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Special Section – Invited Reviews Focused on Important Topics in CR

Rethinking Rehabilitation

A REVIEW OF PATIENT POPULATIONS WHO CAN BENEFIT FROM CARDIAC REHABILITATION

Overstreet, Brittany PhD; Kirkman, Danielle PhD; Qualters, Wanda Koester MS; Kerrigan, Dennis PhD; Haykowsky, Mark J. PhD; Tweet, Marysia S. MD; Christle, Jeffrey W. PhD; Brawner, Clinton A. PhD; Ehrman, Jonathan K. PhD; Keteyian, Steven J. PhD

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: November 2021 - Volume 41 - Issue 6 - p 389-399
doi: 10.1097/HCR.0000000000000654
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Cardiac rehabilitation (CR) is a class 1 guideline-based therapy that provides comprehensive secondary prevention strategies. Best practices for CR include exercise training, outcome assessments, risk factor management, and nutritional/behavioral education to individuals who qualify. Research indicates that CR participation provides many health benefits including reduced risk for morbidity and mortality, increased cardiorespiratory fitness (CRF), enhanced quality of life, and improved mood and symptoms.1,2 Furthermore, CR is cost-effective by reducing the rate of recurrent myocardial infarctions (MIs) and hospital readmissions.3 Several meta-analyses have demonstrated the benefits of CR programs, specifically examining the individual components of these programs and their impact on patient well-being.4,5 Despite the large number of different cardiovascular diseases (CVD), only seven diagnoses or procedures qualify an individual for CR (Table 1).

Table 1 - Medical Conditions Eligible for Cardiac Rehabilitation Approved by the Centers for Medicare & Medicaid Services
Eligibility Criteria Class of Indication
Myocardial infarction within the last 12 mo Class 1a indication
Coronary artery bypass graft surgery Class 1 indication
Current stable angina Class 1 indication
Heart valve repair or replacement Class 1 indication
Percutaneous coronary angioplasty or coronary stent Class 1 indication
Heart or heart-lung transplant Class 1 indication
Stable chronic heart failure with New York Heart Association class II-IV and left ventricular ejection fraction ≤35% Class 2ab indication
aStrong recommendation.
bModerate recommendation.

While this list may seem robust to some, it is only a fraction of the chronic health conditions that physical activity and lifestyle interventions (ie, education, counseling, and social support) have been shown to benefit. Specifically, exercise is beneficial for individuals with conditions that are strongly associated with CVD including chronic kidney disease (CKD)6–11 and breast cancer (BC).12–15 Given the observed associations between these diseases and CVD, it seems appropriate to consider the inclusion of these individuals in CR as a strategy to help manage their CVD risk.

Additionally, some patients who attend CR present with cardiovascular comorbid conditions (eg, spontaneous coronary artery dissection, [SCAD]; left ventricular assist device, [LVAD]), not easily identified in Table 1. Often, these individuals will make up a relatively small proportion of the populations that traditionally participate in CR and thus professionals may be less familiar with the current guidelines for patient-centered care.

The purpose of this review is to present relevant information for the CR practitioner about patient populations that either do not currently qualify for (ie, chronic and end-stage CKD, BC survivor) or who are eligible but less commonly cared for in CR (ie, SCAD and LVAD). We also address special CR-related considerations and expected outcomes to better inform clinicians and researchers. Additionally, randomized control trials and clinical trials from the past decade, which support the benefits of exercise programming for CKD, SCAD and LVAD patient populations, have been summarized in Tables 2, 3, and 4. While not a systematic review, our tables provide important references for CR professionals to better understand the potential benefits of exercise for these populations. A summary for BC survivors was not provided, as a recent systematic review by Furmaniak et al16 provides the information CR professionals would find beneficial regarding this population.

