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Exercise physiology, testing, and training in patients supported by a left ventricular assist device Renzo Y. Loyaga-Rendon, MD, PhD,a Eric P. Plaisance, PhD,b Ross Arena, PhD, PT,c and Keyur Shah, MDd From the aDivision of Cardiovascular Diseases; bDepartment of Human Studies, Center for Exercise Medicine, and Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, Alabama; cDepartment of Physical Therapy and Integrative Physiology Laboratory, College of Applied Sciences, University of Illinois at Chicago, Chicago, Illinois; and the dDivision of Cardiovascular Diseases, Virginia Commonwealth University, Richmond, Virginia.

KEYWORDS: left ventricular assist device; exercise capacity; exercise training; quality of life; heart failure

The left ventricular assist device (LVAD) is an accepted treatment alternative for the management of end-stage heart failure. As we move toward implantation of LVADs in less severe cases of HF, scrutiny of functional capacity and quality of life becomes more important. Patients demonstrate improvements in exercise capacity after LVAD implantation, but the effect is less than predicted. Exercise training produces multiple beneficial effects in heart failure patients, which would be expected to improve quality of life. In this review, we describe factors that are thought to participate in the persistent exercise impairment in LVAD-supported patients, summarize current knowledge about the effect of exercise training in LVAD-supported patients, and suggest areas for future research. J Heart Lung Transplant ]]]];]:]]]–]]] r 2015 International Society for Heart and Lung Transplantation. All rights reserved.

Heart failure (HF) exerts changes in multiple organ systems, leading to profound and progressive impairments in functional capacity (FC) and quality of life (QoL). Cardiac rehabilitation (CR) and exercise training are now accepted standards of care that produce multiple benefits in patients with HF.1–3 Mechanical circulatory support has evolved rapidly during the last decade, and the left ventricular assist device (LVAD) is now an established therapy for the management of end-stage HF.4,5 Continuous flow (CF) LVADs improve survival, FC, and QoL,6,7 and

Reprint requests: Renzo Y. Loyaga-Rendon, MD, PhD, Cardiovascular Diseases Division, University of Alabama at Birmingham, 321 Tinsley Harrison Tower, 1900 University Blvd, Birmingham Alabama, 352940006. Telephone: þ1-305-409-2863. Fax: þ1-205-934-3411. E-mail address: [email protected]

may become an alternative to heart transplantation (HTx).8 Clinical trials are ongoing to determine the efficacy of LVAD implantation in higher functioning HF patients. The increasing volume of implantations correctly forces scrutiny over the value of LVAD implantation on FC and QoL. Despite the hemodynamic support provided by LVAD, patients are unable to achieve a normal (i.e., age-predicted and sex-predicted values) aerobic capacity post-implantation. Therefore, developing a more thorough understanding of these limiting factors is a critical area for research in the field. Cardiac rehabilitation and exercise training in LVAD-supported individuals appear to be safe9; however, there are no specific exercise prescription guidelines for these patients. The purpose of this review is to: 1. describe changes in the physiology of exercise secondary to HF;

1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.12.006

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2. describe factors that are thought to participate in the persistent exercise impairment in LVAD supported patients; 3. summarize current knowledge regarding the impact of exercise training in patients supported by LVAD; and 4. identify knowledge gaps and areas for future research.

output (CO) during exercise, right ventricular (RV) dysfunction, chronotropic incompetence, impaired pulmonary function, skeletal myopathy, endothelial dysfunction, and anemia appear to play a synergistic role in the observed exercise intolerance (Figure 1).

Type of LVAD This review focuses predominantly on CF-LVAD, and pulsatile flow (PF)-LVAD is used in some areas for comparison. A PubMed English literature search was performed by one author (R.L.) using the keywords “LVAD and exercise,” “LVAD and rehabilitation,” “LVAD and peakVO2,” and “heart failure and exercise.” Relevance of original and review manuscripts was assessed for inclusion in this publication by all authors.

Physiologic responses to exercise in the presence of HF Exercise requires the coordinated response of multiple organ systems to ensure an adequate energy supply to meet increased metabolic demands and to eliminate associated metabolic end products. In healthy individuals, the hemodynamic changes during exercise occur without significant changes in filling pressures.10 Exercise intolerance due to dyspnea on exertion and fatigue is one of the earliest and most important HF symptoms. The adaptations to exercise and the pathophysiologic changes in the neurologic, cardiovascular, respiratory, and musculoskeletal systems that lead to exercise impairments with HF have been thoroughly described11–17 and are summarized in Table 1. Cardiopulmonary exercise testing (CPX) is a sophisticated yet non-invasive method to assess the physiologic response to exercise. A broad range of variables are captured, and several of them have been convincingly shown to accurately predict poor outcome in HF patients and are used to identify individuals who are in need of a HTx or LVAD implantation.18–21 CPX is also used as a gold standard to quantify improvement in FC after HF therapies, including devices such as cardiac resynchronization therapy.22 Another method for measurement FC is the 6-minute walk test (6MWT). Several studies have described the improvement in 6MWT distance in LVAD patients23 and described its usefulness as a predictor of poor outcome.24 However, the 6MWT measures submaximal exercise capacity, and although reproducible, is subjective and could be affected by other variables besides cardiovascular status.25 The improvement in FC measured by the 6MWT was reported recently,24,26 and in this review, we will focus on maximal exercise capacity as determined by CPX (Table 2).

