With the rise in the number of left ventricular assist devices (LVADs) as therapy for patients with advanced heart failure,1 there is a need to assess the clinical response after implantation. The traditional paradigm of clinical response is driven by improvements in survival and a reduction in adverse clinical events.2 In recent years, there has been a drive to understand clinical response using patient-reported outcome metrics such as health-related quality of life in cardiovascular clinical trials,3 particularly among patients with LVAD.4 Measuring patient-reported outcomes is critical because health-related quality of life can vary drastically among patients with heart failure post–LVAD implantation, and importantly, not all patients have improved health-related quality of life after LVAD implantation.5,6 Health-related quality of life is a complex phenomenon that encompasses clinically relevant aspects of life related to physical and mental health dimensions.7 Although health-related quality of life is largely influenced by symptoms, treatment effects, social well-being, and functionality,8 particularly in heart failure,9 there is also a need to understand variability in health-related quality of life as a function of biological and physiological mechanisms. Understanding the biological and physiological mechanisms of health-related quality of life is particularly important among patients receiving an LVAD given the drastic physiologic changes that occur postimplantation. In turn, this understanding could help identify who will have better or worse health-related quality of life after LVAD implantation.
Underlying differences in health-related quality of life could involve pathophysiological mechanisms such as the sympathetic nervous system, which is chronically activated in heart failure and leads to the deterioration of left ventricular function, remodeling, and worsening symptoms.10 One method to assess sympathetic activity involves measuring biomarkers, such as plasma β-adrenergic receptor kinase-1 (βARK1; aka G protein-coupled receptor kinase-2), and plasma catecholamines, specifically norepinephrine (NE). Increases in both plasma βARK1 and NE levels signal sympathetic overactivation. Specifically, βARK1 causes desensitization and internalization of β-adrenergic receptors after augmented and chronic stimulation by NE.11 The expression of βARK1 in myocardial cells and lymphocytes has been linked with prognosis in heart failure12 and has been shown to decrease after LVAD implantation13 and heart transplantation.14 Recently, we showed that an elevated plasma βARK1 level is associated with worse physical heart failure symptoms.15 Additionally, plasma NE level is commonly used as an index of sympathetic activity, and an elevated plasma NE level is associated with poor left ventricular function and mortality in heart failure.16 Concurrently measuring the principal metabolite of NE, 3,4-dihydroxyphenylglycol (DHPG), also provides insight into NE dynamics; specifically, the ratio of NE:DHPG helps to discern whether increased NE level is caused by sympathetic overactivation or blunted NE reuptake.17–19
The purpose of this study was to compare changes in plasma βARK1, NE, and DHPG levels between health-related quality of life clinical responders and nonresponders from pre– to post–LVAD implantation. We hypothesized that clinical responders would have greater reductions in plasma βARK1, NE, and DHPG levels from pre– to post–LVAD implantation compared with nonresponders.
This was a secondary analysis of a subset (n = 39) of biorepository data and plasma samples collected as part of a US National Institutes of Health–funded cohort study examining biobehavioral responses after continuous-flow LVAD placement (n = 101).20,21 Given limited resources, we were only able to measure sympathetic markers in a subset of plasma samples from the parent study. In the parent study, data and plasma samples were collected at baseline or pre–LVAD implantation (median of 4 days preimplantation) and at 1, 3, and 6 months post–LVAD implantation. Key inclusion criteria for the parent study were age 21 years or older, ability to read and comprehend fifth-grade English or Spanish, and eligibility for implantation of a commercially available, US Food and Drug Administration–approved continuous-flow LVAD as a bridge to transplantation/decision or as destination therapy. Potential participants were excluded if they had documented major cognitive impairment (eg, Alzheimer's disease), major psychiatric illness, previous heart transplantation, or mechanical circulatory support or if they had a concomitant terminal illness that impeded participation in a 6-month study. The participants were recruited through a single center in the Pacific Northwest between April 2012 and May 2016. Our institutional review board approved both this study and the parent study; written informed consent was obtained from all participants for the parent study and to have their data and samples stored in a deidentified biorepository for future research.
