Mechanical circulatory support with a left ventricular assist device (LVAD) is now a well-established therapy for patients with advanced heart failure.1 Newer continuous-flow LVAD systems have improved survival for patients waiting heart transplantation and for those receiving lifetime or “destination” therapy.2–5 LVAD-supported patients report marked improvements in their functional capacity and quality of life with over 50% of patients improving to New York Heart Association (NYHA) functional class I or II within 1 month after implantation and over 80% achieving this by 6 months. These improvements are sustained for at least 2 years after implantation.5,6
We hypothesized that such subjective increases in functional capacity should be associated with objective improvements in peak oxygen consumption (VO2 max), as measured by cardiopulmonary exercise testing (CPET). We also hypothesized that patients who were more critically ill at the time of implantation would not recover to the same extent as those with lesser critical presentations.
We performed a retrospective review of all patients implanted with a HeartMate II (Thoratec Corporation, Pleasanton, CA) LVAD at our center, as either a bridge to transplantation or destination therapy, from June 2009 to June 2012. Per protocol, all patients were scheduled to undergo transthoracic echocardiography, right heart catheterization, and CPET once functional capacity appeared maximal and no sooner than 3 months after implantation. Baseline characteristics including laboratory values, hemodynamic data, previous CPET results, NYHA functional class, and Intermacs Level were obtained before LVAD implantation. The principal outcomes were VO2 max, percent-predicted VO2 max, and NYHA functional class at the time of CPET. Patients were also stratified based on Intermacs level at implantation, with Intermacs levels 1 and 2 being compared with Intermacs levels ≥3. Those patients with CPET data before LVAD implantation had their pre-LVAD VO2 max compared with their post-LVAD VO2 max. Predicted VO2 max was calculated using the Wasserman/Hansen equation, which is a validated method of determining predicted VO2 max in heart failure patients.7,8 Patients were excluded from analysis if they failed to reach anaerobic threshold.
No specific protocol was in place after LVAD implantation to adjust pump speed. In general, pump speed was increased to a level which alleviated exertional fatigue and dyspnea. We targeted a pump output which would be the equivalent of a cardiac index of at least 2.2 L/min/m2 while avoiding speeds which might produce suck down events. Although pump speed was not adjusted to a certain frequency of aortic valve opening, the speed was increased to reduce mitral regurgitation, if present, to a severity not greater than mild, and pump speed was lowered to avoid shifting of the interventricular septum past midline toward the left ventricle.
Cardiopulmonary exercise testing was performed using the Innocor ergospirometry system (Medset Medical Technology, Hamburg, Germany) with treadmill exercise using the modified Naughton protocol. Those patients unable to follow the modified Naughton protocol were exercised by a manual protocol at the discretion of the cardiologist supervising the CPET. Data generated from the Innocor system include serial measurements of VO2, minute ventilation (VE), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) at 15 second intervals, allowing for calculation of anaerobic threshold and ventilatory efficiency (VE/VCO2 slope).
Statistical analysis was performed using IBM SPSS Statistics 20. Descriptive statistics are presented as mean ± standard deviations or percentages where appropriate. Means between groups were compared with the Mann–Whitney U test for continuous variables and the Fisher’s exact test for categorical variables. The Pearson’s correlation coefficient was calculated when comparing Intermacs level and VO2. Statistical significance was defined as p < 0.05.
One hundred six patients received a HeartMate II during the study period (Figure 1). Twenty-three patients died before CPET. Twenty-eight patients were transplanted and one patient had his device explanted before CPET. Fifteen patients declined or did not attend their CPET, and two patients were amputees who could not participate in CPET. Thirty-seven (29 male, mean age 56 ± 15 years) patients completed CPET an average of six months (178 ± 87 days) after implantation (Table 1). The modified Naughton protocol was used in 33 of the 37 patients, with the other four using a manual protocol. Two patients failed to reach anaerobic threshold and were excluded from analysis. The mean duration of exercise was 7.5 ± 3.4 min, with a mean time to anaerobic threshold of 4.5 ± 1.6 min. Patients achieved a mean 3.9 ± 1.1 metabolic equivalents and a mean RER of 1.0 ± 0.1. Ten patients had CPET performed an average of 4 months (121 ± 82 days) before LVAD implantation.