Table 2 - Key Randomized Controlled Trials Investigating the Effects of Exercise on Cardiovascular Disease-Related Outcomes in CKD
Author Groups Exercise Intervention CV Outcome Measures Findings
Mustata et al (2011)20 Exercise (n = 10)
Control (n = 10)
F: 5x/wk (60 min)
I: 40-60% V˙o 2peak
T: Aerobic
T: 52 wk
Arterial compliance
CRF
No change in pulse wave augmentation index
Increase in V˙o 2peak with ExT
Headley et al (2012)21 Exercise (n = 10)
Control (n = 11)
F: 3x/wk (45 min)
I: 50-60% V˙o 2peak
T: Aerobic and resistance
T: 48 wk
Ambulatory BP
Autonomic function
Blood lipids
Inflammatory biomarkers
Vascular biomarkers
CRF
No change in 24-hr BP
Increase in 1-min exercise heart rate recovery with ExT
Decrease in total cholesterol and LDL-C in control group
No change in IL-6 or hs-CRP
No change in ADMA
Increase in V˙o 2peak with ExT
Howden et al (2013)22 Exercise (n = 36)
Control (n = 36)
F: 2x/wk (75 min)
I: 11-13 RPE
T: Aerobic
T: 18 wk
Central BP
Blood lipids
Ventricular-vascular interaction
Arterial compliance
Cardiac function
CRF
No change in central BP
No change in blood lipids
Improvement in arterial elastance with ExT
No change in pulse wave velocity or pulse wave augmentation index
Improvement in left ventricular systolic and diastolic function
Increase in V˙o 2peak with ExT
Headley et al (2014)23 Exercise (n = 25)
Control (n = 21)
F: 3x/wk (55 min)
I: 50-60% V˙o 2peak
T: Aerobic
T: 16 wk
BP
Arterial compliance
Inflammatory biomarkers
Vascular biomarkers
Body composition
CRF
No change in BP
No change in pulse wave velocity
No change in hs-CRP
Decrease in circulating Endothelin-1 with ExT
No change in % fat mass
Increase in V˙o 2peak with ExT
Greenwood et al (2015)24 Exercise (n = 8)
Control
(n = 10)
F: 3x/wk (40 min)
I: 80% HRR
T: Aerobic and resistance
T: 52 wk
BP
Blood lipids
Arterial stiffness
Inflammatory biomarkers
Body composition
CRF
No change in BP
No change in blood lipids
Decrease in pulse wave velocity with ExT
No change in hs-CRP
Decrease in waist circumference with ExT
Increase in V˙o 2peak with ExT
Van Craenenbroeck et al (2015)25 Exercise (n = 19)
Control (n = 21)
F: 4x/wk (10 min)
I: 90% AT
T: Aerobic
T: 12 wk
BP
Blood lipids
Vascular endothelial function
Arterial compliance
Vascular biomarkers
Inflammatory biomarkers
CRF
No change in BP
Decrease in total cholesterol in control group
No change in flow-mediated dilation
No change in pulse wave velocity or pulse wave augmentation index
No change in endothelial progenitor cell proliferation or circulating cell migratory capacity
No change in hs-CRP
Increase in V˙o 2peak with ExT
Headley et al (2017)26 Exercise (n = 25)
Control (n = 21)
F: 3x/wk (55 min)
I: 50-60% V˙o 2peak
T: Aerobic
T: 16 wk
Ambulatory BP
Post-exercise hypotension
No change in daytime or nighttime BP
No change in post-exercise hypotension
Kirkman et al (2019)9 Exercise (n = 15)
Control (n = 16)
F: 3x/wk (45 min)
I: 60-85% HRR
T: Aerobic
T: 12 wk
Central BP
Microvascular function
Vascular endothelial function
Arterial compliance
Arterial hemodynamics
Oxidative stress biomarkers
CRF
No change in central BP
Improvement in microvascular conductance with ExT
Flow-mediated dilation preserved with ExT
No change in pulse wave velocity or pulse wave augmentation index
No change in forward or reflect traveling waveform amplitudes
No change in urinary F2-isoprostanes
Increase in V˙o 2peak with ExT
Huppertz et al (2020)28 Exercise (n = 81)
Control (n = 80)
F: 2x/wk (75 min)
I: 11-13 RPE
T: Aerobic
T: 18 wk
Autonomic function
CRF
No change in heart rate variability and 1-min exercise heart rate recovery
Increase in V˙o 2peak with ExT
Kirkman et al
(2020)27
Exercise (n = 14)
Control (n = 12)
F: 3x/wk (45 min)
I: 60-85% HRR
T: Aerobic
T: 12 wk
Autonomic function
Cardiac function
Ventilation-perfusion matching
CRF
No change in autonomic function
Improvement in indexed O2pulse with ExT
No change in V˙E/V˙co 2 and V˙E/V˙o 2 slopes
Increase in V˙o 2peak with ExT
Abbreviations: ADMA, asymmetric dimethylarginine; AT; BP, blood pressure; CKD, chronic kidney disease; CRF, cardiorespiratory fitness; ExT, exercise training; F, frequency of exercise; GSH, glutathione; HRR, heart rate reserve; hs-CRP, high-sensitivity C-reactive protein; I, intensity of exercise; IL-6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; LPO, lipid peroxidation product; RPE, rating of perceived exertion: T, type of exercise; T, time of exercise training intervention.