Sample of Clinical Responders and Nonresponders
To detect differences in sympathetic markers between clinical responders and nonresponders, we selected a subset of patients (n = 39) from the larger parent study who either had distinct clinical response from pre– to post–LVAD implantation (n = 19) or had distinct clinical nonresponse (n = 20). In the absence of a clear definition of clinical response to LVAD by health-related quality of life, we based our definition of response on clinically meaningful improvements on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score.22,23 The Kansas City Cardiomyopathy Questionnaire is an heart failure-specific measure of health status used to quantify physical limitation, symptoms, quality of life, social limitation, and self-efficacy.23 For the purposes of this study, and to focus on health-related quality of life, we used the Clinical Summary Score, which is a composite of the physical limitation, symptom, quality of life, and social limitation domains. Scores range from 0 to 100, with higher scores reflecting better health-related quality of life. Clinical response was defined by an increase of 5 points or higher on the Kansas City Cardiomyopathy Questionnaire Clinical Summary score between pre– and 6 months post–LVAD implantation. Clinical nonresponse was defined by less than 5 points increase or decrease on the Kansas City Cardiomyopathy Questionnaire Clinical Summary score between pre– and 6 months post–LVAD implantation and/or an average of lower than 45 across the 1, 3, and 6 months postimplantation time points.6,22
Sociodemographic and Clinical Data
Baseline data on age, gender, marital status, race, and education were obtained using a sociodemographic questionnaire. Baseline data on history, etiology, and treatment of heart failure, as well as New York Heart Association functional class, were collected through an in-depth review of the electronic medical record. Data were also collected on baseline clinical and laboratory characteristics, including parameters from echocardiographic assessments and from catheterization procedures of the right side of the heart. Comorbid conditions were summarized using the Charlson Comorbidity Index.24 Postimplantation treatment characteristics and events (infection, neurologic event, and hemorrhagic event) were recorded at 1, 3, and 6 months post–LVAD.
Plasma Sympathetic Markers
Whole blood was collected from participants and centrifuged at 2800 rpm for 10 minutes at 5°C to separate plasma, which was stored at −80°C. When ready to be processed, frozen plasma samples were thawed and centrifuged. We used a commercially available enzyme-linked immunosorbent assay (Cusabio, College Park, Maryland) to quantify plasma βARK1 based on a quantitative sandwich immunoassay technique according to the manufacturer's instructions. We ran samples in duplicate in parallel with a standard curve composed of known βARK1 concentrations (18.75–1200 pg/mL). After subtracting the blank readings and log transforming the concentrations, we used a sigmoidal 4-parameter logistic curve to quantify βARK1 in each of the samples as interpolated from the standard curve; mean values of the duplicates were reported. The potential range for plasma βARK1 level was 0 to 1200 pg/mL, but there is no identified cut point to indicate healthy levels. The average intra-assay coefficient of variation was 10.5%, and the interassay coefficient of variation was 21.2%.
We used high-performance liquid chromatography with electrochemical detection to measure the plasma catechols, NE, and DHPG, as previously described.25 Briefly, the internal standard, dihydroxybenzylamine, was added to plasma samples and to standards, and the catechols were prepurified by alumina extraction. The catechols were separated by reversed-phase chromatography on C18 column (Agilent Microsorb, 150 × 4.6 mm, 5 μm) using a filtered and degassed mobile phase (75 mM sodium phosphate (pH 3.0), 1.7 mM sodium octane sulfanate, 1.5% acetonitrile). An electrochemical detector (Coulochem III; ESA, Bedford, Massachusetts) was used to detect and quantify the catechols. We adopted an oxidation-reduction protocol (electrodes set to +300 mV, +150 mV, and − 350 mV based on previous research26) to eliminate a contaminating peak of uric acid that coeluted with DHPG. Uric acid was undetectable, and recoveries of both NE and DHPG in the plasma samples were adequate using this method.25 The potential range of plasma NE level is dependent on the assay method but generally averages about 0.5 to 3 pmol/mL18,27; plasma DHPG levels are about 5 to 6 times higher than plasma NE levels.18 In each of the assays, we also included samples of deidentified pooled plasma stored from healthy volunteers as a comparison. The average intra-assay coefficient of variation was 5.3%, and the interassay coefficient of variation was 4.6%.