New York Heart Association functional class improved significantly after LVAD implantation (Figure 2A and B). Overall, 91.4% of patients improved by at least two NYHA classes, with 34.3% improving by three classes. All Intermacs level 1 or 2 patients (n = 17) improved by at least two NYHA classes, with 47.1% improving by three classes. Of those patients Intermacs level 3 and greater (n = 18), 85.5% improved by at least two classes, with 16.7% improving by three classes.
For all 35 patients, post-LVAD VO2 max was significantly less than predicted (14.7 ± 3.1 vs. 29.8 ± 6.6 ml/kg/min, p < 0.001; percent-predicted 51% ± 12%). For the 10 patients with pre- and post-LVAD studies, VO2 max increased significantly from 11.6 ± 5.0 to 15.4 ± 3.9 ml/kg/min, p = 0.009, but remained markedly less than predicted (40% ± 17% vs. 54% ± 16%; p = 0.010; Figure 3). In these 10 patients, VO2 max increased, on average, 3.8 ± 3.6 ml/kg/min per patient. VO2 max for patients classified as Intermacs levels 1 or 2 (n = 17) did not differ significantly from those classified as Intermacs levels ≥3 (n = 18; 14.1 ± 2.7 vs. 15.2 ± 3.4 ml/kg/min; p = 0.309). Likewise, Intermacs level at implantation did not correlate with post-LVAD peak VO2 max (r = 0.213; p = 0.218). The mean VE/VCO2 slope was 41.3 ± 7.9, and did not differ significantly when stratified by Intermacs level (38.8 ± 7.1 for Intermacs levels 1 or 2 vs. 43.5 ± 8.3 for Intermacs levels ≥3; p = 0.094). VO2 max and VE/VCO2 slope also did not differ significantly between etiologies of heart failure (Table 2).
The principle finding of our study is that VO2 max improves significantly with continuous-flow LVAD support but fails to normalize to predicted age-, gender-, and BMI-matched values, despite improvement in NYHA functional class. We found no difference in postimplantation VO2 max or VE/VCO2 when stratifying by Intermacs levels or between etiologies of heart failure.
Measurement of peak oxygen consumption (VO2 max) is a well-established method of risk stratifying heart failure patients. In 1991, Mancini et al.9 showed that heart failure patients achieving VO2 max >14 ml/kg/min had 94% 1 year survival, comparable with cardiac transplant recipients, whereas those ≤14 ml/kg/min had only a 47% 1 year survival. VO2 max is an ideal marker of cardiopulmonary fitness in heart failure patients, combining cardiac output, oxygen delivery, and oxygen utilization by skeletal muscle. More recently, ventilatory efficiency, the relation between VE and carbon dioxide production (VE/VCO2 slope), has been shown to be of prognostic significance in chronic heart failure patients, and may be a better discriminator than VO2 max.10,11 When combined with VO2 max, VE/VCO2 slope improves the identification of the highest-risk patients at each level of peak oxygen consumption.12
Our results complement those of studies of first-generation pulsatile LVADs which demonstrated improvements in peak oxygen consumption of 3–4 ml/kg/min, 3–6 months after implantation.13–15 More recently, a few small studies demonstrated similar results with continuous-flow LVADs achieving peak oxygen consumption of 15–16 ml/kg/min, though none of these cohorts had preimplantation data for comparison.16–18 Two small studies with paired pre- and postimplant VO2 showed similarly small increases in VO2 max after 3–6 months of support.19,20 Recently, Nahumi et al.21 measured VO2 max and 6 min walk distance in 26 patients supported with a continuous flow LVAD. When compared with a matched cohort of chronic heart failure patients, those supported with an LVAD were able to walk a longer distance in 6 min (80 m), but failed to reach a similar peak oxygen consumption (VO2 max 12.4 vs. 15.0 ml/kg/min). This suggests that measurable differences in exercise capacity exist between heart failure and LVAD-supported patients with the latter demonstrating a greater submaximal capacity for any given level of VO2.
