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Am J Physiol Heart Circ Physiol 295: H29-H38, 2008. First published May 2, 2008; doi:10.1152/ajpheart.01373.2007
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Persistent alterations in heart rate variability, baroreflex sensitivity, and anxiety-like behaviors during development of heart failure in the rat

Marcus Henze,1 Davin Hart,2 Allen Samarel,2 John Barakat,2 Laurie Eckert,1 and Karie Scrogin1

1Department of Pharmacology and 2The Cardiovascular Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

Submitted 27 November 2007 ; accepted in final form 29 April 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Depressed heart rate variability and mood are associated with increased mortality in patients with congestive heart failure (CHF). Here autonomic indexes were assessed 3 and 7 wk after left coronary artery ligation in telemetered rats, after which anxiety-like behaviors were assessed in an elevated plus maze. Low frequency (LF) and high frequency (HF) heart rate variability were reduced in CHF rats 3 wk after infarction (LF, 1.60 ± 0.52 vs. 6.97 ± 0.79 ms2; and HF, 1.53 ± 0.39 vs. 6.20 ± 1.01 ms2; P < 0.01). The number of sequences of interbeat intervals that correlated with arterial pressure was decreased in CHF rats at 3 and 7 wk (week 3, 26.60 ± 10.85 vs. 59.75 ± 11.4 sequences, P < 0.05; and week 7, 20.80 ± 8.97 vs. 65.38 ± 5.89 sequences, P < 0.01). Sequence gain was attenuated in CHF rats by 7 wk (1.34 ± 0.06 vs. 2.70 ± 0.29 ms/mmHg, P < 0.01). Coherence between interbeat interval and mean arterial blood pressure variability in the LF domain was reduced in CHF rats at 3 (0.12 ± 0.03 vs. 0.26 ± 0.05 k2, P < 0.05) and 7 (0.16 ± 0.02 vs. 0.31 ± 0.05 k2, P < 0.05) wk. CHF rats invariably entered the open arm of the elevated plus maze first and spent more time in the open arms (36.0 ± 15% vs. 4.6 ± 1.9%, P < 0.05). CHF rats also showed a tendency to jump head first off the apparatus, whereas controls did not. Together the data indicate that severe autonomic dysfunction is accompanied by escape-seeking behaviors in rats with verified CHF.

telemetry; blood pressure; elevated plus maze; myocardial infarction; congestive heart failure

CONGESTIVE HEART FAILURE (CHF) afflicts nearly 20% of the US population, resulting in ~1 million hospitalizations per year (43). CHF patients are susceptible to ventricular arrhythmias and experience sudden cardiac death at 6–9 times the rate of the normal population (30). Decreased heart rate variability (HRV) is a predictive risk factor for arrhythmia and sudden cardiac death (18). Loss of cardiac vagal drive combined with loss of baroreceptor reflex sensitivity (BRS) is thought to mediate the decreased HRV and autonomic instability that exacerbate arrhythmia susceptibility in CHF patients (4).

Heart rate fluctuations are indicative of the ability of the autonomic nervous system to respond to physiological perturbations and environmental stimuli that impact the cardiovascular system (34). Measurement of HRV in the time domain gauges the SD of normal R-R intervals (SDNN) and provides an assessment of overall variability (18). Fast Fourier transformation of a series of interbeat intervals provides information on the degree to which heart rate oscillates over a range of frequencies. Spectral analysis of heart rate over relatively small sampling times (5 min) has been used to assess the relative contribution of oscillations at different frequencies to overall variability (1). Pharmacological studies indicate that low frequency (LF) oscillations in heart rate represent, in part, both the sympathetic and parasympathetic contributions to the arterial baroreflex control of heart rate (1, 2). In contrast, high frequency (HF) fluctuations in heart rate are driven largely by respiratory-dependent reflex effects on parasympathetic function as well as some, as yet, unidentified nonneuronal influences (24).

Results from frequency analyses of HRV in human heart failure patients suggest that LF oscillations are exaggerated or that the LF-to-HF ratio is elevated during the early stages of heart failure, presumably due to increased sympathetic tone (4). In later stages, however, LF oscillations decline coincident with the loss of BRS and continued absence of vagal-mediated respiratory oscillations (4, 11, 48).

