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Adult Circulatory Support

Association Between Neurohormone Levels and Exercise Testing Measures in Patients with Mechanical Circulatory Supports

Grosman-Rimon, Liza*; Kachel, Erez; McDonald, Michael A.; Lalonde, Spencer D.*; Yip, Paul§; Ribeiro, Roberto V.P.*; Adamson, Mitchell B.*; Cherney, David Z.; Rao, Vivek*

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doi: 10.1097/MAT.0000000000001082
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Abstract

Surgical implantation of a continuous-flow left ventricular assist device (CF-LVAD) is a standard treatment option for eligible patients with advanced heart failure (HF). However, despite the improvement of cardiac output with circulatory support, CF-LVAD recipients often exhibit significantly low exercise capacity measured as peak oxygen uptake (VO2).1 Other cardiopulmonary exercise testing (CPT) measures such as peak oxygen pulse (O2 pulse), heart rate recovery (HRR), and chronotropic responses in HF are also impaired and are commonly used as predictors of clinical outcomes and survival.2–5

In addition, there is increasing evidence that long-term nonpulsatile blood flow, as provided by CF-LVAD, is associated with increased levels of neurohormones, such as norepinephrine (NE) and aldosterone (Aldo), from the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), respectively.6,7 Indeed, in patients supported with CF-LVADs, NE and Aldo levels are abnormally elevated despite restoration of hemodynamic functions.8,9 High levels of both NE and Aldo are associated with increased mortality in the setting of HF.10,11 In fact, infusion of NE was shown to impair oxygen utilization.12 Although the relationship between NE and peak VO2 remains unclear.13–18 NE levels are associated with reduced chronotropic responses.14,18,19 For Aldo, limited data are available describing the relationships between Aldo levels and peak VO213,17; blockade of Aldo has been shown to improve exercise tolerance and increase peak VO2.20 Furthermore, studies in animal models have demonstrated a positive association between Aldo and chronotropic responses.21,22 To date, the relationships between peak VO2, chronotropic responses, and the levels of both NE and Aldo have not been investigated in HF patients with CF-LVAD.

Accordingly, our objective was to assess CPT measures and their association with NE and Aldo levels in CF-LVAD recipients. Ultimately, a more comprehensive understanding of the relationship between exercise measures and neurohormonal activation may provide important insights into mechanisms underlying functional capacity in CF-LVAD recipients. Furthermore, this may reveal neurohormones as prognostic markers in this setting.

Methods

Study Participants

The study protocol was approved by the University Health Network Ethical Review Board. Patients were recruited from the Heart Function Clinic at Toronto General Hospital. Informed consent was obtained from all study participants. Fifteen HF patients who were at least 3 months post–CF-LVAD implantation participated in the study, either as destination therapy or bridge to transplantation. Patients underwent medical screening before participation, and detailed medical histories were obtained. Patients’ medical histories were reviewed, and the etiology of HF was recorded, including ischemic and nonischemic cardiomyopathy. Inclusion criteria for HF patients who were candidates for CF-LVAD were (1) New York Heart Association (NYHA) class IV, (2) medically refractory, and (3) ejection fraction < 25%. The exclusion criteria were (1) physical inability to perform CPT on the cycle ergometer or the treadmill, (2) musculoskeletal limitations likely to interfere with exercise, (3) severe chronic obstructive pulmonary disease, (4) renal failure (glomerular filtration rate < 30 ml/min/1.73 m2), (5) recent embolism (within the last 3 months), (6) right ventricular failure, (7) liver failure (total bilirubin > 2 mg/dL), and (8) active infection.

Cardiopulmonary exercise testing.