Table 3 - Exercise Intervention in Those With Spontaneous Coronary Artery Dissection
Study Patients Exercise Assessment Exercise Intervention Sessions Attended Outcomes Notes
de Carvalho Pinto et al (2014)56 1 female (age 36 yr) 6MWT 3x/wk, 1 hr (20-min WU, 15-min TM, 15-min bike, 4-min supine recovery) 21 445-m pre-, 540-m post-exercise intervention (21% improvement) Time to enrollment not reported
Silber et al (2015)54 9 women, 0 men (average age 47 yr) Pre and post-CPX or 6MWT 1-3x/wk (5-min WU, 30- to 45-min CV exercise, 5-min CD). RT/core 10-20 min. THRR 60-70% HRR and/or RPE 12-14. HIIT performed once able to complete 20-min MICT (1-2 min at RPE 15-17 interspersed with moderate-intensity intervals of RPE 12-14). 28 (5-39) visits CPX: peak oxygen uptake increased by 18% (4.4 mL/kg/min, average). 6MWT increased 22%. CR initiated 1-2 wk post-MI. Education and counseling regarding nutrition, weight control and stress management
Chou et al (2016)61 70 women, 0 men (average age 52 yr) Pre and post-ETT 1 hr, 1x/wk (15-min WU, 30 min-CV exercise, 15-min CD). RT with 2-12 lb. THRR 50-70% of HRR. SBP <130 mm Hg. Advised not to lift >20 lb. 12.4 ± 10.5 wk 10 METs at program initiation ± 3 METs; at exit 11.5 ±3.5
At entry, 63% had recurrent CP, at exit 37%
Enrollment median 0.6 yr after event. Supervised exercise in open gym available in addition to 1x/wk session. 20-min education/wk on nutrition, risk factors, stress management; counseling and peer support available.
Patterson et al (2016)53 1 female (age 39 yr) Submax CPX 1 mo post-event. Submax ETT (no CPX) at 3 and 6 mo post-event Initial 2 mo: CV exercise ≤30 min, longer WU than usual, RPE 3-5 (on 1-10), HR <140 bpm, avoided jogging. RT: 3-7 d, light effort. At mo 3: HR <150 bpm up to 1 hr, added interval jogging. RT moderate effort. At mo 6: no limit to duration, HR <165 bpm, 6-7 on RPE 1-10, avoided training for marathon distances. RT: up to moderate/vigorous effort, avoiding Valsalva. NA Max ETT at 6 mo post-event: 13 METs ET initiated 1 mo post-event. At 8 mo post-event, patient was running 3-5 mi 3x/wk, elliptical 30-45 min and/or spin cycle for 45 min 1x/wk.
Weber et al (2018)55 1 male (age 22 yr) CPX post-exercise intervention only WU and CD. Initial 23 sessions: low-/moderate-intensity TM, bike and RT; then 32 sessions over 11 mo with simulated competitive cycling. 55 over 3 yr Achieved 14 METs Time to enrollment not reported. Training was symptom limited (no limits on HR, BP, RPP, RPE).
Brown et al (2019)60 1 female (age 53 yr) Final CR session: peak transient change in BP over time (dP/dt) was continuously recorded during RT and core exercise as well as during cough, forced Valsalva, and provoked sneeze 5-min WU before 20-30 min jogging or stepper. Two sets of 10 (moderate intensity) of 1 RT activity and 2 sets of 1 core activity for 30 sec. 18 Cough, Valsalva and sneeze were shown to have the greatest dP/dt over RT and core exercise. Enrolled 1 yr post-event to specifically perform RT and core activities
Abbreviations: BP, blood pressure; CD, cool down; CP, chest pain; CPX, cardiopulmonary exercise test; CR, cardiac rehabilitation; CV, cardiovascular; dP/dt, derivative of pressure over time; ET, exercise training; ETT, exercise treadmill test; HIIT, high-intensity interval training; HR, heart rate; HRR, heart rate reserve; MET, metabolic equivalent of task; MI, myocardial infarction; MICT, moderate-intensity continuous training; NA, not applicable; RPE, rating of perceived exertion; RPP, rate pressure product; RT, resistance training; SBP, systolic blood pressure; THRR, target heart rate range; TM, treadmill; WU, warm up; 6MWT, 6-min walk test.

Table 4 - Exercise Intervention in Those With Left Ventricular Assist Devices
Study Patients(Female, Male), n Age, yr Device Type Exercise Testing and QOL Metrics Exercise Intervention Outcomes Average Sessions Attended Signs, Symptoms and/or Adverse Events Notes
Laoutaris et al (2011)70 1, 14 38 ± 16 First-generation pulsatile and second-generation continuous flow o 2peak, 6MWT, PFT, MLWHFQ 10-wk training period. 45 min, on a bike or treadmill at an RPE of 12-14 on the Borg scale. Within group improvements in V˙o 2peak, V˙E/V˙co 2 slope, 6MWD, inspiratory muscle endurance, and MLWHFQ for the training group Not reported None reported Randomized control design. Combined home and supervised exercise.
Hayes et al (2012)71 2, 10 47 ± 15 VentrAssist o 2peak, 6MWT, SF-36 8-wk training period. 60 min, 3 d/wk using combined stationary cycling, treadmill, and 6 strength training exercises. Cycling intensity was 50% of heart rate reserve or an RPE of >13 on the Borg scale. Both groups showed improvements in V˙o 2, and 6MWD. No significant difference between groups. Some domains of the SF-36 improved in the training group 21.3 ± 1.5 out of 24 sessions None reported Randomized control design. First randomized exercise trial in patients with LVADs
Karapolat et al (2013)68 2, 9 46 ± 14 EXCOR HeartWare o 2peak, Beck Depression Scale, SF-36 8-wk training period. 90 min, 3 d/wk using various aerobic modalities and 8 upper and lower body resistance exercises. Aerobic exercise was at 60-70% V˙o 2peak Within group improvements in V˙o 2peak, symptoms of depression, and some domains of the SF-36 Not reported None reported Retrospective study comparing patients with heart failure, to transplant, to LVAD who participated in CR.
Kerrigan et al (2014)69 7, 19 55 ± 13 HeartMate II HeartWare o 2peak, 6MWT, isokinetic leg strength, KCCQ 6-wk training period 30 min, 3 d/wk of combined stationary cycling, treadmill, or recumbent stepper. Intensity was set at 60% or heart rate reserve or an RPE of 11-14 on the Borg scale. Within group improvements in V˙o 2peak, V˙o 2 at VT, and 6MWD for the training group. Within and between group improvements for treadmill time, KCCQ, and isokinetic leg strength 17.8 ± 3.2 out of 18 sessions One patient had a syncopal event associated with nonsustained ventricular tachycardia immediately after exercise Randomized control design. Training was conducted within CR classes
Marko et al (2015)72 8, 33 55 ± 12 HeartMate II HeartWare o 2peak, resistance training workloads ∼32 CR sessions using a combination of stationary cycling and free walking at an RPE of 13 on the Borg scale. Lower extremity strength training 2 sets, 12 reps Within group improvements in V˙o 2peak and leg strength based upon increased training workload 32 ± 6 sessions. No predetermined total expected One patient experienced an episode of nonsustained ventricular tachycardia Retrospective analysis. Training was conducted within CR classes
Villela et al (2021)73 5, 10 51 (29-71) HeartMate II HeartMate III o 2peak, KCCQ, and LV echocardiogram measures 5-wk training period, 3 d/wk−1 of high-intensity exercise training on a cycle ergometer. HIIT protocol: 30-sec warm-ups. Six 30-sec high-intensity intervals followed by 4-min active recovery. Within group improvements in V˙o 2 at VT and LV end-diastolic volume Median 13 out of 15 sessions One subject had recurrent asymptomatic supraventricular tachycardia that occurred after the planned increase in workloads during the fourth training session Prospective, observational study. Supervised training was conducted individually with a physician. Median time of LVAD support prior to training was 18 mo (range 3-64 mo).
Abbreviations: CR, cardiac rehabilitation; HIIT, high-intensity interval training; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVAD, left ventricular assist device; MLWHFQ, Minnesota Living With Heart Failure Questionnaire; PFT, pulmonary function test; QOL, quality of life; RPE, rating of perceived exertion; SF-36, Short-form 36-item Health Survey Questionnaire; THRR, target heart rate range; TM, treadmill; VT, ventilatory threshold; V˙o2peak, peak oxygen uptake; WU, warm up; 6MWT, 6-min walk test.

