Reverse Electrophysiologic Remodeling After Cardiac Mechanical Unloading for End-Stage Nonischemic Cardiomyopathy

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Reverse Electrophysiologic Remodeling After Cardiac Mechanical Unloading for End-Stage Nonischemic Cardiomyopathy Stavros G. Drakos, MD, John V. Terrovitis, MD, John N. Nanas, MD, PhD, Efstratios I. Charitos, MD, Argirios S. Ntalianis, MD, Konstantinos G. Malliaras, MD, Nikolaos Diakos, MD, Dimitrios Koudoumas, MD, Stergios Theodoropoulos, MD, Magdi H. Yacoub, MD, and Maria I. Anastasiou-Nana, MD Third Cardiology Department and Department of Clinical Therapeutics, University of Athens, and Cardiothoracic Division, IASO General Hospital, Athens, Greece; and Harefield Heart Science Center and Magdi Yacoub Institute, Harefield, United Kingdom

Background. Left ventricular assist devices (LVAD)induced unloading appear to cause reverse cardiac remodeling. However, its effect on arrhythmogenicity is a controversial issue, and prospective data are lacking. We sought to investigate the impact of LVAD-induced unloading on the electrical properties of the failing heart. Methods. We prospectively studied the effects of LVAD therapy on QRS, QT, and QTc durations and ventricular arrhythmias from electrocardiograms and 24hour ambulatory electrocardiograms recorded before and during 6 months of mechanical support in 12 LVAD patients and 7 other patients with advanced nonischemic cardiomyopathy untreated with LVAD. Results. After 1 week of LVAD support, QTc duration had decreased from 479 ⴞ 79 ms to 411 ⴞ 57 ms (p ⴝ 0.037), and QRS duration from 150 ⴞ 46 ms to 134 ⴞ 32 ms (p ⴝ 0.029). At 6 months, QTc was found to be 372 ⴞ 56 ms (p ⴝ 0.046 versus baseline, 15% shortening) and QRS 118 ⴞ 25 ms (p ⴝ 0.028 versus baseline, 11% shortening).

A strong correlation was found between QTc shortening and increase in left ventricular ejection fraction and decrease in left ventricular filling pressures. After 2 months of LVAD support, premature ventricular contractions had decreased from 3,507 ⴞ 4,252 to 483 ⴞ 417 in 24 hours (p ⴝ 0.043), ventricular couplets from 82 ⴞ 99 to 29 ⴞ 25 in 24 hours (p ⴝ 0.05), and ventricular runs from 9 ⴞ 8 to 10 ⴞ 9 (not significant). No patient died suddenly or suffered a symptomatic arrhythmic event during followup. No significant electrocardiographic, functional, or hemodynamic change was observed in the 7 patients untreated with LVAD. Conclusions. The LVAD support caused progressive shortening of QTc and QRS intervals, consistent with reverse remodeling of the failing heart’s electrical properties, accompanied by a decrease in frequency of ventricular arrhythmias. (Ann Thorac Surg 2011;91:764-9) © 2011 by The Society of Thoracic Surgeons

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heart [10 –13]. The QT interval, which reflects the duration of ventricular repolarization on the surface electrocardiogram (ECG), is often prolonged in patients who suffer from heart failure (HF). Prolongation of the action potential delays repolarization of the myocyte and cellular relaxation. Moreover, both QT prolongation and conduction abnormalities, reflected by an increased QRS duration, have been associated with an increased mortality among patients presenting with chronic HF [14]. We sought to prospectively examine the early or delayed changes in ventricular activation or repolarization, or both, that occur in the failing human heart after LVAD implantation. We also studied the effects of LVAD on the electrical stability of the unloaded failing heart. The impact of LVAD therapy on ventricular electrical stability is a highly controversial issue, and prospective data are lacking.

ardiac mechanical support with left ventricular (LV) assist devices (AD) reverses the complex process of LV remodeling to an extent that allows the weaning of a subset of patients from the device, after the restoration of essential cardiac functions [1– 4]. Specifically, by profoundly unloading LV volumes and pressures, LVAD reverse the compensatory and stress responses of the overloaded myocardium, and the structural and functional remodeling of the tissue [5–7]. The mechanisms that facilitate reverse remodeling are the subject of intensive research, in the hope of identifying reliable predictors of a sustained cardiac recovery and of developing adjunctive therapies to enhance the recovery of the failing heart [8, 9]. Limited data from mostly retrospective studies have been published on the effects of mechanical unloading on the electrophysiological properties of the failing human Accepted for publication Oct 28, 2010. Address correspondence to Dr Nanas, 24 Makedonias, Athens 104 33, Greece; e-mail: [email protected].

© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc

Patients and Methods This study was limited to patients who have idiopathic dilated cardiomyopathy, whose ECG before LVAD im0003-4975/$36.00 doi:10.1016/j.athoracsur.2010.10.091

DRAKOS ET AL LVADS AND ELECTROPHYSIOLOGIC REMODELING

plantation showed sinus rhythm and absence of left bundle branch block. Among 14 consecutive recipients of LVAD who presented with nonischemic heart disease, 12 fulfilled these criteria. The LVAD implantation was performed as either bridge to transplant, bridge to recovery, or destination (permanent) therapy. The study protocol was approved by our Institutional Review Board, and after they had granted their informed consent, the patients were followed prospectively. All patients were in New York Heart Association HF functional class IV, refractory to optimal medical therapy. Two patients had noninsulin-dependent diabetes mellitus, and 1 patient had insulin-dependent diabetes mellitus. Other individual demographic, clinical, and laboratory characteristics are shown in Table 1. The implanted devices were HeartMate XVE in 11 patients and the HeartMate II in 1 patient (Thoratec Corp, Pleasanton, CA). The HeartMate XVE were set to “auto” mode to offer optimal ventricular unloading. The HeartMate II was set to a fixed rate of rpm to reach a pulsatility index (estimated by the device’s software) between 3 and 4. The patients’ long-term medications regimen included lisinopril, carvedilol, spironolactone, and digoxin. At enrollment into the study and at 6 months after LVAD implantation, the patients underwent echocardiographic evaluation (the echocardiographic technique utilized for volume measurements and ejection fraction calculations was the Simpson’s biplane method) and right-side heart catheterization for hemodynamic measurements. The ECG was recorded, using a Mortara ELI 250 12-lead system (Mortara Instruments, Milwaukee, WI) before LVAD implantation, at the first week after Table 1. Baseline Patient Characteristics (n ⫽ 12) Characteristic

Value

Age, years Sex, male/female Heart failure duration, years Heart rate, beats per minute Systemic arterial blood pressure, mm Hg Systolic Diastolic New York Heart Association functional class Left ventricular End-diastolic diameter, mm Ejection fraction, % Central blood pressures, mm Hg Mean right atrial Systolic pulmonary artery Pulmonary capillary wedge Cardiac index, L · m⫺2 · min⫺1 Pulmonary vascular resistance, Wood units Brain natriuretic peptide, pg/mL Sodium, mmol/L Creatinine, mg/dL Hemoglobin, g/dL Daily furosemide dose, mg

49 ⫾ 12 11/1 6.0 ⫾ 3.5 82 ⫾ 7 93 ⫾ 9 62 ⫾ 10 IV 79 ⫾ 12 20 ⫾ 5 9⫾7 49 ⫾ 13 24 ⫾ 8 2.1 ⫾ 0.5 2.5 ⫾ 0.8 1,152 ⫾ 548 135 ⫾ 4 1.6 ⫾ 0.4 12 ⫾ 1.4 377 ⫾ 194

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LVAD implantation, and monthly for the next 6 months. All ECGs included 10 s of digital signals recorded at a sampling frequency of 250 Hz, to a resolution of 5 ␮V. The recordings were scanned, using an Epson Expression 1680 instrument (Epson America, Long Beach, CA), and measured by the same author who was unaware of the patients’ information, using custom-developed image analysis software. The ECG measurements (QRS complex and QT interval) were performed using the limb leads. The start of the QT interval was defined as the first deflection of the QRS complex. The end of the QT interval was defined as the intersection of the descending part of the T wave (positive T wave) with the isoelectric line. In case the T waves and U waves were superimposed or could not be separated, then the down slope of the T wave was extended by drawing a tangent to the steepest proportion of the down slope until it crossed the TP segment. The corrected QT interval (QTc) was calculated by Bazett’s formula, as previously described [15]. Ventricular runs were defined as three or more consecutive premature ventricular complexes. Ambulatory ECGs were recorded for 24 hours, at baseline and 2 months after LVAD implantation, using a MARS 5000 Arrhythmia Review Station (General Electric Healthcare Technologies, Waukesha, WI). Patients with advanced chronic HF due to dilated cardiomyopathy, LV systolic dysfunction, and an ejection fraction less than 30%, untreated with LVAD, were also included in our study if they fulfilled the same electrocardiographic criteria as the LVAD-treated group and had been optimally treated medically for 6 months or more. These patients were randomly chosen from the population followed in our long-term HF program. They underwent the same baseline and follow-up evaluation, were followed for a similar period of observations, and were treated with similar HF medications as the LVAD patients.