Physiology of exercise with LVAD Although the benefits of LVAD support are unquestionable, patients still exhibit significant impairment in their ability to achieve a normalized maximal exercise capacity. Given the multiorgan damage caused by HF, the limitations to exercise in LVAD patients are also complex and multifactorial. Factors such as device type, inability to increase cardiac

Currently, PF-LVADs are seldom used as durable support but offer the opportunity to analyze the physiologic response to exercise and provide comparisons with CFLVADs. The PF-LVADs use a pneumatically/electrically driven ventricle that operates in the complete fill/empty mode. Thus, CO during exercise will increase as a function of preload and pump rate. PF-LVADs are afterload independent and produce a maximal CO (COmax) of 10 liters/min with a pump rate of 120 beats/min.27 On the other hand, the CF-LVAD is free of valves, unloads the ventricle both in systole and diastole, and operates at a fixed speed. The 2 types of CF-LVADs are axial and centrifugal. Pump flow varies according to the differential pressure between the inflow and outflow cannulas. The sensitivity of axial and centrifugal pumps to changes in preload is similar, whereas centrifugal pumps are more sensitive to after load .28 During exercise, pump flow increases in the CF-LVAD as a function of changes in preload and afterload. Mancini et al29 studied the hemodynamic responses during exercise in 20 patients supported by PF-LVADs. The CO was 4.9 ⫾ 0.9 liters/min at rest and increased with exercise to 11.2 ⫾ 2.6 liters/min, which was associated with a concomitant increase in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) from 5 ⫾ 3 to 14 ⫾ 6 mm Hg and from 3 ⫾ 3 to 8 ⫾ 4 mm Hg, respectively. Patients achieved a mean peak oxygen consumption (VO2) of 16 ⫾ 3.8 ml/kg/min. Haft et al30 compared the exercise hemodynamic responses between PF-LVAD and CF-LVAD. Resting central venous pressure, mean arterial pressure, and PCWP were similar in both groups. Peak VO2 was not different between groups (15 ml/kg/min, 48% of predicted), and pump flow increased in both groups. However, the increase in pump flow was greater in the PF-LVAD than in the CF-LVAD (4 ⫾ 0.5 vs 3.4 ⫾ 0.4 liters/kg/m2). The significance of this finding is unclear given the flow through for the CF-LVAD is not directly measured but estimated. A more recent report evaluated the hemodynamic response of 30 patients who received a CF-LVAD. Patients achieved a peak VO2 of 18 ⫾ 6.2 ml/kg/min (55% ⫾ 12% of predicted) and total COmax of 8.5 ⫾ 2.8 liters/min.31 Taken together, patients appear to achieve a similar peak VO2 independently of the type of LVAD, and although COmax increases with exercise, it does not reach levels observed in healthy individuals with normal cardiac function.

The effect of speed on LV unloading in CF-LVAD LV unloading is important during LVAD support, and as a result, device speed is adjusted to optimize LV unloading.

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Table 1 Adaptations and Changes of Physiologic Parameters With Exercise in Healthy, Heart Failure and Left Ventricular Assist Device– Supported Individuals Organ system Healthy individual Cardiovascular

      

↑ ↑ ↓ ↑ ↓ ↑ ↑

in HR in preload in afterload in contractility SVR CO (20 liters/min) in RR and VT

Heart failure       

LVAD

Chronotropic insufficiency ↑ in preload with ↑ in filling pressures ↑ afterload Impaired contractility ↑ SVR Inability to ↑ CO ↑ RR and VT

      

Respiratory

   

↑ VE ↓Physiologic dead space ↓PVR and ↑ in pulmonary artery capacitance ↑ muscle metabolism

         

Peripheral

(15 resting levels)  Predominant use of type I over type II fibers.  Increase in muscle flow due to local and neurogenic factors

    

Neural



↑ Sympathetic drive and parasympathetic withdrawal



↑ VE ↑ Physiologic death space ↓ Surface tension ↓ Respiratory muscle strength ↑ Airway congestion ↑ cardiac volume ↓ Lung distensibility ↑ PVR and ↓ in pulmonary artery capacitance Restrictive pattern (PFT) Switch from type I to type II muscle fibers.



Muscle atrophy and wasting ↓ Mitochondrial density Endothelial dysfunction, unable to increase blood flow to exercising muscle Muscle ischemia ↓ Oxygen diffusion to muscle



Overstimulation of sympathetic system through metaboloreceptors with increased in HR and SVR





 



  

Chronotropic insufficiency ↑ In preload with ↑ in filling pressures ↓ Afterload ↑ Contractility depending on LV function ↓ SVR ↑ CO, but not to normal levels Improvement in ventilatory function Improvement in ventilatory efficiency Improvement in respiratory muscle strength ↓ In PVR with LVAD support Unknown muscular function

Improvement in endothelial function Improvement in muscle flow with exercise

Preserved baroreflex activitya ↓ Plasma norepinephrine and dopamine levelsa Improvement in sympathetic functiona No studies evaluated neural function with exercise

CO, cardiac output; HR, heart rate; LV, left ventricle; LVAD, left ventricular assist device; PFT, pulmonary function test; PVR, pulmonary vascular resistance; RR, respiratory rate; SVR, systemic vascular resistance; VE, minute ventilation; VT, tidal volume. a Studies of neural function in LVAD patients were performed at rest not with exercise.

The effect of CF-LVAD speed on exercise capacity was assessed in 12 patients undergoing CPX for evaluation of myocardial recovery.32 Patients exercised at their usual LVAD speed and with minimal LV unloading (speed: 6,000 rpm). Hemodynamic variables at rest were similar, but with maximal exercise, peak VO2 was significantly lower in the reduced-speed group (14.1 ⫾ 5.3 vs 18.2 ⫾ 4.5 ml/kg/min). Recently, due to concerns of aortic regurgitation, some centers are reducing LVAD speed to allow intermittent opening of the aortic valve (AV). Camboni et al33 evaluated 8 patients in whom their LVAD (INCOR; Berlin Heart, Berlin Germany) speed was adjusted to allow normal AV function (speed, 6,800–7,100 rpm; flow, 4.0 ⫾ 0.3). From rest to maximal exercise, PCWP and RAP increased from

9 ⫾ 3.3 to 17 ⫾ 5.3 mm Hg and from 5 ⫾ 1.1 to 11 ⫾ 3.6 mm Hg, respectively, and patients achieved a low peak VO2 (12.2 ⫾ 2 ml/kg/min). These results highlight the importance of LV unloading and LVAD speed on exercise tolerance and the unintended effects on FC that may occur with changes in speed designed to improve aortic valve function or pulsatility. Brassard et al34 performed an elegant study in 8 CFLVAD patients who performed 2 CPX assessments: (1) a fixed-speed protocol and (2) an increased speed-protocol (increase of 400 rpm per each CPX stage). At maximal exercise, CO increased from 7 to 11.3 liters/min during the fixed-speed protocol and from 6 to 12.1 liters/min during the increased-speed protocol (difference not significant).