Standard descriptive statistics of frequency, central tendency, and dispersion were used to describe the sample. Raw values of plasma βARK1, NE, and DHPG levels were natural log-transformed to approximate normality; both raw values and log-transformed values were used in analyses. We used traditional comparative statistics (ie, Student t, Mann-Whitney U, Fisher exact, or the Pearson χ2 tests) to compare differences in clinical characteristics between clinical responders and nonresponders at baseline and differences in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores, logβARK1, logNE, logDHPG, and logNE:logDHPG ratio at each time point. The Pearson χ2 test (or Fisher exact tests with small cell sizes) was used to compare treatment and event rate characteristics between clinical responders and nonresponders postimplantation.
We used latent growth curve modeling to quantify trajectories in raw values of the sympathetic markers (ie, βARK1, NE, and DHPG and the ratio of NE:DHPG) between clinical responders and nonresponders. Latent growth curve modeling allows for the estimation of interindividual variability in intraindividual patterns of change using latent intercepts (ie, the preimplantation values) and latent slopes (ie, rate of change over 6 months).28 Although originally developed in the social sciences, latent growth curve modeling has been applied to other areas such as the study of biomarkers.29 It is particularly robust in situations with missing data, unequally spaced time points, nonlinear trajectories, and nonnormally distributed repeated measures. In our analysis, we used a known group growth model to compare changes in sympathetic markers (ie, mean intercepts and mean slopes) between clinical responders and nonresponders. Scores on the Kansas City Cardiomyopathy Questionnaire Clinical Summary were available for the patients at every time point; however, plasma samples were not available for 5 participants at the 6-month time point. Full information maximum likelihood estimation was used to handle these missing data for the trajectories. Significance was set at α < .05. With a minimum sample size of 38 (19 in each group) and an α of .05, we were powered at 0.80 to detect a Cohen d greater than 0.95 (large effect size) using a Student t test between clinical responders and non-responders. GraphPad Prism 7.0 (GraphPad Software, San Diego, California) was used to interpolate the βARK1 levels based on standard curves and to prepare the figures. All other analyses were performed using Stata/MP v.15 (StataCorp LLC, College Station, Texas) and MPlus v.8 (Muthén & Muthén, Los Angeles, California).
The young, mostly male sample had primarily nonischemic heart failure etiology (primarily idiopathic dilated cardiomyopathy), and most were implanted as a bridge to transplantation (Table 1). The sample had, on average, between 2 and 3 comorbidities, and about half the sample had concurrent atrial fibrillation. Patients had, on average, high filling pressures and low ejection fractions, and most were treated with evidence-based therapies at baseline. There were significant differences in body mass index and plasma N-terminal pro-B-type natriuretic peptide level between clinical responders and nonresponders, and more clinical responders had preoperative intra-aortic balloon pump support; otherwise, the remaining clinical characteristics were similar between groups at baseline.
Postimplantation, there were no significant differences in treatment characteristics or event rates. By 6 months postimplantation, 73.7% of clinical responders and 70.0% of nonresponders were being treated with a β-blocker (χ2 = 0.07, Fisher exact P = 1.00), and 84.2% of clinical responders and 65.0% of nonresponders were being treated with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (χ2 = 1.89, Fisher exact P = .27). There were no deaths in either group postimplantation. By 6 months postimplantation, there were no significant differences between clinical responders and nonresponders in infection rates (26.3% vs 40.0%; χ2 = 0.82, Fisher exact P = .50), neurological events (5.3% vs 10.0%; χ2 = 0.31, Fisher exact P = 1.00), or hemorrhagic events (15.8% vs 20.0%, χ2 = 0.12, Fisher exact P = 1.00).
Clinical responders had significantly lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores at baseline compared with nonresponders (40.3 ± 16.5 vs 62.6 ± 19.9, P < .001). Because of our study design, clinical responders had significantly higher Kansas City Cardiomyopathy Questionnaire Clinical Summary scores at 1 month (73.8 ± 19.0 vs 48.4 ± 21.1, P < .001), 3 months (81.7 ± 12.5 vs 62.7 ± 15.8, P < .001), and 6 months (83.0 ± 13.9 vs 57.4 ± 15.7, P < .001) post–LVAD implantation compared with nonresponders. In latent growth curve modeling, the change (slope) in scores was also significantly different between the groups (Figure 1).
Clinical responders had significantly lower plasma logβARK1 levels compared with clinical nonresponders at the preimplantation (P = .001) and 6 months post–LVAD implantation (P = .01) time points (Table 2). In latent growth curve modeling, we found that preimplantation plasma βARK1 level (intercept) was significantly lower in clinical responders compared with nonresponders (z = −3.201, P = .001), but change (slope) in plasma βARK1 level over time was not significantly different between the groups (z = −1.187, P = .235) (Figure 2).