REVIEW OF RELEVANT LITERATURE

CHRONIC AND END-STAGE KIDNEY DISEASE

Chronic kidney diseases represent a major public health problem, affecting at least one in seven adults in the United States.17 The disease progresses through five stages, classified according to the estimated glomerular filtration rate, with the fifth stage requiring some form of renal replacement therapy (eg, dialysis or a kidney transplant). Patients with CKD experience a substantial CVD burden, the etiology of which is not fully explained by traditional risk factors.17 Despite advancements in the development of pharmaceutical agents targeting hypertension and diabetes, patients with CKD are more likely to die from CVD than progress to end-stage renal disease (ESRD).17 Furthermore, statin therapies are ineffective at improving outcomes in the ESRD population.18 As a result, there is a critical unmet clinical need to develop and implement strategies to improve cardiovascular health in this patient population. Targeted interventions, such as CR, that address the prevention and management of CVD progression, would be notably beneficial in the earlier stages of the disease. In this respect, clinical guidelines specify the management of CVD progression as a treatment for CKD as early as stages one and two.19

There is a wealth of evidence documenting a myriad of health benefits of exercise training across the spectrum of kidney diseases (Table 2).9,20–28 Regular exercise on most, if not all days of the week, is currently recommended by the Kidney Disease Quality Initiative clinical guidelines.19 Despite the current evidence and clinical guidelines, exercise is still not integrated as part of standard of care treatment in nephrology. One consistently cited barrier to implementing exercise in this patient population is a lack of time and information among nephrology health care providers to effectively counsel and prescribe exercise.6 Therefore, referral to CR represents an attractive strategy to facilitate the integration of exercise for CVD prevention and management in these patients.

Exercise Testing

Exercise testing prior to enrollment in CR can provide clinicians valuable information regarding underlying disease, contraindications to starting exercise, and current CRF. Protocols including a 6-min walk test (6MWT), intermittent shuttle walk test, and timed get up and go assessment are commonly used to assess functional fitness in this population. These tests are typically easy to administer and relatively safe for higher risk populations. While these assessments provide information such as heart rate (HR) and blood pressure (BP) responses, which are very useful for exercise programming, cardiopulmonary exercise tests (CPX) can provide other values useful to the CR team. Prior studies involving CPX reveal lower CRF levels (peak oxygen uptake [V˙o2peak] = 17.4 vs 28 mL/kg/min), ventilatory-perfusion mismatch (V˙E/V˙co2 slope 32 vs 28 and PetCO2: 27 vs 31 mm Hg), as well as blunted maximal HR (134 vs 159 bpm) and 1-min HR recovery responses in patients with CKD compared with healthy controls (15 vs 20 bpm, respectively).7 In this respect, CPX is a useful tool for identifying subclinical cardiovascular abnormalities in this population.