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4 Table 2

Studies Evaluating Functional Capacity by Cardiopulmonary Exercise Testing in Patients With Left Ventricular Assist Device

Publication

Study characteristics

Findings

Jaski (1997)

N: 10 Age: 47 ⫾ 7 years LVAD type: PF Support time: 46 ⫾ 25 days

CPX: Bicycle ergometer: Exercise time: 10.4 ⫾ 2.6 min, pVO2: 8.2 ⫾ 1.7. Exercise treadmill: pVO2 14.1 ⫾ 2.9 Hemodynamics: (with bicycle ergometer) Rest: RA: 6 ⫾ 4, mPA: 17 ⫾ 3, PCWP: 5.3, CO: 5 ⫾ 1.2, SVR: 1,478 ⫾ 369 Exercise: RA: 7.8 ⫾ 2.5, mPA: 21 ⫾ 7, PCWP: 13 ⫾ 8, CO: 7.8 ⫾ 2.5, SVR: 899 ⫾ 357 Echocardiography: Rest: LVEDD: 3.9 ⫾ 1.3, RVEDD: 3.2 ⫾ 1 Exercise: LVEDD: 4.8 ⫾ 1.6, RVEDD: 2.3 ⫾ 0.9 Comments: No evidence of RV failure as limiting factor in FC. Note the significant differences in pVO2 between type of CPX

Mancini (1998)

N: 20 Age: 50 ⫾ 9 years LVAD type: PF

CPX: Bicycle ergometer: pVO2: 16 ⫾ 3.8, AT: 12.1 Hemodynamics: Rest: HR: 95 ⫾ 15, MAP: 95 ⫾ 15, RA: 3 ⫾ 3, mPA: 18 ⫾ 4, PCWP: 5 ⫾ 3, CO: 4.9 ⫾ 0.9 Exercise: HR: 148 ⫾ 24, MAP: 92 ⫾ 12, RA: 8 ⫾ 4, mPA: 30 ⫾ 5, PCWP: 14 ⫾ 6, CO: 11.2 ⫾ 2.6 Comments: These patients had better hemodynamics and FC than HF patients

Support time: 2.6 months

George (2006)

N: 7 Age: 53 ⫾ 17.2 years

CPX: Bicycle ergometer: Exercise time: 11.9 min, pVO2: 14.4 ⫾ 3.7 Comments: These patients had repeated CPX after clembuterol treatment with no improvement in FC

LVAD type: HM-XVE (PF) Support time: 23.1 ⫾ 14.8 weeks Haft (2007)

N: 16 (HM-XVE), 18 (HM-II, axial) Age: 51 ⫾ 14 (HM-XVE), 52 ⫾ 14 (HM-II) years Support time: 3 ⫾ 0.5 months

CPX: Modified Naughton protocol XVE: Exercise time 10.25 ⫾ 3.04, pVO2: 15.4 ⫾ 4 (46.8% ⫾ 10.2%) HM-II: Exercise time: 9: 31 ⫾ 3.19, pVO2: 15.6 ⫾ 4.7 (49.1% ⫾ 4.7%) Hemodynamics: (at rest) XVE: CVP: 7 ⫾ 5, mPA: 20 ⫾ 8, PCWP: 10 ⫾ 5, CI: 2.9 ⫾ 0.7, RVSWI: 483 ⫾ 227, MAP: 83 ⫾ 11 HM-II: CVP: 3 ⫾ 0.8, mPA: 20 ⫾ 6, PCWP: 11 ⫾ 5, CI: 3 ⫾ 0.8, RVSWI: 480 ⫾ 143, MAP: 86 ⫾ 12 Echocardiography: XVE: LVEDD: 5.0 ⫾ 0.9 HM-II: LVEDD: 6.0 ⫾ 1.0 Comments: Patients had similar FC and hemodynamics either with HM-XVE or HM-II. LV unloading was better with HM-XVE

Andersen (2010)

N: 12 Age: 38 (20-65) years

CPX: Bicycle ergometer Hemodynamics: Rest: HR: 73 ⫾ 8, mPA: 19v 6, CO: 6.3 ⫾ 2.2 Exercise: HR: 131 ⫾ 23, mPA: 19 ⫾ 6, CO: 13 ⫾ 3 Echocardiography: Rest: LVEDD: 60 ⫾ 10, LVESD: 55 ⫾ 11, S’: 4.1 ⫾ 1.3, E’: 7.4 ⫾ 2.4, E/e’: 11.2 ⫾ 2.5

LVAD type: HM-II (axial) Support time: 299 (60-634) days

Exercise: LVEDD: 60 ⫾ 10, LVESD: 54 ⫾ 10, S’: 8.7 ⫾ 3.7, E’: 13.4 ⫾ 4.5, E/e’: 7.8 Comments: No changes in echocardiographic dimensions in the LV with exercise, increased E/e’ ratio Jakovljevic (2010) N: 12 Age: 33 ⫾ 13 years LVAD type: HM-II (axial) LVAD support time: 169 ⫾ 97 days Regular speed: 9,000–9,600 rpm Reduced speed: 6,000 rpm

CPX: Modified Bruce Protocol Regular speed: Exercise time: 628 ⫾ 192, pVO2: 18.2 ⫾ 4.5, VE/VCO2 slope: 35.5 ⫾ 4.6 Reduced speed: Exercise time: 516 ⫾ 119, pVO2: 14.1 ⫾ 5.3, VE/VCO2 slope: 41.3 ⫾ 7.1 Hemodynamics: Rest: Regular speed: MAP: 74.1 ⫾ 16.6, HR: 74 ⫾ 16, CO: 5.3 ⫾ 1.7 Reduced speed: MAP: 67.3 ⫾ 13.6, HR: 79 ⫾ 13, CO: 4.6 ⫾ 1.4 Exercise: Regular speed: MAP: 85.4 ⫾ 15.4, HR: 138.8 ⫾ 27, CO: 12.2 ⫾ 2.1 Reduced speed: MAP: 74.3 ⫾ 14.9, HR: 126 ⫾ 26, CO: 8.6 ⫾ 2.5

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Table 2 (Continued ) Publication

Study characteristics

Findings Comments: These patients had significant impairment of FC and hemodynamics with acute reduction of LVAD speed

Brassard (2011)

N: 30 Age: 39 ⫾ 18 years LVAD type: HM-II (axial) Support time: 329 ⫾ 190 days 9,775 rpm INCSpeed: 11,500 rpm FIXSpeed:

Noor (2012)

N: 30 Age: 35 ⫾ 13 years

LVAD type: HM-II (axial) Support time: 4 6 months

Liebner (2013)

