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J Appl Physiol 102: 1462-1468, 2007. First published December 7, 2006; doi:10.1152/japplphysiol.00965.2006
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Acute volume overload elevates T-wave alternans magnitude

Sanjiv M. Narayan,1 Darrel D. Drinan,2 Robert P. Lackey,2 and Carl F. Edman2

1University of California, San Diego, and 2PhiloMetron Inc., San Diego, California

Submitted 31 August 2006 ; accepted in final form 16 November 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
The objective of this study was to determine whether acute volume loading elevates T-wave alternans (TWA) in dogs with structurally normal hearts. TWA predicts sudden cardiac arrest in patients with left ventricular dysfunction and congestive heart failure. However, volume load and ventricular stretch may themselves precipitate arrhythmias. It is unclear to what extent volume load causes TWA. In six male mongrel dogs [25.8 kg (SD 4.2)] under general anesthesia, we measured TWA during progressive atrial pacing to 160 beats/min. Pacing was performed at baseline, at the midpoint and peak of a saline infusion designed to induce acute CHF, and then during diuresis. Dog 1 was hypothermic throughout the protocol and excluded from analysis. For dogs 2–6, 102 ml/kg (SD 30) were infused over 315 min (SD 50), causing pulmonary capillary wedge pressure to rise from 9.6 (SD 3.5) to 21.2 mmHg (SD 1.6) (P < 0.01), and heart rate variability to fall (P < 0.01). TWA magnitude (Valt) rose in all dogs with volume load (P < 0.001). Compared with baseline, TWA at peak infusion had higher magnitude [Valt 3.4 (SD 1.95) vs. 0.5 µV (SD 0.35); P = 0.011] and occurred at lower heart rates [128 (SD 6) vs. 151 beats/min (SD 12); P = 0.008]. Net volume load was linearly related to Valt (P < 0.01), with each 10 ml/kg net volume load increasing Valt by 0.23 µV. Acute volume overload elevates TWA in normal canine hearts. Although dramatic, however, this effect may contribute clinically to abnormal TWA only in patients with marked volume overload. Future studies should examine the interaction of fluid overload, myocardial disease, and arrhythmia susceptibility.

sudden death; heart failure; dextrocardia; mechanoelectric feedback

SUDDEN CARDIAC ARREST (SCA) from ventricular arrhythmias affects 400,000 individuals per year in the US alone, and its primary identifiable risk factors are left ventricular dysfunction and congestive heart failure (CHF) (6). T-wave alternans (TWA) is an increasingly used ECG predictor for SCA, yet it is also abnormal in patients with CHF who do not succumb to SCA (2, 13). Moreover, TWA relates to the severity of structural disease (9) or CHF (22).

Thus it is unknown whether TWA reflects the mechanisms of volume overload, which may be ameliorated, or intrinsic myocardial disease, which is likely to be more permanent. A stretch-related contribution to TWA is plausible, since acute volume load alters ventricular repolarization and conduction and induces premature beats (4, 24). A direct contribution of myocardial disease to TWA is also plausible, since CHF patients at low SCA risk are more likely to have normal TWA, although it is unclear whether they also have less volume overload (2, 9). Volume load has a complex interaction with myocardial disease and may alter arrhythmic risk differentially, whether regional or global (19, 24). Thus studies in normal hearts may clarify the contribution of volume load to TWA, independent of this interaction.

We hypothesized that acute volume overload would elevate TWA magnitude (Valt) in normal hearts. We tested this hypothesis in dogs during controlled, volume infusion, measuring TWA from atrial pacing at baseline, peak volume infusion, and after diuresis, calibrated against infused volume, pulmonary capillary wedge (PCWP), and pulmonary and systemic arterial pressures.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
This study was funded by the National Institutes of Health (Small Business Innovation Research no. 1R43HL80815-1), and the protocol was approved by Perry Scientific Institutional Animal Care and Use Committee (San Diego, CA). We studied six male mongrel dogs of 25.8 kg (SD 4.2) weight who were in normal health for at least 1 wk preceding the study. All animal use was performed in accordance with standards set by the National Institutes of Health.