Depressed patients and patients suffering from recurrent panic attack also show decreased HRV (50). Loss of HRV following myocardial infarction among patients with depression or anxiety has been associated with decreased BRS and reduced vagally mediated sinus arrhythmia (38, 49). Anxiety is a common comorbidity found with depression, and both depression and anxiety are associated with the poor outcome in heart failure (19). Rats subjected to coronary ligation sufficient to produce severe left ventricular dysfunction within 1 wk of ligation exhibit anhedonia (reduced ability to take pleasure in normally pleasurable activities), a characteristic feature of depression in humans (13). However, it is not known whether rats with heart failure also exhibit features of increased anxiety or whether reported decreases in HRV among rats with heart failure represent a loss of HRV in the LF and/or HF domains as has been observed in patients with anxiety and depression. Therefore, this study sought to characterize the frequency changes in HRV that develop in rats subjected to coronary ischemia sufficient to cause CHF and to determine whether the loss of HRV is coincident with the loss of BRS and indexes of increased anxiety.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. All experiments were performed in accordance with the American Physiological Society Guiding Principles for Research Involving Animals and Human Beings (2002) and were approved by the University's Institutional Animal Care and Use Committee. Male Sprague-Dawley rats between 300 and 350 g (Harlan, Indianapolis, IN) were acclimated for 1 wk before surgery with ad libitum access to food and water. The rats were housed at a constant temperature of 22 ± 2°C with a 12-h:12-h light-dark cycle.

Coronary artery ligation. Animals were anesthetized with ketamine-xylazine (100 mg/kg + 7 mg/kg im), intubated, and ventilated with room air supplemented with 100% O2. A left thoracotomy was performed through the third intercostal space to expose the anterior surface of the heart. The pericardium was removed, and the left anterior descending coronary artery was ligated [coronary artery ligation (CAL)] with a 6-0 silk suture as described previously (36). Animals subjected to sham-operated ligation (Sham) underwent identical procedures excluding the removal of the pericardium and ligation. After surgery, the thoracotomy was closed around a drainage tube with a 4-0 chromic gut. Negative pressure (–2 mmHg) was applied through the drainage tube during its removal while closing the thoracotomy. Rats were given lidocaine (10 mg/kg sc) just before and every 2 h for 8 h after ligation to reduce the incidence of arrhythmia. All rats were given buprenorphine (50 µg/kg sc) following arousal from surgery and again 18 h later.

Echocardiography. Rats were anesthetized with ketamine-xylazine (100 mg/kg + 7 mg/kg im) and subjected to echocardiography (Acuson Sequoia C256; Siemens AG) to determine left ventricular function 1 and 8 wk after ligation. All Sham and CAL rats with fractional shortening (FS) <25% (determined 1 wk after ligation) were included in the study.

Telemetry probe implantation. Eight CAL and eight Sham rats were instrumented with radio-telemetry probes (C50-PXT; Data Sciences, St. Paul, MN) to enable 24-h sampling of blood pressure, heart rate, ECG, and locomotor activity as described previously (6). Probes were implanted subcutaneously under ketamine-xylazine anesthesia (100 mg/kg + 7 mg/kg im). Blood pressure catheters were placed in the left femoral artery, and ECG leads were sutured subcutaneously to record lead II ECG. The positive lead was placed 2 cm right of the sternum at the level of the second rib, and the negative lead was placed 1 cm left of center at the level of the xiphoid process. Rats were given buprenorphine (50 µg/kg sc) upon waking from anesthesia. Data acquisition began 1 wk following telemetry probe implantation.

Elevated plus maze. Rats were allowed to explore a custom made, Plexiglas elevated plus maze (EPM) to measure indexes of anxiety. The EPM was built as specified previously (35). Briefly, the maze consisted of two opposed open arms situated perpendicularly to two arms enclosed in Plexiglas walls 40 cm high. The maze was elevated 91.4 cm off the floor. Each arm measured 50.2 x 10.8 cm and was joined in the center by a 10.8-cm square without walls. Behavior was recorded on video for 5 min after the placement of the rat in the center of the EPM according to previously published methods (35). All animals were placed in the center square facing the same open arm. Rats that jumped off the apparatus were quickly placed back on the EPM at the center of the apparatus. The type of arm first entered and the total time spent in the open and closed arms, as well as total open and closed arm entries, were determined by an independent observer blinded to the rat's condition. Falls (unanticipated falls rump first or sideways) and head-first jumps that were preceded by the rat leaning its head over the side of the apparatus were also determined.

Data acquisition and analysis. Telemetry recordings of blood pressure, ECG, and locomotor activity were acquired continuously over a 24-h period once per week for 5 wk using Dataquest A.R.T. 3.1 Gold software (Data Sciences, St. Paul, MN). Blood pressure, heart rate, and locomotor activity data were recorded at 500 Hz and averaged into 1-h moving averages. Single values for the dark and light portions of the diurnal cycle were determined as the means of the 12 1-h values obtained during the dark or light portions of the cycle. Electrocardiogram waveforms were analyzed with Chart v. 5.2.2 and the HRV Module v. 1.1 (ADInstruments, Colorado Springs, CO). HRV was determined from 5-min segments of ECG data recorded at 1 kHz. The segments chosen for analysis were based on the absence of movement and arrhythmia artifacts. Arrhythmic beats (beats not initiated in the atria, as determined by visual inspection of ECG) were manually removed. SDNN was determined from 5-min segments of data from each hour and averaged over the course of 24 h to determine the SD of averaged normal R-R intervals (SDANN). Fast Fourier transformation of the same 5-min segments of ECG data was performed after the removal of linear trend and the application of Welch window with a fast Fourier transformation setting of n = 1,024 points with 50% overlap. Spectral power was quantified within the following frequency bands: total power (TP), 0 to 5 Hz; LF power, 0.04 to 1.00 Hz; and HF power, 1.00 to 3.00 Hz (21).