Exercise Prescription and Training

Regular exercise training improves CRF, muscular strength, and quality of life in patients with CKD.8 In nondialysis CKD, moderate- to vigorous-intensity aerobic exercise improves endothelial and microvascular function, both of which are precursors to the development of atherosclerosis.9 Additionally, in these patients regular aerobic exercise reduces chronic inflammation, a consistently cited nontraditional risk factor of CVD that is a hallmark of CKD.10 Given the independent association between muscular strength and CVD,29 improvements in muscular strength that accompany exercise training in these patients8 may also be beneficial in mitigating cardiometabolic risk. As CKD progresses to require renal replacement therapy, exercise training is a powerful tool for improving CRF and counteracting muscle wasting and frailty while also improving prognosis once a patient initiates dialysis or receives a kidney transplant.11

For individuals who receive a kidney transplant, exercise training may be helpful to counteract the cardiometabolic risk factors associated with immunosuppression medication therapy.30 Once a patient initiates dialysis, it may be more difficult to enroll them in CR on their dialysis day due to the time burden of their dialysis treatments. For these patients, exercising during hemodialysis (intradialytic exercise) may be an alternative strategy that has proven benefits for improving physical function, lessening hemodialysis-related myocardial stunning, sarcopenia, dialysis adequacy, and dialysis-related symptoms.31–33 While it is understood that exercise training in these patients during hemodialysis would not be practical within the traditional CR class setting, CR staff do have the ideal clinical skill set to supervise such training and provide surveillance.

Current recommendations are to implement aerobic, resistance, balance, and flexibility exercises according to current guidelines for older adults and to take into account special considerations for any comorbidities that the patient may present with.34,35 A summary of the current exercise recommendations from the American College of Sports Medicine35 can be found in Table 5. Lastly, patients should avoid exercise if acute infection, hyperkalemia, excess intradialytic weight gain, or peripheral or pulmonary edema is present.35

Table 5 - American College of Sports Medicine's Exercise Recommendations for Chronic Kidney Disease and Cancer Survivorsa
Aerobic Exercise Resistance Exercise Flexibility Exercise
CKD
Frequency 3-5 d·wk−1 2-3 d·wk−1 2-3 d·wk−1
Intensity Moderate intensity (40-59% V˙o 2R, RPE 12-13 on a scale of 6-20) 65-75% estimated 1-RM. Performance 1-RM is not recommended unless medically cleared for such effort; instead, estimate 1-RM from a ≥3-RM test. Static: Stretch to the point of tightness or slight discomfort. PNF: 20-75% maximum voluntary contraction.
Duration 20-60 min·d−1 of continuous activity; however, if this cannot be tolerated, use 3- to 5-min bouts of intermittent exercise aiming to accumulate 20-60 min·d−1. A minimum of 1 set of 10-15 repetitions, with a goal in most individuals to achieve multiple sets. Choose 8-10 different exercises targeting the major muscle groups. 60 sec/joint for static (10- to 30-sec hold/stretch); 3- to 6-sec contraction followed by 10- to 30-sec assisted stretch for PNF.
Modality Prolonged, rhythmic activities using large muscle groups (eg, walking, cycling, and swimming) Machines, free weights, bands, body weight Static or PNF
Cancer survivors
Frequency 3-5 d·wk−1 2-3 d·wk−1 with a minimum of 48 h/sessions 2-3 d·wk−1 up to daily
Intensity 40 to <60% V˙o 2R or HRR. Survivors may find RPE useful to gauge exercise intensity. 60-80% 1-RM or allow for 6-15 repetitions. Increase weight as tolerated and when repetitions >15. RPE is correlated with % 1-RM in cancer survivors. Stretch within limits of pain to the point of tightness or slight discomfort.
Duration ≥30 min·d−1. No lower limit on bout length. During treatment, exercise length may need to be modified due to chemotherapy or radiation-related toxicities. ≥1 set, ≥8 repetitions/set; ≥60-sec rest between sets Static: 10-30 sec/stretch
Modality Walking, cycling, swimming. Swimming should not be prescribed for survivors with central lines, those with ostomies, those in an immunocompromised state or who are currently receiving radiation therapy. 8-10 exercises of major muscle groups, machines, or free weights Static stretches (passive and/or active), for all major tendon groups. Tai chi and yoga may be preferred.
Abbreviations: BC, breast cancer; CKD, chronic kidney disease; HRR, heart rate reserve; PNF, proprioceptive neuromuscular facilitation; RPE, rating of perceived exertion; V˙o2R, oxygen uptake reserve; 1-RM, 1-repetition maximum, 3-RM, 3-repetition maximum.
aThese tables have been re-created, with permission, from the 11th edition of the American College of Sports Medicine's Guidelines for Exercise Testing and Prescription.35

BREAST CANCER SURVIVORS

Breast cancer is the most commonly diagnosed malignancy and the leading cause of cancer mortality among female patients worldwide.36 In the United States, female BC mortality has decreased by 41% since 1989 due to advances in prevention, early detection, and adjuvant therapy.37 A consequence of improved survival and population aging is that BC survivors face an important new set of health challenges. Specifically, CVD is a leading cause of death in older BC survivors.38 The increased CVD risk has been attributed to unfavorable lifestyle factors (eg, sedentary lifestyle and obesity) combined with the adverse effects of anticancer therapy.39,40 Accordingly, an important goal is to improve overall health and CRF across the continuum of BC survivorship.41 A recent scientific statement from the American Heart Association by Gilchrist et al42 provides an excellent example of a multimodal model like CR for cancer patients and survivors (ie, cardio-oncology rehabilitation) and emphasizes the need for research to determine the full impact that such services could have on the overall health of BC survivors. Furthermore, Dolan et al43 observed improvements to physical (CRF, functional assessments) and mental (depression, quality of life) outcomes when implementing personalized exercise programs based on the CR model in BC survivors. Below is a summary of the current literature that supports the benefits of exercise testing and programming for this patient population.