N: 57 Age: mean 59.4-63.9 years LVAD type: HM-II (axial) and HVAD (centrifugal) Support time: 3-6 months, 1 year, 4 1 year

Kerrigan (2013)

N: 26 Age: 55 ⫾ 13 years LVAD type: HM-II 20 (axial) HVAD 6 (centrifugal). Support time: 82 ⫾ 38 days

Martina (2013)

Dunlay (2014)

N: 30 Age: 43 ⫾ 14 LVAD type: HM-II (axial)

CPX: Bicycle ergometer Exercise time: 698 ⫾ 270 sec Speed: Exercise time: 700 ⫾ 300 sec INC Hemodynamics: Rest: FIXSpeed: HR: 75 ⫾ 12, mPA: 20 ⫾ 7, CO: 7 ⫾ 0.9 INCSpeed: HR: 76 ⫾ 7, mPA: 18.8 ⫾ 8, CO: 6 ⫾ 2.1 Maximal exercise: FIXSpeed: HR: 129 ⫾ 24,mPA: 29 ⫾ 12, CO: 13.6 ⫾ 2.5 INCSpeed: HR: 129 ⫾ 25, mPA: 29 ⫾ 14, CO: 12.1 ⫾ 3.6 Comments: Increased speed with exercise did not change FC or hemodynamic parameters FIXSpeed:

CPX: Modified Bruce protocol Regular speed: EF 4 40%: Exercise time 12.4 ⫾ 2, EF: 63% ⫾ 12%, pVO2: 21.4 ⫾ 4.8 (58% ⫾ 11%), AT: 18 ⫾ 5.5. VE/VCO2 slope: 31.9 ⫾ 6.8 EF o 40%: Exercise time 11.1 ⫾ 3.4, EF: 23 ⫾ 9%, pVO2: 17.2 ⫾ 5.3 (48% ⫾ 9%), AT: 12.6 ⫾ 2.1. VE/VCO2 slope: 38.4 ⫾ 5.3 Reduced speed: EF 4 40%: Exercise time 11.18 ⫾ 2.47, pVO2: 20.8 ⫾ 5.5 (57 ⫾ 14%), AT: 18 ⫾ 5.5. VE/VCO2 slope: 35.8 ⫾ 9.9 EFo 40%: Exercise time 9: 36 ⫾ 5: 09, pVO2: 14.7 ⫾ 5.9 (39 ⫾ 9%), AT: 9.9 ⫾ 1.5 VE/VCO2 slope: 47.1 ⫾ 16.2 Comments: Patients with LVEF 4 40% had better FC and were not affected after acute reduction of LAVD speed CPX: Bicycle ergometer Pre-LVAD: pVO2: 11.1 ⫾ 3 (40.4% ⫾ 9.3%), VE/VCO2: 42.3 ⫾ 7.8 3-6 months post LVAD: pVO2: 12.6 ⫾ 3.5 (46.9% ⫾ 10.1 %), VE/VCO2: 39.8 ⫾ 6.8 1 year: pVO2: 10.7 ⫾ 2.6 (46.8% ⫾ 11.4 %), VE/VCO2 38 ⫾ 6.4 41 year: 11.1 ⫾ 1.7 (50 ⫾ 6.1%), VE/VCO2: 35 ⫾ 3.8 Comments: Patients were older than most studies of exercise in LVAD patients, pVO2 increased at 6 months but then remained unchanged or deteriorated CPX: Modified Naughton protocol pVO2: 12.9 ⫾ 3.1, VE/VCO2 slope: 36.8 ⫾ 8.7 Muscular function: Peak torque: 92.5 ⫾ 26.3 Endurance: 32.3 ⫾ 9.1 Comments: Authors showed that muscular function was related with FC in LVAD supported patients

Support time: 6 months, 12 months

CPX: Bicycle ergometer At 6 months: Exercise time: 11.1 ⫾ 3.2 min, pVO2: 18 ⫾ 6.2 (55% ⫾ 12%) At 12 months: Exercise time: 11.1 ⫾ 3.3 min, pVO2: 18.8 ⫾ 5.7 Hemodynamics: At 6 months: Rest: MAP: 83 ⫾ 7, HR: 87 ⫾ 17, CO: 4.1 ⫾ 1.1, SVR: 1,776 ⫾ 750 Exercise: MAP: 97 ⫾ 15, HR: 140 ⫾ 32, CO: 8.5 ⫾ 2.8, SVR: 1,013 ⫾ 383 At 12 months: Exercise: MAP: 94 ⫾ 12, HR: 148 ⫾ 27, CO: 8.7 ⫾ 2.4. SVR: 935 ⫾ 334 Comments: There were no improvements in FC after 6 months of LVAD support

N: 25

CPX: Modified Naughton protocol

Continued on page 6

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6 Table 2 (Continued ) Publication

Study characteristics

Findings

Exercise time: 6.3 ⫾ 1.9 min (57% of predicted), pVO2 12.4 ⫾ 2.8 (48% ⫾ 12%), AT: 77% ⫾ 8%. LVAD type: HM-II Support time: VE/VCO2 nadir: 35.7 ⫾ 7.1 12 months Comments: These patients were compared with heart transplant patients and had worse FC Age 63 .4 ⫾ 9.9

CPX: Bicycle ergometer: Exercise time: 6 ⫾ 1.2 min, mWork: 69 ⫾ 13 W (35% ⫾ 7% of predicted), pVO2: 12,2 ⫾ 2 (38 ⫾ 8%), AT: 7.8 ⫾ 1.3 (24 ⫾ 6%),VE/VCO2 slope: 42.3 ⫾ 11.7 LVAD type: Berlin Incor (axial) BR: 49 ⫾ 15% Hemodynamics: Support time: 465 ⫾ 257 days Rest: RA: 5 ⫾ 1.1, mPA: 16 ⫾ 2.4, PCWP: 9 ⫾ 3.3, CO 4.7 ⫾ 0.5, PVR: 117 ⫾ 35.4 Exercise: RA: 11 ⫾ 3.6, mPA: 27 ⫾ 2.8, PCWP: 17 ⫾ 5.3, CO: 6.2 ⫾ 1, PVR: 125 ⫾ 35.1 Comments: These patients had low LVAD support and had worse FC and hemodynamics that literature of patients with full support