Spontaneous BRS was determined from 5-min, simultaneously recorded segments of R-R interval (RRI) and mean blood pressure (MBP) data obtained during the dark cycle between 9:00 and 11:00 PM. This time span was chosen for assessment based on observations that animals showed the lowest tendency toward ectopic beats and aberrant ECG during this period. Segments were prepared by resampling the ECG data at 500 Hz followed by the manual removal of artifacts. Data were analyzed with Nevrokard SA-BRS software v. 3.2.4 to determine BRS by the sequence method (31). Gain was determined as the average slope of linear regressions obtained from a minimum of three sequences that satisfied the following constraints: three or more consecutive RRIs with variation in the same direction, >0.5 ms that correlated (r2 > 0.85) with mean arterial pressure (MAP) variations of >0.5 mmHg, and with a three-beat delay. These parameters were chosen based on preliminary analyses demonstrating that they retrieved the most sequences with the highest gain in both Sham and CHF rats. In addition, the respiratory modulation of blood pressure in rats with a high respiratory rate, such as rats with CHF, limits the number of consecutive beats in which pressure and interbeat interval rise or decline. Cross-spectral analysis was performed on RRI and MBP data using fast Fourier transformation with a smoothed Hamming window. Coherence between RRI and MBP variability was determined as the square root of the ratio of the RRI and MBP power spectra with a segment length of 128 points, 50% overlap, and zero padding of 8. The average coherence in the LF and HF domains was calculated as the area under the curve within the specified frequency domains.

Left ventricular pressure. Measurements of left ventricular pressure and contractility [change in pressure over time (dP/dt)] were determined under ketamine-xylazine (100 mg/kg + 7 mg/kg im) anesthesia using a 2F Millar pressure catheter (SPD-320; Millar Instruments) on the final day of the experiment.

Statistical analysis. Two- and three-way ANOVA with repeated measures were used to compare blood pressure, heart rate, and locomotor activity between groups over light and dark portions of the diurnal cycle as well as over 24 h. Two-way ANOVA with repeated measures was used to assess between group differences in SDANN and body weight gain as well as the time in the open or closed arms of the EPM and numbers of entries into the open and closed arms. Follow-up Newman-Keuls post hoc tests were used where appropriate for further analysis of significant main effects or interactions. A {chi}2-test was used to compare the first arm entered and number of jumps from the EPM. Student's t-tests were used to determine between group differences in ventricular function and heart- and lung-to-body weight ratios, as well as spontaneous BRS. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
CAL surgery was performed on 22 rats, 16 (73%) of which survived. Eight of the surviving rats had FS between 12% and 25% 1 wk after surgery and were implanted with telemetry probes. Sham surgery was performed on eight rats, all of which survived and were implanted with probes. One CAL rat died 1 wk after probe implantation. Two additional rats that did not meet the criterion for the development of CHF by the end of the study (see Echocardiography and hemodynamic measurements) were also removed. Body weight data and the experimental time line are shown for the remaining rats in Fig. 1. Rats subjected to CAL immediately lost weight following surgery. Both groups gained body weight at approximately the same rate throughout the remainder of the experiment.


Figure 1
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  		Fig. 1. Experimental time line and body weight for congestive heart failure (CHF) and sham-operated rats throughout the experiment. Values are group means ± SE; n, number of rats/group. *P < 0.05; **P < 0.01, between groups. EPM, elevated plus maze; LAD, left anterior descending coronary artery.

 
Echocardiography and hemodynamic measurements. Representative M-mode echocardiograms are shown for Sham and CAL rats 1 wk following surgery (Fig. 2A). FS is shown for CAL and sham-operated rats at 1 and 8 wk postsurgery (Fig. 2B). FS increased in Sham but not CAL rats between weeks 1 and 8.


Figure 2
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  		Fig. 2. A: representative M-mode recordings from Sham and CHF rats. B: fractional shortening at weeks 1 and 8. Values are group means ± SE; n, number of rats/group. **P < 0.01, between groups; ++P < 0.01, within group.