Canine preparation.   Animals were preanesthetized with xylazine (2 mg/kg im) and ketamine (20 mg/kg im) and then anesthetized with isoflurane (0.6–1.5%). They were intubated and then ventilated with 100% O2 at 16 breaths/min, with tidal volume of 10 ml/kg and a 1:2 inspiratory-to-expiratory ratio. After routine surgical preparation, we performed cutdowns to cannulate the left femoral and external jugular veins and a branch of the left femoral artery. Under digital fluoroscopic guidance (OEC Medical Systems, model 9600), a Swan-Ganz catheter was advanced transvenously to the pulmonary artery, and pressures were electronically transduced (Hewlett-Packard model 78353B, Sunnyvale, CA). A 6-F quadrapolar catheter was advanced to the right atrial appendage for pacing from an external pacemaker (Medtronic 5336, Minneapolis, MN). Catheter placement is shown in Fig. 1A (dog 2). Dog 5 was found to have dextrocardia during fluoroscopy (Fig. 1B).


Figure 1
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  		Fig. 1. Fluoroscopic views of right heart catheterization in a typical dog (dog 2; A) and dextrocardia (dog 5; B), each showing Swan-Ganz catheter in right pulmonary artery and transvenous pacing catheter in right atrium. B: the forceps handle is over the left torso, and positions of the Hi-Res electrodes have been reversed appropriately. C: ECG tracings (lead I) from dog 2 during sinus rhythm and pacing.

 
Animal temperature was maintained at 100–102°F using a controlled heating pad, warm saline bags applied to the body, and warm saline infusions, except for dog 1 in which core temperature could not be maintained and which was excluded from analysis (see below). We measured urine output with a transurethral catheter.

Volume infusions and hemodynamic measurements.   After an acclimatization period of anesthesia lasting 45–60 min, we maintained constant anesthesia while infusing isotonic fluid (0.9% saline with 20 meq/l KCl) at 500 ml/h.

The endpoint of infusion was PCWP >20 mmHg for >30 min or acute pulmonary congestion, whichever came first. Pilot observations suggested that 80–100 ml/kg net infusate (2–3 liters) were needed after adjusting for urinary and estimated insensible losses. Every 15 min we measured heart rate and femoral arterial pressure (Criticare Systems, model 1100, Waukesha, WI), pulmonary arterial pressure and PCWP, oxygen saturation, temperature, and infused volume. Mean pressures were recorded directly. At the infusion end point, we paused for 15 min. We then commenced diuresis with 0.5 mg/kg iv furosemide and recorded measurements every 15 min until urine output slowed to <40 ml/h. At the end of the study, the dog was resuscitated, if possible.

Measurement of TWA.   We applied clinical Hi-Res electrodes (Cambridge Heart, Bedford, MA) to the canine torso in positions analogous to those used for clinical TWA testing. Dog 5 had dextrocardia, and so we transposed right and left electrode positions (Fig. 1B). Meticulous, careful skin abrasion was used to achieve good electrode contact (1). TWA was measured using HeartWave (Cambridge Heart) in right atrial pacing at baseline, at the infusion midpoint, at peak infusion, and in diuresis. Prior studies report TWA in dogs at heart rates of 140 beats/min (17). Therefore, we measured TWA by accelerating heart rate from baseline (typically 90–110 beats/min) to 160 beats/min in 10 beats/min steps every 90 s, followed by symmetrical deceleration to baseline (14).

Quantification and classification of TWA.   We described TWA by its magnitude (Valt). When TWA was detectable, Valt was measured to the nearest 0.5 µV for the 1 min of peak TWA, using the method of least squares (25). We also recorded onset heart rate (i.e., threshold) for the contiguous period of TWA, including this peak.