Exercise Testing

While exercise testing is not required for BC survivors to begin an exercise program, reduced oxygen uptake at peak exercise is commonly observed in this population. Jones et al44 reported that BC survivors (n = 248, mean age: 55 yr, mean left ventricular ejection fraction: 62%) have a V˙o2peak that is 27% lower than age-matched healthy sedentary female populations. Also, 32% of BC survivors had a V˙o2peak below the threshold level required for functional independence.44 Exercise testing may be beneficial in identifying initial CRF levels as well as the mechanisms underpinning their reduced CRF. In accordance with the Fick principle, the reduced V˙o2peak may be the result of cardiac and “noncardiac” peripheral factors that result in decreased convective and diffusive oxygen transport and reduced oxygen utilization by the exercising muscles.12,41 Specifically, evidence to date suggests that the lower V˙o2peak is due to a lower peak exercise cardiac output39,45 secondary to a lower peak exercise stroke volume39,45 and end-diastolic volume index,45 as peak exercise HR39,45 and arterial-venous oxygen difference39 are not significantly different between BC survivors and controls. The finding of normal oxygen extraction despite a lower cardiac output suggests that peripheral vascular and/or skeletal muscle abnormalities that result in decreased muscle oxygen diffusive conductance may also limit V˙o2peak in BC survivors.12 Indeed, Beaudry et al46 found that BC survivors had a significantly higher thigh and lower leg intermuscular fat to skeletal muscle ratio compared with controls, and this was inversely related to whole body V˙o2peak. Accordingly, therapies targeted to reduce intermuscular fat may be an important therapy to improve V˙o2peak following BC therapy.46

Exercise Prescription and Training

A systematic review and meta-analysis by Scott et al13 found that exercise training is an effective therapy to increase V˙o2peak in cancer survivors. The mechanisms responsible for the exercise training-mediated increase in V˙o2peak in BC survivors are not well known, however appear to be due to favorable peripheral (vascular and/or skeletal muscle) adaptations.12 Howden et al,14 using a nonrandomized controlled trial in female patients with early-stage BC, found that exercise training during anthracycline chemotherapy attenuated the decline in both V˙o2peak and estimated arterial venous oxygen difference when compared to usual care, with no significant difference observed between groups for change in peak HR, stroke volume, or cardiac output. Finally, Mijwel et al15 compared the effects of 16 wk of moderate-intensity aerobic training combined with high-intensity interval training (aerobic training-HIIT) and resistance training combined with HIIT (resistance training-HIIT) versus usual care on skeletal muscle morphology and function in female patients with BC undergoing chemotherapy. A main finding was that both aerobic training-HIIT and resistance training-HIIT counteracted the decline in citrate synthase activity, type I muscle fiber cross-sectional area, and capillaries/fiber found in the usual care group after 16 wk. Also, the change in cancer-related fatigue was inversely related to the change in citrate synthase activity. In addition to the improvements in overall V˙o2peak and the central and peripheral factors, which influence CRF, exercise has been shown to reduce risk of cancer-specific mortality, improve lean body mass, reduce fatigue and depression, improve sleep, and improve overall quality of life for BC survivors. A summary of the current aerobic, resistance, and flexibility exercise recommendations,35 which elicit these benefits for cancer survivors, can be found in Table 5.

SPONTANEOUS CORONARY ARTERY DISSECTION

Spontaneous coronary artery dissection is an infrequent, but increasingly recognized, event that can lead to acute coronary syndrome (ACS) including MI or sudden death.47 Dissection of a coronary artery is characterized by the spontaneous formation of an intramural hematoma. When an intimal tear is present, it can result in the creation of a false lumen where blood can enter but not exit, leading to the creation of the hematoma. Pressure-driven expansion of the false lumen and enlargement of the hematoma can lead to worsening myocardial ischemia due to compression and narrowing of the true lumen, causing a reduction of blood flow in the affected artery.

Physical and emotional stressors are considered triggers of SCAD. In a cohort of 327 patients who suffered SCAD, 62% had a precipitating stressor within 1 wk prior to the event. Of these 48% were related to an emotional event, 28% to a physical event, and 12% triggered due to heavy isometric exertion.48

The diagnosis of SCAD is made with coronary angiography and current recommended treatment is conservative, including the use of β-blockers to reduce intracoronary shear stress and risk of reoccurrence.47–50 Saw et al48 reported that 83% of those suffering SCAD were initially treated conservatively, without stent or coronary artery bypass. Despite two different scientific statements suggesting optimal management,47,49 there are currently no clinical practice guidelines.

Spontaneous coronary artery dissection occurs most often in young to middle-aged female populations, frequently at a time of high emotional stress, during intense exercise, or during childbirth.47,49 It is responsible for up to 35% of ACS in female patients age ≤50 yr.47 Additionally, there is a high probability of reoccurrence, leading to related anxiety and depression.47,51,52 Frequently and paradoxical to most individuals with ACS and MI, those who suffer SCAD are in good health, physically fit, and often present with few risk factors for coronary artery disease.50 Despite this, exercise training is recommended. However, little information exists about exercise training in patients with SCAD (Table 3).