There were no significant differences in plasma logNE between clinical responders and nonresponders at any of the time points (Table 2), and the latent growth curve modeling intercepts (z = 0.895, P = .371) and slopes of changes (z = −0.861, P = .389) were not significantly different (Figure 3A). There were, however, significant differences in plasma logDHPG levels at preimplantation (P = .003), 1 month post–LVAD implantation (P = .003), and 6 months post–LVAD implantation (P = .01) (Table 2). In latent growth curve modeling, we found that preimplantation plasma DHPG level (intercept) was significantly higher in clinical responders compared with nonresponders (z = 3.149, P = .002), but change (slope) in plasma DHPG level over time was not significantly different between the groups (z = 0.150, P = .881) (Figure 3B). Interestingly, the DHPG levels in the clinical responders were closer to our healthy plasma comparison. There were no significant differences in plasma logNE:logDHPG ratio between clinical responders and nonresponders at any of the time points (Table 2), and the latent growth curve modeling intercepts (z = −1.000, P = .317) and slopes of change (z = −1.496, P = .135) were not significantly different (Figure 3C). The NE:DHPG ratio for clinical responders, however, more closely approximated the healthy plasma NE:DHPG ratio compared with the nonresponders (Figure 3C).
The purpose of this study was to examine changes in sympathetic markers in relation to clinical response after LVAD implantation, based on a health-related quality of life metric, as a way to begin pinpointing pathophysiological processes underlying better or worse response after LVAD. Our key findings were as follows: (1) clinical responders have significantly lower preimplantation plasma βARK1 and higher plasma DHPG (the primary metabolite of NE) levels compared with nonresponders to LVAD and (2) the differences in plasma βARK1 and DHPG levels between clinical responders and nonresponders at preimplantation are maintained through 6 months post–LVAD implantation. These differences potentially signal differing levels of sympathetic activation in relation to clinical response that can be identified at preimplantation.
There was a clear differentiation in the trajectories of plasma βARK1 levels between clinical responders and nonresponders, which is in line with our previous work that showed that higher plasma βARK1 levels are associated with worse physical heart failure symptoms.15 Among clinical responders to LVAD, βARK1 levels started low and remained low through 6 months post–LVAD implantation. On the other hand, among clinical nonresponders to LVAD, βARK1 levels started high and remained high through 6 months post–LVAD implantation. This finding indicates that the preimplantation βARK1 level may be the most informative data point in predicting who will have a better clinical response. In other words, if the βARK1 level is low preimplantation, then it will likely remain low through 6 months post–LVAD implantation and, without considering other variables, could be associated with improved health-related quality of life.
The significant differences in plasma DHPG levels between clinical responders and nonresponders, coupled with nonsignificant differences in plasma NE levels, could indicate blunted NE reuptake, as previously noted by Eisenhofer et al.18 Notably, even though clinical responders had higher plasma DHPG levels at every time point, their levels more closely approximated our healthy plasma reference line. Additionally, the ratio of NE:DHPG in clinical responders was closer to the ratio of NE:DHPG observed in healthy plasma compared with nonresponders, although the difference in trajectories was not statistically significant. Because DHPG arises from deamination of NE by monoamine oxidase, we can use the ratio to identify whether there is increased sympathetic stimulation (NE:DHPG ratio remains constant) or whether there are problems with NE reuptake (NE:DHPG ratio increases).19 If similar results are found in larger prospective studies, the ratio of NE:DHPG could be helpful in identifying the lack of NE reuptake as underlying poor clinical response.
