In the era of continuous-flow (CF) left ventricular assist device (LVAD) use, with improved patient survival owing to the device superiority and sophisticated perioperative management,1 development of aortic insufficiency (AI) still remains one of the major postoperative concerns that reduces patients’ quality of life.2–4 Progressed AI decreases exercise capacity, worsens congestive symptoms, and increases the risk for thrombosis because of a reduced forward flow and enhanced retrograde flow through the native aortic valve (AV) and formation of turbulence in the remodeled aortic root.5
We previously demonstrated that opening of the native AV at rest prevented the development of AI.6 However, some patients did not experience AI despite their native AV remaining closed at rest. Although opening of the native AV at rest has been analyzed,2,3,7,8 no observational study has been conducted on this during exercise. We hypothesized that patients who achieved opening of the native AV only during exercise (the opening AV group) also had lesser AI along with a better clinical course compared with those with a continuously closed native AV (the closed AV group). Therefore, we assessed the relation between opening of the native AV during exercise and development of AI during CF LVAD treatment.
A total of 58 consecutive patients who had received CF LVAD were followed at our institute from 2006 to 2014; this included postoperative scheduled echocardiography. Of these, we enrolled 37 patients (axial pump, 16; centrifugal pump, 21), in whom the native AV remained closed at rest at 3 months. Twenty-one patients were excluded because they had already achieved native AV opening at rest. No patients had preoperative AI.
All patients had received guideline-directed medical therapy and had been listed for transplant preoperatively. No patients were assigned to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1. Written informed consent was obtained from all participants before the surgery. The study protocol was approved by the Ethics Committee of Graduate School of Medicine, University of Tokyo.
After LVAD implantation, antiheart failure medications were titrated considering patient hemodynamics. Rotation speeds were adjusted considering the results of scheduled hemodynamic and echocardiographic studies.
All enrolled patients underwent symptom-limited cardiopulmonary exercise testing (CPXT) at 3 months. Baseline variables including demographic and echocardiographic parameters were obtained at the same time. Left ventricular ejection fraction (LVEF) was calculated using Simpson’s method. The grade of mitral regurgitation was classified as: none, 0; mild, 1; moderate, 2; and severe, 3. Opening of the native AV was observed for a minute using the M-mode. Less than 30% of opening per native heart beat was defined as “native AV remained closed,” based on Slaughter’s suggestion.8
Demographic, echocardiographic, and hemodynamic parameters within a week before LVAD implantation were also obtained. Heart failure (HF) duration was calculated as the duration between the time of HF diagnosis and LVAD implantation. The cumulative dose of anti-HF medication was calculated considering each daily dose of anti-HF medication and the prescribed duration.
Cardiopulmonary Exercise Testing
Symptom-limited CPXT was carried out using a cycle ergometer with a ventilator expired gas analysis (AE-300S; Minato Igaku, Osaka, Japan) at 3 months. The procedure was initiated as 4 minutes warm-up at 20 W, which was followed by a 10 W/minute ramp protocol, as we have previously described.9 Oxygen consumption (VO2), carbon dioxide production (VCO2), and minute ventilation (VE) were measured continuously during the procedure on a breath-by-breath basis.
An echocardiographic study also was executed during exercise. Opening of the native AV was observed in the same manner as described above for a minute just after the initiation of the ramp test. The LVAD flow was estimated based on its algorithm at rest and during exercise.
Echocardiography was performed at 6 months. The end-point was the development of AI at 6 months, which was defined as mild or worse aortic regurgitation, as we have previously defined.10 Readmission because of cardiovascular events or all-cause death was counted, and heart transplantation or LVAD explantation was eliminated.
Statistical analyses were carried out using SPSS Statistics 22 (SPSS Inc., Chicago, IL). The statistical tests were two tailed, and a p value less than 0.05 was considered significant. All data were expressed as mean ± SD. Continuous variables were compared using the unpaired t-test or Mann–Whitney U test, as appropriate, and categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Baseline variables between the opening and closed AV groups were compared using the unpaired t-test or Mann–Whitney U test, as appropriate. Logistic regression analyses were performed to identify the preoperative predictors of AV opening. Kaplan–Meier analyses were performed to assess the readmission-free ratio or survival in patients with/without native AV opening during exercise in the postoperative 2 years study period. Cox analyses were performed to analyze predictability of AV opening and age for readmission.