Exercise Testing

Published data regarding exercise testing in this population are sparse. Although not required, testing prior to enrollment in CR may be useful for guiding the exercise prescription, especially in those highly active prior to their SCAD event. Several studies include completion of a CPX before and/or after an exercise regimen,47,53–55 but there is no consensus as to protocol; 6MWTs have also been used.54,56 Regardless of the testing method, improvements in functional capacity in the range of 1.5 metabolic equivalents (METs) of task have been observed. No adverse events were reported. Standard testing methods are likely appropriate, and the exercise testing protocol selected will likely be similar to that used in other patients who experienced ACS or a MI, including a pre-test assessment of functional capacity.

Exercise Prescription and Training

The American Heart Association recommends that all patients with MI caused by SCAD be referred to CR, and health care providers overwhelmingly support this,57 yet referral rates remain low. This is possibly due to provider fear of reoccurrence (range for rate of recurrence: 0-37%) or the belief that young, fit patients without coronary artery disease may not benefit from CR.47 Unfortunately, because of low referral rates and lack of specific exercise guidelines, CR staff frequently adopt the methods used with other CR patients. However, this can be frustrating for those patients with SCAD because they are often younger and engaged in higher levels of physical activity prior to their event. Not feeling challenged and/or being treated as if they have coronary artery disease may lead to low CR participation rates among patients with SCAD.58,59 A few case reports address an individualized (1:1) or sports-specific approach for SCAD survivors,53,55,60 but currently many CR programs may not have sufficient staffing or resources to allow for this level of care.

A multidisciplinary CR program in Vancouver, British Columbia, has published the largest experience of exercise in patients with SCAD. Exercise was performed 1 d/wk in a dedicated session that included peer support and consisted of 15 min of warm-up, 30 min of aerobic exercise, and 15 min of cool-down. Resistance training was performed with two 12-lb free weights and high repetitions. Target HR was set at 50-70% of HR reserve based on an entrance exercise treadmill test. Systolic BP during exercise was limited to <130 mm Hg. Exercise, HR, and BP thresholds were chosen with the intention of decreasing arterial wall stress and providing a conservative return to activity.61 Outside of formal classes, participants were encouraged to exercise in a supervised gym setting.

In the Vancouver experience, patients were recommended to lift ≤20 lb during daily activities, as some in the cohort suffered their SCAD event after lifting more than 20 lb.61 Other published reports have recommended that, after SCAD, females lift ≤20-30 lb and male patients ≤30-50 lb.50,62,63 Because acute, high levels of exercise are associated with SCAD, some have recommended patients avoid activities performed to exhaustion, any highly competitive or contact sports, exercise performed in extremes of terrain or temperature, or activities that involve a Valsalva maneuver such as intense isometric activities.47,53,63,64

There are very limited data on high-intensity exercise in these patients. Silber et al54 report on nine female patients who had an MI as the result of SCAD and subsequently participated in their CR program. Supervised exercise began within 1-2 wk post-event and was prescribed at 60-70% HR reserve from an entrance CPX and/or 12-14 on the 6-20 Borg rating of perceived exertion (RPE) scale. High-intensity interval training was performed after patients were able to exercise 20 continuous min at their prescribed intensity. One to two-min intervals at RPE 15-17 were interspersed with moderate-intensity intervals of RPE 12-14. Functional capacity increased by 18% (4.4 mL/kg/min) after completion of five 39 CR visits and no adverse events were reported.54

LEFT VENTRICULAR ASSIST DEVICES

Left ventricular assist devices (LVADs) continue to be used increasingly as a therapeutic option for patients with end-stage heart failure (HF). Improvements in LVAD technology have led to better survival. For example, the 2-yr survival rate for the HeartMate III LVAD (Abbott Cardiovascular), a fully magnetically levitated centrifugal continuous-flow pump, is 82.8%, compared with 76.2% for the older HeartMate II (Abbott Cardiovascular), a mechanical-bearing axial continuous-flow pump.65 These advancements have resulted in a nearly six-fold increase in the number of LVAD recipients over the past decade.66,67 However, despite improvements in both LVAD technology and outcomes, many patients on LVAD support have poor exercise capacity, especially compared with similar patients who received a heart transplant.68

Exercise training in this population has shown to be beneficial for both improvements in exercise capacity and patient-reported health outcomes (Table 4).68–75 However, despite this, and despite the fact that the Centers for Medicare & Medicaid Services now covers CR in patients on LVAD support under HF, only 42% of eligible patients in this population utilize CR.76

Exercise Testing

While not widely utilized, performing a CPX on patients with LVAD support can be useful for guiding exercise prescription, risk stratification, and evaluation of native left ventricle recovery.77,78 Imamura et al77 reported that patients on LVAD support with a V˙o2peak >14 mL∙kg−1∙min−1 had significantly lower 2-yr hospital readmission rate. More recently, the use of CPX testing has shown potential to help decide whether selected patients on LVAD support have recovered substantial native function.78 Specifically, the preservation of V˙o2peak following serial CPX testing with full and minimal LVAD support (ie, LVAD speed is reduced) can show whether a patient might be a candidate for LVAD explanation (the so-called bridge to recovery).78