Measurement of heart rate variability.   To assess variations in autonomic activity during the protocol, we analyzed R-wave-to-R-wave intervals in sinus rhythm for two consecutive 5-min intervals at baseline and peak infusion. R-wave-to-R-wave intervals adjacent to an ectopic beat were excluded from analysis. Using standard methods (23), we computed power spectral density after applying Hanning Window in the frequency range of 0–0.5 Hz and then computed area integrals of total power (<0.40 Hz), low-frequency power (LF; 0.04–0.15 Hz), and high-frequency power (HF; 0.15–0.40 Hz), and the LF-to-HF ratio, at each volume state. We ensured constant anesthesia to minimize the effects of anesthetic fluctuations on heart rate variability (HRV) (7).

Statistical analysis.   Continuous data are presented as means (SD) and were compared using the two-tailed t-test. The relationship between Valt and net volume infusion was assessed using linear regression. The {chi}2 test was applied to contingency tables of TWA vs. baseline or volume overload. A probability level of 5% was considered statistically significant.


   RESULTS
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 ABSTRACT
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 RESULTS
DISCUSSION
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 REFERENCES
 
All six dogs survived acute volume overload and diuresis. However, the first dog was smaller than the others, suffered prolonged hypothermia (core temperature <91°F, despite corrective measures), and was excluded from analysis. Dog 5 was found to have dextrocardia (Fig. 1B), but the protocol proceeded uneventfully. The characteristics of each animal are summarized in Table 1.


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  		Table 1. Subject characteristics

 
Volume loading.   All dogs tolerated the infusion until the final stages. Sinus tachycardia was seen during infusion, from a baseline rate of 97 (SD 8.6) to 115 (SD 5.3) per minute at peak infusion (P = 0.015; Table 1).

As shown in Fig. 2A, infusion provided 2,784 ml (SD 924) [102 ml/kg (SD 30)] over 315 min (SD 50) to peak. This increased PCWP significantly from 9.7 mmHg (SD 3.1) at baseline to 21.3 mmHg (SD 1.5) (P < 0.0001; Table 1, Fig. 2B). Pulmonary mean arterial pressure rose in parallel from 12.8 mmHg (SD 2.6) at baseline to 24.8 mmHg (SD 3.5) at peak infusion (P = 0.004; Table 1). After peak infusion, in dogs the diuresis end point was reached at 438 min (SD 44). At this stage, subjects had a residual net volume overload of 2,090 ml (SD 837) [76 ml/kg (SD 27); Fig. 2A].


Figure 2
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  		Fig. 2. Profiles of fluid load infused (A) and pulmonary capillary wedge pressure (PCWP) for each dog (dogs 2–6) (B). Dogs 2 and 3 showed the greatest rises in PCWP.

 
The hypotension seen at baseline in some animals (e.g., dog 3) likely reflected overnight fasting and induction anesthesia, since systemic pressure subsequently rose during fluid infusion in all dogs (Table 1). At the infusion midpoint, systolic pressure was 122 mmHg (SD 19) (P = 0.024 vs. baseline). At peak infusion, arterial pressure fell precipitously, as some animals developed decompensated pulmonary congestion [Table 1; 74.8 mmHg (SD 20.7), P = 0.12 vs. midinfusion].

Response of TWA to volume overload.   TWA rose and fell with volume load, PCWP, and pulmonary arterial pressure, as shown in Table 2. Valt was higher at peak infusion than baseline [3.4 (SD 1.6) vs. 0.5 µV (SD 0.35); P = 0.011] and occurred at a lower onset heart rate [128 (SD 6) vs. 151 beats/min (SD 12); P = 0.008]. Postdiuresis, Valt fell [1.2 µV (SD 1.6)] and the TWA onset heart rate rose [142 beats/min (SD 19)] to levels similar to baseline (P > 0.3 for each). These results occurred in each dog, with Valt being 4- to 10-fold higher at peak infusion than baseline (Table 2).


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  		Table 2. TWA results

 
Figure 3 illustrates data for dog 4, in whom TWA was negative at baseline (Fig. 3A), positive at peak infusion (PCWP = 20 mmHg; 2,297 ml infused; Valt = 2 µV; Fig. 3B), and resumed baseline postdiuresis (Fig. 3C). This paralleled PCWP (Fig. 2B). All analyzed dogs showed this relationship (Table 2).