Statistical Analysis The data are expressed as means ⫾ SD. The significance of differences among measurements made at consecutive time points was tested with the nonparametric Wilcoxon test. Correlations between the change observed in various variables were evaluated using the Pearson’s correlation coefficient (correlations were calculated using the individual data and not the mean values). Statistical significance was set at a p value less than 0.05. Statistical analysis was performed using the SPSS 15.0 software (SPSS, Chicago, IL).

Results Electrocardiographic Changes Electrocardiographic measurements were made between day 7 and day 180 after LVAD implantation, representing a follow-up of 2,026 patient-days. After 1 week of LVAD support, QTc duration had decreased from 472 ⫾ 79 ms to 411 ⫾ 57 ms (p ⫽ 0.037, n ⫽ 12), and QRS duration decreased from 150 ⫾ 46 ms to

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134 ⫾ 32 ms (p ⫽ 0.029, n ⫽ 12). At 6 months, QTc was found to be 372 ⫾ 56 ms (p ⫽ 0.046 versus baseline, n ⫽ 6, 15% shortening), and QRS was 118 ⫾ 25 ms (p ⫽ 0.028 versus baseline, n ⫽ 6, 11% shortening). A plot of all QRS and QTc measurements derived from ECGs obtained on these patients is shown in Figure 1. Furthermore, during the first 2 months of LVAD support (n ⫽ 8; Fig 2), the mean number per 24 hours of premature ventricular contractions decreased from 3,507 ⫾ 4,252 to 483 ⫾ 417 (p ⫽ 0.043), ventricular couplets decreased from 82 ⫾ 99 to 29 ⫾ 25 (p ⫽ 0.05), and ventricular runs remained unchanged, from 9 ⫾ 8 to 10 ⫾ 9 (p ⫽ 0.993). No patient died suddenly or had a symptomatic arrhythmic event during follow-up. Patients were specifically interrogated at frequent time intervals for any symptoms suggestive of tachyarrhythmias.

Echocardiographic, Hemodynamic, and Biochemical Measurements Between baseline and 6 months of follow-up, changes were observed in echocardiographic, hemodynamic, and biochemical measurements indicative of a significant improvement in overall cardiovascular function (n ⫽ 6; Table 2). Furthermore, a strong inverse correlation was found between change in QTc and LV ejection fraction (Pearson’s correlation coefficient R ⫽ 0.9, p ⫽ 0.007). Strong correlation was also observed between change in QTc and change in pulmonary capillary wedge pressure (Pearson’s correlation coefficient R ⫽ 0.9, p ⫽ 0.006). Noteworthy, the correlations between QRS or QTc and

Fig 1. Plot of all QRS (green circles) and QTc (blue circles) measurements. The horizontal parallel lines indicate mean value and 95% confidence intervals. Regression equations: Y ⫽ a ⴱ x ⫹ b, Y: value (QTc , QRS), X: days on left ventricular assist device (LVAD) support, a: slope, b: intercept. For QRS: Y ⫽ (⫺0.1 ⫾ 0.03) ⴱ X ⫹ (139.4 ⫾ 4.4), R2 ⫽ 0.1 , p ⫽ 0.002; and for QTc: Y ⫽ (⫺0.35 ⫾ 0.06) ⴱ X ⫹ (437.1 ⫾ 8.5), R2 ⫽ 0.26, p ⬍ 0.001. The number of patients evaluated at each time point is as follows: before left ventricular assist device, n ⫽ 12; week 1, n ⫽ 12; month 1, n ⫽ 8; month 2, n ⫽ 8; and month 6, n ⫽ 6.

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left ventricular end-diastolic diameter were not significant (Pearson’s correlation coefficient R ⫽ 0.2, p ⫽ 0.7; and R ⫽ 0.1, p ⫽ 0.9, respectively). The same applies to the correlation between QRS and LV ejection fraction (Pearson’s correlation coefficient R ⫽ 0.08, p ⫽ 1.0).

Observations in Patients Untreated With LVAD The mean age of the patients who did not receive LVAD support was 51 ⫾ 10 years. In this group of patients, no significant difference was observed between measurements made at baseline and those made 6 months later (Table 3). In particular, the QRS and QTc, measured at the same time points as the LVAD group, did not change significantly throughout the 6-month period (data not shown).