Symptom-limited CPT on a treadmill, using the modified Bruce protocol was performed in CF-LVAD recipients. Breath-by-breath analysis of expired air was obtained and averaged every 30 seconds by a calibrated computerized metabolic cart (Medgraphics Cardi O2 Ultima, Minneapolis, Minnesota). Oxygen uptake (VO2), peak VO2, percent predicted VO2 max, carbon dioxide production (VCO2), minute ventilation (VE), VE/VCO2 slope, and the ventilatory anaerobic threshold (VO2 VAT) using the V-slope method and respiratory exchange ratio (RER) were calculated online. The ventilatory anaerobic threshold (AT) was determined using the V-slope method. Heart rate (HR) was recorded continuously from 12 lead electrocardiograms (ECG) at rest, during exercise, and during the 5 minutes of recovery phase. Abnormal autonomic function assessed as attenuated 1 minute HRR after exercise cessation (> 12 peak HR – 1 minute HRR). Peak O2 pulse, a measure of oxygen extraction per heart-beat and a combined measure for stroke volume and peripheral oxygen extraction during exercise, was calculated (peak VO2/HR). Chronotropic incompetence (CI) was calculated ([peak HR/ 220 – age] × 100) and defined as failure to achieve maximal HR of greater or equal to 85% of the age-predicted maximal HR.23

Biochemical assays.

Resting blood samples were obtained and collected in chilled tubes containing ethylendiaminetetraacetic acid (EDTA). All blood samples were collected before performing the exercise testing on the same day. Samples were centrifuged at 2056g for 15 minutes at 4°C and plasma was stored at −80°C until analysis. Concentrations of all neurohormones were measured in duplicate. For analysis of NE, the internal standard (3,4 dihydroxybenzylamine hydrobromide) was added, and the catecholamines were adsorbed onto aluminum oxide. The aluminum oxide was washed with Sodium EDTA and catecholamines were eluted with 0.1 M HClO4. This catecholamine rich eluent was separated by a WATERS 2695 HPLC system (Milford, MA) using reverse-phase chromatography on a Spherisorb ODS2 Column (Milford, MA). The catecholamines were quantitated by electrochemical detection. Standards for NE and the internal standard were purchased from Sigma and prepared in 0.1 M HClO4. Aldo measurement was performed on the DiaSorin LIAISON (Sallugia, Italy) analyzer using manufacturer’s reagents (Saluggia, Italy). The method for the quantitative determination Aldo assay was a competitive assay that used sheep monoclonal antibody for capture of the Aldo molecule, using chemiluminescence immunoassay technology.

Statistical analysis.

All statistical analyses were performed using the statistical package SPSS (Version 22.0. IBM Corp, Armonk, NY).

A Spearman rank correlation coefficient was performed to examine the relationship between the levels of neurohormone and exercise capacity. Data were presented as median and 25th–75th interquartile range (IQR) and percentages. Univariate linear regression analysis was performed to assess the association of each CPT measures, Aldo, and NE with exercise capacity levels. A p value ≤ 0.05 was considered statistically significant.

Results

All 15 CF-LVAD recipients were clinically stable, and eight were men. Patients’ characteristics are described in Table 1. Eight CF-LVAD recipients were implanted with HeartMates and seven with Heartwares. Patients had adequate HRR values after exercise cessation. O2 pulse (7.6 ml/beat) and VO2 VAT (7.6 ml/kg/min) were considered lower than normal. Peak VO2 (13.5 ml/kg/min) and age and sex percent predicted VO2 max (50.0%) were lower than normal. VE/VCO2 slope value (36.0) was clinically considered elevated. Patients were on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocker, β-blocker, mineralocorticoid receptor antagonists (Table 1).