Figure 3
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  		Fig. 3. For dog 4, negative T-wave alternans (TWA) during baseline (A), positive TWA at peak volume load (B), and negative TWA after diuresis (C), measured after heart rate (HR) acceleration to 160 beats/min (BPM). RR, R-wave-to-R-wave %Bad, % of "bad" beats; VM, vector magnitude lead; X, Y, Z, Frank orthogonal chest leads; Resp, respiratory alternans tracing; Max Neg HR, maximum heart rate at which TWA was not present; Max, maximum.

 
Changes in HRV with volume load.   Table 3 summarizes HRV during the experiment. From baseline to peak infusion, dogs exhibited a significant fall in total spectral power (P = 0.006), a nonsignificant trend for higher LF-to-HF ratio (P = 0.07), and a significant rise in sinus rate (P = 0.015, Table 1).


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  		Table 3. Heart rate variability results

 
Quantitative relationship between Valt and net volume overload.   Figure 4 plots the relationship between Valt and net volume during infusion and diuresis phases. From the slope of this best fit line (P < 0.01), Valt rose by 0.23 µV for each 10 ml/kg of net infused volume.


Figure 4
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  		Fig. 4. Relationship between TWA magnitude (Valt, in µV) and net fluid infused (in ml/kg) for dogs 2–6.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
The primary result of this study is that acute volume overload elevates Valt, even in the absence of structural heart disease. This effect was consistent only at peak infusion and, therefore, may contribute to abnormal clinical TWA only in patients with marked volume overload. These results strengthen the predictive value of TWA in patients with CHF and suggest that abnormal TWA in this population reflects proarrhythmic myocardial substrates rather than volume overload per se. Further studies are required to study the interaction of ventricular stretch and sympathetic nervous activation on TWA in the presence of regional and global myocardial disease.

Mechanisms of elevated TWA during volume overload.   Volume overload in this study significantly elevated Valt in all dogs, by 4- to 10-fold, and significantly reduced its onset heart rate threshold (Table 2). TWA reflects exaggerated dispersion of repolarization that may reflect abnormal rate response of repolarization or conduction (13). Studies of mechanoelectric feedback have shown that acute volume load may shorten or lengthen ventricular action potential duration and slow conduction (21, 24, 26).

The elevation of TWA with volume load in this study may reflect ventricular stretch that exaggerates physiological (24) or pathological (19) nonuniformities in repolarization or conduction and may be proarrhythmic. Notably, pulmonary and systemic arterial pressures rose with volume infusion in our study. Although blood pressure fell in dogs with decompensated pulmonary congestion (an infusion end point), this is typical for patients with decompensated CHF who continue to show evidence for ventricular stretch via hemodynamic measurements and elevated levels of brain natriuretic peptide (12). Further studies using invasive hemodynamic measurements should define the effects of stretch on the rate response and spatial dispersion of conduction velocity and repolarization in the presence and absence of regional disease.

Elevations in TWA in our study could also reflect elevated sympathetic nervous activity. Studies in dogs and humans show that beta-blockers suppress TWA, suggesting an etiological role for the sympathetic nervous system (3, 10, 11, 20), although, conversely, isoproterenol may not consistently elevate TWA during constant pacing (8). Compared with baseline in our study, dogs at peak infusion exhibited sinus tachycardia, reduced total spectral power of HRV that, over 10 min, is analogous to SD of normal R-wave-to-R-wave interval and primarily reflects VLF power and nonsignificant trends for an elevated ratio of LF to HF frequency power. These results are consistent with an elevated sympathetic and/or markedly decreased parasympathetic control of heart rate (23). Studies could further support the contribution-increased sympathetic activity by documenting vasoconstriction at peak infusion or by testing whether beta-blockers attenuate the effects of volume load on TWA, or whether anticholinergic agents augment them.