Comment To our knowledge, ours is the first prospective study of the effects of long-term mechanical unloading on ventricular arrhythmias and the second prospective study of its effects on electrocardiography. As patients having ischemic cardiomyopathy are generally considered unlikely to recover, the majority of patients included in published studies of LVAD as a bridge-to-recovery had nonischemic heart disease [1– 4, 16, 17]. Therefore, we chose to limit this study to patients having nonischemic cardiomyopathy. However, the impact of the etiology of HF on the potential for LVAD-induced reverse remodeling and myocardial recovery warrants further investigations.

QRS Complex Shortening During Mechanical Unloading We found that QRS duration shortened significantly within the first week, and this decrease tended (without reaching statistical significance) to continue for as long as 6 months of LVAD support. Other studies of the effects of mechanical unloading on QRS duration have yielded variable results. In particular, Harding and colleagues [11] reported a shortening of the QRS complex on ECG recorded less than 6 hours after LVAD implantation, and no further shortening during prolonged LVAD support. However, in that retrospective study, the last ECG, instead of being recorded at a fixed time point, was recorded just before cardiac transplantation, at intervals that varied markedly among patients. In contrast, in the prospective study by Xydas and coworkers [12], a significant shortening of QRS duration was observed at 48 hours after LVAD implantation, which continued to shorten progressively to a 20% overall decrease, over 90 days of follow-up. The mechanisms behind the effects of mechanical unloading on QRS duration are poorly understood. Studies in isolated myocytes suggested that overstretching slows conduction velocity; however, more recent studies in rabbit and canine models detected no change in conduction velocity attributable to cardiac distention induced by volume loading [18, 19]. One might hypothesize that the QRS shortening reflects a shorter conduction distance due to the smaller dimensions of the post-unloading failing heart, instead of an increase in conduction velocity. In our study, though, no correlation

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Fig 2. Mean (⫾SD) numbers of premature ventricular complexes (PVC [blue bars]), couplets (green bars), and runs of ventricular tachycardia (VT [beige bars]) recorded before left ventricular assist device (LVAD) implantation (preOP) and at 2 months on LVAD support (y-axis: logarithmic scale, n ⫽ 8). *p less than 0.05 versus preOP.

was identified between the changes in QRS and LV dimensions.

QTc Shortening During Mechanical Unloading We observed a statistically significant shortening of QTc within the first week that continued (without reaching Table 2. Characteristics of Patients Who Completed 6Month Evaluation* (n ⫽ 6)a Characteristic

Baseline

Left ventricular End-diastolic diameter, 77 ⫾ 9 mm Ejection fraction, % 19 ⫾ 5 Heart rate, beats per minute 82 ⫾ 11 Systemic arterial blood pressure, mm Hg Systolic 91 ⫾ 8 Diastolic 61 ⫾ 7 Central blood pressures, mm Hg Mean right atrial 7⫾6 Right ventricular systolic 46 ⫾ 11 Mean pulmonary artery 34 ⫾ 11 Pulmonary capillary 21 ⫾ 9 wedge Cardiac index, L · m⫺2 · 2.1 ⫾ 0.5 min⫺1 Pulmonary vascular 2.5 ⫾ 0.8 resistance, Woods units Brain natriuretic peptide, 1,094 ⫾ 630 pg/mL 377 ⫾ 194 Daily furosemide dose, mgb New York Heart Association IV functional class

6 Months

p Value

62 ⫾ 9

0.04

41 ⫾ 4 78 ⫾ 11

0.03 0.6

109 ⫾ 11 68 ⫾ 8

0.03 0.07

2⫾2 26 ⫾ 3 15 ⫾ 1 6⫾3

0.09 0.03 0.03 0.03

2.8 ⫾ 0.4

0.07

2.0 ⫾ 0.3

0.1

87 ⫾ 77

0.05

0 I

N/A 0.008

Values are means ⫾ SD. a Echocardiographic and hemodynamic data were obtained with the left ventricular assist device functioning at full b support. No patient was treated with diuretics at the 6-month follow-up. N/A ⫽ not applicable.

statistical significance) up to 6 months after LVAD support initiation. In the retrospective study by Harding and coworkers previously mentioned [11], an initial shortening of QTc was measured in ECGs recorded less than 6 hours after LVAD implantation, whereas a “delayed” ECG, recorded immediately before transplantation, revealed a nonsignificant further shortening of QTc. In another retrospective study published later, the same group of investigators [10] reported an immediate increase in QTc duration in 10 of 17 patients, associated with the development of major ventricular arrhythmias. In contrast, in the prospective study by Xydas and associates [12], no significant change in QTc was observed at 48 hours after LVAD implantation, although QTc was significantly decreased by 7% at 30 days, and remained stable thereafter for as long as 90 days of follow-up. In vitro experiments support the hypothesis that the shortening of QTc observed during mechanical unloading reflects a shortening of the action potential duration. Specifically, action potential duration at 50% repolarization was, on average, considerably shorter in isolated LV myocytes after LVAD unloading [11]. Since prolongation of the action potential is one of the main electrophysiologic abnormalities occurring in the failing human heart [20], the progressive shortening of QTc suggests a reversal of electrophysiologic remodeling conferred by LVAD support.