Table 1. - Characteristics and Exercise Testing Outcomes of Patients With CF-LVAD Support
Characteristics CF-LVAD Recipients (n = 15)
Age (years) 51.0 (44.2–61.7)
Height (cm) 175.0 (162.7–181.5)
Weight (kg) 72.4 (64.7–81.9)
Norepinephrine (nmol/L) 2.9 (1.9–3.9)
Aldosterone (pmol/L) 1073.5 (336.5–2085.0)
Peak VO2 (ml/kg/min) 13.5 (11.5–15.5)
Predicted VO2 max (%) 50.0 (43.0–59.0)
Resting HR (bpm) 78.0 (70.0–84.0)
Peak HR (bpm) 107 (101.0–143.0)
HR reserve (%) 52.7 (29.1–70.6)
Predicted max HR (%) 67.0 (58.8–85.0)
Oxygen pulse (ml/beat) 7.6 (6.6–10.3)
HRR 1 min (bpm) 94.0 (80.0–106.0)
HR (peak- recovery) (bpm) 18.0 (7.0–32.0)
RER, ratio 1.09 (1.04–1.12
Peak VO2 AT (ml/kg/min) 7.6 (7.0–9.2)
Time to Exercise (min) 7.8 (5.1–8.5)
VE/VCO2 36.0 (31.0–39.0)
Pace makers (%) 73 (n = 11)
Statin (%) 36 (n = 5)
β-blockers (26 mg) (%) 57 (n = 8)
ACE inhibitors (5.5 mg) (%) 71 (n = 10)
ARBs (50 mg) (%) 7 (n = 1)
Aldosterone antagonist (23 mg) (%) 93 (n = 13)
Warfarin (4.5 mg) (%) 93 (n = 13)
Aspirin, mg) (%) 100 (n = 14)
Calcium channel blocker (5 mg) (%) 7 (n = 1)
Furosemide (50 mg) (%) 64 (n = 9)
Amiodarone (230 mg) (%) 57 (n = 8)
Digoxin (0.1 mg) (%) 14 (n = 2)
Hydralazine (45 mg) (%) 21 (n = 3)
Sildenafil (75 mg) (%) 21 (n = 3)
Data presented as median and 25th–75th (IQR) and percentages. Medication doses presented as average.
ACEs, angiotensin-converting enzymes; ARB, angiotensin receptor blockers; AT, anaerobic threshold; CF-LVAD, continuous-flow left ventricular assist device; HR, heart rate; HRR, heart rate recovery; IQR, interquartile range; RER, respiratory exchange ratio; VE/VCO2, minute ventilation/carbon dioxide output.

Age was negatively associated with relative peak VO2 ml/kg/min (r = −0.85, p < 0.01) and absolute peak VO2 L/min (r = −0.52, p = 0.04) (Figure 1, A and B). The levels peak VO2, L/min positively correlated with exercise time (r = −0.85, p < 0.000), indicating that patients who had the highest peak VO2 had the longer time to exercise. Advancing age was associated with lower exercise time (r = −0.52, p = 0.04).

Figure 1.
Figure 1.:
A and B. The relationships between peak VO2 and age of CF-LVAD recipients. A and B, There were significant negative relationships between absolute (L/min) and relative (ml/kg/min) peak VO2 and the age of CF-LVAD recipients. The solid line represents line of best fit. CF-LVAD, continuous-flow left ventricular assist device.

The Relationship Between NE Levels and Exercise Measures

The median levels of resting NE were 2.9 nmol/L, ranging from 0.9 to 5.6 nmol/L. The NE levels modestly correlated with chronotropic responses, measured as the percentage of the ratio of achieved peak HR to the age-predicted maximal HR (r = 0.61, p = 0.01) (Figure 2A) and with HRR (r = 0.57, p = 0.02) (Figure 2B). NE levels negatively correlated with peak VO2 AT (r = −0.57, p = 0.02) (Figure 2C). NE levels also modestly negatively correlated with O2 pulse values (r = −0.53, p = 0.03). There was no association between NE and VE/VCO2.

Figure 2.
Figure 2.:
The relationships between norepinephrine levels and chronotropic responses, HR Recovery, and VAT-VO2 in CF-LVAD recipients. A, B, and C, The levels of NE (nmol/L) were positively correlated with chronotropic responses and HR recovery and negatively correlated with peak VO2 AT (L/min) and oxygen pulse in CF-LVAD recipients. The solid line represents line of best fit, and the dashed-line represents line of best fit after sensitivity analysis. CF-LVAD, continuous-flow left ventricular assist device; HR, heart rate; NE, norepinephrine; VO2 VAT, ventilatory anaerobic threshold.

The levels of O2 pulse were modestly associated with peak VO2 ml/kg/min (r = 0.57, p = 0.02) and peak VO2, L/min (r = 0.89, p < 0.001) (Figure 3A and 3B).

Figure 3.
Figure 3.:
The relationships between peak VO2 and oxygen pulse of CF-LVAD recipients. A and B, There were significant positive relationships between absolute (L/min) and relative (ml/kg/min) peak VO2, and oxygen pulse in CF-LVAD recipients. The solid line represents line of best fit. CF-LVAD, continuous-flow left ventricular assist device.