Camboni (2014)

N: 8 Age: 45 ⫾ 13 years

Jung (2014)

N: 14 Age: 55 ⫾ 13 years LVAD type: HM-II (axial) FIXSpeed: 9357 ⫾ 238 INCSpeed: 10843 ⫾ 835 Support time: 465 days

CPX: Bicycle ergometer Exercise time: 470 ⫾ 219, pVO2: 14.1 ⫾ 6.3, VE/VCO2 slope 41.4 ⫾ 14.9. mWork: 111 ⫾ 47 W INCSpeed: Exercise time: 474 ⫾ 221, pVO2: 15.4 ⫾ 5.9,VE/VCO2 slope 36 ⫾ 11.7. mWork: 114 ⫾ 46 W Comments: Authors concluded automated algorithm to increase speed with LVAD could improve FC FIXSpeed:

AT, anaerobic threshold (ml/kg/min); BR, breathing reserve (%); CI, cardiac index (L/min/m2); CO, cardiac output (L/min); CPX, cardiopulmonary exercise test; CVP, central venous pressure (mm Hg); DH, DuraHeart; FC, functional capacity; HF, heart failure; HM-XVE, HeartMate XVE; HM-II, HeartMate II; HR, heart rate; HVAD, HeartWare Assist device, LVAD, left ventricular assist device; LVEDD, left ventricular end diastolic dimension (cm); LVESD, left ventricular end systolic dimension (cm); MAP, mean arterial pressure (mm Hg); mPA, mean pulmonary artery (mm Hg); mWork, maximal work (watts); PCWP, pulmonary capillary wedge pressure (mm Hg); PF, pulsatile flow; pVO2, peak oxygen consumption (ml/kg/min); pVCO2, peak carbon dioxide production; PVR, pulmonary vascular resistance (dyn  sec/cm5); RA, right atrial (mm Hg); RV, right ventricle; RVEDD, right ventricular end diastolic dimension (cm); RVSWI, right ventricular stroke work index; SVR, systemic vascular resistance (dyn  sec/cm5); VE, minute ventilation; VE/CO2, ventilatory efficiency; W, watts.

Diastolic pulmonary artery pressure increased from 14 to 19 mm Hg in the fixed-speed protocol and from 11 to 16 mm Hg in the increased-speed protocols. Interestingly, cerebral perfusion was decreased in patients who exercised during the fixed-speed protocol but was preserved during the increased-speed protocol. These results were expanded in 16 patients with CF-LVAD using the same protocol.35 There were no differences in exercise time, workload, postRV funcon

Aerload

Contraclity

Speed

LVADflow

NaveCO Pulmonary funcon

Heart rate

Preload

TotalCO

Venlaon Oxygenaon

Hemoglobin Muscle vasodilaon

Gas exchange Oxygen delivery to muscle

Endothelium Neural reflex Local factors

Oxygen extracon Peak Oxygen Consumpon (Peak Exercise Capacity)

Figure 1 Factors affecting maximal exercise capacity in left ventricular assist device (LVAD)–supported patients. CO, cardiac output.

exercise blood lactate, or anaerobic threshold. However, there was a 9% increase in peak VO2 with the increased speed protocol. An important note is that the improvement in peak VO2 occurred without a concomitant increase in COmax. This suggests that the increase in peak VO2 could have been due to increased oxygen extraction or increased flow during sub-maximal levels of exercise. Thus, integrating automated algorithms in CF-LVAD to adjust device speed during physical activity could lead to improvements in exercise capacity.

Contribution of native contractility At rest, the CF-LVAD provides most of the CO, whereas during exercise, there is a variable contribution of the native heart to COmax. This was shown by Brassard et al,34 who described that the AV remained closed in 7 of 8 patients at rest, whereas the AV opened in 5 patients during exercise. After LVAD support, most patients experience reverse remodeling and improvement in LV ejection fraction (LVEF),36 which is important because patients with improved LVEF would be expected to have a higher COmax. In fact, Noor et al37 evaluated 30 patients who performed CPX at regular device speed and at 6,000 rpm of support. In patients with LVEF 4 40%, the effect of speed reduction was minimal, whereas in patients with

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Exercise in LVAD-Supported Patients

LVEF o 40%, there was a significant drop in peak VO2 from 17.2 to 14.7 ml/kg/min. These results highlight the importance of native heart contractility and its contribution to exercise capacity in CF-LVAD supported patients.

Time after LVAD implantation The observed exercise limitations in patients with LVAD could be a function of time, because most of the available studies were performed between 2 and 6 months after LVAD implantation. Therefore, it is possible that patients had not completely recovered from the deleterious effects of HF. Martina et al31 evaluated 20 patients with CF-LVAD at 6 months and 1 year after implantation. There were no differences in exercise time, peak VO 2 (18.7 vs 18.8 ml/kg/min), or total CO between those time points. In addition, Jakovljevic et al38 evaluated habitual physical activity, energy expenditure, and QoL after LVAD implantation. At 4 to 6 weeks after LVAD implantation, patients accumulated 25% of the daily physical activity expected for an apparently healthy individual. At 3 months, their physical activity increased significantly, but no further improvements were seen at 6 or 12 months. Liebner et al39 examined an older cohort at different times after LVAD implantation and showed mild improvements in peak VO2 after 3 to 6 months of support but not thereafter. These findings suggest that CF-LVAD implantation provides initial improvement in FC, but it plateaus after 3 to 6 months. Future studies are needed to promote physical activity and to determine optimal exercise training modalities, which could provide further improvement in FC after the implantation of CF-LVAD.

Chronotropic incompetence The role of HR in the impairement to exercise in LVAD patients is not clear. Dimopoulos et al40 studied the chronotropic response during exercise in 7 patients 3 months after CF-LVAD implantation. All patients were in sinus rhythm and had a resting heart rate (HR) comparable with healthy controls and HF patients. The HR increased with exercise in CF-LVAD patients, but their chronotropic reserve was severely impaired compared with healthy individuals, although similar to patients with advanced HF. These findings could have been partially explained by the use of β-blockers in CF-LVAD patients. However, Grosman-Rimon et al41 described that exercise chronotropic response improved after LVAD implantation. Muthiah et al42 recently demonstrated that changes in body position affect pre-load and LVAD flows, whereas wide changes in HR (53.6 ⫾ 17.3 to 126 ⫾ 17.6, controlled by pacing) did not. Although the increase in HR due to pacing does not necessarily mimic what occurs with exercise,43 this study suggests that chronotropic incompetence may be less important than initially suggested in the functional impairment of LVAD patients.