 
Left ventricular systolic diameter was higher and the ejection fraction lower in CAL rats by 1 wk of surgery (Table 1). Both the diastolic and systolic diameter increased over time in CAL rats, although the ejection fraction did not change. Terminal measurements of left ventricular end-diastolic pressure (LVEDP), as well as heart- and lung-to-body weight ratios, were elevated in CAL rats (Table 2). Left ventricular contractility and rate of relaxation were both decreased in CAL rats. Two CAL rats showed ventricular contractility (5,540 and 5,702 mmHg/s) and rates of ventricular relaxation (–3,116 and –3,685 mmHg/s) that fell between values from Sham and CAL rats. Neither rat developed congestion as evidenced by normal LVEDP (7.9 and 5.1 mmHg) and normal heart (3.16 and 3.66 g/kg)- and lung (4.84 and 6.48 g/kg)-to-body weight ratios. Data from these two CAL rats were excluded from parametric tests since all their congestion marker values, i.e., LVEDP and heart- and lung-to-body weight ratios, were >2.5 SD from the mean of the CAL group. However, data from these rats are shown for comparison with other groups.


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  		Table 1. Left ventricular function

 

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  		Table 2. Terminal parameters of congestion and ventricular function

 
Diurnal blood pressure, heart rate, and locomotor activity. MAP was significantly lower throughout the experiment in CAL rats that developed CHF (Fig. 3A). Sham rats had higher MAP during the dark cycle, whereas rats with CHF showed no diurnal difference. Heart rate was decreased in the light cycle in both Sham and CHF rats but did not differ between groups (Fig. 3B). Locomotor activity was similar between groups. Activity was higher in the dark cycle in both groups (Fig. 3C).


Figure 3
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  		Fig. 3. Diurnal mean arterial blood pressure (MAP; A), heart rate (HR; B), and locomotor activity (C) in CHF and Sham rats. Values are group means ± SE; n, number of rats/group. **P < 0.01, between group light cycle; ++P < 0.01, between group dark cycle; {dagger}{dagger}P < 0.01, within Sham group; #P < 0.05; ##P < 0.01, within coronary artery ligation (CAL) group. bpm, Beats/min.

 
HRV. Although CAL animals with CHF showed arrhythmias during some recording periods, the average number of interbeat intervals analyzed per segment did not differ between groups after the removal of artifacts (e.g., week 7, 1,629 ± 26 vs. 1,622 ± 28 beats for CAL and Sham rats, respectively). Ligated rats with CHF had decreased SDANN throughout the duration of the experiment (P < 0.01; Fig. 4A). Qualitatively, ligated rats without CHF initially had slightly lower SDANN than that of the Sham rats but had similar values by the end of the experiment. SDANN at week 7 and LVEDP at the end of the experiment were significantly correlated both when all animals were included (r2 = 0.40, P < 0.05; Fig. 4B) as well as when rats subjected to CAL that did not develop CHF were excluded (r2 = 0.53, P < 0.01).


Figure 4
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  		Fig. 4. A: SD of averaged normal R-R intervals (SDANN) weeks 3 through 7 for CHF and Sham rats. CAL rats that did not develop CHF are included for comparison (gray line). B: correlation of week 7 SDANN vs. week 8 left ventricular end-diastolic pressure (LVEDP) for all rats. Values are group means ± SE; n, number of rats/group. **P < 0.01, between groups.

 
Representative power spectra from data collected during week 7 are shown in Fig. 5A. Note the dramatic reduction in variability throughout the LF and HF ranges in the CHF rat. Note also the rightward shift of the HF peak, representing respiratory arrhythmia. The respiratory rate of CAL rats was increased at both weeks 3 and 7 as determined by the increased frequency of the maximum HF peak (Fig. 5B).


Figure 5
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  		Fig. 5. A: representative power spectra from Sham and CHF rats at week 7. B: respiratory-related maximum high frequency (HF) peak at weeks 3 and 7 for Sham and CHF rats. Values are group means ± SE; n, number of rats/group. *P < 0.05, between groups. LF, low frequency; RRI, R-R interval.

 
Spectral analyses of HRV averaged over 24 h showed severe decrements in HRV among CAL rats at weeks 3 and 7 (Fig. 6A). Both LF and HF power were reduced 3 wk after surgery, whereas only LF power was reduced at 7 wk (Fig. 6A). Lower TP was evident in CHR rats throughout the 24-h cycle both 3 and 7 wk after surgery (Fig. 6B). A significant interaction between the presence of CHF and diurnal phase was found in LF power 3 wk after surgery. Sham animals tended to show reduced power during the dark cycle. However, the within-group difference was not significant. The interaction likely resulted from the more consistent difference between CHF and Sham rats over the duration of the light (P < 0.001) compared with the dark (P < 0.005) cycle. No such interaction was observed 7 wk after ligation. A similar pattern was seen in the HF domain with evidence of a CHF by diurnal cycle interaction (P < 0.01) 3 wk after surgery. The comparison of HRV during the dark and light cycles in Sham animals also failed to demonstrate a difference in the HF domain. However, differences between Sham and CHF rats were greater during the light (P < 0.01) than during the dark (P < 0.05) cycle 3 wk after surgery. The TP and LF and HF power of CAL rats that did not develop CHF fell between Sham and CHF levels at 3 wk and showed variable but higher levels that approached the Sham group by 7 wk after ligation.