Improvement in Ventricular Electrical Stability by Cardiac Mechanical Unloading The effect of LVAD support on ventricular electrical stability is controversial, and prospective data are lacking. Several case reports have described the use of LVAD to treat frequent episodes of drug refractory ventricular tachyarrhythmias with variable success [21–27]. Furthermore, retrospective studies of prevalence of arrhythmias before and after LVAD implantation have yielded conflicting results [13, 28 –31]. These retrospective studies, which examined mainly the incidence of clinically significant tachyarrhythmias occurring after LVAD implanta-

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Table 3. Baseline and 6-Month Electrocardiographic, Clinical, Hemodynamic, Biochemical, and Functional Characteristics of 7 Patients Untreated With LVAD Characteristic

Baseline

6 Months

p Value

QRS, ms QTc, ms Left ventricular End-diastolic diameter, mm Ejection fraction, % Heart rate, beats per minute Systemic arterial pressure, mm Hg Systolic Diastolic Central pressures, mm Hg Mean right atrial Right ventricular systolic Mean pulmonary artery Pulmonary capillary wedge Cardiac index, L · m⫺2 · min⫺1 Brain natriuretic peptide, pg/mL Daily furosemide dose, mg New York Heart Association functional class

119 ⫾ 30 512 ⫾ 84

120 ⫾ 40 545 ⫾ 63

1.0 0.1

74 ⫾ 4

73 ⫾ 4

25 ⫾ 3 71 ⫾ 11

28 ⫾ 5 70 ⫾ 8

0.7 0.6 0.7

97 ⫾ 11 63 ⫾ 8

101 ⫾ 10 68 ⫾ 9

0.2 0.07

10 ⫾ 3 58 ⫾ 9

9⫾4 49 ⫾ 16

0.6 0.4

38 ⫾ 6 23 ⫾ 4

33 ⫾ 13 18 ⫾ 9

0.3 0.07

2.0 ⫾ 0.6

2.2 ⫾ 1.0

0.07

1,024 ⫾ 442

950 ⫾ 226

1.0

402 ⫾ 221

386 ⫾ 196

1.0

3.1 ⫾ 0.4

2.8 ⫾ 0.4

0.2

hemodynamic and echocardiographic data provided were obtained during full LVAD support and may not represent the native heart’s functional performance during increased pressure and volume loading conditions. Finally, in the current study, we have included mostly pulsatile LVADs. The newer generation continuous flow LVADs are increasingly being used and have been reported to induce a similar degree of pressure unloading but less volume unloading [32]. Consequently, whether pulsatile compared with continuous flow LVAD-induced unloading would have different effects on specific remodeling features (including electrophysiologic indices) requires further investigation. In conclusion, LVAD support caused shortening of QTc and QRS duration consistent with reverse remodeling of the electrical properties of the failing heart, which was accompanied by a decrease in the frequency of ventricular arrhythmias.

References

Values are means ⫾ SD.

tion based on patients’ records, did not include prospective 24-hour ambulatory ECG recorded at fixed time points. Other differences between these studies and ours is our choice of patients, limited to nonischemic heart disease, and in addition, our protocol mandated that they be treated with optimal doses of all standard medications recommended for the management of HF. The hemodynamic benefit conferred by the LVAD may have played a major role in the suppression of ventricular arrhythmias observed in this study. On the other hand, the apical scar created by the insertion of the LVAD in-flow cannula may also be arrhythmogenic.

Study Limitations The limitations of this study include the small number of patients studied and that the follow-up period was relatively short. Therefore, results of borderline significance may become nonsignificant when the beta (type II) error is considered in the context of multiple testing. It also needs to be emphasized that any positive results observed in our small scale study need to be confirmed in larger patient populations. Our findings might not apply to patients having ischemic cardiomyopathy. The impact of LVAD therapy on arrhythmias in that patient population requires further in-depth investigation. Of note, the

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