7

RV dysfunction RV failure is common in advanced HF patients and is a frequent cause of morbidity and mortality after LVAD implantation.44 Thus, it is possible that RV dysfunction could limit COmax during exercise in CF-LVAD patients. There is limited examination of the effect of the RV on exercise tolerance. Jung et al35 measured tricuspid annular plane systolic excursion, a known marker of RV function, in 16 patients supported by CF-LVAD who performed CPX. The mean tricuspid annular plane systolic excursion value at rest was 12 mm, and the mean RV diastolic dimension was 3.5 cm; these variables did not correlate with peak VO2. Although these patients had moderate RV dysfunction at rest, the fact that there was no correlation between resting parameters of RV function and peak VO2 may be due to the inability of these parameters to predict RV function during exercise. Invasive hemodynamic studies performed by Camboni et al33 showed that there was a concomitant increase in RAP and PCWP with exercise, suggesting the increase in right-heart filling pressures were secondary to increases in left-heart filling pressures. Similarly, Mancini et al29 described the same pattern in PF-LVAD. In a seminal study by Jaski et al,45 10 patients supported by PF-LVADs had a significant decrease in RV dimensions, an increase in RV stroke volume, and an increase in LV dimensions with exercise, suggesting that the limitations to exercise observed in these patients were not dependent on the RV. Evaluation of the RV function in LVAD patients is complex,46 but these studies suggest that RV function may not be a limiting factor for exercise capacity in LVAD patients. It should be cautioned that the method used for determination of RV function might not have been optimal and that selection bias could have accounted for some of these findings. Thus, in our opinion, further research aimed at specifically evaluating the contribution of the RV function on exercise capacity is needed.

Pulmonary function Dimopoulos et al47 evaluated 8 CF-LVAD patients using CPX and pulmonary function testing (PFT) at 1, 3, and 6 months after implantation. At 1 month after implantation, all patients demonstrated a restrictive respiratory impairment, with forced expiratory volume in 1 second of 1.8 ⫾ 0.5 liters (69% ⫾ 19% predicted), forced vital capacity of 2.2 ⫾ 0.6 liters (51% ⫾ 13% predicted), and maximal inspiratory pressure of 59 ⫾ 19 cm H2O (54% ⫾ 16% predicted). These values increased at 6 months of support with forced expiratory volume in 1 second of 2.4 ⫾ 0.5 liters, forced vital capacity of 3.1 ⫾ 0.7 liters, and maximal inspiratory pressure of 93 ⫾ 20 cm H2O (85% ⫾ 20% predicted). Peak VO2 increased from 12.6 ⫾ 2 ml/kg/ min at 1 month to 14.9 ⫾ 1.6 ml/kg/min at 6 months, with a concomitant improvement in exercise duration from 5.2 ⫾ 1.5 to 8.5 ⫾1.1 minutes. In addition, LVAD unloading also decreases pulmonary congestion and dead space ventilation and improves

8

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ventilatory efficiency. This is supported by Jung et al,35 who demonstrated that the minute ventilation/carbon dioxide production (VE/VCO2) ratio at peak exercise decreased from 41 ⫾ 14.9 to 36 ⫾ 11.7 in CF-LVAD patients when an increased LVAD speed was used. These data demonstrate an improvement in respiratory muscle function and in ventilatory-perfusion coupling (i.e., decreased VE/VCO2). However, respiratory function and ventilatory efficiency do not appear to completely normalize (i.e., normal percentage predicted PFT values and VE/VCO2 o 30) after LVAD support. Hence, continued impairments in respiratory muscle function and ventilation-perfusion coupling may at least partly contribute to the exercise limitations observed in these patients. Adaptations of the pulmonary circulation during exercise are very important. In HF patients, the total pulmonary resistance and pulmonary vascular resistance (PVR) increase due to secondary pulmonary hypertension and decreased CO. In HF patents, peak VO2 correlates better with PCWP rather than PVR.48 LVAD support decreases PCWP and leads to a normalization of pulmonary artery pressures in most individuals with secondary pulmonary hypertension.49 Camboni et al33 reported the PVR in patients supported by LVAD before and after exercise. Values were within normal ranges33; thus, PVR probably does not play an important role in the limitation to exercise in this population.

Peripheral factors Limited investigations have focused on changes in peripheral factors after LVAD implantation. Kerrigan et al50 evaluated muscular strength/endurance, 6MWT, CPX, and QoL, as measured by the Kansas City Cardiomyopathy Questionnaire, in 23 patients with CF-LVAD. After adjusting for body weight, peak knee extensor torque production had the strongest correlation with the Kansas City Cardiomyopathy Questionnaire (r ¼ 0.58, p ¼ 0.006), and this relationship was independent of cardiorespiratory fitness because there was no correlation between peak VO2 and peak torque. Muscle endurance, as measured by the decline in knee extensor torque over 15 repetitions, was not associated with any variables. This was the first study to show that muscular strength was associated with patient health reported status. In a different setting, George et al51 evaluated 7 PF-LVAD patients who were treated with clenbuterol (a β2-agonist used in Europe as a bronchodilator and in veterinary medicine for muscular development), which was previously described to enhance myocardial recovery during LVAD support.52 They showed that clenbuterol increased lean body weight, increased quadriceps maximum voluntary contraction and cross-sectional area, and increased respiratory muscle strength. Despite these positive physiologic adaptations, peak VO2 did not improve after 12 weeks of treatment. These studies signal the important influence of musculoskeletal function on exercise capacity and oxygen dynamics in patients supported by CF-LVAD.

Anemia is a marker of poor prognosis in HF53 and occurs frequently in CF-LVAD patients.54 Hemoglobin is the main oxygen carrier in blood and an important determinant of total arterial oxygen content. Therefore, a low hemoglobin concentration could affect oxygen delivery to the skeletal muscle and contribute to the impaired peak VO2 observed in these patients. Endothelial dysfunction55 and impairment in flowmediated vasodilation56 have been described in HF and are thought to contribute to exercise intolerance.57 Exercise training may improve endothelial dysfunction.58 Limited information exists regarding endothelial function in CFLVAD patients, with some claiming normalization of endothelial function59 whereas others report no changes in the microcirculation.60 However, a 3-fold increase in flow to exercising muscle was determined in CF-LVAD–supported patients.34 Thus, it appears unlikely that blood flow to active skeletal muscle would be a significant contributor to the exercise limitation in these patients.