Figure 6
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  		Fig. 6. A: average total power (TP) and LF and HF power of CHF and Sham rats at 3 and 7 wk postsurgery. B: TP and LF and HF power over 24 h at 3 and 7 wk postsurgery. Shaded region represents the dark cycle. CAL rats that did not develop CHF are included for comparison (gray line). Values are group means ± SE; n, number of rats/group. *P < 0.05; **P < 0.01, between groups.

 
BRS. The number of sequences that displayed baroreflex control was lower in CAL rats both 3 and 7 wk after ligation (P < 0.05; Fig. 7A). The average gain of the detected sequences of CHF rats was different from that of the Sham rats 7 wk after surgery (P < 0.01; Fig. 7B). This was due to a significant increase in baroreflex gain in Sham rats over the course of the study (P < 0.01). To ensure that the lack of difference in baroreflex gain between Sham and CHF rats was not due to an acute effect of telemetry probe-implantation surgery, similar analyses were performed on data obtained 4 wk after surgery. Sham rats showed a slight increase in baroreflex gain between 3 and 4 wk (1.74 ± 0.15 vs. 1.95 ± 0.41 mg/mmHg) that did not reach significance, and there was no difference between Sham and CHF rats at this time point.


Figure 7
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  		Fig. 7. A: number of sequences detected that met baroreflex criterion for CHF and Sham rats at 3 and 7 wk postsurgery. B: baroreflex gain of detected sequences for CHF and Sham rats at 3 and 7 wk postsurgery. Values are group means ± SE; n, number of rats/group. ++P < 0.01, within Sham group; *P < 0.05; **P < 0.01, between groups.

 
Figure 8 demonstrates coherence between RRI and MAP variability from 0 to 3 Hz for individual rats in Sham and CHF groups 3 and 7 wk after surgery (Fig. 8, A and B). As can be seen, CHF rats had much lower coherence between the two variables at the lower frequency, whereas coherence tended to recover at the higher frequencies. The average coherence (measured as the total area under the curve within each domain) was reduced among CHF rats within the LF range but not within the HF domain at both 3 and 7 wk (Fig. 8, C and D). Despite evidence for the recovery of coherence in the HF domain among CHF rats, there was no difference between values determined at 3 and 7 wk.


Figure 8
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  		Fig. 8. Coherence between RRI and MAP variability within the LF and HF domains of individual CHF and Sham rats at 3 (A) and 7 (B) wk postsurgery. Dashed line marks the 1-Hz division between LF and HF domains at 0.5 K2 coherence. Mean coherence across the LF domain for CHF and Sham rats at 3 (C) and 7 (D) wk is shown. Values are group means ± SE; n, number of rats/group. *P < 0.05, between groups.

 
EPM. In the EPM test, CHF rats invariably chose to explore an open arm first, whereas all but one Sham rat chose to explore a closed arm first (Fig. 9 A). The {chi}2 analysis demonstrated a significant effect of CHF on the type of arm first entered (P < 0.05). The time spent in the open arms was higher in CHF rats (P < 0.05; Fig. 9B), whereas the time spent in the closed arms did not differ between groups. Similarly, the number of entries into the open arms (P < 0.05) was significantly higher for CHF rats, whereas entries into the closed arms did not differ between groups (Fig. 9C). Two of the CHF rats leaned over the side of an open arm and jumped head first off the apparatus twice, whereas no Sham rats jumped from the maze. The {chi}2 analysis failed to demonstrate a significant group difference in the numbers of animals that jumped, head first, from the maze (P = 0.067).


Figure 9
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  		Fig. 9. A: first-arm choice of CHF and Sham rats in the elevated plus maze. B: time spent in the open and closed arms of the elevated plus maze measured as percent total time (5 min). C: number of entries into open and closed arms of the elevated plus maze. Values are group means ± SE; n, number of rats/group. *P < 0.05, between groups.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, only ~72% of rats that developed severe left ventricular dysfunction (i.e., FS, <25%) by 1 wk after coronary ligation surgery went on to developed CHF. Heart failure was confirmed by evidence of significant changes in multiple parameters including increased ventricular diameter, reduced contractility, and increased heart- and lung-to-body weight ratios as well as highly elevated LVEDP (>18 mmHg). The remaining ligated rats died before the end of the study (1 of 8) or the ventricular damage did not progress to heart failure by 7 wk after surgery (2 of 7). Animals that developed CHF showed reduced SDANN by 3 wk after surgery. SDANN remained low throughout the remainder of the study. In addition to the expected loss of HF HRV, rats with CHF also showed a substantial decrease in LF variability that was accompanied by the loss of BRS.