Patients supported with an LVAD are similar to heart transplant recipients in that they, too, fail to normalize VO2 to predicted values. Within 6–12 months after transplantation, VO2 max improves significantly to approximately 20–21 ml/kg/min (60% of predicted values), but fails to normalize despite the fact that patients anecdotally report excellent quality of life and experience greater functional capacity.22,23 This apparent disconnect between modest improvements in peak oxygen consumption and marked improvements in self-reported functional class suggest that improvements in the latter are less dependent upon improvements in cardiac output. Nonetheless, the inability to increase peak VO2 to predicted levels may be a result of persistent right ventricular dysfunction, pulmonary hypertension, changes in skeletal muscle and deconditioning, as well as an inability to sufficiently augment cardiac output during maximal exercise.
In our cohort, no preimplantation hemodynamic parameters, including right atrial pressure, pulmonary artery pressure, or right ventricular stroke work index correlated with postimplantation VO2. This suggests that peripheral mechanisms such as skeletal muscle atrophy or diaphragmatic weakness may have a more significant effect limiting peak oxygen consumption independent of cardiac output.
The finding that patients implanted with Intermacs levels 1 and 2 had VO2 max and VE/VCO2 slopes that did not differ significantly from those patients implanted with Intermacs levels ≥3 was somewhat surprising. We hypothesized that those patients with more severe heart failure at the time of LVAD implantation would not improve their peak oxygen consumption as much as those with less severe heart failure. There are multiple potential explanations for the lack of VO2 max and VE/VCO2 differences when stratifying by Intermacs level. First is the very nature of Intermacs level 1 patients who are defined as “critical cardiogenic shock with life-threatening hypotension and profound low cardiac output with rapidly escalating inotropic and pressor support,” and are frequently postmyocardial infarction (MI). In our study, 75% of Intermacs level 1 patients were post-MI. Myocardial recovery has been reported in some patients implanted with LVADs, though successful device explantation remains rare.24 The duration and etiology of the heart failure syndrome may predict the likelihood of myocardial recovery sufficient for explantation, as demonstrated by Maybaum et al.,15 with successful pulsatile LVAD explantation occurring in 4 of 21 (19%) of those presenting with acute heart failure, and just 2 of 46 (4%) of those with chronic heart failure. This improved myocardial recovery capacity in the most severe acute heart failure cases could potentially skew the VO2 max correlation and bring the Intermacs levels 1 and 2 group closer to the Intermacs ≥3 group. In addition, the low power of our study, which included only eight Intermacs level 1 patients and nine Intermacs level 2 patients, does not lend itself detecting statistically significant differences. To this end, when analyzing our cohort by etiology of heart failure, separating chronic ischemic, chronic nonischemic, and acute MI, there were no significant differences in VO2 max and VE/VCO2.
In advanced heart failure patients requiring mechanical circulatory support, the restoration of cardiac output and adequate peripheral blood flow is necessary but insufficient for full recovery. The failure to objectively normalize VO2 suggests there are ongoing physiologic derangements which LVAD therapy is insufficiently able to reverse. This may be less of a concern in short-term support, but more important when trying to achieve durable, long-term results in destination therapy patients. Ongoing physical reconditioning and training regimens improve exercise capacity in patients with LVADs. Efforts should be directed toward treating, medically optimizing, and, if possible, reversing, other significant comorbidities in these patients.
Our study was limited by its retrospective nature and the possibility of selection bias and confounding. The number of patients studied was small when viewed as a percentage (35%) of all patients receiving LVADs at our center. Only 10 patients had matched studies before and after LVAD placement, and these studies did not include VE/VCO2 slope data for comparison. Because many of our patients who completed exercise testing had other noncardiac comorbidities which could limit exercise, these conditions may have contributed to submaximal tests. Specifically regarding the low RER, our use of the Innocor device may explain the occasionally observed low RER as similar findings have been corroborated in verbal and written communication with other centers using this inert gas rebreathing system. Despite the lower than expected RER, 35 out of 37 patients studied reached anaerobic threshold, and the two who did not were excluded from the analysis. RVEF could not be quantified as this was not systematically recorded in our echocardiography studies.
Peak oxygen consumption improves significantly with continuous-flow LVAD support but fails to normalize to predicted age-, gender-, and BMI-matched values, despite improvement in NYHA functional class. There is no difference in postimplantation VO2 max or VE/VCO2 between heart failure etiologies or when stratifying by Intermacs levels. Further investigation is required to elucidate the mechanisms responsible for the profound symptomatic improvement despite an inability to normalize peak oxygen consumption.
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