Other possible explanations for elevated TWA during volume load include hypothermia, which we avoided in all but dog 1, and electrolyte alterations, although electrolytes were repleted during infusion. Theoretically, variations in anesthesia could alter TWA, although we maintained constant anesthesia. Moreover, TWA tracked infusion volume (from baseline to peak to diuresis) rather than anesthestic time (which varied for each dog; Fig. 2). Finally, TWA has previously been studied in anesthetized dogs (17, 18).

Volume load, mechanoelectric feedback, and arrhythmias.   There has been considerable recent interest in the relevance of mechanoelectric feedback to clinical arrhythmias (12). In patients with CHF, indexes of ventricular stretch, such as elevated brain natriuretic peptide, are associated with elevated TWA (22) and improve the predictive value of left ventricular dysfunction for SCA (12). In normal rabbit ventricles, acute volume load causes extra systoles from afterdepolarizations and alters action potential duration and conduction velocity that may facilitate reentry (4, 21, 24, 26).

Our results allow us to define a relationship between volume load and TWA under "idealized" conditions, independent of interactions with regional disease. This is relevant to emerging studies of TWA in individuals without identifiable myocardial disease (5) and may help to dissect the effects of volume overload from intrinsic myocardial disease in the genesis of TWA.

In the presence of myocardial disease, TWA may become exaggerated with less dramatic volume infusion, since volume load interacts unfavorably with regional disease to facilitate arrhythmias (19). Clinically, larger Valt has recently been linked to more extensive myocardial damage (9), to regional scar (16), and to the effects of premature beats (15) and adverse outcome (9, 25). However, studies are still needed to understand how volume overload, which may be ameliorated, and structural disease, which is more likely to be permanent, each contribute to TWA and arrhythmic risk. Such studies will enable better risk stratification for SCA in the face of dynamic changes in clinical status.

Technical issues in TWA analysis.   Measuring TWA in dogs is well established, from the earliest reports in the contemporary literature to recent studies of ischemia-related arrhythmias (17, 18). TWA in dogs is similar to that in humans, but has a higher onset heart rate (1, 17).

Limitations.   The major limitation of this study is its small sample size. Although results were consistent for all animals, this study needs to be extended to larger populations. Second, our study hypothesis was confined to normal heart limits, and ongoing studies will examine this interaction in the presence of myocardial disease. Third, we did not assess stretch using echocardiography or other tools, due to technical limitations. Fourth, anesthesia could influence both TWA and HRV, yet we maintained this at a constant level, and this study could not have been realistically performed without anesthesia. Fifth, we did not study the direct link between volume load and arrhythmias, and future studies in animals with structural disease could use arrhythmia induction or ambulatory ECG monitoring to further define that relationship.

In conclusion, acute volume loading elevates Valt in the absence of structural heart disease. Although dramatic, this effect was marked only at peak infusion and thus may operate clinically only in patients with marked volume overload. This canine study strengthens the value of abnormal TWA in most CHF patients, suggesting that it reflects proarrhythmic substrates rather than loading conditions per se. Studies are now required to define the interaction of volume load with regional myocardial disease and arrhythmic tendency.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
DISCLOSURES
 ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by National Institutes of Health Small Business Innovation Research Grant 1R43HL80815–1 and by American Heart Association, Western Regional Affiliate Grant 0265120Y to S. M. Narayan.


   DISCLOSURES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
ACKNOWLEDGMENTS
 REFERENCES
 
S. M. Narayan is a member of the Scientific Advisory Board of, and holds equity in, PhiloMetron Inc.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 DISCLOSURES
 ACKNOWLEDGMENTS
REFERENCES
 
We are indebted to Dr. Phyllis Stein for review of the manuscript and advice on HRV analyses. We also thank Scott Jacobs for technical assistance during these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. M. Narayan, San Diego Veterans Affairs Medical Center, Univ. of California, San Diego, Cardiology/111A, 3350 La Jolla Village Dr., San Diego, CA 92161 (e-mail: snarayan{at}ucsd.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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 ACKNOWLEDGMENTS
 REFERENCES
 

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