Two unique challenges to performing a CPX on these individuals are obtaining an accurate exercise BP and managing the LVAD equipment. Due to the nature of current second-generation LVAD models (eg, HeartMate II, HeartWare), which operate as continuous flow pumps, there is no detectable pulse, which makes both manual and automatic BP unreliable.79 Therefore, it is recommended that BP be obtained using a Doppler and a sphygmomanometer.79 While the third-generation HeartMate III does have a built-in artificial pulse, the use of a Doppler remains recommended at this time.80

The technique of measuring a Doppler BP is an acquired skill that takes practice. Therefore, performing periodic competencies for Doppler measurement is recommended. In addition, using a stationary cycle for testing is preferred to help reduce motion artifact when attempting a Doppler BP during exercise. Another consideration when choosing an exercise modality is the additional weight of the LVAD batteries and controllers, which may affect the patient balance with treadmill walking. Assessment of gait and balance should be done before determining an exercise modality. It is also important to be aware of the external driveline and battery lines, which supply power to the LVAD. Unnecessary exposure of these external lines may increase the risk of the power being disconnected. To avoid this, covering external lines with a driveline stabilization belt should be considered before beginning the test.81

Finally, the 6MWT is an additional exercise test to consider. Due to the low functional capacity in this population, the 6MWT can be used to show a training response from CR. Importantly, it has also been shown to be an independent prognostic predictor of survival with patients who achieved <300 m having an increased risk for mortality.82

Exercise Prescription and Training

The LVAD device itself is set at a fixed therapeutic speed (eg, typical speed of the HeartMate III is 5400 RPM, although this differs between devices) and thus does not adjust regardless if a person is at rest or exercise. Despite this, cardiac output can increase from 3-5 to ∼10 L/min.79 Factors, which contribute to this, are increased preload through the skeletal muscle pump, a reduction in afterload, which decreases the differential pressure between the LVAD device and the aorta, thus allowing greater pump flow and increased contribution by the native left ventricle to move blood through the aorta (independent of the LVAD).

Despite the presence of a foreign device augmenting cardiac output, the relationship between HR and V˙o2 remains intact.83 An exception to this would be in patients who display chronotropic incompetence or are paced with inadequate HR responsiveness.83 For these patients prescribing exercise at a RPE level of 11-14 on the Borg 6-20 scale would be appropriate. For patients on LVAD support who do have an intact HR response, a target HR range set at 40-80% HR reserve can be used.35

In this population, HIIT has shown promise with some preliminary data.73,84 However, more research is needed on the safety of HIIT in this population and should only be considered in select patients, based upon factors such as age, balance, and overall functional abilities.

Muscular strength is an important fitness component related to patient-reported quality of life as well as length of hospital stay following LVAD implantation.85,86 The few training studies that incorporated strength training showed favorable improvements in strength, and as a result, strength training should be incorporated as part of a comprehensive exercise program. As with other patients with a procedure requiring a sternotomy, precautions should be taken to limit upper-body strength training until 8-12 wk post-surgery. In addition, avoiding excessive trunk flexion (eg, sit-ups) or contact sports is necessary.

SUMMARY

The four patient populations discussed in this review have important clinical considerations that should be supervised by trained exercise professionals. Despite the uniqueness of the patient populations, compared with individuals without these health conditions, exercise testing and training appear to be safe and well tolerated, suggesting these individuals can greatly benefit from services commonly offered in CR. However, high-quality randomized controlled trials, multisite clinical trials, and additional in-clinic experience working with these patients are needed to develop more specific recommendations and ensure patient safety while maximizing the effectiveness of individualized exercise programming. Such research may also lead to the support necessary for insurance reimbursement for exercise training programs for patients with CKD or BC, similar to what has been approved by Medicare for individuals with symptomatic peripheral artery disease. It is worth noting that other clinical populations, such as individuals who have suffered a stroke, may also benefit from CR services. Recent studies have addressed the need for inclusion of this population in CR as well as benefits and barriers to participation.87,88 To conclude, understanding these comorbid conditions that are seen in CR is important to be able to provide safe and effective therapy for these patients. As summarized in Tables 2, 3, and 4, current evidence suggests that each of these populations could experience physical and mental benefits from regular exercise participation including but not limited to increased CRF, maximal MET level during a graded treadmill test, 6MWT duration, muscular strength as well as improvements to depression symptoms, left ventricular end-diastolic volume, and oxygen uptake at ventilatory threshold. Thus, it is important to consider the inclusion of new populations to CR programs as well as better understand those who are less commonly seen in CR to help all patient populations maximize health outcomes and better manage their chronic disease(s).

ACKNOWLEDGMENTS

Individual author contributions are outlined as follows: CKD: Danielle Kirkman, PhD, Brittany Overstreet, PhD; BC: Mark J. Haykowsky, PhD; SCAD: Wanda Koester Qualters, MS, Marysia S. Tweet, Jonathan K. Ehrman, PhD, Clinton A. Brawner, PhD, and Steven J. Keteyian, PhD; LVAD: Dennis Kerrigan, PhD, MD, and Jeffrey Christle, PhD.

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Keywords:

cardiac rehabilitation; exercise; special populations

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