Clinically speaking, higher plasma βARK1 levels, lower plasma DHPG levels, and higher NE:DHPG ratios may signal chronic sympathetic dysregulation in this group of clinical nonresponders compared with a group of clinical responders. Despite being on similar therapies at baseline, the clinical nonresponders have a significantly different sympathetic profile, compared with the clinical responders, and the difference in sympathetic profiles did not change with LVAD implantation. These findings indicate that this group of clinical nonresponders, who had poor health-related quality of life post–LVAD implantation, also had a higher level of sympathetic overactivation and dysregulation, which was not mitigated post–LVAD implantation. Given these preliminary signals, it would be worthwhile to explore sympathetic dysregulation, in part, as underlying patient-reported outcomes, including symptoms and health-related quality of life.30
Chronic sympathetic stimulation is a hallmark of heart failure pathophysiology and a target for heart failure therapies such as beta-blockade.10 However, the exact mechanisms for the sympathetic changes that occur after implantation of a continuous-flow LVAD are unclear, particularly given the loss of pulsatility that could affect baroreceptor unloading.31 Markham et al32 showed that patients with nonpulsatile LVADs had higher muscle sympathetic nerve activity than patients with pulsatile LVADs despite similar hemodynamic and medical therapy profiles. Grosman-Rimon et al27 recently demonstrated that NE levels remain elevated after implantation of a continuous flow LVAD and are similar to those of heart failure controls. We have taken this 1 step further and showed that although overactivation of the sympathetic nervous system persists post–LVAD implantation, there is a different sympathetic profile between clinical responders and nonresponders, using a patient-reported outcome metric. Our findings show that there is a graded difference in sympathetic dysregulation, which may help to pinpoint 1 potential mechanism underlying stagnantly poor health-related quality of life post–LVAD implantation.
There are a few noted limitations to this study. First, this was a small sample of clinical responders and nonresponders, and we were likely underpowered to detect some significant differences. Despite the small sample size, however, our analysis identified a signal of 2 sympathetic biomarkers that track with health-related quality of life among patients with LVAD and can provide a starting point for further research. Moreover, the small sample size precluded the inclusion of time-varying covariates such as plasma N-terminal pro-B-type natriuretic peptide. Future research should account for other factors that may influence pre– and post–LVAD implantation health-related quality of life and sympathetic markers, including the Interagency Registry for Mechanically Assisted Circulatory Support score and implant strategy. Second, this sample was composed of mostly male non-Hispanic whites with a nonischemic heart failure etiology from 1 advanced heart failure clinic in the Pacific Northwest. Given the known gender and racial differences in heart failure etiology, presentation, and patient-reported outcomes, these findings may not be generalizable to the advanced heart failure population at large. Third, it is important to note that regulation of sympathetic activity is complex, and we did not assess other inputs to sympathetic activation. Future research should examine other techniques to assess sympathetic activity (eg, measuring NE kinetics33 or microneurography34). Finally, while the Kansas City Cardiomyopathy Questionnaire has been well validated and used extensively among patients with heart failure in general, there is no gold standard measure to assess health-related quality of life in patients with LVAD, a group of patients with unique concerns and burdens.35
In addition, future research should prospectively investigate changes in these and other sympathetic markers in a larger cohort of patients with advanced heart failure receiving an LVAD. If future work supports the finding that sympathetic markers underlie differing health-related quality of life trajectories, it may be possible to identify clinical interventions that target sympathetic overactivation (eg, pharmacological, exercise, and/or self-care interventions10,36,37) as a means to improve health-related quality of life post–LVAD implantation. Additionally, future research should focus on identifying and building a multimarker profile that will further differentiate those who are likely to have poor health-related quality of life post–LVAD implantation. Specifically, future work should examine the role of traditional markers like N-terminal pro-B-type natriuretic peptide along with novel markers in predicting better or worse response. Finally, clinical responders in this sample had significantly lower health-related quality of life preimplantation and therefore had more room for improvement postimplantation compared with clinical nonresponders; as such, future research should dissect apart the reason certain groups of patients start at varying degrees of health-related quality of life preimplantation.
In this study, we provided preliminary evidence that sympathetic markers differentiate health-related quality of life clinical responders compared with nonresponders after continuous-flow LVAD implantation. With the movement toward understanding changes in patient-reported outcomes comes the need to understand the biological mechanisms underlying these patient-reported outcomes. These findings help lay the foundation toward improving patient-reported outcomes for patients undergoing LVAD implantation.
What’s New and Important
- Health-related quality of life can be used as a metric of clinical response after LVAD implantation.
- Two sympathetic markers (plasma βARK1 and DHPG) were different between clinical responders and nonresponders.
- Preimplantation differences in plasma βARK1 and DHPG persisted through 6 months postimplantation.
The authors would like to thank Antoinette Olivas, BA, for assisting with the sympathetic marker assays.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved
β-adrenergic receptor kinase-1; health-related quality of life; left ventricular assist device; norepinephrine; sympathetic nervous system