Comparison with heart transplant As LVADs compete with HTx as an alternative for the management of end-stage HF, it is important to compare not only their survival benefit but also their ability to improve FC and exercise tolerance. Kugler et al61 evaluated changes in exercise capacity (measured by CPX) in 54 HTx and 36 LVAD patients. Both groups had a similar improvement in exercise tolerance as determined by maximum workload, but HTx patients achieved a higher percentage increase in age-corrected peak VO2 (10% vs 7%). Dunlay et al62 compared the changes in exercise tolerance in 25 CF-LVAD and 74 HTx patients. All patients had similar exercise time, peak VO2, and the VE/VCO2 ratio at maximal exercise before surgery. LVAD patients had a small improvement in exercise time and the VE/VCO2 nadir but no significant change in peak VO2 compared with pre-LVAD status. HTx patients did exhibit an increase in peak VO2 of 11.6%. Jakovljevic et al38 compared habitual activity among HTx, LVAD, and HF patients using an accelerometer. Physical activity and energy expenditure patterns were evaluated. At 3 months post-surgery, HTx and LVAD patients increased their habitual physical activity compared with 6 weeks post-surgery. However, only HTx patients continued to improve at 6 and 12 months, whereas LVAD patients did not experience any further improvement after 3 months. As described previously, these results suggest that LVAD patients accumulate low amounts of physical activity and exercise compared with HTx patients. The results further highlight the need to explore whether exercise training can produce long-term continuous improvements in FC and reduce the disparity between the magnitude of improvement in HTx and LVAD patients.

Exercise prescription and rehabilitation CR results in numerous physiologic, functional, and clinical benefits in patients with cardiovascular diseases, such as

Loyaga-Rendon et al. Table 3

Exercise in LVAD-Supported Patients

9

Studies With Intervention Strategies To Improve Functional Capacity in Left Ventricular Assist Device–Supported Patients

Publication

Study characteristics

Findings

Laoutaris (2011)

N: Training group: 10 Control group: 5

CPX: Treadmill, Dargie protocol Training group: Prior to randomization: Et: 9.7 ⫾ 2.2, pVO2: 16.8 ⫾ 3.7, VE/VCO2: 40 ⫾ 6.5 6MWT: 462 ⫾ 88 m Post randomization: Et: 10.1 ⫾ 1.9, pVO2: 19.3 ⫾ 4.5, VE/VCO2: 35.9 ⫾ 5.6. 6MWT: 527 ⫾ 76 m Control group: Prior to randomization: Et: 8 ⫾ 2.9, pVO2: 14.9 ⫾ 4, VE//VCO2: 41.4 6MWT: 430 ⫾ 41 m Post randomization: Et: 8.4 ⫾ 2.9, pVO2: 14.8 ⫾ 4.2,VE/VCO2: 40.2 ⫾ 7.3 6MWT: 448 ⫾ 55 m Comments: Training protocol consisted on exercise (bike or treadmill) for 45 minutes 3–5 times a week and a high-intensity inspiratory muscle training. Increased of pVO2, decrease in VE/VCO2 and improvement in 6MWT with exercise also improvement in respiratory muscle function. Training group: 4 BIVAD (pulsatile) 2 LVAD (axial) 4 LVAD (pulsatile). Control group: 3 BIVAD (pulsatile) 2 LVAD (pulsatile)

Age: Training group: 37.2 ⫾ 17.7 years Control group: 41.8 ⫾ 14.6 years LVAD type: Training group: LVAD, BiVAD (pulsatile and axial) Intervention: 10 weeks of exercise

Hayes (2012)

N: Exercise group: 7 Control: 7 Age: Exercise group: 48.7 ⫾ 14.5 years Control: 45.9 ⫾ 14.6 years LVAD type: VA (centrifugal)

CPX: Bicycle ergometer Baseline: Intervention: pVO2: 10.5 ⫾ 2.3, Work: 42 ⫾ 15.4 W, 6MWT: 351 ⫾ 77 Control: pVO2: 12.4 ⫾ 1.7, Work: 50.4 ⫾ 21.6 W, 6MWT: 367 ⫾ 129 Post-intervention (8 weeks): Intervention: pVO2: 14.8 ⫾ .9, Work: 74.5 ⫾ 31.3 W, 6MWT: 531 ⫾ 131 Control: pVO2: 15.3 ⫾ 4.4, Work: 79.4 ⫾ 45 W, 6MWT: 489 ⫾ 95 Comments: Exercise consisted on 1 hour of gym work 3 times per week for 8 consecutive weeks. Patients exercised on a stationary bicycle, on treadmill and strength muscle training. No differences in pVO2 or 6MWT

Intervention: 8 weeks of exercise training Control: Encouragement to walk (mobilization protocol) Kugler et al (2012)

N: Intervention: 34 Control: 36 Age Intervention: 52 ⫾ 2 years Control: LVAD type: HM-II 55% (axial), HVAD 45% (centrifugal) Intervention: 18 months

Compostella (2013)

N: 26 Age: 63.4 ⫾ 7.4 years LVAD type: Jarvik, Berlin Incor (axial) Duration of support:o 2 months of support

CPX: Bicycle ergometer Baseline: Intervention: pVO2: 18.5 ⫾ 0.8 (61%), Workload: 80 ⫾ 5.1 Control: pVO2 16.3 ⫾ 0.6 (59%), Workload: 70 ⫾ 3.7 Post-intervention (18 months): Intervention: pVO2 (69% ⫾ 2.9 %) Control: pVO2 (62% ⫾ 3.7%) Comments: Multimodal intervention included dietary counseling, psychosocial support and a home-based physical reconditioning program. Increased pVO2 in patients who received intervention CPX: Bicycle ergometer (performed after CR) pVO2 12.5 ⫾ 3 (48.8% ⫾ 13.9%) AT 10.4 ⫾ 2.5 VE/VCO2 slope 32.2 ⫾ 3.6 Wmax 36.3 ⫾ 9 Comments: patients performed 3 daily sessions of exercise (respiratory, aerobic and calisthenics exercises) 6 days per week for a total of 2 weeks