A total of 37 patients (age, 42 ± 13 years; 26 men), in whom the native AV remained closed at rest at 3 months, were enrolled (Table 1). All patients had a hemodynamically stable condition, with cardiac index greater than 1.8 L/min/m2, pulmonary capillary wedge pressure less than 18 mm Hg, and an average LVEF 18% ± 8%.
Native AV Opening During Exercise
All participants underwent CPXT at 3 months, and 7 patients (19%) achieved native AV opening during all exercise procedures (a typical case is shown in Figure 1). These patients were significantly younger than those in the closed AV group. There were no differences in the maintenance doses of anti-HF agents between those with/without native AV opening. Hemodynamic and echocardiographic variables at rest were comparable between the opening and closed AV groups (Table 2), whereas the opening AV group had more improved exercise capacity along with more improved left ventricular (LV) contractility during exercise compared with the closed AV group (Table 2).
Relation Between Native AV Opening During Exercise and Development of AI
All seven patients in the opening AV group did not experience AI at 6 months. Of the remaining 30 patients in the closed AV group, 13 developed AI (43%) (Figure 2).
Preoperative Predictors of Native AV Opening During Exercise
Among the preoperative parameters, the lower cumulative dose of carvedilol was the only significant predictor of native AV opening during exercise (p < 0.05) (Table 3).
Preoperative Predictors of AI-Free Status Among Those With Closed AV
Among the remaining 30 patients with a closed AV, logistic regression analyses revealed that the use of the centrifugal pump was the only significant predictor of AI-free status (p = 0.036 and odds ratio, 5.400) (Table 4).
Prognosis and Native AV Opening During Exercise
The opening AV group had a higher readmission-free ratio because of cardiovascular events including cerebrovascular thrombosis, heart failure, and ventricular tachyarrhythmia (100% vs. 56%, p = 0.005; Figure 3A) or survival (100% vs. 84%, p = 0.308; Figure 3B) compared with the closed AV group during the postoperative 2 years study period.
Cox regression analyses showed a significant predictability of AV opening for readmission-free rate (p = 0.048; hazard ratio, 0.018), whereas younger age was not a significant predictor (p = 0.241).
We demonstrated here that 1) some patients could achieve native AV opening during exercise at 3 months although their native AV remained closed at rest, 2) these patients had better exercise tolerability and more improved LV contractility during exercise compared with the closed AV group, 3) no patients in the opening AV group experienced AI development at 6 months, and 4) these patients had a higher readmission-free ratio because of cardiovascular events during the 2 years CF LVAD treatment.
Clinical Evil of AI Development in the Era of Long-Term CF LVAD Treatment
Aortic insufficiency remains one of the unsolved concerns even in the era of CF LVAD because it reduces systemic circulation and increases intracardiac pressure.3 Clinically, AI facilitates congestive symptoms, ventricular tachyarrhythmia, and dyspnea on effort and may reduce patients’ quality of life or survival.2,5,7,10
Despite the recently proposed surgical interventions such as AV replacement or repair, no procedures with few complications have been established thus far.4 Therefore, optimal patient selection and a prophylactic strategy should be established to prevent the development of AI.
Here, we assessed AI at 6 months because we previously demonstrated that no de novo AI developed after 6 months,5 and some patients were eliminated because of death or transplant soon after the 6th month.
Opening of Native AV at Rest and Development of AI
The opening of native AV at rest is sufficient to prevent development of AI,2,6,7,10,11 probably because daily opening of native AV would avoid fusion of native AV, increase pulse pressure in the aortic root, and prevent degenerative remodeling of the aortic root.12–14
Opening of the native AV is achieved by sufficient recovery of LV contractility during LVAD support because intracardiac pressure in the systolic phase should exceed that of the aortic root to open the native AV.2 In this study, we assessed opening of the native AV at 3 months because LV reverse remodeling is accomplished by approximately the 3rd month after LVAD implantation.15
Opening of Native AV During Exercise and Development of AI
Among those with a closed AV at rest, approximately 20% of patients achieved opening of the native AV during exercise. To the best of our knowledge, this is the first study to discuss opening of the native AV during exercise under LVAD support.