Regression analysis revealed that O2 pulse is an independent predictor of peak VO2 (F=20.9, standardized β coefficient = 0.85, R2 = 0.72, p < 0.001), but chronotropic responses and NE did not predict peak VO2.

Aldo levels in CF-LVAD recipients were not related to any of the CPT measures.

Discussion

CPT reveals that CF-LVAD recipients had impaired exercise capacity, low O2 pulse, and elevated VE/VCO2 slope. CPT is an established method for evaluating the severity of HF and peak VO2 and is used in risk stratification.3 Moreover, an anaerobic threshold 11 ml/kg/min is a predictor of early death with a 5.3 fold-increased risk.24 A peak O2 pulse of <10 ml/beat is also a strong independent predictor of clinical events and cardiac mortality in HF patients.5 Furthermore, an abnormally high ventilator parameter of VE/VCO2 >34 is also associated with a worse prognosis in chronic HF patients.2

Additional prognostic measures of CPT are related to autonomic functions and control of HR. In this study, CF-LVAD recipients exhibit adequate HRR but chronotropic responses were impaired. HR recovery, which is considered to be a function of parasympathetic nervous system reactivation and a marker of vagal activity, is a powerful predictor of mortality in HF patients.25 Our findings suggest that parasympathetic reactivation and vagal activity was adequate. However, in this study, CF-LVAD recipients exhibited CI. Peak HR response to exercise is determined by withdrawal of vagal tone, the magnitude of increase in sympathetic outflow to the heart,26 and the sensitivity of the sinoatrial node to the catecholamine NE.14 In fact, impaired chronotropic responses to exercise is independently predictive of cardiac mortality and all-cause mortality.27

The mechanisms for CI in HF is explained by a chronic increase in catecholamine levels, which leads to a decrease in β1-adrenergic receptor density and sensitivity.28 We previously documented a significant but modest improvement in chronotropic responses following CF-LVAD implantation from HF baseline levels.1 In our study, NE levels were associated with increased HR levels, suggesting that some β1-adrenergic receptor responsiveness may be restored following CF-LVAD implantation. Nevertheless, despite this modest improvement, HR reserve did not normalize, and chronotropic responses were well below 80% predicted maximal value in patients with CF-LVAD.

The main findings were that NE levels negatively correlated with VO2 AT and O2 pulse values, but not with peak VO2. The levels of NE were positively correlated with chronotropic responses and with HR recovery. In addition, O2 pulse was significantly positively correlated with peak VO2, but chronotropic responses were not associated with peak VO2. Taken together, since O2 pulse represents peak VO2 corrected for HR, based on the Fick Equation, chronotropic responses may not be the primary factor for the low peak VO2 in CF-LVAD recipients. This suggests that the limiting factors for peak VO2 in this patient population may be arteriovenous oxygen difference, and stroke volume, which its maximal increase during peak exercise is already limited by the amount of blood that is pumped by the CF-LVAD. Importantly, during peak exercise in patients with CF-LVAD the pump flow increases as a function of change in preload and afterload29 to accommodate approximately up to 13.0 L/ min.30 Unlike healthy normal individuals of whom the cardiac output increases from rest to peak exercise four to six fold, from 5 L/ min at rest to 20–30 L/ min at peak exercise, patients with CF-LVAD, flow output increases only up to about 10–13 L/ min. Thus, limited pump output may limit exercise capacity in CF-LVAD recipients.

The pathophysiological mechanisms responsible for severe exercise intolerance in HF patients are related not only to central abnormalities (impaired cardiac function and CI – an inadequate increase in HR from rest to exercise) but also to peripheral abnormalities. This may include factors that affect arteriovenous oxygen difference, such as impaired skeletal muscle blood flow or endothelial dysfunction. Elevated NE may contribute to impaired vasodilatory capacity, limiting blood flow to exercising muscles. NE has not only inotropic and chronotropic effects in the heart through β1 adrenergic receptors, but in the vasculature, it increases vasoconstriction through α1 and α2 adrenergic receptors31 which potentially decreases blood to the exercising muscle. Indeed, a low-dose NE infusion in HF patients was shown to result in a modest impairment in oxygen utilization that may contribute to exercise tolerance in these patients.12 Thus, NE may contribute to impaired exercise capacity in CF-LVAD by reducing vasodilatory capacity and blood flow to the exercising muscles. Future studies should assess the role of the peripheral circulation in the pathogenesis of impaired elevation of exercise tolerance in patients supported by CF-LVAD. Norepinephrine levels may be elevated as a result of activation of the SNS in CF-LVAD recipients, which may be attributed to the low pulsatile blood flow. In fact, reductions in pump speed increase pulse pressure, distension of the carotid artery, and reduce muscle sympathetic nerve activity.32