Intervention: CR for 2 weeks Kaparolat (2013)

N: 11 Age: 45.6 ⫾ 14 years LVAD type: Berlin Excor 3 and 8 HM-II

CPX: Modified Bruce protocol Baseline: pVO2 14. 7 ⫾ 3.6 Post intervention: pVO2: 15.1 ⫾ 3.42

Continued on page 10

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10 Table 3 (Continued ) Publication

Study characteristics

Findings

Duration of support: 2.8 ⫾ 2.13 months

Intervention: ,90 minute sessions, 3 times a week for 8 weeks. Flexibility, aerobic, strengthening, and relaxation exercises. Significant improvement in pVO2 in LVAD patients. Authors compared LVAD patients with HTx and HF patients with no significant differences

Intervention: 8 weeks Alsara (2014)

N: 47 Age: 60 ⫾ 1 years LVAD type: HM-II (89%, axial), HM-XVE (3.2% pulsatile), VA (6.4% centrifugal), DH (1 (1.1%, centrifugal) Support time: 19 .5 ⫾ 12.7 days Intervention: 6.6 ⫾ 3.9 days

Patients admitted to in-patient rehabilitation program. FIM Score: admission: 77.1 FIM Score discharge: 95.2 Comments: Patients had a significant improvement in FIM score at the time of discharge from inpatient rehabilitation unit

6MWT, Six minute walk test; AT, anaerobic threshold; BiVAD, biventricular assist device; CPX, cardiopulmonary exercise test; CR, cardiac rehabilitation; DH, Duraheart; ET, exercise time; FIM; Functional Independence Score; HF, heart failure; HM-II, HeartMate II; HTx, heart transplant; HVAD, HeartWare Assist device; LVAD, left ventricular assist device; pVO2, maximal oxygen consumption; VA, VentrAssist; VE/VCO2, ventilatory efficiency; Wmax, maximal work.

myocardial infarction63 or HF.64 European guidelines led by Piepoli et al13 demonstrate that exercise training improves FC and peak VO2, reduces the VE/VCO2 slope in HF patients, and is associated with a host of positive physiologic adaptations, including enhanced endothelial function, muscle perfusion, oxygen supply, and aerobic characteristics in skeletal muscle. However, there are no guidelines regarding the best approach to CR or exercise prescription for patients with LVAD. As a result, LVAD patients undergo rehabilitation protocols designed for other types of cardiovascular diseases or cardiac surgeries. Patients undergoing LVAD implantation are profoundly deconditioned, and a recent report showed that 50% of these patients are admitted to an in-patient rehabilitation program,65 with improvements in FC.66,67 A descriptive study by Hu et al68 showed that even after 1 year post-LVAD implantation, patients preferentially performed low-intensity activities. In a recent publication, Alsara et al9 reviewed the literature regarding LVAD patients undergoing CR and concluded that exercise training is safe and recommended early mobilization (7 to 10 days post-implant) and treadmill exercise beginning 21 days post-implant. It is important to recognize there is scarce information regarding the improvements derived from CR in patients supported by LVAD (Table 3). Karapolat et al69 compared QoL and maximal exercise capacity among HF, post-HTx, and LVAD patients after an 8-week exercise program. All patients benefited from the program, with slight improvements in peak VO2 and QoL measurements with no difference in peak VO2 between HTx patients and LVAD patients. Compostella et al70 evaluated 26 patients with CFLVAD as destination therapy who were admitted to CR and compared their exercise tolerance with patients who had a recent HF exacerbation. Patients underwent exercise training 3 days per week for 2 weeks. Peak VO2 did not differ between the groups. In addition, Hayes et al23 described the effects of an 8week exercise training program in patients who received

CF-LVAD and compared outcomes with patients who received standard of care. Peak VO2 increased in both groups, from 10.5 to 14.8 ml/kg/min in the exercise group and from 12.4 to 15.3 ml/kg/min in the control group. The 6MWT distance increased by 51%, from 351 to 531 meters, in the exercise group, and by 33%, from 367 to 489 meters, in the control group. There were no differences between groups, and the authors attributed this result to the small number of enrolled patients. However, Loutaris et al71 performed a small intervention study in which patients received 10 weeks of moderateintensity exercise and had an improved peak VO2 and VE/ VCO2 compared with control; of note, patients had a combination of CF-LVADs, PF-LVADs, and biventricular assist devices. Kugler et al72 monitored 70 CF-LVAD patients, who were assigned to an intervention group (dietary counseling, weight management, and physical intervention) or usual care. After 18 months, patients in the intervention group had an increase in peak VO2 compared with patients in the usual-care group. These data suggest that prolonged periods of rehabilitation are probably needed to observe significant benefits. As suggested previously, little information is available regarding the efficacy of aerobic and resistance exercise in LVAD-supported patients. Thus, further studies are needed to clarify if and which exercise training modalities could exert maximal benefit on FC and QoL in LVAD patients. It seems plausible, based on the known pathophysiologic responses to HF and the ensuing mechanical/physiologic consequences of LVAD implantation, that in addition to aerobic training, low-moderate intensity resistance exercise may be an effective strategy to improve metabolic and cardiovascular health. Future studies are needed to evaluate the safety and efficacy of resistance exercise in this population, particularly concerning hemodynamic responses and improvements in FC. In conclusion, limitation to exercise in LVAD patients is multifactorial. Although LVAD improves hemodynamics in

Loyaga-Rendon et al.

Exercise in LVAD-Supported Patients

end-stage HF patients at rest, the device is unable to provide full support during exercise. Thus, significant limitations in exercise capacity persist. Maximizing LV unloading and improving native myocardial function in association with an automated increase of LVAD speed could provide improvements in maximal exercise capacity. Further studies are needed regarding the role of RV function, changes in skeletal muscle after CF-LVAD, and their contribution to endurance exercise. Individualized exercise prescriptions that could lead to optimal improvements in exercise capacity in CF-LVAD–supported patients are not known and should be a top priority for research in the field.

Disclosure statement The authors acknowledge the Junior Faculty and Trainee Council for the opportunity given to the Junior Faculty to participate in this manuscript. Dr Shah discloses institutional and research grants from Thoratec Corp and institutional grants from HeartWare. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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