The opening AV group had significantly improved LVEF during exercise, whereas these patients had a comparatively low LVEF at rest compared with the closed AV group. Such patients would have an LV contractile reserve.16 They also had a significantly greater improvement in exercise capacity, probably because of enhanced cardiac contractility during exercise. Younger patients had such a higher cardiac reserve. Young age may be an important factor for AV opening during exercise although it was not a significant predictor of the readmission-free ratio by Cox regression analyses.
Surprisingly, no patients in the opening AV group experienced AI (Figure 2). The native AV started opening soon after the initiation of CPXT. They will achieve native AV opening during light-labor activities in daily life. Echocardiography performed only at rest may not always be sufficient for assessing the cardiac condition including the opening of the native AV during daily living activities.
Insufficient preoperative β-blocker treatment was the only significant predictor of native AV opening during exercise. These patients have a higher possibility of being responders to β-blocker treatment under LVAD treatment because they have a lesser chance of undergoing trial β-blocker titration because of acute worsening of HF, as we have previously demonstrated.17
Among the remaining 30 patients with a closed AV, 17 were able to avoid AI development. Logistic regression analyses revealed that use of the centrifugal pump was the only preoperative predictor of AI-free status in this population. Those receiving centrifugal LVAD have higher pulse pressure compared with those receiving the axial type. Preserved pulse pressure prevents both remodeling of the aortic root and degeneration of AV, which facilitates the development of AI.5 Therefore, use of the centrifugal pump would be another factor that prevented AI.
Clinical Impact of Opening of Native AV During Exercise
Patients in the opening AV group had a higher readmission-free ratio because of cardiovascular events compared with those in the closed AV group (Figure 3). They were free from AI, which would increase intracardiac pressure because of a retrograde flow through the native AV that facilitates congestion and ventricular tachyarrhythmia. Forward flow through the native AV, probably observed during daily activity, would reduce the formation of turbulence and a thrombus in the aortic root, which may prevent occurrence of fatal cerebrovascular thrombosis.5,18 Those with the opening AV were younger, but young age was not found to be a significant predictor of the readmission-free rate.
Intervention for Facilitating Opening of Native AV
There has been no established strategy to facilitate the opening of the native AV and prevent development of AI thus far.
Native AV has a tendency toward opening under a lower rotation speed,11 but the cardiac output is often decreased to a lower level, which is required by the patients for daily living activities. Three-fifths of patients who received Jarvik 2000, which has an intermittent lower speed mode, experienced AI. Adjustment of rotation speed may be insufficient to open the native AV.
Aggressive cardiac rehabilitation, as recommended in the 2013 International Society of Heart and Lung Transplantation (ISHLT) guidelines improves exercise tolerability and contractile reserve,19 which may facilitate opening of the native AV during daily activity as seen in our results. However, implementation of a specific rehabilitation program to open the native AV would remain a future concern.
1. The current study was performed retrospectively in a very small population in a single center. In the analysis using the unpaired t-test, the power was 0.5 with an effect size of 0.8 and error probability of 0.05. The results should be confirmed in a future multicenter large-scale study that includes prospective cardiac rehabilitation.
2. All participants had preserved exercise tolerance and could undergo CPXT. Our result would not be adopted in those with low exercise tolerability. However, native AV would not open in patients who are sick. Opening of the AV is expected in those with sufficient exercise tolerability and cardiac reserve.
3. We enrolled only five patients who were receiving Jarvik 2000. The advantage of its intermittent lower speed mode in facilitating opening of the native AV and preventing AI remains unconfirmed.
4. We performed echocardiography at 3 and 6 months after LVAD implantation. Monthly procedures would have strengthened our results.
Opening of the native AV during exercise was sufficient to prevent the development of AI in patients with a closed native AV at rest. Aggressive cardiac rehabilitation to improve exercise tolerability may have a prophylactic impact on development of AI during CF LVAD treatment.
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ventricular assist device; cardiopulmonary exercise; reverse remodeling; heart failure