Numerous studies have contributed to our current understanding of HRV. The variability in heart rate assessed by SDNN and SDANN and other analyses in the time domain represents the overall variability in HRV without regard to specific oscillation frequencies. Further analyses that break down the overall HRV into specific frequencies provide additional information regarding autonomic input to the heart (1). For instance, a decline in overall HRV can represent either a reduction in LF or HF oscillations, as well as a loss of oscillation in the ultralow frequency domain, if data are collected over a long enough time frame. Although the origins of ultra LF variations are not well understood, LF oscillations represent, in large part, fluctuations in sympathetic and vagal input to the heart that result from variations in blood pressure (i.e., baroreflex control) (33). In contrast, HF fluctuations in heart rate are thought to arise from higher frequency oscillatory inputs to cardiac vagal preganglionic neurons (47). Thus the loss of overall HRV that is predictive of mortality in cardiovascular disease may represent a decline in fluctuations within the LF and/or HF domains. In addition, the ratio of LF to HF oscillations has been used as a rough index of sympathetic tone (33). One underlying assumption of this index is that the vagal contribution to the HF oscillations is proportional to the vagal contribution to the LF oscillations such that the vagal contribution to HRV is factored out. This latter assumption has not, so far, been validated. Nevertheless, the LF-to-HF ratio remains a popular tool for the evaluation of overall sympathetic tone to the heart. However, this may only be an adequate index of sympathetic tone when baroreflex oscillations are still intact. Indeed, the ratio becomes meaningless when cardiac receptors become less receptive to autonomic input, as occurs during late-stage heart failure (48).

The effect of ligation on HRV found in the present study confirms those of an earlier study that demonstrated a persistent suppression of overall HRV in rats with CHF (47a). The present study extends these findings by demonstrating that HRV is reduced both in the HF domain that reflects sinus arrhythmia as well as in the LF domain purported to reflect the baroreflex modulation of heart rate. An analysis of spontaneous BRS confirmed the loss of baroreflex control of heart rate by demonstrating decreased spontaneous baroreflex gain 7 wk after surgery. The group difference in BRS was due to a progressive increase in gain over time in Sham rats that was not matched by CHF rats. The rise in gain among Sham rats was not likely the result of recovery from telemetry probe implantation since gain had only risen to a modest, insignificant extent by the fourth week. Others have documented that cardiovascular parameters are normalized within 1 wk after intraperitoneal telemetry probe implantation in the rat (12a). Instead, the observed elevation in baroreflex gain among Sham rats was more likely due to developmental changes. Wistar-Kyoto rats show a progressive increase in cardiac baroreflex gain from 6 to 20 wk of age, coupled with a decrease in heart rate over the same time period (14a). The latter effect is due to a progressive rise in the vagal contribution to heart rate during maturation. In the present study, Sham rats of the same age range also showed a progressive decline in heart rate over the course of the study. However, CHF rats showed the same decline in heart rate over time without a rise in baroreflex gain.

The reduced number of baroreflex-modulated sequences observed in CHF rats was likely not due to differences in BRS but rather to the effect of the respiratory modulation of blood pressure during tachypnea. In CHF rats, the respiratory rate increased without a concomitant increase in heart rate. When respiratory modulation of blood pressure develops, a predictable decline in the number of consecutive cardiac cycles that exhibit pressure changes in the same direction occurs if heart rate remains constant. Nevertheless, significant numbers of sequences were still detected in CHF rats, and the average gain of the sequences was not different 3 wk after surgery. The spontaneous baroreflex gain of Sham and CHF rats measured at week 3 was comparable with previously reported gains in normal Sprague-Dawley rats (31). The lack of difference in baroreflex gain between CHF and Sham rats at 3 wk was surprising given the substantial fall in LF HRV power in CHF rats early after ligation. Indeed, evidence of a lasting decrease in BRS beginning early after ligation in CHF rats was observed in the decreased coherence between RRI and MAP variability in the LF domain both 3 and 7 wk after surgery.