In HF patients, resting plasma NE is also a marker for the severity of disease measured by hemodynamic response. However, findings on the relationship between NE and exercise capacity in HF are conflicting. Several studies reported negative correlations between resting NE levels with peak VO2,14,15 whereas other studies reported a positive correlation between resting supine NE and peak VO216 and the ratio of the change of HR/log NE levels immediately after exercise but not resting levels.18 Other studies showed no significant correlation between peak VO2 and NE.13,17 Consistent with these previous observations, in our CF-LVAD recipient cohort, we also did not find an association between the levels of NE and peak VO2. Notably, in one study treatment with clonidine markedly suppressed NE levels during exercise and was associated with increased leg blood flow and reduced leg vascular resistance during exercise, but maximal systemic VO2 was unchanged.33 In this study, we did not measure blood flow and or vascular function. Future studies should investigate the association between NE blood flow and vascular resistance.

Systemic NE levels appear to be negatively correlated with chronotropic responses in HF patients.14,18,19 In contrast, our findings showed a positive association between NE and chronotropic responses. Studies have demonstrated blunted chronotropic responses to exercise in CF-LVAD recipients.1,34 However, a modest but significant improvement in chronotropic responses following CF-LVAD implantation has been documented,1 suggesting that to some extent, these patients may regain β1-adrenergic receptor responsiveness. This may explain the high levels of NE and the positive association with peak VO2. Further research is required to clarify the association between NE and chronotropic responsiveness in CF-LVAD recipients.

Limited data are available on the relationships between peak VO2 and Aldo levels. Some studies in HF showed no association between peak VO2 and resting Aldo levels immediately after exercise.13,17 Whereas one study observed a negative correlation between peak VO2 and Aldo levels in patients with HF,15 another study showed that Aldo blockage improved peak VO2.20 Studies in animal models have reported a positive association between Aldo and chronotropic responses.21,22 In our study, no associations were observed between Aldo levels and exercise measures. Our observations suggest that Aldo may not be responsible for impaired exercise capacity.

The major limitations of the study are that we did not measure peripheral determinants of peak VO2 such as vasodilatory capacity and skeletal muscle blood flow. Future studies should assess the contribution of peripheral determinants to impaired exercise capacity in these patients. In addition, our study was a relatively small single-center study, and we used surrogate outcomes for determining factors that are responsible for the impaired peak VO2, such as O2 pulse. Additional limitations are that we did not assess cardiac output and device flow during the exercise testing. Future studies may modify CF-LVAD flow during exercise testing in CF-LVAD recipients and should assess whether different flow patterns—provided by axial versus centrifugal CF-LVAD—affects exercise testing and their relationship with neurohormones. Larger multicenter studies should investigate factors that contribute to exercise capacity limitation in CF-LVAD recipients.

In conclusion, CF-LVAD recipients exhibit impaired exercise capacity and CI. However, neither chronotropic responses nor NE predict peak VO2, suggesting that chronotropic responses may not be the primary factor responsible for the low peak VO2. O2 pulse, which is a combined measure for stroke volume and peripheral oxygen extraction during exercise,5 was found to be an independent predictor of peak VO2 in patients with HF. It is possible that in addition to peak blood flow output that is already limited by the pump, peripheral factors, such as vasodilatory capacity and muscle blood flow, may be responsible for impaired peak VO2 in CF-LVAD recipients. Future studies should focus on investigating the contribution of peripheral factors to exercise capacity limitations and whether exercise training improves vasodilatory capacity and blood flow to the exercising muscle.

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Keywords:

continuous-flow left ventricular assist device; neurohormones; exercise testing

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