutional Animal Care and Use Committee. Rabbits were assigned to one of five groups. Group I was a normal control group (n = 21). Group II was a CHF control group (n = 13) that received 5 ml/day of carrot juice. Groups III–V were CHF groups fed oral simvastatin at a dose of 0.3, 1.5, or 3 mg · kg^-1 · day^-1 dispersed in 5 ml carrot juice (n = 6, 6, and 8), respectively. Control animals were otherwise treated in the same manner over the same time period.

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

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Hemodynamics. Table 1 summarizes the group characteristics and select hemodynamics that validate the CHF model. Simvastatin did not significantly affect hemodynamics in this model. Pacing rabbits exhibited a significant cardiac dilation and a reduction in fractional shortening and the maximal first derivative of cardiac shortening.

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).

View larger version (9K): [in this window] [in a new window]   Fig. 1. Heart rate variability in normal (Norm) and chronic heart failure (CHF) controls and in CHF rabbits treated with 0.3, 1.5, and 3 mg · kg-1 · day-1 simvastatin per os (CHF0.3S, CHF1.5S, and CHF3S, respectively). Values are means ± SE. Significant difference: *P < 0.05, **P < 0.01, ***P < 0.001.

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).

View larger version (9K): [in this window] [in a new window]   Fig. 2. Total power resulting from power spectral analysis in normal and CHF controls and in CHF rabbits treated with 0.3, 1.5, and 3 mg · kg-1 · day-1 simvastatin per os. Values are means ± SE. Significant difference: *P < 0.05, **P < 0.01, ***P < 0.001.

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

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The novel findings of this study are that HRV is partly reversed toward normal by simvastatin in this CHF model and, second, that LF, HF, and total power are increased uniformly (Figs. 1 and 2). Last, vagal tone, as determined by baseline HR change after ATR blockade, was found to be improved in statin-treated animals with CHF. In addition to data presented previously (15), these data support the concept of statin effects on the autonomic nervous system as part of their pleiotropic efficacy.

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

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This study was supported by National Heart, Lung, and Blood Institute Grant HL-38690 and a postdoctoral fellowship from the American Heart Association.

	ACKNOWLEDGMENTS

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The authors thank Pamela Curry and Johnnie F. Hackely for expert technical assistance in these experiments. Simvastatin was a gift from Merck and Co. Inc.

	FOOTNOTES

 

Address for reprint requests and other correspondence: I. H. Zucker, Dept. of Physiology and Biophysics, 984575 Nebraska Medical Center, Omaha, NE 68198-4575 (E-mail: izucker{at}unmc.edu).

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

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 95/2/700    most recent 00265.2003v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Pliquett, R. U. Articles by Zucker, I. H. Search for Related Content PubMed PubMed Citation Articles by Pliquett, R. U. Articles by Zucker, I. H.