Accurate calculations of baroreflex gain from the coherence of RRI and blood pressure oscillations require that sufficient coherence exist between the two variables. The original studies validating this method arbitrarily set the threshold for the sufficient coherence at or above 0.5 K2 (42). When coherence falls below this threshold, it is presumed that the relationship between RRI and blood pressure oscillations is insufficient to calculate meaningful baroreflex gain values. As such, this method cannot be used to compare gains between groups when coherence is low in either group. In our studies, only a minor portion of the data from Sham rats and very limited data from CHF rats met this criterion, preventing a direct comparison of gain between groups using the coherence method. Nevertheless, Sham rats demonstrated strong coherence peaks at the Mayer-wave frequency (~0.4 Hz) as well as at the respiratory frequency (~1.15 Hz) 3 wk after surgery, indicating that coherence likely does reflect the baroreflex modulation of heart rate even below the arbitrarily set threshold of 0.5 K2. More recent studies have suggested that averaging coherence across the LF domain of interest is a reliable method of comparing BRS between groups (37).

In contrast to our findings, Kruger et al. (20) showed no decrement in SDNN, LF, or HF power in rats either 28 or 56 days after coronary ligation. However, the LVEDP of ligated rats only reached ~13 mmHg by 56 days after surgery. Moreover, neither lung-to-body weight ratios nor plasma catecholamines were elevated in their ligated rats. Nevertheless, their ligated rats did demonstrate decrements in baroreflex function characterized by an attenuated bradycardic response to phenylephrine-induced increases in pressure within 3 days of infarct. However, the slope of the bradycardic response normalized over time. A similar normalization of HRV among ligated rats that did not develop CHF was likewise observed in the present study. Together, these data indicate that rats with extensive left ventricular dysfunction detected immediately after infarct may recover left ventricular and autonomic function quite effectively. The factors that determine whether an animal recovers or develops CHF remain to be determined.

Patients with heart failure display a shift in the relative dominance of LF and HF heart rate oscillations. Those with mild-to-moderate heart failure show a decrease in the HF component, due to a loss of respiratory-related oscillations governed primarily by cardiac vagal drive (4). In contrast, patients with mild to moderate heart failure demonstrate a relative increase in LF oscillations (4, 11, 17). The rise in LF power may reflect a relative shift in the normalized balance of HF-to-LF power due to the loss of vagal tone. Alternatively, it may indicate increased sympathetic tone that is still subject to modulation (and thus more vigorous oscillations) by a still functional baroreflex. Similar elevations in LF HRV have been described in the early stages of a canine-pacing model of heart failure (10). However, as heart failure progressed, paced dogs demonstrated a loss of LF power. Human patients with more severe heart failure also demonstrate a loss of LF power despite continued elevations in sympathetic tone (48). In fact, a daytime decrease of power in the LF domain is prognostic of sudden cardiac death in CHF patients (11).

The loss of LF oscillations occurs coincident with the loss of BRS, supporting claims that LF oscillations are mediated primarily by baroreflex-induced waxing and waning of sympathetic tone (46). The loss of the LF component in severe heart failure may reflect a progressive loss of the baroreflex modulation of sympathetic tone but likely not a loss of cardiac sympathetic drive since plasma catecholamines remain elevated in the late stages of heart failure (17). Depression of LF oscillations may be due to the saturation of adrenergic receptors (i.e., lack of receptor reserve) through a combination of elevated sympathetic activity and loss of cardiac β-receptor density (7). Downregulation of β1-adrenergic receptors and reduced cardiac contractility to β1-adrenergic receptor agonists have been observed in rats by 4 to 8 wk after myocardial infarction (45). A parallel downregulation of β-adrenergic receptors in the sinoatrial node may account for the lack of tachycardia among rats with heart failure as well as the reduced HRV in the LF domain. LF oscillations in muscle sympathetic activity are also reduced in patients with severe heart failure despite a higher tonic level of sympathetic activity, suggestive of a central or afferent origin of oscillatory loss (48). Implantation of left ventricular assist devices in humans completely abolishes blood pressure oscillations but restores LF HRV, further supporting a central origin of LF heart rate oscillations (9). Whether the loss of LF oscillation in heart rate is due to central or peripheral mechanisms in the rat coronary ligation model remains to be determined.

Parasympathetic withdrawal is common after myocardial infarction and the development of heart failure. Consistent with human and canine heart failure studies, CHF rats in the present study exhibited decreased HF power from initial recordings made 3 wk post-CAL surgery. The overall difference between groups was lost by 7 wk due to the increased within-group variability of Sham animals and a slight increase in HF HRV in CHF rats. Others have noted that the HF nonneuronal respiratory modulation of heart rate increases during spontaneous breathing in patients with worsening heart failure. The effect is increased with the increasing severity of the disease but is masked during paced breathing. This effect is speculated to result from the exaggerated stretch of the sinoatrial node during labored breathing. The increased stretch of the sinoatrial node increases intrinsic pacemaker activity, possibly due to mechanosensitive Cl– channel activation (3, 14, 22).

The loss of overall HRV in patients after myocardial infarct is more severe in patients diagnosed with depression and anxiety (25). Indeed, the loss of HRV and mood disorders are prognostic of cardiovascular mortality in heart failure (29, 40). Interestingly, patients with anxiety disorders such as panic attack and posttraumatic stress disorder show consistent decreases in HRV, particularly in the LF domain (26). These studies suggest that underlying anxiety disorders may increase the vulnerability of these patients to cardiovascular disease by attenuating their ability to buffer sympathetic activation. However, it is not known whether cardiovascular disease per se is a risk for the development of anxiety. We utilized the EPM test to gauge anxiety-like behaviors in the rats with verified CHF. Naïve rats placed in an EPM typically show some latency to enter and investigate the open arms of the maze (15). This model is based, in part, on studies that demonstrate that nondefensive behaviors such as locomotion, exploration, and grooming are inhibited during risk assessment of a novel environment (15, 27). Benzodiazepines consistently decrease the latency and increase the duration of open arm exploration in the EPM by both mice and rats (23, 35). The ability of anxiolytic drugs, particularly benzodiazepines, to increase open arm exploration is predictive of their efficacy in the treatment of generalized anxiety in humans. Thus the degree of behavioral inhibition during exposure to novel, potentially dangerous stimuli such as the open arms of the EPM has been developed as an index of defensiveness or anxiety (8, 27).

Contrary to our expectations, CHF rats showed less behavioral inhibition in the EPM as demonstrated by increased numbers of entries into the open arms, increased time spent in the open arms, and increased choice of the open arm as the first entry into the EPM. The only prior study of EPM behavior of rats subjected to myocardial infarction reported no difference in the time spent in the closed arms but did not report open arm activity (41). However, the same subjects demonstrated reduced open field exploration and limited social interaction, as well as an overall reduction of locomotor activity in the open field (41, 44). At least two studies suggest that increased activity in the open arm of the EPM can alternatively represent more severe anxiety-like behavior (16, 39). Rats exposed to amygdala kindling, a method that decreases seizure threshold, showed decreased open field activity but increased open arm activity in the EPM as well as increased numbers of head-first jumps off the maze (16). Increased activity in the open arms of the EPM and increased numbers of head-first jumps from the apparatus have also been reported in adult rats subjected to severe sporadic stress in adolescence (39).

Ethological studies indicate that increased locomotion, flight, and escape are the final set of behaviors elicited by threatening stimuli of increasing intensity (5). The extent to which a given drug decreases latency to escape from the open arm of an elevated T maze, a somewhat similar apparatus to the EPM, is not affected by benzodiazipines but has predictive validity for drugs that ameliorate panic attack in humans (12). Selective serotonin reuptake inhibitors, but not benzodiazepines, are effective at reducing escape from imminent danger in mouse ethological studies (12). Thus it has been suggested that the extent of risk assessment (i.e., behavioral inhibition) indicates the level of generalized anxiety, whereas a distinct set of behaviors characterized by disorganized locomotion and escape may represent more severe panic. Our studies suggest that dramatic increases in open arm exploration and the tendency for head-first jumps from the EPM may represent panic rather than lack of anxiety in rats with heart failure. Interestingly, the single study that has assessed the incidence of specific forms of anxiety in human heart failure indicates that 9.3% of heart failure patients meet criterion for a diagnosis of panic disorder compared with the 1–3% of the normal population (28).

In summary, the present study demonstrates that rodents subjected to coronary ligation show significant variability in their progression to heart failure. Those rats found to develop frank heart failure, but not those with mild ventricular dysfunction, show autonomic anomalies similar to human patients with severe failure including prolonged loss of BRS and profound loss of LF and HF HRV. However, in the rat coronary ligation model, significant ventricular dysfunction is necessary before lasting decrements in cardiac autonomic control develop. The absence of tachycardia coupled with an apparent lack of increase in LF HRV among rats that develop severe CHF suggests that ventricular damage sufficient to stimulate the progression to heart failure leads to profound and rapid suppression of cardiac sensitivity to the autonomic regulation in the rat coronary ligation model. Data in the current study also support the intriguing possibility that the suppression of autonomic control of the heart that result from ventricular damage is paralleled by altered central nervous system control of fight or flight mechanisms that may result in a reduced threshold for panic. These results further suggest that the increased incidence of panic disorder observed in human patients with heart failure may, in part, be a result of, rather than a cause of, ventricular dysfunction. To date, the mechanism by which heart failure affects the central regulation of anxiety behaviors remains to be determined.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
These studies were supported, in part, by the American Heart Association Mid-West Affiliate Predoctoral Fellowship 0715566Z (to M. Henze).


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. Scrogin, Dept. of Pharmacology, Loyola Univ. Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153 (e-mail: kscrogi{at}lumc.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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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 

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